EDITION

2020

DZINO’S
MEDICINE

NYASHA DZINOTYIWEI

A compilation by E. Ziumbwa
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 History taking
History taking is the collection of information from the patient during an examination. It is
the first thing that takes place when a patient comes for a consultation. The history is a 2-
direcitonal process in which a patient narrates the condition they are feeling while at the
same time the clinician is also enquiring about any other information. The patient’s words
should be preserved (although it may need to be paraphrased to medical language when
recorded by the clinician). Histories should be taken in the correct manner.

Histories are essential in making a diagnosis. The history is what the clinician uses to map his
course of examination & tests. An accurate history therefore suggests the correct diagnosis.
There are a number of components that constitute a good history, and there are other
components of a history that establish a good doctor-patient relationship.

Establishing rapport with the patient

The treatment of a patient begins when one approaches the bedside and begins to talk to
the patient. The doctor should look smart and presentable and the patient should feel
comfortable around you. It is therefore essential that throughout the consultation the
doctor ensures that the patient feels at ease with the doctor. There are a number of ethical
issues that the doctor needs to uphold, including confidentiality, autonomy, beneficence
and non-maleficence.

Usually, to establish rapport, the doctor begins by introducing themselves and why they are
there. It is important to maintain a good air in the environment. If the patient is standing
you direct them to the chair and ask them to sit down. You then request the patient’s name
if you are meeting the patient for the first time. You should always show genuine interest in
the welfare of the patient – be attentive to what they are saying. You should also probe the
patient. This allows them to let out all their issues.

Presenting complaint
The presenting complaint is the symptom that the patient presents with that prompts the
patient to seek treatment. The best way to start this part of the conversation is, “what has
been the trouble recently?” The patient will then tell the doctor about their problem. During
the interview, you should not stop the patient. You should let the patient run through and
say everything they need to say, as they may end up mentioning things the doctor didn’t
expect.

It may be necessary to ask the patient questions to test diagnostic hypotheses. For example,
the patient may not have noticed that they experience chest pain each time they exercised

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(stable angina). It also helps to give the patient an option of answers to choose from or to
give them a scale. It allows the patient to answer a directed question but with the fullest
idea of what they are trying to say. A patient may be prompted to describe conditions that
they may not necessarily feel if one asks the patient a yes/no question. Furthermore, a
patient may change their descriptions after a more senior clinician asks them the questions.

Throughout the interview, you must prompt the patient to state the problem that bothers
them the most. The patient may feel uncomfortable if they do not state the true presenting
complaint. For example, maybe they have a violent cough, but their main problem is that
they are vomiting blood. You need to invite the patient to mention this condition of theirs.
As you ask the patient these questions, you need to ask yourself:

1. Where is the problem?

2. What is the nature of the symptom?
3. How does it affect the patient?
4. Why did the patient get it?

History of presenting symptom

The clinician should collect information on the progression of the disease over time. Apart
from just the presenting symptom, the clinician should also seek other symptoms that the
patient has experienced, and the progression of these other symptoms. These symptoms’
progression should be organised and superimposed on the presenting symptom’s
progression. This final structure is called a timeline and it gives a more holistic picture of the
patient’s sickness. The timeline is important because different conditions have different
progressions despite having similar symptoms. Constructing a timeline therefore allows the
clinician to make a better prediction of the diagnosis and therefore order the necessary
tests.

For each symptom that a patient presents with, there is a set of questions that the clinician
should ask. These questions can be represented by the acronym SOCRATES:

1. Site – where is the symptom? Some conditions cannot be localised. Only a general
picture can be given.
2. Onset – when did the symptom present and how rapidly did it present. Some
conditions such as cardiac arrhythmias have an instantaneous onset.
3. Character – what is the character of the symptom? Is it localised or diffuse? This
question prompts details of the symptom to as specific a description as possible.
4. Radiation. This mainly applies to pain. Sometimes pain spreads to other regions. The
clinician should ask if the pain being experienced is spread to surrounding regions.
Certain patterns of distribution are diagnostic, e.g. herpes zoster.

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 5. Timing. Find out how the frequency of presentation of the symptom varies during
the day (how often it occurs). If the condition is long-standing it is often helpful to
ask the patient what prompted him to visit the clinician now.
6. Exacerbating & relieving factors. Ask the patient what makes the condition the
patient has better or worse.
7. Severity. Severity of the condition is subjective and it depends on the patient. A
patient’s appraisal of a symptom – especially pain – is relative. It is usually advised to
ask them to give a scale of the pain they are feeling out of 10. The numbers given will
not be universal to everyone, but they guide the clinician on what the patient is
experiencing. Other symptoms can be quantified as they can be measured. However,
the interpretation of the severity differs as one severity level for one person may not
affect the patient as much as another patient.

Systems review
The idea behind a systems review is to create a safety net. The patient may have forgotten
some things or deemed them irrelevant. If you ask them questions directed towards specific
systems, then it allows you to include or discard other possible conditions. The systems
enquired are: the cardiovascular system, respiratory system, GIT, genitourinary system, CNS,
musculoskeletal system and skin. Chronological sequence of events should also be noted,
especially when listing neurological symptoms. It may be important to list important
negative answers (e.g. if a person has diarrhoea, you may want to take note of the fact that
they did not have a fever).

In order to establish a better relationship between the doctor and the patient, it may be
important to ask about the patient’s feelings about their condition, especially if it is a
chronic condition. It also allows the clinician to decipher what else is needed to help the
patient – both medical and non-medical. It shows genuine concern for the patient’s welfare.

Past medical history

Under this heading, you ask the patient if they have ever been treated or admitted for a
medical condition before. If they have, you need to understand what it was as a past
procedure or infection may add different dimensions to the intended course of treatment.
You should also enquire about childhood sickness. Interrogation on such medical conditions
allows the patient to describe their condition, but it also prevents them from stating a
condition they were not diagnosed with but claim they had. For example, a patient may say
they had ulcers, but only interrogation on the diagnosis of the ulcers reveals they didn’t
have them. The clinician must maintain objective scepticism.

Some patients who are chronically ill may have or may have had numerous medical
professionals supervising them. Chronic conditions include diabetes, hypertension, asthma,

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epilepsy. Also enquire about a history of TB, and if the patient was tested for HIV. The
clinician needs to find out what this supervision was and how often treatment was received.
You may be able to contact the doctor keeping the patient under surveillance.

Drug & treatment history

The clinician should find out whether a patient has ever taken medication for an illness
before. The patient may describe these by colour and size rather than by name 1 and
therefore the clinician should know these shapes & colours. One should note the dose,
duration of use, indication for the drugs taken and their side effects. It usually helps the
doctor to construct a drug list in order to store as much information as possible on the
drugs. You should also ask whether a drug was taken as prescribed.

Past drug history also includes medicine from the traditional healers. Under this heading,
information about allergies to drugs should be collected too. You should find out what the
reaction was in order to determine if the reaction was an allergic reactions or a side effect.
The clinician may also want to know if the patient takes drugs for recreational use, or if they
used to (it is important to emphasize confidentiality when asking such sensitive questions).

Family history
Asking the patient on their family history with respects to the presenting symptoms may
help pick out some familial forms of conditions. Many diseases are family-linked and most of
them are chronic non-communicable diseases. Drawing a family pedigree may help decipher
the possible condition. This is especially beneficial in this modern age of genetic
engineering.

Social history
A patient’s social life says a lot about what possible conditions they are exposed to. For
example, if a patient is a recreational drinker they may be predisposed to cirrhosis; domestic
violence may lead to a woman repeatedly reporting to the hospital with trauma.

Other aspects of social life are:

• Upbringing and education level. Education level may explain how much you need to
explain the patient’s condition.
• Diet & exercise. An unbalanced diet and inadequate exercise may predispose the
patient to chronic disease like diabetes and hypertension. They may also cause
atherosclerotic plaques which would be risk factors against myocardial infarction and
stroke.

1
Some patients will not take medication if it changes shape & colour even if it is the same medication.

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 • Marital status, social support and living conditions. Marital status & social support
is important because it lets the doctor know how strong their relationships at home
are. Knowing these is important in the case of someone suffering from a debilitating
condition which requires family support.
• Travel history. This is a recap of any places the patient went to in the near past. If a
patient from a temperate region travels to a tropical region, he may return with a
highly infectious disease that he would not have encountered before.
• Substance use. The major drugs you need to look for are alcohol and tobacco. Ask
the patient how long they used to smoke and how many cigarettes they took every
day. You need to calculate the pack years to effectively quantify how much the
patient smoked. The pack years are calculated as follows:
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑟𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦 × 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑦𝑒𝑎𝑟𝑠 𝑠𝑚𝑜𝑘𝑖𝑛𝑔
𝑝𝑎𝑐𝑘 𝑦𝑒𝑎𝑟𝑠 =
20
Alcohol quantity is represented in units, of which a single unit is 10ml of pure alcohol
taken. It is important to know how many units the patient takes in a week and how
many drink-free days the patient has. It is generally recommended that males take
no more than 21 units a week and females no more than 14 units a week, and this
week should have at least 2 drink-free days. A binge drink is described as taking
more than 3 units in a single day for females and more than 4 units for males. The
number of units is calculated as follows:
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑢𝑛𝑖𝑡𝑠 = 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑙𝑖𝑡𝑟𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 × 𝑝𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑎𝑙𝑐𝑜ℎ𝑜𝑙

Occupational history
Occupational history is particularly important for some conditions, such as respiratory
conditions that are linked to mining. Ask the following questions (abbreviated as WHACS)

1. What is it that you do?

2. How do you do it?
3. Are you concerned about any of your exposures or experiences?
4. Colleagues or any other exposed?
5. Satisfied with your job?

Summarising history
In summarising the history, you list down your positive findings and your negative findings.
The positive findings are the symptoms that the patient presents with and they direct the
clinician towards the probable differentials. The negative findings are important in then
ruling out from the wide pool of differentials that the clinician has compiled.

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 General examination
The general examination is conducted in order to provide a general description of general
symptoms that are not system specific. It is done to bring to light the presence of general
signs, e.g. anaemia, jaundice, clubbing, etc. The general examination is conducted with a
systematic approach. This systematic approach is followed because it ensures that the
examination is thorough and important aspects are not overlooked. As you learn
examination skills, experience and acquisition of new evidence-based data will help the
clinician to perfect their skills. In the general exam, it is important that a person points out
signs that are obvious to see. Symptoms should not be manufactured.

The most common examination technique carried out is the objective structured clinical
examination (OSCE). Other formats used include the long case and the short case. During
the examination, you may need to check vital signs such as pulse, blood pressure,
respiratory rate and temperature. These may be present on some automated machine, but
they are vital for examination. The most common sequence of examination of a system is as
follows:

1. Inspection. You should be able to observe the patient for any scars, abnormal
pigmentation and for certain movements. Everything should be noted and perhaps
said, as you may find relevance of certain paraphernalia later on during the
examination.
2. Palpation. You should feel for deep structures through the skin. Typical structures
palpated for are the lymph nodes, abdominal organs and growths & masses.
3. Percussion. You should percuss over certain areas for resonance and dullness.
Dullness is normally associated with fluid accumulation among many things.
4. Auscultation. Auscultation allows you to listen for different sounds produced by
different structures. Structures auscultated for include the heart, the lungs and the
abdominal viscera.

Before you start

When you are about to start your examination, there are a number of procedures one
needs to follow. These can be represented by the acronym WIPER:

1. W – Wash your hands. Hands should be washed before and after the examination.
Good hand-washing techniques should be employed.
2. I – Introduce yourself. Introduce yourself to your patient. Let them know who you
are and what you want to do. You should stand on the right side of the bed as you do
so. You’re not allowed to stand on the left side.

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 3. P – Permission: ask for permission. Ask them for permission to conduct the exam.
You should let them know that you intend to expose them. In the event that the
genitals are being examined, ask them if they need a chaperone to be present and if
they are comfortable with you touching them.
4. E – Expose your patient. You then expose the part you intend to examine. It may not
be necessary to expose every part of your patient. The patient should be exposed in
a secluded room, or there should be curtains lowered around the bed. This makes
the patient feel more comfortable when they are exposed.
5. R – Recline the bed rest. Depending on the examination, you may need to recline the
bed to various angles. The general exam does not require that a patient lie on a bed
– they can be seated in a chair.

As you prepare to observe for signs, you should be able to:

1. Describe the signs that you see.

2. Recall conditions that are associated with the sign.
3. Outline the mechanism behind the development of the sign.
4. Assess the sign value.

Before you start touching the patient anywhere, you should ask them if they are feeling pain
anywhere, so that you don’t hurt them unwillingly.

First impressions of patient & environment

As the patient walks in, the clinician needs to make a general impression of the patient’s
condition. It usually helps as part of the description of progression of disease – whether it is
improving or worsening – if you can describe how the patient’s general appearance has
changed. You should also observe the patient as they undress because it allows you to
determine by observation if the patient is feeling pain or is failing to carry out certain
movements.

After the patient has sat down, you should describe the patient’s appearance: age, stature,
race (this is sensitive) and gender (these days this is sensitive too). You comment on their
posture, state of their face (enlightened or dull), natural breathing and their consciousness.

In addition, you should be prepared to describe their immediate environment. You should
state whatever you see around them, be it catheters, food, empty cans or plastics, dirt,
sputum bowl, vomiting buckets, everything. To do this, you will need to go to the end of the
bed and look at them straight-on. This is the only part of the exam that you’re allowed to do
from any position other than the right side of the bed. This is because from the right side of
the bed you may not be able to see important features on the left side, such as catheters,
which are important to state.

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Hand & nail signs
The hand is the first thing to check when conducting a general examination. Examination of
the hands is by looking, feeling and moving. There is no subspecialty of internal medicine in
which examination of the hands is unrewarding. On the hands you check for:

• Shape of nails. The nails change shape during clubbing. To test for clubbing, you
slightly squeeze the nail by the lateral nail folds to bring the nail out. Alternatively,
you ask the patient to appose the dorsa of one set of corresponding fingers (e.g. the
index finger) to each other. The two fingers should form a small diamond-shaped gap
called Schamroth’s sign. This sign disappears when there is clubbing. Clubbing occurs
when megakaryocytes that are normally broken down in the lungs are not, resulting
in these cells becoming lodged in capillaries in the nail beds. Here, they release
growth factors (such as PDGF) and recruit cells & promote proliferation of muscle
cells and fibroblasts. This is what accounts for the increased nail bed bogginess this
develops in any process that disrupts normal pulmonary circulation. This is not the
only process believed to cause clubbing. It is also believed that
There are 5 grades of clubbing:
Grade 1 Nail bed bogginess
Grade 2 Disappearance of Schamroth’s window1
Grade 3 Increased nail curvature
Grade 4 Drumstick appearance of fingers
Grade 5 Osteoarthropathy (wrist involvement)
Clubbing is usually bilateral. Unilateral clubbing is rare, but possible. It can be caused
by: arteriovenous shunts (used for dialysis), bronchial arteriovenous aneurysm and
axillary artery aneurysm.
Clubbing may be familial and therefore physiological in 5-10% of individuals. The
causes of pathological clubbing are:
• Respiratory (70%). The respiratory causes of clubbing are: chronic suppurative
lung conditions (such as bronchiectasis, empyema, cystic fibrosis, lung abscess),
infections (e.g. tuberculosis and HIV), degenerative conditions (e.g. idiopathic
pulmonary fibrosis, asbestosis, sarcoidosis, hypertrophic pulmonary
osteoarthropathy) and neoplasms (lung carcinoma2, mesothelioma, pleural
fibroma, neurogenic diaphragmatic tumours and lymphomas).
• Cardiovascular. The cardiovascular causes are: cyanotic congenital heart disease
(e.g. tetralogy of Fallot, persistent truncus arteriosus), infective endocarditis,
arteriovenous shunts and aneurysms.
• Gastrointestinal. These include: cirrhosis, inflammatory bowel disease and
coeliac disease. Gastrointestinal causes are not very common.

1
This represents loss of the normal nail bed angle. The normal nail bed angle is less than 165°.
2
Small cell carcinoma usually doesn’t cause clubbing.

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 • Others. These include thyrotoxicosis (causing thyroid acropatchy), pregnancy,
and secondary parathyroidism.
• Pallor of the hands. Pale hands could be an indicator of anaemia. It is often a
sensitive indicator of anaemia.
• Colour. Yellow discolorations on the fingers could indicate that a person has been
smoking for a long period of time. Furthermore, if a person is jaundiced they can
have the characteristic yellowish-orange. Nail colour can also be an indicator of
underlying conditions. Blue nails can be an indicator of cyanosis; red nails could
indicate polycythaemia.
• Size. In some endocrine disorders such as GH excess the hand increases in size.
• Gross distortions in architecture. A person may have muscle wasting in their hands or
a slight tremor, indicating some neurological disorder.
• Temperature. You feel for warmth in the patient’s hands. Absence of warmth may
indicate that blood is not flowing adequately through the patient’s arms. Warm arms
are characteristic of people suffering from chronic obstructive pulmonary disease, as
the increased partial pressure of carbon dioxide causes vasodilation which increases
the flow of blood.
• You can also use the dorsum of the hands to test for oedema.

In addition to all these, the clinician may check for the patient’s pulse. This is done using the
radial pulse. To feel for the radial pulse, you use the middle three fingers, as they are more
accurate in sensing for the pulse.

Neck
The neck is mainly palpated for lymph nodes. The lymph nodes are enlarged when they are
greater than 0.5cm in diameter. When examining lymph nodes, assess if they are attached
to deep structures or they are mobile (those attached to deep structures suggest
malignancy). Also assess their consistency: normal nodes feel soft. Rubbery nodes are found
in Hodgkin’s disease, matted nodes are found in TB and hard nodes are found in metastatic
disease. Some nodes may be tender, as in infectious mononucleosis, dental sepsis, tonsillitis
and other acute bacterial or viral infections.

There are 2 chains of lymph nodes in the neck – there is the anterior chain found in the
anterior triangle of the neck, and there is the posterior chain found in the posterior triangle.
There are also supraclavicular lymph nodes found in the root of the neck and the
submandibular & submental lymph nodes. The lymph nodes are usually swollen when there
is an infection. The axilla (axillary lymph nodes) is a common site of inflamed lymph nodes.

When doing the lymph node examination, first inspect the neck for any visible
lymphadenopathy. Palpate one side at a time bimanually in turn. Assess the lymph nodes
for site, size, consistency, mobility and tenderness, and compare lymph node on both sides.

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Cervical lymph nodes are examined from behind. The anterior chain is examined from the
back while the posterior chain is examined from the front. From the front you also examine
the posterior auricular & occipital nodes. Other lymph nodes to examine are the epi-
trochlear & inguinal lymph nodes.

Causes of lymphadenopathy are divided into causes of generalised and localised

lymphadenopathy. Causes of generalised lymphadenopathy include:

• Viral: EBV, CMV and HIV infections.

• Bacterial: brucellosis, syphilis.
• Protozoal: toxoplasmosis.
• Malignancy: lymphoma, ALL, CLL.
• Inflammatory: rheumatoid arthritis, SLE, sarcoidosis.

Localised causes are:

• Infectious: acute or chronic bacterial/viral infections.

• Malignancies: lymphomas or metastases.

Face
The face is a gateway into the way a person is feeling. When a person enters the doctor’s
room, you can tell what the patient is feeling just by looking at the patient’s face.
Furthermore, during the exam, you can tell if the patient is feeling discomfort when certain
procedures are done on them.

A specific diagnosis can be made by inspecting the face. However, other physical signs need
to be sought in order to complete the diagnosis. There are a number of abnormalities that
need to be looked for in the face:

• Jaundice. This is a yellow discoloration of the skin that is a result of an increased level
of serum bilirubin. Bilirubin is deposited in the skin of people with this elevated level
of bilirubin. Jaundice can be caused by a blockage of the biliary tree, leading to
retention of bilirubin in the circulation. It can also be caused by a large instantaneous
increase in the bilirubin levels, such as haemolysis or hepatitis. Jaundice is often
checked using the sclera. However, the sclera is usually visibly discoloured when the
condition is moderate to severe. Mild jaundice does not usually cause discoloration
because bilirubin is broken down by light and therefore the part of the eye that is
exposed to the sun is not yellow. One would need to lift the patient’s upper eyelid
and ask the patient to look down.
• Cyanosis. This is a condition in which the patient has a reduced oxygen tension in
circulation resulting in a bluish discolouration of the skin & mucous membranes.
Cyanosis can be central or peripheral. It only appears if the levels of deoxygenated

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 blood rises above 5g/dL, which corresponds to a saturation level of <90%3. Cyanosis
does not occur in anaemic hypoxia because anaemic hypoxia is caused by a drop in
the concentration of haemoglobin in blood not the oxygen tension. There are 2
types of cyanosis:
o Central cyanosis occurs due to deoxygenated blood in the arterial circulation,
and the blue discoloration is seen in tissues with a good circulation such as
the mouth & tongue. The easiest way to check for central cyanosis is to check
the tongue. The presence of central cyanosis should prompt careful
examination of the cardiovascular & respiratory systems. Patients with
polycythaemia can be cyanosed at normal oxygen tensions.
o Peripheral cyanosis is found is tissues where there is reduced circulation. The
tissue then extracts more oxygen from the blood than normal, resulting in
the blood appearing bluer than normal. This is seen in the nails & lips on a
cold day. On a cold day, the tongue is usually spared.
• Pallor. Pallor can occur in the eyes of individuals with anaemia. Anaemia is
noticeable in the inner sclera when the anaemia is severe (<7g/dL). Normally, the
palpebral conjunctiva is nice & red, sharply contrasting the bulbar conjunctiva &
sclera. However, in anaemia, the palpebral conjunctiva is pale and whitish. Facial
pallor can occur in individuals with shock. The patients appear cold & clammy and
are hypotensive.

Weight, body habitus & posture

You should observe for obesity & fat distribution: if the patient apple-shaped (abdominal
obesity) or pear-shaped (general obesity including the hips & thighs). Obesity is measured
using the body mass index, which is found by dividing the weight in kilograms by the height
squared4. Obesity is defined as a BMI greater than 25kg/m2.

The waist-hip ratio also predicts health risk. Waist-hip ratio is measured by dividing the
circumference around the waist (the waist is found halfway between the costal margin and
the iliac crest) by the circumference around the hips. If the waist-hip ratio exceeds 1.0 in
men and 0.86 in women, the patients are at increased risk. Waist measurements can also be
conducted. If the waist is greater than 94cm in males and 80cm in females, the patient is at
increased risk while greatly increased risk is found in waists greater than 102cm in men and
88 in females.

The clinician should inspect the patient’s stature & posture, which may be hard if the
patient is lying in bed. You should inspect for limb deformities & missing limbs. You should

3
This depends, however, on the haemoglobin concentration. It occurs at lower saturations in anaemic people
and at higher saturations in people with polycythaemia.
4
This gives an estimate of the body’s surface area.

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also observe if the patient’s physique is consistent with the patient’s age. As the patient
walks in, you should examine the patient’s gait.

Hydration status
All doctors must be able to assess the patient’s hydration status, albeit being very difficult.
Excessive dehydration can cause death by acute renal failure. An overhydrated patient may
develop fluid overload and pulmonary oedema. Excessive rehydration with water leads to
reduced sodium levels which could lead to confusion and loss of consciousness (due to
cerebral oedema).

For assessment of dehydration, you should:

1. Inspect for sunken orbits.

2. Dry mucous membranes.
3. Reduced skin turgor. This usually occurs in severe cases.
4. Dry axillae.
5. Tachycardia.
6. Hypotension. This also occurs in severe cases.

These signs should often be sought for in combination.

One can also assess for postural hypotension. You measure the patient’s blood pressure
while they are lying down. You then ask the patient to stand, and then measure their blood
pressure again after a minute. If the blood pressure has dropped, it means that the patient
has postural hypotension.

Oedema is another common sign that occurs. Oedema occurs when there is increased
interstitial fluid, and often occurs when there is fluid shift from either the vascular or
intracellular compartments to the interstitial compartments. Interstitial fluid is a result of
the balance between the hydrostatic pressure from the action of the heart and the colloid
oncotic pressure from plasma proteins. Any condition that increases hydrostatic pressure
(e.g. heart failure) or reduces colloid pressure (e.g. nephrotic syndrome & hepatic disease)
causes oedema. It can also be a result of increased fluid shift from the intracellular space, as
seen in malnutrition in children. Often oedema is pitting, and this may not be demonstrated
until body weight has increased by 10-15%.

Oedema may be generalised or localised. Generalised oedema is caused by:

• Fluid overload:
o Heart failure. This occurs through: renal under-perfusion stimulating the
RAAS system and increasing salt & water retention; renal under-perfusion
leading to increased salt & water reabsorption; and pulmonary oedema from
increased hydrostatic pressure when a patient lies flat.

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 o Renal disease decreases GFR, thus increasing circulating volume and
therefore the hydrostatic pressure. Reduced GFR also increases tubular
reabsorption of sodium.
o Iatrogenic causes include rapid intravenous fluid replacement.
• Hypoalbuminaemia:
o Nephrotic syndrome. This is due to the massive proteinuria accompanying
the condition.
o Chronic liver disease. This results in reduced protein synthesis by the liver.

Localised oedema is caused by the following:

• Venous causes. Increased venous pressure in an isolated vessel increases the

backward hydrostatic pressure in capillaries. Examples include DVTs, external
pressure from a tumour, pregnancy (the gravid uterus places pressure on the inferior
vena cava when lying supine), and decreased venous valve competence such as from
thrombosis or previous surgery. Conditions which impair normal pumping action of
the veins also cause oedema: examples include hemiparesis & forced immobility.
• Lymphatic causes. Impaired lymphatic flow causes increased accumulation of tissue
fluid, which normally drains into the lymphatic circulation. Localised impaired
lymphatic drainage is called lymphedema. Impaired lymphatic flow occurs in:
intraluminal or extra-luminal obstruction. If the condition persists, fibrous tissue
proliferates in the interstitial space and the area no longer pits on pressure. The
commonest lymphatic cause of oedema in the UK is hypoplasia of leg lymphatics:
also called Milroy’s disease. It can also occur after lymph node removal, as in radical
mastectomy and/or irradiation following breast cancer. Some infections
(elephantiasis/filariasis) are causes of lymphoedema, particularly in Africa.
• Inflammatory causes. Any cause of tissue inflammation liberates vasodilators such
as histamine, bradykinin and cytokines. These increase capillary permeability and as
such increase fluid leakage. Inflammatory oedema is often accompanied by other
features of inflammation – redness (rubor), warmth (calor) and pain (dolor).
• Allergic causes. This is due to local release of histamine during exposure to an
allergen. A specific form is angioedema, which affects the face, lips and mouth.
Angioedema may be life-threatening if the airway is involved.

Technique of general examination

The sequence of actions to conduct during a general examination is as follows:

1. Start by greeting the patient, introducing yourself and then telling the patient what
you intend to do to them. You also ask for their permission to conduct the test.

Page 14 of 455
2. You then move to the end of the bed and comment on the general appearance of
the patient and the surroundings of the patient. This is called an end-of-the-bed
examination.
3. You then move back to the right side of the bed and check the patient’s hands. You
feel the temperature, check for pallor (anaemia), and examine the patient’s hands
for clubbing, discolorations (jaundice & cyanosis) and contractures.
4. You then palpate the patient’s neck and check for swollen lymph nodes. You must
check the anterior triangle lymph nodes and the posterior triangle lymph nodes.
5. You must then check the mouth & tongue for cyanosis.
6. You must then check the eyes to observe for jaundice.
7. Lastly, you check the feet and confirm if the patient is oedematous. You may want to
comment on the extent of the oedema. A sacral oedema test may help to make a
rough estimate of this assessment.

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 Management of potassium
derangements
Potassium derangements are common complications of either disease or treatment. The
normal potassium levels in serum is 3.5-5.2mM, and this is the potassium concentration in
ECF. Potassium is an important anion in the body. Its extracellular concentration is
important for maintaining the transmembrane gradient in the body. This is important
particularly in excitable tissues, which can become highly excitable.
The distribution of potassium in the body depends on many factors:
1. The sodium-potassium pump. This is the main structure that maintains the
potassium & sodium gradients across the cell membrane.
2. The pH of plasma. Changes in plasma pH lead to changes in ECF potassium
concentration. Acidosis causes hyperkalaemia while alkalosis causes hypokalaemia.
3. Insulin. Insulin stimulates uptake of potassium by cells. Therefore, changes in insulin
levels influence potassium levels in the body.
4. Epinephrine. This hormone increase uptake of potassium through β1-receptors.
5. Glucose distribution. In patients with diabetes, the extracellular glucose
concentration rises, leading to rises in ECF osmolality. This leads to exit of water
from cells, and this raises the intracellular concentration of potassium. This rise in
concentration promotes exit of potassium ions.
6. RAAS (renin-angiotensin-aldosterone system). This system leads to increased
excretion of potassium in exchange for sodium retention. Aldosterone secretion is
also independently influenced by potassium levels; high levels stimulate its secretion
while low levels abolish it. This aims to maintain potassium levels at a homeostatic
level. However, because aldosterone is also under influence from body fluid volume
status, potassium levels are more likely to be deranged when anything happens to
the body.
7. Dietary intake. The normal dietary potassium intake is usually 80-150mM per day.
8. Extra-renal losses. These are mainly through the GIT. They can result from either
vomiting or diarrhoea. Only about 10% of dietary intake is lost in the GIT.
The major potassium derangements that occur in the body are hyperkalaemia and
hypokalaemia.

Hyperkalaemia
Hyperkalaemia is a condition in which serum potassium levels rise above 5.2mM.
hyperkalaemia is either a result of inappropriate release from cells or inability to excrete.
The causes of hyperkalaemia are:

Page 16 of 455
 • Vascular. Transfusion of stored blood & massive blood transfusions can cause
hyperkalaemia.
• Inherited. Some patients have familial pseudo-hyperkalaemia.
• Trauma. Acute kidney injury causes hyperkalaemia. This is one of the commonest
causes. Rhabdomyolysis & tissue necrosis also cause hyperkalaemia due to
widespread release of potassium. Excessive exercise also causes hyperkalaemia.
• Autoimmune diseases.
• Metabolic disorders. Acidosis, diabetic ketoacidosis causes hyperkalaemia.
• Iatrogenic. Drugs can cause hyperkalaemia. They are also amongst the most causes.
A lot of drugs have been implicated: potassium-sparing drugs (e.g. amiloride,
spironolactone), ACE inhibitors, NSAIDs, heparin, cyclosporine.
• Neoplasms. Tumour lysis causes hyperkalaemia. Leukaemia, infectious
mononucleosis and
• Degenerative diseases. Addison’s disease and Gordon’s syndrome cause
hyperkalaemia.

Clinical features
A serum potassium level of above 7mM is a medical emergency.

• Concerning signs include: a fast irregular pulse, chest pain, palpitations and light-
headedness.
• Muscle weakness.
• Kusmaul respiration. This is associated with acidosis.
• Decreased cardiac excitability with eventual asystole (cardiac arrest).
• Hypotension & bradycardia.
• On ECG, you will see (in sequence) tall tented T-waves, reduced P-wave, widened
QRS complex and a sine-wave pattern just before cardiac arrest. The patient may
also be in ventricular fibrillation.

Treatment
The management of severe hyperkalaemia should be as follows:
1. Setting up ECG monitoring & IV access.
2. Protect myocardium. You use calcium gluconate to protect the myocardium from
sudden arrest. You give 10ml of 10% calcium gluconate solution over 5 minutes. The
dose can be repeated after 15 minutes, as the effect is temporary.
3. Drive potassium into cells. This you do in 2 ways.
a. You can use insulin 10IU with 50ml of 50% glucose given over 10-15 minutes.
You need to make regular checks of blood glucose & potassium.
b. You can also administer salbutamol instead. You can give it intravenously at a
dose of 0.5mg in 100ml of 5% dextrose over 15 minutes. This is rarely used,
however. You can also nebulise the salbutamol.

Page 17 of 455
 To correct severe acidosis (<6.9), infuse 1.26% sodium bicarbonate instead of the
hypertonic type1.
4. Deplete body potassium. This is done later on over the next 24 hours. You give
polystyrene sulphonate resins, which bind potassium in the gut. They make use of
ion fluxes in the gut to remove potassium from the body and are the only way (save
for dialysis) to remove potassium from the body. They may, however, cause fluid
overload because they contain sodium, and they can cause hypercalcaemia due to
the calcium they contain. You give up to 15g 3-times daily with laxatives, or you can
give 30g followed by an enema.
5. Haemodialysis or peritoneal dialysis. This is done when the above measures fail. At
this point, the hyperkalaemia is said to be refractory. It is usually used in patients
with end-stage kidney disease ESKD.

Hypokalaemia
Hypokalaemia is produced by potassium levels below 3.5mM. The causes of hypokalaemia
are:

• Vascular.
• Infection. Severe diarrhoea can cause hypokalaemia.
• Trauma. The “traumatic” causes include:
o Release of urinary tract obstruction.
o Acute myocardial infarction.
• Autoimmune.
• Metabolic. Correction of megaloblastic anaemia can cause hypokalaemia. Dietary
deficiency also leads to hypokalaemia. Alkalosis also causes hypokalaemia.
• Iatrogenic. Iatrogenic causes include:
o Potassium-wasting diuretics lead to hypokalaemia. These include thiazides &
loop diuretics.
o Excess corticosteroid administration also leads to stimulation of
mineralocorticoid receptors, resulting in aldosterone-like effects.
o Nephrotoxic drugs such as aminoglycosides, amphotericin B and cytotoxic
drugs exert their effects by causing renal injury.
o Excessive insulin administration leads to hypokalaemia by increasing shunting
of potassium intracellularly.
o B-agonists such as salbutamol can also shunt potassium intracellularly.
o Other drugs include carbenoxolone and liquorice2.
o Administration of IV drugs without potassium, e.g. normal saline.
• Neoplastic. Neoplasms that cause hypokalaemia include:
o Acute leukaemia.
o Villous adenoma.
o ACTH-producing tumours.

1
The hypertonic type is associated with volume expansion.
2
Liquorice potentiates renal effects of cortisol.

Page 18 of 455
 • Degenerative. Degenerative causes include:
o Hepatic failure.
o Heart failure.
o Kidney & adrenal disease. This includes nephrotic syndrome, Barter’s
syndrome and Conn’s disease. renal tubular acidosis (both types) and renal
tubular damage both cause hypokalaemia.
o Syndromes such as Liddle’s syndrome and Gitelman’s syndrome.
o Pyloric stenosis.

Clinical features
Hypokalaemia is usually asymptomatic, and is only symptomatic when it is severe (<2.5mM).
The clinical features of hypokalaemia are:

• Muscle weakness. This is due to low intracellular potassium.

• Symptomatic hyponatraemia.
• Increased frequency of atrial & ventricular ectopic beats. This is more common,
however, in patients with cardiac disease.
• Increased risk of digoxin toxicity. It leads to increased binding of digoxin to the Na +-
K+ pump.
• Interstitial renal disease. This happens, however, with chronic hypokalaemia.
• On ECG, there are small T-waves with prominent U-waves, a prolonged PR interval
and ST segment depression.

Management
The underlying cause should be identified and treated as soon as possible.
Acute hypokalaemia may correct spontaneously. You do the following:
1. Withdraw oral contraceptives & purgatives.
2. Administer oral potassium supplements as slow-release potassium or effervescent
potassium.
3. Intravenous potassium is indicated in conditions such as cardiac arrhythmias, muscle
weakness or severe diabetic ketoacidosis. Do not give more than 20mmol/hour3 and
no more concentrated than 40mmol/minute.
4. Serum magnesium levels must be measured when the hypokalaemia has not been
corrected. They should be measured & corrected.
When a patient has poor renal function, the replacement rate should be less than
2mM/hour. There is also need for hourly monitoring for ECG changes. Potassium ampoules
should be mixed with normal saline, as dextrose will make hypokalaemia worse.

3
You can give more provided that there is ECG monitoring.

Page 19 of 455
 Meningitis
Meningitis is inflammation of the meninges, and this is usually a serious infection.
Organisms can reach the meninges in a variety of ways: by extension from the ears,
nasopharynx or sinuses, by direct inoculation from cranial injuries or congenital meningeal
defects, or by haematogenous spread from another primary source. Other non-infectious
causes of meningitis include: malignant meningitis, intrathecal drugs and blood in the
subarachnoid space.

Causative agents
The different meningitis syndromes are:

• Acute bacterial meningitis. This is often caused by acute bacterial infection. The
causative agents include: S. pneumoniae, H. influenzae, N. meningitidis, S. aureus,
group B streptococcal species, L. monocytogenes, Gram-negtaive bacilli (e.g. E. coli),
etc. The pia & arachnoid mater are usually congested with polymorphs and form a
layer of pus. This pus layer may organise and form adhesions, which can complicate
with hydrocephalus & cranial nerve palsies. Cerebral oedema can also develop.
• Tuberculous meningitis. Tuberculous meningitis usually causes chronic meningitis.
There is formation of a thick exudate at the base of the brain, which also results in
cranial nerve palsies. There are also numerous meningeal tubercles. Adhesions are
invariable. There is a predominance of lymphocytes in the CSF. Cerebral oedema is
also present.
• Viral meningitis. The viral causes of meningitis are: Enteroviruses (e.g. ECHO virus &
Coxsackie viruses), poliomyelitis, mumps, herpes simplex, HIV, West Nile virus and
EBV. There is predominantly a lymphocytic inflammatory reaction without pus
formation. There are also no polymorphs or adhesions and there is little or no
cerebral oedema (unless encephalitis develops).
• Fungi. Fungal infections often develop in immunocompromised individuals.
Cryptococcal meningitis is a common infection in HIV infected individuals. Other
causes include Candida, Coccidioides, Histoplasma and Blastomyces. There usually
give rise to chronic meningitis.
• Protozoa. Malaria can cause meningitis.

Risk factors
The risk factors for developing meningitis are:

• Age. In immunocompetent individuals, meningitis is common in the very young and

very old. This is related to the immune statuses of individuals at these ages.

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 • Comorbid conditions. These include diabetes, chronic kidney disease, adrenal
insufficiency, hypoparathyroidism and cystic fibrosis. Alcoholism & cirrhosis are also
risk factors.
• Immunosuppression. HIV is a common risk factor in sub-Saharan Africa. Chronic
causes such as tuberculosis & fungal meningitis are common in this population.
• Splenectomy & sickle cell disease. This increases the likelihood of meningitis
secondary to encapsulated organisms. Hyposplenism predisposes to infections.
Thalassemia major also predisposes to meningitis.
• Crowding. This predisposes to meningitis from meningococcal infection, which often
spreads in outbreaks in such populations.
• Introduction of foreign bodies into CNS. Ventriculoperitoneal shunts predispose to
meningitis, as they can get infected. Dural defects caused by trauma or surgery can
also introduce infection.
• Pre-existing infection. Common infections that spread contiguously include rhinitis,
sinusitis, otitis media and mastoiditis. Other infections that predispose to meningitis
include Ludwig’s angina. Bacterial endocarditis also predisposes to meningitis. Any
other pre-existing infection elsewhere, e.g. pulmonary TB, can result in meningitis.
• Malignancy. L. monocytogenes is often found in this population.

Clinical presentation
The presentation of meningitis is as follows:

History

44% of patients present with the classic triad of symptoms:

• Fever. This is absent in aseptic (including viral) meningitis.

• Headache.
• Neck stiffness.

Other symptoms include:

• Photophobia.
• Altered mental status.
• Nausea & vomiting.
• Malaise & rigors.
• Loss of consciousness. This occurs in complicated cases. Some patients can even
present in a coma.
• Seizures. They may be the sole presentation if the patient has been treated with
antibiotics before.

Other features suggestive of aetiologies include:

• Petechial rash – meningococcal infection.

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 • Travel history – malaria.
• Skull fracture, ear disease or congenital CNS lesion – S. pneumoniae.
• Concomitant otitis media or sinusitis.
• HIV – Cryptococcus or TB. For TB, also screen for symptoms, history of TB infection
and look for history of contact.

Examination

Examination findings include:

• Pyrexia.
• Nuchal rigidity.
• Altered mental status.
• Signs of extracranial infection.
• Infants: bulging fontanels, irritability, high-pitched cry and hypotonia.
• Lymphadenopathy may be present in TB.
• Cranial nerve palsies. The common nerves affected are CNIII, CNIV, CNVI and CNVII.
They are present in 10-20% of patients.

Complications of meningitis
These include:

• Septic shock. This can degenerate into DIC (which causes haemolytic anaemia).
Shock is common with bacterial infections. However, it can occur with fungal
infections as well, and this is usually more difficult to deal with.
• Seizures. These occur in 30% of adults and 40% of children.
• Cranial nerve dysfunctions. These include hearing impairment.
• Focal signs. This includes paralysis, and is due to cerebral ischemia which results
from vascular inflammation and thrombosis.
• Cerebral oedema. This is common with bacterial meningitis and is an important
cause of death.
• Hydrocephalus. This produces ventriculomegaly. Hydrocephalus can be
communicating or obstructive. Obstructive is due to exudates forming at the
foramina of Magendie & Luschka, while communicating hydrocephalus is due to
exudates forming over the arachnoid granulations.

Investigations
The investigations done for meningitis are:

Page 22 of 455
 •
Lumbar puncture. This is indicated for most cases with fever, headache and neck
stiffness, as meningitis needs to be ruled out early1. In a lumbar puncture, you need
to take note of the opening pressure2 (which is directly proportional to morbidity &
mortality), take the 1st tube for biochemistry (glucose & protein), the 2nd for
haematology (white cell count with differential), the 3rd to microbiology &
immunology (for microscopy with Gram stain, ZN stain, India ink, culture [bacterial &
fungal] and Cryptococcal antigen [CrAg] testing) and the 4th tube is held for a repeat
cell count with differential if needed. The findings in the different types of meningitis
are as follows:
Opening White cell Glucose Protein Organisms
pressure count (mg/dL) (mg/dL)
(cm H2O) (cells/µL)
Normal 8-20 0-5 50-75 15-40 None
values lymphocytes
Bacterial 20-30 100-5000 Reduced Elevated (>100) Specific
meningitis (elevated) (very high) (<40) pathogen
Polymorphs identified in
60% of Gram
stains & 80%
of culture
Viral 9-20 10-300 Mostly Normal/slightly Viral isolation,
meningitis (normal) (elevated) normal. elevated. PCR
Lymphocytes Reduced
in LCM &
mumps
Tuberculous 18-30 100-500 (very Reduced Elevated (>100) AFBs, positive
meningitis (elevated) high) (<40) on culture &
Lymphocytes PCR.
Cryptococcal 18-30 10-200 Reduced 50-200 Positive on
meningitis (elevated) (elevated) (elevated) India ink, CrAg
Lymphocytes and culture
Aseptic 9-20 10-300 Normal Normal/slightly Negative on
meningitis (normal) (elevated) elevated workup
Lymphocytes
• Blood studies. An FBC is required, particularly in cases of acute bacterial meningitis.
In bacterial meningitis, there will be leukocytosis with left shift (increase in the
number of blasts). LFTs & U&Es are also required for assessing organ function and
adjusting doses to prevent toxicity. A coagulation profile & platelet count is indicated

1
Lumbar puncture should not be done if there is a suspicion of a space-occupying lesion
2
Normal opening pressure is 8-20cm H2O.

Page 23 of 455
 for patients with chronic alcohol use or suspected DIC. Blood cultures should also be
done.
• Neuroimaging. These may show signs of meningeal enhancement, but are not
necessary for diagnosis of meningitis. They may be necessary, however, for
identification of complications such as hydrocephalus, cerebral oedema, infarcts,
brain abscesses and venous sinus thrombosis.

Management
Management needs to be prompt, as delay in management increases the risk of mortality.
Even with optimal management, mortality is about 15%. The management is as follows:

• Acute bacterial meningitis. While waiting for results to return, you should start
empirical treatment. You can start cefotaxime, benzylpenicillin or chloramphenicol
(generally not used). When meningococcal infection has been confirmed (either by
culture or by other clinical features), you give intravenous antibiotics immediately.
Lumbar puncture is unnecessary if clinical features suggest meningococcal infection,
and you can rely on blood cultures alone. In other types of acute bacterial
meningitis, lumbar puncture is indicated. However, if a mass lesion is suspected do a
CT scan first. In adults with pneumococcal meningitis, dexamethasone should be
given with the initial antibiotics. Both pneumococcus & Haemophilus respond to
cefotaxime/ceftriaxone.
• TB meningitis. Treatment with anti-TB drugs should be commenced. You give HRZ
for 2 months (initiation phase) followed by HR for 6-9 months (continuation phase).
Ethambutol has ocular complications. Adjuvant corticosteroids are now
recommended, and you give high dose corticosteroids (e.g. prednisolone 60mg for 3
weeks). Relapses & complications are common.
• Cryptococcal meningitis. This is treated in 3 phases. You start with an intensive
phase of amphotericin B (0.7mg/kg/day) with fluconazole (800mg orally once daily)
for 2 weeks [or fluconazole 1200mg orally daily for 2 weeks if amphotericin B is
contra-indicated], followed by a consolidation phase which consists of fluconazole
alone (800mg orally once daily) for 8 weeks, followed by a maintenance phase which
consists of fluconazole (200mg orally once daily) until CD4+ count is above
200cells/µl for 6 months.

Page 24 of 455
 Guillain-Barré syndrome
Guillain-Barré Syndrome (GBS) is a collection of clinical syndromes that manifest as an acute
inflammatory polyradiculopathy. It is the most common acute polyneuropathy, with an
incidence of 3 per 100 000 population. It is a demyelinating disease, and is one cause of
acute flaccid paralysis. It has no racial predilection, but it is more common in males. It has a
bimodal distribution, being common at ages 15-35 and 50-75 years.

Pathophysiology
GBS develops as a result of molecular mimicry. It develops after a preceding infection. The
infections known to cause GBS include:

• Viral: CMV, herpes zoster, HIV, and EBV.

• Bacteria: Campylobacter jejuni and Mycoplasma.
• Vaccinations: influenza, rabies.

The infection is often trivial & unidentified, but the disease develops about 1-3 weeks
afterwards. As part of the immune response, the immune system produces antibodies to
liposaccharides on the infectious agents. It is thought that there is homology between these
liposaccharides and cerebral gangliosides, and these homologous molecules are attacked.
This leads to destruction of myelinating cells (predominantly Schwann cells), particularly
when GM1 is attacked.

Pathologic findings include lymphocytic infiltration of spinal roots and peripheral nerves,
followed by macrophage-mediated stripping of myelin. This leads to defective propagation
of nerve impulses (which typically becomes slower). In some patients with severe disease,
there is axonal disruption & loss.

Variants of GBS
The 4 main variants of GBS are:

• Acute inflammatory demyelinating polyradiculopathy (AIDP). This is the most

common variant of GBS. It is also preceded by a bacterial or viral infection1.
Symptoms generally resolve with remyelination.
• Acute motor axonal neuropathy (AMAN). This is a purely motor subtype that
principally affects paediatrics. It is characterised by rapidly progressing symmetrical
weakness with ensuing respiratory failure. 70-75% of patients are seropositive for C.
jejuni infection. Patients have high titres to GM1, GD1a and GD1b. Inflammation may

1
Nearly 40% of patients are seropositive for C. jejuni.

Page 25 of 455
 1
lead to disruption of the blood-brain barrier. of patients may actually have
3
hyperreflexia. The prognosis is often quite favourable, and recovery is rapid within
days.
• Acute motor-sensory axonal neuropathy (AMSAN). This is a severe acute illness that
also affects the sensory nerve roots. It also typically affects adults. In AMSAN, there
is usually marked muscle wasting, and recovery is poorer than with AMAN. It is also
associated with C. jejuni. There is marked axonal degeneration with little
demyelination.
• Miller-Fisher syndrome (MFS). This is observed in 5% of all cases of GBS. It consists
of a triad of: ataxia, areflexia and ophthalmoplegia2. Patients have mild limb
weakness, ptosis, facial palsy and/or bulbar palsy. Anti-GQ1b antibodies are
prominent in MFS, and these are found in CNIII, CNIV and CNVI.

Other variants of GBS include:

• Pure sensory GBS. This is typified by sensory loss, sensory ataxia and areflexia in a
symmetrical widespread pattern. The prognosis is often good.
• Acute pan-autonomic neuropathy. This is the rarest variant. It involves the
sympathetic & parasympathetic systems. Patients develop postural hypotension,
bowel & bladder retention, anhidrosis, decreased salivation & lacrimation and
pupillary abnormalities. Cardiovascular involvement is common, with presence of
arrhythmia. Motor & sensory involvement is lacking. Recovery is gradual & often
incomplete.

Clinical features
The clinical features are as follows:

History

Patients come complaining of:

• Muscle weakness. The muscle weakness usually starts in the distal extremities, and it
is proximal muscle weakness. It ascends to affect more proximal limbs, and it is
symmetrical. Patients may be unable to stand or walk, especially when
ophthalmoparesis and/or impaired proprioception are present. Weakness develops
acutely and progresses over a few days.
• Cranial nerve involvement. This is seen in 45-75% of patients. It includes facial droop,
diplopias, dysarthria, dysphagia, and ophthalmoplegia & pupillary disturbances.

2
Acute onset of ophthalmoplegia is a cardinal feature.

Page 26 of 455
 • Sensory changes. Most patients complain of paraesthesia or numbness. Paraesthesia
usually starts at the toes or fingertips and progresses upwards, but usually does not
pass the wrist or ankles.
• Pain. This is present in more than 50% of patients. The mechanism of pain is not well
understood. It is most severe in the shoulder girdle, back, buttocks and thighs, and it
is aching & throbbing in nature.
• Autonomic changes. These include tachycardia/bradycardia, facial flushing,
paroxysmal hypertension, orthostatic hypotension, anhidrosis and/or diaphoresis.
There may also be urinary retention & constipation, but these are rarely early or
persistent. Patients can also develop arrhythmias.
• Respiratory involvement. 40% of patients present with any of: dyspnoea on exertion,
shortness of breath, difficulty swallowing and slurred speech. This is due to
weakness of the diaphragm.
2
• Antecedent illness. Up to 3s of patients will remember an antecedent illness 1-3
weeks prior to their current symptoms. Often the illness is acute diarrhoea which
may have been bloody. Also find out about any recent vaccines.

Examination

The examination findings include:

• General – patients may present with a tachycardia or bradycardia. Blood pressure is

often labile,
• Neurologic assessment – patients often have facial weakness. Patients present with
other palsies, such as limitation of lateral gaze (CNVI), ptosis (CNIII) and pupillary
abnormalities. The lower limbs are usually affected first. This then progresses
upwards. The motor features are consistent with a lower motor neuron lesion:
hypotonia, symmetrically reduced power, areflexia with a down-going plantar reflex.
Objective sensory changes are minimal.

Investigations
The diagnosis of GBS is often clinical, based on the history & examination. Investigations are
done to rule out other diagnoses and rule out other comorbidities. The investigations are:
1
• Blood tests. LFTs are elevated in as many as 3 of patients. SIADH may occur, leading
to true dilutional hyponatraemia.
• Peripheral neuropathy workup. These include: TFTs, rheumatologic profiles, vitamin
B12 & folate screen, HbA1c, ESR, RPR, serum protein and tests for heavy metals.
• Serum antibodies. These are indicated when the diagnosis of GBS is questionable, or
you want to identify a variant of GBS. Anti-GM1 antibodies are found in AIDS &

Page 27 of 455
 AMAN and are closely associated with antecedent C. jejuni infection. Anti-GQ1b
antibodies are found in patients with MFS.
• Lumbar puncture. This will demonstrate increased protein to 1-3g/dL (a
phenomenon called albumin cytoplasmic dissociation) with a normal white cell
count.
• Nerve conduction studies. Abnormalities associated with GBS include: nerve
conduction slowing, prolongation of distal latencies, prolongation/absence of F-
waves, and conduction block/dispersion of responses. Changes should be seen in
more than 2 nerves (such as the arm & leg). You can also use electromyography
(EMG) to detect slowed conduction, and this is more specific.
• Pulmonary function tests. You need to measure the forced vital capacity (FVC) to
assess respiratory status and the need to ventilate. You use the 20-30-40 rule to
determine whether intubation is necessary:
o The FVC is less than 15-20ml/kg (or 1L).
o The maximum inspiratory pressure is less than 30cm H2O.
o The maximum expiratory pressure is less than 40cm H2O.
• Imaging. MRI can reveal nerve root enhancement.

Management
Patients diagnosed with GBS should be admitted into hospital for close monitoring until the
disease has reached plateau or is in reversal. This is because symptoms can rapidly progress.
1
of patients require admission into ICU because of respiratory failure.
3

Management of GBS is divided into supportive treatment and definitive treatment

Supportive management

Supportive management entails:

1. Ventilatory support. It is important to assess the airway, breathing and ventilation of

a patient. Administration of oxygen and assisted ventilation may be necessary. You
need to regularly monitor for respiratory failure, bulbar weakness and difficulties in
swallowing. Intubation is performed on patients with rapidly declining respiratory
function, hypoxia, poor/weak cough and suspected aspiration. Intubation is also
indicated when there is the “20-30-40 rule” indication (FVC <1.5l or 20ml/kg,
maximum inspiratory pressure <30cm H2O, maximum expiratory pressure <40cm
H2O).
2. Analgesia. Pain is treated using NSAIDs or aspirin. You can add opioids if necessary,
although these are only required for the first few weeks. Adjuncts to pain medication
include TCAs, gabapentin and carbamazepine. Non-pharmacologic pain therapies

Page 28 of 455
 include frequent passive limb movements, gentle massage and frequent position
changes.
3. Cardiac monitoring. Dysautonomia can produce both hypertension & hypotension.
Hypertension can be treated using a β-blocker or nitroprusside. Hypotension can be
treated using intravenous fluid & supine positioning.
4. DVT prophylaxis. This is done by giving compression stockings and administering
LMW heparin. The compression stockings used are true gradient compression
stockings, which exert their highest pressure at the distal extremities (toes) and the
lowest at the most proximal part of the limb (thigh) to reduce the capacitance
volume of the lower limbs and prevent pooling of blood. They exert a pressure of 30-
40mm Hg. Standard white or TED stockings produce a maximum compression of
18mm Hg and are rarely fitted to provide adequate gradient compression. They are
therefore not advised.
5. Nutrition. Patients require feeding when on mechanical ventilation, whether enteral
or parenteral. This is to ensure that caloric intake is adequate when metabolic needs
are high. You should avoid aspiration pneumonia from developing.
6. Bowel & bladder management. This is usually transient, but is required to prevent
development of other complications.
7. Physiotherapy. About 40% of hospitalised patients require physiotherapy. The aim is
to reduce functional deficits and to target impairments & disabilities resulting from
GBS. Speech therapy helps promote speech and safe swallowing skills for patients
with significant oropharyngeal weakness.
8. Recreational therapy. Recreational activities are beneficial to a patient to promote
growth, development and independence of a long-term hospital patient.

Definitive management

Definitive management entails:

• Intravenous immunoglobulins. You give 0.4g/kg per day for 5 days. It is an easy
intervention to implement. This is safe for use in children, but safety in pregnancy
has not been demonstrated. Intravenous immunoglobulins are also preferred in
haemodynamically unstable patients and in those unable to ambulate
independently.
• Plasma exchange. This is carried out over 10 days, and aims to remove auto-
antibodies, immune complexes and cytotoxic constituents from serum. This has been
shown to reduce recovery time by 50%. This has equal efficacy as intravenous
immunoglobulins.
• Immune adsorption. This is a new alternative treatment being tried.

Outcomes

Page 29 of 455
The spectrum of outcomes from GBS is wide, from complete recovery, to tetraplegia, to
death. In most cases, however, there is peak weakness in 10-14 days followed by recovery
within weeks to months. 80% walk independently at 6 months and 60% gain full motor
function within a year.

The mortality from GBS is 2-12%, and causes of death include ARDS, sepsis, pneumonia,
venous thromboembolic disease and cardiac arrest. Deaths often occur amongst those
patients requiring ventilator support. The leading cause of death amongst the elderly is
arrhythmia. Mortality rates increase with the age of the patient. 15-20% of patients develop
moderate residual deficits, while 1-10% of patients are severely disabled.

The prognostic factors for GBS are:

• Preceding GIT infection or diarrhoeal illness.

• Older age.
• Poor upper extremity muscle strength.
• Acute hospital stay of more than 11 days.
• ICU requirement.
• Need for mechanical ventilation.
• Discharge to rehabilitation.

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 Multiple sclerosis (MS)
Multiple sclerosis (MS) is an autoimmune neurological disorder of the CNS. It results in
formation of multiple plaques in the brain. Multiple sclerosis is a common disorder in
temperate regions. In the UK, the incidence is greater than 42 cases per 100 000 population,
and in South-East Scotland the incidence is greater than 200 cases per 100 000 population.
In the US, the incidence is 58-95 cases per 100 000 population. It is rarer amongst black
Africans and Asians. Adult migrants take their risks with them, while children acquire the
risks where they settle. The mean age of onset is 30 years, and it is 3-times more common in
females.

Pathophysiology
MS is an autoimmune disorder leading to inflammatory demyelination of the spinal cord.
The autoimmune process is T-cell mediated and it causes an inflammatory process within
the white matter of the brain & spinal cord. There may also be a humoral component, as
evidenced by presence of elevated IgG levels in the CSF of these patients. The exact cause of
MS is not understood.

One of the earliest processes in MS is the breakdown of the blood-brain barrier, leading to
crossing of leukocytes into neural tissue. These leukocytes acquire adhesive molecules that
allow them to cross this barrier. IL-12 is expressed early in MS lesions. There may also be
reduced activity of Treg-cells, which function in regulating the immune system.

MS produces numerous plaques within the white matter of the brain. These plaques can
form anywhere, but they have a predilection for the optic nerve, the periventricular region,
corpus callosum, brainstem & its cerebellar connections and the cervical spinal cord
(corticospinal tracts & posterior columns). In these lesions, there is destruction of
oligodendrocytes, myelin loss and reactive astrogliosis. In some patients there is aggressive
destruction of the axon. There is also infiltration of neural tissue with leukocytes
(predominantly lymphocytes & macrophages).

MS is characterised by acute relapses which are caused by focal inflammation causing

conduction block. Recovery occurs as inflammation subsides and re-myelination takes place.
The disease progresses due to progressive axonal damage.

Aetiology
The exact cause of MS is unknown, but there are many risk factors:

• Genetics. The concordance amongst monozygotic twins is 20-35%, which suggests

that genetics only have a minor role to play. The risk of you developing MS if your

Page 31 of 455
 family member has MS is 7-times higher than in the general population. The only
chromosomal locus that is consistently associated with MS susceptibility is HLA-
DRB1.
• Age. Patients typically present at age 20-40 years. Presentation after 60 is rare,
although diagnosis may be delayed and occur years after initial symptoms.
• Sex. MS is 3-times more common amongst females than males. This ratio is
widening.
• Viral infection. It is believed that viruses may infect individuals, activate self-reactive
T-cells and initiate autoimmune processes. Viral reactivation within infected immune
& nervous cells may be responsible for acute attacks. Viruses associated with this are
EBV and HHV-6. Exposure to these infections during childhood, however, appears to
be protective due to the hygiene hypothesis.
• Vitamin D. There is evidence that MS is more common amongst patients with low
vitamin D and little sunlight exposure.
• Geographic aviation. MS is predominantly a disease of temperate climates. The
incidence is higher in Europe & America and low in Africa & Asia. This, however, may
be related to vitamin D exposure.

Clinical patterns
The clinical patterns of MS are:

• Remitting-relapsing MS. This accounts for 85-90% of presentations. Symptoms occur

in attacks and the attacks develop over days. Recovery may be complete or
incomplete (in terms of disability) and occurs over weeks. On average patients have
1 relapse per year, but relapses can be separated over several years. If relapses do
not recover adequately, patients may develop disability over time.
• Secondary progressive MS. This is a late stage of MS and develops after remitting-
relapsing MS. 75% of patients with remitting-relapsing MS will develop secondary
progressive MS by 35 years after onset. Relapses may sometimes occur in this stage.
• Primary progressive MS. This is the least common presentation, accounting for 10-
15% of cases. It is characterised by gradual worsening disability without relapses or
remissions. It typically presents later and is associated with fewer inflammatory
changes on MRI.

The clinical patterns of involvement in MS are:

• Optic neuritis. Optic neuritis occurs in about 40% of patients. 20% present with optic
neuritis as a first presentation.
• Spinal MS. 55-75% of patients develop spinal cord lesions at some point in their
lives. It is often associated with concomitant brain lesions. Spinal MS has a

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 predilection for the cervical cord, and it often involves the dorsal & lateral tracts
abutting the subarachnoid space.
• Myelocortical MS. This is a new variant of MS marked by demyelination of the spinal
cord & cerebral cortex, but excluding the cerebral white matter. In these patients,
neurodegeneration can be independent of demyelination.
• Brainstem MS. A relapse affecting the brainstem contains combinations of diplopia,
vertigo, facial numbness, dysarthria and dysphagia. Bilateral inter-nuclear
ophthalmoplegia is pathognomonic of MS.

Clinical presentation
The clinical presentation is as follows:

History

Patients are usually monosymptomatic: they have single complaints. The presenting
features:

• Optic neuritis: pain in eye movement, rapid deterioration in central vision, diplopia
on lateral gaze, hemianopia.
• Sensory spinal cord symptoms: paraesthesia, loss of vibration & proprioception
(leading to useless hand/leg).
• Motor spinal cord symptoms: leg weakness, unsteadiness, falls
• Autonomic spinal cord symptoms: bladder hyperreflexia (frequency & urgency),
constipation, sexual dysfunction, temperature sensitivity1.
• Other symptoms: fatigue, depression, neuropathic pain (particularly in the face),
swallowing difficulties, seizures,
• Higher functions: reduced attention span, concentration, memory and judgement.

Examination

On examination:

• General examination: patients may have an intention tremor.

• Neurologic examination. Patients have features of UMN lesions: hypertonia
(spasticity) & hyperreflexia with reduced power. Patients will have reduced somatic
sensation & vibration sense.
• Eye examination. There is loss of visual acuity, deficits in colour & contrast and visual
field defects. On fundoscopy, however, you may not find any abnormal features.
However, you may see optic disc pallor months after optic neuritis. Other rare

1
Worsening of symptoms after an increase in temperature (e.g. hot bath or exercise) is called Uhthoff’s
phenomenon.

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 findings include anterior uveitis, vitreitis, vascular sheathing, disc & papillary
haemorrhage and compromise of central arterial & venous circulations.

Investigations
These are supposed to support the diagnosis of MS by providing evidence of dissemination
in time & space. The investigations done in MS are:

• MRI scans. An MRI scan of the brain & spinal cord has high sensitivity but low
specificity for MS lesions in the brain. MRI demonstrates areas of demyelination.
Typical lesions are oval in shape, about 2cm in diameter and often perpendicular to
the lateral ventricles. Acute lesions show gadolinium enhancement for 6-8 weeks. Its
low specificity is due to the differentiating MS plaques from small ischemic lesions
(in the elderly) and other non-inflammatory lesions (in young patients) such as
sarcoidosis, Behçet’s syndrome and vasculitis. There are fewer inflammatory lesions
in the spinal cord that mimic MS, so a spinal MRI is more specific. Things to look for
on MRI include:
o Dissemination of lesions in space, i.e. different anatomical locations.
o Dissemination of lesions in time, i.e. different ages.
• CSF examination. CSF examination is often unnecessary because of the usefulness of
MRI in diagnosis. This shows oligoclonal IgG antibodies in over 90% of cases.
However, these are not specific for MS. The CSF cell count may be elevated.
• Evoked responses. These may help demonstrate clinically silent lesions, such as
visual evoked responses in the optic nerve.
• Blood tests. These are used to exclude other inflammatory lesions, such as
sarcoidosis, SLE and other causes of para-paresis such as vitamin B12 deficiency, HIV,
HTLV-1 and adreno-leukodystrophy. An FBC may show infections, such as Lyme
disease. also screen for thyroid diseases.

Diagnosis of MS
Diagnosis of MS is a clinical one, although clinically you cannot diagnose MS based on a
single episode of symptoms. To make a diagnosis from a single episode, you need to be
supported by evidence from investigations. The diagnosis requires 2 or more episodes
attacking different parts of the CNS.

You can make use of the McDonald criteria for diagnosing MS. The criteria are as follows:

Clinical presentation Additional data needed for MS diagnosis

≥2 attacks with objective clinical evidence No additional data needed. Additional evidence
of ≥2 lesions with reasonable history (e.g. MRI of brain) is desirable but must be
evidence of prior attack. consistent with MS.

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≥2 attacks with objective clinical evidence MRI required to demonstrate dissemination in
of 1 lesion. space
OR
nd
Await 2 clinical attack suggesting different
site.
1 attack with objective clinical evidence MRI to determine dissemination in time
of ≥2 lesions. OR
nd
Wait for 2 clinical attack.
OR
Demonstration of CSF-specific oligoclonal bands
1 attack with objective clinical evidence Dissemination in space demonstrated by MRI
of 1 lesion (also called clinically isolated OR
syndrome. Await a 2nd clinical attack implicating 2nd CNS
site AND dissemination in time demonstrated
by MRI or 2nd attack.
Insidious neurologic progression One year of disease progression and
suggestive of MS dissemination in space demonstrated by:
• One or more T2 lesions in regions
characteristic of MS.
• 2 or more T2 focal lesions in the spinal
cord.
• Positive CSF.
An attack is a neurological disturbance that lasts at least 24 hours. For 2 attacks to be
separate, there needs to be at least 30 days between the onset of 1 attack and the onset of
the other.

Management of MS
There is no cure for MS, so treatment is aimed at minimising progression, preventing
complications and improving the quality of life. Treatment is divided into immunotherapy
for the underlying immune disorder, and supportive therapy to relieve symptoms.

Management of acute relapses

In the acute setting, the main aim is to abolish the immediate inflammatory process and
achieve remission. you need to stabilise acute life-threatening conditions, initiate supportive
care & seizure prophylaxis and monitor for increasing intracranial pressure. The
management of acute relapses includes:

1. Definitive therapy. Remission of relapses is achieved by administration of

corticosteroids. You can use intravenous methylprednisolone 1g per day for 3 days,

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 or high-dose oral corticosteroids. You can also use plasma exchange if steroids are
contraindicated or they are ineffective.
2. Identification & control of known precipitants. This includes: aggressive control of
infections, normalising body temperature (using antipyretic agents) in patients with
fever, and providing urine drainage & skin care.

Long-term management of MS

Long-term management of MS aims at minimising relapses and progression of the disease,

as well as preventing disability. The interventions are:

• Interferons. The interferon analogues include interferon-β1a & interferon-β1b. They

reduce relapses by 30% in active relapse-remitting MS. They also reduce lesion
accumulation.
• Monoclonal antibodies. These include alemtuzumab & natalizumab. Alemtuzumab
acts against T-cells. It has been shown to be better than interferon in reducing
relapse rates. They are mainly indicated for aggressive MS. Its side effects include
infections and development of other autoimmune diseases. Natalizumab reduces
relapse rates by 68%. It acts against VLA-4 receptors that allow T-cells to cross the
blood-brain barrier. It reduces MRI lesions by 91%.
• Non-immunosuppressive agents. These include glatiramer, cyclophosmaide and
mitoxantrone2. Glatiramer is used in relapsing-remitting MS. Cyclophosphamide &
mitoxantrone agents are useful in secondary progressive MS. They are also useful for
stabilising aggressive MS.
• Immuno-modulator therapy for primary progressive MS. There are very few
treatments effective for primary progressive MS. They include ocrelizumab,
siponimod and cladribine. You can also use mitoxantrone.
• Stem cell transplantation. Autologous transplantation helps slow the course of MS
and repairing damage to the nervous system.

Management of symptoms

The symptoms are managed as follows:

• Depression. This is managed using standard depression management. You can use
SSRIs.
• Fatigue. Fatigue is one of the most common complaints. You can use amantadine
100mg orally twice-daily. You can also try methylphenidate and fluoxetine. Non-
pharmacologic interventions include energy conservation, work simplification,
scheduled rest periods and use of cooler garments.
• Pain management. This may be primary or secondary. Primary pain is due to
neuronal dysfunction secondary to the demyelination process. This often produces a

2
Mitoxantrone has a lot of side effects, such as cardiotoxicity and AML.

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 burning or shooting pain. It is treated by TCAs as 1st-line agents, with carbamazepine,
phenytoin and gabapentin are used as 2nd-line agents. Secondary pain is
musculoskeletal in nature, primarily due to poor posture, poor balance or abnormal
use of muscles or joints.
• Heat intolerance. This can be managed by lifestyle changes. They include: placing
activities during early morning & later afternoon to avoid heat of the day; use of air-
conditioning; avoid saunas, hot tubs and hot shower baths; avoid excessive humidity;
and treat fevers.
• Spasticity. This can be done pharmacologically & non-pharmacologically. Non-
pharmacologic management is through physiotherapy. Pharmacologic management
includes use of baclofen, benzodiazepines, dantrolene, gabapentin, tizadine and
intramuscular botulinum toxin.

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 Neuromuscular junction
disorders
Neuromuscular junction disorders constitute a type of myopathy that is the result of
pathology at the neuromuscular junction. Examples of neuromuscular junction disorders
include myasthenia gravis, Lambert-Eaton syndrome and botulism.

Myasthenia gravis Lambert-Eaton Botulism

syndrome
Ocular/bulbar + - ++ (early)
paresis
Limb weakness + + +
Fatigability + + +
Post-exercise - + +
enhancement
Reflexes ↔ ↓ ↓
Anticholinergic - + ++
symptoms
Sensory symptoms - - -
Associated Thymoma Small cell Gastrointestinal signs &
conditions carcinoma symptoms
Repetitive EMG Decremental Incremental • Incremental response
stimulation response response with rapid stimulation.
• Decremental response
with slow response
Neuromuscular junction disorders lead to muscle weakness.

Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular junction disorder that is the result of
autoantibodies against the acetylcholine receptor. The prevalence of myasthenia gravis is
about 4 in 100 000. Under 50 years of age, it is twice more common in females than in
males1, and it has a peak age incidence of around 30 years.

Pathogenesis

The antibody groups in myasthenia include:

1
In males, the opposite is true.

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 • Anti-AChR antibodies. In 70-80%, the disease is caused by autoantibodies against
the nicotinic ACh receptor. Immune complexes of anti-ACh IgG and complement are
deposited on the postsynaptic membrane. These cause interference with and later
destruction of the ACh receptors. However, the plasma concentration of antibodies
does not necessarily correlate with the severity of the disease. Changes in antibody
levels can be used to monitor treatment efficiency, nonetheless.
• Anti-MuSK antibodies. A second group of antibodies has been identified which react
against muscle-specific receptor tyrosine kinase (anti-MuSK antibodies). These
antibodies have been detected in 40-70% of patients that are seronegative to the
anti-AChR antibodies. However, they are found in 10% of seropositive patients.
• Ocular muscle MG. Another group is the ocular muscle MG group. In 15% of
patients, myasthenia gravis is limited to ocular muscles alone.

The autoantibodies are thought to originate in the hyperplastic germinal centres in the
thymus. Most patients have thymic abnormalities: 70-80% of patients below 40 have thymic
hyperplasia and 10-12% have a thymoma (whose incidence increases with age). The role of
the thymoma in autoimmunity, however, is unknown. Thymic hyperplasia & thymoma is less
common in individuals with anti-AChR-negative disease. Young patients have an increased
association with HLA-B8 & -DR3.

Clinical features

Muscle weakness is the predominant feature of myasthenia gravis. Based on this, there are
2 types of myasthenia: generalised and ocular myasthenia gravis. Generalised myasthenia
gravis involves a range of muscle groups, while ocular myasthenia gravis only involves ocular
muscles. The involved muscle groups in myasthenia gravis are (in order):

• Extra-ocular muscles: ptosis (eyelid muscles, starts out bilateral but may become
unilateral during the course of the day, may switch from one eye to the other),
binocular diplopia (horizontal/vertical)2, weak eye movements (not limited to one
muscle). The pupils are always spared. 50% of patients present with ocular
symptoms.
• Bulbar muscles: fatigable chewing (weakness with prolonged chewing), dysarthria
(oral muscle weakness; palatal muscle weakness causes nasal and/or hypophonic
speech; worsens with prolonged speech), dysphagia (oral muscles, imminent risk of
aspiration leads to aspiration crisis), dysphonia (on counting to 50, the fades; rare
presentation). 15% of patients present with bulbar symptoms.
• Facial muscles: expressionless appearance (lost their smile/myasthenic snarl3 when
smiling; weakness of orbicularis oris muscle), peek sign (after brief opposition of
gentle sustained eye closure, the lids separate to show white sclerae)4.

2
This may start as episodes of blurred vision before the diplopia is apparent.
3
When the patient smiles, the midlip rises while the corners remain down.

Page 39 of 455
 • Neck & limb muscles: dropped head syndrome (weight of head overcomes neck
extensors during the course of the day, leading to drooping of head; secondary neck
ache), proximal muscle weakness (arms more often affected than legs). Less than 5%
present with proximal weakness alone. Reflexes preserved, but are fatigable.
Wasting may occur after many years.
• Respiratory muscles: respiratory failure (myasthenia crisis) may occur
spontaneously, or may be precipitated. A respiratory infection is the most common
precipitant. Patients often develop increasing muscle (especially bulbar) weakness.
The warning features include:
o Dyspnoea that occurs/worsens when the patient lies supine.
o Severe dysphagia with difficulty clearing secretions.
o Signs of respiratory muscle weakness (e.g. hypophonia), pausing during
speech to take a breath, tachypnoea, use of accessory muscles of respiration,
and paradoxical abdominal breathing.
o Low baseline vital capacity (<30ml/kg ideal body weight), even if the patient
is not in distress.

Symptoms are worsened by infection, pregnancy, hypokalaemia, menses and drugs

(anaesthetic agents, gentamycin, β-blockers, corticosteroids). Cardiac muscle is spared. It
has an association with SLE.

Investigations

The investigations are done to confirm the clinical diagnosis. The investigations that can be
done include:

• Antibodies. You can test for & measure anti-AChR and anti-MuSK antibodies. These
antibodies are not found in healthy controls. In generalised myasthenia gravis, anti-
AChR antibodies are detected in 80-90% of cases. In ocular myasthenia gravis,
however, anti-AChR antibodies are found in less than 30%. Antibody titre levels,
however, correlated poorly with disease severity. However, changes in antibody
titres can be used to monitor response to treatment. There is a group of patients
who do not test positive for any of the antibodies; they are said to have seronegative
myasthenia gravis, and they constitute 6-12% of patients.
• Electrophysiological tests. These are an important supplement to immunological
assays. They include:
o Repetitive nerve stimulation (RNS). This is the most frequently used
electrodiagnostic test for myasthenia gravis. The test is performed by placing
an electrode at the endplate region of a muscle and stimulating the motor
nerve of the muscle. The nerve is stimulated 6-10 times at a low frequency
(2-3Hz). The compound muscle action potential amplitude produced after

4
Tests orbicularis oculi muscle.

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 electrical stimulation is recorded. In normal muscle, the amplitude remains
the same with repetitive nerve stimulation. However, with myasthenia gravis,
the amplitude progressively decreases with the first 4-5 stimuli. An RNS study
is considered positive if there is a greater than 10% decline in amplitude. RNS
studies have a sensitivity of 75% in generalised MG and 50% in ocular MG.
The sensitivity is increased by 5-10% when an exercise protocol5 is used.
o Single fibre electromyography (SFEMG). This test is more technically
demanding. In SFEMG, a specialised needle electrode is inserted into the
muscle to simultaneously record the action potentials of 2 muscle fibres
innervated by the same motor axon. The special electrode has a 25µm
recording window and a low frequency filter set at 500Hz. The needle
electrode measures what is called a jitter, which is the variability in time of
the second action potential relative to the first. Any disorder that reduces the
safety factor of transmission at the neuromuscular junction will produce
increased jitter. Myasthenia gravis produces increased jitter. SFEMG has a
sensitivity of 85-95%. Its specificity is low, but it is highly suggestive of
myasthenia gravis when a standard needle EMG has no abnormalities.
• Imaging. Imaging of the mediastinum is important in evaluation of patients with
myasthenia gravis. You can do a chest CT or MRI to look for thymic abnormalities,
either hyperplasia or thymoma6.
• Beside tests. These are considered an extension of the neurologic examination
rather than lab tests. They include:
o Ice pack test. The ice pack test is used in patients with ptosis. Neuromuscular
transmission increases with cooling of muscle fibres, so when a closed eyelid
is cooled by a bag filled with ice blocks for 2 minutes, the ptosis improves by
more than 2mm.
o Tensilon® test. This test is seldom required and is used only in patients with
obvious ptosis & ophthalmoplegia. In this test, you inject edrophonium 10mg
intravenously (following a 1-2mg test dose). If there is substantial
improvement in weakness within seconds, the test is positive.
• Other antibodies. Other autonomic conditions are more common amongst patients
with myasthenia than those without. Autonomic thyroid disease is the commonest
abnormality (occurring in 3-8%). Screening for thyroid abnormalities is part of the
initial evaluation. Other conditions include SLE & rheumatoid arthritis. Antibodies to
striated muscle indicate the presence of thymoma.
• Spirometry. The forced vital capacity (FVC) & maximum inspiratory effort (MIF) are
the main parameters measured. These tests are measured when there is increasing

5
In an exercise protocol, the RNS study is carried out, then the patient is asked to exercise the muscle
maximally for 30-60 seconds and the study is retaken immediately afterwards. A smaller decrement in
amplitude is seen than that done at rest, reflecting post-exercise & post-activation facilitation.
6
Myasthenia gravis may be considered a paraneoplastic effect of thymoma.

Page 41 of 455
 generalised muscle weakness (which may mask the respiratory weakness). FVC is
typically measured every 4 hours. These tests are done to detect impending
myasthenia crisis and are used to determine the need for elective intubation. These
should always be interpreted in context: patients with facial weakness who cannot
make a good seal with the mask may have a falsely low VC.

Management

There are 4 basic therapies for myasthenia gravis. The interventions done for myasthenia
include:

• Symptom control. Symptom control is achieved using anticholinestrase inhibitors.

These simply improve symptoms but do not alter course of disease. They work by
slowing down breakdown of acetylcholine, thus allowing prolonged action of the
neurotransmitter in the synapse. This leads to a variable improvement in strength.
Symptom improvement is variable; limb & bulbar symptoms generally respond
better than ocular symptoms. Diplopia is resistant in most patients. Pyridostigmine is
usually the 1st-line drug. It has a rapid onset of action (15-30 minutes), peaks after 2
hours and it lasts 3-4 hours. It is started at 30mg 3-times daily, and titrated according
to response up to a maximum of 120mg 4-times daily. For children, you give 0.5-
1.0mg/kg every 4 hours up to a maximum total daily dose of 7mg/kg. Be wary of side
effects: colic, diarrhoea, increased salivation, increased bronchial secretions, nausea,
sweating and bradycardia. These can be reduced by taking oral atropine.
• Chronic immunotherapy. This is used in patients that don’t respond to
pyridostigmine or relapse on treatment. Moderate- & high-dose glucocorticoids are
commonly used in these patients: start with 5mg prednisolone on alternate days,
and increase the dose by 5mg per week until you reach a dose of 1mg/kg on each
treatment day. During remission, wean treatment in a step-wise process. Remission
is seen in 30% while improvement is seen in a further 50%. A transient deterioration
occurs 5-10 days after initiation of high-dose glucocorticoids in up to 50% of
patients, and it lasts 5-6 days7. Glucocorticoids can be used in combination with
other agents, such as azathioprine, cyclosporine, methotrexate and mycophenolate
mofetil.
• Rapid therapies. Rapid therapies are also immunomodulating, but they are
predominantly used in selected situations.
o During myasthenic crisis.
o Preoperatively before thymectomy or any surgery.
o As bridge therapy to slower-acting immunotherapy.
o Periodically to maintain remission in patients with poorly-controlled MG
despite use of chronic immunotherapy.

7
For this reason, high-dose corticosteroids are only started in hospitalised patients receiving concurrent
plasmapheresis for myasthenic crisis.

Page 42 of 455
 They work quickly but are only short term (a couple of weeks). The therapies include:
o Plasmapheresis. This is plasma exchange, in which you replace the plasma of
the patient with plasma from a donor blood pack or with albumin. This works
by removing the plasma containing anti-ACh/anti-MuSK antibodies and
replacing it with plasma that does not have such antibodies. The beneficial
effects are seen within days but only last weeks. A typical treatment course
involves 5 exchanges over 7-14 days.
o Intravenous immunoglobulins. Intravenous immunoglobulins are pooled
immunoglobulins from many patients. The mechanism of action is uncertain.
The total dose is 2g/kg given over 2-5 days. Side effects include headache,
chills, dizziness and fluid retention, and these are related to the infusion rate.
Acute nephrotoxicity is a potential side effect.
• Surgery. Thymectomy is considered for patients on symptomatic treatment &
chronic immunotherapy because of the potential long-term benefits. Those with
thymomas have a clear need for surgery, but those with non-thymomatous tissue
have a less clear need. Nonetheless thymectomy is encouraged. Thymectomy is
encouraged as soon as the degree of weakness is sufficient to allow surgery. If
bulbar/respiratory symptoms are present, surgery is usually deferred until symptoms
resolve. If they persist, plasmapheresis or intravenous IG is administered 2 weeks
prior to surgery.
• Respiratory support. Elective intubation is done for patients that are developing
acutely-worsening symptoms. Succinylcholine is safe to use in myasthenia gravis, but
increased doses are required. Elective intubation is done if successive VC values are
lower than 20ml/kg of if MIF is less than -30cm H2O. after intubation, positive
pressure mechanical ventilation should be initiated. After intubation, anti-
cholinestrase therapy is temporarily hauled to prevent production of secretions.
Weaning from ventilation should only be initiated when plasmapheresis and/or
intravenous immunoglobulins have been initiated.

Lambert-Eaton myasthenic syndrome (LEMS)

Lambert-Eaton myasthenia syndrome (LEMS) is an autoimmune disorder that results from
antibodies produced against presynaptic voltage-gated calcium channels. It is a rare
disorder, and its true incidence is unknown. The disease is associated small cell carcinoma of
the lung (in 50-66% of cases), and therefore its early detection is important for investigation
of this invasive cancer.

Pathogenesis

This disease is caused by auto-antibodies produced against the voltage-gated calcium

channels. These channels mediate entry of calcium into the presynaptic nerve terminal with
the arrival of an action potential. The entry of calcium allows synaptic vesicles to fuse with

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the presynaptic membrane and release acetylcholine into the synaptic cleft. The
autoantibodies therefore block the action of these channels and this leads to reduced
release of acetylcholine. This causes muscle weakness.

From a series of intracellular muscle recordings, the following features were determined:

• Normal miniature endplate potential amplitude, thus showing normal postsynaptic

sensitivity to acetylcholine.
• Marked reduced evoked endplate potential amplitude, suggesting a significant
reduction in acetylcholine release.

In patients with LEMS without small cell carcinoma, 64% have family members with
autoimmune thyroid disease or type 1 diabetes.

Clinical features

The clinical features of LEMS are:

• Proximal muscle weakness. This is usually a slow progressive muscle weakness in

the absence of significant atrophy. It often begins as a gait abnormality or difficulty
in rising from the chair. There are no abnormalities in sensation or coordination.
Reflexes are diminished/absent, unlike in myasthenia gravis. Hyporeflexia &
weakness, however, improve after sustained contraction of the muscle for 10-15
seconds8. Muscles are symmetrically involved.
• Bulbar & ocular involvement. This is present in 25%, and occurs after proximal
muscle weakness, unlike in myasthenia gravis.
• Anti-cholinergic symptoms. These are present in LEMS, unlike in myasthenia gravis.
The symptoms (in decreasing order) are: dry mouth, impotence, constipation, and
blurred vision. On examination, there may be sluggish pupillary light responses and
reduced salivation.
• Respiratory failure. Despite most patients not presenting with significant
diaphragmatic involvement, respiratory failure can occur later during the course of
disease.

You can also do a respiratory examination to look for signs of lung cancer.

Investigations

The diagnosis of LEMS is made based on clinical findings and is supported by investigations.
These include:

• Antibody testing. When LEMS is suspected, antibodies against voltage-gated calcium

channels (VGCC) are tested & measured (particularly anti-P/Q-type VGCC

8
This is called post-exercise/post-activation facilitation and is a feature of LEMS.

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 antibodies). These are present in 85-95% of patients, and the test has high
specificity; the tests are not commonly found in other autoimmune diseases.
Nonetheless, the test has also been detected in individuals with other neurologic
paraneoplastic disorders, those with cancer without signs & symptoms and those
with ALS (amyotopic lateral sclerosis). Therefore, the test is not diagnostic in the
absence of clinical signs & symptoms.
• Neurophysiologic testing. Most patients have a characteristic electrophysiological
pattern typical of presynaptic neuromuscular disorders (as opposed to the
postsynaptic neuromuscular disorder of myasthenia gravis).
o Repetitive nerve stimulation. The CMAP of resting muscle in LEMS has
significantly lower baseline amplitude than in normal individuals. Following
high-frequency (>10Hz) RNS or brief maximum isometric contraction, there is
a significant increment in the amplitude (incremental response9).
o Electromyography (EMG). On standard EMG, the motor unit action potentials
are unstable. SFEMG has significant jitter & transmission blocking that is
often improved at higher firing rates.
• Chest X-ray. This can be done to look for lung malignancies. You can also do a chest
CT since it has better resolution.

Treatment

The treatment for LEMS is as follows:

• Symptomatic treatment. These aim to increase the amount of acetylcholine

released into the synaptic cleft. The agents include:
o Aminopyridines. Aminopyridines are the primary treatment option for LEMS.
They work by prolonging depolarisation of the membrane potential and thus
increase the time that the calcium channels remain open. This enhances
calcium entry and allows more acetylcholine to be released into the synapse.
The major agent used is 3,4-diaminopyridine. This drug is the best agent in
this class as it has the least CNS penetration. It is typically administered as
20mg 4-times daily.
o Acetylcholinesterase inhibitors. These drugs work by increasing the duration
of action of acetylcholine in the synaptic cleft by delaying degradation.
Pyridostigmine is the most commonly tolerated drug. They are often used as
an adjunct to 3,4-daminopyridine. Pyridostigmine is the best tolerated drug.
o Guanidine. Guanidine works by inhibiting voltage-gated potassium channels
on the presynaptic membrane and thus enhances the release of acetylcholine
by slowing repolarisation of the membrane. Its toxicity, however, has limited
its use.
9
This is considered diagnostic of LEMS or any other presynaptic condition if the amplitude increases by more
than 100%, although a significant number do not have an amplitude rising above this.

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• Immunologic therapies. Immunologic therapies can be used when there is
progressive weakness and a limited response to symptomatic therapies. The agents
include:
o Intravenous immunoglobulin. The mechanism of action of intravenous
immunoglobulin is unknown. You give 1g/kg per day for 2 days. The benefits
of this intervention peak at 2-4 weeks, and their half-life is about 1 month.
Maintenance therapy is achieved with repeat therapy at 4-12 weeks
intervals.
o Immunotherapy. You can use oral prednisolone (1mg/kg per day) ±
azathioprine (corticosteroid-sparing agent).
o Plasmapheresis. LEMS patients, however, do not respond as rapidly to
plasmapheresis as those with myasthenia gravis. Furthermore, the benefits
are short-lived, and therefore it needs to be repeated for it to work for long.
• Surgery. If the small cell carcinoma is small enough, it can be excised surgically.

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 Stroke
A stroke is a focal neurological deficit that arises from a cerebrovascular origin and lasts for
24 hours or longer, or leads to death. It therefore differs from a transient ischaemic attack
(TIA), which is one that lasts a few hours or minutes and may herald a stroke. The arbitrary
of lasting less than 24 hours is no longer used. Stroke is the 3rd most common cause of death
in developed countries and it is the leading cause of adult disability. The mortality after a
person’s first stroke is about 12% in the United Kingdom.

Pathophysiology
In a stroke, the primary deficit comes from poor blood flow. Typically, the poor blood flow
results in death of brain neurons. Based on this, there are 2 kinds of strokes:

• Ischemic strokes. These are strokes that result from reduced blood flow to part of
the brain. This results first in ischemia followed by infarction of the brain in that
area. Ischaemic strokes account for 80% of all strokes.
• Haemorrhagic strokes. These are strokes that result from bleeding into the brain.
There are 3 kinds of haemorrhagic stroke: there are intra-parenchymal
haemorrhage, subarachnoid haemorrhage and intra-ventricular haemorrhage.
Epidural & subdural haemorrhages are not included in haemorrhagic strokes.
Haemorrhagic strokes account for about 17% of all strokes, and of these 12% are
intracerebral (intra-ventricular & intra-parenchymal) while 5% are subarachnoid.

Other causes of stroke include venous sinus thrombosis, arterial dissection and vasculitis.

Aetiology
The aetiology of strokes depends on the type of stroke.

Ischemic strokes

Ischaemic strokes are a result of reduced blood flow to a section of the brain. This can occur
in 4 main ways:

• Thrombosis. Atheromas can develop in the arteries of the brain, resulting in gradual
occlusion of the blood vessels supplying the brain. Rupture of these atheromas
results in the initiation of the coagulation cascade, and this completely occludes the
blood vessels. The mechanism is similar to that which occurs in unstable angina &
NSTEMI myocardial infarctions.
• Embolism. Emboli that go to the cerebral circulation mainly come from the heart or
the arterial supply to the brain. Sources of emboli from the heart include: left
ventricular aneurysms, atrial fibrillation, atrial flutter, valvular heart diseases

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 (rheumatic & degenerative), infective vegetations, mural thrombi, patent foramen
ovale (paradoxical embolism).
• Large & small artery disease. Large artery diseases involve the large arteries – the
aortic arch, common & internal carotid arteries and the vertebral arteries. Large
artery diseases include large artery stenosis, aortic, carotid or vertebral artery
dissection, large vessel vasculitides and other diseases. Large artery stenosis acts as a
source of emboli rather than as a source of occlusion. Small arteries include the
branches of the circle of Willis: the anterior, middle and posterior cerebral arteries
and the distal vertebral & basilar arteries. They also include the small penetrating
arteries. Small vessel diseases include lipohyalinosis (which occurs in hypertension
and causes thrombi), fibrinoid degeneration and microatheroma. Sickle cell anaemia
can also cause occlusion of blood vessels in the brain, leading to ischemia.
• Systemic hypoperfusion. This is most commonly due to heart failure, cardiac arrest
and arrhythmias. Myocardial infarction, pulmonary embolism and pericardial
effusion can also cause reduced cardiac output and therefore reduced perfusion to
the brain. The most vulnerable areas are watershed regions, which are the boundary
regions between areas supplied by the main branches of the circle of Willis.

Haemorrhagic stroke

The aetiology of haemorrhagic strokes also depends on the type of haemorrhage in

question:

• Intra-cerebral haemorrhages – both intra-parenchymal & intraventricular – are

caused by rupture of micro-aneurysms1 and degeneration of small deep penetrating
arteries. These are usually massive and often fatal. They occur in chronic
hypertension and in well-defined sites: basal ganglia, pons, cerebellum and
subcortical white matter.
• Subarachnoid haemorrhages are often caused by saccular aneurysms (also called
Berry aneurysms; 70% of cases). Other causes include arteriovenous malformations,
bleeding disorders, mycotic aneurysms from endocarditis, acute bacterial meningitis,
tumours, marfan’s syndrome and arteritis. About 15% of cases have no identifiable
arterial lesion.

Mortality from haemorrhagic strokes is higher than in ischemic strokes.

Arterial dissection

These account for 1 in 5 strokes in individuals below 40. They can be a result of trivial neck
trauma or from hyperextension injuries, such as whiplash injuries, osteopathic
manipulation, hair wash in salons or exercise. The majority are in large extracranial vessels.
Blood may seep into the subintimal space, leading to formation of a false aneurysm.
However, thrombosis of this blood can lead to formation of potential embolic material that
1
These are also known as Charcot-Bouchard aneurysms.

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may embolise and cause ischemic stroke. Arterial dissection should be suspected by facial
pain, Horner’s syndrome or lower cranial nerve palsy.

Venous stroke

Venous strokes occur in 1% of all strokes. Thrombosis within intracranial venous sinuses or
cortical veins leads to congestion and build-up of pressure within the cerebral circulation.
This leads to cerebral oedema and numerous petechial haemorrhages which coalesce to
form haematomas. Sinus thrombosis leads to reduced reabsorption of CSF, which leads
raised intracranial pressure. There is, however, no difference in the pressure between
various parts of the brain and therefore no hydrocephalus.

Risk factors for strokes

The risk factors for developing stroke are:

• Age. The risk of developing a stroke increases with age.

• Race. Strokes are more common in black and Asian people.
• Hypertension. Hypertension is the most common modifiable risk factor for causing
strokes. Poorly-controlled blood pressure leads to increased vessel degeneration,
making them more susceptible to degeneration that leads either to occlusion or to
rupture. The relative risk reduction in controlling hypertension is 28%.
• Diabetes. Diabetes increases the development of atheromas, which could cause
strokes as well as emboli.
• Smoking. Smoking increases the likelihood of developing atheromas. Therefore,
stopping smoking reduces the risk of developing stroke by 33%.
• Lifestyle. Exercise decreases the chance of developing stroke.
• Alcohol. High alcohol intake increases the risk of developing stroke.
• High cholesterol. High cholesterol increases the risk of developing strokes by causing
thrombi and increasing the risk of MIs.
• Atrial fibrillation. Atrial fibrillation increases the likelihood of developing arterial
emboli, which could embolise to the brain.
• Obesity. Obesity increases the chances of developing diabetes, which could also
increase the risk of developing atheromas and occluding blood vessels.

Pathophysiology
The pathophysiology of strokes depends on the type of stroke in question.

Ischemic strokes

Ischaemic strokes occur because of a loss of blood supply to an area of the brain. This
initiates an ischemic cascade, which eventually leads to infarction. Brain tissue ceases to

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function if deprived of oxygen for 60-90 seconds, and after 3 hours will suffer irreversible
injury. When a blood vessel is blocked, a number of things happen:

1. The brain tissue supplied by the artery downstream from the blockage is deprived of
oxygen and resorts to anaerobic respiration. This leads to reduced ATP production as
well as build of lactic acid. Lactic acid is a cerebral irritant and disrupts the acid-base
balance in the brain.
2. A reduction in high-energy phosphate compounds such as ATP leads to reduced
activity of ion channels, most of which rely on the action of the Na +-K+ ATPase to
function. One major defect is the impaired reuptake of glutamate from neuronal
synapses. This leads to increased glutamate-mediated stimulation, leading to an
influx of calcium into neurons. The calcium influx leads to activation of autolytic
enzymes within cells, and it also causes mitochondrial failure & induction of
apoptosis.
3. Ischemia also causes production of oxygen free radicals. These react with various
cellular components and cause damage. They also mediate apoptosis through redox
signalling.
4. Ischemic injury can also lead to loss of structural integrity of brain tissue & blood
vessels. It leads to release of matrix metalloproteases that break down connective
tissue components such as collagen and hyaluronic acid. This leads to the breakdown
in the integrity of the blood-brain barrier and causes cerebral oedema. Cerebral
oedema also occurs because of impairment of the sodium-potassium pump leading
to an intracellular shift of sodium that causes absorption of water.

All these processes constitute the ischemic cascade.

In ischaemic strokes, the area of damage follows the vascular territory of the blocked vessel.
For example, an occlusion of a middle cerebral artery will lead to ischemia of the lateral
outermost surface of the frontal, temporal and parietal lobes, leading to impairment of
movement, sensation, speech, neglect, etc. An occipital stroke may lead to homonymous
hemianopia. Generally, the affected regions can be divided into 2 regions: the ischemic core
and the ischaemic penumbra. The ischemic core is the main region that is deprived of blood
and undergoes the most extensive injury. The ischemic core can receive less than
10ml/100mg/minute. The cells in the core are expected to die within a minute of the onset
of the stroke. Zones of decreasing or marginal perfusion around the ischemic core are
known as the ischemic penumbra and receive a blood flow rate of less than
25ml/100mg/min. tissues in this region can remain viable for several hours because of
marginal tissue perfusion. Within hours to days of the stroke, however, there is activation of
genes encoding cytokines that mediate inflammation. These cause inflammatory injury and
further microvascular compromise. The ischaemic penumbra is therefore consumed by
these additional insults, resulting in the penumbra coalescing with the ischemic core.

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Ischemic strokes lead to death of brain cells. This is also accompanied by infarction of
astrocytes, oligodendrocytes and microglial cells. The infarcted tissue eventually undergoes
liquefactive necrosis and is removed by macrophages. This produces a cavity filled with CSF
that produces a radiolucent lesion on head CT.

Haemorrhagic strokes

Haemorrhagic strokes cause damage to brain tissue in a number of ways:

• Intraparenchyma haemorrhages can mediate damage through the direct exposure of

brain neurons to blood.
• Bleeding causes compression of brain tissue around the bleed. This results in direct
tissue injury. It also results in impairment of blood flow to the compressed regions.
This results in an infarction.
• The pathologic effects of subarachnoid haemorrhages are multifocal. They result in
elevated intracranial pressure and impaired cerebral auto-regulation.
• Inflammation contributes to secondary brain injury after the haemorrhage.
• Some haemorrhagic strokes arise as a result of haemorrhagic transformation of
ischemic strokes. This occurs in 5% of uncomplicated ischemic strokes in the absence
of fibrinolytic treatment. One proposed mechanisms is reperfusion of ischemically
injured tissue. The ischemic tissue already has damaged blood vessels, which
become leaky to red blood cells. The bleeding can be petechiae or a frank
haematoma. Haemorrhagic transformation is more likely to occur from large volume
strokes.

Classification of strokes
Ischemic strokes are classified using the Bamford/Oxford classification. This classification is
purely a clinical classification and allows rapid categorisation of the patient. The subtypes of
stroke in accordance with this classification are:

• Total anterior circulation stroke (TACS). TACS is a stroke that involves occlusion of
both anterior & middle cerebral arteries, leading to infarction of zones supplied by
both vessels. All 3 of the following needs to be present for this diagnosis to be made:
o Unilateral weakness and/or sensory deficit of the face, arm and leg.
o Homonymous hemianopia.
o Higher cerebral dysfunction, e.g. dysphasia or visuospatial disorder.
• Partial anterior circulation stroke (PACS). PACS is a stroke in which only part of the
anterior circulation has been affected. Only 2 of the criteria above need to be
present for these effects to be seen.
• Posterior circulation stroke (POCS). This is a stroke involving occlusion of the
posterior part of the circle of Willis (such as brainstem & cerebellum). Only 1 of the
following need to be present for this diagnosis to be made:

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 o Cranial nerve palsy & contralateral motor/sensory deficit (called Weber’s
syndrome if it involves cranial nerve III [oculomotor nerve]).
o Bilateral motor/sensory deficit.
o Conjugate eye movement disorder (e.g. horizontal gaze palsy).
o Cerebellar dysfunction (e.g. vertigo, nystagmus, ataxia).
o Isolated homonymous hemianopia (due to cortical blindness – called Anton’s
syndrome).
The syndromes that present as a posterior circulation stroke include
o Lateral medullary syndrome. This is caused by PICA (posterior inferior
cerebellar artery) thrombosis, vertebral artery thrombosis/dissection and
Wallenberg’s syndrome. Lateral medullary syndrome presents with acute
vertigo with cerebellar & other signs.
o Pseudo-bulbar palsy. This is a syndrome in which you have dysfunction of
cranial nerves IX to XII. It differs from a bulbar palsy in that a bulbar involves
the motor nuclei and is therefore a lower motor neuron lesion, whilst a
pseudo-bulbar palsy is an upper motor neuron lesion.
• Lacunar syndrome (LACS). This is a stroke that occurs subcortically and is secondary
to small vessel disease (in the lenticulostriate vessels). There is no loss of higher
cortical function, such as speech. The features of a LACS are:
o Purely sensory stroke.
o Purely motor stroke.
o Sensorimotor stroke.
o Ataxia hemiparesis.
Lacunar strokes are common in hypertensive patients. They generally have a better
prognosis than MCA syndromes.

The most common pattern is occlusion of a branch of the middle cerebral artery, leading to
2
infarction in the internal capsule. This accounts for 90% of all infarcts and 3s of all strokes.
MCA syndromes have a bad prognosis.

Other stroke patterns that do not fit into the Bamford classification include:

• Hypertensive encephalopathy. This develops in patients with severe hypertension

with multiple acute infarcts. Cerebral oedema raises intracranial pressure, leading to
severe headaches, nausea and vomiting. Agitation, confusion, fitting and coma can
occur if the hypertension is untreated. Papilloedema often occurs.
• Multi-infarct/vascular dementia. This results from multiple lacunar strokes or large
infarcts. They cause intellectual loss seen with advanced cerebrovascular disease. In
the late stages, there is dementia, pseudo-bulbar palsy and a shuffling gait (called
marche à petit pas/atherosclerotic Parkinsonism).

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 • Watershed/borderzone infarction. This occurs at the junctional regions between 2
vascular territories, and is due to prolonged periods of systemic hypoperfusion.
Common features are cortical visual loss, memory loss and intellectual impairment.

Clinical presentation
When a patient comes with what appears to be a stroke, you do the following:

• History. In the history you ask the following:

o Symptoms. The most common presentation is a sudden onset of limb
weakness on the contralateral side (hemiplegia or hemiparesis), sudden loss
of sensation of one side of the body (hemisensory deficits), facial weakness
and aphasia (and/or dysarthria)2. These occur with most ischemic infarcts,
since the most commonly affected blood vessel is the middle cerebral artery
(which supplies the majority of the cerebral hemispheres, including the
regions controlling movement and speech). The duration is used to
differentiate it from a TIA. Other possible features include: homonymous
hemianopia, diplopia and other visual deficits. The presence of generalised
symptoms such as nausea & vomiting, severe headache and altered level of
consciousness may indicate increased intracranial pressure, which may point
to bleeding. Rapid progression to coma should also raise the suspicion of an
intracranial bleed.
Quadriplegia, disturbance of gaze and locked-in syndrome should point
towards a brainstem infarct. Lacunar infarcts have the following symptoms:
ataxic hemiparesis, pure motor hemiparesis, pure sensory hemi-deficits,
sensorimotor deficits and dysarthria with a clumsy hand. Cognition &
consciousness are usually intact except in a thalamic stroke. Lacunar infarcts
are often symptomless. Seizures occur in venous sinus thrombosis,
particularly when they occur peripartum.
o Risk factors. Ask about modifiable risk factors, such as hypertension, diabetes
mellitus, tobacco use and high cholesterol. Also ask about a history of stroke,
atrial fibrillation, coronary artery disease and coronary bypass surgery. Also
ask about recent head trauma3, coagulopathies, illicit drug use (especially
cocaine), migraines and oral contraceptive use.
• Physical examination. The goal of physical examination is to detect the source of any
extracranial cause of stroke symptoms, distinguish stroke from stroke mimics,
determine & document the degree of neurological deficit, identify comorbidities and
identify conditions that may influence treatment decisions. It includes:
o Head & neck examination. This is done to look for signs of trauma, infection
and meningeal irritation. You also need to establish the level of

2
Aphasia occurs when the dominant hemisphere is affected.
3
Arterial dissections can occur from trauma.

Page 53 of 455
 consciousness by using the Glasgow Coma Scale (this is usually normal, but
may be depressed in venous sinus thrombosis).
o Neurological examination. This to establish for the presence of upper motor
neuron lesions. Strokes initially cause hypotonia & arreflexia, which then
progresses to hypertonia & hyperreflexia with an extensor response. You also
need to examine the cranial nerves, cerebellar function, gait, language and
mental status.
o Cardiovascular system. This comprises the following examinations: ocular
fundi for retinopathy & papilloedema, emboli and haemorrhage; the heart
for irregular rhythm, murmur and gallop; and peripheral vasculature
(palpation of carotid & femoral pulses and auscultation for carotid bruits4).
Also check the patient’s blood pressure for hypertension as well as testing
blood sugar to screen for diabetes.

After you have collected the clinical details from the history, & examination, you then
classify according to the Bamford classification of strokes.

• Investigations. The diagnosis of a stroke is actually a clinical one, based on: sudden
onset of facial weakness; sudden weakness of one or both arms; and difficulty
speaking or slurred speech (dysphasia). Nevertheless, investigations are done to
confirm clinical diagnosis, to distinguish between haemorrhage & ischemia, to look
for underlying causes that could direct therapy and to exclude other causes such as
tumours. The investigations to be done in stroke patients include:
o Blood pressure. The blood pressure on each arm should be measured. A
difference of greater than 20mm Hg should suggest subclavian stenosis.
Blood pressure measurement is important because the majority of stroke
patients have hypertension as an underlying risk factor, and hypertensive
patients may actually develop strokes as an initial presentation.
o Routine blood tests. FBC can be done to check for polycythemia,
thrombophilia and signs of infection.
o Other blood tests. These include coagulation profile, glucose level, electrolyte
levels, ESR, U&Es and LFTs.
o Imaging. CT & MRI scans are indicated during the acute phase of
management mainly to differentiate between ischemic and haemorrhagic
causes. On a CT scan, an infarct will appear as a darkened area, usually of
subcortical matter. These changes, however, are not seen initially in the
immediate period. The early changes, however, include loss of grey-white
differentiation and sulci effacement. A non-contrast CT can be used to
demonstrate a haemorrhage, which is normally whiter. A CT scan with
contrast may be used to check for any aneurysms being the source of the
bleeding. An MRI is more sensitive in detecting infarctions during the early
4
These are detected in carotid artery stenosis.

Page 54 of 455
 stages. A diffusion-weighted MRI, however, is even more sensitive in
detecting ischemia, while being as accurate as CT in detecting haemorrhage.
Later on, you can employ vascular imaging modalities such as MR or CT
angiography and carotid Doppler/duplex scanning. MR/CT angiography is
valuable in determining surgically-accessible arterial stenosis (mainly internal
carotid stenosis). These imaging modalities are indicated mainly in patients
with TIA/strokes who are normotensive.

Complications of stroke
The complications of ischemic stroke are:

• Neurologic: cerebral oedema, haemorrhagic transformation of ischemic stroke,

seizures, hydrocephalus, raised intracranial pressure and depression.
• Respiratory: aspiration pneumonia, hypostatic pneumonia, airway obstruction,
hypoventilation and atelectasis.
• Cardiovascular: MI, congestive cardiac failure, hypertension, orthostatic
hypotension, and DVT & PE.
• Nutritional, GIT and metabolic: stress ulcers, GI bleeding, constipation, dehydration,
electrolyte disturbances, hyperglycaemia and malnutrition.
• Musculoskeletal: pressure sores, contractures, adhesive capsulitis and falls &
fractures.

Differential diagnoses
The differentials for an anterior circulation stroke are:

• Cerebral aneurysms.
• Head injury.
• Hypoglycaemia.
• Intracranial haemorrhage.
• Malignancy, such as low-grade astrocytoma, meningioma or metastatic disease to
the brain.
• Subarachnoid haemorrhage & subdural haematoma.
• Viral encephalitis.

Management of stroke
Management of stroke is divided into the immediate management and long-term
management.

Immediate management

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The initial management is to prevent secondary brain injury and to prevent continued
worsening of symptoms.

The diagnosis of a stroke is made based on a quick history – the FAST acronym:

• F – Sudden facial weakness. This can be tested by asking the patient to smile. You
will see facial deviation.
• A – Sudden weakness of one or both arms and/or legs. This can be tested by arm
drift.
• S – Difficulty speaking or slurred speech.
• T – Timing: the sooner the treatment can be started, the better. Also establish the
last known well-time (i.e. the time just before symptoms occured).

This FAST acronym should be done within 10 minutes of arrival.

The initial management includes:

1. Admit to multidisciplinary stroke unit. Check BP, pulse rate, respiratory rate,
temperature and random blood glucose level. If the patient is on hormone
replacement therapy, stop it. Also do a swallow test:
For a swallow test, you sit the patient up and you give them 5ml of fluid to drink. If
they do not choke, you give 15ml to drink. If they do not choke, they have passed the
test. If they choke on any of the 2 stages, they have failed the test.
2. Protect the airway. This is to prevent hypoxia. Ensure its patency and take the
oxygen saturation value using an oximeter. Give oxygen to the patient if SpO2 is less
than 94%, although you can consider it if the patient is not hypoxaemic.
3. Support the circulation. Make sure you establish intravenous access to the patient.
4. Blood glucose. Aim for a blood glucose of 4-11mM. If the patient is a diabetic patient,
give insulin per sliding scale. If the patient is hypoglycaemic, give dextrose.
5. Blood pressure. The blood pressure of patients who are candidates for fibrinolytic
therapy should be controlled, as they are at risk of intracerebral haemorrhage after
administration of tissue plasminogen activators. If the blood pressure is below
220
mm Hg, you can observe unless there is other end-organ damage. If the systolic
120
220
blood pressure is greater than 120mm Hg but the diastolic pressure is still below
140mm Hg, give labetalol 10-20mg iv over 1-2 minutes. You can repeat the dose
every 10 minutes until you achieve a 10-15% reduction in blood pressure. Do not
reduce blood pressure too rapidly as you can impair cerebral perfusion. If the
diastolic pressure is above 140mm Hg, give nitroprusside 0.5µg/kg per minute IV
infusion with continuous blood pressure monitoring.
6. ECG. This is done to look for arrhythmias for possible sources of emboli. This is
guided by the regularity of the pulse (an irregularly irregular pulse with a very high

Page 56 of 455
 tachycardia is suggestive of atrial fibrillation). This should be done if immediately
available, otherwise it should not postpose imaging.
7. Immediate imaging. This is considered particularly if thrombolysis is considered. You
should always have a CT scan available, as it is faster & cheaper than MRI. Order a
non-contrast CT scan of the brain. Look for any bleeds or infarcts. If bleeds are
absent, start on thrombolysis.
8. Thrombolytic therapy. This is indicated ONLY if the patient has an ischemic stroke
AND they have no contraindications. Thrombolysis is considered if the last known
well-time is less than or equal to 4.5 hours from the time of intervention (albeit
alteplase being licensed within 3 hours of the last known well-time). Give a
recombinant tissue plasminogen activator such as alteplase 0.9mg/kg over 1 hour;
10% is given as bolus over 1 minute, and the rest is given over 60 minutes. Take a CT
scan 24 hours afterwards to rule out haemorrhage after administration. Alteplase is
contraindicated in: patients with major infarcts/haemorrhage on CT, mild/non-
disabling deficits, recent birth, surgery, trauma or artery/venous puncture at
uncompressible site, past CNS bleed, AV malformations or aneurysms, INR greater
than 1.7 (or patient on anticoagulants), thrombocytopaenia (less than 100 × 109
185
cells/L) and BP above 110mm Hg. In contraindicated patients, you can give high-dose
aspirin (300mg daily) or consider a flow-restoration device (such as the Solitaire) in
large vessel strokes. In large vessel occlusion, you can also consider mechanical
thrombectomy.
9. Anti-platelet therapy. This is only initiated when there is proven ischemic stroke. You
start with high-dose aspirin (300mg daily initially, followed by 75mg after several
days).
10. Haemorrhagic strokes. For haemorrhagic strokes, thrombolytic and anti-platelet
therapies are contraindicated. In these cases, definitive management is employed if
the clot is large. You can do urgent neurovascular evacuation if there is deepening
coma or there is coning. If a subarachnoid haemorrhage has occurred, treatment is
mainly supportive unless an aneurysm has been identified. For aneurysms, you place
platinum coils endovascularly.

Long-term management

Long-term management of strokes is to prevent recurrence of stroke and to prevent

complications from developing. The interventions are as follows:

• Antihypertensive therapy. Recognition & good control of high blood pressure is the
major primary & secondary control intervention. Transient hypertension usually
does not require treatment unless diastolic blood pressure rises above 100mm Hg.
• Antiplatelet therapy. You give long-term aspirin at 75mg daily. You can also give
clopidogrel (75mg) as an alternative to aspirin. If clopidogrel is contraindicated, you
can also give dipyridamole 200mg twice daily.

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 • Anticoagulants. These are given if there is atrial fibrillation, paroxysmal arrhythmias,
cardiac valve lesions, cardiomyopathies or any other lesion that can throw emboli.
Prior to this, brain haemorrhage must be excluded through a CT scan. You can give
warfarin or heparin, but for long-term anticoagulation you give warfarin.
• Rehabilitation. This is of value during the first few weeks following a stroke to
relieve spasticity, prevent contractures and teach patients to use walking aids.
Baclofen or botulinum toxin is sometimes useful to relax the muscles. Speech &
language therapists have a vital understanding of aphasic patients’ problems &
frustrations. If swallowing is unsafe, you can place a nasogastric tube. Physiotherapy,
occupational therapy and speech therapy have a vital role in assessing & facilitating
the future care pathway. Patients require aids at home that make life easier.
• Anti-depressants. Stroke is particularly devastating to the patient, as it often leads to
loss of work, independence, finances and in some cases spouses.

Outcome
Strokes generally have a poor prognosis. About 25% of patients die within the first year,
with nearly 10% dying within the first month. The mortality is higher with haemorrhagic
strokes than with ischemic strokes. Poor outcome is likely when there is a coma, a defect in
conjugate gaze and hemiplegia. Recurrent strokes are also common, and many patients die
from subsequent myocardial infarction. Of the initial survivors, about 30-40% remain alive
after 3-4 years.

Of note, however, is the great deal of disability that this condition causes. Gradual
1
improvement usually follows, but 3 develop disability requiring institutional care, while
1
another 3 developing some milder form of disability.

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 Respiratory history
The respiratory system consists of the upper airway, which is also called the conduction
system, and the lower airway, which is also called the respiratory airway. The lungs are the
respiratory structures in the lung. They contain alveoli through which respiration takes
place. In addition to the lungs, there are other supportive structures that allow breathing to
take place. The diaphragm & external intercostal muscles are inspiratory muscles that allow
the chest cavity to increase in capacity and allow air into the lungs.

There are a number of symptoms that serve as indicators of respiratory pathology. The
commonest presenting symptoms that should give a person indication of respiratory
pathology are cough, breathlessness, wheezing and chest pain.

Coughing
Coughing is a forced manoeuvre in which a person breathes against an initially closed glottis
and then rapidly opens it, causing a jolting action of anything obstructing the airway. There
are a number of factors that need to be known when the history is being taken:

• Production. A cough can either be dry or productive. A productive cough is one in

which there is sputum production. There are 4 main types of sputum: serous
mucoid, purulent and rusty. There are various properties of the sputum that must be
taken down in order to determine what the cough is like.
o Amount. The amount of sputum produced varies from a teaspoon full to a
teacup full. Different pulmonary conditions lead to production of large
amounts of sputum. The other characteristics of the sputum are what
differentiate the sputum produced. Sudden production of purulent sputum
suggests that there has been a rupture of a lung abscess.
o Colour. The colour of the sputum determines the conditions being suffered.
There are different colours of sputum. Green sputum indicates infection in
COPD or in bronchiectasis (it is green because of the lysis of neutrophils
which releases a green-pigmented enzyme called verdoperoxidase).
Pneumococcal pneumonia causes a rusty red sputum to be produced (this is
because pneumonia causes lysis of red blood cells). Yellow sputum occurs in
lower respiratory tract infection. Chronic bronchitis and COPD without
infection produces white clear mucus.
o Taste & smell. If the sputum is foul-tasting, it may suggest that there is an
anaerobic bacterial infection in the chest. This can occur in bronchiectasis,
lung abscess and empyema.
o Solid material. In asthma & allergic bronchopulmonary aspergillosis, viscid
secretions can accumulate in the airways and be coughed up like worm-like

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 structures. Other solid material coughed up may include necrotic tumours
and inhaled foreign bodies.
A dry cough may be produced from reflux of oesophageal contents in GERD causing
acid irritation of the lungs. Dry cough may also be a sign of interstitial lung disease
and a side effect of use of ACE inhibitors. Sometimes, there is a pink frothy secretion
secreted in patients with pulmonary oedema that is confused with sputum.
• Haemoptysis. This is coughing up blood-stained sputum. It is an important sign of
lung cancer. Before haemoptysis is characterised, the doctor needs to determine
whether the blood was coughed up, vomited or suddenly appeared in the mouth
without coughing. If the blood tinge has puss in it, one must suggest that the
condition is infective. The condition must always be investigated. Haemoptysis varies
with amount of blood. Mild haemoptysis may be characterised by no more than
20ml blood in 24 hours. In other conditions, however, there may be more 250ml of
blood produced every 24 hours.
• Sound. Some conditions produce a cough with a characteristic sound. Patients with
severe asthma or chronic obstructive pulmonary disease have a wheezing cough. A
feeble non-explosive bovine cough with hoarseness may be indicative of lung cancer
that invaded the left recurrent laryngeal nerve. A moist cough suggests there are
secretions from the upper airways as a result of bronchial infection & bronchiectasis.
• Duration & frequency. The duration of a cough is important as it tells the clinician
how long the patient has endured the cough as well as how long it took to progress
to the level at which it worried the patient. An acute cough (occurred for only 3
weeks) can be a sign of pneumonia or acute bronchitis. A chronic cough (more than
8 weeks) can be a sign of asthma. The change in character of a chronic cough is
usually a result of the development of a new underlying condition and should be
taken seriously.

Breathlessness
This is also known as dyspnoea. It is the awareness that an abnormal amount of effort is
required for breathing. It can be a result of lack of physical fitness, anxiety and cardiac &
respiratory disease. Dyspnoea can be classified into 4 classes according to the New York
Heart Association (NYHA).

1. Class I. in this class of dyspnoea, there is disease but there is no dyspnoea felt at rest
or during physical work.
2. Class II. In this class of dyspnoea, there is dyspnoea present on moderate exertion.
3. Class III. In this class of dyspnoea, there is dyspnoea present on mild exertion.
4. Class IV. In this class of dyspnoea, there is dyspnoea felt at rest.

Usually it is also helpful to give the extent of exertion that produces dyspnoea.

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The nature of the dyspnoea determines what differential diagnosis can be given to it. In
interstitial lung disease, there is dyspnoea that progressively worsens. If dyspnoea is more
rapid in onset, it may be due to acute respiratory infection or pneumonitis. Dyspnoea that
varies from day-to-day and hour-to-hour suggests a diagnosis of asthma.

The description of dyspnoea by the patient is entirely subjective as it is merely a description

of the patient’s feeling. To give a more objective approach of dyspnoea, you make the
patient conduct exercise tolerance tests. You assess how far the patient can walk without
stopping. You can also hear from the patient’s recount of the count on how the distance the
patient could walk without breathlessness decreased with time.

Breathlessness depends on the patient’s position.

• If the patient is breathing fine in the upright seated position, but becomes breathless
when they lie in the supine position, the patient has orthopnoea/paroxysmal
nocturnal dyspnoea. It can be caused by left ventricular failure.
• If the patient is breathing okay while lying in bed but become restless when
standing. This is called platypnoea.

Wheezing
This is a high-pitched whistling sound produced by air passing through narrow airways. It is
heard maximally during expiration, although patients may refer to other inspiratory sounds
(rattling sounds from secretions; inspiratory sound of stridor) as wheezing. Asthma & COPD
can cause wheezing, just as infections like bronchiolitis and airway obstruction. Night
wheezing suggests asthma, but wheeze in the morning upon waking up suggests COPD.

Stridor is a sound that is similar to wheezing but is loudest over the trachea and is produced
upon inspiration. It is a sign of obstruction of the upper airway.

Chest pain
Chest pain due to respiratory disease is usually different from that due to myocardial
ischaemia. There are different types of chest pain.

• Pleural pain. Pleural pain is characteristically pleuritic in nature: it is sharp and made
worse by deep inspiration. It may be of sudden onset in patients with lobar
pneumonia, pulmonary embolism & infarction or pneumothorax. It is often
associated with dyspnoea, and if dyspnoea occurs together with chest pain the
patient must seek attention urgently. Common causes are pulmonary embolism,
pneumonia, pneumothorax and fractured ribs.
• Chest pain. This suggests respiratory, cardiac or musculoskeletal disease. Patients
with a chronic cough usually have a feeling of tightness in their chest but rarely
mention it when they come to the doctor. The source of pain depends on the

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 causative agent, and it usually involves irritation of the intercostal nerves.
Sometimes, the causative agent may involve other non-thoracic structures, such as
the arm (Pancoast’s tumour erodes the first rib and the brachial plexus, causing pain
along the medial side of the arm & Pancoast’s syndrome).
• Mediastinal pain. Mediastinal pain is central, retrosternal and unrelated to cough. It
is caused by irritant dust or infection of the tracheobronchial tree.

Past history
For respiratory history, as with every other history, you should take a past history of the
previous medical conditions that the patient has experienced. Typical conditions to ask
about are tuberculosis, pneumonia and chronic bronchitis. You should also enquire about
abnormal X-rays. Many lung investigations may have been performed on the patient, such
as biopsy, bronchoscopy and spirometry.

Occupational history
Occupational history is of no greater importance in any other system examination than in
the respiratory system. Occupational history is important because a lot of lung conditions
are chronic and they develop over time with long-term exposure to certain gas
environments. There are various occupations in which workers deal with poisonous fumes.
Asbestos is one such example, and almost every asbestos worker is going to suffer from
asbestosis. To make matters worse, workers’ wives who wash the asbestos workers’ clothes
after work also inhale asbestos and are likely to develop asbestosis too. Other dangerous
gases/fumes include coal, sulphur, silver, nitrogen dioxide and so on. Nonetheless, there has
been great effort to minimise such diseases. The most common occupational disease today
is asthma.

To find out about the occupational history, you need to ask the patient where he used to
work and what his occupation was. You also need to find out the duration of the job. You
may also want to ask if he smokes, as smoking has an additive effect on these fumes.

Family history
Some respiratory conditions are familial. A typical familial respiratory condition is cystic
fibrosis. Other examples include α1-atitrypsin deficiency, which causes emphysema. A family
history of infection with tuberculosis is also important.

Social history
The incidence of most respiratory conditions increases in smokers. The prevalence of COPD
and lung cancer is reflective of smoking patterns in the general population. An estimate of
the number of pack years that a person has smoked should be made. A pack year is when a

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person smokes one pack of cigarettes (1 pack = 20 cigarettes) per day for an entire year.
Most COPD patients have more than 20 pack years. Stopping smoking before the age of 40
is crucial to improving health. After 40, you lose on average 3 months of life per extra year
you continue smoking. Cigarette smoking may be worsened by the fact than someone works
in an asbestos mine.

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 Respiratory examination
In a respiratory examination, you need to be aware of the surface anatomy of the various
respiratory organs so as to known what the various findings mean after examination. In
addition, one needs to have an appreciation of the systemic effects of respiratory problems.
This is why, in addition to the chest, one also examines the hands, arms, neck and face.

Before starting the respiratory exam, as with every other exam, one should start with the
WIPER sequence: wash your hands, introduce yourself, gain permission to conduct the
exam, expose the patient and then recline the patient to the appropriate angle. In a
respiratory exam, the patient should be undressed to the waist and the angle at which the
patient’s seat is reclined to 45°. Women should be covered by a towel, gown or some
clothing (bra) when the front of their chest is not being examined. The general sequence of
check points in an exam are that one starts with the hands, then moves on to the arms &
axillae, then to the neck, to the face and finally focuses on the system-specific region. In the
respiratory system, this specific region is the chest.

When you ask the patient to breathe in & out, ask them to do it through their mouth. This is
because if their nose is blocked, they will have difficulty breathing properly. Furthermore,
during auscultation, the sounds produced in the nose may be heard in the chest.

General inspection
The general inspection is done from the end of the bed. Upon inspection, one should start
off by commenting on the patient, so that the examiner knows that your focus is on the
patient. You should comment on the patient’s breathing – are they in distress, are their
nares flaring and is there tracheal tug? This gives a clue as to what possible conditions the
patient is suffering from. The signs to look for on the patient are:

• Dyspnoea. This is breathlessness. You should check if the patient is not breathless
• Breathing pattern. You assess the patient’s breathing pattern. The patient can have
periodic breathing, in which the patient has a cyclically increasing rate & depth of
breathing followed by a decreased respiratory effort & rate. This ends in a period of
apnoea or hypopnoea. This relates to altered sensitivity of the respiratory centres
and a delay in circulation between central chemoreceptors and the lungs. It is called
Cheyne-Stokes breathing. It can occur in normal elderly individuals, but it is frequent
in stroke involving the brainstem and in severe heart failure. Also check for
hyperventilation, which is a common response to anxiety or emotional stress. It
often leads to respiratory alkalosis and reduced carbon dioxide tension in blood.
Hyperventilating patients often complain of an inability to fill their lungs.
Hyperventilation can also be associated with deep sighing respirations (this is called

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 Küssmaul respiration). This type of breathing is seen people suffering from diabetic
ketoacidosis, acute renal failure, lactic acidosis and salicylate & methanol poisoning.
• Other hints. Patients with COPD may have elevated shoulders with inspiration. This
aids chest expansion, and chronic breathing in this manner may lead to the
development of a barrel-shaped chest. Some patients have pursed lips, which is also
indicative of COPD.
• Use of accessory muscles. The accessory muscles of respiration are the
sternocleidomastoid, platysma, pectoral muscles and the strap muscles of the neck.
These muscles are used for forced breathing and use of accessory muscles is usually
a sign of COPD or severe asthma. Most women make use of their intercostal muscles
more than their diaphragm and therefore their breathing is predominantly thoracic
while men use their diaphragm and therefore their breathing is predominantly
abdominal.
• Stridor. This is a harsh rasping and croaking sound produced on inspiration. This is
often aggravated by coughing and should always be investigated. It is caused by
foreign bodies in the airway as well as tumours. You ask the patient to cough, and
then take a deep breath in & out, and then you listen for the noise.
• Hoarseness. This may be due to damage to the left recurrent laryngeal nerve. This
can be caused by a Pancoast tumour. The left vocal cord cannot adduct to the
midline and therefore a prolonged low-pitched bovine-sounding cough is produced.
• Blood pressure. A diastolic pressure below 60mm Hg is associated with increased
mortality in patients with community acquired pneumonia. In pneumothorax,
hypotension indicates tension with reduced venous return. This raises the risk of
cardiac arrest.
• Skin appearance. Erythema nodosum may indicate acute sarcoidosis. Some skin
nodules may signify metastasised lung cancer.
• Examination of sputum. One should observe the colour, volume and type of sputum.
Furthermore, one should also analyse for the presence of blood streaks in the
sputum of it.

Hands
You then return to the right side of the bed to conduct the hand examination. You ask the
patient to raise their hands to observe for signs. There are a number of signs to look for on
the hand which are relevant to the respiratory examination:

• Clubbing. Clubbing is a result of respiratory disease in up to 80% of cases. It can also

be associated with gastrointestinal & cardiac disease. It can also be familial. Clubbing
involves the loss of the normal angle between the nail and the nail bed. There is
increased nail bed fluctuation and increased nail end curvature in the later stages.
There is also increased soft tissue in the distal phalanges. Clubbing is associated with

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 hypertrophic pulmonary osteoarthropathy (HPO). This condition is often a result of
lung carcinoma, and there is pain & swelling of the ankles & wrists due to periosteal
inflammation. It is important to note that clubbing does NOT occur with COPD. To
test for clubbing, you place your thumbs under the pulp of the terminal phalanx and
then attempt to move the nail over the nail bed. If there is a spongy feel in the
movement of the nail, then the nail is clubbed. It is often usually to test 2 fingers on
one hand and the other hand. This helps to validate the clubbing and also establish
that it is bilateral.
• Finger staining. Finger stains are found in cigarette smokers. The staining is caused
by tar, as nicotine is colourless. The amount staining does not depend on the
number of cigarettes smoked. Rather, it depends on the manner in which the
cigarette is held.
• Nails. The nails can develop a yellow stain, called yellow staining syndrome. It is
caused by exudative pleural effusion and lymphoedema. You can also check for
cyanosis in the nails, which will appear bluish.
• Wasting & weakness. Wasting & weakness is usually caused by a lung tumour
infiltrating the lower trunk of the T1 nerve root. This leads to wasting of the small
muscles of the hand.
• Tremor. A tremor is associated with the excessive use of β-agonists like theophylline.
• Asterixis. This is the downward flapping of the hands when they are extended. You
ask your patient to hold out their hands and extend their wrists. If the wrists flap,
then they have carbon dioxide retention. Alternatively, you can ask your patient to
squeeze your index or middle finger for 30-60 seconds. A person with asterixis
cannot do this for more than 30 seconds.

While still at the hand level, you can check the patient’s pulse. Here, you will not be testing
the patient’s pulse rate. Rather, you will be checking for a bounding pulse, which is present
in patients with severe carbon dioxide retention. Furthermore, you can also take this
opportunity to measure the respiratory rate. You count the patient’s breathing cycles over
30 seconds and then multiply the number by 2.

Neck
At the neck, you might need to ask the patient to sit up. Therefore, you may do this when
examining the patient’s back so that you avoid the inconvenience of repeatedly making the
patient sit up (this may waste your time if the patient takes time sitting up). However, you
do this after taking the jugular venous pulse level. The things to look for in the neck are:

• Jugular venous pressure. The jugular venous pressure can be checked while the
patient is still reclined. This is because the jugular venous pulse is sensitive to the
posture of the patient. The JVP is raised in patients with right-sided heart failure.
Also, chronic hypoxia in patients with COPD leads to pulmonary artery

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 vasoconstriction, leading to pulmonary hypertension and heart failure. This is called
cor pulmonale1. JVP is also raised in patients with tension pneumothorax and severe
acute asthma. In superior vena caval obstruction, there is raised jugular venous
pressure that is not sensitive to the abdomino-jugular reflex. Most of such cases are
lung cancer that obstructs the superior vena cava. Other causes include lymphoma,
thymoma and mediastinal fibrosis.
• Neck lymph nodes. Lymph nodes may enlarge as a result of metastatic lung cancer,
and the first lymph nodes to sense this are the cervical nodes. Localised cervical
lymphadenopathy is a common presenting feature of lymphoma. To palpate the
neck lymph nodes, you ask the patient to sit up and you feel for the scalene nodes
above the first rib next to the insertion of the scalene anterior muscle. You also feel
for the anterior cervical chain going up, all the way to the submandibular,
submental, preauricular & post-auricular nodes. You also feel for the posterior lymph
nodes, which are along the anterior margin of the trapezius muscle. The neck lymph
nodes may have characteristic textures in different pathologies:
o In Hodgkin’s disease, they are rubbery.
o In dental sepsis & tonsillitis, they are tender.
o In TB and metastatic cancer, they are usually matted together to form a large
mass.
o Calcified lymph nodes feel stony.
o Palpable lymph nodes fixed to underlying structures are usually malignant.
• Trachea. The position of the trachea should be assessed, as it can serve as an
important indicator of chest pathologies. This examination is uncomfortable so you
must be gentle and tell the patient that this test is uncomfortable. You must test for
the position of the trachea in the neck just before it enters the chest; whether it is
deviated or not. You push your first finger into the suprasternal notch until the
trachea is felt. You must feel its middle. If the trachea is displaced, you will feel its
edge, and one space to the side of the trachea will have a larger paratracheal space
on one side than the other. Deviation of the trachea is characteristic of a number of
conditions:
o If the trachea deviates to the side of the lung lesion, the patient may have
upper lobe collapse, upper lobe fibrosis and pneumonectomy.
o If the trachea deviates away from the side of the lung lesion, the patient may
have tension pneumothorax or pleural effusion2.
o Upon palpation, one may feel a tracheal mass. This may be a retrosternal
goitre, a lymphoma or a lung cancer.
You also measure the crico-sternal length, which is the length between the lower
margin of the cricoid cartilage and the suprasternal notch. It is usually 3

1
Cor pulmonale is a condition in which there is a disorder/dysfunction of the right ventricle due to a problem
in the pulmonary system.
2
At this stage, the condition is usually advanced.

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 fingerbreadths. If it is smaller than this, then suspect that there has been tracheal
tug. This sign is seen in COPD

Face
The face can be examined while the patient is lying on the bed. The things to look for are:

• Nose. You may want to inspect the inside & outside of the nose. You ask the patient
to tilt their head backward. You may need a nasal speculum & torch. You may find
polyps associated with asthma, a deviated septum associated with nasal blockage
and engorged turbinates which are associated with various allergic conditions.
• Tongue & mouth. You can look at the tongue to observe for central cyanosis (you
may be able to observe this around the mouth). A reddened pharynx & engorged
tonsils may indicate an upper respiratory tract infection. The engorged tonsils may or
may not have pus. You can also look for a reduced velopharyngeal lumen, which is
present in people with sleep apnoea.
• Facial skin. Look at the patient’s face. Smokers have red leathery wrinkled skin.
There may also be facial plethora and peripheral cyanosis if the superior vena cava is
blocked.
• Sinuses. Patients with sinusitis have tenderness on the skin overlying the sinuses.
This is excluded by normal trans-illumination.
• Eyes. Look for signs of Horner’s syndrome, which may be a sign of apical lung
carcinoma (Pancoast’s tumour).

Chest
The chest is the area of interest in the respiratory system. Both the front and the back of the
chest must be examined for signs. The back needs to be examined because most of the
chest’s pathologies are in the back and the lungs’ position in the chest cavity is mainly
posterior, hence examining the back gives a more holistic picture. When examining the
chest you follow 4 procedures: inspection, palpation, percussion and auscultation. When
doing all these procedures, you don’t test the front & back repeatedly between the
procedures. You conduct all procedures for the front, and then you move to the back. While
on the back, you then conduct the neck examinations. With each examination, it is
important to examine both sides.

Inspection
In inspection, you mainly observe. You may need to physically measure the dimensions of
the chest using a tape measure. The things to look for are:

• Shape. When the anteroposterior diameter of the chest is significantly larger than
the lateral diameter, the chest is described as barrel-shaped. Other shapes include:

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 o Pigeon chest/pectus carinatum. This is an outward bowing of the sternum &
costal cartilages, leading to a localised prominence. It may be a manifestation
of a chronic childhood respiratory illness thought to result from repeated
strong contractions of the diaphragm while the thorax is still pliable. It also
occurs in rickets.
o Funnel chest/pectus excavatum. This is a developmental defect involving a
localised depression of the lower part of the sternum. The problem is usually
an aesthetic one, although in some cases lung capacity may be reduced.
o Kyphosis & scoliosis. Kyphosis is an exaggerated forward curvature of the
spine while scoliosis is lateral bowing of the spine. These conditions may be
idiopathic or secondary to poliomyelitis. Severe thoracic kyphoscoliosis may
reduce lung capacity and increase the work of breathing.
• Symmetry. You should inspect for asymmetrical chest wall expansion anteriorly &
posteriorly. Uneven movement indicates underlying lung disease, such as collapse,
consolidation, lung fibrosis, pleural effusion or pneumothorax. Alternatively, there
could be bilateral reduced movement, indicating a diffuse abnormality such as COPD
and interstitial lung disease. Analysis of expansion of the upper lobes is best done by
observing the patient posteriorly, looking down at the clavicle. Lower lobe expansion
is best observed posteriorly.
• Scars. Scars should be noted on the chest wall, both anteriorly & posteriorly. Scars
from a lobectomy (removal of a lobe of the lung) or pneumonectomy (removal of an
entire lung) leave a long diagonal scar on the back. However, if there are 3 scars 2-
3cm long, it indicates that there was video-assisted thoracoscopic surgery. There
may also be erythema on the skin, indicating radiated skin. That patch of skin may be
thickened too, and there may be small tattoo marks indicating the limits of the
irradiated area. Other non-respiratory-related scars may be present. A scar along the
left side of the sternum may be indicative of open heart surgery. Diagonal scars on
the back close to the costal margin may be indicative of nephrectomy or
adrenectomy.

Palpation
Palpation reveals a number of conditions:

• Chest expansion. To assess evenness of chest expansion, you place your hands
around the patient’s chest. The hands are placed with the fingers extended &
wrapped around the lateral aspects of the chest. The thumbs are only placed
slightly off the chest and they should almost meet in the midline. You then ask the
patient to take a deep breath in & out. The thumbs should separate at least 5cm
during inspiration. This test allows the clinician to determine even inflation as well
as whether there is reduced inflation or not. Lower lung expansion is assessed from
the back in this way. You can also place your arms on the upper front chest to

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 assess expansion of the upper lobes of the lung, although this can only help you
determine if expansion is uniform.
• Apex beat. The apex of the heart can be shifted in the event that there is a lung
lesion. Displacement of the apex beat towards the side of the lesion may indicate
collapse of the lower lobe of a lung or localised interstitial lung disease. Movement
of the apex beat away from the side of the lesion may indicate pleural effusion or
tension pneumothorax. The displacement of the apex beat and the deviation of the
trachea both indicate a shift in the mediastinum. The apex beat is often impalpable
in a chest that is expanded secondary to COPD.
• Tactile vocal fremitus. This is a palpable vibration that can be felt when a person
speaks. This test is subjective to the person conducting the test, and it is a difficult
sign to interpret. The front & back are both palpated in 2 variable positions to test
the upper & lower lobe. It depends on the recognition of the changes in vibration in
the chest wall. Vocal fremitus is more obvious in men because of their low-pitched
voices. Vocal fremitus is abnormal if it is different between the two sides.

Percussion
Percussion allows you to listen for changes in the pitch of sound as you percuss different
regions of the chest. Percussion is done by placing your left hand over the area being
percussed, with the fingers separate. The middle finger must be firmly placed on the point
to be percussed. The middle finger on the right hand should then beat on the middle
phalanx of the left hand on the chest. This beating action should be done by swinging your
hand about the wrist in a pendulous fashion.

When percussing, you feel for resonance & dullness. Resonance is produced in regions
where there is air, such as in a normal lung, and is therefore the normal sound produced
when a person with normal healthy lungs is percussed. Dullness is a sign that the lung is
filled with something, be it fluid or puss, or merely consolidation. The different sounds are
as follows:

• Resonance. This is the sound heard in a normal lung.

• Hyper-resonance. Hyper-resonance is heard in a lung with pneumothorax or the
hyper-expanded lung of COPD.
• Apple dullness. This heard in a lung with consolidation, a collapsed lung and a lung
with severe pulmonary fibrosis.
• Stony dullness. Stony dullness is heard in lungs with pleural effusion & haemothorax.

The points to percuss are:

• The supraclavicular fossae, just anterior to the anterior margin of the trapezius
muscle. The apices of the lungs are found here.

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 • The clavicle (this is usually used as the baseline sound for dullness). The clavicle is
not percussed with the left middle finger overlying it. You just strike the clavicle
directly with the right middle finger.
• The axilla, which is where the lateral aspect of the lungs is found.
• The front of the chest3. In the front of the chest, you percuss down the mid axillary
line.
• The back. On the back, you should make sure the patient roles their scapulae aside
so that you can access the ribcage. You do not move down a straight line. Rather,
you move in a divergent pattern downward. You start off closer to the midline in the
upper chest (to stay clear of the scapulae), and then you move laterally downwards.

The feel of the percussion note is as good as its note. The note is affected by the thickness
of the skin.

There are 2 regions of dullness that are expected. There is liver dullness, which is due to
percussion over the anterior aspect of the liver. This is usually below the right 6th intercostal
space. If there is resonance felt in this region, there is hyperinflation of the lung, and this
may be a sign of emphysema or asthma. There is also cardiac dullness which is felt over the
area where the heart is. If this area is reduced, it may indicate emphysema or asthma.

Auscultation
Most sounds reaching the chest wall are low pitched and are best heard using the bell of the
stethoscope. The diaphragm can be used to detect higher-pitched sounds such as pleural
friction rubs. Stretching the skin & hair underneath the diaphragm may produce a sound
that sounds like crackles. Ask the patient to breathe deeply & calmly. Make sure as you
auscultate, you hear the breath sound from the beginning of inspiration to the end of
expiration. You must auscultate anteriorly in the midclavicular line from the clavicle down to
the 6th rib; laterally from the axilla down to the 8th rib and; posteriorly down to the 11th rib.

There are a number of things to look for when auscultating. You do not just look for breath
sounds. The breath sounds must be assessed based on the following:

• Quality of the breath sounds. There are 2 types of breath sounds based on the
quality of the sound.
o Vesicular sounds. These are the normal breath sounds. These are heard over
nearly all parts of the chest. The sounds heard during inspiration are probably
produced near the part you’re listening to. The sounds of expiration are
produced in the larger airways rather than in the alveoli. Vesicular sounds are
louder and last longer on inspiration than on expiration. In addition, there is
no gap between inspiration & expiration.

3
In women, you should lift the breast. The breast is lifted using the back of the hand.

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 o Bronchial sounds. These sounds are not normally heard when one is listening
to the lungs. However, they are normal when the trachea is auscultated as
well as the right upper chest (where the right bronchus opens into the
trachea). They are caused by pneumonia, bronchiectasis, lung collapse and
fibrosis. The expiratory sound has a higher intensity & pitch than the
inspiratory sound. They are heard in areas of consolidation, as solid lungs
conduct the turbulent sounds of the larger airways to the peripheral areas
without filtering.
Occasionally, bronchial sounds over a large cavity have exaggerated bronchial
quality.
• Intensity of the breath sounds. The intensity of breath sounds is not an indicator of
the amount of air entering the lungs. Rather, it is a reflection of the intensity with
which air enters the lungs. Breath sounds are reduced in individuals with COPD,
pleural effusion, pneumonia, a large neoplasm and pulmonary collapse. Breath
sounds are older when a person breaths deeply.
• Presence of other sounds. There are various other sounds that can be produced in
addition to the normal breath sounds. These are usually pathological:
o Crackles. These are produced mainly by abnormally large obstruction of the
airways. There are 2 types of crackles. There are coarse crackles which result
from large occluding structures such as puss & fluid and have an unpleasant
gurgling quality. Bronchiectasis is a common cause. There are also fine
crackles which are only heard in interstitial lung fibrosis. They are heard at
the end of inspiration. They are the result of the loss of stability of the
peripheral airways that collapse at the end of expiration. These airways are
then snapped open during deep inspiration, thus causing the characteristic
sounds.
o Wheezes. These are continuous sounds produced by fixed or variable opening
of smaller collapsed airways. They tend to be louder on expiration because
airways dilate on inspiration but narrow on expiration, thereby raising the
resistance against which the air has to flow out. This produces friction which
is converted to sound energy. High-pitched wheezes arise from smaller
bronchi while low-pitched wheezes arise from larger bronchi. They are
caused by conditions such as COPD (low-pitched), asthma (high-pitched).
They are, however, a poor guide to severity of airway obstruction
o Stridor. These sound similar to wheezes and are also caused by airway
obstruction. However, they are louder in the trachea and are always
produced in inspiration (wheezes are heard in both processes but are mainly
heard in expiration).
o Pleural rub. This is a condition caused by pleural irritation and can be
detected by the diaphragm of the stethoscope. When the pleura are irritated,

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 they become thicker and rub against each other during breathing. The sound
is a continuous grating sound.
• Vocal fremitus. The patient is asked to say something, such as 99 or “nyama
nyama”. Over a normal lung, the low-pitched components of speech are heard with
a booming quality while high-pitched are attenuated. In consolidated lungs, the high-
pitched sounds are heard with a bleating quality – a trait called aegophony.

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 Pneumonia
Pneumonia is an acute lower respiratory tract illness caused by infection of the lungs. The
infections typically cause inflammation within the lung parenchyma. Pneumonia is a
common condition in a variety of settings.

There are different types of pneumonia. These are:

• Community-acquired bacterial pneumonia.

• Hospital-acquired bacterial pneumonia.
• Aspiration pneumonia.
• Fungal pneumonia.
• Hypostatic pneumonia.

Pneumonia affects a wide variety of individuals, with different types of pneumonia affecting
different subgroups.

Classification of pneumonia
The different types of pneumonia are:

Community-acquired pneumonia

Community-acquired pneumonia is the commonest form of pneumonia encountered in the

world. The majority of causes of pneumonia are bacterial, but viruses such as rhinovirus,
influenza virus, parainfluenza virus, RSV, adenovirus and measles can cause community-
acquired pneumonia. Of the bacterial causes, community-acquired pneumonia is divided
into typical & atypical pneumonia.

• Typical pneumonia is caused by organisms that are commensals in the respiratory

tract, and so typically cause disease that is limited to the lungs & respiratory tract.
The commonest organism is S. pneumoniae, and other common organisms include H.
influenzae, Moraxella catarrhalis, K. pneumoniae and S. aureus.
• Atypical pneumonia is caused by organisms that are not normally commensals in the
respiratory tract. This type of pneumonia produces signs & symptoms that are
subtle, with non-lobar infiltrates and extrapulmonary manifestations of pneumonia
(cardiac symptoms, rashes, haemolysis, neurologic symptoms, etc.). Atypical
organisms are M. pneumoniae, Clamydia pneumoniae, Legionella pneumophila, viral
infections (such as CMV, herpesviruses) and fungi.

Hospital acquired pneumonia

Hospital-acquired pneumonia is a type of nosocomial infection acquired while in hospital

more than 48-hours after admission, or within 2 days of discharge. It also includes

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healthcare workers who acquire pneumonia while working in hospital. It is the 2nd most
common type of hospital-acquired infarction after UTIs. A different spectrum of organisms is
implicated in hospital-acquired pneumonia. The common aetiological agents include K.
pneumoniae, P. aeruginosa, S. aureus (including MRSA), Acinetobacter and anaerobic
bacteria (e.g. Enterobacter).

Aspiration pneumonia

This is the aspiration of gastric contents into the respiratory tract. This is extremely severe
and can be fatal, due to the destructiveness of gastric acid. It can also be a complication of
anaesthesia, particularly during pregnancy. It can also complicate patients unable to protect
their airway, e.g. patients with strokes, myasthenia, bulbar palsies, reduced consciousness.
It also occurs in patients with oesophageal conditions, such as dysphagia, achalasia, reflux
and tracheoesophageal fistula. In the majority of patients, contents enter the right side due
to the right bronchus being wider & more vertical. They usually end up in the middle lobe or
apical and/or posterior segments of the lower lobe.

Aspiration causes 4 respiratory syndromes:

• Aspiration pneumonia. This is due to infection with oral & pharyngeal bacteria. The
common causes are oral anaerobes, S. pneumoniae, H. influenzae, S. aureus and
Gram-negative bacteria.
• Chemical pneumonitis. This is also called Mendelson syndrome and is due to
aspiration of gastric juices.
• Exogenous lipoid pneumonia. This is caused by aspiration of oils, such as vegetable
or mineral oil.
• Acute respiratory emergency. This is due to inhalation of a foreign body. This may
be complicated by bacterial infection.

Pneumocystis jirovecii pneumonia (commonly known as pneumocystis carinii pneumonia,

or PCP)

PCP is a type of pneumonia caused by infection with Pneumocystis jirovecii, which is a fungal
infection. This infection is common in immunocompromised individuals, particularly those
living with HIV/AIDS. In patients with HIV, it used to be an AIDS-defining illness, and is
commonly associated with a CD4+ count of less than 200cells/mm3. The organism is found in
the air, and it establishes infection in immunocompromised individuals alone (despite being
a normal resident in the respiratory tract of most individuals).

Pneumocystis jirovecii pneumonia is the 2nd commonest opportunistic infection in HIV after
TB.

Pathophysiology

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For an organism to cause infection in the respiratory system, it needs to be able to bypass
the defence systems in the respiratory tract. They are physical barriers to infection, such as
the cough reflex and the muco-ciliary apparatus. Immunological barriers include alveolar
macrophages and lymphocytes. When any of these are impaired, the risk of infection
increases. Other factors that increase the risk of infection are pulmonary congestion &
oedema.

The processes that occur in pneumonia are:

1. Congestion. This is when there is dilation of blood vessels within the infected region.
It is due to bacterial infection of the lung tissue. The affected lung is red, heavy and
boggy, and the alveoli are filled with proteinaceous fluid, bacteria and scattered
neutrophils.
2. Red hepatisation. This is when the lung develops consistency similar to the liver. The
alveoli are packed with red cells, neutrophils and fibrin.
3. Grey hepatisation. This lung is dry, grey and firm. The red cells have been broken
down while the fibrinopurulent exudate still remains within the alveoli.
4. Resolution. This usually happens in uncomplicated pneumonia. The exudate are
actively broken down to form granular semi-fluid debris.

The organisation of the exudate produces consolidation, in which the alveoli are clogged up
with fluid and are resistant to distension.

There are 2 pathologic patterns of pneumonia.

• Lobar pneumonia. In lobar pneumonia, the pathologic process is confined to a single

lobe of the lung. This typically affects young & middle-aged healthy adults. Most of
the patients that develop lobar pneumonia can resolve without needing to come to
hospital. Furthermore, those that fall ill can be treated with penicillin. 90% of cases
are caused S. pneumoniae.
• Bronchopneumonia. In bronchopneumonia, there are patchy areas of lung infection
& inflammation with involvement of multiple lobes. This type of pattern is seen in
the very young, very old and immunocompromised individuals. The lesions are well-
developed, about 3-4cm in size and slightly elevated. The lung area immediately
around the lesion is hyperaemic & oedematous, and the intervening areas are
normal.

In atypical pneumonia, the infectious reactions are in the interstitium rather than in the
alveoli. This accounts for the more subtle clinical features.

Risk factors for developing pneumonia

The risk factors for developing pneumonia are:

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 • Extremes of age. Individuals younger than 16 and older than 65 are at risk of
developing pneumonia. This pattern is more typical in individuals that are not
immunocompromised.
• Other respiratory conditions. These include cystic fibrosis, COPD, bronchiectasis and
obstructive lesions such as inhaled foreign bodies or endoluminal cancer.
• Comorbidities. These include HIV, diabetes mellitus, chronic kidney disease,
malnutrition, and recent viral respiratory infection.
• Lifestyle. Cigarette smoking, excess alcohol and intravenous drug use all increase the
risk of pneumonia.
• Iatrogenic. Immunosuppressant therapy (such as prolonged steroids) predisposes to
pneumonia.

Clinical features
The clinical features of pneumonia are:

History

Pneumonia patients often present with:

• Cough. It may be dry or productive. In pneumococcal pneumonia, sputum is often

rust coloured. Haemoptysis may also occur.
• Chest pain. The pain is often pleuritic (localised, sharp)
• Shortness of breath. This is due to pus & debris clogging up the alveoli.
• Fever. Temperature can be as high as 40°C.
• Extrapulmonary features. These may be present in atypical pneumonia. They include
jaundice (haemolysis), epistaxis (thrombocytopaenia), confusion, heart failure, etc.
• Signs of sepsis & septic shock. These occur particularly in aspiration pneumonia,
where more virulent organisms are involved.

The symptoms often occur acutely, although some conditions such as pneumocystis jirovecii
pneumonia & other fungal pneumonias take a more protracted course. In atypical
pneumonia, the symptoms are not as florid, and sputum is often non-purulent.

Also ask about risk factors: any pre-existing respiratory conditions, history of TB, HIV co-
infection, smoking & alcohol, etc.

Examination

On examination you will find:

• General examination: pyrexia, hypotension, tachypnoea, breathless, wasting in some

cases, tachycardia, cyanosis, jaundice and pallor.
• Inspection of chest: reduced movement on affected side, intercostal recessions, and
use of accessory muscles of respiration.

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 • Palpation: reduced chest expansion, increased tactile fremitus if there is
consolidation; decreased tactile fremitus if there is an effusion.
• Percussion: apple core dullness in affected lung regions. Stoney dull if there is a
concomitant effusion.
• Auscultation: bronchial breath sounds may be present in affected regions. There may
also be fine crackles in consolidated areas. There may be an effusion, with reduced
breath sounds in the affected area. There will be bronchial breathing just above the
effusion.

Complications of pneumonia
The complications of pneumonia are:

• Lung abscess. An acute bacterial pneumonia is one of the causes of a lung abscess.
Often, the abscess cavity is not ventilated and therefore anaerobic bacteria grow in
it. They can be a result of aspiration pneumonia, and they are often single well-
localised lesions. If they occur in the setting of community-acquired pneumonia, they
are most likely due to S. aureus or Klebsiella pneumoniae. TB can also cause a lung
abscess. A lung abscess will present with a productive cough with purulent sputum,
spiking fever & malaise, clubbing, weight loss and normocytic anaemia. Secondary
amyloidosis can occur.
1 1
• Para-pneumonic effusion & empyema. Para-pneumonic effusions complicated 3 to 2
of all cases of community-acquired pneumonia. They are usually simple exudative
effusions. An empyema can develop in this effusion when it becomes infected1. Early
indications of an empyema are a spiking fever and rising/persistently elevated
inflammatory markers. TB can also result in an effusion.
• Organisation & fibrosis. Fibrosis can occur, particularly with conditions that result in
chronic consolidation of the lungs. The lung reduces in volume and becomes less
distendable.
• Sepsis. Pneumonia can act as a focus of infection for sepsis. The sepsis can lay
ground for other infections, such as meningitis, infective endocarditis and arthritis.

Investigations for pneumonia

The investigations done for pneumonia are:

• Sputum studies. These are done for patients with productive cough. The sputum
specimen is taken for microscopy, culture and sensitivity. The sputum should be
stained using both Gram & Ziehl-Neelsen staining (to check for TB).

1
Para-pneumonic effusions are the commonest cause of empyema thoracis.

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 • Blood culture. A positive blood culture in a S. pneumoniae community-acquired
pneumonia indicates more severe disease and poor prognosis. If the pneumonia is
not severe, blood culture is not necessary.
• Blood workup. This includes FBC, U&Es and LFTs. FBC will reveal leukocytosis in S.
pneumoniae pneumonia, and it is usually normal in M. pneumoniae pneumonia. The
FBC shows leukocytosis with an elevation in neutrophil count. Anaemia may be
present, and if M. pneumoniae is the causative organism, haemolytic anaemia should
be ruled out by a direct Coombs test. A CD4+ count is indicated in individuals living
with HIV.
• Bronchoscopy. This is required for patients with PCP as they do not produce much
sputum. The bronchoscopy is done for bronchoalveolar lavage to obtain a specimen
for microscopy. When stained using Giemsa or methenamine silver, you will see
Pneumocystis cysts.
• Chest X-ray. Typical bacterial pneumonias will reveal lobar or multilobar
heterogenous opacification characteristic of consolidation. In the region with
consolidation, air bronchograms will also be present. There may also be cavitation,
although this is more suggestive of TB. An effusion can also be identified. Atypical
pneumonias have variable features, ranging from lobar involvement to bilateral
interstitial disease. In PCP, there may be a normal chest X-ray in early mild disease.
In most PCP patients, there are diffuse bilateral infiltrates extending from the peri-
hilar region. Pleural effusions in PCP are rare.
• CT scan. This is indicated when an underlying bronchogenic carcinoma is suggested.
For PCP patients, lung windows will demonstrate a ground glass appearance with a
background of interlobar septal thickening.
• Arterial blood gases. This is done to check for the oxygen saturation (when oxygen
saturation is below 94% or when there is severe pneumonia), and to check for
respiratory acidosis.
• Serum biochemistry. LDH levels can be measured in patients with suspected PCP.
They are usually elevated (>220U/L) and they reflect the degree of lung injury.
• Pleural fluid. Microscopy can be done to identify any infective processes present.
Cytology is usually done to rule out malignancies. You can also biochemistry studies,
(and you use the Light‘s criteria to determine whether it is exudative or transudative
if the protein level is between 20g/L & 30g/L), and you can culture to determine
whether it is an empyema or not.

Severity of pneumonia
The severity of pneumonia can be quickly determined using the CURB 65 scoring system

C – confusion A GCS score of less than 8

U – urea Urea above 7mM

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R – respiratory rate Tachypnoea of 30bpm or more
90
B – blood pressure Hypotension of less than 60mm Hg
65 – age Age above 65 years

Each parameter scores 1 point. If the patient scores 0-1, they can be treated as an
outpatient. If they score 2, they require hospital therapy. If they score 3 or more, they have
severe pneumonia. Severe pneumonia has a very high mortality (15-40%) and therefore
requires ICU.

Other parameters that predict risk of death include:

• More than 1 lobe involved on chest X-ray.

• Cyanosis.
• Tachycardia of more than 124bpm.
• PaO2 less than 8kPa or 60mm Hg.
• Hypoalbuminaemia (less than 35g/L).
• Leukocytosis (>20 × 109 cells/L) or leukopenia (<4 × 109 cells/L).
• Positive blood culture.
• Other comorbidities, e.g. HIV, cystic fibrosis, COPD, malignancy.
• Absence of fever in the elderly.

Management of pneumonia
The definitive management of pneumonia is tailored for the severity of the patient. The
general management interventions done for most patients are as follows:

1. Oxygen. Oxygen is given to patients to maintain saturation at 94-98%, provided the

patient is not at risk of carbon dioxide retention. In COPD patients, oxygen saturation
is maintained at 88-92%2.
2. Intravenous fluids. This is given in patients showing evidence of hypotension
requiring fluid replacement.
3. Analgesia. A simple analgesic such as paracetamol or NSAID can help treat the
pleuritic chest pain. Pain management is important as pleuritic pain can cause
restricted breathing, which leads to complications such as sputum retention,
atelectasis and secondary infection.
4. Antibiotics. The choice of antibiotics will depend on the aetiological agent, the type
of pneumonia and the severity of pneumonia. Initially, you institute empirical
therapy, after which your choice of antibiotic is guided by the organism grown from
specimens. The first antibiotic should be given within 4 hours of presentation, and

2
This is important in COPD patients, as restoring oxygen saturation will lead to abolishment of the hypoxic
response required to maintain alveolar ventilation. This will lead to respiratory failure.

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 you should not wait for specimen results. The choice of antibiotic regime is as
follows:
Community- Low-risk
acquired • If CURB65 = 0, Home care is appropriate. No need for
pneumonia microbiological tests.
CURB 65 = 0-1 • If CURB65=1, patients only require a short ambulatory
(mild disease; stay. No microbiological tests required unless outbreak
<3% mortality) suspected or there is a Mycoplasma epidemic.
• Give oral medications:
o Amoxicillin 500mg tds.
o Clarithromycin 500mg bd.
o Doxycycline 200mg loading dose then 100mg od.
Course of antibiotics is given for 7 days.
Community- CURB65 2:
acquired • You need to admit and do blood cultures, sputum
pneumonia studies, test for pneumococcus antigen and serology/PCR
CURB 65 = 2 if there is an epidemic.
(moderate • Give oral combination therapy:
disease; 9% o Amoxicillin 500-1000g tds, OR doxycycline 200mg
mortality) loading dose then 100mg od, OR levofloxacin
500mg bd
o Clarithromycin 500mg bd OR erythromycin 500mg
qid
This is administered for suspected/confirmed
pneumococcal infection. It is given for 7 days.
• For confirmed staphylococcal infection, give cloxacillin 1-
2g IV 6-hourly OR clindamycin 600mg IV 3-4 times daily.
Give medication for 14 days, although after day 7
consider changing to oral medication.
• For Klebsiella & other Gram-negative organisms, give
ceftriaxone 1g IV bd + gentamycin 120mg IV bd for 10-14
days.
Community- CURB65 of 3-5
acquired • You need to admit the patient into ICU and take blood
pneumonia culture & sputum samples for microscopy, culture and
CURB 65 = 3-5 sensitivity.
(severe disease; • Antibiotics should be administered as soon as possible:
15-40% o Co-amoxiclav 1.2g IV tds + clarithromycin 500mg
mortality) IV bd3.

3
Consider a fluoroquinolone, e.g. levofloxacin, if Legionnaire’s disease is considered

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 o Ceftriaxone 2g IV od + clarithromycin 500mg
bd/erythromycin 500mg qid.
o Benzylpenicillin 1.2g qid + erythromycin 500mg
qid
The course of anitbiotics should be taken for 7 days.
• For confirmed staphylococcal infection, give cloxacillin 1-
2g IV 6-hourly OR clindamycin 600mg IV 3-4 times daily.
Give medication for 14 days, although after day 7
consider changing to oral medication.
• For Klebsiella & other Gram-negative organisms, give
ceftriaxone 1g IV bd + gentamycin 120mg IV bd for 10-14
days.
Hospital- Benzylpenicillin 1.5g IV 6-hourly + gentamycin 120mg IV 12-
acquired hourly for 7-10 days.
pneumonia
Aspiration IV cephalosporin + metronidazole.
pneumonia
Pneumocystis •Cotrimoxazole 1920mg (4 tablets) orally tds for 21 days.
jirovecii OR
pneumonia Clindamycin 600mg tds + primaquine 15mg od for 21
days.
• Prednisolone is given if the patient has tachypnoea
and/or cyanosis. Give 40mg bd for 5 days, then 40mg od
for 5 days, then 20mg od for 11 days.
• If patient is on ART, give cotrimoxazole prophylaxis
indefinitely – 960mg od.
5. Thrombophylaxis. This is required for all patients admitted for longer than 12 hours.
You can give subcutaneous LMW heparin, unless it is contraindicated and TED
stockings are fitted.
6. Chest physiotherapy. This is indicated when sputum retention is an issue.
7. Nutritional supplementation. This is particularly assessed in severe disease, and the
assessment is made by a dietician.
8. Surgery. Surgery is mainly indicated for complications.
a. Lung abscess. Lung abscesses need to be drained surgically. This is followed
by antibiotic therapy which is normally guided by culture results. You then
give benzylpenicillin 1.5mg IV 6-hourly + metronidazole 400mg orally tds, for
4-8 weeks4. Alternatively you can use co-amoxiclav 625mg po tds for 4-8
weeks.

4
If the patient ceases to be toxic before 4 weeks are up, continue intravenous benzylpenicillin for about 7 days
then switch to oral amoxicillin and discharge the patient for the remainder of the course.

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b. Empyema. For an empyema in the exudative & fibrinopurulent stage, you can
place a large intercostal tube connected to an underwater seal drain. If the
empyema is in the organising stage, you surgically remove the pleura in a
decortication procedure. After inserting the drain, you give benzylpenicillin
2.5MU IV 6-hourly + metronidazole 400mg po tds for 10-14 days. If the
suspected pneumonia was staphylococcal, give cloxacillin 1g 6-hourly +
metronidazole 400mg po tds for 10-14 days. Also institute thrombophylaxis
with heparin or warfarin.

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 Tuberculosis (TB)
TB is a chronic infectious disease caused by Mycobacterium tuberculosis. It is a disease
characterised by formation of multiple granulomata in various body tissues. TB is the 9th
leading cause of death worldwide, and is the single leading cause of death from a single
infectious agent (including HIV).

There is a very large disease burden across the world. More than 2 billion individuals are
thought to be infected with TB in the world. In 2016, there were 10.4 million new TB cases,
equivalent to 140 cases per 100 000 population. The incidence varies from 10 per 100 000
population in low incidence countries to 150-300 cases per 100 000 population, with some
countries reaching over 500 per 100 000 population. The top 5 countries with the highest
number of cases are (in descending order) India, Indonesia, China, the Philippines and
Pakistan1. 90% of patients were adult, and 65% were male. 10% of patients worldwide were
infected with HIV. However, in countries with high HIV prevalence, TB-HIV co-infection is
often above 50%. In addition, 74% of patients with HIV-TB confection came from Africa. In
Zimbabwe in 2016, the number of incident TB cases was 34 000 (or 208 cases per 100 000
population), of which the number of cases with HIV-TB co-infection was 23 000 (139 cases
per 100 000, or 67.6%).

About 2 million people die every year (1.7 million in 2017), although the mortality rate is
declining by 3% every year. The mortality rate is about 4-times higher amongst those living
with HIV. The mortality rate in Zimbabwe is 7.2 deaths per 100 000 amongst HIV-negative
individuals and 27 cases per 100 000 amongst HIV-positive patients. There were an
estimated 1300 MDR-TB cases amongst notified pulmonary TB cases.

Mycobacterium tuberculosis complex

Mycobacterium tuberculosis is divided into 2 groups: the slow-growing, pathogenic
organisms termed M. tuberculosis complex, and the fast-growing, non-pathogenic
organisms termed M. avium complex2. Mycobacterium tuberculosis complex defines a
group of 4 main mycobacterial species responsible for causing clinical TB. The species in this
group are: M. tuberculosis (most common), M. bovis, M. africanum and M. microti.
Mycobacterium avium complex defines bacteria that are normally non-pathogenic but can
cause opportunistic infections. The members of this group include M. avium, M.
intracellulare, M. fortuitum and M. xenopi.

Under the microscope, they appear as thin curved rods. They are hydrophobic.
Mycobacteria contain a complex lipid-rich cell wall that protects the bacteria (acid-fastness,

1
45% of the global burden of TB is carried by China, India and Indonesia alone.
2
Most of these, however, are slow-growing

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resistance to detergents & common antibacterial agents, slow growth) and has antigenic
properties. The surface glycolipids constitute 25% of the bacterium’s dry weight. The major
component of the cell wall is mycolic acid. The plasma membrane of the bacterium contains
many proteins, including phosphatidylinositol and lipoarabinomannan (LAM). Mycobacteria
are sensitive to heat & sunlight and are susceptible to formaldehyde, glutaraldehyde and
phenol. They can survive in milk.

Mycobacterium tuberculosis is mostly transmitted by inhalation of infected air droplets.

Therefore, the majority of primary infection is established in the respiratory system. It can
also be ingested in food, particularly unpasteurised milk.

Risk factors
The risk factors for developing TB are:

• Frequent contact with high-risk groups:

o Living in a high-incidence country, e.g. Zimbabwe.
o Frequent travel to a high-incidence country.
• Immunodeficiency:
o HIV infection.
o Corticosteroids or immunosuppressive therapy.
o Chemotherapeutic drugs.
o Nutritional deficiency (particularly vitamin D).
o Diabetes mellitus.
o CKD.
o Malnutrition or underweight (body weight more than 10% below ideal body
weight).
• Lifestyle factors:
o Drug & alcohol abuse.
o Overcrowding: homelessness, hostels, slums.
o Prison inmates.

Pathogenesis
M. tuberculosis is an obligate aerobic organism and facultative intracellular organism. It
often gains access into the body through respiratory droplets, and the organism gets
phagocytised, primarily by mononuclear phagocytes such as macrophages. M. tuberculosis is
able to prevent fusion of the phagosome with a lysosome, but allows fusion of the
phagosome with other intracellular vesicles. It also prevents antigenic killing by catabolising
the reactive oxygen species formed in macrophages, and thus prevents macrophage-
mediated killing.

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The immune system has a prominent role in limiting spread of infection. In response to
infection, macrophages release IL-12 & TNF-α which increase local inflammation. These
activate T-helper cells which differentiate into TH1- cells with release of a TH1-cytokine profile
(IFN-γ, IL-2, IL-12, TNF-β) & cell-mediated immunity and phagocyte-dependent inflammation
(delayed type hypersensitivity reaction). This is a favourable response for clearance of
infection as it allows granuloma formation & therefore containment of disease. There is also
concurrent activation of a TH2-response (with release of IL-4, IL-5, IL-9, IL-10 and IL-13),
which is a humoral/antibody response. The antibodies include IgE release, and there is also
eosinophil accumulation. This response, however, inhibits phagocyte function and leads to
free bacterial proliferation & disease dissemination.

The most important event in TB pathogenesis is formation of a granuloma. This is a

histologic structure composed of a necrotic core of macrophages, epithelioid cells and
Langerhans giant cells with intracellular mycobacteria, surrounded by a rim of lymphocytes
& NK cells. This is the structure responsible for containing the infection. If the antigenic
burden is small, the granuloma formed is small, the infection is easily contained and the
bacteria are destroyed with minimal tissue damage. However, if the antigenic burden is
high, the necrotic mass formed is large, some of the bacteria protect themselves from
destruction and the infection is not easily contained.

Clinical syndromes
The majority of individuals exposed to TB do not develop infection; only 10% develop
detectable infections. In infected individuals, the infection can be an overt clinical infection
with signs & symptoms, or there can be latent infection. Clinical infection can be primary
infection or reactivation.

Primary TB

Primary TB describes a first time infection in an individual who has never been infected or
sensitised before. Elderly & immunosuppressed individuals can lose their sensitivity to the
bacterium and therefore get repeated primary infection.

Primary infection is almost always established in the lungs. Once inhaled, the alveolar
macrophages ingest the bacteria and the bacteria proliferate within them. This leads to an
inflammatory reaction leading to neutrophil chemoattraction & release of cytokines. The
usual affected areas are the upper lobes & the upper parts of the lower lobes. The infection
usually begins close to the pleura where there is most air, and leads to the formation of a
Ghon focus in which a granulomatous reaction forms with caseous necrosis. These are
usually peripheral and located close to the pleura & along fissures. The bacteria travel up
the lymphatic channels to the lymph nodes, in which granulomata also form. An involved
hilar lymph node is called a Ghon complex, and if it calcifies it is called a Ranke complex.

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The primary infection can be cleared, or go into clinical latency where it hides and reappears
(reactivation) many years later.

Secondary TB/reactivation TB

This is TB that develops in a previously sensitised host. It arises from:

• Reactivation of latent infection.

• Reinfection following waning of immunologic memory from the first infection.
• Progression from primary infection.

Secondary TB takes a number of clinical courses.

• Secondary pulmonary TB. This is the most common form, and occurs in 55% of
cases. Because of the pre-existing hypersensitivity, the bacilli initiate a prompt
immune response which walls off the infection. This increases the likelihood of
cavitation. It also means that the lymph nodes are less likely to be involved.
Secondary pulmonary particularly likes to affect the apex of the lung. It may progress
and lead to expansion of the cavity, with erosion into bronchi or blood vessels. With
progressive pulmonary TB, there is invariable pleural involvement, with formation of
a serous pleural effusion3.
• Military TB. Military TB occurs when the bacilli enter the systemic circulation and
seed in different organs across the body. They can even return to the lungs. There
are numerous white foci in affected organs which consist of caseating granulomas.
• Lymphadenitis. This is the most common form of extra-pulmonary disease. It usually
occurs in the cervical region, producing scrofula. The lymphadenopathy tends to be
unifocal, and extra-nodal disease is not usually present. HIV-positive patients,
however, almost always tend to have multifocal disease.

Clinical features
Clinical features are seen in patients with clinically active disease. Latent disease is
asymptomatic. The majority of cases are pulmonary tuberculosis cases. The clinical features
are:

• Constitutional symptoms. These include: unexplained fever, significant weight loss

and night sweats. They are due to an inflammatory reaction.
• Pulmonary symptoms: chronic productive cough, ±haemoptysis & pleuritic chest
pain (with pleural involvement).
• Laryngeal symptoms: hoarse voice, severe cough.
• Lymph node symptoms: smooth, non-tender enlargement of cervical or
supraclavicular nodes. The node can become fluctuant due to central necrosis. There

3
This can complicate with a tuberculous empyema or an obliterative fibrous pleuritis.

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 may be sinus tract formation with a purulent discharge but no erythema (the so-
called cold abscess).

Investigations
The diagnostic investigations done for TB are:

• Chest X-ray. The chest X-ray may be normal in some symptomatic patients. In
others, chest X-ray findings may be suggestive while the patient is asymptomatic.
The chest X-ray findings include: consolidation ± cavitation, fibrosis, calcification
(Ranke complex), hilar lymphadenopathy, and pleural effusion/thickening.
• Microscopy. M. tuberculosis does not take up the Gram stain well. For microscopy,
therefore, you use the Ziehl-Neelsen stain and use it to stain the bacterial sample.
Mycobacteria are resistant to decolorisation by acid during the staining procedure,
and therefore they stain red on a blue background. This test is very sensitive, and has
the advantage of only showing live mycobacteria and not dead organisms. You can
also use an auramine-rhodamine stain which is more sensitive but less specific than
the ZN stain. It requires fluorescent microscopy and highlights bacilli as yellow-
orange on a green background.
• Tuberculin skin test/Mantoux test. This is an immunologic test which makes use of
delayed hypersensitivity which occurs after exposure to TB antigens. You inject TB
antigens (5 tuberculin units of purified protein derivatives, PPDs) intradermally and
then wait for 48-72 hours. Skin test reactivity is defined by the diameter of the area
of induration. If the diameter is greater than 10mm, then the test is positive and is
highly suggestive of TB infection. The test can also be used for patients with
suspected latent TB. However, it also tests positive in patients with immunity to TB
and those that have been vaccinated. In individuals with immunosuppression (HIV,
sarcoidosis, military TB, lymphoma), the indurated area is usually small and so you
can get a false negative. For all these reasons, therefore, it is unreliable to use alone
for diagnosis of TB.
• Culture. Culture is the gold standard for diagnosis of TB. However, because it takes
time to produce results, it is not routinely ordered for diagnosis of every patient. You
can use:
o The LJ (Lowenstein-Jensen) medium, which produces results after 8 weeks.
o The Middlebrook agar.
o The microscopic-observation drug-susceptibility (MODS) assay.
o The Mycobacterium Growth Indicator Tube (MGIT), which produces results
within 2 weeks.
• Molecular tests. The prototypical test used is the GeneXpert® test, which uses a
device and a cartridge to conduct PCR on a sputum specimen. It is fast and therefore
can be used on initial contact. However, it remains positive even after treatment as
it also detects dead bacteria. Molecular tests are also useful in detecting rifampicin

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 resistance. You can also use the Line Probe Assay (LPA), which is a drug susceptibility
test
• IFN-γ release assays. The test uses immunoassays to measure the amount of IFN-γ
released by sensitised T-cells after introduction of TB antigens. The antigens used
include ESAT-6 (early secreted antigenic target 6) and CFP-10 (culture filtrate
protein). An example of such a test includes Quantiferon-TB gold kit.
• Biopsy. Biopsies can be obtained, particularly for extra-pulmonary cases. The
pathognomonic feature is a central-caseating granuloma.
• Antigen test. You can also do a urine LAM assay, in which you measure LAM
(lipoarabinomannan) levels in urine. LAM is shed from metabolically active or
degenerating bacterial cells. It only tests positive in individuals with active TB
disease.

Supportive tests done for TB include:

• FBC. Routine FBC is usually normal in early stages. However, patients may develop
normocytic normochromic anaemia. There may also be a leukocytosis (rich in
lymphocytes) or monocytosis (rarely).
• U&Es. Hyponatraemia can occur due to SIADH or due to adrenal insufficiency.
• CRP. This is raised in up to 85% of cases.
• LFTs. Hypoalbuminaemia and hypergammaglobulinaemia (widened γ-gap) are late
features.

Management
Patients are divided into drug-susceptible & drug-resistant TB cases based on whether their
rifampicin resistance testing results on GeneXpert are positive or negative. All patients that
are diagnosed with TB must be notified & registered in the facility’s TB register.

Drug-susceptible TB

For all cases of drug-susceptible TB, whether primary or reactivation TB, you treat with first-
line antiTB drugs: rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E). For
pulmonary TB and most forms of extra-pulmonary TB, you start with an intensive phase of
HRZE for 2 months followed by a continuation phase of HR for 4 months. For meningo-
cerebral and skeletal TB, the continuation phase is extended to 6 months, with the option of
continuing for up to 12 months. The duration of treatment is extended due to the poor
penetration of medicines to these sites.

All first-line drugs are orally administered. Direct observed therapy (DOT) is encouraged for
treatment of tuberculosis. It is defined as treatment supervised by a healthcare professional
or family member. The patient is observed swallowing their medication. DOT achieves
treatment completion rates of over 85%.

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The side effects to watch out for include:

• Rifampicin: induction of liver enzymes (reduced bioavailability of other drugs),

discoloration of body fluids (orange), and thrombocytopaenia in some cases.
• Isoniazid: peripheral neuropathy4, allergic reactions (skin rash, fever, hepatitis).
• Pyrazinamide: hepatotoxicity, hyperuricaemia.
• Ethambutol: optic retrobulbar neuritis (blue-green colour blindness, reduced visual
acuity, central scotoma).

Drug-resistant TB

Drug-resistant TB is defined as TB that has been confirmed through laboratory studies to be

resistant to at least one first-line anti-TB medication. This can be done through in-vitro
growth of M. tuberculosis in culture or through molecular tests such as GeneXpert® MTB/Rif
assay (for rifampicin resistance), line probe assay (LPA: detects resistance to 2 nd-line agents)
or gene sequencing.

2nd-line agents are classified into 4 classes:

Class A Fluoroquinolones Levofloxacin, moxifloxacin, gatifloxacin

Class B 2nd-line injectable agents Kanamycin, amikacin, capreomycin
(aminoglycosides)
Class C Other core 2nd-line agents Ethionamide, cycloserine, linezolid,
clofazimine
Add-on agents D1 Z, E, Hh (high dose isoniazid)
(not part of D2 Bedaquiline, delamanid
core regimen) D3 Ρ-aminosalicylic acid, imipenem-cilastatin,
meropenem, thioacetazone, co-amoxiclav
There are 2 treatment regimens:

• Short course. This consists of 4-6 months5 of levofloxacin, kanamycin, clofazimine, Z,

E, HH, and ethionamide (intensive phase) followed by 5 months of levofloxacin,
clofazimine, Z and E (continuation phase). The short course is used for patients in
whom fluoroquinolone or 2nd-line injectable resistance has been excluded and there
are no contraindications to the use of any of the medications.
• Long course. This consists of 6 months of kanamycin, levofloxacin, cycloserine (with
vitamin B6), Z, ethionamide [intensive phase] followed by 14 months of levofloxacin,
cycloserine (with vitamin B6), ethionamide and Z.

4
This is prevented by co-administering pyridoxine 10mg daily.
5
The duration of the intensive phase depends on culture conversion. The intensive phase is extended to 6
months if culture conversion has not occurred by the 4th month.

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According to WHO, there should be at least 5 effective TB medicines in the intensive phase.
They should include pyrazinamide and 4 other 2nd-line agents: 1 from class A, 1 from class B
and 2 from class C.

There are 3 main delivery strategies for drug-resistant TB:

• Hospitalisation (institutional approach). Patients are hospitalised if:

o The patient is too ill to commence treatment on an ambulatory basis.
o DOT & adherence support not guaranteed.
o Implementation of adequate infection control measures not feasible at
home.
o Patient monitoring cannot be implemented on an outpatient basis.
When admitted, provisions for infection control must be strengthened & maintained
at high levels, according to the customised facility infection control plan. The patient
may be referred to a provincial hospital where necessary. Patients can be discharged
if: their clinical condition improves such that they can be managed on an ambulatory
basis, and adequate infection control measures can be ensured at home.
• Clinic-based approach (OPD). This involves the patient visiting the clinic every day to
receive DOT from the healthcare worker. Facilities providing this DOT must
implement standard infection control measures.
• Community-based approach. Trained community workers may observe DR-TB
patients during the continuation phase. These community workers do the following:
o Direct observation of treatment on a daily basis.
o Treatment literacy for DR-TB patients (including TB infection control &
nutrition).
o Monitoring patients for side effects.
o Reminding patients of their follow-up dates.
These DOT observers are accountable to the DMO and are supervised by primary
healthcare centre nurses. They should meet with the nurses every month to report
their activities.

Adjuvant therapy

Corticosteroid therapy is used as adjuvant therapy in

• TB meningitis.
• TB pericarditis.
• Patients with paradoxical massive lymphadenopathy.
• Severe hypersensitivity reactions to anti-TB medication.
• Hypoadrenalism.
• Renal tract TB (to prevent scarring).
• TB laryngitis with life-threatening airway obstruction.

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The dosing regimens are as follows:

• For TB meningitis, you give prednisolone 60mg orally per day for 4 weeks then taper
off, OR dexamethasone 8-12mg day tapered off over 6-8 weeks (for those that
cannot take prednisolone orally).
• For TB pericarditis, you give prednisolone 60mg orally daily for 4 weeks, then 30mg
orally daily for another 4 weeks then taper off over several weeks.
• For hypersensitivity reactions to anti-TB medicines, you give 20-80mg daily and taper
off over 2-8 weeks.

Monitoring of therapy
Once a patient is started on treatment, he/she must be followed-up regularly. At a
healthcare facility, this is done every 2-4 weeks by a clinician or daily by the DOT nurse. At
community level, this is done daily during the intensive phase and weekly during the
continuation phase by the treatment supporter. All TB patients must be monitored for
adherence, response to treatment and adverse drug events. At the end of treatment, it is
compulsory to assess outcomes of patients.

Adherence to treatment

It is not only the duty of the patient to adhere to treatment, but also of the healthcare
system (particularly the healthcare workers who are treating the patient) to ensure this.
Adherence should therefore be emphasised at every visit.

Assess adherence in the following manner:

1. Ask the patient if he/she is taking their medications.

2. Carry out a pill count.
3. Ask what time she takes his/her medications and whether he/she takes them
before/after meals.
4. Check if the patient is regularly obtaining treatment: review health cards and check if
medicines were collected.

Response to treatment

The primary aim of treatment is cure. Treatment should result in improvement/decrease in

symptoms, resolution of documented fever and gain in weight. These should begin to occur
within 2 weeks of treatment. The majority of patients become completely well within 1-2
months of treatment, and any patient whose symptoms have not subsided within this time
should be evaluated for concurrent disease such as diabetes, a complication of the disease,
poor treatment adherence and drug resistance.

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 • Clinical monitoring. This is done for all patients. It includes retaking the history,
examining the patient, and checking the weight. This may be the only way of
monitoring in situations like extra-pulmonary TB where repeated samples cannot be
taken.
• Bacteriological monitoring. This is done using sputum smear microscopy, as it is
more sensitive in detecting live organisms6. It is the best indicator that treatment is
being taken regularly and is effective. After 2 months of treatment, more than 80%
of new pulmonary bacteriologically-confirmed cases should be smear-negative. After
3 months, the rate should increase to at least 90%. A positive sputum result at the
end of the intensive phase should prompt a review of the supervision & support
provided by the programme and adherence to treatment. Sputum should be
examined at 2, 5 and 6 months.

Repeated use of chest X-rays for monitoring is unnecessary and wasteful of resources. Chest
radiograph changes may take longer to resolve than clinical and laboratory changes.

Adverse drug monitoring

All patients must be monitored and managed appropriately for adverse drug reactions.

6
GeneXpert® will still test positive even with dead organisms.

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 Asthma
Asthma is a chronic inflammatory condition characterised by reversible airway obstruction.
It affects 5-8% of the population, and it commonly starts in childhood from ages 3-5 years.
The prevalence of asthma, however, is increasing in many countries, and it is more common
in developed countries. It is thought that the incidence increases as the country adopts a
more westernised lifestyle.

Pathogenesis
Asthma classically has 3 characteristics:

• Airflow limitation. Airflow limitation arises from a number of factors, including

bronchial muscle contraction, mucosal swelling/oedema and increased mucus
production. Mucosal swelling is a result of inflammation. The airflow limitation is
reversible, either spontaneously or with treatment.
• Airway hyper-responsiveness. The bronchi have excessive responsiveness to various
stimuli. This can be demonstrated by carrying out the bronchial provocation tests. In
this test, you make the patient breath increasing concentrations of histamine or
methacholine to induce transient airflow limitation. The concentration/dose at
which a 20% fall in FEV1 is produced (called PD20/PC20 FEV1) is the one that
demonstrates airway hyper-responsiveness, and a low PD20/PC20 FEV1 demonstrates
a hyper-responsive airway.
• Bronchial inflammation. Bronchial inflammation occurs in response to an antigen
that elicits it. It is mainly caused by mast cell & basophil degranulation leading to
release of inflammatory mediators. The accompanying inflammation leads to plasma
exudation, oedema, smooth muscle hypertrophy & matrix deposition1, epithelial
damage and mucus impaction. There is accumulation of cells within the bronchial
wall (mast cells & eosinophils), and there is accumulation of eosinophils in bronchial
secretions.
Asthma is believed to arise from an inherent tendency of TH2-cells to stimulate production of
IgE antibodies. This is called atopy. The factors associated with development of asthma are
divided into genetic & environmental. The genetic factors include:

• IL-4 gene cluster located on chromosome 5q31-33.

• Polymorphic variation in the IL-4/IL-13 signalling pathway.
• Novel asthma genes – PHF11 focus on chromosome 2 and transcription factors.
These are associated more with atopy than asthma.
• ADAM33 located on chromosome 20p13. This is associated with airway hyper-
responsiveness & tissue remodelling.
Any environmental exposure can lead to asthma. Environmental factors include:

1
These constitute airway remodelling.

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 • Environmental allergens: grass pollen, domestic pets, fungi (Dermatophagoides
pteronyssinus).
• Occupational sensitizers. These can be divided into low & high molecular weight.
Low molecular weight allergens (e.g. wood dust, bleaches and dyes) do not elicit an
IgE response, while high molecular weight allergens (e.g. platinum salts, acid
anhydrides) do. Low molecular weight allergens bond chemically to epithelial cells
and therefore stimulate them to release cytokines. The allergens also act as haptens.
Some forms of occupational asthma are increased in smokers.
• Cold air & exercise. These cause the fluid film lining the airways to be hyper-
osmolar, leading to degranulation of mast cells & basophils (releasing histamine,
leukotrienes and prostaglandins) and stimulation of neural reflexes.
• Atmospheric pollution and irritants, dusts, vapours and fumes. Irritants directly
irritate the airway, eliciting inflammation in an already hyper-responsive mucosa.
Acute exacerbations increase in areas with summer & winter pollution associated
with climate temperature inversions.
• Diet. Intake of fresh fruits & vegetables is protective. This is believed to be related to
the anti-oxidants in food.
• Drugs. The drugs implicated in asthma include:
o NSAIDs. NSAIDs block production of prostaglandins (particularly PGE2), which
induces increased production of cysteinyl leukotrienes by eosinophils, mast
cells and macrophages. This causes increased inflammatory responses in
patients. The response is more marked with NSAIDs that inhibit COX-1 such
as aspirin, ibuprofen, indomethacin, etc.
o B-blockers. These cause bronchoconstriction by lifting the sympathetic tone
that opposes bronchoconstriction by parasympathetic innervation. This is
through inhibition of β2-receptors that induce relaxation of bronchial smooth
muscle. B1-blockers (e.g. atenolol) can also induce bronchoconstriction.

Clinical assessment of asthma patient

The assessment of an asthma patient is as follows:
History
Asthma is characterised by intermittent episodes of:

• Dyspnoea.
• Cough. The cough is usually nocturnal, and may be the only presenting feature in
children. The cough may be productive.
• Wheezes.
Symptoms are usually worse during the night, and attacks vary in frequency & duration.
Other things to ask about include:

• Precipitating factors, e.g. cold air, dust, exercise, specific allergens, infections,
smoking, pollution and drugs (NSAIDs & β-blockers).

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 • Diurnal variation in symptoms. Marked morning dipping is common.
• Quantify exercise tolerance.
• Quantify disturbed sleep as nights per week.
• Ask about acid reflux. This is present in 40-60% of patients.
• Other atopic conditions such as eczema, hay fever, allergies. Also ask about family
history.
• Any potential irritants at home, such as pets, carpets, feather pillows/duvets.
• Occupation.
Examination
The findings you will get on examination are:

• Mild attack. The patient will present with tachypnoea, audible wheeze, and a hyper-
inflated chest. On percussion, the patient will have a hyper-resonant percussion
note. On auscultation, there is reduced air entry and a widespread polyphonic
wheeze.
• Severe attack. The patient is unable to complete sentences on a single breath. The
pulse rate is above 110bpm and respiratory rate is greater than 25bpm. The wheezes
are more prominent.
• Life-threatening attack. The patient is exhausted and can barely talk. The patient
may be cyanosed, hypoxic and hypercapnic. The patient may also have a
bradycardia.
Investigations
The investigations done in a suspected asthma patient are:

• Peak expiatory flow rate (PEFR). This is used to demonstrate the airflow limitation
that classifies the disease. It can also be used to monitor progress of the condition
after treatment. Chronic asthma is diagnosed on PEFR by a diurnal variation of more
than 20% on more than 3 days a week. PEFR can also classify an acute asthma attack,
although clinical features are used to do this.
PEF predicted value
Mild-moderate 50-75%
Severe 33-50%
Life-threatening <33%
• Spirometry. On spirometry, you can demonstrate the obstructive picture that is
typical of asthma: reduced FEV1/FVC ratio and increased residual volume. You can
also demonstrate the reversibility of asthma by an increase in FEV 1 of greater than
15% after administration of a bronchodilator (β2-agonist) or corticosteroid.
• Blood tests. The patient must have an FBC taken. This may demonstrate elevated
eosinophil count & fraction. You can also take U&E and blood cultures (to rule out

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 infection). ABG (arterial blood gas analysis) usually demonstrates reduced paO2 &
paCO2 levels (due to hyperventilation)2.
• Sputum tests. These can also help diagnose asthma. Sputum eosinophilia is more
diagnostic of asthma than eosinophilia on FBC. You can also do sputum microscopy,
culture and sensitivity to exclude superimposed infection.
• Chest X-ray. This may show a hyper-inflated chest in an acute episode or in chronic
disease. it is also helpful in excluding a pneumothorax and infection (particularly
pulmonary infiltrates of allergic bronchopulmonary aspergillosis).
• Allergen tests. You can do a skin prick test, in which you aim to identify an offending
allergen based on the history provided. Allergen-specific IgE can then be measured.
A proper allergen provocation test is usually done for research purposes.
• Histamine/methacholine provocation challenges. These are used to demonstrate
airway hyper-responsiveness. They are mainly useful in investigating patients in
whom the main symptom is cough. It should not be performed in patients with poor
lung function (FEV1 < 1.5L) or a history of “brittle” asthma.

Management of asthma
Management of asthma aims to:

• Abolish symptoms.
• Restore normal/best possible lung function.
• Reduce cases & risks of severe attacks.
• Enable normal growth in children.
• Minimise absence from work or school.
Management of asthma is divided into management of chronic asthma and management of
acute asthma.
Management of chronic asthma
Management of chronic asthma is the control of day & night-time symptoms, preventing
occurrence of attacks, no limitations on exercise and normal lung function (FEV1 and/or
PEFR > 80% predicted or best). It consists of the following:

• Lifestyle modifications. Patients are encouraged to stop smoking, and to avoid

allergens such as pets, dust, carpets, and certain foodstuffs. The patient must also
avoid certain drugs (particularly NSAIDs & β-blockers). The rapid removal of
offending agents is necessary.
• Patient education. It is important to check the patient’s inhaler technique.
Depending on the device used, the patient and/or caregiver should be shown how
the device is operated. Different devices can be used in asthma, such as inhalers,
vacutainers, volume spacers, etc. Also teach the patient how to measure their PEFR

2
A normal or elevated paCO2, however, warrants transfer to the HDU or ICU because of impending failing
respiratory effort.

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 using a peak flowmeter. Also give specific advice on what to do in an emergency.
Also teach relaxed breathing.
• Pharmacologic therapy. There are many drugs used in asthma, and they serve
different functions. The drugs used in asthma include:
o B2-agonists. These are the most widely used agents in asthma. They work by
stimulating β2-receptors, which cause bronchial smooth muscle relaxation.
Being selective agents, they usually do not stimulate the β1-receptors on the
myocardium. They are divided into short-acting β2-agonists (SABA), such as
salbutamol & terbutaline, and long-acting β2-agonists (LABA), such as
salmeterol & formoterol. The agents used are mainly inhalational agents, and
they are used in different situations. It is not advised to use LABAs for long
periods of time, particularly if they are not working. LABAs are also always
used with corticosteroids.
o Anti-muscarinic agents. These drugs work by blocking parasympathetic M3-
receptors found on bronchial smooth muscle, which normally contracts
under parasympathetic stimulation. These drugs are not encouraged for use
in chronic asthma, but they can be used in acute attacks. They are mainly
used for COPD. They can also be taken as inhaled agents.
o Corticosteroids. These agents are used to inhibit bronchial inflammation
which can cause airway obstruction. They usually work over days. They are
best given inhaled to minimise systemic side effects. However, they can also
be given orally or intravenously depending on the precise indication. After
taking inhaled corticosteroids, the mouth should be rinsed to prevent oral
candidiasis from developing. Inhalational corticosteroids include
beclomethasone, budesonide, fluticasone and mometasone. Asthmatic
patients who smoke are less responsive to corticosteroids. Therefore,
smoking cessation should be offered before corticosteroids are considered.
o Leukotriene receptor antagonists (LTRAs). These drugs act by inhibiting the
cysteinyl leukotriene receptor (LT1). Examples include montelukast,
pranlukast and zafirlukast. They are mainly used in patients who are
uncontrolled on inhaled corticosteroids. However, you cannot predict who is
going to benefit from them, and therefore they are tried for 4 weeks before
the decision to continue or stop them will work.
o Methylxanthenes. These drugs include theophylline, caffeine and
theobromine. They are known to cause bronchodilation, but the mechanism
is not well known. One proposed mechanism is that they inhibit
phosphodiesterase, thus increasing cAMP levels and inhibiting
bronchoconstriction.
o Anti-inflammatory drugs. Sodium cromoglycate used to be used regularly in
asthma treatment. They mainly act on eosinophils, mast cells and epithelial
cells but not lymphocytes.
o Anti-IgE monoclonal antibody. Omalizumab is a recombinant humanised
monoclonal antibody that chelates free IgE and downregulates the number &

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 activity of mast cells & basophils. It is effective in patients with persistent
allergic asthma. It is given as a subcutaneous injection for 2-4 weeks.
In accordance with the British Thoracic Society guidelines, asthma is treated in a step-wise
approach aimed at stopping symptoms quickly and improving peak expiratory flow. The
steps are as follows:
1. Step 1: Mild intermittent asthma. In this case, PEFR may even be 100% predicted.
Symptoms are occasional and they occur less frequently than once daily. You use
inhaled SABAs such as salbutamol (100-200µg up to 4-times daily). You can also use
short-acting antimuscarinic drugs e.g. ipratropium, but SABAs are preferred. You
move to step 2 if: the patient has more than 2 attacks in a week; the patient has
night symptoms more than once a week; the patient has had an acute exacerbation
(asthma attack) in the last 2 years.
2. Regular preventer therapy. In this case, the PEFR is usually less than 80% predicted.
In this stage, symptoms may even appear daily. You place the patient on an inhaled
SABA (salbutamol 100-200µg up to 4-times daily) combined with an inhaled
corticosteroid (such as beclomethasone 200-800µg daily). Alternatives to inhaled
corticosteroid include leukotriene receptor antagonist, theophylline or sodium
cromoglycate, but these are less effective than corticosteroids.
3. Initial add-on therapy. In this case, you consider using a LABA (e.g. formoterol or
salmeterol 50µg twice daily) in addition to the SABA & inhaled corticosteroid. It is
done for patients with PEFR of 50-80% predicted, and not controlled on regular
preventer therapy. This prevents the need for continuously increasing corticosteroid
doses. If control is better but still inadequate, you continue the LABA and increase
the dose of inhaled corticosteroid. You can also add leukotriene antagonists or
modified release theophylline instead. LABAs should not be continued if they are not
benefiting.
4. Persistent poor control. Persistent poor control is when there are severe symptoms
or symptoms persist despite high-dose inhaled corticosteroids. You consider:
increasing inhaled corticosteroids to up to 2000µg/day; adding leukotriene receptor
antagonist, modified-release theophylline or oral β2-agonist. These are considered in
patients on initial add-on therapy (with PEFR being 50-80% predicted).
5. Regular oral corticosteroids. This is done for patient with PEFR of less than 50%
predicted. You can add oral prednisolone at the lowest possible dose (usually 7.5mg
daily, but target being 5mg). you also continue with high-dose inhaled
corticosteroids, and you refer to the asthma clinic.
Patients can develop an asthma attack, which occurs as a result of lack of adherence, acute
viral infection, or exposure to allergen or triggering drug.
Management of acute asthma
Acute severe asthma is typically indicated by:

• Inability to complete sentences on a single breath.

• Respiratory rate of greater than 25bpm.

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 • Tachycardia greater than 110bpm. Bradycardia or hypotension is life-threatening.
• PEFR less than 50% predicted.
• Wheezes. A silent chest is life-threatening.
The management is as follows:
1. Oxygen per face mask.
2. High-dose inhaled SABA, such as salbutamol 5mg or terbutaline 10mg. an oxygen-
driven nebuliser is advised in patients with life-threatening asthma.
3. Systemic corticosteroids. Oral prednisolone once daily for 5 days is preferred.
Alternatively, you can use intravenous hydrocortisone or intramuscular
methylprednisolone.
4. Nebulise ipratropium bromide.
5. Magnesium sulphate.

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 Chronic obstructive
pulmonary disease (COPD)
COPD is a chronic progressive irreversible disease characterised by persistent airflow
limitation and destruction of lung parenchyma. It is characterised by an abnormal
inflammatory response to noxious substances in the lungs. It is also associated with other
comorbidities such as ischemic heart disease, hypertension, diabetes, heart failure and
cancer, and this suggests that it is part of a bigger inflammatory process.

COPD is believed to affect 10-20% of individuals over 40 years of age. This is largely
associated with smoking & environmental exposure.

Aetiology
The risk factors for COPD are:

• Smoking. In developed countries, smoking accounts for 90% of cases. Nonetheless,

only 10-20% of heavy smokers get COPD. The risk of developing COPD in a patient
who smokes 30 cigarettes per day is 30-times higher than in a non-smoker. Passive
smoking is also a risk factor.
• Indoor & outdoor pollution. Inhalation of fumes from biofuels is a big contributor in
developing countries, where majority of cooking is done using firewood1. Poor
ventilation is a major contributory factor. Outdoor pollution is a minor factor, but
deaths from COPD increase dramatically during periods of heavy atmospheric
pollution.
• Occupational dusts & chemicals.
• Socioeconomic status. This may be related to smoking & exposure to indoor
pollution.
• Infections. A history of respiratory infections such as TB predisposes to COPD. HIV is
also a risk factor for the development of TB.
• Age. COPD is more common in the elderly. The age of onset is commonly above 35
years of age.
• Genetics. In some patients, there is a genetic predisposition to develop COPD. These
include patients with α1-antitrypsin deficiency.

Pathophysiology

1
Wood & paraffin smoke both cause what is called the hut lung disease.

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The condition is characterised by increased airflow resistance, resulting in limitation in
airflow. There are 2 disease processes constituting COPD:

• Chronic bronchitis. This is a condition with a clinical diagnosis – a persistent cough

with sputum production for at least 3 months per year in at least 2 consecutive
years. The distinct feature of this condition is that the pathologic process gives rise
to small airway disease. The processes that take place are: inflammation (with an
inflammatory infiltrate), goblet cell proliferation & metaplasia, hypertrophy of
mucus glands2 and mucus overproduction (causing plugging of the small airways).
Ultimately there is bronchial wall fibrosis & squamous metaplasia of the respiratory
epithelium as a result of repeated inflammation.
• Emphysema. This is a condition characterised by abnormal permanent dilatation of
the air spaces distal to the terminal bronchioles. It is characterised by parenchymal
destruction, although it may occur as a consequence of small airway disease. In this
condition, there is destruction of alveolar walls without obvious fibrosis. There is
therefore loss of alveoli & alveolar capillaries, and there is loss of bronchial tree
architecture. There is a tendency for the small airways to collapse during expiration
because of lack of radial traction of the small airways. Emphysema is the result of
unchecked destruction of interstitial elastic tissue in the lungs, particularly by
elastases. In smokers, this is caused by induction of inflammation by cigarette smoke
irritants which cause release of elastases from leukocytes. You can also get α1-
antitrypsin deficiency, in which there is lack of inhibition of tissue elastase, thus
resulting in unchecked destruction. There are different patterns of emphysema:
centri-acinar (involving respiratory bronchioles but sparing distal alveoli), pan-acinar
(involving everything distal to respiratory bronchioles), irregular (patchy involvement
associated with scarring) and paraseptal (peripheral and associated with bullae
formation). Destruction of lung parenchyma causes an increase in TLC (total lung
capacity), albeit having reduced diffusion capacity and reduced expiratory flow & air
trapping due to premature closure of the airways.

Patients are classified into 2 groups depending on the prevailing disease process.

• Emphysema often produces pink puffers. Emphysematous patients present with

dyspnoea. They develop hypoxia which causes a V/Q mismatch that drives them to
hyperventilate and thus increase alveolar ventilation. The CO2 levels are not affected
that much, and therefore they are not cyanosed. In fact, the hyperventilation causes
the paCO2 levels to be low normal. Because of the normal CO2 levels, they may
progress to type I respiratory failure.
• Chronic bronchitis often produces blue bloaters. This is because they develop
ventilator dysfunction with reduced alveolar ventilation. Reduced alveolar
2
This is assessed by looking at the ratio of the submucosal layer (which contains the glands) to the bronchial
wall. This is called the Reid index and it is normally 0.4 or less. If it is greater than this, there is mucus gland
hypertrophy.

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 ventilation leads to hypoxia and carbon dioxide retention (∴ elevated paCO2 which
ultimately leads to cyanosis). Initially, the hyperventilatory response is driven by
both hypoxaemia & hypercapnia but later it becomes insensitive to hypercapnia and
responds to hypoxaemia alone. The patients become less breathless. Hypoxaemia
causes renal hypoxia, and this leads to retention of fluid & increase electrolyte
production. They then become bloated & plethoric.

There may be overlap between these 2 disease patterns.

Clinical features
The clinical features of COPD are:

History

The patients will present complaining of the following:

• Chronic progressive dyspnoea, which is worse on exercise. This is more indicative of

emphysematous changes.
• Productive cough with white/clear sputum (it could also be blood-stained). This is
more prominent in chronic bronchitis, even if it is superimposed on top of
emphysema. The cough may or may not be intermittent.
• Wheezing. This is due to closure of the airways during expiration, resulting in
oscillatory vibration being produced in the walls of the airways. This produces the
musical note characteristic of wheezing.

The symptoms may be worsened by cold, foggy weather and atmospheric pollution. You
should also look for:

• Other systemic effects include hypertension, osteoporosis, depression, weight loss

and reduced muscle mass with general weakness.
• Risk factors. Ask about smoking, occupational exposure, past TB infection, present
HIV status and family history of COPD.

Examination

The examination findings that you can get with COPD include:

• General examination. The patient may be tachypnoeic, in respiratory distress (chest

in-drawing, use of accessory muscles of respiration, pursing of the lips) and may have
central cyanosis. Patients may have peripheral oedema if they have concomitant
heart failure. Those with hypercapnia will have peripheral vasodilatation, a bounding
pulse and a carbon dioxide retention flap.
• Respiratory examination. On inspection, the patient has a barrel chest, which
signifies increased AP diameter with loss of normal chest flatness. The lungs are
hyper-inflated and chest movements are reduced. There is reduced chest expansion,

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 and there is a reduced cricosternal distance. On percussion, the chest is resonant or
hyper-resonant on percussion3, with loss of normal liver & cardiac dullness. On
auscultation, there may be a wheeze in emphysematous regions. There are no
breath sounds over bullae.
• Cardiovascular examination. This is done to rule out cor pulmonale. You need to
check for signs of heart failure: peripheral oedema, tachycardia, raised JVP,
distended neck veins and hepatomegaly.

Investigations

The findings on investigation are:

• Lung function tests. The lung function test will reveal an obstructive profile. This will
show a reduced FEV1 of less than 80% the predicted for age, as well as FEV1/FVC
ratio of less than 0.7/70%, with individual values for FEV1 & FVC being reduced as
well. Spirometry findings can be used to grade the severity of COPD:
Gold stage % predicted FEV1
Mild ≥80
Moderate 50-79
Severe 30-49
Very severe <30
• Chest X-ray. On chest X-ray, you will see chest hyperinflation with flattening of the
diaphragm. There will be large central pulmonary arteries with reduced lung
markings in the peripheries. You may be able to see bullae in the lung fields. Chest X-
ray is seldom used for diagnosis and is used for identifying other things
• FBC. On a full blood count, there will an elevated haemoglobin level & haematocrit
• ECG. This will demonstrate right atrial & ventricular enlargement due to pulmonary
hypertension. This results from chronic hypoxia, which causes vasoconstriction of
pulmonary vessels.
• Arterial blood gases. This will demonstrate reduced paO2 with/without hypercapnia
(elevated paCO2).
• A1-antitrypsin deficiency screening. This is done mostly in white patients who
develop symptoms before the age of 45 years with a strong family history of disease.

Management
Management of COPD is composed of 2 aspects. The first aspect is management used for
long-term symptom relief and delaying the progression of disease. The second aspect of
management is the management of acute exacerbations of symptoms.

1. Non-pharmacological interventions. These include:

3
A hyper-resonant chest may be a result of an ensuing spontaneous pneumothorax as a result of a ruptured
bulla.

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 a. Cessation of smoking. This is the single most useful non-pharmacologic
intervention you can ask the patient to do. The Fletcher & Peto studies have
demonstrated that cessation of smoking delays progression of the disease
even if disability has appeared. If the patient is having trouble, you can also
use nicotine replacement therapy.
b. Exercising. All patients benefit from physical activity.
c. Diet & body weight. If the patient is underweight, encourage them to eat
healthy food. You may also prescribe supplements. If they’re overweight,
encourage them to exercise to lose weight.
2. Bronchodilators. Bronchodilators modify the long-term decline in lung function. The
agents used in COPD are:
a. B-adrenergic agonists. These act on smooth muscle in the bronchi to bring
about vasodilation (by acting on β2-receptors). They are divided into short-
acting β-adrenergic agonists (SABA) and long-acting β-adrenergic agonists
(LABA). For long-term management, LABAs are more effective & convenient.
You can use formoterol 12µg inhaled powder twice daily, or salmeterol 50µg
inhaled powder twice daily. Indacaterol 150-300µg daily can be used as well.
b. Antimuscarinic agents. These drugs block cholinergic stimulation
(vasoconstriction) of bronchial smooth muscles by blocking muscarinic (M3)
receptors. Long-acting muscarinic antagonists (LAMA) such as tiotropium
(18µg daily) & oxitropium (200µg twice daily) are used for long-term relief.
You can also use ipratrophium (40µg 4-times daily) for short-term relief
[SAMA]. Tiotropium affects quality of life & improves function but does not
affect decline in FEV1.
c. Theophylline. Long-acting preparations of theophylline are of little benefit in
long-term management of COPD.
d. Phosphodiesterase 4 inhibitors. These include roflumilast. The drug has both
bronchodilator & anti-inflammatory properties. It is useful as an adjunct to
bronchodilators for maintenance treatment of COPD patients and in
reduction of exacerbations.
3. Inhaled corticosteroids. Corticosteroids are effective for management of
moderate/severe COPD. They improve symptoms, lung function and reduce chances
of exacerbations in patients with FEV1 of less than 60%. The long-term benefit of
corticosteroid management in all cases of COPD has not been proven. High-dose
inhaled corticosteroid use is also not encouraged. For long-term use, they are often
combined with LABAs or antimuscarinic agents to slow down lung function decline
(albeit not reducing mortality). The agents used include betamethasone. You can use
oral agents in patients with acute exacerbations.
4. Vaccines. Infection (pneumonia) can easily complicate COPD and causes acute
exacerbations. They can be avoided by administering pneumococcal & influenza
vaccines.

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 5. Other treatments. Patients may require antidepressants either to treat depression
or as depression prophylactic agents. You can also use mucolytic agents, which are
useful for patients with chronic productive coughs (chronic bronchitis). They work by
reducing mucus viscosity and reduce the number of acute exacerbations. The
mucolytic agent used is carbocysteine, given at a dose of 2.25g daily.
6. Long-term oxygen therapy. This is used to prevent the development of cor
pulmonale (by alleviating pulmonary hypertension). The aim is to maintain paO2 at
more than 8kPa (60mm Hg) for 15 hours a day. In studies, this was shown to improve
the 3-year survival improved by 50%. Long-term oxygen therapy is used for:
a. Clinically-stable non-smokers with paO2 less than 7.3kPa (55mm Hg) on room
air despite maximal treatment. These values should be stable on two
occasions more than 3 weeks apart.
b. Patients with paO2 less than 8kPa (60mm Hg) with: secondary polycythaemia,
nocturnal hypoxaemia4, peripheral oedema and evidence of pulmonary
hypertension (right ventricular hypertrophy, loud P2).
c. Patients with carboxyhaemoglobin of no more than 3% (patients who have
stopped smoking).
d. Terminally ill patients.
You can either use an oxygen cylinder, in which oxygen is concentrated and
delivered using nasal prongs or an oxygen face mask, or you can employ domiciliary
oxygen, where you use an oxygen concentrator that makes the air in the room
contain a certain concentration of oxygen. Domiciliary oxygen allows the patient to
breathe freely without having to wear a mask and carry a tank around. Domiciliary
oxygen is cheaper than oxygen cylinders.
Non-invasive ventilation (NIV) can be used for patients who are still hypercapnic on
long-term oxygen therapy.
7. Lung surgery. Lung surgery for COPD entails a number of interventions.
a. Lung volume reduction surgery. Lung volume reduction surgery is indicated
for patients with recurrent pneumothoraxes and isolated bullous disease. The
ideal patients for surgery are those with heterogeneous emphysema that has
apical predominance. These areas can be demonstrated to have a physiologic
lack of function with no perfusion to those areas. By excising those regions,
you restore respiratory mechanics to the chest cavity, thus allowing adequate
respiratory movement as well as correcting V/Q ratios.
b. Lung transplantation. COPD & idiopathic pulmonary fibrosis are the most
common indications for lung transplantation. Older patients are offered a
single lung transplant, while younger patients and patients with α1-
antitrypsin deficiency & severe hyperinflation are offered a double lung

4
This is the drop in the arterial paO2 due to respiratory depression during sleep.

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 transplant. Lung transplantation is indicated for COPD in severe cases where
the FEV1 has fallen to less than 25% of predicted.

Long-term management

Long-term management of COPD is done to control progression of the disease, to improve

quality of life and to prevent exacerbations. It is taken in a step-wise approach, depending
on the stage of disease. Smoking cessation, exercising, optimising diet and vaccinations are
encouraged for every patient.

The additional steps taken are:

• Mild & moderate disease. For patients with mild & moderate disease (FEV1 is
greater than or equals to 50% of predicted), you can start with a LABA or LAMA. If a
SAMA had been used, it should be discontinued before the LAMA is introduced. You
can combine a LABA with a corticosteroid, and the combination has been
demonstrated to be of greater benefit than either of the drugs used alone.
• Severe disease. For patients with severe disease (FEV1 less than 50% predicted), you
use a LABA/LAMA in combination with a corticosteroid in a combination inhaler. If
the patient remains breathless, you add a LAMA (e.g. tiotropium) to a LABA to make
it triple therapy. If the patient remains symptomatic you should try steroid trial
(30mg prednisolone po for 2 weeks5), theophylline, roflumilast and mucolytic drugs.
• Long-term oxygen therapy (LTOT). This is indicated when the patient has a paO2 of
less than 7.3kPa (55mm Hg), or less than 8kPa (60mm Hg) with cor pulmonale,
polycythemia, peripheral oedema or nocturnal hypoxia.
• Surgery. Surgery is indicated in patients with recurrent pneumothoraxes and isolated
bullous disease.
• Palliative/end-of-life care. This is indicated for advanced cases.

Specialist referral is indicated when:

• The diagnosis of COPD is uncertain.

• The patient has severe COPD or has a rapid decline in FEV1.
• Development of cor pulmonale.
• Patient has bullous lung disease.
• The patient has less than 10 pack year smoking history and/or is less than 45 years
old6.
• Symptoms disproportionate to lung tests.
• Frequent infections – bronchiectasis needs to be excluded.

Management of acute exacerbations

5
If after 2 weeks, the patient’s FEV1 increases by more than 15%, the patient is steroid responsive and can be
continued on an inhaled corticosteroid.
6
This suggests some other aetiology apart from smoking, such as α1-antitrypsin deficiency.

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Acute exacerbations refer to sudden worsen symptoms, commonly caused by infections of
the upper tract. On assessment, patients usually have a productive cough with purulent
sputum with abnormal ABG values (paO2 <60mm Hg, paCO2 >45mm Hg) and electrolyte
disturbances (metabolic acidosis & hyperkalaemia). Patients may also develop secondary
diabetes as a complication of corticosteroids, and may have poor nutrition.

The management of a patient with exacerbations is as follows:

1. Oxygen. Oxygen needs to be given to these patients. The saturation must be

maintained at 88-92%.
2. Bronchodilators. You give a SABA/SAMA for acute relief, and you can give it through
a nebuliser.
3. Oral corticosteroids. You give a short course (7-14 days) of oral corticosteroids such
as prednisolone 40-60mg.
4. Non-invasive ventilation. This can be administered if the patient remains
hypercapnic.
5. Antibiotics. This is given if the patient becomes more dyspnoeic, the sputum
becomes more purulent & voluminous than usual or if there are other signs of
infection.

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 Atelectasis
Atelectasis is lung collapse, which can happen to a part of the lung (particularly a lobe) or
the whole lung on one side. It is almost always a secondary phenomenon following another
underlying cause, and it has no sex or race predilections. However, it is more common in
younger children. Atelectasis causes direct transient hypoxaemia from arteriovenous
shunting of blood in the kidneys, resulting in blood flowing through sections of the lung
without being oxygenated.

Aetiology
The causes of atelectasis can be classified according to either obstructive causes or causes
that result in diminished alveolar distension. The causes are:

Obstruction: Diminished alveolar distension:

• Mucus plugs or other airway secretions. • Small/dysmorphic chest wall.
• Asthma. • Severe scoliosis.
• Cystic fibrosis. • Neuromuscular disease.
• Abnormal airway clearance, as with ciliary • Anaesthesia or sedation.
dyskinesia syndrome (Katagener’s). • Pain from upper abdominal
• Foreign bodies. surgery.
• Extrinsic compression of the airways e.g. • Chest wall & upper abdominal
enlarged vessels or lymph nodes. pain.
• Neoplasms in the chest. • Abdominal distension.
• Cardiomegaly & enlarged outflow vessels.

Pathophysiology
Atelectasis develops through 4 main mechanisms:

• Resorption/obstructive atelectasis. This is due to intrinsic or extrinsic airway

obstruction. It is the commonest cause of atelectasis in children. Intrinsic obstruction
(inside the airways) may be due to foreign bodies, asthma, bronchiolitis, aspiration
from a swallowing disorder, endobronchial tuberculosis, cystic fibrosis and increased
airway secretions for other reasons. Extrinsic obstruction may be due to lymph node
enlargement, lymphomas & other neoplasms, an enlarged heart (causing obstruction
of left main or lower lobe bronchus) and left-to-right intracardiac shunts that
increase blood flow through the pulmonary arteries.
• Passive atelectasis. This is due to diaphragmatic dysfunction or hypoventilation. It
occurs in children with neuromuscular disease, those with recent

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 thoracic/abdominal surgery, those on medications that decrease minute ventilation
(e.g. opioids) and those with dysmorphic chest walls. It also occurs in children that
undergo sedation for imaging.
• Compressive atelectasis. This is a result of lung tissue compression, which may be
intrinsic or extrinsic. It occurs more often when there is air, blood, pus or chyle in the
pleural space. Intra-abdominal contents, chest wall masses, cardiomegaly and an
abnormal chest wall can all compress lung tissues. A healthy portion of the lung may
develop atelectasis due to compression from another hyper-inflated region of the
lungs.
• Adhesive atelectasis. This is often due to lack of surfactant. Lack of surfactant causes
increased surface tension and therefore increased likelihood of alveolar collapse.
Conditions leading to this include respiratory distress of prematurity, meconium
aspiration, pneumonia and acute respiratory distress syndrome.

Clinical presentation
The clinical features of atelectasis are:

• History. Most symptoms of atelectasis are non-specific and are usually related to the
underlying disorder and the degree of lung volume loss. If present alone, the child
may present with tachypnoea to compensate for decreased tidal volume. If serious
enough, the child may present with grunting to create PEEP (positive end-expiratory
pressure). If a child has underlying cardiopulmonary or neuromuscular disease,
sudden decrease in oxygen saturation may be a sign of atelectasis.
• Examination. Breath sounds may be decreased in the affected region of the lung
(changes may not be perceived, however). If the portion is large enough, dullness on
percussion may be elicited. The anterior chest wall must be auscultated for possible
atelectasis, since the right middle lobe and the lingula of the left lung are best heard
from the anterior chest wall.

Investigations
The investigations to do in a person with atelectasis are:

• Arterial oxygen saturation. This can be done using pulse oximetry or by measuring
arterial blood gases for hypoxaemia.
• Pulmonary function tests. These may detect obstruction, restrictive causes or
decreased respiratory muscle pressures.
• Imaging. A chest X-ray is often the first to reveal atelectasis. It may fail, however, to
detect small areas of lung collapse. CT scanning may help in assessing compression
of the airway or other underlying pathology that may cause collapse. Lung
ultrasound is also accurate & reliable in diagnosing atelectasis, particularly in
neonates.

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Management
The treatment options for atelectasis are:

• Chest physiotherapy. This has been used for children on mechanical ventilation. A 4
step procedure can be employed – it involves: bagging with 100% oxygen;
endotracheal instillation of 0.25-0.5ml/kg sterile saline; bagging with momentary
inspiratory hold; and then release of hold and simultaneous forced exhalation &
vibration. This stimulates coughing, and the phlegm can be suctioned.
• Pharmacotherapy. The medications in use include DNAse, bronchodilators and
surfactant. DNAse has been used successfully in children with cystic fibrosis and
other patients with acute atelectasis. It improves flow properties & clearance of
mucus. Success of the medication, however, depends on the amount of DNA in the
secretions. N-acetylcysteine is also used as a mucolytic.
• Fibre-optic bronchoscopy. This can be used if the degree of lung collapse is severe
and response to therapy is suboptimal. It has both diagnostic & therapeutic value.
Flexible bronchoscopy helps define the nature of intrinsic obstruction and distinguish
it from extrinsic obstruction. You can also employ rigid bronchoscopy to remove
thick mucus plugs, thick secretions and foreign bodies. Surfactant can also be
administered bronchoscopically.
• Treatment of the underlying condition. Children with asthma require oral & inhaled
corticosteroids with frequent inhaled bronchodilators. Antibiotics are not indicated.
Patients with cystic fibrosis, however, require aggressive antibiotic therapy together
with chest physiotherapy and postural drainage. If pain is causing atelectasis,
appropriate pain therapy is indicated.

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 Pulmonary embolism
Pulmonary embolism is a condition in which the pulmonary artery or its branches are
obstructed by material, be it a blood clot (thrombus; most common cause), air, fat, tumour,
or anything else. This condition is a medical emergency. From post-mortem studies, it is
thought to be a very common condition. It has a mortality rate of 30%.

Pathogenesis
Embolic blood clots mainly originate from thrombi formed in deep systemic veins. Most
blood clots are formed in the iliofemoral veins. It is thought that 50-80% of blood clots in
the iliofemoral veins (iliac, femoral and popliteal veins) originate from below the popliteal
vein and propagate proximally. Thrombi can also form in pelvic & abdominal veins as well as
the axillary vein. Clots can also originate from other sources, such as the right atrium, right
ventricle or septic emboli (from right-sided infective endocarditis).

Clots form as a result of a disturbance of the Virchow’s triad (endothelium, blood flow,
coagulability). This can be due to sluggish flow (which can be generalised or localised to a
precise region), damage to the endothelium and a hypercoagulable state.

Since they vary in size, emboli can lodge in different parts of the pulmonary arterial tree.
Large thrombi obstruct larger proximal vessels and have more devastating effects. Examples
include saddle emboli, which lodge at the junction between the pulmonary trunk and the
pulmonary arteries. Smaller emboli continue travelling downstream and obstruct arterioles.
Examples include showers/microemboli, which are often multiple.

The principal haemodynamic consequence is a reduction in the cross-sectional area of the

pulmonary arterial bed, leading to pulmonary vasoconstriction, elevation in the pulmonary
arterial pressure and a reduced cardiac output (ultimately leading to hypotension). When an
embolus obstructs a branch of the pulmonary tree, a portion of the pulmonary circulation is
not perfused. This means that a portion of the lung is ventilated but not perfused. This
produces intrapulmonary dead space and results in impaired gaseous exchange, leading to
hypoxaemia. After some hours, the non-perfused part of the lung stops producing
surfactant1, and this causes atelectasis of the affected region of the lung. This worsens
hypoxaemia. Emboli rarely cause infarction because the affected part of the lung still
receives oxygen from the bronchial circulation. The right heart attempts to compensate for
the raised pulmonary resistance by increasing systolic blood pressure. However, when more
than 75% of the pulmonary vascular bed is obstructed, the right ventricle needs to generate
a systolic pressure of more than 50mm Hg (against a normal 25mm Hg) and a mean

1
This is due to the release of inflammatory mediators.

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pulmonary pressure of approximately 40mm Hg to preserve pulmonary perfusion. A normal
right ventricle is usually unable to accomplish this and will eventually fail.

Risk factors
The risk factors for pulmonary embolism are those for deep vein thrombosis. They are as
follows:

Stasis: Endothelial damage: Hypercoagulable tastes:

• Immobilisation: • Post-operative • Underlying carcinoma
paralysis, stroke, injury. (particularly
bed rest, prolonged • Trauma. adenocarcinoma).
sitting during travel, • Cancer chemotherapy &
prolonged hormonal therapy.
immobilisation after • Exogenous oestrogen
a fracture. administration (HRT &
• Obesity. OCP).
• Congestive cardiac • Pregnancy & post-
failure. partum.
• Chronic venous • Prior history of DVT/PE.
insufficiency. • Family history of PE/DVT.
• Increasing age. • Nephrotic syndrome.
• Coagulopathies.

Clinical features
The presentation of pulmonary embolism depends on the size, number and distribution of
emboli. The typical symptoms are:

• Shortness of breath. The most common presentation (73%) is a sudden onset of

breathlessness at rest, and it is often the only symptom at rest.
• Pleuritic chest pain. It occurs in as many as 44% of patients.
• Haemoptysis. At times there may just be a cough.

Pleuritic chest pain & haemoptysis only occur when there has been pulmonary infarction.

The signs include:

• General examination: fever, tachypnoea, tachycardia, hypotension, cyanosis, DVT (if

present).
• Respiratory examination: decreased breath sounds, coarse crackles, pleural rub,
signs of pleural effusion.
• Cardiovascular: usually normal, but there may be a raised JVP & loud P2.

There are 3 typical clinical pictures.

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 • Small/medium pulmonary embolism. This happens when a small embolus impacts
in a terminal pulmonary vessel. The symptoms are pleuritic chest pain &
breathlessness, with haemoptysis in 30% of patients often more than 3 days after
the initial event. On examination, the patient may be tachypnoeic, with a localised
pleural rub & coarse crackles over the involved area. An exudative pleural effusion
may develop. In this case, the CVS examination is usually normal, and the patient
occasionally has a fever.
• Massive pulmonary embolism. This is a rarer condition. It occurs when there is
sudden circulatory collapse due to acute obstruction of the right ventricular outflow
tract. The patient presents with severe chest pain (due to cardiac ischemia), and is
shocked, pale and sweaty. Syncope can result if cardiac output is sufficiently
reduced. On examination, the patient is tachypnoeic, tachycardic, with hypotension
and peripheral shutdown. The JVP is raised with a prominent a-wave. On
cardiovascular examination, there is a right ventricular heave, gallop rhythm and a
widely split S2. There are usually no abnormal chest signs.
• Multiple recurrent pulmonary emboli. This leads to increased breathlessness over
weeks or months. It is accompanied by weakness, syncope on exertion and
occasional angina. The physical signs are due to pulmonary hypertension, leading to
signs of right ventricular overload – parasternal heaves & loud P2.

Diagnosis
The investigations done for pulmonary embolism are:

• Pulmonary angiography. This is the gold standard for diagnosis of pulmonary

embolism. It reveals a filling defect or abrupt cut-off, which is indicative of embolus,
and a negative angiogram excludes clinically-significant PE. However, it is technically
more difficult to conduct and is invasive.
• CT angiography. This test is sensitive (83%) & specific (96%) for PE. It has an
advantage of identifying alternative diagnoses if pulmonary embolism is not likely.
• Chest X-ray. This has limited role in diagnosis of PE, because the findings are not
unique to PE. Chest X-ray findings are usually absent in small PEs, but they include
linear atelectasis & blunting of the costophrenic angle (pleural effusion). With time, a
wedge-shaped pulmonary infarct may be seen. A massive PE will reveal oligaemia,
sometimes with dilation of the pulmonary artery at the hila.
• V/Q perfusion scanning. This test makes use of a radionuclide (99mTc), and in PE it
demonstrates under-perfused areas in the absence of a ventilator defect. This test,
however, has some limitations. For example, it will show a matched reduction in
ventilation if a pulmonary embolus causes an infarct or if there are emphysematous
bullae. It is rarely conducted now.

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 • Echocardiography. This shows a vigorously contracting left ventricle, an occasionally
dilated right ventricle, a clot in the right ventricular outflow tract, decreased right
ventricular function (EF) and tricuspid regurgitation. There may also be McConnell’s
sign, which are regional wall motion abnormalities that spare the right ventricular
apex.
• ECG. ECG abnormalities are present in many patients with PE without pre-existing
cardiovascular disease. Sinus tachycardia is the commonest finding, and there may
be atrial fibrillation or any other tachyarrhythmia. The classical findings of PE are
abbreviated as S1Q3T3 – deep S-waves in lead I, pathologic Q-waves in lead III and
inverted T-waves in lead III. This pattern, however, is now rare. Other features
include: right atrial dilation, RBBB, right ventricular strain pattern (right axis
deviation, dominant R-wave & T-wave inversion2 in leads V1 & V2).
• Arterial blood gas (ABG). This has a limited role in diagnosis of PE. It does, however,
reveal hypocapnia, hypoxaemia and respiratory alkalosis3. These are prognostic
indicators: SpO2<95% on admission is associated with an increased risk of in-hospital
complications such as respiratory failure, cardiogenic shock and death.
• D-dimers. D-dimers are measured when there is low probability of a DVT or PE. This
is determined using the Well’s criteria for PE. For quantitative assays, a value of
above 500ng/mL is considered abnormal. If it is high, it is followed by a diagnostic
test.
Risk factors Points
Clinical signs & symptoms of DVT. 3
No alternative diagnosis better explains 3
the illness (after investigation).
Immobilisation for 3 days or more 1.5
OR
Surgery in the previous 4 weeks.
Tachycardia > 100bpm. 1.5
Prior history of PE or DVT. 1.5
Haemoptysis 1
Malignancy 1
Clinical probability of PE (as a percentage)
Low (0-2 points) 3%
Intermediate (3-6 points) 28%
High (>6 points) 78%
Modified Wells score ≤4 – PE unlikely
>4 – PE likely

Management

2
There may be ST depression instead.
3
This is a type I respiratory failure pattern.

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Management of PE is divided into emergency treatment and definitive treatment.

Emergency treatment

A patient with confirmed PE should be admitted. The immediate management of PE is as

follows:

1. Oxygen. Supplemental high-flow oxygen (60-100%) should be administered if the

patient is hypoxaemic or short of breath. This is excluded in patients with chronic
lung disease.
2. Analgesia. Analgesia & bed rest is administered for patients with chest pain (with
pulmonary infarcts). You can give paracetamol or morphine 5-10mg IV with an anti-
emetic.
3. Immediate anticoagulation. You can also use LMWH subcutaneously, fondaparinaux
or unfractionated heparin followed by warfarin therapy.
4. Fibrinolytic therapy. If the patient is critically ill, you can start immediate fibrinolytic
therapy. You can give a 50mg bolus of alteplase (tissue plasminogen activators). You
can also use streptokinase.
5. If hypotensive (massive PE): if the patient has a systolic blood pressure is below
90mm Hg, you start rapid colloid infusion or plasma expanding fluid. If blood
pressure is still low after infusing 500ml, give dobutamine 2.5-10µg/kg/min. If the
patient is still hypotensive, consider IV noradrenaline. If the patient is still
hypotensive, with clinically-definite PE and no contraindications, you can consider
interventional thrombolysis. You can use catheter-directed thrombolysis.

Definitive therapy

Definitive therapy for PE is done after resuscitation of the patient. It includes:

1. Long-term anticoagulation therapy. Warfarin should be started on the same day as

LMWH/unfractionated heparin and should be overlapped with heparin for at least 5
days and until INR is within the range of 2-3 for at least 2 days. You can use LMWH
instead of warfarin in: pregnancy, active cancer and highly-bleeding patients.
anticoagulation should be continued for 3-6 months

Prevention

Prevention of DVT & pulmonary embolism includes:

• Early post-op mobilisation.

• Anti-thromboembolic (TED) stockings.
• Subcutaneous LMWH prophylaxis.
• Avoid contraceptive pill if you are a high-risk patients, e.g. major/orthopaedic
surgery.

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• Anticoagulation to prevent recurrent PEs. Vena caval filters can be used if the patient
cannot be anticoagulated.

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 Cardiovascular history
The cardiovascular system consists of the heart and the network of blood vessels, and it is
responsible for transporting blood around the body. Dysfunction of this system manifests
mainly as circulatory abnormalities such as hypertension/hypotension and shock. These
abnormalities also degenerate into other systemic symptoms occurring extravascularly, such
as oedema. The cardiovascular history therefore aims to pick out cardiovascular dysfunction
through “fishing” for these symptoms.

Chest pain
A presenting complaint of chest pain is usually treated as a medical emergency because
ischaemic heart disease normally presents as chest pain (angina pectoris). Chest pain is a
common presentation of patients with heart problems and chest pain ranges from trivial to
life-threatening. The severity of chest pain is normally unrelated to the severity of the heart
disease. Chest pain due to heart disease develops as a result of accumulation of metabolites
released by injured myocardial cells following the obstruction (partial or complete) of a
coronary artery. These metabolites stimulate the cardiac sympathetic nerves. Patients with
heart transplants, therefore, are usually unable to feel angina pain. Patients with diabetes
may be diagnosed with silent infarcts.

When a patient presents with chest pain, it is important to determine whether the pain is of
cardiac origin or not. Non-cardiac origin chest pain may be caused by acute pulmonary
embolism, mediastinal conditions or pneumonia. To help determine the cause of chest pain,
one needs to assess the four cardinal features: duration, location, quality and precipitating
& aggravating factors. When asking a patient about chest pain, it is normal to ask them
about chest discomfort rather than chest pain, because ischaemic heart disease usually
starts by causing discomfort. The pain/discomfort is usually central rather than left-sided.
The pain may radiate to the shoulder, medial arm, neck & jaw and it rarely reaches below
the umbilicus.

Angina pectoris
Angina is the most common cardiac chest pain experienced by patients. It is usually because
of myocardial ischaemia of a coronary artery, by may also be caused by aortic stenosis or
hypertrophic cardiomyopathy which increased cardiac oxygen demand. It is a diffuse pain or
discomfort which is felt in the centre of the chest and lasts about 10 minutes. It is
unaffected by inspiration, twisting or turning. Stable angina is triggered by exercise, cold or
windy weather, walking uphill or carrying a heavy load and exercise following a heavy metal
meal. All these causes result in either an increase in oxygen demand, an increased force of

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contraction or an increase in heart rate & blood pressure, thereby leading to increased work
of the heart.

Angina is relieved by rest and by glycerol trinitrate. In some instances, warming up relieves
symptoms as warming up results in peripheral vasodilation resulting in reduced resistance.

Myocardial infarction
This is a condition in which the heart muscle infarcts (dies) due to the occlusion of an artery.
The condition begins as ischaemia which progresses to infarction. The symptoms of
myocardial infarction are similar to those of angina pectoris, but they are more severe and
last longer. The development of unstable angina (angina developing at rest) usually signifies
the onset of myocardial infarction. In addition to angina, other presenting symptoms include
restlessness, breathlessness and a feeling of impending death. Autonomic stimulation
produces sweating, pallor, nausea, vomiting and diarrhoea. Pain is absent in up to 30% of
patients.

Other causes of chest pain

Chest pain can also be caused by:

• Pericardial pain. Pericardial pain is caused by inflammation of the pericardial sac and
may coexist with angina (it occurs on the anterior chest wall). This may be secondary
to myocardial infarction, viral infection, after surgery, catheter ablation, angioplasty
or radiotherapy. Pericardial pain is exacerbated by inspiration and movement,
particularly leaning forward. Pericardial pain is a form of pleuritic chest pain.
• Pleuritic pain. This pain is similar to pericardial pain. However, it is caused by either
inflammation of the pleura as a primary problem or secondary to pneumonia and
pulmonary embolism. It is also worsened on inspiration.
• Aortic dissection. Tearing of the intima of the aorta results in blood gushing into the
medial layer, causing tearing. This is called a dissection. An abrupt tearing chest pain
occurs which can radiate to the back depending on the origin & extent of dissection.
It is also associated with profound autonomic stimulation. Predisposing factors
include Marfan’s syndrome & hypertension.
• Massive pulmonary embolism. This causes pain of very sudden onset. The pain may
be retrosternal and associated with collapse, dyspnoea and cyanosis. It is often
pleuritic, but can be confused with angina especially if associated with right
ventricular ischaemia.
• Spontaneous pneumothorax. This produces a sharp localised pain and severe
dyspnoea.
• Gastro-oesophageal reflux disease. This typically causes a sharp angina-like pain
without heartburn. Oesophageal spasm may cause retrosternal chest pain or
discomfort.

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 • Cholecystitis. This causes chest pain that can be confused with abdominal pain. Right
upper quadrant tenderness is usually present.
• Herpes zoster. This causes chest pain that is not very apparent until the
characteristic vesicular rash appears that follows the thoracic nerve root distribution.

Breathlessness (Dyspnoea)
Breathless is another common cardiovascular symptom. It is also a common respiratory,
neuromuscular & metabolic symptom and it can also be caused by toxins and anxiety.
Dyspnoea is normal in people after they exercise. However, it is pathological if it occurs at a
significantly lower threshold than expected.

Dyspnoea due to ischaemic heart disease has similar precipitations to angina. It may also be
associated with extreme fatigue. The relieving symptoms depend on the causative agent. If
the dyspnoea is caused by pulmonary oedema resulting from left heart failure, the patient
prefers to sit upright. Those with dyspnoea coming from pulmonary embolism prefer to lie
flat and may faint if they sit uptight.

Dyspnoea can be graded using the New York Heart Association (NYHA) grading system:

New York Heart Association classification of heart failure symptom severity

Class No limitations. Ordinary physical activity does not cause fatigue, dyspnoea or
I palpitation. (asymptomatic left ventricular failure)
Class Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary
II physical activity results in fatigue, palpitation, dyspnoea or angina pectoris.
(symptomatically mild heart failure)
Class Marked limitation to physical activity. Less than ordinary activities will lead to
III symptoms (symptomatically moderate heart failure)
Class Symptoms of congestive heart failure are present even at rest. With any physical
IV activity discomfort is experienced (symptomatically severe heart failure)

Orthopnoea
This is dyspnoea that occurs when the patient is lying flat on their back, and is relieved when
the patient sits up. This kind of dyspnoea is a sign of heart failure, and lying on one’s back
increases venous return. This increases the volume of blood that the pulmonary circulation
deals with and because there is left ventricular failure, there is increased left atrial pressure,
leading to pulmonary oedema. This is the cause of the breathlessness. Furthermore, sitting
upright redistributes the fluid in the lungs so that the upper regions of the lungs have less
fluid & are more aerated. The severity of the condition can be gauged by the number of
pillows that the patient requires to sleep on in order to relieve the orthopnoea.

Paroxysmal nocturnal dyspnoea

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This is a sudden breathlessness that wakes a patient from their sleep choking or gasping for
air. It has a similar mechanism as orthopnoea and it is a result of gradual accumulation of
fluid in the alveolar space. Patients often sit at the edge of the bed & open windows in order
to relieve symptoms. It may be confused with asthma which can also cause night-time
symptoms. Patients with heart failure produce frothy blood-stained sputum.

Palpitations
This is an unexpected awareness of the heart beating in the chest. The patient usually
experiences a rapid, forceful & irregular heartbeat. They usually occur in sinus rhythm with
anxiety, intermittent irregularities of the heartbeat such as extra beats or dropped beats.
Palpitations are normally associated with cardiac arrhythmias and/or sinus tachycardias.

To investigate this heartbeat, you ask the patient to tap out the pattern of beats they can
feel. If the heartbeat is rapid, it is important to ask the patient if the palpitations are of
sudden or gradual onset & offset. Cardiac arrhythmias are associated with sudden onset &
offset, while sinus tachycardia is associated with gradual onset & offset. It is also beneficial
to ask the patient about the precipitating factors as well as the frequency & duration of the
palpitations. The supraventricular (sinus) tachycardia can be reversed using the Valsava
manoeuvre.

Syncope & dizziness

Syncope is fainting with a loss of consciousness, and this is a result of cerebral anoxia due to
inadequate blood flow. Patients who are dizzy often describe vertigo or light-headedness. It
is therefore important for patients to describe exactly how their dizziness is. Vertigo is rarely
cardiologic in origin, while light-headedness or presyncope (an impending sense of loss of
consciousness). To investigate syncope, one must discover whether the patient actually
loses their consciousness. One must also ask about the circumstances under which the
patient loses their consciousness. You should also ask about any warning signs of impending
syncope – dizziness, presyncope or palpitations.

There are 4 causes of syncope:

• Postural hypotension. This is a condition in which the systolic blood pressure falls by
more than 20mm Hg upon standing. It is commonly caused by hypovolaemia and
antihypertensive drugs. It is also a symptom of autonomic neuropathy.
• Neurocardiogenic syncope. This is a group of conditions that are caused by
abnormal autonomic reflexes. It occurs in healthy people forced to stand for a long
time in a warm environment or subjected to painful or emotional stimuli. If the
patient is held in an upright position, continued cerebral hypoperfusion precipitates
a cerebral anoxic seizure.

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 • Arrhythmias. Supraventricular tachycardias, such as atrial fibrillation, cause syncope.
The most common cause is a syndrome that slows the heartbeat, such as sick sinus
syndrome or AV block. Drugs including digoxin, β-blockers and calcium channel
blockers may aggravate the attacks. Ventricular arrhythmias can also cause syncope
& presyncope.
• Mechanical obstruction of cardiac output. Severe aortic stenosis & hypertrophic
cardiomyopathy can cause syncope. This is a result of obstructed blood flow, leading
to hypoperfusion of the brain. In addition, pulmonary embolism can obstruct
outflow of blood from the right ventricle, leading to cor pulmonale. Other causes
include a defective mitral valve, tetralogy of Fallot and atrial myxoma/thrombus.

Oedema & ankle swelling

Oedema is excess fluid in the interstitial space, and it causes swelling in peripheral tissue
sites. Oedema is poorly correlated with heart failure. Some patients, however, present with
bilateral ankle swelling. Patients with a recent onset of oedema will have noticed a weight
gain of 3kgs or more due to the retained fluid. Generally, if the jugular venous pressure is
not elevated then the oedema is not cardiogenic. This is because the oedema is due to
congestion, and with congestion there is increased central venous pressure, which radiates
into the great veins, hence raising the JVP.

Ankle swelling of cardiac origin is usually symmetrical and is worsened in the evening with
improvement during the night. As heart failure progresses, the oedema progresses from the
ankles to the legs, thighs, genitalia and abdomen.

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 Cardiovascular examination
In the cardiovascular examination, you need to know the surface anatomy of various
aspects of the heart which can be examined. The examination of the cardiovascular system
requires that you examine the hands, arms, neck & face for systemic signs of cardiac
disease, which may help point to certain pathologies.

As with every examination, start with the WIPER sequence: wash your hands, introduce
yourself, gain permission to conduct the examination, expose your patient appropriately
and recline the seat to the appropriate angle. In a cardiovascular examination, you expose
your patient completely up to their waste (in a female patient, you want to delay this until
you are examining the precordium). The bed should be reclined to 45°.

After this, you move on to the examination. The examination of the cardiovascular system
consists of a general examination, arterial pulses, blood pressure, jugular venous pulse and
precordial examination. On examination, you start with inspection from the end of the bed,
followed by a general examination incorporating cardiovascular signs. You examine the
hands, arms, axillae, neck & face. You then move onto the IPPA sequence (inspection,
palpation, percussion & auscultation) although percussion is unnecessary in a cardiovascular
examination.

General inspection
From the end of the bed, you want to comment on the patient first before you comment on
their surroundings. Comment on the general status of the patient: are they in any distress?
Are they lying comfortably on the bed? Are they conscious & fully aware of their
surroundings? Do they have obvious oedema? Do they have an obvious scar on their chest1?

• Comment on whether the patient is cachexic (severe weight loss with muscle wasting).
This may be a sign of a malignant disease, but severe cardiac failure may also cause this
condition (cardiac cachexia). It may be a combination of anorexia, impaired intestinal
absorption and increased levels of inflammatory chemokines such as TNF-α.
• There are other syndromes associated with cardiovascular disease, such as Marfan’s
syndrome, Down’s syndrome and Turner’s syndrome.

After commenting on their general appearance, comment on their surroundings: look for
paraphernalia relevant to the cardiovascular system, such as fluid restriction sign above the
bed, obvious weight chart

1
If they have a scar on their chest indicating a sternotomy, look at their legs for evidence of harvesting of the
saphenous vein.

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Hands
After general inspection, you move closer to them and inspect their hands. The things to
look for are:

• Temperature & general feel of the hand. The hand should feel warm, although it may
feel cold in cold weather. However, you should be able to look at the colour of the hand
and also exclude other indications of ischaemia. The hands may be clammy or
diaphoretic. Cold clammy hands must make you suspicious of shock.
• Clubbing. Clubbing is an increase in the soft tissue in the distal part of the fingers & toes.
The true mechanism is unknown, but it is suspected to be a result of release of platelet-
derived growth factor (PDGF) by platelets & extra-medullary megakaryocytes lodged in
the nail beds. This PDGF causes proliferation of fibro-vascular tissue. The most common
cardiovascular condition manifesting as clubbing is cyanotic congenital heart disease and
infective endocarditis. Other conditions that are not as common are bronchial
arteriovenous aneurysm and axillary artery aneurysm2. Clubbing is confirmed by
Schamroth’s sign (the disappearance of the diamond sign between the nails when
corresponding nails are placed together) and an increased interphalangeal depth ratio.
This is the ratio between the distal phalangeal depth (anteroposterior length of the
distal phalanx at the point where the nail “joins” the skin) and the interphalangeal depth
(anteroposterior length at the distal interphalangeal joint). The interphalangeal depth
ratio is ≥1.
• Splinter haemorrhages. These are linear haemorrhages lying parallel to the long axis of
the nail. In the cardiovascular system, they are due to infective endocarditis. They are
also due to trauma (especially in manual workers), scleroderma and systemic lupus
erythematosus. They are thought to be caused by emboli causing blood clots in
capillaries under the nail, thus resulting in haemorrhage. These, however, are only seen
in 15% of cases and are therefore not very sensitive. One or two splinter haemorrhages
are normal and therefore you should also look at the toes to confirm.
• Osler’s nodes. These are red raised tender palpable nodules on the pulp of the fingers or
toes or on the thenar & hypothenar eminences. Their incidence is 5-25%. They are
thought to be a result of underlying immunologic or vasculitic process, and histologic
evidence reveals the likelihood of an embolic process. The condition is also present in
SLE, gonococcal infection and the region distal to an arterial catheter.
• Janeway lesions. These are red non-tender haemorrhagic macules or papules on the
palmar aspect of the hand, especially on the thenar & hypothenar eminences. It is most
commonly found in bacterial endocarditis. Their mechanism is not fully understood,
although it is believed that they are caused by septic micro-emboli deposited in
peripheral sites. It has also been shown that an immunological vasculitic process could
be developing. They appear in 4-10% of patients.

2
These 2 conditions cause unilateral clubbing.

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• Tendon xanthomata. These are orange or yellow lipid deposits found in the tendon
areas in patients with type II hyperlipidaemia. Palmar & tubo-eruptive xanthomata over
the elbows & knees are characteristic of type III hyperlipidaemia.
• Signs of tobacco staining. This could be tar staining or nicotine staining.
• Peripheral cyanosis. This is a bluish discoloration of skin, especially beneath the nail
beds. It is a sign of hypoxia and is a result of reduced blood flow to peripheral tissues. It
is common in normal people when they are feeling really cold.
• Petechiae. These are minute bleeding areas beneath the skin which could occur in heart
failure. They most often present on the legs & conjunctivae. They are caused by
vasculitis and are a rare sight in infective endocarditis. They can easily be confused with
meningococcal rash.
• Capillary refill time. The capillary refill time in a patient with reduced perfusion of
peripheries is reduced. Capillary refill time is increased in patients with shock.

Arterial pulses
Normally, it is easiest to feel the pulse of the radial artery, and this pulse can be
characterised.

• Locating pulses. The radial pulse is located on the distal end of the radius just lateral to
the flexor carpi radialis tendon. The brachial pulse is detected in the antecubital fossa
medial to the tendon for biceps brachii. The carotid pulse can be detected by placing
your fingers between the angle of the jaw and the anterior margin of the
sternocleidomastoid muscle (alternatively, you can tuck your fingers beneath the
sternocleidomastoid muscle just lateral to the trachea). The femoral pulse is felt below
the inguinal ligament midway between the anterior superior iliac spine and the
symphysis pubis. The popliteal pulse is felt at the level of the knee creases. The posterior
tibial artery is felt 2cm below & posterior to the medial malleolus. The dorsalis pedis
artery is felt at the proximal end of the 1st intertarsal space lateral to the tendon of the
flexor hallucis longus.
• Radial pulse. You should make a number of observations based on this pulse. To
measure pulse rate, you count the number of beats you feel in 30 seconds and multiply
by 2 (or count the number of beats in 15 seconds and multiply by 4). Patients may also
have a pulse deficit, which is a pulse that is higher when listened to using a stethoscope
than when counted on pulsation. This may be present in ectopic heart beats or in atrial
fibrillation.
• Rhythm of pulse. The rhythm of the pulse should also be described (regular or irregular)
as well as the character of the pulse. The rhythm may be regularly irregular. There may
be ectopic beats that come after every normal beat (bigeminy) or every 2 normal beats
(trigeminy). There may also be an inspirational sinus arrhythmia in which the heart rate

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 slows down during inspiration. An irregularly irregular heart beat is typically found in
atrial fibrillation.
• Pulse rate. The average adult pulse rate at rest in a normal person is 60-100
beats/minute. Bradycardia is defined as a heart rate slower than 60 beats per minute
while tachycardia is defined as a heart rate over 100 beats per minute.
• Radio-radial or radio-femoral delay. This is the comparison of two pulses (both radial
pulses and the radial & femoral pulses). Radio-femoral delay may indicate coarctation of
the aorta, which is narrowing of the aorta around the region of the ductus arteriosus.
Radio-radial delay may indicate a large arterial occlusion by an atherosclerotic plaque or
aneurysm, subclavian stenosis or dissection of the thoracic aorta.
• Character & pulse. This is better assessed by palpating the brachial or carotid pulses.
These also better reflect the form of the aortic pulse wave. Nonetheless, a collapsing
pulse and a pulsus alternans are detectable on a radial pulse.
o A collapsing pulse is a bounding pulse that is followed by a brief silence when
the examiner lifts the arm of the patient.
o A pulsus alternans is an alternating strong & weak pulse. It is a feature of
severe cardiac failure & is due to prolonged recovery time of damage
myocardium. It indicates a very poor prognosis.
• Blood pressure. The blood pressure is supposed to be measured in a cardiovascular
examination. You need to determine whether a patient is hypertensive or hypotensive,
and whether the pulse pressure is wide or narrow. A wide pulse pressure suggests aortic
regurgitation while a narrow pulse pressure suggests aortic stenosis.

Neck
In the neck, you look for:

• Jugular venous pressure. The jugular pressure is measured with the patient lying down
on the bed at an angle of 45°. It is measured by placing 2 rulers perpendicular to each
other: one vertically at the sternal notch, another horizontally at the uppermost part of
the waveform. You then read the height on the vertical ruler where it is crossed by the
horizontal ruler.
• Carotid pulse. The carotid pulse is inspected & palpated. If it is visible on inspection, it is
a sign of aortic regurgitation and is called Corrigan’s sign. You then test the volume &
character on both sides.

Face
The inspection of the face involves the inspection of the eyes, face & mouth. There are
different signs to look for. In the eyes, the signs to look for are:

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• Xanthelasma. This is an intra-cutaneous yellow cholesterol deposit found around the
eye. These deposits are relatively common and may be normal. They may also indicate
type II or III hyperlipidaemia (high levels of LDL and low levels of HDL). In these patients,
cholesterol enters subcutaneous tissue through the capillaries. They therefore serve as
an indicator for possible atherosclerotic disease and other lipid-related cardiovascular
disease.
• Corneal arcus. This is a deposit of lipid around the margins of the iris, and it is associated
with some risk of cardiovascular disease, although it is not an independent risk factor. It
is more common in black male patients. it is common in elderly patients.
• Jaundice. This appears as a yellowish discoloration of the sclera covered by the superior
eyelid. Jaundice can occur with congestive heart failure or hepatic congestion. Another
uncommon cause is haemolysis induced by prosthetic heart valves due to excessive
turbulence.
• Pallor. This is a sign of anaemia. You look at the subtarsal conjunctiva of the lower
eyelid.
• Petechiae. These may also be associated with cardiovascular disease.

In the face, look for:

• Malar flush. This refers to rosy cheeks with a blue tinge to them. It is due to dilation
of malar capillaries. It is associated with pulmonary hypertension & low cardiac
output, such as occurs in mitral stenosis. This, however, is now rare.

In the patient’s mouth, look for:

• High arched palate. A high arched palate is found in Marfan’s syndrome. This
syndrome is associated with congenital heart disease (including aortic regurgitation
secondary to aortic root dilation and mitral regurgitations due to mitral valve
prolapse).
• Dentition. Diseased teeth may be a source of infection which could cause infective
endocarditis.
• Pallor. This is seen in the tongue & floor of the mouth. The tongue appears pink. It is
a sign of anaemia, and the tongue is a sensitive indicator of pallor as it is well
perfused.
• Central cyanosis. Central cyanosis is indicated with a dark purplish tongue. Central
cyanosis is due to reduced oxygenation of arterial blood, resulting from respiratory
disease or from right-to-left shunting of blood in the heart. It may also be due to
heart failure.

Precordium

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The precordial examination consists of inspection, palpation & auscultation. There is no
percussion on cardiovascular examination.

Inspection
On inspection, you look for scars on the chest. The location of the scar is important as it
gives an indication to the type of procedure carried out.

• Most heart surgery requires cardiopulmonary bypass so a median sternotomy (cut

down the middle of the sternum) is used. The scar is commonly hidden under a
forest of chest hair.
• There may also be left- or right-sided lateral thoracotomy scars which may be hidden
under pendulous breasts.
• A horizontal scar from the apex to the lateral part of the chest may indicate previous
closed mitral valvotomy.
• In the case of coronary bypass surgery, one may have had a scar in the leg which
confirms harvesting of the saphenous vein.
• A clavicular scar may suggest the insertion of a pacemaker. You may then need to
look for apical activity.

Skeletal abnormalities such as pectus excavatum and kyphoscoliosis may be present. These
may distort the position of the heart and its apex. You also look for pacemakers or
cardioverter-defibrillator boxes.

Palpation
There are a number of items that are palpated for:

• Apex beat. The apex is located by first placing the whole palm of the hand on the left
side of the chest and then localising the apex using two fingers. When it has been
localised, you determine the intercostal space in which it is found. The apex is only
palpable in about 50% of adults. The apex is normally palpable in the 5 th intercostal
space in the mid-clavicular line3.
The character of the apical beat should be determined also. The normal character
gently lifts the fingers. Other characters include:
o Pressure loaded/heaving. This is a forceful & sustained impulse and may
occur with left ventricular hypertrophy. It occurs in aortic stenosis,
hypertension and hypertrophic cardiac myopathy.
o Volume loaded/thrusting. This is a displaced, diffuse, non-sustained impulse.
It occurs in aortic regurgitation or dilated cardiomyopathy.

3
This is not the anatomical apex. It is a point above. The palpable apex is felt because when the ventricle fills
up, it assumes a spherical shape and this part moves towards the chest wall & can be felt. The true apex is a
point below it and it swings away from the chest wall when the heart fills up.

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 o Dyskinetic. This is a dis-coordinated apex felt over a larger area than normal.
It is usually due to left ventricular dysfunction, as in anterior myocardial
infarction.
o Double impulse. In this apex, there are 2 distinct impulses felt in systole, and
this is characteristic of hypertrophic cardiomyopathy.
o Tapping. This is a palpable first heart sound and is only palpable in mitral
stenosis (it may also be rarely palpable in tricuspid stenosis). Heart sounds
are not palpable.
The patient may have a right-sided heart (dextrocardia), so if you can’t feel the heart
apex, you may want to palpate the right side of the sternum.
• Heaves. These are palpable beats in the left parasternal area. They signify right
ventricular enlargement, which is the case in pulmonary stenosis, cor pulmonale and
pulmonary hypertension.
• Thrills. These are palpable murmurs caused by turbulence in the blood flow. They
should be palpated for using the flat of the hand, first over the apex, then over the
left side of the sternum and then over the base of the heart (around the 2nd
intercostal space). Apical thrills are best felt when the patient is rolled over to the
left side. Basal thrills are best felt when the patient sits up and leans forwards. These
manoeuvres bring the heart closer to the chest wall and therefore allow the
murmurs to be better felt. A thrill that coincides with the heart beat is a systolic thrill
while that which follows the heart beat is a diastolic thrill. The presence of a thrill
usually indicates an organic lesion.

Auscultation
The heart is auscultated with both the diaphragm and the bell of the stethoscope. Left-sided
murmurs (mitral & aortic) are best heart during expiration while right sided murmurs are
best heard during inspiration. The areas to listen to are:

• Heart sounds. The apex is the first part auscultated in order to determine the
character of the heartbeat. Normally, only the 1st & 2nd heart sounds (S1 & S2) are
heard. You should simultaneously palpate the carotid artery in order to determine
which one is the first heart sound. This allows you to time any murmurs you hear.
Listen for S1 & S2 and determine if S3 & S4 are present. You should do the same for
all the other valve areas.
• Mitral area. This is the apical area. You should listen for any murmurs, which are
louder on expiration. Place the bell of your stethoscope and then ask the patient to
roll over to their left side. This brings the apex – and consequently the mitral valve –
closer to the chest wall, allowing it to be more audible. If the murmur is heard louder
using the bell, the murmur is most likely due to mitral stenosis and it is heard as a
rumbling mid-diastolic murmur. You then adjust the stethoscope and listen using the

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 diaphragm. Using the diaphragm you should be able to hear the murmur of mitral
regurgitation, and this radiates to the axilla.
• Tricuspid area. This is found at the lower left sternal edge. You auscultate this area
using the diaphragm of the stethoscope. Murmurs are heard best on inspiration, so
you ask your patient to take a deep breath in and hold it there for a few seconds.
• Pulmonary area. This is best heard in the 2nd intercostal space to the left of the
sternum using the diaphragm. It is also best heard on inspiration and so you ask the
patient to breathe in and hold their breath.
• Aortic area. The aortic area is best heard in the right parasternal area in the 2 nd
intercostal space. Aortic murmurs are best heard by asking the patient to lean
forward. You then ask them to breathe in, breathe out and hold. This brings the
heart closer to the chest wall. An ejection systolic murmur radiating to the carotids
likely signifies aortic stenosis. Aortic regurgitation will most probably radiate to the
lower left sternal edge and can be heard with the patient sitting.

While the patient is sitting forwards, auscultate the lung bases to hear for bibasal crackles.
These can signify pulmonary oedema secondary to congestive cardiac failure. You must also
feel for sacral oedema.

Examining for features of heart failure

Often when the examiner conducts the cardiovascular examination, they need to ascertain
whether the patient is in failure. There are a number of supporting features from the prior
examination milestones, such as raised JVP, displaced apex, S3 heart sound. Other things to
do to identify heart failure are:

• Auscultating the lung bases. Auscultate the lung bases to look for bibasal
crepitations. These signify congestive heart failure. While you do this, you look for
sacral oedema, which indicates extensive oedema if lower limb oedema is present.
• Abdomen. Look for a tender hepatomegaly. This indicates right heart failure. It is
pulsatile in tricuspid regurgitation. Also look for a splenomegaly which may be
present in infective endocarditis. Ascites may occur in severe right heart failure. Also
feel for the pulsations of the abdominal aorta, which may be present in an
abdominal aortic aneurysm.
• Lower limbs. Check for bipedal oedema.

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 Interpretation of an ECG
The electrocardiogram (ECG) tracing is a recording of the overall electrical activity of the
heart. It is useful for many things, such as detecting electrical conduction disturbances such
as arrhythmias, electrolyte imbalances, presence of accessory connections, etc. It can also
be used to determine cardiac chamber size abnormalities, particularly chamber
enlargement in the different atria & ventricles.

When interpreting an ECG, you do determine the following:

1. Sinus rhythm.
2. Rate.
3. Axis.
4. Different ECG segments & intervals and corrected QT interval (QTc).
5. Chamber size.
6. Bundle branch blocks.
7. Other abnormalities where present.

Sinus rhythm
The sinus rhythm is determined using the rhythm strip. Every ECG should have a strip that
has a single lead recorded for 10 seconds. This strip usually records either lead II or V1. The
rhythm strip is also used to calculate the heart rate. The rhythm strip is used to determine
the presence of a sinus rhythm because it provides a more holistic picture of the conduction
of the heart and is therefore reliable.

A sinus rhythm is one in which the P-wave is always followed by a QRS complex. The
presence of a sinus rhythm means that the source of the heart’s impulses is the SA node,
with normal progression of cardiac impulses to the AV node, His-Purkinje system and
ventricular myocardium.

In addition to establishing the sinus rhythm, it is also important to establish the regularity of
the heartbeat. Check (using the rhythm strip) if the RR intervals are constant. If not, use the
card technique or just count the number of small boxes between successive R waves. If the
R interval is irregular, this is called sinus arrhythmia. This is sometimes normal, particularly
in young people, as heart rate increases with inspiration and decreases with expiration. The
difference, however, between the largest and smallest RR intervals should be 80-120ms
(which is 2-3 small boxes).

There is also need for a delay between the T-wave and the subsequent P-wave. If this delay
disappears, the patient is said to have a premature beat. If this premature beat originates
from the atria, it has a P-wave with a normal duration QRS complex, since it mimics the
normal flow of impulses from the atria to the ventricles. However, if the premature beat is

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originating from the ventricles, there is no P-wave and the QRS complex is prolonged
because the impulse is being spread through cardiac myocytes rather than the His-Purkinje
system.

Rate
The heart rate can be calculated from the ECG as well. Since the ECG has standard
progression of 25cms-1, it means that you can employ the same method of calculating the
heart rate with any ECG. To find the heart rate using the ECG, you can do the following:

1. You can count the number of large squares (5cm×5cm or 0.2s) in the RR interval and
divided 300 by that number. For example, if there are 4 large squares, you divide 300
by 4, giving you 75 beats per minute. This is because there are 300 large boxes in 60
seconds and therefore you use the period (RR interval) to determine with frequency
of heartbeats.
2. You can count the number of small squares in the RR interval, multiply it by 0.04s
and then divided 60 by the answer. For example, in the above example, 4 large
squares have 20 small squares. Therefore 20 × 0.04 = 0.8, then 60 ÷ 0.8 = 75 beats
per minute.
3. If the rhythm is irregular, i.e. the RR interval is not constant, you count the number
of R-waves in the rhythm strip and then multiply it by 6 (since the rhythm strip is 10s
long).

The normal heart rate in adults is 60-100 beats per minute. This is due to the high intrinsic
firing rate of the SA node, which would be higher if it were not under tonic control by the
vagus nerve. Taking the rate is important, particularly in conjunction with establishing the
sinus rhythm, because it helps determine the source of pacing of the heart. A normal heart
rate with a sinus rhythm means that the SA node is the pacemaker of the heart. You can get
a sinus rhythm that is either too fast or too slow, leading to sinus tachycardia or
bradycardia. You can also get a rate that is either high or low that not a sinus rhythm. It
could be due to SA nodal block (nodal rhythm), AV block or other arrhythmias, such as atrial
& ventricular fibrillation, atrial flutter, ventricular & supraventricular tachycardia and other
arrhythmias.

Axis
The axis of the heart is the net vector of ventricular forces doing ventricular depolarisation.
It is generally goes anteriorly & infero-laterally to the left for a number of reasons:

1. The SA node, where the impulses of the cardiac potential in the heart originate, is
located in the right atrium, and impulses are conducted from the right atrium to the
left atrium through the Bachman’s bundle. This gives a net vector of impulses in the
leftward direction.

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 2. The left ventricle has close to 4-times as much muscle mass as the right ventricle,
and therefore the magnitude of impulses is greater in the left ventricle. This means
that during ventricular contraction, the electric vector going to the left is greater
than that going to the right.
3. The heart generally faces the left side anyways.

The heart axis, however, is not a constant figure for everyone, as there are inter-individual
variations. The axis, however, deviates when there is left or right ventricular enlargement,
particularly from hypertrophy. It can also deviate to the right/left if there is a disturbance in
the normal progression of impulses of the heart, as in bundle branch blocks. The normal
heart axis is -30 to 90°:

aVR
(-150°) aVL
(-30°)

Lead I
(0°)

Lead III Lead II

(120°) (60°)

aVF
(90°)

Therefore, an axis greater than 90° is a right axis deviation while an axis that is less than -30°
is left axis deviation. Left axis deviation occurs in left ventricular hypertrophy, left anterior
hemiblock, inferior MI, ventricular tachycardia from left ventricular focus and some types of
Wolff-Parkinson-White syndrome. Causes of right axis deviation include right ventricular
hypertrophy, anterolateral MI, pulmonary embolism, left posterior hemiblock and some
types of Wolff-Parkinson-White syndrome. Left axis deviation, however, ends at -90°, while
right axis deviation ends at ±180°. Between -90° and -180°, the heart is said to have extreme
right axis deviation.

There are 2 ways of finding the axis of the heart:

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 1. You take lead I and aVF (oriented at 0° and 90° respectively) and you measure the
relative peaks of the R waves on those leads. You then find the angle from 0° by
using the aVF voltage as the opposite and the lead I voltage as the adjacent and
𝑜𝑝𝑝𝑜𝑠𝑖𝑡𝑒
using the formula tanθ = 𝑎𝑑𝑗𝑎𝑐𝑒𝑛𝑡.
2. You look for the most isoelectric lead, and then you look for the lead that is at right
angles to that one. The direction of the R-wave in that lead determines the general
axis. If the R-wave is positive, then the axis is in the direction of that lead. If the R-
wave is in the opposite direction, then the axis is in the positive direction of that
lead.

As a general rule of thumb, if both leads I & II are positive, the axis is normal.

Different ECG segments

There are different segments & intervals in the ECG, and these are used to assess different
properties.

• PR interval. This interval is from the beginning of the P-wave to the beginning of the
R-wave. This represents conduction from the atria to the ventricles, and it is usually
0.12-0.2s or 3-5 small boxes. Delay or shortening of this interval implies delay or
shortening1 of conduction from atria to ventricles.
• QRS complex. This interval is from the beginning of the Q-wave to the end of the S-
wave. It represents ventricular depolarisation. The normal duration of the QRS
complex is 0.08-0.12s, which is 2-3 small boxes. If it is wide, you should suspect
bundle branch blocks.
• QT interval. The QT interval is the interval from the beginning of the Q-wave to the
end of the T-wave. The interval varies with the sinus rate, and therefore it is more
reliable to calculate the corrected QT interval. This is found by dividing the
measured QT interval by the square root of the RR-interval2.
𝑄𝑇
𝑄𝑇 𝑐 =
√𝑅𝑅
The normal QTc interval duration is 0.38-0.42s. The QT interval assesses ventricular
conduction (depolarisation and repolarisation). The most common QT anomaly is
QTc segment prolongation.
• ST segment. This is the portion between the end of the QRS complex and the
beginning of the T-wave. In a normal heart, all the cells of the ventricular
myocardium are depolarised by this stage, and therefore the ST segment is
isoelectric at 0mV. Elevation above 1mm implies infarction while depression of

1
This is usually through an accessory pathway.
2
This is called the Bazett’s square root formula. There is also a Fridericia’s cube root formula in which the RR
interval is cube rooted instead.

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 greater than 0.5mm implies ischemia. The ST segment can also be elevated or
depressed in a number of other diseases, especially myocarditis & pericarditis3.

Chamber size
The size of the cardiac chambers can be ascertained from the ECG, particularly looking at
enlargement of the chambers.

• Left atrial enlargement. In left atrial enlargement, 3 things happen.

1
o The P-wave is prolonged. It normally lasts 0.08-0.1s (which is 2-22 boxes. If it
1
is more than 22 boxes, it is prolonged).
o The P-wave develops an M-pattern which is more prominent in lead II. In a
normal heart, impulses are relayed from the right atrium (where the SA node
is found) to the left atrium with the help of a bundle called the Bachmann’s
bundle. The M-pattern develops due to depolarisation of both right & left
atria occurring simultaneously. The bifid P-wave is also known as P-mitrale. A
pseudo-P-mitrale can be seen in hypokalaemia.
o Furthermore, there is a larger negative dip in the P-wave seen in V1. This is
because in a normal heart, the P-wave has an upward stroke & a downward
stroke that are both 1mm high & wide (0.1mV and 0.04s respectively), with
the upward stroke representing right atrial depolarisation and the downward
stroke representing left atrial depolarisation. The larger left atrium therefore
has a larger voltage element with a greater dip in the P-wave in V1.
• Right atrial enlargement. In right atrial enlargement, there is a greater P-wave
amplitude rather than duration. This is because when the right atrium enlarges,
transit time around the right atrium does not change, but the enlarged right atrium
leads to P-wave enlargement. It is also known as P-pulmonale and is also found in
lung disease (which can cause severe right heart strain). The larger P-wave can be
seen in lead II (>2.5mm) and V1 (>1.5mm).
• Left ventricular enlargement. A number of things occur in left ventricular
enlargement.
o There is enlargement of the R-wave in leads I, aVL, V5 and V6. In a normal
person, V4 is meant to be at the apex, and therefore V4 & V5 are meant to be
the tallest. However, in left ventricular enlargement, the R-wave is tallest in
lead V6.
o You can also use the Cornell criteria. This criteria states that if you add the R-
wave in aVL and the S-wave in lead III, it is left ventricular hypertrophy if the
sum is greater than 28mm in males and 20mm in females.
𝑅𝑎𝑉𝐿 + 𝑆𝐼𝐼𝐼 ≤ 28𝑚𝑚𝑚𝑎𝑙𝑒𝑠 /20𝑚𝑚𝑓𝑒𝑚𝑎𝑙𝑒𝑠

3
In myocarditis/pericarditis, there will ST elevation in all leads except aVR & V1. In these 2 leads, there will be
ST depression instead (since these leads oppose the cardiac axis).

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 o You can also use the Sokolov-Lyon criteria. This criteria states that the sum
of the depth of the S-wave in lead V1 and the tallest R-wave in lead V5/6
should be less than 35mm.
𝑆𝑉1 + 𝑅𝑉5 /𝑉6 ≤ 35𝑚𝑚
• Right ventricular enlargement. In right ventricular enlargement, there is a greater R-
wave than S-wave in leads V1 & V2. There is also right axis deviation and a dominant
S-wave in leads V5 and/or V6. The QRS complex duration remains normal, which
excludes right bundle branch block. There is also T-wave inversion in leads V1-V3/4.

Bundle branch blocks

Bundle branch blocks are defects in the branches of the His-Purkinje system, which are the
major conducting structures of the heart. The major conducting structures arise from the
bundle of His, which receives impulses from the AV node. The bundle of His divides into 2
main branches – the right & left bundle branches. The left bundle branch is more of a
continuation of the bundle of His, and the right bundle branch branches out of it.
Furthermore, the right bundle branch is thinner and supplies the right ventricle. The left
bundle branch further divided into 2 branches - the left anterior & left posterior fascicles4.
When a bundle branch becomes damaged, it may cease to conduct impulses. This results in
impulses being transmitted by surrounding cardiac myocytes, which are slower and change
the direction of propagation of impulses. This causes of loss of ventricular synchrony and
may lead to a reduction in cardiac output.

When there is a bundle branch block, there is a prolongation of the QRS complex to more
than 0.12s. The QRS duration may be normal if the block is partial. There are different types
of heart block that produce different patterns:

• Right bundle branch block. The QRS complex is prolonged. Furthermore, there is a
terminal R-wave in lead V1 (also called R prime), and this produces an M-shaped QRS
complex. There is also a prolonged S-wave (also called a slurred S-wave) in leads I &
V6. There is also T-wave inversion in leads V1-V3/4. There is usually no axis deviation.
• Left bundle branch block. This is a complex left bundle block and therefore the QRS
complex is prolonged. There is a broad monophasic R-wave in V6 that has a notch,
producing an M-shape. There are also inverted T-waves in leads I, aVL, V5 and V6.
There is also a deep S-wave in V1, and this is sometimes accompanied by a deep Q-
wave.
• Left anterior fascicular block. These are seen in about 4% of cases of acute
myocardial infarction. The QRS complex is prolonged, but not to the same extent as
left bundle branch block. There is also an abnormal left axis deviation, usually
between -45° and -60°. There is also a tall R-wave with a small Q-wave in leads I &

4
Some divide the left bundle branch into 3, with a left septal fascicle as the extra fascicle.

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 aVL. There are also deep S-waves in leads II, III and aVF. These features reflect the
left axis deviation. There is also delayed intrinsicoid deflection in lead aVL5.
• Left posterior fascicular block. The QRS complex in a left posterior fascicular block is
not prolonged. There is right axis deviation (heart axis 90-180°) because the wave of
impulses travels more quickly through the right bundle branch & left anterior
fascicle. There is also a deep S wave with a small R wave in leads I & aVL, and the R-
wave is tall in leads II, III and aVF. This reflects the right axis deviation. There is also
delayed intrinsicoid deflection in lead aVF. Isolated left posterior fascicular block is
very rare.

5
Intrinsicoid deflection is the time it takes from the beginning of the QRS complex to the peak of the R-wave.
It is also known as the R-wave peak time. It reflects the depolarisation vector from the endocardium to the
epicardium.

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 Infective endocarditis
Infective endocarditis is an endovascular infection of the cardiovascular structures, including
the atria, ventricles, heart valves, large intra-thoracic vessels and intra-cardiac foreign
bodies (prosthetic valves, pacemakers and surgical conduits). The incidence of the disease is
higher in developing countries.

Aetiology
The organisms that cause infective endocarditis are:

• Streptococcus viridans. These account for the majority of cases of infective

1 1
endocarditis (3 to 2 of cases – more than 35%). Disease caused by these organisms
follows a slow course and often occurs on pre-existing valve lesions.
• Staphylococcus aureus. S. aureus is the commonest cause of acute infective
endocarditis, accounting for 10-20% of cases of infective endocarditis overall.
• Enterococci species.
• HACEK group. These organisms are rarely encountered, accounting for 5% of cases.
They comprise Haemphilus, Actinobacillus, Cardiobacterium, Eikenella and Kingella.
• Culture-negative infective endocarditis. This is encountered in 5-10% of cases. It
may be due to prior antibiotic therapy, or it is due to infection by fastidious
organisms that do not grow on conventional culture media. Examples of culture-
negative organisms include Coxiella burnetti (which causes Q fever), Chlamydia,
Bartonella (causes trench fever & cat scratch disease) and Legionella.
• Fungi. The fungal causes of infective endocarditis are Candida, Aspergillus and
Histoplasma.

Pathogenesis
Endocarditis is usually the consequence of 2 factors:

1. The presence of bacteraemia in the circulation. This can occur due to patient-specific
reasons (such as intravenous drug use, poor dental hygiene, and soft tissue
infections) or diagnostic/therapeutic factors (dental procedures, intravascular
cannulae, cardiac surgery, permanent pacemakers). There isn’t good evidence that
bacteraemia leads to endocarditis, however.
2. Abnormal endocardium (which facilitates adherence & growth of bacteria). Damaged
endothelium promotes platelet & fibrin deposition, and this allows organisms to
adhere & grow and create an infected vegetation. Pre-existing valvular lesions may
disturb laminar flow. Jet lesions (from septal defects or persistent ductus arteriosus)
result in abnormal cardiac endothelium.

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The most common involved valves are the mitral & aortic valves. The tricuspid & pulmonary
valves are rarely involved, and where they are involved the patient is usually an intravenous
drug user.

There are 2 kinds of infective endocarditis: acute and sub-acute.

• Acute infective endocarditis is usually caused by destructive high-virulence

infections, such as S. aureus, and usually affects previously normal valves. Patients
develop acute heart failure with emboli. It has a mortality of 5-50%, and mortality is
related to age.
• Sub-acute infective endocarditis is caused by less virulent organisms and is the more
common type. The majority of cases are caused by viridans streptococcal species. It
is more common in patients with pre-existing valve lesions, prosthetic valves and
congenital heart defects.

In both forms, the vegetations are friable, bulky and potentially destructive – vegetations
can erode the underlying myocardium and produce a ring abscess, and can also destroy the
chordae tendinae. They are composed of fibrin, inflammatory cells and micro-organisms1.
The vegetations can embolise, and because they are infected they can cause septal infarcts
& mycotic aneurysms. Embolism to other structures can also produce embolic phenomena.
Infective endocarditis can also lead to formation of immune complexes which can be
deposited in blood vessels and cause vasculitis.

Risk factors
The risk factors for infective endocarditis are:

• Dental disease & procedures. Streptococcus viridans is a normal mouth commensal,

and therefore dental procedures can introduce infection into the bloodstream.
However, normal chewing also introduces infection into the circulation2.
• Prolonged indwelling catheter. These introduce skin organisms into the circulation,
which can cause acute endocarditis.
• Prosthetic valves. There are 2 types of prosthetic valve endocarditis. There is the
early type, which occurs within 60 days of valve surgery and is associated with poor
prognosis. It is commonly caused by S. aureus & S. epidermidis3 and it is thought to
be acquired in theatre or in ICU. The late type – occurring more than 60 days after
surgery – is thought to be acquired from the community. S. viridans is commonest
cause (50-70%), followed by S. aureus (25%).
• Intravenous drugs use. This predisposes to infective endocarditis on the right side of
the heart.

1
This is where they differ with other vegetative diseases, which have sterile vegetations.
2
For this reason, porphylaxis for dental procedures does not make sense.
3
Poorer outcomes are associated with MRSA, and this is often hospital-acquired.

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 • Underlying genitourinary disease & procedures. These introduce organisms such as
1
Enterococcus into the circulation. 5 of cases have concurrent urosepsis (particularly if
there is prolonged hospitalisation).
• Bowel malignancy. This predisposes to Streptococcus bovis, but this is very rare.
• Soft tissue infections. These are common in intravenous drug users and patients with
long-standing IV catheters. The often cause staphylococcal infection.
• Pre-existing valve lesions. These can be cause by rheumatic heart disease. 50% of
cases of infective endocarditis, however, occur on normal heart valves. Other heart
diseases that predispose to infective endocarditis include coarctation of the aorta,
PD and VSD.
• Diabetes. This leads to immunosuppression which predisposes to infection.
• Renal failure. This often leads to acute infective endocarditis.
• Organ transplantation. This also leads to acute infective endocarditis.

Clinical features
The clinical features of infective endocarditis are:

History

From the history, the patient will complain of:

• Fever & rigors. Despite being absent in sub-acute infective endocarditis, this is the
most consistent symptom. The other symptoms are non-specific and not consistent.
• Night sweats.
• Weight loss.
• Fatigue.
• Malaise.
• Flu-like syndrome.
• Cutaneous lesions, which can be painful.
• Symptoms of congestive heart failure: chest pain, breathlessness, fatigue, oedema,
poor exercise tolerance, etc.

Ask about pre-disposing factors:

• Previous cardiac surgery.

• Congenital heart lesion.
• IV drug use.
• Indwelling catheter.
• Diabetes.
• Any malignancy.

Acute infective endocarditis can present with rapidly-developing fever, chills, weakness and
lassitude.

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Examination

• General: The patient is usually febrile & anaemic. Patients may have clubbing. They
may also have numerous peripheral abscesses of unknown origin.
• CVS: patient may have insignia of infective endocarditis, such as Janeway lesions,
Osler’s nodes and spinter haemorrhages. Splinter haemorrhages & Osler’s nodes are
vasculitic phenomena, while Janeway lesions are embolic phenomena. Any new
murmur must raise suspicion of infective endocarditis. There is often mitral and/or
aortic regurgitation, or valve obstruction producing stenotic murmurs. Signs of left
ventricular failure should be sought, as this is a common cause of death.
• Fundoscopy: look for Roth’s spots, which are small retinal haemorrhages with pale
centres. Patients may also have conjunctival haemorrhages.

Investigations

The investigations done in infective endocarditis are:

• Blood cultures. You do 3 sets of blood cultures at different times from different sites
at peaks of fever. You often have to space the timing of the specimens. 85-90% of
cases will be diagnosed from the first 2 sets. 10% are culture-negative.
• Echocardiography. A transthoracic echocardiogram may show the vegetations but
only if they are greater than 2mm. It is sensitive for detecting valvular dysfunction,
ventricular function and abscesses. Trans-oesophageal echocardiography is more
sensitive, and it is better for visualising mitral valve lesions and identifying aortic root
abscesses. It is also more sensitive for assessing prosthetic valves.
• Urinalysis. Haematuria is found in 70% of cases of infective endocarditis and should
be done to rule out glomerulonephritis. Proteinuria can also occur.
• ECG. On an ECG, if a patient has a prolonged PR interval or heart block, suspect
aortic root dilatation.
• Blood tests. FBC may reveal a normocytic normochromic anaemia. There is also a
leukocytosis and thrombocytosis/thrombocytopaenia. On LFTs, there is elevated
ALP. On U&Es, there is elevated urea & creatinine. There is also elevated ESR & CRP.
• Serologic tests. These should be considered for culture-negative cases to diagnose
Coxiella, Chlamydia, Bartonella and Legionella.
• Chest X-ray. This may show cardiomegaly with pulmonary oedema or pulmonary
emboli/abscesses.

Diagnosis of infective endocarditis

This is made using the modified Duke’s criteria, which contain major & minor criteria.

Major criteria

The major criteria are:

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 • Positive blood cultures, as evidenced by:
o A positive blood culture for infective endocarditis, as defined by a typical
organism (viridans streptococci, Abiotrophia, HACEK, S. aureus and
Enterococcus) recovered from 2 cultures in the absence of a primary focus.
o A persistently positive blood culture, defined by recovery of an organism
consistent with endocarditis from either blood samples obtained more than
12 hours apart, or all 3 blood samples, or a majority of 4 or more separate
blood samples with the first & last obtained at least 1h apart.
o A positive serological test for Q fever with an immunofluorescence assay
showing phase 1 IgG anitbodies at a titre of more than 1:800.
• Echocardiographic evidence of endocardial involvement.
o An oscillating intracardial mass on the valve or supporting structures, in the
path of regurgitant jets or on implanted material in the absence of an
alternative anatomical explanation.
o An abscess.
o New partial dehiscence of a prosthetic valve.
o New valvular regurgitation.

Minor criteria

The minor criteria are:

• Predisposing heart condition or IV drug use.

• Fever of greater than 38°C.
• Embolic phenomena: major arterial emboli, septic pulmonary infarcts, mycotic
aneurysms, intracranial haemorrhages, conjunctival haemorrhages and Janeway’s
lesions.
• Immunologic phenomena: Osler’s nodes, Roth’s spots, glomerulonephritis,
rheumatoid factor.
• A positive blood culture but not in keep with major criteria.
• Echocardiographic findings that are consistent with infective endocarditis but not in
keep with major criteria.

The diagnosis of infective endocarditis is made when there are 2 major criteria met, or there
is 1 major criterion & 3 minor criteria, or 5 minor criteria. If there is 1 major & 2 minor
criteria, or there are 3 minor criteria alone, infective endocarditis is probable and not
definite.

Treatment
Infective endocarditis is managed medically & surgically

Medical management

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Antibiotics form the mainstay of treatment. The location of the infection means that
prolonged courses are required. The antibiotics given at first are empirical and given after
blood cultures are taken for culture & sensitivity. After blood culture results come out, the
choice of antibiotic will be guided by the organism isolated and its sensitivity. The antibiotics
regimens given are:

• Empirical therapy for native valve: amoxicillin/penicillin & gentamycin. Amoxicillin 2g

per 24 hours, penicillin 1.2g 4-houlry, gentamycin 80mg or 1mg/kg twice daily. If
penicillin-allergic, give vancomycin 1g twice daily. If you suspect Gram-negative
organisms, give vancomycin with meropenem 2g 3-times daily.
• Suspected staphylococcal endocarditis: vancomycin & gentamycin. Give vancomycin
1g 12-hourly, and gentamycin 80-120mg 8-hourly.
• Confirmed staphylococcal endocarditis: vancomycin/flucloxacillin /benzylpenicillin
with gentamycin. Vancomycin & gentamycin same as above. Give flucloxacillin 2g 4-
hourly, and benzylpenicillin 1.2g 4-hourly.
• Streptococcal endocarditis: penicllin & gentamycin.
• Enterococci endocarditis: give ampicillin/amoxicillin 2g 4-hourly with gentamycin 80-
120mg 12-hourly.

Surgical management

Surgery is considered if:

• The patient is in heart failure.

• There is valvular obstruction.
• There are repeated emboli.
• There is persistent bacteraemia.
• There is a myocardial abscess.
• Fungal endocarditis.
• An unstable infected prosthetic valve.

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 Rheumatic fever
Rheumatic fever is an inflammatory disease that occurs as a result of infection with group A
streptococci. It is a multi-systemic disease, affecting the joints, heart, skin and central
nervous system. The most serious complication of rheumatic fever is rheumatic heart
disease, and about 60% of patients develop it.

It is estimated that 33.4 million people across the world have rheumatic heart disease. It is
more common in children & young adults, with a peak age of 5-15 years of age. It is more
common in developing countries: Middle East, Far East, Eastern Europe and South America.
Its incidence is related to hygiene levels and the use of antibiotics.

Pathogenesis
The disease is often initiated by infection with group A streptococci, such as Streptococcus
pyogenes. S. pyogenes can be a normal resident of the oropharynx, and therefore
pharyngitis is a precipitating factor for rheumatic fever. Other infections (such as
streptococcal skin infections) can also cause rheumatic fever. However, rheumatic fever
often develops 2-4 weeks after the primary pharyngeal infection. The risk of developing
rheumatic fever after an acute pharyngitis is 0.3-3%.

In rheumatic fever, it is not the primary disease that causes damage. Rather, it is antibodies
formed against streptococcal antigens that cross react with body antigens and cause
damage. This is an example of molecular mimicry. The antibodies are usually against cell
wall M proteins and streptolysin O. in the different tissues, different proteins are affected.
In the heart, the antibodies react with cardiac myosin & laminin. In the brain, the antibodies
react with brain gangliosides. T-helper 1 & cytokine Th17 appear to be the key mediators of
the disease. There is a suspected genetic susceptibility that accounts for the likelihood of
developing rheumatic fever.

The average duration of an acute rheumatic fever attack is 3 months. A chronic attack
normally lasts 6 months or longer.

Clinical presentation
The clinical information you obtain from a patient with suspected rheumatic fever is:

History

From the history, you should look for:

• A history of a sore throat or scarlet fever. Only 35-65% of patients recall this,
however. If antibiotics were taken for the sore throat, the risk is lower.

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 • Arthritis – Patients will complain of joint pain, which typically affects many joints.
There is often progressive involvement of the joints, such that the joint involvement
is migratory. The joints are often affected early during disease.
• Carditis – patients will present with shortness of breath, dyspnoea on exertion,
cough paroxysmal nocturnal dyspnoea, chest pain and orthopnoea. This occurs in 30-
60% of patients. In severe cases, patients present with congestive cardiac failure.
• Neurological manifestations – this occurs in 25% of patients. Patients may develop
Sydenham’s chorea, which is a movement disorder. It most often affects girls aged
7-14 years. It occurs 1-6 months after the initial infection and is often self-limiting.
The onset is usually gradual, and it often begins as clumsiness when doing regular
household chores. This is followed by involuntary grimacing then purposeless
asymmetric jerky uncoordinated movements. Patient can have emotional lability &
personality change. Speech is usually spared, but may be affected.
• Skin – patients report a painless non-pruritic erythematous eruption on the trunk &
limbs; it usually spares the face. This is called erythema marginatum. It occurs in
10% of cases, and affects children.
• Others – fever, arthralgia, abdominal pain, malaise and epistaxis.

Examination

On examination, you may find:

• CVS: signs of heart failure, new/changed heart murmurs (usually mitral & aortic
regurgitation), pericardial rub. You can also hear a Carey-Coombs murmur, which is
an apical low-pitched mid-diastolic flow murmur.
• Musculoskeletal: warm, swollen, tender joints in frank arthritis. There may be
arthralgia alone, without other signs of inflammation.
• Neurological examination: patients will appear fidgety, and display spasmodic
unintentional movements. they will have lack of coordination, inability to sustain
tetanic contraction, such as clenched fist. Speech is often unaffected. When you ask
them to extend their arms & wrists, their hands & wrists form a typical eating fork
appearance. Shining light into their eyes produces a hippus, which is alternating
constriction & relaxation of the pupil.
• Skin: patients may have subcutaneous nodules found primarily over bony surfaces &
tendons (on extensor surfaces). Patients may also have erythema marginatum
lesions which tend to demonstrate advancing erythematous margins with clearing of
the centre.

Investigations

The investigations done in rheumatic fever are:

• Throat swabs. You can culture these to reveal group A Streptococcus species. This,
however, is usually negative by the time symptoms of rheumatic fever appear.

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 • Antistreptolysin O antibodies. These may be elevated.
• Rapid antigen test.
• ESR & CRP. These are usually elevated.
• FBC. This may reveal a leukocytosis.
• Chest X-ray. This may reveal cardiomegaly in patients with carditis
• Echocardiogram. Echocardiography may reveal valvular heart lesions. Small
vegetations develop along the line of closure of valves. These are called verrucae.
They usually produce little disturbance in cardiac function, although they predispose
to infective endocarditis later. With chronic rheumatic fever, valves become
permanently calcified.
• ECG. This may show conduction defects in 45-70% of cases.

Diagnosis of rheumatic fever

Rheumatic fever is diagnosed using the Jones criteria. It consists of major & minor criteria.

Evidence of streptococcal infection:

• Positive culture result on throat swab.
• Positive rapid streptococcal antigen test.
• Elevated/rising anti-streptolysin O or anti-DNAse B titre.
• History of infection, e.g. scarlet fever.
Major criteria (CCPEN):
• C – Carditis (50%).
• C – Sydenham’s chorea (10%).
• P – Polyarthritis (80%), which is usually a migratory flitting polyarthritis.
• E – Erythema marginatum (<5%).
• N – Subcutaneous nodules (rare).
Minor criteria:
• Fever.
• Arthralgia (if polyarthritis is not a major criterion).
• Raised ESR (>40mm/min) & CRP.
• Previous rheumatic fever.
• Leukocytosis.
• Prolonged PR interval (if carditis is not a major criterion)

To diagnose rheumatic fever you need evidence of streptococcal infection with either 2
major criteria or 1 major and 2 minor criteria.

Management
Management of rheumatic fever is as follows:

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 • Bed rest. Bed rest is absolutely recommended. This is encouraged until CRP is normal
for 2 weeks. Patients with joint involvement should not be allowed to move about
until the arthritis has resolved or the normalisation of ESR/CRP.
• Antibiotics. This is to eradicate residual streptococcal infection and should be given
even if throat swabs do not reveal infection . You first give benzylpenicillin as a stat
dose (0.6-1.2g IV) followed by penicillin V 250-500mg 4-time daily for 10 days. If the
patient is allergic to penicillin, give erythromycin/azithromycin.
• Analgesia. This is indicated for carditis and/or arthritis. Give aspirin 100mg/kg/day
for 2 days then 75mg/kg/day for 6 weeks. These, however, do not improve
cardiovascular sequelae.
• Steroids. Steroids use is controversial. Some studies have shown no cardiovascular
benefit in use of steroids. In other cases, they may be life-saving in cases of
pancarditis.
• Chorea. You give haloperidol 0.5mg 8-hourly (or 0.025-0.05mg/kg/day in divided
doses), sodium valproate, phenobarbitone or diazepam.
• Congestive cardiac failure. You give antifailure treatment – nurse in propped up bed,
oxygen per nasal prongs/face mask, strict fluid input monitoring, daily weights and
monitor urine output. You also start diuretics (furosemide) and slow digitalisation.

More than 50% of patients will develop chronic rheumatic heart disease later (10-20 years
later). Recurrence is precipitated by further infections, pregnancy and use of combined oral
contraceptive pills.

Prevention
Prevention of rheumatic fever is divided into primary prevention, secondary and tertiary
prevention.

Primary prevention

Primary prevention aims at preventing the development of rheumatic fever. The measures
include improving housing conditions as well as preventing progression of the causative
infection. Housing conditions are improved by improving the quality of housing as well as
reducing overcrowding and providing primary healthcare facilities. For those that develop
diseases such as streptococcal throat infections. Streptococcal infections need to be
adequately treated within 1 week of onset of symptoms to prevent the development of
rheumatic fever. You can give any one of the following:

• A single dose of benzathine penicillin G 100 000IU for those below 30kg or 200 000IU
for those above 30kg intramuscularly.
• Oral penicillin V 50mg/kg/day qid for 10 days. it should be given before meals and
the course should be completed.

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 • For patients that are sensitive to penicillin, you can give erythromycin 125-250mg tds
for 10 days.

Secondary prevention

Generally there is little secondary prevention available for detection of subclinical disease
and institution of preventive measures.

Tertiary prevention

Once rheumatic fever has occurred, the most important aspect of treatment is to prevent
recurrences as each subsequent attack inflicts more damage on the heart valves and
therefore predisposes to infective endocarditis & heart failure. Adolescents & young adults
are at risk of developing new infections. Prevention is achieved by antibiotic prophylaxis.

• Oral penicillin V 250mg twice daily. This, however, is not very successful in providing
complete protection.
• Oral sulphonamides 0.5-g twice daily or erythromycin 250mg twice daily in patients
that are allergic to penicillin. Patient compliance must be ensured.

Prophylaxis should be instituted every time there is a dental procedure to be conducted.

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 Aortic stenosis
Aortic stenosis is a chronic progressive disease that produces obstruction to the outflow of
blood from the left ventricle, leading to symptoms of chest pain, breathlessness, pre-
syncope & syncope and fatigue.

Aetiology
The majority of cases of aortic stenosis are a result of disease of the aortic valve. The most
common diseases of the aortic valve that cause stenosis are:

• Calcified aortic valvular disease (CAVD). This is the commonest of aortic stenosis
and occurs mainly in the elderly. It is a result of an inflammatory process involving
macrophages & T-cells, with initial thickening of the sub-endothelium with adjacent
fibrosis. The lesions contain lipoproteins which calcify, thus increasing leaflet
thickness and reducing systolic opening. The risk factors for CAVD are: old age, male
gender, elevated lipoprotein (a) & LDL, hypertension, diabetes and smoking.
• Bicuspid aortic valve. This is a congenital heart disease that occurs in 1-2% of live
births; it is familial in many cases. Patients with CAVD of a bicuspid valve tend to
present earlier than those of a tricuspid one. Bicuspid aortic valve is associated with
coarctation of the aorta, aortic root dilatation and potential aortic dissection. These
patients should therefore receive regular follow-up echocardiography.
• Rheumatic fever. Rheumatic fever can produce progressive fusion, thickening and
calcification of the aortic valve. The aortic valve is affected in 30-40% of cases of
rheumatic fever, and there is usually associated mitral valve disease.

Other causes of aortic valvular disease include: chronic kidney disease, Paget’s disease of
bone, previous radiation exposure and homozygous familial hypercholesterolaemia.

Other forms of aortic stenosis do not involve the aortic valve. They include:

• Supra-valvular obstruction. This is due to a congenital fibrous diaphragm above the

aortic valve. It is often associated with mental retardation and hypercalcaemia 1.
• Hypertrophic cardiomyopathy. This is a condition that causes septal thickening
which obstructs left ventricular flow.
• Subvalvular aortic stenosis. This is a congenital condition in which a fibrous ridge or
diaphragm is situated immediately below the aortic valve.

Pathophysiology

1
This is found in William’s syndrome, which is a congenital disease.

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Obstruction of the aortic outflow tract leads to increased left ventricular pressure, which
results in compensatory left ventricular hypertrophy. This results in relative left ventricular
myocardial ischemia and consequently angina, arrhythmias and left ventricular failure. The
obstruction is more severe during exercise, as it blocks the increase in cardiac output that
normally accompanies exercise. Therefore, the blood pressure falls, coronary ischemia
worsens, the myocardium fails and cardiac arrhythmias develop.

Left ventricular systolic function, however, is preserved.

Clinical presentation
Patients are typically elderly patients. There are usually no symptoms until the obstruction is
1
moderate to severe (when the orifice is reduced to 3 of its original size). At this stage, the
patient develops exercise-induced syncope, angina and dyspnoea. The angina develops due
to myocardial ischemia. The syncope is a result of hypo-perfusion to the brain secondary to
hypotension. Patients may also present with heart failure.

Common signs include:

• The carotid pulse is a low-volume pulse and is slow-rising or plateauing in nature.

This may be combined with diminished & delayed carotid upstroke – a feature called
pulsus parvus et tardus.
• The apex beat is usually not displaced because the hypertrophy does not produce
noticeable cardiomegaly. The pulsation, however, is sustained and obvious – a
heaving apex beat. A double impulse may be felt due to the 4th heart sound or atrial
contraction kick. You may also feel a systolic thrill.
• On auscultation, you will hear an ejection systolic murmur that is crescendo-
decrescendo. It is best heard in the aortic area2. It radiates into the carotid arteries
and the precordium.
• Other findings: systolic ejection click, unless the valve has become immobile &
calcified; soft/inaudible S2 when the valve becomes immobile; reversed splitting of
S2 (splitting on expiration); and a prominent S4 can be heard unless there is a
concurrent mitral stenosis.

When symptoms occur, prognosis is generally poor, and patients die within 2-3 years if no
surgical intervention is offered.

Investigations
The investigations to be done in patients with aortic stenosis are:

2
It can also be heard at the left sternal edge.

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 • Chest X-ray. This reveals a relatively small heart with a dilated aorta. This is because
turbulence above the stenosed area produces post-stenotic dilatation. The aortic
valve may be visibly calcified on the chest X-ray.
• ECG. The ECG shows left ventricular hypertrophy and left atrial delay. There is also a
left ventricular strain pattern, which manifests as a depressed ST segment and an
inverted T–wave. The left ventricular strain pattern is produced by pressure
overloading which leads to subendocardial ischemia. This strain pattern is found in
the leads oriented towards to the left ventricle (leads I, aVL, V 5 and V6) and is more
common when the disease is severe. There may also be poor RR progression.
Ventricular arrhythmias may be recorded, but usually there is a sinus rhythm. There
may also be either left bundle branch block or complete AV block in severe disease
where calcification progresses.
• Echocardiography. On an echocardiogram, you will see thickened, calcified and
immobile aortic valve cusps. You can also appreciate the presence of left ventricular
hypertrophy. You can use a Doppler echocardiogram to determine the flow through
the stenosed valve and therefore the severity of the disease. stenosis is said to be
severe if valve area is less than 1cm2 and the peak gradient is ≥50mm Hg3. The risk of
complications is increased if aortic jet velocity is >4ms-1 or is increasing by more than
0.3ms-1 per year.
• Cardiac catheterisation. This is rarely necessary since most of the information
obtainable from it can be obtained non-invasively. Coronary angiography, however,
is necessary before recommending surgery.
• Cardiac MRI & CT scanning. These are indicated for assessing the thoracic aorta for
the presence of an aneurysm, dissection or coarctation. These, however, are rare
indications.

Management
In patients with aortic stenosis, the presence of symptoms is a good indicator of severity.
Without treatment, prognosis of symptomatic disease is poor. If patients present with
angina or syncope, the mean survival is 2-3 years. Those with heart failure, however, survive
for an average duration of 1 year. If the disease is moderate-to-severe and is treated
medically, mortality can be as high as 50% at 2 years.

The interventions for aortic stenosis are surgical and medical:

• Surgical intervention. Surgical intervention is indicated for: those that develop

symptoms or a drop in blood pressure during an exercise test; a left ventricular
ejection fraction of less than 50%; and moderate-to-severe aortic stenosis
undergoing coronary artery bypass, surgery of the ascending aorta or other cardiac
valve. The available procedures are:

3
The normal valve area is 3-4cm2

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 o Valvotomy, in which the valve is incised to allow it to open more. This
produces temporary relief from the obstruction.
o Aortic valve replacement, in which the whole aortic valve is replaced with a
prosthetic valve.
o Valvuloplasty, in which the aortic valve is dilated using a balloon catheter.
The long-term results of this surgery are generally poor has this has been
used either in patients unfit for surgery or as a bridge to surgery (since it
improves systolic function).
o Percutaneous valve replacement, in which the valve is replaced through
insertion of a catheter with a balloon expandable stent valve. Valve insertion
has generally been successful (86%) with a procedural mortality rate of 2%
and a 30-day mortality of 21%.
• Medical intervention. Most of the vasodilator drugs used to manage other heart
conditions – ACE inhibitors, AT receptor blockers, glycerine trinitrate, isosorbide
dinitrate, hydralazine, calcium channel blockers, etc. – are contraindicated in aortic
stenosis. This is because vasodilation causes a reduction in peripheral vascular
resistance, which leads to reduced blood pressure (since the cardiac output cannot
increase to compensate). This leads to syncope and can precipitate symptoms in an
asymptomatic patient. Nitroprusside can be used in patients with decompensated
heart failure.

Asymptomatic patients should be under regular review for assessment of symptoms and
echocardiography.

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 Myocarditis
Myocarditis is an inflammatory condition involving the myocardium. It usually manifests in
an otherwise healthy person. In a clinical setting, it is synonymous with inflammatory
cardiomyopathy. The incidence in America is estimated to be about 1-10 cases per 100 000
population. The median age of presentation is 42 years, and there is no sex predilection.

Classification
The classification of myocarditis according to Lieberman is as follows:

• Acute myocarditis. This has an indistinct onset, but is characterised by a decline in

ventricular function. This may progress to dilated cardiomyopathy.
• Fulminant myocarditis. This is a form of myocarditis with a distinct onset of illness
characterised by severe cardiovascular compromise with ventricular dysfunction.
There is usually a viral prodrome. On endo-myocardial biopsy, there are multiple foci
of inflammation. It may resolve spontaneously or end in death.
• Chronic active myocarditis. This has a less distinct onset of illness with clinical &
histological relapses. Ventricular failure develops with chronic inflammatory changes
(such as giant cells).
• Chronic persistent myocarditis. This has a less distinct onset of illness and is
characterised by a persistent histologic infiltrate with foci of myocytes necrosis but
without ventricular dysfunction despite symptoms.

In the acute phases, hearts with myocarditis are flabby with focal haemorrhages. In chronic
myocarditis, the hearts are enlarged & hypertrophied. Histologically, there is an
inflammatory infiltrate in the heart. In viral infections, lymphocytes predominate; in
bacterial infections, PMN leukocytes predominate; and in allergic & hypersensitivity
reactions, eosinophils predominate.

Aetiology
The agents causing myocarditis cause damage by either of 4 mechanisms:

1. Direct cytotoxic effects of causative agent.

2. Secondary immune response triggered by causative agent.
3. Cytokine expression in the myocardium. These include TNF-α & nitric oxide synthase.
4. Aberrant induction of apoptosis.

The causes of myocarditis are as follows:

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 • Idiopathic. This accounts for 50% of cases. Often a viral cause is suspected, despite
not being proven.
• Infections. The different infectious causes of myocarditis include:
o Viruses. In western societies, these account for the majority of infectious
cases. The leading causes of viral myocarditis are Coxsackie B & adenovirus
infections. Other viral causes include HIV1, enterovirus, influenza, CMV, EBV,
polio, viral hepatitis, mumps, rubeola, HSV, VZV, parvovirus, etc. Viral isolates
differ in tropism & virulence.
o Bacteria. Strepococcus species (rheumatic carditis), C. diphtheriae2,
Clostridium, TB, meningococcus, Mycoplasma, S. aureus.
o Spirochetes. Syphilis, Lyme disease, leptospirosis.
o Parasites. T. cruzi (Chaga’s disease), T. gondii (new-borns &
immunocompromised), malaria, leishmaniasis, etc.
o Fungi. Candidiasis, aspergillosis, cryptococcosis, histoplasmosis,
actinomycosis, blastomycosis, coccidiomycosis.
• Drugs. The drugs that can cause myocarditis are usually those that cause
hypersensitivity reactions. They include: methyldopa, penicillin, sulphonamides, anti-
TB medication, anti-seizure drugs, cancer chemotherapeutics, and chloramphenicol.
• Autoimmune diseases. These include rheumatoid arthritis, sarcoidosis, SLE, Crohn’s
disease & ulcerative colitis, Wegener’s granulomatosis, and scleroderma.
• Vasculitis. Giant cell myocarditis, Kawasaki disease, etc.
• Substances. Alcohol & recreational drugs can cause myocarditis. Other substances
include carbon monoxide, arsenic, lead, radiation, animal bites (scorpions, snakes,
black widow, wasp and ticks.

Clinical presentation
Myocarditis may be acute or chronic, and it ranges in presentation from being
asymptomatic to fatigue, palpitations, chest pain and dyspnoea, to fulminant congestive
cardiac failure with/without cardiogenic shock. In viral myocarditis, patients may present
with a recent history of flu-like symptoms: fever, arthralgia, malaise, or pharyngitis,
tonsillitis and upper respiratory tract infection. Suspect myocarditis in a patient with prior
history of heart disease.

On examination, patients may develop signs of heart failure, such as tachycardia, gallop,
raised JVP & distended neck veins, mitral regurgitation and oedema. In those with
concomitant pericarditis, there may be a pericardial rub. The first heart sound (S 1) is often
soft.

1
Myocarditis is found in about 20% of HIV patients at post mortem, but only 10% of these develop symptoms.
2
This often causes toxin-induced heart block.

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Investigations
The investigations done for myocarditis are:

• ECG. This reveals ST elevation/depression with T-wave inversion. You may also find
atrial arrhythmias or AV block with Chaga’s disease, diphtheric myocarditis or Lyme
disease. You can also get changes mimicking an MI (called a pseudo-infarction
pattern), and these are associated with a poor prognosis. Right bundle branch blocks
are very common in myocarditis.
• Chest X-ray. This may demonstrate heart enlargement depending on the stage &
virulence of the organism.
• Echocardiography. This is done to exclude other causes of heart failure and to
evaluate the degree of cardiac dysfunction. It is also used to distinguish between
fulminant & acute myocarditis by measuring the left ventricular diastolic dimensions
and septal thickness3.
• Cardiac enzymes. Positive troponin I or T will indicate presence of myocarditis. Anti-
myosin scintigraphy (using anti-myosin antibodies) helps identify the presence of
disease.
• Endomyocardial biopsy. This is the criterion standard for diagnosis of myocarditis. It
is reserved for cases of deteriorating acute heart failure of unknown origin that is not
responding to treatment. The procedure, however, has limited sensitivity &
specificity as inflammation can be diffuse or focal, and adverse events can occur in
6% of cases.
• Viral antibodies & PCR. Antibodies to common aetiological viruses can be taken
from serum. Antibody diagnosis, however, relies on identification of acutely rising
titres. You can do PCR studies on the biopsy sample taken from the heart.

Management
Because many cases of myocarditis are not clinically obvious, a high degree of suspicion is
required. Many patients have mild disease and recover with supportive care. Fulminant
cases, however, need to be managed in tertiary care facilities.

• Emergency management. This includes detection of arrhythmias, administration of

oxygen and management of fluid status (with strict input-output monitoring & salt
restriction).
• Treat the underlying cause. The majority of cases (idiopathic & viral causes) are self-
limiting. Others, such as bacterial causes and the parasitic forms, require
identification, treatment and elimination. Inflammatory diseases must be treated

3
In fulminant myocarditis, the diastolic dimensions of the left ventricle are normal while the thickness of the
septum is increased. In acute myocarditis, however, the left ventricle’s diastolic dimensions are increased
while the septal thickness is normal.

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 accordingly. NSAIDs must be avoided as they impede myocardial healing and actually
exacerbate inflammation.
• Pharmacologic therapy. This is indicated for management of acute heart failure. You
should give diuretics, ACE inhibitors/AT1-receptor blockers and β-blockers, with the
option to add digoxin4 and/or spironolactone. These drugs can then be used for long-
term management. Anticoagulation is advised. Anti-arrhythmic drugs (which are
used particularly in Chaga’s disease) must be used with caution, as they are negative
inotropes which can exacerbate acute failure.
• Immunotherapy. This is indicated for immunologic diseases such as giant cell
myocarditis. However, the decision to use immunotherapy should be supported by
evidence of disease in the small arteries. This disease has a high mortality, and a
rapidly progressive course. Otherwise, conventional use of immunotherapy is not
advised.
• Surgical care. Complete heart block is an indication for temporary transverse pacing.
Myocarditis carries a low threshold for ventilatory & circulatory support using an
intra-aortic balloon pump because of its rapidly progressive course. In cardiogenic
shock, a LVAD (left ventricular assist device) can be placed. Transplantation is
beneficial for individuals with biopsy-proven giant cell myocarditis. However, the
rates of acute rejection & post-transplant vasculopathy are higher.

After management, patients should be encouraged to have adequate bed rest, and should
avoid sporting activities for 6 months. Patients should be monitored every 1-3 months until
they fully recover. Any evidence of residual cardiac dysfunction or remodelling should be
treated as chronic hear failure.

4
Digoxin should be used with caution as it promotes expression of pro-inflammatory cytokines and increases
mortality rate.

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 Pericardial disease
The pericardium is a sac that covers the heart. It consists of a fibrous pericardium, which is a
tough covering, and a serous pericardium which contains mesothelium. The serous
pericardium consists of a visceral & parietal pericardium, and this encloses pericardial fluid.
The normal volume of pericardial fluid is 20-45ml. presentation of pericardial disease
includes: acute & relapsing pericarditis, pericardial effusion, cardiac tamponade and
constrictive pericarditis.

Acute pericarditis
This refers to inflammation of the pericardium. Acute pericarditis has numerous aetiologies,
although in most cases the cause is not identified (idiopathic1). The causes of acute
pericarditis are:

• Infectious. The infectious agents that cause acute pericarditis are:

o Viral. The viral causes of acute pericarditis are: Coxsackie B virus (most
common viral cause), echovirus, HIV, influenza, EBV, Coxsackie A, mumps and
varicella zoster. Viral pericarditis is usually painful, but follows a short time
course and rarely has any long-term effects.
o Bacterial. It is a rare complication of other infections, such as pneumonia,
sepsis or infective endocarditis. It can also result from trauma or post-
thoracic surgery. The aetiological agents are staphylococci, S. pneumoniae,
streptococci and Haemophilus. Meningococcus can also cause pericarditis.
o TB. This usually presents with low-grade fever, particularly in the evening. It is
associated with features of acute pericarditis, malaise, weight loss and night
sweats. Pericardial aspiration is often required to make a diagnosis, and
constrictive pericarditis is a common outcome.
o Fungal infection. This is a common complication of endemic fungal infections,
such as histoplasmosis & coccidioidomycosis. It can also be caused by
Candida infection, particularly in immunocompromised patients, drug addicts
and after cardiac surgery.
• Post-MI. This occurs in about 20% of patients in the first few days following an MI. it
occurs most commonly in anterior STEMI with high cardiac enzymes. However, its
incidence is reduced to 5-6% with thrombolysis. The associated pain may be difficult
to differentiate from recurrent angina. Post-MI pericarditis also occurs as a feature
of Dressler’s syndrome, in which it occurs later on in the recovery phase following
the infarct. It is thought to be a result of an autoimmune response to cardiac damage
2-10 weeks following an MI, and anti-myocardial antibodies may be found.

1
This, however, is assumed to be viral.

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 • Uraemic pericarditis. Pericarditis is one of the manifestations of uraemia.
Accumulating toxins irritate the pericardium. It occurs in 6-10% of patients with
advanced CKD if dialysis is delayed. It is an indication for urgent dialysis.
• Malignant pericarditis. This can happen in a number of ways. You can get a primary
malignancy of the pericardium (a mesothelioma). You can also get secondary
metastasis to the pericardium, or to mediastinal lymph nodes draining the heart and
thus causing an effusion (which is often haemorrhagic). The malignancies that can
cause pericarditis include: bronchogenic carcinoma, breast cancer, Hodgkin’s
lymphoma, leukaemia and malignant melanoma.
• Iatrogenic. Radiation & radiotherapy for thoracic tumours can also cause
pericarditis. Pericarditis can also follow surgery and cardiotomy.
• Autoimmune diseases. This includes SLE, rheumatic fever, rheumatoid arthritis and
scleroderma.
• Drugs. Drugs such as procainamide, hydralazine, isoniazid, doxorubicin and
cyclophosphamide can cause pericarditis.
• Other causes. You can get myxoedematous pericarditis, as well as chylopericardium.
Other causes include: collagen vascular diseases.

Clinical presentation

Patients with acute pericarditis come complaining of:

• Chest pain. The chest pain is central, sharp and exacerbated by movement,
respiration and leaning forward, and relieved by sitting down. It may also be referred
to the neck & shoulders.
• Fever & malaise. This may be present, particularly in tuberculosis.

On examination, you will most likely find a pericardial friction rub occurring in 3 phases
(triphasic): atrial systole, ventricular systole and ventricular diastole. It may also be biphasic
(to-and-fro). The friction rub is best heard with the diaphragm of the stethoscope placed at
left lower sternal edge at the end of expiration with the patient leaning forward. Features of
pericardial effusion or tamponade may be present.

Investigations

The investigations done are:

• ECG. This is diagnostic. The features include:

o Widespread (not limited) concave/saddle-shaped ST-segment elevation.
o Reciprocal ST depression in leads aVR & V1.
o ST segment flattening with T wave inversion. This happens 2-5 days later.
o PR segment depression.
There may also be sinus tachycardia from fever or haemodynamic embarrassment,
and there may also be conduction abnormalities if the myocardium is involved.

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 • Blood tests. Cardiac enzymes are done to check for MI. however, cardiac troponins
may be raised if there is associated myocarditis. On FBC check the white cell count &
differential to look for leukocytosis. This is suggestive of an infective aetiology. The
elevated white cells will point to the infectious agent (neutrophilia for bacterial
infection, lymphocytosis for viral infection or TB).
• Chest X-ray & echocardiogram. A chest X-ray will show cardiomegaly if there is an
effusion, and this must be followed by an echocardiogram to exclude underlying
heart pathology.

Treatment

Treatment principles are:

1. Treat the cause if known.

2. Bed rest.
3. Give oral NSAIDs, e.g. ibuprofen or aspirin. Aspirin is the drug of choice for patients
with a recent MI.
4. You can give colchicine in combination with conventional therapy. It is also used for
recurrent pericarditis2.
5. Corticosteroids are reserved for patients with known immune cause, such as TB. For
TB, you give prednisolone 60mg daily for 2-6 weeks.

Pericardial effusion & cardiac tamponade

A pericardial effusion is a collection of fluid within the pericardial space. It commonly
accompanies an acute episode of pericarditis. If an excessive amount collects, ventricular
filling is compromised, and this to cardiovascular embarrassment. This is called cardiac
tamponade. At times cardiac tamponade is caused by an acute bleeding event, e.g. trauma,
aortic dissection, uraemia and malignancy.

Types of effusion

There are different types of pericardial effusion:

• Transudative serous. Causes include congestive cardiac failure, hypoalbuminaemia

and hypothyroidism.
• Exudative serous. This is caused by rheumatic fever, SLE, scleroderma, viral
infections, some tumours and uraemia. The pericardial fluid has scanty mononuclear
cells.

2
About 20% of patients with acute pericarditis go on to develop recurrent idiopathic acute pericarditis. It may
be incessant (occurring during the 6-week weaning period from NSAIDs) or intermittent (occurring after 6
weeks, which is after weaning)

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 • Fibrous/serofibrous. This is characterised by accumulation of serous fluid with a
fibrous exudate. It occurs in MI & Dressler’s syndrome, uraemia, irradiation, and
trauma & surgery. This is the commonest presentation. The surface of the
pericardium has a dry granular roughening. There may be evidence of organisation &
fibrosis in the pericardium.
• Purulent/suppurative. This is caused by infective organisms invading the pericardial
space. It commonly occurs secondary to bacterial infection. This is exaggerated in an
immunosuppressed individual. Morphologically, the pericardium is inflammated &
purulent, and there is organisation with development of constrictive pericarditis.
Resolution from this type of pericarditis is rare.
• Haemorrhage. Causes of acute bloody effusions are: trauma, MI, myocardial
rupture, aortic dissection. Other causes include TB, malignancy and bacterial
infection.

Clinical presentation

Pericardial effusions may be asymptomatic or similar to acute pericarditis. Patients develop

chest pain, and this is associated with dyspnoea & cough. On examination you will find:

• Raised JVP with dominant x-descent.

• Low-volume pulse, with increased pulse pressure.
• Obscure apex beat.
• Muffled heart sounds on auscultation. There may be a pericardial rub.
• Dullness to percussion below the angle of the scapula, as well as bronchial breathing.
This is called Ewart’s sign and is due to compression of the left lung base.

The features of cardiac tamponade are important and should be picked on examination. The
triad of symptoms (Beck’s triad) is:

• Hypotension.
• Raised JVP, with a sharp rise & y-descent. This is called Friedreich’s sign. There is also
a Kussmaul’s sign, which is a rise in JVP or neck vein distension during inspiration.
• Muffled heart sounds.

There is also pulsus paradoxus.

Investigations

The investigations done are:

• ECG. You can get low-voltage QRS complexes, flattened T-waves and electrical
alternans (alternating QRS morphologies). There may also be sinus tachycardia.
• Chest X-ray. This will show cardiomegaly with a rounded cardiac contour. The
pulmonary veins are not distended.

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 • Echocardiography. This is the most useful tool for detecting an effusion. The
evidence of tamponade on an echo is as follows:
o Late diastolic collapse of right atrium.
o Early diastolic collapse of right ventricle.
o Ventricular septal displacement into left ventricle during inspiration.
o Diastolic flow reversal into hepatic veins during expiration.
o Dilated inferior vena cava with <50% reduction during inspiration.
• CT/MRI. This is considered if loculated pericardial effusions are suspected.
• Pericardiocentesis. This is done when a TB, malignant or purulent effusion is
suspected. The pericardial fluid needs to be sent for microscopy, culture and
sensitivity, and cytology.

Treatment

Most effusions resolve spontaneously. Where necessary, treatment is as follows:

1. The underlying cause should be sought.

2. Pericardiocentesis. This is indicated for large effusions and for cardiac tamponade.
You place a needle at the xiphoid process and direct it towards the angle of the left
scapula at an angle of 45° superolaterally. This is often a measure for acute relief. It
is used for cardiac tamponade. If it is blood, you can tell that is pericardial blood and
not cardia by letting it stand. Pericardial blood does not clot.
3. Pericardial window. This is the insertion of a fenestration in the pericardium that
allows slow release of fluid into surrounding tissues.

You must avoid giving diuretics, as they cause a further decrease in cardiac output. IV fluids
can be given.

Constrictive pericarditis
Constrictive pericarditis is a condition characterised by a rigid pericardium due to fibrosis &
calcification. It usually develops secondary to acute pericarditis. The causes include:

• Idiopathic.
• TB.
• Haemopericardium.
• Bacterial infection.
• Rheumatic heart disease.
• Open heart surgery.
• Drugs, e.g. dopamine agonists (cabergoline, pergolide).
• Radiation.
• Uraemia.
• MI.

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 • Collagen vascular disease.

In most cases, the changes do not cause symptoms or interfere with cardiac function.
However, if the changes interfere with diastolic filling, the pericardium is said to have
constrictive pericarditis.

Clinical features

The clinical features of constrictive pericarditis include:

• Features of right ventricular failure: raised JVP with prominent x- & y-descents,
hepatosplenomegaly, ascites and oedema.
• Features of reduced ventricular filling (similar to cardiac tamponade): Kussmaul’s
sign (engorgement of neck veins during inspiration), Friedrich’s sign (raised JVP with
sharp rise & y descent) and pulsus paradoxus (usually absent).
• Features of left heart failure: dyspnoea, cough, orthopnoea, PND. These are less
common.
• Reduced cardiac output: fatigue, hypotension (although BP is usually normal), reflex
tachycardia.

Patients may have a pericardial knock, which is heard early during diastole at the left lower
sternal border and is due to rapid ventricular filling. 30% of cases have atrial fibrillation.

Investigations

The investigations done are:

• ECG. This shows low-voltage QRS complexes with generalised T-wave flattening or
inversion. There may be atrial fibrillation.
• Chest X-ray. This will reveal a small heart in relation to the ensuing cardiac failure.
Pericardial calcification is present in up to 50% of patients. A lateral X-ray may be
useful in detecting calcifications missed on an anterior film. If there are no
calcifications, an MRI/CT scan will help distinguish this condition from a
cardiomyopathy.
• Echocardiography. This shows a thickened calcified pericardium and small
ventricular cavities with walls of normal thickness. Doppler studies may be useful.

Treatment

The definitive treatment of this condition is complete resection of the pericardium

(pericardiectomy). This is a risky procedure with a high complication rate (due to myocardial
atrophy). Early pericardiectomy is preferred and indicated in non-TB cases before severe
constriction & myocardial atrophy has occurred. In the case of post-TB constrictive
pericarditis, the presence of calcifications implies chronic disease. In these cases, early

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pericardiectomy with anti-TB drugs is indicated. In cases without calcifications, anti-TB
therapy should be attempted first, then pericardiectomy if the condition does not improve.

The prognosis is best with idiopathic & infectious causes, and it is worst with post-radiation
constrictive pericarditis. Death usually occurs due to heart failure.

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 Hypertension
Hypertension is a sustained elevated blood pressure. The precise blood pressure that
defines hypertension will depend on the population in question, as average blood pressures
follow a normal distribution. According to the British Hypertension Society, hypertension is
diagnosed as a systolic blood pressure above 140mm Hg or a diastolic blood pressure above
90mm Hg. The blood pressure value used for definition of hypertension depends on the
blood pressure above which the risk of significant adverse events increases and the benefit
140
of treatment is clear cut. The blood pressure of mm Hg is a clinical value, and is not the
90
same value used for home or for ambulatory monitoring. For home monitoring, the blood
135
pressure value used is mm Hg, while for ambulatory monitoring 24-hour cut-off values
85
125
are above mm Hg.
80

Hypertension affects about 20-30% of the adult population. It predisposes to adverse

vascular events, and the risk increases with a rise in systolic and diastolic blood pressures.

Classification
120
An optimal blood pressure is anything below mm Hg. A systolic blood pressure of 120-
80
129mm Hg or a diastolic blood pressure of 80-84mm Hg is still normal, but not within
optimal range.

• If a patient has a systolic blood pressure of 130-139mm Hg and/or a diastolic of 85-

89mm Hg, the patient has pre-hypertension. This category has been added to reflect
a continuum between normal blood pressures and hypertension.
• If a patient has a systolic blood pressure of 140-159mm Hg and/or a diastolic blood
pressure of 90-99mm Hg, the patient has grade 1/mild hypertension.
• If a patient has a systolic blood pressure of 160-179mm Hg and/or a diastolic blood
pressure of 100-109mm Hg, the patient has grade 2/moderate hypertension.
180
• If a patient has a blood pressure above 110mm Hg, the patient has grade 3/severe
hypertension. Severe hypertension may or may not have end-organ damage. If it has
no end organ damage it is termed hypertensive urgency. It is associated with end-
organ damage (cerebrovascular accident, acute coronary syndrome, etc.), it is
termed hypertensive emergency.
200
• If the patient’s blood pressure rapidly rises above 130mm Hg, it is termed as
malignant hypertension. This usually leads to vascular damage, characterised by
fibrinoid necrosis (a misnomer, as there is no cell death but coagulation of plasma
clotting factors in the tunica media after plasma enters this layer). It can result in

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 rapidly-progressive renal failure (leading to proteinuria and haematuria), heart
failure, aortic dissection and stroke (and hypertensive encephalopathy).

Aetiology
There are 2 types of hypertension: primary/essential hypertension or secondary/non-
essential hypertension.

Primary/essential hypertension accounts for the majority (80-90%) of cases. In these cases,
the precise aetiology is unknown, but there are a variety of risk factors that predispose
individuals to developing hypertension. The suggested risk factors for essential hypertension
are:

• Genetic factors. Family history is a strong predictor of an individual developing

hypertension. This may, however, be explained by the shared environmental
influences.
• Age. The incidence of hypertension increases with age, since the average blood
pressure does so as well.
• Sex. The rise in systolic blood pressure with age is more marked in men than in
women. Therefore, men tend to develop hypertension at a younger age.
• Race. Hypertension is more common in black people (40-45% of the adult
population).
• Alcohol. There is a close relationship between alcohol consumption and blood
pressure levels.
• Obesity. Obesity is associated with a higher risk of hypertension. You should,
however, ensure that you use the correct cuff size. Sleep disordered breathing –
which is associated with obesity – is also an independent risk factor.
• Comorbid conditions. Diabetes is a major risk factor for the development of
hypertension. In some patients, they have hypertension, impaired glucose tolerance,
hyperinsulinaemia, reduced HDL cholesterol levels, hypertriglyceridemia and central
obesity. This has been coined the metabolic syndrome1, and it is a major risk factor
for cardiovascular disease.
• Diet. A high sodium diet has been linked to development of hypertension.
• Foetal factors. A person born with a low birth weight is more likely to develop
hypertension than a person born with a normal birth weight. This may be due to
foetal adaptation to chronic undernutrition in utero, resulting in either long-term
changes in vascular structure or changes in crucial hormonal functions.

Secondary hypertension is that which results from another cause, where the defect is not
intrinsic to the vasculature. Causes of secondary hypertension include:

1
You need at least 3 of the 5 features to diagnose metabolic syndrome.

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 • Renal causes. These account for the majority of secondary causes. 75% of cases are
from intrinsic renal disease, such as glomerulonephritis, polyarteritis nodosa (PAN),
systemic sclerosis, chronic pyelonephritis, adult polycystic kidney disease, chronic
glomerulonephritis, chronic tubulointerstitial nephritis and diabetic nephropathy.
The remaining 25% of causes are from renovascular disease. This mainly entails
atheromatous disease (which is more common in elderly male cigarette smokers) or
fibromuscular dysplasia (young females).
• Cardiac causes. Coarctation of the aorta is the major cardiac cause of secondary
hypertension.
• Endocrine diseases. Endocrine causes include Cushing’s (hypercortisolism), Cohn’s
disease (hyperaldosteronism), phaeochromocytoma (epinephrine-producing
tumour), acromegaly (GH excess), hyperparathyroidism (excess PTH, leading to
excess calcium) and hyperthyroidism (excessive T3 & T4).
• Drugs. Oral contraceptives, NSAIDs, steroids, MAO inhibitors (with tyramine),
vasopressin, sympathomimetics and liquorice.
• Pregnancy. Hypertensive disease of pregnancy is a separate entity with a different
pathophysiology to non-gestational hypertension. It therefore has a different
management. However, it is a risk factor for development of essential hypertension
in the future.

Pathophysiology
The precise pathophysiology is unknown. However, in some young patients there is an
increase in cardiac output associated with an increase in pulse rate and increased
catecholamine levels in the circulation. These are known to decrease baroreceptor
sensitivity, allowing it to tolerate higher pressures.

There are many changes in various systems that occur in hypertension:

• Cardiovascular changes. The cardiovascular changes include:

o Increased peripheral resistance. In hypertension, the small arteries &
arterioles (which are primarily resistance vessels) develop thicker walls and
reduced luminal diameter, leading to increased resistance. This occurs
against a normal cardiac output. There is also reduced vessel density (called
rarefaction), meaning that they have a reduced parallel arrangement that
also aids in reducing resistance.
o Thickening of large vessels. This is due to an increase in the thickness of the
tunica media, an increase in collagen (which is less distensible) and secondary
deposition of calcium. These lead to a loss of arterial compliance, which leads
to large blood pressures being transmitted to smaller vessels.
o Increased pulse wave velocity. The increased pulse wave velocity is due to
increased stiffness of the arteries: a pulse wave moves faster in a stiff vessel.

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 This exerts mechanical stress on the vessel, which interacts with low growth
factors and predisposes to atheroma formation.
o Left ventricular hypertrophy. This is due to the increased afterload increasing
the work of the heart.
• Renal changes. Changes in renal vasculature result in reduced renal perfusion, which
increases renin, angiotensin and aldosterone levels. This leads to sodium & water
retention, and increases the circulating blood volume. In black people, the
hypertension is usually a low-renin, high-fluid hypertension, while in white people
the hypertension is a high-renin, low-fluid hypertension.

Clinical approach to a person with suspected hypertension

The majority of patients with hypertension are asymptomatic. Headaches are no more
common than in the general population. When you meet a person with elevated blood
pressures, always rule out secondary causes, particularly in young individuals.

• Ask about signs of sympathetic overdrive. This may reflect an underlying

phaeochromocytoma, particularly when there is a very high blood pressure.
• Look for features of renal disease: oedema, haematuria, proteinuria, renal bruits
• Look for features of coarctation of the aorta: radiofemoral delay, weak femoral
pulses. The cardiovascular examination may include features of left ventricular
hypertrophy. Also look for signs of cardiac failure.
• Look for features of endocrine diseases.
• Features of malignant hypertension: severe headaches, visual disturbances, fits,
transient loss of consciousness and symptoms of heart failure.

Diagnosing hypertension
When you meet a patient with suspected hypertension, you take their blood pressure while
they are seated. This should be done after the patient has rested for 5 minutes. The
standing blood pressure should be taken in patients who are diabetic and in elderly subjects
140
to rule out orthostatic hypotension. If their blood pressure is below mm Hg, there is no
90
need to refer for treatment. You should, however, encourage the patient to have their
blood pressure monitored routinely at least every 5 years up to the age of 80.
140
If the clinical blood pressure is above mm Hg, you offer ambulatory blood pressure
90
monitoring, since you want to rule out white collar hypertension. White collar hypertension
refers to blood pressures that rise to hypertensive ranges only after clinical visits. Therefore,
you attach an ambulatory pressure monitoring machine and take blood pressure recordings
over 24 hours. In these patients, hypertension is diagnosed by an ambulatory blood

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 125
pressure reading of above mm Hg. These patients have stage 1 hypertension. If the
80
150
ambulatory blood pressure is above mm Hg, the patient has type 2 hypertension.
95

180
If the clinical blood pressure is above 110mm Hg, the patient needs to be started on an
antihypertensive drug immediately, referred and be put on ambulatory blood pressure
monitoring. The blood pressure parameters for 24-hour ambulatory blood pressure remain
the same.

Work-up for hypertensive patient

The work-up for a patient who has been diagnosed with hypertension is as follows:

• Fasting blood glucose & fasting lipid profile. This is to screen for diabetes &
dyslipidaemias.
• ECG. ECGs are done to look for left ventricular hypertrophy and to look for
arrhythmias or past MIs.
• Urinalysis. This may help identify renal disease. Look for proteinuria and haematuria,
and assess renal function. Suspicion of phaeochromocytoma should be followed by
measurement of urinary metanephrines and plasma/urinary catecholamines.
• Urea & electrolytes. If urea & creatinine are both elevated, conduct more specific
renal studies, such as creatinine clearance, renal ultrasound and/or renal isotope
scan or angiography. Low serum potassium may indicate an endocrine disease, and
in this case you need to measure, aldosterone, cortisol and renin levels.
• Echocardiography. This is done when left ventricular hypertrophy or coarctation of
the aorta is suspected.
• MRI. This is done if coarctation of the aorta is suspected.

Management of hypertension
Unless the patient is in the malignant phase of hypertension, there should be a period of
reassessment of the patient with repeated blood pressure measurements together with
advice & non-pharmacological interventions. Treatment is often commenced if blood
160
pressures remain elevated above mm Hg over 4-12 weeks, or if the blood pressure
100
140
remains above mm Hg in a patient with an estimated 10-year cardiovascular risk over
90
20%. However, if there are cardiovascular complications, target organ damage (e.g. stroke,
MI, peripheral vascular disease, renal disease) or diabetes mellitus, start treatment over 1-2
weeks regardless of blood pressure.

The goals of treatment are:

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 140
• To maintain clinical blood pressure below mm Hg. The target for diabetic patients
90
130 10
is mm Hg. For ambulatory blood pressure, the targets are mm Hg lower than
80 5
the clinical targets. Blood pressure should not be reduced too quickly, as this could
be fatal.
• To prevent development of complications.
• To optimise treatment of diabetes, where applicable.

These targets should be explained to the patient prior to treatment.

Lifestyle modification

Lifestyle modification is used for patients in the initial phase in order to reduce blood
pressures non-pharmacologically. The lifestyle interventions are:

• Controlling body weight. Body weight needs to be maintained within physiologic

levels. The target BMI is 20-25kg/m2.
• Exercise. Patients should engage in aerobic exercises. They should engage in a brisk
walk for at least 30 minutes on 4 or more days every week.
• Diet. Fat & saturated fat intake should be reduced. Salt intake should be restricted to
less than 100mmol per day (which is less than 6g NaCl, or 4.2g Na). They should take
more than 5 portions of fresh fruit & vegetables every day. They should also increase
their oily fish intake.
• Smoking & alcohol. Patients should stop smoking as it increases their cardiovascular
risk. They should also limit their alcohol intake to less than 3 units per day in males
and less than 2 units per day in females.

Pharmacological treatment

The drugs used in hypertension are abbreviated using ABCD:

• A – Angiotensin inhibitors. These drugs act by reducing plasma angiotensin II

activity, thus diminishing its vasoconstrictive effects and its effects on stimulating
secretion of aldosterone. They can be either ACE inhibitors or AT1-receptor
antagonists.
o ACE inhibitors work by inhibiting ACE (angiotensin-converting enzyme), thus
preventing conversion of angiotensin I to angiotensin II. This enzyme,
however, is also responsible for breaking down bradykinin, and therefore
inhibition of this enzyme leads to elevated bradykinin levels which induce a
cough. Examples of ACE inhibitors include captopril, enalapril (5-40mg once
daily), lisinopril (5-40mg once daily). Side effects include 1st-dose

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 hypotension, renal dysfunction in patients with bilateral renal artery stenosis 2
and a mild dry cough.
o AT1-receptor antagonists are similar to ACE inhibitors, but they do not cause
cough. They also cause less angioneurotic oedema and renal dysfunction.
Examples of AT1-receptor antagonists are losartan (25-100mg 1-2 times
daily), valsartan (40-320mg) and candesartan (2-32mg).
• B – β-blockers. These work by attenuating the effects of the sympathetic nervous
system & the RAAS system, thus reducing peripheral resistance. These are not used
as 1st-line therapy any more. They are, however, useful in younger patients with
intolerance to ACE inhibitors or in whom angiotensin inhibitors are contraindicated,
and in patients with evidence of increased sympathetic drive. They should be used
with caution in patients on thiazide diuretics, as they increase the likelihood of
developing diabetes. Atenolol (25-100mg once daily) is the main drug used to treat
hypertension. The major side effects are bradycardia, bronchospasm, cold
extremities, fatigue and bad dreams & hallucinations.
• C – Calcium channel blockers. The calcium channel blockers used are
dihydropyridine blockers. Examples of calcium channel blockers include nifedipine
(10-40mg 1-2 times daily) and amlodipine (5-10mg once daily). These drugs work by
inducing arteriolar vasodilation and reducing the contractile force of the heart. They
are useful in patients with concomitant ischemic heart disease.
• D - Diuretics. These work by reducing fluid volume, thus leading to reduced pressure
exertion by intravascular fluid. they can either be thiazide diuretics or loop diuretics.
o Thiazide diuretics have been shown to reduce risk of stroke in hypertensive
patients. They are useful as 1st-line therapy. They are, however, not useful in
patients with an eGFR of less than 30ml/min. side effects include
hypercholesterolaemia, impaired glucose tolerance, hyperuricaemia,
hypokalaemia, hyponatraemia and impotence. Chlorthalidone (25-50mg once
daily) is the drug of choice, but in Zimbabwe most patients take
hydrochlorothiazide (12.5-25mg once daily).
o Loop diuretics have hypotensive effects, but are not routinely used to treat
essential hypertension. They are used in the setting of renal or cardiac
failure. An example is furosemide (40-80mg daily)
o Aldosterone antagonists such as spironolactone (50-400mg daily) &
eplerenone (50-100mg daily) are also useful in combination treatment of
hypertension, and they reduce the risk of hypokalaemia. Spironolactone can
be used alone in treating hyperaldosteronism.
Diuretic therapy is useful in black people because they have low-renin, high fluid
hypertensions and therefore respond better to diuretics.

2
ACE inhibitors are normally reno-protective, because they relax the efferent arterioles and reduce the hyper-
filtration that leads to progressive deterioration in chronic renal disease. however, they also impair renal
autoregulation, and this is a problem in patients with bilateral renovascular disease

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Other drugs include:

• A-receptor inhibitors. These drugs inhibit activation of vascular smooth muscle by

the sympathetic nervous system, leading to vasodilation. Examples include prazosin
(0.5-5mg 2-3 times daily), doxazosin (4-16mg once daily), phenoxybenzamine and
phentolamine. The earlier short-acting agents (e.g. prazosin) cause 1st-dose
hypotension. The newer long-acting agents (e.g. doxazosin) are tolerated better. A-
blockers are also useful for patients with benign prostatic hypertrophy and patients
with phaeochromocytoma crisis.
• Vasodilators. Examples of vasodilators include hydralazine, minoxidil and sodium
nitroprusside.

The choice of drug depends on the age of the patient and the race. Generally the first-line
agents used in hypertension are: angiotensin inhibitors (ACE-inhibitors & AT1-receptors
antagonists), calcium-channel blockers and diuretics (thiazides). In younger (less than 55
years of age) Caucasian individuals, the first choice is usually an angiotensin blocker due to
the high plasma angiotensin levels in these people. However, in older Caucasians and in
black people, you start with calcium channel blockers or diuretics because in older
Caucasians renin levels drop and in black people renin levels are low while fluid levels are
high.

Pharmacologic therapy is commenced in a step-wise approach:

1. Step 1 involves using an angiotensin inhibitor, calcium channel blocker or diuretic.

2. In step 2, you combine an angiotensin inhibitor with either a calcium channel blocker
or a diuretic.
3. In step 3, you combine all 3 drugs.

After this, you add a β-blocker, α-blocker or other diuretic. By this time, a specialist should
be sought.

Management of severe hypertension

Severe hypertension is defined as a systolic blood pressure above 200mg Hg or a diastolic

blood pressure above 120mm Hg (hypertensive urgency). These patients must be admitted
into hospital for immediate initiation of treatment. However, do not reduce blood pressure
too rapidly as this may precipitate cerebral, myocardial, renal and retinal infarction. The
target diastolic blood pressure is 100-110mm Hg.

The indications for emergency treatment in hypertension (hypertensive emergency) are:

• Left ventricular failure with pulmonary oedema.

• Hypertensive encephalopathy.
• Acute aortic dissection.

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 • Severe pre-eclampsia.
• Recent stroke.

The drugs used in both hypertensive urgency and hypertensive emergency are:

• Labetalol 20mg IV infusion stat over 2 minutes, then 10-80mg IV infusion every 10
minutes until the desired blood pressure is attained. You can also give 2mg per
minute through continuous intravenous infusion.
• Hydralazine 6.25-25mg PRN until desired blood pressure is attained.

In patients with encephalopathy or stroke, the target blood pressure should be attained
over 4 hours.

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Coronary artery disease (CAD)
Coronary artery disease refers to a spectrum of diseases of the coronary vasculature that
result in myocardial ischemia. It is due to an imbalance between oxygen/blood supply and
oxygen demand in tissues. Conditions that cause coronary artery disease include:

Mechanical obstruction: Decreased flow of oxygenated Increased oxygen

• Atheroma blood: demand:
(atherosclerosis). • Anaemia. • Hypertrophy from
• Thrombosis. • Carboxy- any cause (e.g.
• Embolus. haemoglobinaemia. hypertension,
• Spasm. • Hypotension (decreased HOCM).
• Coronary ostial coronary perfusion • Increased cardiac
stenosis. pressure) activity (e.g. drug-
• Coronary arteritis, e.g. induced,
SLE. hyperthyroidism).
Coronary artery disease is the single leading cause of death in the UK & many parts of the
developed world. In 2009, 1 in 5 deaths in males & 1 in 8 deaths in females were
attributable to acute coronary syndrome.

Coronary artery syndrome is characterised by dull retrosternal chest pain with various
characteristics. The relation of the chest pain to exertion & rest is important in determining
the type of condition being experienced.

Development of atherosclerosis
In the majority of cases of coronary artery disease, atherosclerosis is the underlying cause.
This is a slow progressive degenerative process which involves gradual obstruction of the
arterial lumen by an atheroma. This atheroma is formed from lipids, macrophages and
smooth muscle, and atheromas predominantly occur in large- & medium-sized blood
vessels.

The process of atheroma formation is as follows:

1. Vascular injury. Chronic vascular injury plays a critical role in the initiation of
atheroma. This can come about by mechanical shear stress (e.g. morbid
hypertension), biochemical abnormalities (elevated cholesterol, diabetes mellitus),
immunologic factors (e.g. free radicals from smoking) and inflammation (infections –
C. pneumoniae). The vascular endothelium is responsible for homoestasis, and
therefore disturbance in the endothelium predisposes to atheroma. Endothelial
injury leads to increased permeability, leukocyte adhesion and thrombosis. However,

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 early human atherosclerotic lesions begin at the site of intact but dysfunctional
endothelium.
2. Cellular migration. The dysfunctional endothelial cells express adhesion molecules
that lead to leukocyte activation. These include VCAM-1 (vascular cell adhesion
molecule), which binds T-cells & monocytes. After this binding the cells migrate into
the intima. Monocytes transform into macrophages, which are activated and thus
contribute to intimal inflammation. T-cells also contribute to the state of chronic
inflammation.
3. Accumulation of lipoproteins. The predominant lipoproteins that accumulate are
oxidised LDL and cholesterol crystals. LDL is oxidised by the oxygen free radicals that
are released by the macrophages.
4. Formation of foam cells. Foam cells are formed by macrophages that engulf oxidised
LDLs & cholesterol crystals. This leads to the local release of growth factors,
cytokines and chemokines. This increases monocyte recruitment and is cytotoxic to
endothelial & smooth muscle cells.
5. Smooth muscle cell recruitment & proliferation. The early lesion formed is a fat
streak. Fatty streaks are just composed of foam cells that are only slightly raised and
do not cause flow disturbance. This later transforms into a mature atheroma
through intimal smooth muscle cell proliferation & ECM deposition. This process
heralds the progressive growth of the atheroma. The intimal smooth muscle cells are
distinct from those in the tunica media. Several growth factors are implicated: PDGF,
FGF and TGF-α. The recruited smooth muscle cells synthesise ECM which stabilised
the plaque. However, activated inflammatory cells also cause smooth muscle cell
apoptosis & breakdown of matrix, leading to development of unstable plaques.
Atheromatous plaques have 3 principal components: cells (smooth muscle cells,
macrophages and T-cells), ECM (collagen, elastic fibres and proteoglycans) and lipid
(intracellular & extracellular). Atheromas are covered by fibrous caps.

A 50% reduction in luminal diameter causes haemodynamically-significant stenosis.

Risk factors
The risk factors for coronary artery disease are divided into modifiable and non-modifiable.
The non-modifiable risk factors are:

• Age. Coronary artery disease increases with age. It is rare in childhood, except in
familial hyperlipidaemias. Atheromatous lesions in the elderly are often
accompanied by calcification.
• Gender. Men have a higher incidence of coronary artery disease than
premenopausal women. After menopause, however, the incidence of coronary
artery disease approaches that of men. This is thought to be due to the loss of the
protective effect of oestrogen.

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 • Family history. CAD is found in members of the same family. It is generally accepted
as being significant if a 1st-degree relative develops the condition before 50 years of
age.

The modifiable risk factors are:

• Smoking. The risk of developing CAD is directly related to the number of cigarettes
smoked per day. 20% of deaths in men & 17% in women are attributable to smoking.
Stopping smoking actually decreases the cardiovascular risk, such that after 10 years
the risk declines to normal.
• Diet. Diets that are high in fats with low antioxidant levels1 are associated with
increased incidence of ischemic heart disease. It is estimated that up to 30% of cases
of CAD are attributable to the diet. Beneficial dietary changes include reduction in
fats, reduction in salt intake, an increase in carbohydrates, and an increase in fruit &
vegetable intake by 50%.
• Weight. 5% of deaths in men and 6% of deaths in women are due to obesity (BMI of
greater than 30kg/m2). The adverse effects of weight gain are more significant when
the weight is mostly concentrated in the abdomen (central obesity).
• Exercise. Reducing weight by diet & exercise reduces incidence of coronary artery
disease as well as insulin resistance. The physical activity needs to be regular &
aerobic. Adults must participate in a minimum of 30 minutes a day at least 5-times a
week.
• Hypertension. Both systolic & diastolic hypertension is associated with an increased
risk. Drug treatment & lifestyle modification can effectively lower cardiovascular risk.
• Hyperlipidaemia. High LDL & low HDL cholesterol are associated with increased
cardiovascular risk. Familial hypercholesterolaemia is associated. All patients at risk
of cardiovascular disease should have their fasting lipid profile taken. A cholesterol
target of less than 5.0mM is suggested for prevention of CAD.
• Diabetes mellitus. Diabetes substantially increases the risk of CAD. Men with type 2
diabetes have 2-4 fold increased risk of CAD.
• Alcohol. Moderate alcohol intake is associated with low risk of CAD. Excessive intake,
however, is associated with increased risk.
• Drugs. Some drugs, such as corticosteroids, increase the risk of atherosclerosis.

Spectrum of diseases
The spectrum of diseases constituting coronary artery disease occurs on a continuum:

1
Supplementation with antioxidants has been shown to be unhelpful.

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 Stable Unstable
NSTEMI STEMI
angina angina

Unstable angina, NSTEMI and STEMI all make up a clinical entity called acute coronary
syndrome.

Stable angina

Stable angina (also known as classical/exertional angina) is a condition that results from
temporary ischemia that develops when there is increased activity by the heart. It is
characterised by typical chest pain: central/retrosternal chest pain that is precipitated by
exertion and relieved by rest. At times the chest pain is atypical, in which case there are only
2 of the 3 features. Stable angina is caused by the presence of an atheroma in the coronary
circulation, causing ischemia when the oxygen demand of the heart rises (such as during
exercise). There is usually no progression of the chest pain symptoms as well as frequency &
severity of attacks.

Acute coronary syndrome (ACS)

Acute coronary syndrome is characterised by worsening frequency & severity of symptoms,

often experienced at rest. The 3 entities that constitute ACS are:

• Unstable angina. This is a sharp chest pain that occurs at rest resulting from
ischemia, but is not due to myocardial infarction.
• Non-ST elevation myocardial infarction (NSTEMI). In this condition, there is
evidence of myocardial necrosis (MI) but the ST segment is not elevated. Other
features are present instead: ST segment depression, T-wave inversion or a normal
tracing.
• ST elevation myocardial infarction (STEMI). This is a myocardial infarction in which
the ST segment is elevated. There may also be a new-onset LBBB (left bundle branch
block)

The common mechanism for ACS is rupture or erosion of the fibrous cap of the coronary
artery plaque. This leads to initiation of thrombosis in the vessel which leads to total
occlusion of the blood vessel. The risk of rupture of a plaque depends on the presence of a
rich lipid pool within the plaque and a thin fibrous cap. After occlusion of the supplying
blood vessel, myocardial necrosis can occur within 15-30 minutes. The sub-endocardium is
initially affected, but with continued ischemia this extends to the sub-epicardium, thus
producing Q-waves.

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Other mechanisms by which myocardial infarctions can occur include: increased oxygen
demand (as in arrhythmias, hypertension, hypertrophy from other causes) and decreased
supply (embolism, hypotension, coronary artery spasm, anaemia).

Other types of disease

Other types of coronary disease include:

• Variable/Prinzmetal angina. This is an episodic type of angina caused by coronary

artery spasms. It is common in women, and there is ST segment elevation during the
pain.
• Cardiac syndrome X. This refers to patients with a good history of angina and a
positive stress test, but with an angiography result demonstrating normal coronary
arteries. It is thought to be caused by small vessel disease, such that grossly the
heart appears normal.

Clinical presentation
The presentation of patients with coronary artery disease is as follows:

History

The history that is important is that of retrosternal chest pain that radiates to the left axilla,
shoulder, neck and jaw and sometimes to the epigastrium. The features are the ones that
differ:

• In angina, the pain is typical – it is precipitated by exertion and relieved by rest or

nitrates. Other precipitants include: after meals, cold windy weather, anger and
excitement.
• In ACS, patients may complain of new-onset chest pain, chest pain at rest, and
deterioration of pre-existing stable angina. The pain also does not respond to
nitrates, particularly STEMI. Some patients with STEMI present with atypical
features: indigestion, pleuritic chest pain, and dyspnoea. This is more common in
diabetic & elderly patients. There may also be syncope. MIs can also precipitate
decompensated heart failure.

Examination

On examination, the features:

• In stable angina, there is usually no prominent physical examination feature, apart

from an occasional 4th heart sound (S4). It is important to exclude aortic stenosis –
harsh mid-systolic murmur over the aortic area radiating to the carotids. You may
find signs suggestive of anaemia, thyrotoxicosis or hyperlipidaemia.

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 • In ACS, the patient may have autonomic signs: clammy hands, pallor and marked
sweating. You may detect other diagnoses, such as aortic dissection, pulmonary
embolism or peptic ulceration.

Ensure that you measure the patient’s blood pressure.

Investigations

The investigations done for a patient who presents with acute retrosternal chest pain are as
follows:

• ECG. The ECG findings differ according to the type of disease:

o In stable angina, you do a non-stress and stress ECG2. This is done to exclude
ACS. In between attacks, the ECG is usually normal but may include signs of
old MIs, left ventricular hypertrophy and left bundle branch block. During
attacks, the ECG may also be normal, otherwise you can get ST segment
depression, flat T-waves or T-wave inversion.
o In ACS, ST depression & T-wave inversion are highly suggestive of an ACS
particularly when there is angina chest pain. The ECG should be repeated
when the patient is in pain. In STEMI, there is ST segment elevation
with/without LBBB. The ECG may also be normal in individuals with MI,
particularly in NSTEMI & unstable angina. The ECG changes usually occur in
the leads that face the infarction.
• Cardiac enzymes. The cardiac enzymes are used to indicate presence or absence of
myocardial necrosis. The cardiac enzymes that are measured are:
o Cardiac troponin complex. This includes troponin I, C and T. Cardiac troponins
are normally undetectable, so you can do antibody-based tests to detect
troponin I & T – these are highly sensitive markers. The troponin levels begin
to rise 3-12 hours after onset of chest pain, peak at 24-48 hours and return to
baseline after 5-14 days3. The serum troponin levels are also important for
prognostication.
o Creatinine kinase-MB. CK-MB used to be the standard marker for myocytes
death in ACS. It has since been superseded by the cardiac troponins. CK-MB
levels rise after 3-12 hours, reach peak at 24 hours and return to baseline
after 48-72 hours. Levels peak earlier if reperfusion occurs.
o Myoglobin. This can be used for rapid diagnosis of ACS as levels are elevated
very early in the course of an MI (1-4 hours after the chest pain). However,
the test has poor specificity.
• Echocardiography. Transthoracic echocardiography is beneficial in patients with
STEMI, as wall-motion abnormalities occur early during a STEMI.

2
Stress ECG, however, has a sensitivity of 67% & specificity of 72%.
3
If the initial troponin assay is negative it should be repeated 6-12 hours after admission.

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 • Chest X-ray. On a chest X-ray, you may see cardiomegaly, pulmonary oedema, or a
widened mediastinum (indicating aortic rupture).
• Other imaging modalities. These include:
o Coronary angiography. This is a contrast radiologic investigation that is done
to visualise the location of the obstruction. It is done in theatre during
intervention, such as percutaneous coronary intervention (PCI). You can also
do CT coronary angiography, which does not need to be done in theatre.
o Functional testing. You can do single positron-emission computed
tomography (SPECT), stress-echocardiography or stress-MRI.
• Blood investigations. These include FBC, U&Es, LFTs, lipid profile and RBS.

The UK NICE guidelines recommend assessing the likelihood of coronary artery disease in
order to determine choice of diagnostic method & intervention. The likelihood depends on
the risk stratification of the patient in terms of:

• High & low risk stratification based on the presence of any of: diabetes, smoking,
hyperlipidaemia (total cholesterol > 6.47mM).
• Sex. Males have higher risk.
• Type of chest pain: non-anginal, atypical anginal or typical angina.

The likelihood is expressed as a percentage. If a patient has known CAD and has typical pain,
no further investigations are indicated. However, if the pain is atypical, you can do exercise
testing or functional imaging.

If a patient has unknown CAD, then you use the patient’s likelihood percentages:

>90% Treat as known CAD

61-90% Cardiac catheterization & angiography or functional imaging if
appropriate.
30-60% Functional testing: SPECT, stress-echocardiography, stress-MRI
10-29% CT coronary angiography with coronary artery calcification
score.
<10% or non-anginal chest Consider alternate diagnosis.
pain
These guidelines do not recommend stress-ECG as a diagnostic test.

Management of CAD
The management of CAD depends on the patient’s presentation:

Stable angina

Patients should be informed of their condition, and that the mortality from disease is low
(<2%). The patient is managed as follows:

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 • Modify risk factors. The patient should stop smoking, start exercising and lose
weight. Control hypertension & diabetes mellitus. Underlying problems (e.g.
anaemia & hyperthyroidism) should be managed.
• Secondary prevention. In secondary prevention, you are preventing development of
overt ACS by giving agents that minimise progression to ACS. You can use: aspirin 75-
150mg daily, ACE inhibitor (e.g. enalapril) and statins. Aspirin is an antiplatelet drug
and it reduces mortality by 34%. ACE inhibitors are useful to use when treating other
conditions, such as hypertension, heart failure and chronic kidney disease. Statins
can be used to reduce total cholesterol to below 4mM and LDL-cholesterol to below
2mM.
• Vasodilators. Vasodilators are used for acute episodes. We mostly prescribe nitrates
to relieve episodes. Nitrates work by releasing nitric oxide which induces
vasodilation in the coronary circulation and improve circulation during an attack. You
can give glyceryl trinitrate 0.3-1.0mg sublingually or 2-3mg bucally. You can also take
glyceryl trinitrate before activities known to precipitate attacks.
• Prophylaxis against attacks. For prophylaxis, you can use calcium channel blockers
or β-blockers. The calcium channel blockers used are: amlodipine 5-10mg once daily;
verapamil 80-120mg tds; and diltiazem 60-120mg tds. The β-blockers you can use
are: atenolol 25-100mg daily; bisoprolol 2.5-10mg daily; and metoprolol 25-100mg 2-
3 times daily. Calcium-channel blockers & β-blockers both have the effect of
reducing the work of the heart. Calcium channel blockers have the added advantage
of reducing peripheral vascular resistance. In patients intolerant to both drugs, you
can use isosorbide mononitrate 20-40mg twice daily is used for prophylaxis against
attacks.
• Other drugs. Other 2nd-line drugs include ivabradine (selective funny channel
inhibitor), nicorandil (potassium channel agonist), ranolazine (late sodium channel
inhibitor) and trimetazidine. They can be used when calcium-channel blockers & β-
blockers are not tolerated. Ivabradine or ranolazine can also be used in combination
with β-blocker to optimise control when β-blockers are failing on their own.
• Revascularisation. This is a procedure in which you restore flow through the
coronary circulation. This can be done in 2 main ways:
o Percutaneous coronary intervention (PCI). This includes percutaneous
coronary transluminal angioplasty4. In PCI, you dilate the coronary artery at
the point of stenosis using a balloon and then you place a stent to hold the
artery open. A discrete soft lesion that does not involve a bifurcation has the
best outcome. Unfavourable vessels include: occluded vessels; calcified
stenoses; tortuous & long vessels; and vessels involving a bifurcation.
Complications include re-stenosis, emergency CABG, MI, stroke, and death.

4
NICE recommends that >70% of angioplasties be accompanied by stenting.

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 Thrombosis is reduced by concurrently using heparin/bivalirudin5 with
antiplatelet drugs. Different stents are in use. They include the Cypher stent
(contains sirolimus, an immunosuppressant – reduces cellular proliferation),
Xience stent (everolimus; a derivative of sirolimus – works the same way)
and Taxus stent (contains paclitaxel, which inhibitis neo-intima formation).
o Coronary artery bypass grafting (CABG). In this procedure, autologous vessels
are anastomosed to the ascending aorta and the native coronary arteries
distal to the obstruction. You can use the internal mammary artery or
gastroepiploic artery. Operative mortality is well below 1% in patients with
good left ventricular function. This procedure is more invasive but is
associated with reduced need for revascularisation than PCI.

Some patients remain symptomatic even after all these interventions. These patients need
enrolment into a pain management program.

Management of unstable angina & NSTEMI

These patients must be managed as a medical emergency, but they are managed medically
until symptoms settle. You need to also take a brief history & examination, and then take an
ECG during pain.

1. Oxygen. You give oxygen if SaO2 is less than 90%, if there is pulmonary oedema, or
continuing myocardial ischemia. Hyperoxia should be avoided.
2. Nitrates. Nitrates are used to relieve pain. You can give 0.5mg glyceryl nitrate
sublingually as required.
3. Morphine. This is given if the pain does not resolve with nitrates alone.
4. Aspirin. You give 75-150mg once daily. You also add another antiplatelet agent, such
as clopidogrel, prasugrel and ticagrelor.
5. Oral β-blocker. These drugs reduce myocardial ischemia by inhibiting circulating
catecholamines. You can give atenolol 25-100mg once daily or metoprolol 50mg
twice daily. If this is contraindicated (e.g. in asthma, COPD, left ventricular failure,
bradycardia or coronary spasm) you can give non-dihydropyridine calcium channel
blockers.
6. Anticoagulation. You give fondaparinux 2.5mg once daily subcutaneously, or LMW
heparin 1mg/kg twice daily subcutaneously. You can also use rivaroxaban.

After doing this, the next phase of management depends on whether the patient is a high-
risk patient or not:

High-risk Low-risk
Criteria: Criteria:
• Rise in troponin • No recurrence of chest pain.

5
Bivalirudin is a direct thrombin inhibitor.

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 • Dynamic ST segment or T-wave changes. • No signs of heart failure.
• Secondary criteria – diabetes, CKD, ejection • Normal ECG tracing.
fraction <40%, early angina post MI, recent • Negative baseline and 6-9
PCI, prior CABG, intermediate- to high-risk hour troponin.
GRACE score. • No inducible ischemia.

Invasive strategy Conservative strategy

Infuse a glycoprotein IIb/IIIa antagonist and refer for The patient may be discharged if
angioplasty as an inpatient6. The urgency depends on the repeat troponin test comes
the risk stratification of the patient: back negative. Treat medically and
• If the patient has: on-going angina despite arrange repeat testing (e.g. stress
treatment, has evolving ST segment changes, test or angiogram).
has signs of cardiogenic shock, or has life-
threatening arrhythmias, treatment needs to
be urgent.
• If the GRACE score is greater than 140 and the
patient is a high-risk patient, the patient needs
early treatment (within 24 hours).
• If the patient is a low-risk patient, you can
delay treatment a little (should be done within
72 hours).

Management of STEMI

Management of STEMI entails supportive management (oxygen, morphine for pain and
nitrates), promoting reperfusion (aspirin, PCI and thrombolytics) and to reduce re-occlusion
& embolization (anticoagulants). Ultimately, the aim is to reduce mortality. In the initial
phases, these patients are also managed as a medical emergency. In these patients you take
a brief history, do a quick general examination and take a 12-lead ECG. On admission you
take bloods for U&Es, FBC, troponin, lipid profile and glucose, and you order a chest X-ray.

1. Oxygen. Oxygen should be given if there is evidence of hypoxia: SaO2<95%, patient is

breathless or in acute left ventricular failure (pulmonary oedema). It is also given to
patients with continuing myocardial ischemia. Care should be taken in patients with
COPD (the target SaO2 should be lower – 89-92%7).
2. Aspirin. Give aspirin 300mg po stat if it has not been given. You can consider
clopidogrel, prasugrel, ticagrelor as alternative antiplatelet agents.
3. Morphine. Give 5-10mg intravenously, and repeat after 5 minutes if necessary. you
can also give diamorphine 2.5-5mg as an alternative. Also give an antiemetic with
the first dose: metoclopramide 10mg iv or cyclizine8 50mg iv.

6
This is done within 72 hours of onset of symptoms.
7
This low saturation helps maintain the hypoxic drive which keeps these patients alive.
8
This should not be given if there is left ventricular failure.

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 4. Glyceryl trinitrate. Glyceryl trinate is used to relieve ischemic pain. It is not
recommended unless the patient has left ventricular failure or is hypertensive. You
give sublingual glyceryl trinitrate 0.3-1mg stat and repeat as required.
5. B-blocker. Early administration of these agents has been shown to be of benefit, and
should be given if there are no contraindications.
6. Restoring perfusion. This can be done medically or endoscopically:
o Thrombolysis. Thrombolysis is indicated for: STEMI, LBBB and posterior
changes (deep ST depression & tall R waves in V1-V3. This can be achieved
using streptokinase/urokinase 1.2MU in 1L normal saline or 5% dextrose run
over an hour. Alternatively, you can give recombinant tissue plasminogen
activators (alteplase, reteplase and tenecteplase). The target time is less than
30 minutes from admission (as this is associated with better survival) and it is
contraindicated after 24 hours. Alteplase should be followed by
unfractionated heparin. The contraindications are:

Absolute contraindications: Relative contraindications:

• Haemorrhagic stroke/stroke of • TIA in last 6 months.
unknown origin. • Oral anticoagulant therapy.
• Ischemic stroke in preceding 6 • Pregnant or within 1 week
months. postpartum.
• CNS damage/neoplasms. • Non-compressible punctures.
• Recent (within preceeding 3 weeks) • Traumatic resuscitation.
major trauma, surgery or head • Refractory hypertension
injury. (systolic > 180mm Hg).
• GIT bleeding within last month. • Advanced liver disease.
• Known bleeding disorder. • Infective endocarditis
o PCI. PCI performed within 90 minutes of the attack is the preferred
reperfusion therapy intervention. It has a higher reduction in 2-year mortality
than thrombolysis. PCI can also be used after thrombolysis, and it improves 1-
year clinical outcomes. Primary PCI must be accompanied by the use of an
anticoagulant. The preferred agent is bivalirudin, but you can use a
combination of enoxaparin (LMW heparin) & a GPIIb/IIIa inhibitor, such as
tirofiban & eptifibatide.
o Coronary bypass. This is usually reserved for the complications of MI rather
than reperfusion. These complications include VSDs & mitral regurgitation.

For long-term management, you do the following:

• Pharmacologic management: give aspirin (with clopidogrel/warfarin), β-blockers

and non-dihydropyridine calcium channel blockers (verapamil & diltiazem)9. You can
also add an ACE inhibitor or AT1-receptor antagonist.

9
The dihydropyridine drugs (nifedipine, amlodipine, etc.) have no benefit.

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 • Lifestyle modifications. These include stopping smoking, managing pre-existing
diabetes & hypertension and managing diet.

The patient also needs to be informed that they are a life-long patient and that they need
regular checkups to ensure that no other changes are occurring. They are also at risk of
repeat MIs.

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 Heart failure
Heart failure is a condition in which the cardiac output is inadequate to match the body’s
requirements. It can result from a structural or functional disorder. The worldwide
prevalence of the condition varies from country to country. The prevalence, however, is
about 1-3% in general, with over 10% of the elderly being affected. The prognosis of heart
failure is generally poor.

Aetiology
The main causes of heart failure are hypertension, dilated cardiomyopathy, ischemic heart
disease, rheumatic heart disease and congenital heart diseases. The full list of causes
includes:

• Congenital. Some congenital heart disease can cause heart failure, whether early in
life or later on. Common congenital malformations include ASD, VSD and patent
ductus arteriosus. Tetralogy of Fallot is one exception.
• Infections. Infections that cause myocarditis can predispose to heart failure. These
include Coxsackie B virus and Chagas disease. Another infectious cause is infective
endocarditis. Infections causing IE can be bacterial (viridans streptococcal species, S.
aureus, Gram-negative organisms) or fungal (Candida).
• Structural anomalies. These include valvular heart diseases (both stenosis &
regurgitation). Dilated, hypertrophic and restrictive cardiomyopathies also cause
heart failure. Pericardial diseases (constrictive pericarditis & pericardial effusion
and/or tamponade) also cause heart failure.
• Conduction defects. Cardiac arrhythmias can cause heart failure. They include atrial
fibrillation, bradycardia, heart block, supraventricular tachycardia and ventricular
tachycardia.
• Hyperdynamic circulation. These include anaemia, thyrotoxicosis,
haemochromatosis, Paget’s diseases.
• Others. Other causes include diabetes, acute & chronic kidney disease (causing
cardio-renal syndrome), dyslipidaemias and some drugs (e.g. ACE inhibitor & AT 1-
receptor blockers in some patients).

Classification of heart failure

Heart failure is classified as follows:

• Systolic vs. diastolic heart failure. Systolic heart failure is the inability of the heart to
contract normally. This results in a reduced cardiac output from a reduced ejection
fraction (<45%). Conditions that do this are those that destroy the myocardium, such

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 as ischemic heart disease, myocardial infarction and dilated cardiomyopathy.
Diastolic heart failure is the inability of the heart to relax adequately for the
ventricles to fill up. This results in a low end-diastolic volume, meaning that while the
ejection fraction is normal (45-50%, or even higher), the cardiac output will still
remain low. Conditions that prevent relaxation of the heart are constrictive
pericarditis, hypertrophic & restrictive cardiomyopathy, cardiac tamponade and
hypertension. At times, systolic & diastolic failures co-exist.
• Left-sided vs. right-sided heart failure. Left-sided heart failure is failure of the left
ventricle to pump blood adequately. This results in build-up of fluid in the pulmonary
circulation, primarily causing respiratory symptoms: productive cough (pink frothy
sputum), dyspnoea, poor exercise tolerance, orthopnoea, paroxysmal nocturnal
dyspnoea, wheeze, fatigue, etc. Right-sided heart failure is failure of the right
ventricle to pump blood adequately. This results in build-up of fluid in the systemic
circulation, leading to peripheral oedema, raised JVP, nausea, anorexia, facial
engorgement, abdominal swelling (ascites), epistaxis, facial & neck pulsations. When
both left-sided & right-sided heart failure coexist, the condition is called congestive
cardiac failure.
• Acute vs. chronic heart failure. Acute heart failure is used exclusively to mean new-
onset heart failure or a decompensation of chronic heart failure with signs of heart
failure with or without signs of hypoperfusion. Chronic heart failure is compensated
heart failure that develops slowly and progressively. Venous congestion is common
but arterial pressure & perfusion is maintained until very late.
• Low-output vs. high-output heart failure. In low-output failure, cardiac output is
reduced and fails to increase with exertion. Low-output failure can be caused by:
pump failure (systolic & diastolic heart failure, bradycardia and negative inotropic
drugs), excessive preload (mitral regurgitation, fluid overload) and chronic excessive
afterload (hypertension, aortic stenosis). High-output failure is rare: the cardiac
output is normal or increased but there is increased demand in the body for oxygen.
Causes include anaemia, pregnancy, hyperthyroidism, Paget’s disease, AV
malformations and beriberi (dietary thiamine deficiency).

Pathophysiology
The cardiac output is the product of the stroke volume and the heart rate:

𝐶𝑂 = 𝑆𝑉 × 𝐻𝑅

Heart failure in most cases is caused by a decrease in cardiac output, which is caused by
either a drop in the stroke volume or a drop in the heart rate. The stroke volume is
determined by ventricular filling (preload), cardiac muscle contractility and peripheral
vascular resistance (afterload). Any condition affecting preload, contractility, afterload and
heart rate subsequently leads to cardiac failure.

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Initially when the heart begins to fail, certain changes occur in the heart & peripheral
vascular systemic that aim to maintain cardiovascular function. These are the compensatory
changes that occur in heart failure. They include:

• Venous return (preload). In mild myocardial dysfunction, there is an increase in

venous return & filling pressure which compensates for a decrease in ejection
fraction. This means that the absolute cardiac output will remain normal despite the
heart handling larger volumes. A sinus tachycardia will also ensure that a reduction
in stroke volume will be compensated by an increase in heart rate. In more severe
myocardial dysfunction, there is a much greater increase in ventricular pressures and
marked sinus tachycardia. Increased venous pressure results in dyspnoea,
hepatomegaly, ascites and peripheral oedema. The cardiac output, however, may
still be compensated at this stage (although cardiac output response to exercise is
diminished). In very severe heart failure, the cardiac output at rest is decreased, and
blood is shunted to the heart, brain and kidneys (the vital organs) at the expense of
skin & muscle.
• Outflow resistance (afterload). Outflow resistance is determined by the pulmonary &
systemic resistance (determined by blood vessel diameter), physical characteristics
of the blood vessels, and the volume of blood ejected. An increase in afterload
increases the work of the heart, and therefore it has to work harder (i.e. contract
more) to maintain the cardiac output. Therefore, when the ventricular myocardium
fails, the cardiac output drops and leads to a reduced ejection fraction & increased
end-diastolic volume. This increases the ventricular filling pressure, which increases
the resistance. This sets up a vicious cycle that further exacerbates the afterload
problem.
• Myocardial contractility. In heart failure, the sympathetic nervous system is
activated through activation of baroreceptors. This is an early compensatory
mechanism, and it serves to offer inotropic support & maintain cardiac output.
However, chronic sympathetic activation leads to increased neurohumoral activation
& myocyte apoptosis, although this is compensated by downregulation of β-
receptors.
• Salt & water retention. The increase in venous pressure during ventricular failure
leads to retention of salt & water. This occurs through activation of the renin-
angiotensin-aldosterone system (RAAS), which results from hypoperfusion of the
kidneys due to the reduced cardiac output. Retention of salt, however, is partly
compensated by the release of BNP (B-type natriuretic peptide), which leads to
excretion of sodium, and ADH, which leads to reduced osmolality1. Prolonged
activation of RAAS also exerts toxic effects on myocardial cells.
• Myocardial remodelling. There is progressive alteration in ventricular size, shape and
function, which occurs under the influence of mechanical, neurohumoral and genetic

1
This manifests as hyponatraemia, which is an ominous prognostic indicator.

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 factors. The hallmark changes in heart failure are ventricular hypertrophy, loss of
myocytes and interstitial fibrosis. Remodelling is initiated by many pathologic
processes, such as dilated cardiomyopathy, myocardial infarction, hypertension and
valvular heart disease. It continues for months after the initial insult.

Clinical presentation of heart failure

History

The symptoms of heart failure depend on which side of the heart is failing. In right heart
failure, there will be symptoms of fluid overload in the systemic veins. These symptoms are:

• Peripheral oedema.
• Ascites.
• Facial engorgement.
• Pulsations in neck & face (in tricuspid regurgitation).
• Fatigue.

In left ventricular failure, the symptoms are mostly pulmonary as the pulmonary veins
become engorged. They include:

• Dyspnoea on exertion.
• Orthopnoea.
• Paroxysmal nocturnal dyspnoea.
• Fatigue.
• Nocturnal cough with pink frothy sputum.

A combination of both will result in congestive cardiac failure. In both cases, there is often
poor exercise tolerance.

The symptoms of heart failure can be classified using the New York Heart Association
(NYHA) classification, based on severity of symptoms.

New York Heart Association (NYHA)

Class I No limitation to activity – no fatigue, chest pain or dyspnoea on regular
exercise.
Class II Mild limitation to function: normal physical activity produces symptoms.
Class III Moderate limitation to function: gentle physical activity produces symptoms.
Class IV Severe limitation to function: symptoms present at rest and exacerbated by
physical activity.

Examination

On examination, you will find:

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 • General: tachycardia, hypotension, cool peripheries, elevated JVP, distended neck
veins, bilateral pedal oedema.
• CVS: active precordium in some cases, displaced apex with left ventricular
hypertrophy, heaves in right ventricular hypertrophy, presence of 3 rd or 4th heart
sounds (often as a gallop).
• Respiratory system: stony dull on percussion (pleural effusion), bibasal crackles.
• Abdomen: tender hepatomegaly on palpation. The liver is pulsatile in tricuspid
regurgitation.

Investigations

The investigations done in heart failure are:

• Chest X-ray. This is used to assess for signs of heart failure. These can be abbreviated
by ABCDE:
o A – Alveolar oedema. This is demonstrated by the presence of bat’s wing
sign.
o B – Kerley B lines. These signify interstitial oedema. There may also be fluid in
the fissures.
o C – Cardiomegaly. Cardiomegaly can be suspected if the cardiac shadow is
1
more than 2 the transthoracic diameter in a well-inspired PA film.
o D – Dilated upper lobe vessels. This is due to upper lobe diversion of blood
secondary to pulmonary congestion.
o E – Pleural effusion. This is secondary to fluid overload.
• ECG. On an ECG, you look for signs of ischemia, MI, arrhythmias or left ventricular
hypertrophy (e.g. hypertension). It is rare to get a completely normal ECG in chronic
heart failure.
• Natriuretic peptides (ANP & BNP). These are elevated in heart failure. Their
measurement is a good indicator of the presence of failure in a patient. The normal
level of natriuretic peptides is less than 100pg/mL.
• Echocardiography. This is the key investigation in heart failure. It is often done when
the other tests – chest X-ray, ECG and natriuretic peptides – are positive and
suggestive of heart failure. In addition, an echocardiogram will demonstrate the
presence of left ventricular dysfunction and possibly the cause of failure. You can use
an echocardiograph to determine: cardiac chamber dimensions, systolic & diastolic
function, regional wall motion abnormalities, valvular heart diseases and
cardiomyopathies.
• Blood tests. You can do FBC (to rule out anaemia & active infection), U&E, LFTs and
cardiac enzymes (if there is suspicion of an MI).

Diagnosis of heart failure

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The diagnosis of heart failure is made based on objective evidence of cardiac dysfunction.
You need to use measures of left ventricular structure & function. Usually an
echocardiogram is required for ventricular function to be demonstrated. The underlying
cause of heart failure should also be established in each patient. You should follow the
following algorithm:

Heart failure suspected based on signs & symptoms

Take ECG, CXR and BNP

Normal Abnormal

Take echocardiogram
Heart failure unlikely

Normal Abnormal

Heart failure unlikely Assess:

• Aetiology.
• Degree of failure.
• Precipitating factors.
• Type of cardiac
dysfunction.

Choose treatment

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The diagnosis of heart failure can also be made using the Framingham criteria. This requires
that you have at least 2 major criteria or 1 major criterion and 2 minor criteria.

The major criteria are: The minor criteria are:

• PND. • Bilateral ankle oedema.
• Neck vein distension. • Nocturnal cough.
• Increased JVP (>16cm H2O from right • Dyspnoea on minimal exertion.
atrium or >11cm from sternal angle). • Tachycardia.
• Crepitations (bibasal crackles). • Hepatomegaly.
• S3 gallop. • Pleural effusion.
• Acute pulmonary oedema. •
1
Decreased vital capacity by 3
• Cardiomegaly on CXR. maximum recorded.
• Weight loss of more than 4.5kg after
treatment.

Management of chronic heart failure

Management of heart failure aims to relieve symptoms, controlling aetiological disease,
prevent progression of disease, and improving quality & length of life. The interventions are:

• Lifestyle advice.
• Treat the cause.
• Pharmacological therapy.
• Surgical intervention.
• Hospice care.

Lifestyle advice

Lifestyle changes include:

• Stop smoking. This may predispose to other cardiovascular events which may
worsen heart failure and the prognosis. If necessary, an anti-smoking clinic can be
used.
• Stop alcohol. It has a negative inotropic effect on the heart.
• Weight control. Obesity is associated with poor prognosis. You need to maintain a
certain body mass index.
• Diet. Large meals should be avoided, and a weight-reduction diet may also be
instituted. Salt restriction is necessary to reduce solute load – less salt should be
added to food and placed on the eating table. Fluid restriction is necessary in severe
heart failure. Patients are encouraged to eat foods rich in omega-3 polyunsaturated
fatty acids, such as fish.

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 • Exercise. Prolonged bed rest predispose to deep venous thrombosis. Daily leg
exercises prevent this from happening. Low-level endurance exercises, such as 20-30
minutes per day 3-5 times a week, are encouraged.
• Potassium supplements are contraindicated with some medications.
• Patients are allowed to drive. However, symptomatic heart failure disqualifies
patients from driving large buses & Lorries.

Treat the cause

Examples of causative factors for heart failure include arrhythmias & valvular heart diseases.
Until these are corrected, heart failure may continue to recur in patients.

Pharmacologic therapy

The drugs used in heart failure are:

1. Diuretics. Diuretics can reduce the risk of worsening heart failure & death. They are
mostly used for symptomatic relief, and they work by relieving fluid overload
(through promoting renal excretion of fluid). You can use loop diuretics such as
furosemide 40-80mg orally 1-2 times daily, or bumetanide 1-2mg orally once daily.
You can also use thiazide diuretics (metozalone 5-20mg once daily) for patients with
mild failure & good renal function2. You can add a thiazide diuretic if the patient has
severe heart failure and the oedema is refractory to loop diuretics. Diuretics are
mostly potassium-wasting and therefore they pose the risk of hypokalaemia and
renal impairment.
2. ACE inhibitors. These drugs act by inhibiting formation of aldosterone II, resulting in
vasodilation and reduced sodium & water retention. ACE inhibitors have been shown
to improve symptoms & reduce mortality in all classes of heart failure. They also
prevent cardiac remodelling (by inhibiting the RAAS pathway). The typical drug used
is enalapril 5-20mg once daily. The main adverse effects are cough, hypotension,
hyperkalaemia and renal dysfunction (which occurs in renal artery stenosis,
pregnancy and patients with previous angioedema).
Angiotensin II receptor inhibitors are indicated in patients intolerant to ACE
inhibitors (the cough), and they also inhibit the RAAS system. They include losartan,
valsartan and candesartan. Losartan is given at a dose of 50-100mg once daily.
Candesartan can be given at a dose of 4mg once daily.
3. B-blockers. B-blockers have been shown to decrease mortality in heart failure due to
left ventricular dysfunction. They also inhibit cardiac remodelling by blocking the
cardiac effects of chronic activation of the sympathetic nervous system. Examples of
β-blockers used in heart failure include carvedilol (3.125-25mg twice daily),
bisoprolol, and nebivolol. Carvedilol & bisoprolol are indicated for any grade of heart

2
Good renal function is a must.

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 failure, while nebivolol is indicated for stable mild-moderate disease in elderly
patients (over 70 years of age). They are usually initiated after starting diuretics &
ACE inhibitors. It is advised to start with a low dose and increase doses slowly (more
than 2 weeks between each dose increment).
4. Aldosterone antagonists. Spironolactone & eplerenone decreases mortality by 30%
when added to conventional therapy in patients with severe heart failure. They have
also been shown to slow cardiac remodelling through an unknown mechanism. They
also reduce development of hypokalaemia when added to standard diuretic therapy.
It is added to diuretics when there is hypokalaemia, predisposition to arrhythmias,
pre-existing potassium-losing condition and concurrent digoxin therapy.
Spironolactone is given at a dose of 25-50mg once daily. However, spironolactone
can cause gynaecomastia. Eplerenone, however, has a lower association with
gynaecomastia.
5. Cardiac glycosides. The prototypical cardiac glycoside is digoxin. It is indicated in
patients with atrial fibrillation. It can also be considered for patients with left
ventricular dysfunction with a sinus rhythm. It alleviates symptoms. However, it does
not improve mortality. It is used as add-on therapy to ACE inhibitors & β-blockers. It
is given at a dose of 0.25-0.5mg 3-times daily, and it is usually given in the first 24
hours. It produces adverse effects in hyper- & hypokalaemia. Digoxin levels require
therapeutic drug monitoring.
6. Vasodilators. Examples of drugs that can be used include a combination of
isosorbide dinitrate & hydralazine. These drugs reduce preload & afterload and
therefore they slow progression of disease and improve survival. They can also be
taken in patients unable to take ACE inhibitors or AT1-blockers. Hydralazine is started
at 25mg tds while isosorbide is given at a dose of 20mg tds.
7. Neprilysin inhibitors. These are drugs that inhibit neprilysin (also known as neutral
endopeptidase). The enzyme is responsible for breakdown of ANP & BNP, and
therefore the drugs increased excretion of sodium & water in the kidneys. The drug
significantly reduces blood pressure. An example is sacubitril. Often they are given in
combination with AT1-receptor inhibitors as sacubitril/valsartan. The drugs, however,
cause angioedema which can be life-threatening.
8. Anticoagulation. This is indicated for bed-ridden patients. You can give enoxaparin
40-80mg once daily orally, or subcutaneous heparin 5000U 3-times daily.

Surgery

Surgical intervention for heart failure is as follows:

• Interventional surgery. This is indicated for specific causes of heart failure. You can
do myocardial revascularisation, although this procedure’s role in heart failure is
unclear. Patients with angina & left ventricular dysfunction are at highest risk of
mortality from surgery, but stand to benefit most from surgical intervention.

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 • Cardiac re-synchronisation therapy with/without implantable cardioverter
defibrillator. These are indicated in patients with SA & AV conduction block.
Pacemakers are also valuable in patients with prolonged PR intervals (1st-degree
heart block), LBBB (left bundle branch block) and severe mitral regurgitation. In
patients with heart failure, left bundle branch block and NYHA class III symptoms,
biventricular pacing was found to be more beneficial. Other indications include:
systolic heart failure (ejection fraction less than 35%), a non-reversible cause, highly
symptomatic patients, patients refractory to optimal medical therapy, patients with
atrial fibrillation3 and patients with significant mitral regurgitation. One trial
demonstrated that there is a 21% decrease in mortality & admissions in patients
receiving biventricular pacing.
• Ventricular assist device (VAD). This is a mechanical device that physically pumps
blood around the vessels in a heart that is unable to function. It is used: as a bridge
to transplantation, as destination therapy (palliative), and as an emergency
procedure for cardiogenic shock. VADs are usually not pulsatile, but can be as a
result of the ventricle pumping into it. Blood pressure can still be measured using an
automatic machine or manual inflatable cuff, or a Doppler ultrasound. The
complications of a VAD include: suction events, right ventricular failure (acute or
chronic) and pump thrombosis.
• Cardiac transplantation. Cardiac transplantation is the transfer of a functioning
heart from a dead person (who has opted to be a donor) to a living person. It is
indicated for:
o Young patients with severe intractable heart failure requiring inotropic
support.
o Patients whose life expectancy is less than 6 months.
o Cardiogenic shock.
o Refractory life-threatening arrhythmias.
The 1-year survival for patient with heart transplants is 90%, and the 5-year survival
is 75%. There are 2 types of transplantation: exclusive heart transplantation and
heart-lung transplantation. Heart allografts do not function exactly as normal hearts.
They usually operate at very high heart rates due to denervation which results in
lifting of vagal tone. There is also loss of diurnal blood pressure variation and
impaired RAAS regulation. The complications of transplants are:
o Organ rejection (leading to a graft versus host reaction). This can be hyper-
acute (within hours; due to preformed antibodies), acute (within a few days)
or chronic (6 months to 10 years; a cellular event). You can also have
combined heart-lung rejection, leading to interstitial fibrosis.

3
Amiodarone was not shown to be of any benefit in heart failure patients with atrial fibrillation.

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 o Cardiac allograft vasculopathy. In this condition, there is intimal hyperplasia
of coronary arteries. Patients often do not complain of symptoms, and the
condition is diagnosed by traditional stress testing.
o Infections. Early infections are often nosocomial and are caused by S. aureus
& Gram-negative organisms (e.g. Klebsiella). Late infections are mostly
opportunistic infections such as histoplasmosis, toxoplasmosis, CMV, fungi
and Pneumocystis.
o Chronic kidney disease.
o Malignancies. Transplants predispose to lymphomas, Kaposi sarcoma and
skin cancer.

Step-wise management of chronic heart failure

The step-wise management of chronic heart failure is as follows:

1. Stage A – high-risk patient with no symptoms. You start with risk factor reduction
(cessation of smoking & alcohol, controlling diet, control exercise) and patient &
family education. You should also treat comorbid conditions, such as dyslipidaemias,
hypertension and diabetes.
2. Stage B – structural heart disease with no symptoms. In these patients, you start on
ACE inhibitors (enalapril 5-20mg once daily) or AT1-receptor antagonists (losartan 50-
100mg daily). You can also give β-blockers (carvedilol 3.125-25mg twice daily)4.
These drugs are known to slow down remodelling of the heart, and this is the
primary aim in asymptomatic patients.
3. Stage C – structural heart disease with previous or current symptoms. In these
patients, symptom relief is one of the priorities. All patients should be on a
combination of an ACE inhibitor/AT1-receptor blocker and a β-blocker. You can also
add digoxin & diuretics. In these patients, you need to watch for hypokalaemia, and
be prepared to administer potassium chloride to the patient. If a bundle branch
block is present or the failure is unresponsive for 3 months, consider cardiac
resynchronisation therapy (a pacemaker).
4. Stage D – refractory symptoms requiring specialist interventions. You can use
inotropic agents. These are generally not recommended for heart failure, but are
indicated for intractable heart failure. You can use bipyrimidines (such as amrinone
& milrinone), levosimendan and β-agonists such as dobutamine. If these do not
work, consider a VAD while working towards transplantation, otherwise hospice
care.

Management of acute heart failure

4
B-blockers are started after ACE-inhibitors because ACE inhibitors provide rapid haemodynamic benefit,
while β-blockers have delayed onset.

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Acute heart failure describes a condition in which there is decompensation. There is rapid
onset of signs & symptoms of heart failure. This condition has a poor prognosis, with 10%
dying within 60 days. The pathophysiology of acute heart failure is similar to that of chronic
heart failure, with the difference being that in acute conditions, there is a strain placed on
the body that overcomes the compensatory mechanisms operating in the heart.

The causes of acute decompensation can be abbreviated by the acronym HEART FAILURE:

• H – Hypertension. Poor blood pressure control leads to heart failure. Hypertension

can also produce flash pulmonary oedema even in patients with preserved left
ventricular function.
• E – Endocrine. Thyrotoxicosis,
• A – Anaemia. Anaemia reduces oxygen delivery to tissues, which results in a
compensatory increased cardiac output which strains the body.
• R – Renal disease. Acute & chronic kidney disease both predispose to acute heart
failure. These conditions cause fluid overload, which strains the heart and also
increases the pressures it handles.
• T – Trauma. Myocardial infarction and pulmonary embolism both lead to acute
failure.
• F – Fluid overload.
• A – Arrhythmias. Atrial fibrillation is frequently associated with acute heart failure.
• I – Infections. Sub-acute bacterial endocarditis and chest infections also cause
decompensation. They lead to a hyperdynamic circulation.
• L – Lifestyle change: increased fluid & salt intake, reduced exercise, etc.
• U – Upregulation of hormones (pregnancy).
• R – Rheumatic heart disease.
• E – Electrolytes (hypokalaemia), emboli

Drugs such as digoxin, NSAIDs and β-blockers can tip patients into failure.

You diagnose acute heart failure using an ECG, echocardiogram, a chest X-ray, FBC & U&E,
blood glucose, and blood cardiac enzymes & plasma BNP.

Treatment of acute heart failure aims to relieve symptoms, reduce mortality and reduce
hospital stay. Patients must be managed in a high-care area with regular temperature, blood
pressure and heart rate monitoring.

1. Nurse the patient in a propped up position.

2. All patients require anti-coagulation, such as heparin 5000U 3-times daily or
enoxaparin 40-80mg once daily.
3. Oxygen. This is indicated particularly if the patient is presenting with pulmonary
oedema. You give 40% oxygen per face mask at a rate of 2-4L per minute. Non-

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 invasive CPAP ventilation has been demonstrated to improve symptoms, but not
outcomes.
4. Establish IV access and ECG monitoring. treat any arrhythmias if present.
5. Analgesia. You can give morphine or diamorphine (heroin) 1.25-5mg IV slowly. Use it
carefully in individuals with liver failure & COPD.
6. Diuretics. Give furosemide 50mg intravenously. You repeat as required. Add
vasodilators (GTN 2 puffs or 2 × 0.3mg tablets sublingual, then isosorbide dinitrate
infusion) if the blood pressure is maintained above 90mm Hg. After the patient has
responded, you can add ACE inhibitors.
7. Inotropic support. You can give dobutamine, phosphodiesterase inhibitors or
levosimendan. This is added to patients who do not respond to initial therapy or who
have a systolic BP below 100mm Hg.
8. Carry out investigations while you continue treatment – FBC, U&Es, blood glucose,
cardiac enzymes, plasma BNP, chest X-ray, ECG and echocardiogram.
9. Intra-aortic balloon pump. This pump works by decreasing afterload, while
improving mean arterial pressure & coronary circulation. It is indicated for
cardiogenic shock, valvular decompensation, bridge to mechanical support, failure to
wean from bypass and acute MI. it is contraindicated in aortic aneurysms, aortic
dissection, and history of vascular surgery, severe aortic insufficiency and active
infection. It can complicate with clots, limb ischemia, renal injury and haemolysis &
thrombocytopenia.
10. VAD. This can be placed in intractable cases.

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 Cardiac arrhythmias
A cardiac arrhythmia is an abnormality in the cardiac rhythm. They may be asymptomatic or
range from mild symptoms such as chest pain, dizziness and dizziness to heart failure,
syncope and sudden death. Some arrhythmias occur in patients with otherwise normal
hearts, while others occur in patients with diseased heart tissue. When myocardial function
is poor, arrhythmias are more symptomatic and potentially life-threatening.

Cardiac arrhythmias are classified into 2 types:

• Bradycardias. The heart rate is below 60 beats/min during the day or below 50
beats/min during the night.
• Tachycardias. The heart rate is above 100 beats/min.

The majority of arrhythmias are tachycardic arrhythmias.

Mechanisms of arrhythmia production

The mechanisms of arrhythmia formation include:

• Abnormal automaticity. Automaticity of the heart is generated by the SA node. The

mechanism behind automaticity of the SA is slow depolarisation of the membrane
potential during diastole. Altering this rate can lead to either an increased or a
decreased heart rate. This can be done by changing the rate at which threshold is
reached, or changing the threshold potential. Sinus bradycardia is a result of delayed
automaticity.
• Triggered activity. Myocardial damage causes oscillation of the membrane potential
at the end of the action potential. This oscillatory activity can lead to production of
potentials that reach potential and cause what are called “after-depolarisations”. If
they occur during phase 3 of the cardiac potential (depolarisation to resting potential
before threshold has been reached), they are called early after-depolarisations. If
they occur after threshold has been reached, they are called delayed after-
depolarisations. The abnormal oscillations can be exaggerated by catecholamines,
electrolyte imbalances, hypoxia, acidosis and some medications (e.g. digoxin).
Ventricular arrhythmias in long QT syndrome may be triggered by this mechanism.
• Re-entry circuits (also known as circus movements). These are rings of excitable
tissue that surround an unexcitable section of tissue, such as scarred myocardium.
Normally, the myocardium depolarises as a wave in a single direction, meaning
instead of acting as a closed circuit, the waves split and the impulses in the separate
limbs move together in a single direction. They eventually coalescing in the normal
tissue distal to the unexcitable region. However, if there is an ectopic beat that finds

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 one limb refractory with the other excitable, it excites one limb first and then goes
round the unexcitable area to depolarise the other limb in a retrograde direction.
This limb then depolarises the other limb, and eventually a closed circuit is formed.
The re-entry circuit acts as an autonomic source of impulses. The majority of
paroxysmal tachycardias occur through this mechanism.

Bradycardias
Bradycardias may be due to failure of impulse formation or failure of impulse conduction
from the atria to the ventricles. The different bradycardias are:

Sinus bradycardia

This is a pulse rate of less than 60beats/min during the day or less than 50beats/min during
the night. The common causes of sinus bradycardia are:

Extrinsic: Intrinsic:
• Hypothermia, hypothyroidism, cholestatic • SA nodal acute
jaundice, raised intracranial pressure. ischemia/infarction.
• Drugs – β-blockers, digitalis and other • Chronic degenerative disorders
arrhythmic drugs. of the atrium/SA node.
• Neurally-mediated syndromes.

The common syndromes that constitute sinus bradycardia include:

• Sick sinus syndrome (also known as sinoatrial disease). This is usually caused by
idiopathic fibrosis of the SA node, but the fibrosis can be secondary to ischemic heart
disease, cardiomyopathy or myocarditis. The syndrome is characterised by episodes
of sinus bradycardia or sinus arrest. They also commonly experience paroxysmal
atrial tachy-arrhythmias called the tachy-brady syndrome.
• Neurally-mediated syndromes. These are due to a reflex called the Bezold-Jarisch
which results in bradycardia & reflex peripheral vasodilation. These syndromes
present as syncope or pre-syncope. They include: carotid sinus syndrome, neuro-
cardiogenic syncope and postural orthostatic tachycardia syndrome (POTS).

Sinus bradycardia is treated by first identifying any extrinsic causes and removing them.
Other treatment options include:

1. Temporary pacing. This is done in acute extrinsic conditions until the offending
agent is removed. For chronic degenerative conditions, this is put in place until a
permanent pacemaker is put in place.
2. Permanent pacemaker. Chronic symptomatic sick sinus syndrome requires a
permanent pacemaker. These devices are also beneficial in patients with malignant
neuro-cardiogenic syncope.

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 3. Anti-arrhythmic therapy. This can be used to supplement permanent pacemaker use
in chronic sick sinus syndrome.
4. Anticoagulation. This is indicated in tachy-brady syndrome, where
thromboembolism is common. However, this does not need to be done if there is a
contra-indication.

AV heart block

A blockage of conduction of impulses in the AV node or the His bundle results in AV block.
There are 3 main types of heart block.

• 1st-degree heart block. This is a simple sustained prolongation of the PR interval. It

represents slowed conduction across the AV node, but with definite conduction of
every impulse from the atria to the ventricles. Therefore, every P-wave is followed
by a QRS complex. 1st-degree heart block is usually caused by AV nodal disease,
increased vagal tone, myocarditis, acute MI, electrolyte disturbances and
medication.
• 2nd-degree heart block. This is the incomplete conduction of P-waves from the atria
to the ventricles, with some P-waves being conducted and others not. There are
various types of 2nd-degree heart block:
o Mobitz type I. this is also known as the Wenckebach block phenomenon. This
is progressive lengthening of the PR interval until the P-wave fails to conduct
to the ventricles. The following P-wave that comes after the blocked P-wave
has a short or normal PR interval, and the cycle starts again. The block in the
Wenckebach block phenomenon is mainly due to blockage of conduction in
the AV node. This block usually is not progressive, and therefore no
pacemaker is required immediately; only monitoring is required.
o Mobitz type II. This is when the QRS complex is dropped after every set
number of beats (2 or 3) with no prolongation of the PR interval. Usually the
QRS complex is wide (>0.12s). Mobitz type II is mainly due to blockage of
impulse conduction at an infranodal level such as the His bundle. Progression
to complete heart block is more likely with this phenomenon. Therefore
pacing using a pacemaker is required.
o Advance (2:1 or 3:1) heart block. This is the appearance of a QRS complex
after every 2nd or 3rd P-wave. This is a more serious form of 2nd-degree heart
block, and the management depends on the clinical setting within which the
block occurs.
An acute MI can produce a 2nd-degree heart block.
• 3rd-degree heart block. This is also known as complete heart block and is due to
complete dissociation between the SA node and AV node & His-Purkinje system. Life

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 is maintained by a spontaneous escape rhythm (either a junctional escape rhythm1or
ventricular escape rhythm2). A junctional escape rhythm is tolerable and compatible
with life. For these cases you can give IV atropine or a pacemaker. A ventricular
escape rhythm is usually symptomatic, with blackouts & dizziness (called Stokes-
Adams attacks). In these cases, an implantable left ventricular cardioverter-
defibrillator is indicated.

Bundle branch block

Bundle branch block occurs when there is a block in one of the bundle branches of the His-
Purkinje system rather than the whole system. Various disturbances can occur. The
disturbances that can occur are:

• Bundle branch conduction delay. This produces slight widening of the QRS complex.
It is also known as incomplete bundle branch block.
• Complete bundle branch block. This produces a widened QRS complex. The ECG
features depend on the branch that is blocked.
o Right bundle branch block. This produces late activation of the right ventricle
and therefore produces deep S-waves in leads II & V6 and an additional late
R-wave (called rsR’) in lead V1.
o Left bundle branch block. This produces late activation of the left ventricle. It
results in deep S-waves in lead V1 and tall wide, notched or M-shaped R-
waves in leads I & V6. There are also abnormal Q-waves.
• Hemiblock. In a hemiblock, there is a block in a single division of the fascicles into
which the left bundle branch divides. There is a change in the axis of the heart.
o When the anterior division is blocked, the left ventricle is activated from
infection to superior and therefore there is left axis deviation.
o When the posterior division is blocked, the left ventricle is activated from
inferiorly to superiorly and therefore there is right axis deviation.
• Bifascicular block. This is a combination of block of any of the following: the right
bundle branch, anterior division of left bundle branch, and posterior division of left
bundle branch. In this type of block, only one fascicle remains.

Bundle branch blocks are usually asymptomatic. Right bundle branch block may cause wide
but physiologic splitting of the 2nd heart sound.

Tachycardias

1
A junctional/narrow complex escape rhythm means that the new dominant pacemaker activity is coming
from the AV node. The junctional escape rhythm operates at a rate of 40-60bpm. On an ECG, the P-waves may
or may not be present and the QRS is of normal morphology & duration.
2
A ventricular/broad complex escape rhythm means that the new dominant pacemaker activity is coming
from the ventricular myocytes themselves. The ventricular escape rhythm operates at a rate of 15-40 beats per
minute. On an ECG, the QRS complex is widened.

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Tachycardia is defined as a heart rate going above 100 beats per minute. They are classified
as follows:

• Supraventricular vs ventricular. Supraventricular tachycardias arise from the atria or

AV junction. They include sinus tachycardia, atrial fibrillation, atrial flutter, atrial
tachycardia and AV junctional tachycardia (AVNRT & AVRT). Ventricular tachycardias
arise from ventricular tissue. They include ventricular flutter, ventricular fibrillation
and ectopic ventricular beats.
• Narrow-complex & wide-complex. Narrow-complex tachycardias are those in which
the QRS complex is normal. For this to happen, there needs to be normal conduction
in the ventricular system with normal progression from the AV node down the His-
Purkinje system and eventually to the myocytes. Narrow-complex tachycardias are
mainly supraventricular tachycardias. Wide-complex tachycardias are those in which
the QRS complex is widened. In this case, either there is an abnormal conduction
pathway, or impulses are being transmitted through an alternate pathway. Wide-
complex tachycardias are mostly ventricular tachycardias, but also include
supraventricular tachycardias with aberrant conduction.

Long-term management of cardiac arrhythmias

Long-term management of cardiac arrhythmias involves use of:

• Anti-arrhythmic drugs.
• Ablative techniques.
• Device therapy.

To determine which choice is reliable, you need to answer 2 questions:

1. What is the principal aim of treat? Is it to relieve symptoms or to prevent sudden

death?
2. What are the treatment goals? Is it maintaining sinus rhythm or to control the
ventricular rate?

Anti-arrhythmic drugs

Anti-arrhythmic drugs are drugs that are used to treat arrhythmias. They bind avidly to
activated or inactivated channels, but poorly to resting ones. Therefore, they act on highly
active tissue. Anti-arrhythmic drugs are divided into 4 classes according to the Vaughan-
Williams classification based on the part of the cardiac potential they affect.

• Class 1 drugs. These are membrane-depressing drugs that block sodium channels.
They all slow the entry of sodium channels and therefore increase the duration
phase 0. Class 1 drugs are further divided into 3 groups based on their effects on the
length of the action potential, their reaction kinetics and their potency.

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 o Class 1a. These drugs have intermediate potency & reaction kinetics, and
they lengthen the duration of the action potential. They include quinidine,
procainamide and disopyramide.
o Class 1b. These drugs have fast reaction kinetics but low potency, and they
shorten the duration of the action potential. They include lignocaine &
mexiletine.
o Class 1c drugs. These drugs have slow reaction kinetics but high potency, and
they have no effect on the duration of the action potential. They include
flecainide and propafenone.
All drugs can be used to treat ventricular tachycardias, but only classes 1a & 1c can
be used for supraventricular tachycardias. Class 1 drugs increase mortality from
supraventricular & ventricular tachycardias in post-MI patients. They are reserved
for patients without structural heart disease.
• Class 2 drugs. These are β-blockers. They exert their effects by blocking β1-receptors
on cardiac myocytes. They mainly exert their effects on slow-conduction tissues,
such as the SA & AV node, and they increase phase 4 of the action potential. They
reduce the rate of automaticity, reduce conduction rate and prolong refractoriness.
They are mainly used for supraventricular tachycardias, such as atrial fibrillation,
atrial flutter, AV nodal re-entry and AV re-entry tachycardias. They can also be used
for some types of ventricular tachycardias3. They are anti-ischemic & anti-adrenergic,
and they are beneficial in heart failure or post-MI patients. They can be used alone
or in combination, particularly in patients with cardiac disease.
• Class 3 drugs. These are membrane stabilising agents, and they block potassium
channels. They therefore prolong phases 2 & 3 of the action potential. They increase
the duration of the action potential as well as prolong refractoriness of fast & slow
conduction tissues. Examples of such drugs include amiodarone, sotalol4, ibutilide,
dofetilide, azimilide, bretylium and dronedarone. Sotalol may result in acquired long
QT syndrome & torsades de pointes, and this risk is increased in patients with
hypokalaemia. Amiodarone carries low risk of arrhythmias in patients with structural
heart disease. However, it has a number of toxicities, including hyper- &
hypothyroidism5, corneal micro-deposits, bradycardia and heart block.
• Class 4 drugs. These are non-dihydropyridine calcium channel blockers. They prolong
phase 2 of the cardiac action potential. They are also particularly effective at slowing
conduction in nodal tissues. They prevent attacks in junctional tachycardias and help
control ventricular rates during paroxysms of other forms of SVT.

3
Their effect on ventricular ectopics, however, is lower than that of class 1 drugs.
4
Sotalol is also a β-blocker.
5
This is due to its iodine content. Dronedarone carries a lower risk and therefore can be used to avoid this side
effect.

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Drug therapy is mainly used for symptomatic relief in patients who do not have life-
threatening arrhythmias. They have not been shown to improve mortality. The choice of
anti-arrhythmic agent is largely determined by patient safety.

Ablation therapy

Radiofrequency ablation (RFA) is frequently employed for the management of symptomatic

arrhythmias. It is used for the following conditions:

1
• Paroxysmal SVT, of which AVNRT accounts for more than 2 of cases.
• Accessory pathways (present in 30% of all SVTs), such as WPW syndrome. In these
patients, RFA is indicated as 1st-line therapy if they have a pre-excited ECG & are
symptomatic. In those that conduct retrograde from the ventricles, RFA is offered if
simple methods (e.g. AV nodal slowing) do not work. RFA can also be offered
prophylactically in asymptomatic patients.
• Atrial flutter (in which the focus is in the right atrium). Ablation of a typical flutter is
effective in 90-95% of cases, and it is used for cases of flutter that are not responsive
to medical therapy.
• Atrial fibrillation (potential for pulmonary vein ablation).
• Normal heart ventricular tachycardia (focus in right ventricular outflow tract or
infero-septal left ventricle near apex)6.

To perform ablation, you first place 3 or 4 electrode catheters into the heart chambers to
record & pace from various sites. Pacing is used to trigger the arrhythmia and study the
tachycardia mechanism. Radiofrequency energy (low-frequency, high voltage) is then
passed into this focus, and it produces small homogeneous necrotic lesions approximately
5-7mm in diameter and 3-5mm in depth.

Major complications occur in 1% of patients. They include:

• Cardiac: high-grade AV block requiring permanent pacemaker, tamponade,

pericarditis.
• Vascular: thromboembolism, haematoma, vascular injury, and TIA & stroke.
• Pulmonary: PE.
• Death in 0.1-0.2%.

Implantable cardioverter defibrillator (ICD)

ICDs are used to recognise ventricular tachycardias & ventricular fibrillation and
automatically pacing or administer a shock to the heart. This causes cardioversion to sinus
rhythm. This is an important intervention in preventing sudden cardiac death from life-
threatening ventricular tachycardias in at-risk patients. There is also a considerable

6
The majority of ventricular tachycardias are due to scarring from MI and cannot be ablated.

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mortality benefit of ICDs over anti-arrhythmic agents in primary & secondary prevention.
However, the majority of patients have significant structural heart disease, and overall
cardiac mortality from progressive heart failure is still high. The indications for ICD insertion
include:

• Preventing sudden cardiac death in patients with life-threatening ventricular

tachycardia.
• Coronary artery disease with significant left ventricular dysfunction (LVEF < 35-40%).
• Spontaneous non-sustained ventricular tachycardia in those in which sustained
ventricular tachycardia was induced by pacing the heart during an
electrophysiological study.
• Those with NYHA class III/IV heart failure in combination with cardiac
resynchronisation therapy.
• Those with NYHA class I/II heart failure when LBBB is present.
• Those with poor LV function (LVEF≤30%) post-MI.
• Dilated & hypertrophic cardiomyopathy.
• Long QT syndrome.
• Brugada syndrome.

Modern ICDs are only a little larger than pacemakers and are placed in the chest in the
pectoral position. They have lithium batteries to power over 100 shocks at 30J. ICD shocks
are painful if the patient is conscious. Ventricular tachycardia may be terminated by
overdrive pacing the heart, and this is painless.

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 Supraventricular tachycardias
Supraventricular tachycardias (SVTs) are cardiac arrhythmias that originate from the atria or
the AV junction. The abnormality is usually in the atria & AV node and therefore the His-
Purkinje system is intact. This means that the QRS complex is usually of normal size
(therefore called a narrow complex tachycardia) & morphology, and if present the
abnormalities are in the P-waves.

You can divide supraventricular tachycardias anatomically: sinus abnormalities, atrial

abnormalities and AV junctional abnormalities.

Sinus tachycardia
A sinus tachycardia can be a normal finding if there is physical or emotional stress. However,
if the tachycardia is persistent & out of proportion with the level of stress, then it is termed
inappropriate sinus tachycardia. It is predominantly found in young women and is
uncommon in health professionals. Sinus tachycardia due to intrinsic sinus node
abnormalities is extremely rare.

A sinus tachycardia is generally a secondary phenomenon, and the root cause needs to be
investigated. The causes include:

Acute: Chronic:
• Exercise. • Pregnancy.
• Emotion. • Anaemia.
• Pain. • Hyperthyroidism.
• Fever & infection. • Catecholamine excess (as in
• Acute heart failure. phaeochromocytoma).
• Acute PE.
• Hypovolaemia.

You can use β-blockers or ivabradine to slow down the heart rate if it is excessively high.

Atrial tachycardias
Atrial tachycardias arise from the atrial myocardium. They include atrial fibrillation, atrial
flutter, atrial tachycardia and atrial ectopic beats. The causes of atrial tachycardias can be
classified into cardiac & non-cardiac:

Cardiac Non-cardiac
Systemic causes: Endocrine:
• Hypertension • Thyrotoxicosis.

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 • CCF • Phaeochromocytoma.
Endocardial causes: • Diabetes.
• Valvular heart disease Infections:
• Infective endocarditis • Chaga’s disease.
Myocardial disease: Pulmonary causes:
• Coronary heart disease & MI • Pneumonia.
• Cardiomyopathy • COPD.
• Myocarditis • Pulmonary embolism.
Pericarditis. Autonomic:
Conduction abnormalities: • Increased sympathetic tone.
• Sick sinus syndrome • Increased parasympathetic tone.
• Wolff-Parkinson-White syndrome Drugs:
Cardiac tumours • Alcohol misuse.
1
Iatrogenic: cardiac surgery (occurs in 3 of • Caffeine.
patients) • Smoking.
Other causes: • Recreational drugs.
• Familial tachy-arrhythmia Electrolyte imbalances
• Genetic predisposition Myotonic dystrophy type 1

Atrial fibrillation

Atrial fibrillation is a condition in which there is a chaotic irregular atrial rhythm with
intermittent AV response, resulting in a very high atrial rhythm (300-600 bpm) that differs
from the ventricular rhythm. Atrial fibrillation is the most commonly-encountered cardiac
arrhythmia, occurring in 1-2% of the general population and 5-10% of patients older than 75
years. In younger patients it can occur in a paroxysmal form. The classification of atrial
fibrillation is as follows:

Paroxysmal atrial Episodes of atrial fibrillation that terminates spontaneously

fibrillation within 7 days1.
Persistent atrial Episodes of atrial fibrillation that last longer than 7 days.
fibrillation
Long-standing persistent Atrial fibrillation that has persisted for more than 12 months
atrial fibrillation (due to failed cardioversion or it has not been attempted).
Permanent atrial When both patient & clinician have decided to abort any
fibrillation further restoration methods.

Pathophysiology

Atrial fibrillation seems to require an initiating event and a permissive atrial substrate. It is
thought that in atrial fibrillation there is an autonomic focus of impulses in the heart. The
pulmonary vein (that containing cardiac muscle) seems to be the most common source of

1
Most episodes last less than 24 hours.

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these foci. There is also a theory (called the multiple wavelet hypothesis) suggesting that
fractionation of waves spreading through the atrial wall lead to production of daughter
wavelets that then activate the myocardium. The number of daughter wavelets is influenced
by shortening the refractory period, decreasing the conduction velocity, and increased atrial
muscle mass.

3 forms of atrial remodelling cause during the progression of atrial fibrillation have been
described.

• Electrical remodelling. This s a consequence of high atrial rates. It includes

shortening of the refractory period of atrial myocytes and slowing of atrial
conduction velocity.
• Structural remodelling. This is characterised by changes in atrial myocytes &
interstitium and changes in extracellular matrix composition with deposition of
fibrous tissue.
• Contractile remodelling. This includes loss of contractile structures, expression of
foetal-like proteins and accumulation of glycogen in the atrial interstitium.

Because of these remodelling changes, most patients with paroxysmal AF will progress to
persistent or permanent AF.

Clinical features

Asymptomatic presentation is found in 90% and in these patients it is an incidental finding.

The range of presentations is as follows:

• Mild symptoms: fatigue, palpitations, dyspnoea, dizziness, angina.

• Decompensated CCF: dyspnoea with orthopnoea & PND, ankle swelling,
• Cerebrovascular accident (due to thrombi forming in the left atrium): unilateral facial
deviation, arm/leg weakness, homonymous hemianopia, etc.
• Cardiogenic shock: syncope.

On examination, the key feature is an irregularly irregular pulse that is tachycardic. Findings
include:

• General: low blood pressure may indicate ensuing shock.

• Cardiac: presence of murmurs with/without thrills points towards valvular heart
disease. A displaced apex with an S3 gallop may indicate heart failure. A loud P2 may
indicate pulmonary hypertension.
• Pulmonary: bilateral basal crepitations or a pleural effusion may be found in a
patient with cardiac failure. Diminished breath sounds & wheezes suggest other
underlying pulmonary disease.
• Neurologic: unilateral facial deviation or upper motor neuron weakness may indicate
a stroke.

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Investigations

The investigations done are:

• ECG: this will reveal absence of discrete P-waves, which are replaced by irregular F-
waves (flutter waves). The ventricular rate is irregular.
• Blood studies: FBC (anaemia, infection), U&Es (electrolyte imbalances), TFTs
(thyrotoxicosis),
• Echocardiography: to estimate chamber size, identify valvular heart lesions and
ascertain ventricular function. It also helps identify thrombi.

Management

The management of atrial fibrillation centres on rate control, anticoagulation and rhythm
control for those who are symptomatic. It divided into management of new-onset AF,
paroxysmal AF and persistent AF.

Acute management

Acute management of atrial fibrillation includes:

1. Oxygen.
2. Ventricular rate control. This is achieved by AV node blockers. You can use β-blockers
& non-dihydropyridine calcium channel blockers as 1st-line agents, or you can use
digoxin in heart failure patients. If patients are unresponsive to these agents, you
can use amiodarone.
3. Treat the provoking cause. This includes thyrotoxicosis, alcohol toxicity, chest
infection, etc.
4. Anticoagulation. This is done to prevent further growth of thrombi. It is often
necessary to anticoagulate prior to cardioversion, as cardioversion can dislodge
emboli. Anticoagulate using heparin, warfarin (aiming for INR 2-3) or dabigatran
150mg twice daily for 3 weeks.
5. Cardioversion. This is usually achieved by direct current shock, which achieves sinus
rhythm in 80% of patients. Biphasic defibrillation is more effective than conventional
monophasic defibrillation. Prior to electric cardioversion you need to ensure that the
patient is full anticoagulated. If cardioversion is urgently required without having
time to wait for anticoagulation, you can do transoesophageal echocardiography to
rule out the presence of significant emboli. You can also cardiovert medically using
amiodarone, flecainide and propafenone.

Long-term management

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This aims at reducing recurrence & progression of AF, reducing AF-related symptoms,
control of the ventricular rate and reducing stroke risk. Rhythm control is important in some
patients. Long-term control is achieved as follows:

• Anticoagulation. This is achieved using warfarin or other new oral anticoagulants

such as dabigatran, rivaroxaban, apixaban and edoxaban. These are all employed to
prevent formation of thrombi within the dysfunctional atria, which could cause
embolic diseases. The target INR for warfarin therapy is 2-3, or 2.5-3.5 in patients at
risk of stroke. The stroke risk is calculated using the CHADS2 score
Parameter Score
Congestive heart failure 1
Hypertension 1
Age > 75 1
Diabetes mellitus 1
Stroke/TIA 2
If the score is greater than 2, oral anticoagulation is indicated. You can also use the
CHADS2VASc score, which includes additional risk factors:
Parameter Score
Congestive cardiac failure 1
Hypertension 1
Age ≥75 2
Diabetes 1
Stroke/TIA or thromboembolism 2
Vascular disease 1
Age 65-74 1
Sex category (female) 1
Anticoagulation is also started when the CHA2DS2-VAS. The efficacy of
anticoagulation using warfarin does not decrease with age.
• Rate control. Long-term rate control is achieved using AV nodal blocking agents. In
the absence of an accessory pathway, you can use non-dihydropyridine calcium
channel blockers, β-blockers and digoxin. Amiodarone may contribute. The resting
heart rate is considered controlled if it is below 110beats/min. if symptoms persist,
however, a resting heart rate of 60-80beats/min and a rate 110beats/min after
moderate exercise is aimed for. To assess adequacy of rate control, an ECG strip is
adequate in older patients, but in younger patients you need a 24-hour Holter
monitor (a 24-hour ambulatory ECG monitor) or an exercise-stress test.
• Rhythm control. This requires management of cardiovascular risk factors as well as
any other underlying disorder. It is indicated for patients who are young,
symptomatic and physically active. Any class Ia, Ic or III drug can be used. However,
amiodarone should be used as a last resort due to its wide extra-cardiac side effects.
If patients are in failure or have left ventricular hypertrophy, only amiodarone is

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 indicated. Rhythm control can also be achieved using cardioversion, or ablation of
pulmonary venous ectopics using cryo-thermal energy or radio-ablation.

Atrial flutter

This is an arrhythmia in which the heart produces organised atrial rhythms. The atrial rate is
often in the range of 240-400beats/min, and often every second atrial beat conducts to the
ventricles producing a ventricular rate of about 150bpm. There is usually some degree of AV
nodal block. 30% of patients have coronary artery disease, 30% have hypertensive heart
disease, and 30% have no identifiable heart pathology.

Pathophysiology

The majority of cases of atrial flutter occur as a result of a macro-re-entrant right atrial
circuit around the tricuspid annulus. The wave travels down the lateral wall of the right
atrium, down through the Eustachian isthmus (which is an area of slow conduction between
the tricuspid valve annulus and the ostium of the inferior vena cava & coronary sinus) and
up the inter-atrial septum. This is called typical/isthmus-dependent atrial flutter and is also
referred to as a counter-clockwise atrial flutter. Atrial flutter can also occur in the opposite
direction (atypical flutter).

Clinical presentation

Symptoms of atrial flutter are related to the degree of AV block. They are a result of reduced
cardiac output as a result of the rapid ventricular rate. The symptoms include:

• Palpitations.
• Fatigue/poor exercise tolerance.
• Mild dyspnoea.
• Presyncope.

Patients can easily degenerate into atrial fibrillation or sinus rhythm. Chronic stable atrial
flutter is rare. If there is a history of pre-excitation syndrome (e.g. Wolff-Parkinson-White
syndrome) there is a risk of 1:1 conduction, which can lead to ventricular fibrillation.

On examination, determine the vital signs (pulse rate, respiratory rate, blood pressure, SpO 2
and temperature) to determine the urgency of restoring sinus rhythm.

Investigations

The investigations done are:

• ECG. This will demonstrate saw-tooth flutter (F) waves. In a typical flutter, the F-
waves are inverted in leads II, III and AVF, positive in lead V 1 and are negative in lead
V6. In an atypical flutter, the opposite occurs. A clue to pre-excitation syndrome is a
very short PR interval with no delta wave.

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 • Echocardiograph. This is preferred for evaluating the size of the right & left atria,
thus facilitating diagnosis of valvular heart disease, left ventricular hypertrophy and
pericardial disease.

Management

Treatment approaches for atrial flutter are similar to those for acute atrial fibrillation.

• Cardioversion. This is the treatment of choice for an acute episode. Patients who
have had atrial flutter for more than 1-2 days need to be anticoagulated for 3 weeks
prior to cardioversion. Atrial flutter generally requires less energy than atrial
fibrillation. Cardioversion can also be achieved by using class Ic & III drugs.
• Rate control. Rate control may alleviate symptoms while awaiting cardioversion.
However, it is more difficult for atrial flutter than for atrial fibrillation. You can use
non-dihydropyridine calcium channel blockers & β-blockers, although negative
inotropic effects & hypotension are considerable concerns.
• Ablation. This is indicated for repeated episodes. You can use catheter ablation or
radiofrequency ablation. This creates a line of conduction block in the Eustachian
isthmus which prevents the re-entry circuit. This offers almost definite cure in
individuals in whom the atrial flutter is the only problem. However, atrial fibrillation
can occur later.

Atrial tachycardia

This is a rare type of tachycardia, accounting for less than 1% of all cases of cardiac
arrhythmias. It may be idiopathic or it may be related to structural heart disease. It can also
occur after open surgery for congenital heart diseases (causing macro-re-entrant circuits). It
can also occur as a result of digitalis poisoning. The mechanisms of atrial tachycardia are:

• Enhanced automaticity. This presents with high rates (125-250bpm). It is often

characterised by increasing atrial rates with onset of the tachycardia (warm-up) and
progressive decrease prior to termination.
• Triggered activity.
• Intra-atrial re-entry. This is usually relatively slow (125-150bpm). The PR interval
depends on the heart rate and it is longer than the PR interval in normal sinus
rhythm at the same rate.

On an ECG, you will see abnormal P-waves in front of QRS complexes. There may also be a
concomitant right bundle branch block particularly in digitalis toxicity.

Treatment options include cardioversion, anti-arrhythmic drug therapy (to maintain sinus
rhythm) and AV nodal slowing agents (to slow the rate). In some cases you can use ablative
techniques. In cases due to digoxin toxicity you need to stop digoxin and maintain
potassium at 4-5mM.

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AV junctional tachycardias
AV junctional tachycardias are usually referred to as paroxysmal SVTs. These are episodic
conditions with an abrupt onset & termination. They are often seen in young people with
little or no structural heart disease. They can also be seen in people with congenital
anomalies, such as tetralogy of Fallot, ASD and Ebstein’s anomaly. The first presentation of
these tachycardias is usually ages 12-30 years, and the prevalence is 2.5 per 100 000
population.

The junctional tachycardias are re-entry tachycardias where the AV node is an essential
component of the re-entry circuit. This may be induced by premature atrial or ventricular
beats. Other extrinsic triggers include hyperthyroidism and stimulants (caffeine, drugs and
alcohol).

Classification

The 2 types of AV junctional tachycardias include:

• AV nodal re-entrant tachycardia (AVNRT). This form of AV junctional tachycardia is

found in people older than 20, and are more common in women. It is characterised
by the presence of an anatomical variation in the AV node where there are 2
alternate pathways of conduction in the AV node. One pathway is called the α/slow
pathway which is a slow-conducting, short refractory period pathway, while the
other (called the β/fast pathway) is a rapid-conducting, long refractory period
pathway. A premature atrial beat triggers this pathway. It may reach the AV node
when the fast pathway is still refractory but the slow pathway is not. The impulse is
then transmitted down the slow pathway, and when it gets to the distal end it is
transmitted up the fast pathway (which is now excitable) in a retrograde direction.
When it gets to the proximal end of the AV node, it enters the slow pathway once
more (which has a short refractory period) and thus the cycle repeats itself. This sets
up a re-entry circuit with its own automaticity. This is the typical type of AVNRT, and
it results in a PR interval that is longer than the RP interval (therefore called short RP
interval tachycardia). You can get an atypical type of AVNRT in which the
anterograde signal is conducted down the fast pathway while the retrograde impulse
is conducted through the slow pathway. These produce an RP interval that is longer
than the PR interval (hence the name long RP interval tachycardia). On an ECG, you
will see a high tachycardia of 140-240 beats/min, and the P-waves are either not
visible or seen immediately before the QRS complex (due to simultaneous atrial &
ventricular depolarisation). Sometimes the QRS complexes will show a typical bundle
branch block.
• AV re-entrant tachycardia (AVRT). This one is more common in males and these
patients present at a younger age than those with AVNRT. In AV re-entrant
tachycardia, there are 2 or more conducting pathways between the atria &

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 ventricles, with the AV node being one of them. The most common accessory
pathways are the Kent bundles, which cause an AV re-entrant tachycardia known as
Wolff-Parkinson-White (WPW) syndrome. In WPW syndrome, there is also a delta
wave which is an initial deflection of the QRS complex owing to depolarisation of the
ventricles. There are different AV re-entrant patterns.
o Anterograde conduction. After atrial activation by the SA node, impulses
travel down these accessory pathways and activate the ventricles prior to
activating the atria. These are the most common ones. On an ECG you will
see the P wave between the QRS & T-waves if the patient is not in sinus
rhythm. If the patient is in sinus rhythm, you will see P-waves before the QRS,
although the PR interval will be shortened.
o Retrograde conduction. Some conduct in a retrograde direction, carrying
impulses from the ventricles to the atria. These are concealed pathways, and
they can only be seen as a sinus tachycardia. The concealed pathways set up
re-entry circuits, and this is called an orthodromic AVRT. Orthodromic AVRT
produces narrow-complex QRS complexes.
o Anterograde conduction with retrograde conduction of the atria. At times,
the accessory pathways conduct in an anterograde direction to depolarise
the ventricles and then then impulses travel in a retrograde direction through
the AV node to depolarise the atria. This is called antidromic AVRT. It
produces wide-complex QRS complexes.
o Bidirectional conduction.
Patients with accessory connections can get atrial fibrillation or atrial flutter. In these
cases, the P-waves on the ECG are not very distinct and most impulses generated in
the atria are conducted to the ventricles. This is called a pre-excitation atrial
fibrillation/flutter with irregularly irregular broad QRS complexes running at a fast
rate. This can degenerate into ventricular fibrillation, which is an emergency. These
patients should not be treated with agents that slow conduction across the AV node
(such as digoxin) as they increase conduction through the accessory pathways.

Clinical features

The clinical features of AV junctional tachycardias are:

• Sudden onset & termination of palpitations. This occurs in greater than 96% of
patients. These may be spontaneous or precipitated by movements or certain states.
These may be terminated by Valsaver manoeuvre. This is often associated with
dizziness.
• Cardiovascular compromise. This occurs in patients that do not have a good
functional reserve. The symptoms include fatigue, shortness of breath, chest pain
and syncope.

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 • Polyuria. This may be due to release of ANP due to raised atrial pressures during
atrial fibrillation or AVNRT.

On physical examination, patients are often distressed, and tachycardia may be the only
finding. In AVNRT, you can find prominent jugular venous pulsations. Patients may also
present with decompensated heart failure.

Investigations

The tests done are generally to rule out other differentials for symptoms as well as
identifying other causes.

• Cardiac enzymes. These are done to rule out acute coronary syndrome.
• U&Es. Electrolyte abnormalities can cause paroxysmal SVTs.
• FBC. This is used to assess whether anaemia is contributing to the tachycardia or
ischemia.
• TFTs to rule out hyperthyroidism.
• Digoxin levels for patients on digoxin.

Management

Management of AV junctional tachycardias is divided into acute & long-term management.

Acute management

In an emergency setting, the distinction between AVNRT & AVRT is not important as both
respond to the same treatment. Patients may be haemodynamically stable, and the only
problem they have is the on-going palpitations & dizziness. Other patients, however, may be
haemodynamically unstable, as indicated by hypotension, pulmonary oedema, chest pain
with ischemia or be unstable in general. These patients require emergency treatment. The
interventions include:

• Vagal manoeuvres. These are non-invasive interventions that increase output

through the vagal nerve. Vagal manoeuvres are the 1st-line interventions in
haemodynamically stable patients. They include breath-holding & the Valsaver
manoeuvre. These interventions slow conduction through the AV node and can
potentially interrupt a re-entrant circuit. You can also do a carotid massage on the
side of the non-dominant cerebral hemisphere. The carotid massage is reserved for
young patients. You can also employ facial emersion in cold water.
• Short-term pharmacologic agents. These agents work for paroxysmal SVTs in stable
patients who do not respond to vagal manoeuvres. These include adenosine (6mg by
iv push, followed by 12 mg if needed), verapamil (5-10mg over 5-10mins), diltiazem
and β-blockers (metoprolol & esmolol). Adenosine terminates 90% of paroxysmal
SVTs. The adverse effects of adenosine include flushing, chest pain, dizziness,

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 bronchospasm, heaviness of the lower limbs and a sensation of impending doom.
Verapamil can be used as an alternative.
• Electrical cardioversion. This is done as an emergency in patients with
haemodynamic instability. It is the most effective method of restoring sinus rhythm.
Synchronised cardioversion is started at 50J. If a patient has been in atrial fibrillation
for more than 24-48 hours, defer electrical cardioversion until the patient has been
adequately anticoagulated. Patients who are haemodynamically unstable require in-
patient admission.

Long-term management

Patients with a suspected arrhythmia should always be referred to a cardiologist for

electrophysical evaluation, long-term evaluation and pharmacologic management. Long-
term management includes:

• Pharmacologic intervention. The choice of long-term therapy depends on the

arrhythmia in question. Non-dihydropyridine calcium channel blockers (verapamil &
diltiazem) are effective, as well as β-blockers. These have been proven to have an
effectiveness of 60-80%. Less frequently, you can use class Ia & Ic (sodium channel
blockers) and class III blockers (potassium current blockers), such as amiodarone.
• Non-pharmacologic intervention. Radiofrequency ablation has been used to cure
many AV junctional tachycardias. Modification of the slow pathway is effective in
96% of patients with AVNRT. In AVRT, the target is the accessory pathway. The
success of ablation of a single pathway is 95%, with a recurrence rate of 5% requiring
a repeat procedure.

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 Ventricular tachycardias
Ventricular tachycardias are arrhythmias with heart rates above 100 beats per minute that
arise from the ventricles. The arrhythmias often cause wide-complex tachycardias, with
QRS complexes longer than 120ms, and ventricular tachycardias account for more than 80%
of these cases. The types of ventricular tachycardias include: life-threatening ventricular
tachycardias, QT syndromes, normal heart ventricular tachycardias, non-sustained
ventricular tachycardia and ventricular premature beats.

Non-life threatening ventricular tachycardias

The non-life threatening ventricular tachycardias are those that do not pose an immediate
threat to life when they present. However, they can predispose to other more dangerous
tachyarrhythmias. They include: normal heart ventricular tachycardia, non-sustained
ventricular tachycardia and ventricular ectopic beats.

Normal heart ventricular tachycardia

Monomorphic ventricular tachycardia in patients with structurally-normal hearts (the

idiopathic form) is usually a benign condition with an excellent long-term prognosis. It may
also be repeated, and this may lead to cardiomyopathy1. Normal heart ventricular
tachycardia arises from either a focus in the right ventricular outflow tract or in the left
ventricular septum. At times it is difficult to distinguish normal heart ventricular tachycardia
from arrhythmogenic right ventricular hypertrophy.

Treatment of symptoms is usually using β-blockers. There is also a verapamil-sensitive form

which responds to non-dihydropyridine calcium channel blockers. In symptomatic patients,
radiofrequency catheter ablation can be used, and it has a cure rate of greater than 90%.

Non-sustained ventricular tachycardia

This is a ventricular tachycardia that is sustained for at least 5 consecutive beats but lasts no
more than 30s. It can be found in 6% of patients with normal hearts, and it is documented in
60-80% of patients with heart disease.

An implantable cardioverter defibrillator has been shown to improve survival of patients

particularly with poor ventricular function (EF ≤ 30%). Antiarrhythmic treatment is usually
not encouraged, but β-blockers may improve quality of life in symptomatic patients.

Ventricular premature beat

1
This is called Galavardin’s tachycardia.

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 This is a beat that arises spontaneously prior to a signal from the atria. They are the
commonest post-MI arrhythmias. They may also be found in healthy patients, and in these
patients, they are significant if there are 10 or more beats per hour. They may be
uncomfortable, especially when frequent, and the patient complains of extra-beats, missed
beats or heavy beats, as they correspond to the premature beat, post-ectopic pause or next
sinus beat respectively. The pulse is irregular, although some early beats may not be felt at
the wrist.

On an ECG, the QRS complex is broad (>120ms) with a bizarre morphology and there is no
preceding P-waves. There is often a complete compensatory pause following the ectopic
because the AV node & ventricle are refractory. Early R-on-T ventricular beats (in which the
R-wave of the ectopic beat coincides with the upstroke/peak of the previous T-wave) may
induce ventricular fibrillation in patients with heart disease, particularly following MI.

Ventricular ectopic/premature beats are usually treated only when they are symptomatic.
Usually reassurance & β-blocker therapy is indicated. If the ectopics are very frequent, left
ventricular dysfunction may develop and if they come from a single focus (especially in the
right ventricle), catheter ablation can be very effective.

Life-threatening ventricular tachycardias

The life-threatening ventricular tachycardias include: ventricular fibrillation (with
haemodynamic compromise) and sustained ventricular tachycardia.

Sustained ventricular tachycardia

A ventricular tachycardia is defined by the presence of 3 or more consecutive ectopic

ventricular beats together with a tachycardia of above 100bpm (usually 140-200bpm). It is
defined as sustained when it lasts longer than 30s seconds, in which case it is life-
threatening. It is called ventricular flutter when the rate is above 200bpm and the
complexes resemble a sinusoidal pattern.

There are 2 types of ventricular tachycardias:

• Monomorphic VTs. In this form there are identical complexes with uniform
morphology. This is the most common type. They typically result from
intraventricular re-entry circuits. Potential causes include:
o Idiopathic.
o Chronic infarct scarring.
o Acute ischemia/MI.
o Cardiomyopathies.
o Myocarditis.
o Arrythmogenic right ventricular dysplasia.
o Drugs (e.g. cocaine).

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 o Electrolyte imbalances.
• Polymorphic VTs. In this form, the complexes are constantly changing in
morphology, amplitude and polarity. They are more frequently associated with
haemodynamic instability due to faster rates, as compared to the monomorphic VTs.
Potential causes include:
o Acute MI.
o Severe/silent ischemia.
o Predisposing factors to QT prolongation.

Clinical features

Patients develop presyncope, syncope, hypotension and cardiac arrest. In some patients,
this condition may be well-tolerated. There are often clinical signs of atrioventricular
dissociation, such as cannon a-waves in the JVP and variable intensity of the first heart
sound.

On ECG

On the ECG you will see a tachycardia with widened QRS complexes. AV dissociation will
result in visible P waves which march through the tachycardia and cause capture beats
(normal-morphology QRS complexes caused by conduction through the normal conduction
pathway from the atria to the AV node) and fusion beats (QRS complexes that are
intermediate between widened and capture beats).

A supraventricular tachycardia with LBBB/RBBB may resemble a ventricular tachycardia on

an ECG. However, these can be differentiated using the Brugada criteria:

VT SVT
Broad complexes + RBBB morphology
Lead V1 Monophasic R, QR or RS waves. Triphasic RSR
Lead V6 R-wave smaller than S-wave. Triphasic R wave.
QS/QR R-wave greater than S-wave.
Monophasic R-wave
Broad complexes + LBBB morphology
Lead V1/2 R-wave > 30ms.
>60s to nadir of S-wave.
Notched S-wave.
Lead V6 Presence of any Q, QR or QS No Q-wave

Treatment

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Sustained ventricular tachycardias are a medical emergency, and they need prompt
treatment2. The patients require supportive therapy initially:

1. Give high-flow oxygen per face mask.

2. Insert 2 wide-bore cannulae, and take bloods for FBC, U&E, cardiac enzymes and
CAMP. Correct any hypokalaemia.
3. Obtain a 12-lead ECG.

Treatment depends on the haemodynamic status of the patient upon presentation.

• If the patient is haemodynamically unstable, immediate DC cardioversion is

indicated.
• If the BP & cardiac output are well maintained, intravenous therapy with class I drugs
or amiodarone can be used. 1st-line drug treatment is IV lignocaine 50-100mg
infusion over 5 minutes, followed by slow infusion of 2-4mg/minute. Amiodarone is
given as a loading dose of 5mg/kg infusion over 1 hour followed by 1200mg over 24
hours. If medical therapy is unsuccessful, DC cardioversion is indicated.

After stabilising the patient, a full history & examination needs to be taken and the
diagnosis needs to be made backed by investigations. Maintenance cardioversion using
amiodarone may be required. To prevent recurrent VTs, you can use implantable automatic
defibrillators. In refractory cases, radiofrequency VT ablation may be tried.

Ventricular fibrillation

This is a chaotic ventricular activation with no mechanical effect. The condition is usually
provoked by an ectopic ventricular beat. The patient is pulseless, becomes rapidly
unconscious and develops cardiac arrest. It is usually a terminal event unless advanced
cardiac life support (ACLS) procedures are promptly initiated to maintain ventilation &
cardiac output, and electrical defibrillation is carried out. It is the most frequent cause of
death. On ECG, you will see shapeless rapid oscillations, and there is hint of organised
complexes.

To treat these patients, ACLS is needed. If the attack happened within 1-2 days of an acute
MI, prophylactic therapy is unlikely to be necessary. If the attack was not linked to a recent
MI, the long-term risks of recurrent cardiac arrests & sudden death are high. Implantable
cardioverter-defibrillators are the 1st-line therapy in the management of these patients.

Brugada syndrome

This condition accounts for some patients with idiopathic ventricular fibrillation who have
no evidence of causal structural cardiac disease. It is common in young male adults in SE

2
Even if you’re not sure of the diagnosis between ventricular & supraventricular tachycardias, treat the
disorder as a VT.

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Asia. The diagnosis is made by identifying ECG changes in patients that present
spontaneously, or by provocation using class I antiarrhythmic drugs. Classical changes
include RBBB & coved ST-segment elevation in leads V1-V3. In 20% of cases it is a monogenic
inherited condition associated with loss of sodium channel function due to a mutation in
SCN5A gene.

The condition can present with sudden death during sleep, resuscitated cardiac arrest and
syncope. The patient may also be asymptomatic and diagnosed incidentally or during family
assessment. The only successful treatment is an implantable cardioverter defibrillator. Use
of β-blockers is not useful and may actually be harmful.

QT syndromes
QT syndromes include long QT syndrome and short QT syndrome.

Long QT syndrome

Long QT syndrome describes a condition in which the QT interval is prolonged (the

corrected QT interval is usually more than 0.50s/500ms). The causes are divided into
congenital & acquired.

• Congenital long QT syndrome. 2 syndromes have been described – Jervell-Lange-

Nielsen syndrome and Romano-Ward syndrome. Jervell-Lange-Nielsen syndrome
may be associated with congenital deafness, while Romano-Ward syndrome is
usually not. The disorders are usually monogenic disorders associated with cardiac
sodium & potassium channel genes.
• Acquired long QT syndrome. Acquired long QT syndrome is more common. it is
usually provoked by bradycardia. The causes include:
Electrolyte imbalances: Drugs:
• Hypokalaemia. • Antiarrhythmic drugs - quinidine,
• Hypomagnesaemia. disopyramide, sotalol, and amiodarone.
• Hypocalcaemia. • TCAs, e.g. amitryptilline.
• Antipsychotic drugs, e.g. phenothiazines
(chlorpromazine), haloperidol, olanzapine.
• Macrolides.
• Quinolones.
• Methadone.
Poisons: Miscellaneous:
• Organophosphates. • Bradycardia.
• Insecticides. • Mitral valve prolapse.
• Acute MI.
• Diabetes.
• Prolonged fasting and long-term liquid protein
diets.

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 • CNS diseases, e.g. dystrophia & myotonia.

Clinical features

Patients with long QT syndrome develop syncope & palpitations secondary to a polymorphic
ventricular tachycardia. They usually terminate spontaneously, but may evolve into
ventricular fibrillation.

On ECG, the most notable feature is a prolonged QT segment, which is more notable
between spells of tachycardia or immediately before the onset of tachycardia. It may evolve
into Torsades de pointes (twisting of the points), which is characterised by rapid irregular
sharp complexes that rotate around the baseline, changing their axis & amplitude.

Treatment

The treatment of acquired long QT is as follows:

1. Treat the cause: correct electrolyte imbalances, stop any causative drugs.
2. Maintain the heart rate. This is done with atrial/ventricular pacing.
3. Magnesium sulphate. You give 2g IV over 10 minutes. Alternatively, you can use
isoprenaline3.

Congenital long QT syndrome is treated using β-blockers, pacemaker therapy and

(occasionally) left cardiac sympathetic denervation.

Short QT syndrome

There are 5 types of short QT syndromes described. They are caused by genetic
abnormalities leading to faster repolarisation. Ventricular arrhythmias & sudden death can
occur. Implantable cardioverter defibrillator is the best treatment.

3
Isoprenaline is contraindicated in congenital long QT syndrome.

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 Deep vein thrombosis (DVT)
Deep vein thrombosis is the formation of a thrombus in one of the large veins, particularly
those draining the limbs or major organs. Thrombosis usually occurs after periods of
immobilisation, but can occur in normal individuals for no obvious reasons. It is most
common in the veins of the lower limb, and it is commonest in the veins of the calf.

DVTs are common in hospitalised patients; they occur in 25-50% of surgical patients and
many non-surgical patients. They are often undetected; 65% of below-knee DVTs are
asymptomatic. Axillary vein thrombosis may also occur, sometimes related to trauma.

Risk factors
The risk factors for developing DVTs are related to anything that disrupts the Virchow’s
triangle. It consists of: endothelium, blood flow and coagulability. In other words, condition
that increase risk of DVT formation are those that disrupt the endothelium, interrupt/slow
blood flow or increase the coagulability of blood (by increasing its constituents/making it
more viscous, or by activating clotting factors).

The risk factors for DVT are:

• Age. Increasing age predisposes to DVT formation. It may be related to a number of

factors, such as decreased mobility as one gets older.
• Pregnancy. Pregnancy predisposes to DVTs through an increase in clotting factors
(factors VII, VIII, IX, X, XII and fibrinogen). Von Willebrand factor levels also increase.
There is also a decrease in the activity of protein S. Furthermore, the reduced
mobility and increased lower limb venous congestion increase the chances of DVT
formation.
• Synthetic oestrogen. Synthetic oestrogens increase the risk of DVT formation. They
are mainly found in oral contraceptive pills and in drugs used for hormone
replacement therapy.
• Trauma.
• Surgery.
• Past DVT.
• Cancer.
• Obesity.
• Immobility. Immobility induces stasis of blood in the venous system, particularly in
the lower limbs. This leads to a reduced flow of blood in the veins.
• Thrombophilia. Thrombophilia increases the number of platelets, thus increasing the
coagulability of blood.

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Clinical features
Patients may be asymptomatic. Nonetheless, they may present with:

• Calf pain.
• Swelling & redness.
• Engorgement of superficial veins.
• Mild fever.
• Pitting oedema may be present.
• Cyanotic discoloration of the limb. This can occur with complete occlusion of a large
vein. It is usually accompanied by severe oedema.
• Pulmonary embolism. This can occur from any deep venous thrombosis. It is most
common, however, with iliofemoral thrombosis.

Investigations
The tests done in investigating a DVT are:

• D-dimer levels. D-dimers are fibrin degradation products that signify breakdown of
an already-made fibrin clot. Their levels signify the presence of secondary
haemostatic activity. High D-dimer levels would point towards the presence of
thromboembolic phenomena. Nonetheless, they are not specific, and they are
elevated in infections, pregnancy, malignancy and post-operative period. A negative
result, however, is highly suggestive of absence of disease.
• Doppler ultrasound. This is an ultrasound test that is done to assess the patency of
blood vessels. It can be used to rule out occlusions as a definitive test. The Doppler
ultrasound has a sensitivity & specificity of over 90%. If the Doppler ultrasound is
negative, do a repeat ultrasound after 1 week to pick out early but propagating
DVTs.
• Thrombophilia testing. This should be done in a patient before commencing
anticoagulant therapy if there are no predisposing factors, in recurrent DVTs or when
a family history is present.
• Screening for underlying malignancy. Do FBCs, LFTs, serum calcium, chest X-ray and
CT scan of the pelvis and/or abdomen.

Treatment
The primary aim of treatment is to stop the progression of the thrombus as well as prevent
pulmonary embolism. Anticoagulation is therefore indicated for patients with above- &
below-knee thrombi. Bed rest is advised until the patient is fully anticoagulated. Afterwards,
they should be allowed to mobilise and given a pressure stocking to give graduated pressure
on the leg.

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Low-molecular weight heparin (LMWH) is used to anticoagulate patients in the acute period.
You can use enoxaparin 1.5mg/kg/24 hours. You can also use fondaparinux, an activated
factor X (factor Xa) inhibitor. LMWH is superior to unfractionated heparin because it is
associated with less heparin-induced thrombocytopaenia, it can be taken at home and it has
a lower risk of bleeding. Warfarin can be started concurrently, and it is beneficial to start the
2 together because warfarin has a slow onset of action and in the initial stages warfarin
actually increases the risk of thrombosis1.

The duration of warfarin treatment is debatable. 3 months is the recommended period, but
4 weeks is long enough if a definite risk factor has been present. Cancer patients should
receive LMWH for 6 months.

You can also use an inferior vena cava filter if the patient is actively bleeding or when
anticoagulants fail to reduce the risk of pulmonary embolism. Thrombolytic therapy may be
employed for thrombi in large veins, but there is the risk of bleeding.

Prevention of DVT
DVTs can be prevented. Because a large number of thrombi develop in hospitalised patients,
we can significantly prevent them by employing measures to prevent their development.
The principles are:

• All patients should be assessed for presence & risk of DVT on admission and 24 hours
after admission or when their condition changes.
• Use the Wells score to assess for the likelihood of developing a DVT.

Wells score
Clinical features Score
Active cancer with treatment in the last 6 months, or palliative. +1
Paralysis, paresis or recent plaster immobilisation of leg. +1
Recently bed-ridden for more than 3 days, or major surgery in last 12 weeks. +1
Local tenderness along distribution of deep venous system. +1
2
Calf swelling of greater than 3cm compared with asymptomatic leg. +1
Pitting oedema. +1
Collateral superficial veins. +1
Previously documented DVT. +1
Alternative diagnosis to DVT as likely as DVT. -2
If the patient’s Wells score is 1 or below, a DVT is unlikely. The patient should have a D-
dimer test done and excluded if the D-dimer level is low. If D-dimer test is positive, do a
Doppler ultrasound test to confirm or exclude a DVT. If the patient’s Wells score is 2 or
more, do a D-dimer test & Doppler ultrasound. If both are negative, the DVT is excluded. If

1
In this case, heparin is stopped when INR is in the target range.
2
This is measured 10cm below tibial tuberosity.

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Doppler ultrasound is positive, treat as DVT. If D-dimer is positive and Doppler ultrasound is
negative, repeat the Doppler ultrasound after 1 week. If it is negative, exclude DVT. If
positive, treat as DVT.

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 Shock
Shock is acute circulatory failure resulting ultimately in reduced tissue perfusion. There is
generalised tissue hypoxia and it may be accompanied by an inability to utilise oxygen. It is
often defined by a hypotension of less than 90mm Hg systolic pressure or less than 65mm
Hg mean arterial pressure. Urine output is often reduced.
The types of shock are:

• Hypovolaemic shock.
• Cardiogenic shock.
• Septic shock.
• Anaphylactic shock.
• Neurogenic shock.
• Spinal shock.

Mechanism of shock
The blood pressure is a product of cardiac output and peripheral vascular resistance. Cardiac
output is determined by the stroke volume & heart rate, while peripheral resistance is
determined by arterial vascular tone. Therefore there are 2 ways in which shock can
develop:

• Shock can develop when the cardiac output decreases. It can be a result of a
reduction in the circulating volume, as is the case in hypovolaemic shock or in
obstructive shock. It can also be a result of pump failure (cardiogenic shock).
• Shock can also develop as a result of reduced peripheral vascular resistance. This is
the case in septic shock, anaphylactic shock and neurogenic & spinal shock.

Hypovolaemic shock
Hypovolaemic shock is the common type of shock around. It is a result of reduced
circulatory volume, and it is usually serious when it overwhelms the cardiovascular
compensatory mechanisms. Causes of hypovolaemic shock can be divided into exogenous
and endogenous. Exogenous causes are ones in which fluid leaves the body through the skin
or a visceral compartment. They include haemorrhage and ECF losses from burns or from
vomiting & diarrhoea. Endogenous causes include 3rd-spacing.
Pathophysiology
In response to acute fluid or blood loss, the following happens:

• Haematologic changes. The initial response to blood loss is contraction of blood

vessels supplying the bleeding part (mediated by thromboxane A2). This is followed
by formation of the platelet plug, which is also under the influence of thromboxane
A2. This is then followed by formation of a fibrin clot. The success of the whole

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 process depends on many factors, such as the size of the wound and the flow rate of
blood out of the lesion.
• Cardiovascular changes. The heart initially responds to volume contraction by
increasing heart rate & myocardial contractility and constricting peripheral blood
vessels. These effects are caused by the sympathetic nervous system and reduced
vagal tone. They aim to maintain blood pressure so as to keep the tissues well-
perfused. There is also redistribution of blood to the heart, brain and kidneys and
away from skin, muscle and the GIT.
• Renal changes. The kidneys respond by activating the RAAS system, which aims to
maintain extracellular fluid volume. The end products are angiotensin II &
aldosterone. Angiotensin II & aldosterone both stimulate reabsorption of water from
the tubular fluid, while angiotensin II has the added effect of causing
vasoconstriction of vessels.
• Neuroendocrine system. There is an increase in circulating ADH hormone in
response to decreased blood pressure & ECF sodium (hyponatraemia). This hormone
also helps in reabsorption of sodium & water from the tubular fluid.
Clinical features
In the initial stages, shock can be recognised by pallor, tachycardia, weak thread pulses and
signs of diminished tissue perfusion (such as prolonged capillary refill). The patient may feel
dizzy, faint, nauseated and very thirsty. Blood pressure usually falls after significant
blood/fluid loss. Children usually compensate for longer periods than adults, but when they
deteriorate they deteriorate faster than adults. In the history you need to determine the
source of bleeding, whether it is from haemorrhage or from vomiting, diarrhoea or burns
scar. You should do a secondary survey to check for all signs suggestive of major trauma and
therefore a likely source of bleeding.
The stages of haemorrhagic shock are:

Stage 1 Stage 2 Stage 3 Stage 4

Blood loss <15%/750ml 15-30% / 30-40% / 1.5-2L >40%/2L
750ml-1.5L
Blood Compensated Increased Systolic below Systolic below 70mm
pressure (normal) diastolic BP1 100mm Hg Hg
Heart rate Normal Slight Tachycardia > Extreme tachycardia
tachycardia 120 (>140) and weak
>100 thread pulses
Respiratory Normal Increased Tachypnoea Extreme tachypnoea
rate (>30)
Mental normal Slightly Altered mental ↓LOC, lethargy, coma
status anxious state, confused
Skin Pallor Pale cold Diaphoresis Extreme diaphoresis.
clammy hands Mottling possible

1
This indicates narrowing of the pulse pressure.

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Capillary Normal Delayed Delayed Absent
refill
Urine Normal 20-30ml/h 20ml/h Negligible
output

Investigations
The investigations to be done include:

• Blood pressure.
• Oxygen saturation monitoring.
• FBC (anaemia, infection), cross-matching, U&E (renal function: rule out AKI), blood
glucose and blood cultures for screening for infection.
• Urine output measurement.
Management
In the initial setting, the most important thing is to identify the source of bleeding and
control bleeding. This is in the event that the cause of shock is haemorrhagic. You should
also raise the legs to increase venous return.
The management of a hypovolaemic patient in resuscitation is indicated for patients in
stages 2 going forward. The management is as follows:
1. Insert 2 wide-bore cannulas (e.g. 14-gauge cannulas; grey).
2. Take blood samples for FBC & cross-matching.
3. Run 10-20ml/kg of crystalloid (2L in an average adult) in the patient over 10 minutes.
4. Have 2 units prepared for possible blood transfusion.
5. Insert a urinary catheter to monitor urine output.
6. Insert an NGT tube to decompress stomach.
The subsequent management depends on the response to resuscitation:

• Rapid responders. These are patients whose haemodynamic status is restored after
initial resuscitation. The patients are usually those in stage 1 shock.
• Transient responders. These are patients who initially respond after resuscitation,
but when the bolus infusion is slowed to maintenance their vitals & perfusion
deteriorate. The patients either need more fluid or have on-going losses. They need
blood and they need surgical control of haemorrhage.
• Non-responders. These are patients who do not respond to initial resuscitation. They
need immediate surgical referral to locate & stop the source of bleeding. Blood
transfusion is withheld until the bleeding source is stopped.

Cardiogenic shock

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Cardiogenic shock is shock caused by cardiac dysfunction: it is defined by decreased cardiac
output & evidence of tissue hypoxia with adequate intravascular volume. It is a medical
emergency. It can occur acutely or after progressively worsening heart failure.
Aetiology
The causes of cardiogenic shock can be classified into:

• Myocardial dysfunction. This can occur as a result of myocardial infarction,

myocarditis and heart failure. The vast majority of cases are a result of acute MI, and
cardiogenic shock is associated with more than 40% loss of left ventricular
myocardium. Furthermore, complications of MI including ruptured interventricular
septum can also cause cardiogenic shock.
• Valvular heart disease. The valvular heart lesions that can cause shock are:
endocarditis, mitral/aortic regurgitation, valve obstruction due to thrombus or
myxoma, papillary muscle dysfunction/rupture and mitral stenosis. Valvular
disorders cause cardiogenic shock by either reducing forward flow (e.g. aortic
regurgitation) or by obstructing outflow (e.g. myxoma or thrombus).
• Arrhythmias. Ventricular arrhythmias are associated with cardiogenic shock.
Bradycardias can aggravate shock due to other aetiologies. Sinus tachycardias and
atrial tachy-arrhythmias contribute to hypoperfusion and aggravate shock.
• Regional pathology. Diseases within the lungs, chest and pericardial cavities can
cause cardiogenic shock, mainly through pressure effects that restrict the filling of
the heart or restrict ejection of blood. Regional causes include: cardiac tamponade,
pulmonary embolism, pulmonary disease (e.g. COPD & ARDS), tension
pneumothorax, aortic dissection and coarctation of the aorta.
• Systemic disease. Systemic conditions and states can complicate with cardiogenic
shock. These include acidosis, hypocalcaemia, hypophosphataemia, hypoxia and
sepsis. Other conditions include malignant hypertension and sleep-breathing
disorders.
• Drugs. Medications that cause cardiogenic shock include ACE inhibitors, β-blockers2
and doxorubicin. Cocaine use is also associated with cardiogenic shock.
Clinical features
Patients with cardiogenic shock have similar features to those that have hypovolaemic
shock: tachycardia, weak thread pulse, cool clammy mottled skin, oliguria and
hyperventilation. However, unlike hypovolaemic shock, cardiogenic shock patients are fluid
overloaded: distended jugular veins, pulmonary oedema and peripheral oedema. There may
also be an abnormal/absent pulse in patients with arrhythmias.
Patients with cardiogenic shock may also develop symptoms of acute myocardial infarction
prior to the shock. You can ask about severe chest pain in the cardiac area radiating to the
left arm, neck or abdomen. Patients should also be asked about cardiovascular symptoms:

2
Β-blockers & ACE inhibitors usually cause cardiogenic shock in the setting of acute coronary syndrome.

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exertional dyspnoea or dyspnoea at rest, orthopnoea, PND and diaphoresis. When taking a
history, ask about a history of an MI, cocaine use, or previous cardiac surgery.
Investigations
The investigations done in a patient with cardiogenic shock include:

• ECG. This can be done in the immediate setting as a patient comes in. it helps
identify features linked to the aetiology: abnormal heart rhythm (arrhythmias), acute
MI (ST elevation, deep Q-waves) and signs suggestive of cardiomyopathy (left
ventricular enlargement).
• Echocardiography. This will show the calibre of heart muscles and their function. It
may show poor ventricular function, rupture of interventricular septum, an
obstructed outflow tract or cardiomyopathy.
• Biopsy. This is done for patients in whom cardiomyopathy is suspected.
• Cardiac index. This relates the cardiac output from the left ventricle to the patient’s
total body surface area. It relates cardiac performance to the size of the individual.
𝐶𝑂
𝐶𝐼 =
𝑇𝐵𝑆𝐴
The normal range is 2.6-4.2L/min. A cardiac index of less than 2.2L/min is suggestive
of cardiogenic shock.
• Blood investigations. FBC can be used to exclude anaemia, infection and
coagulopathy3. Cardiac enzymes can be measured for patients with anaemia. Arterial
blood gas measurement can be done to assess the overall acid-base balance of the
patient as well as degree of oxygenation of the patient.
• Filling pressure. This can be measured using a Swan-Ganz catheter. It measures the
filling pressure of the heart. The normal filling pressure is 8-10mm Hg.
Management
Cardiogenic shock is a medical emergency, and patients require prompt admission into an
intensive care unit. The majority of patients should be treated as though they have a
myocardial infarction. Treatment is as follows:
1. Oxygen & ventilator support. In patients that are not able to breathe properly, you
may need to ventilate them. Positive pressure ventilation is not advised because it
may compromise venous return & preload to the heart. Oxygen should be titrated to
maintain oxygen saturations of 94-98%. The target may be lowered to 88-92% in
patients with COPD.
2. Analgesia. You can give diamorphine (heroine) 1.25-5mg stat intravenously.
diamorphine also helps ease anxiety.
3. Fluid administration. Fluid can be given unless pulmonary oedema is present. This is
to optimise filling of the heart, provided the patient is under-filled. The patient is
given 100ml intravenously every 15 minutes. You should aim for a mean arterial
pressure of 70mm Hg and a central venous pressure of 8-10mm Hg.

3
This may be low due to sepsis.

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4. Inotropic support. This is given for patients that are well/over-filled. Dobutamine
can be infused intravenously at a dose of 2.5-10µg/kg/minute. Other agents you can
give include milrinone & inamrinone.
5. Thrombolysis. Thrombolytic therapy is considered for patients with concurrent
cardiogenic shock and acute MI or pulmonary embolism. Its benefits in these
patients, however, are poor.
6. Surgery. You can do prompt revascularisation surgery for patients with myocardial
infarction: you can employ acute angioplasty or fibrinolysis. In extreme cases, you
can use a ventricular assist device or a heart transplant.

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 Abdominal history
The abdomen is a large cavity that houses a large number of visceral organs (it is “a bag of
viscera”). Unlike the thorax, the abdomen does not have a profound skeletal cage that
protects it. Rather, most of its stability & protection comes from the muscular wall which is
covered by subcutaneous fat. Most of the organs found in the abdomen form part of the
alimentary canal: the lower third of the oesophagus, the stomach, the duodenum, the
jejunum & ileum, the colon, the rectum & anus, the liver & gall bladder and the pancreas. In
addition to these organs, there are other organs that do not form the alimentary canal, such
as the spleen, kidneys and ureters.

The major presenting abdominal symptoms are:

• Abdominal pain.
• Abdominal distension.
• Loss of appetite & weight change.
• Nausea & vomiting.
• Heartburn.
• Diarrhoea & faecal incontinence.
• Constipation.
• Bloating.
• Postprandial fullness/early satiety.
• Jaundice & pruritus.
• Dark urine.
• Pale stool.

Abdominal pain
Abdominal pain is a common presentation in abdominal disease. When a patient presents
with abdominal pain, you need to enquire about the exact site of the pain and its character,
timing/pattern, severity, radiations, aggravating factors. A correct description of the pain
will usually give a clue to the exact illness that a patient has. Abdominal pain is mainly a
result irritation of the peritoneum. There are 3 types of abdominal pain.

• Parietal pain. Parietal pain is a result of irritation of the parietal peritoneum. Parietal
peritoneum has numerous receptors, such as pain, temperature, stretch and others.
Parietal pain is conducted by somatic nerve fibres that have pin-point distribution in
the abdomen. It is therefore sharp & well localised. It is also aggravated by
movement. Peritonitis is a cause of parietal pain, and in this case is it associated with
tenderness on light palpation and rebound tenderness.

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 • Visceral pain. Visceral pain is a result of pathology from the visceral organs in the
abdomen. Unlike the parietal peritoneum, the visceral peritoneum is only sensitive
to stretch. Therefore, abdominal pathology can only felt as pain if it stretches or
twists its peritoneal covering. Furthermore, visceral pain is not well-localised. It is
perceived as though the entire organ is affected rather than as a specific point. It is
carried by splanchnic nerves that merge with nerves from other somatically-
innervated structures in the spinal cord1. The pain will be felt as a dull pain felt over
a wide area.
o Pain from foregut derivatives – oesophagus, stomach, 1st & 2nd parts of the
duodenum, liver and pancreas – will be felt in the epigastrium.
o Pain from midgut derivatives – 3rd & 4th parts of the duodenum, the rest of
the small intestine, the caecum & appendix2, the ascending colon and the
2
proximal 3s of the transverse colon – are referred to the umbilical region.
1
o Pain from the hindgut derivatives – distal 3 of the transverse colon, the
1
descending colon, the sigmoid colon, rectum and proximal 2 of the anus – are
referred to the pubic region.
• Referred pain. Pain may be referred from other structures and felt in the abdomen.
For example, pain of cardiac origin may be felt in the epigastrium. Other abdominal
organs also cause radiation to other sites, e.g. the kidneys & ureters and the testes
and/or ovaries.

The onset of abdominal pain is a good indicator of the cause of the pain. Sudden onset of
pain suggests intestinal obstruction/perforation, ruptured abdominal aortic aneurysm or
mesenteric infarction (these would be further supported by other comorbid conditions,
such as hypertension, peripheral vascular disease, heart failure or atrial fibrillation). Sudden
onset conditions are therefore those conditions in which there is mechanical obstruction or
damage to abdominal viscera.

Pain radiating from the right hypochondrium to the shoulder or inter-scapular region
suggests diaphragmatic irritation. There are various other radiations. The combination of
severe back & abdominal pain may suggest ruptured or disseminated abdominal aortic
aneurysm.

Some of the common pain patterns that are produced abdominal pathology are:

• Peptic ulcer disease. This produces a dull & burning pain in the epigastrium
(described as a gnawing pain) that radiates into the back. It is typically episodic and
may occur at night, and each episode lasts for 30 minutes to 2 hours. It is relieved to
some degree by food & antacids, although it is not always related to meals. It is

1
The nerves will fuse with the nerves from structures that arise from the same dermomyotome as the viscous
in question.
2
The appendix, however, has a spectrum of pain symptoms that are unique to it.

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 exacerbated by stress, spicy foods, alcohol and NSAIDs. Patients may have
remissions for weeks or months between attacks. The pain is mild.
• Pancreatic pain. This produces constant epigastric/hypochondriac pain that radiates
into the back. It is relieved by sitting forwards, and exacerbated by drinking alcohol.
The pain is sudden in acute pancreatitis. Attacks last more than 24 hours and attacks
are enumerable. The pain is usually severe. Vomiting is common.
• Biliary pain. This produces severe constant pain in the epigastrium or right
hypochondrium. The pain radiates to the region just beneath the right scapula.
Episodes are enumerable and they typically last 4-24 hours. Patient is unable to eat
during bouts and there are no relieving factors. Biliary pain can be caused by
obstruction of the cystic duct by cholelithiasis and cholecystitis. Biliary pain is often
associated with nausea & vomiting.
• Renal colic. This is colicky pain that is superimposed on a background of constant
pain at the renal angle. In the abdomen, this pain can be found in the loin region and
it radiates into genitalia & the inner thigh. The attack is usually a discrete episode
that lasts 4-24 hours.
• Bowel obstruction. This is a colicky pain that is more pronounced in small bowel
obstruction. It is colicky due to peristaltic movements, and therefore small bowel
obstruction is less frequent (every 2-3 minutes) than large bowel obstruction (every
10-15 minutes). If it is found in the paraumbilical region, it is most likely small bowel
obstruction. Obstruction is often associated with vomiting, constipation and
abdominal distension.

Anorexia & weight loss

Nausea & vomiting

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 Diarrhoea
Diarrhoea is the passage of more than 250g of stool per day in teenagers & adults (or more
than 10ml/kg/d in children). The stool is made up mostly of water. It is due to an imbalance
between absorption & secretion of water into GI contents. It can be acute diarrhoea, where
diarrhoea occurs as an abrupt onset of 3 or more episodes of loose stools per day occurring
over less than 14 days. It can also be chronic/persistent diarrhoea, where the diarrhoea
episode lasts longer than 14 days. This distinction is important in marking out the different
possible aetiologies of diarrhoea.

Pathophysiology of diarrhoea
Diarrhoea is caused by an imbalance between absorption & secretion of fluid into the GIT.
Normally, when food passes through the GIT, there is secretion of large amounts of water
into the GIT in the form of digestive secretions. This water is then reabsorbed in the
intestines, and enterally-taken water is also absorbed. Any process that increases secretion
and impairs absorption leads to diarrhoea.

The different mechanisms by which diarrhoea occurs are:

• Osmotic diarrhoea. Osmotic diarrhoea is a result of a non-absorbable osmotic agent

trapping water in the lumen of the GIT. The proportion of water in stool is
proportional to the amount of non-absorbable osmotic agent taken up. This is the
result of 3 actions.
1. It could be the result of ingestion of a non-absorbable agent, e.g. lactulose or
magnesium sulphate.
2. It could be the result of generalised malabsorption leading to high
concentrations of normally absorbed solutes (e.g. glucose) remaining in the
intestines.
3. It could be the result of a specific absorptive defect, such as disaccharidase
deficiency leading to lactose intolerance.
• Secretory diarrhoea. Secretory diarrhoea is the result of an active process occurring
in the intestinal mucosa leading to the pumping of ions into the intestinal lumen,
resulting in concomitant secretion of water. This is the result of an agent stimulating
active secretion of these ions by binding to receptors or ion channels. Examples of
stimulating agents include enterotoxins (e.g. cholera toxin, E. coli heat-labile & heat-
stable toxins, C. dificile), hormones (e.g. VIP), bile salts & fatty acids (following ileal
resection), and some laxatives (e.g. docusate sodium).
• Inflammatory diarrhoea. This is the result of inflammatory destruction of the
intestinal mucosa. This results in the loss of fluid and blood into the stool. Examples

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 of causes include infections (such as Shigella) and inflammatory conditions (e.g.
inflammatory bowel disease).
• Abnormal motility. Increased GIT motility decreases the passage time of stool and
therefore decreases the time allowed for absorption of water. This can be the result
of diabetes, post-vagotomy and hyperthyroidism. Symptoms may be exacerbated by
small bacterial overgrowth.

The location of the pathologic process of the diarrhoea is also important in determining the
cause. Small intestinal diarrhoea is associated with large amounts of watery diarrhoea
associated with abdominal cramps. Fever and weight loss are rare features. Large intestinal
diarrhoea is associated with frequent low-volume toilet visits associated with colicky
abdominal pain, urgency1, tenesmus2 and incontinence. Fever and bloody stool are
common.

Aetiology
The causes of diarrhoea can be classified into infectious & non-infectious.

Infections

The infectious causes are the most common causes of diarrhoea.

Bacteria are not the most common causes of diarrhoea, but they are the most common
causes of severe diarrhoea with complications. The bacterial causes of acute diarrhoea are:

• E. coli. E. coli possesses a wide range of virulence factors, which are either
endotoxins or exotoxins. E. coli is a normal GIT commensal, and infection occurs due
to acquisition of virulence factors. Majority of infections arise endogenously. There
are 5 major subgroups of E. coli. These are:
o Entero-toxigenic E. coli (ETEC). ETEC is one of the most common forms,
accounting for 650 million cases per year. It is acquired by ingesting
contaminated food or water. It produces secretory small intestinal diarrhoea.
ETEC produces both heat-stable & heat-labile toxins, and the heat-labile toxin
1 is structurally similar (has an α-subunit and 5 β-subunits) & has similar
actions to the cholera toxin. The heat-labile toxin binds to the cholera
receptor and the α-subunit leads to activation of a Gs-protein which leads to
an increase in intracellular cAMP. The heat-stable toxin binds to a
transmembrane guanylyl cyclase receptor which leads to an increase in
cGMP. Both these toxins lead to secretion of chloride ions and inhibition of
sodium & chloride reabsorption. The diarrhoea is profuse & watery.

1
Faecal urgency is the inability to postpone urges to defecate.
2
Tenismus is the continuous/recurrent sensation of wanting to evacuate bowel.

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 o Entero-pathogenic E. coli (EPEC). EPEC is a major cause of infantile diarrhoea
in developing countries. It is rare in older children & adults probably due to
acquired protective immunity. EPEC is spread by person-to-person spread,
and the infectious dose is low. The bacterium attaches to enterocytes of the
small intestines and leads to effacement of microvilli. The attachment is
mediated by BFP (bundle-forming pili). EPEC causes a watery diarrhoea that
may be severe & protracted.
o Entero-aggregative E. coli (EAEC). This bacterium causes chronic/persistent
watery diarrhoea with dehydration in infants. It is associated with growth
retardation. The bacteria are characterised by their auto-agglutination in a
stacked brick arrangement. Aggregation is mediated by aggregative
adherence fimbriae (AAF). After adherence, EAEC stimulates mucus
production, which helps protect the organism from antibiotics & phagocytic
cells. EAEC also produces toxins: entero-aggregative heat-stable toxin and a
plasmid-encoded toxin.
o Entero-haemorrhagic E. coli (EHEC). EHEC is the most common cause of
disease in developed countries. Most cases are caused by undercooked beef
& meat products, water, unpasteurised milk & fruit juices and undercooked
vegetables. Person-to-person spread can occur, and the infectious dose is
very low. Disease ranges from uncomplicated watery diarrhoea to
haemorrhagic colitis with severe abdominal pain & bloody diarrhoea. The
diarrhoeal process occurs in the large intestine. Vomiting is seen in half of
patients but high fever is absent. HUS can develop as a complication in
untreated disease. Some strains also acquire the Shiga toxin which is similar
to the Shiga toxin produced by Shigella dysenteriae.
o Entero-invasive E. coli species (EIEC). This one is rare. The bacteria infect the
colonic epithelium and they invade & destroy colonic epithelial cells. The
diarrhoea is initially watery but may progress to dysentery in a minority of
patients, associated with fever & abdominal cramps and blood & leukocytes
in stool specimens.
• Shigella. Shigella organisms are actually biogroups within the species E. coli, but it
would be confusing to refer to them as such. Shigella invades & replicates
intracellularly in the cells lining the colon, although it initially infects the small
intestine. They appear unable to attach & replicate within differentiated cells.
Rather, they invade the M cells in Peyer’s patches instead. The organisms survive
phagocytosis by inducing apoptosis in the cells they infect. S. dysenteriae is the one
that mostly causes dysentery, and other species include S. sonnei & S. flexneri. It
produces a Shiga toxin similar to the one produced by EHEC. Humans are the only
reservoir for this genus, and therefore spread by person-to-person contact through
the faecal-oral route. It also has a very low (100-200 bacteria) infectious dose.
Shigellosis is predominantly a disease of childhood, although the disease is endemic

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 in adult child-handlers and homosexual men. Shigellosis is characterised initially by
profuse watery diarrhoea (mediated by an enterotoxin), followed by abdominal
cramps, tenesmus and blood- & pus-stained stool. The infection is often self-limiting,
although antibiotic treatment is encouraged to prevent spread to others.
• Salmonella. The Salmonella genus consists of S. typhi and S. paratyphi, as well as
other less significant types such as S. enterica, S. choleraesuis, S. typhimurium and S.
enteritidis. Most Salmonella species (more than 2500), however, have been noted to
be subtypes of S. enterica. This organism also replicates intracellularly in M cells, but
within vesicles rather than within the cytosol (as with Shigella). The bacterium can
also be released into the circulation, therefore leading to effects elsewhere other
than the GIT. Salmonella can colonise virtually all animals (even reptiles), but S. typhi
& S. paratyphi are highly adapted to humans. Most infections are due to ingestion of
contaminated food & water. Most Salmonella species often requires a high
infectious dose to cause infection, although that for S. typhi is low. The spectrum of
diseases that can result from Salmonella infection are: asymptomatic colonisation,
gastroenteritis, septicaemia and enteric fever. Gastroenteritis is most common, and
often the initial presentation consists of nausea, vomiting and non-bloody diarrhoea.
Fever, abdominal cramps, myalgias and headaches are common.
• Vibrio cholerae. V. cholerae is the causative agent for cholera. The bacterium
produces an exotoxin which has 2 subunits – α- & β-subunits – which lead to
constitutional secretion of chloride ions into the intestinal lumen. It also produces a
zonula occludens toxin and an accessory cholera enterotoxin. It leads to production
of a profuse watery diarrhoea, leading to loss of up to 1L per hour. The diarrhoea is
described as a rice water diarrhoea. Vibrio species are able to survive in
contaminated water with increasing salinity. Asymptomatic humans can also be a
reservoir in areas where cholera is endemic. The bacterium is spread by
contamination of food & water, rather than direct person-to-person contact due to a
high inoculum being required. It often occurs in epidemics in areas where sanitation
is a problem. The disease has a mortality of 60% in untreated individuals.
• Campylobacter. Campylobacter primarily causes gastroenteritis & septicaemia, and it
is the most common cause of gastroenteritis in the US. The causative species are C.
jejuni and C. coli, with C. coli being more common in developing countries.
Campylobacter is difficult to grow with conventional culture media – it requires
special culture media with decreased oxygen (5-7%) & increased carbon dioxide (5-
10%). C. jejuni also grows best at 42°C. Campylobacter is primarily zoonotic, and
animals act as the reservoir. Contaminated poultry are responsible for more than
50% of infections. C. jejuni primarily damages the mucosa of the jejunum, and it has
been linked to the development of Guillain-Barre syndrome. Infection with
Campylobacter produces an acute gastroenteritis with diarrhoea, fever and
abdominal pain. Stool may become bloody. The disease is usually self-limiting.
Chronic infection can develop in AIDS patients.

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 • Other causes. Other bacterial causes of diarrhoea include Bacillus cereus, Clostridium
species (including C. dificile) and Staphylococcal species. Abdominal TB is a cause of
chronic diarrhoea.

Viruses are the most common causes of diarrhoea, although the majority are self-limiting.
Viral causes of diarrhoea are:

• Rotavirus. Rotavirus is the most common cause of diarrhoea amongst children under
5 years. The virus is stable in extreme pH environments (3.5-10), detergents and
repeated freezing & thawing. Rotavirus possesses a NSP4 protein which acts like a
toxin by inhibiting calcium influx into enterocytes, releasing neuronal activators and
neuronal alteration of water reabsorption. The virus is spread by faecal-oral route
through person-to-person contact. Patients present with vomiting, profuse
diarrhoea, fever and dehydration.
• Noroviruses. The prototypical Norovirus is the Norwalk virus. The Norwalk virus is a
positive-sense single-strand RNA virus with a naked capsid. The norovirus strains that
infect humans can only infect humans. These viruses are often spread during
outbreaks from a common source of contamination. They cause acute onset
diarrhoea with nausea & vomiting. Bloody stool does not occur.

The protozoal causes of diarrhoea are:

• Entamoeba histolytica. E. histolytica is one of the pathogenic Entamoeba organisms,

which are normally commensal organisms. It is spread through ingestion of cysts,
which release trophozoites after exposure to stomach acids. Tissue destruction is
thought to arise from production of a cytotoxin, leading to lysis of colonic epithelial
cells. Clinical entities include asymptomatic infection, intestinal amoebiasis and
extra-intestinal amoebiasis. Patients with intestinal amoebiasis develop abdominal
pain, cramping and colitis with diarrhoea. In more severe disease, stool is bloody. In
extra-intestinal disease, patients develop fever and rigors with leukocytosis.
Trophozoites can get trapped in the liver and form amoebic abscesses.
• Giardia lamblia. Giardia is spread by ingestion of cysts, and the cysts are lysed by
gastric acid to release trophozoites. It is asymptomatic in 50% of individuals, but
where it is symptomatic it causes diarrhoea, which can be mild or lead to a severe
malabsorption syndrome. Spontaneous resolution occurs in 10-14 days, but it can be
chronic in patients with vitamin A deficiency and intestinal diverticulae.
• Cryptosporidium. Cryptosporidium is different from other coccidians/sporozoa in that
it survives intracellularly within the epithelial cells of the small intestines. The
commonest species is C. parvum. It is found worldwide and it is found in many
animals such as mammals, reptiles and fish. Waterborne transmission is
documented. Cryptosporidium usually causes a mild watery diarrhoea. In
immunocompetent individuals, the disease is usually self-limiting, with spontaneous

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 remission after 10 days. In immunocompromised patients, however (such as AIDS
patients), the diarrhoea can be severe & include tremendous fluid loss, and last for
months to years. It can also be disseminated.
• Cystoisospora/Isospora. The common pathogenic species in this genus is C. belli. C.
belli multiplies sexually & asexually within the intestinal epithelium, resulting in
production of multiple oocysts that are present in stool. The diarrhoea is typically a
malabsorption syndrome producing loose foul-smelling stool. The diarrhoea is
chronic and associated with weight loss, anorexia, malaise and fatigue. Cystoisospora
is common in patients with AIDS.
• Cyclospora. Cyclospora is a coccidian parasite which is also found in patients with
AIDS. It is spread by contaminated water, fruits and vegetables. It produces a watery
diarrhoea with mild nausea, abdominal cramping and anorexia.

Non-infectious

The non-infectious causes of diarrhoea are:

• Inflammatory conditions. These include inflammatory bowel disease, radiation

proctitis, irritable bowel syndrome and chronic pancreatitis. Inflammatory bowel
disease consists of Crohn’s disease & ulcerative colitis.
• Malabsorption syndromes. These include lactose intolerance, coeliac disease and
bile acid malabsorption.
• Endocrine causes. These include: thyrotoxicosis, Zollinger-Ellison syndrome, VIP
adenoma, somatostatinoma, carcinoid syndrome, thyroid medullary carcinoma,
Addison’s disease and diabetic autonomic neuropathy.
• Drugs. Most drugs can cause diarrhoea. Examples of drugs that cause diarrhoea are
metformin, laxatives, statins, digoxin, NSAIDs, propranolol, anticancer drugs and
proton pump inhibitors. Alcohol can also cause diarrhoea.
• Surgical procedures. These include ileal/gastric resection and post-cholecystectomy.
• Malignancies. These include gastrointestinal lymphoma, colorectal carcinoma and
KS.
• Others. Faecal impaction can cause overflow incontinence which presents as a
diarrhoea. Microscopic colitis is also a cause of diarrhoea, and is often diagnosed by
taking a biopsy of the colon on colonoscopy.

Clinical assessment
When assessing a patient who presents with diarrhoea, you need to ask the following
questions:

• Duration. Acute diarrhoea is that which develops over less than 14 days. If it is acute,
suspect infectious causes such as bacteria or viruses and some parasites. If it is
chronic (longer than 14 days), suspect other non-infectious causes as well.

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• Stool characteristics. The characteristics of stool you need to ask are:
o Volume & frequency. Small intestinal diarrhoea is usually a large-volume
diarrhoea with high frequency. Large intestinal diarrhoea is often small
volume, but with a very high frequency. Chronic causes are hardly associated
with large volume losses. Volume losses are important in determining the risk
of dehydration and other complications.
o Presence of blood (also known as dysentery). Bloody diarrhoea usually points
towards large intestinal diarrhoea. Infectious causes include Shigella,
Campylobacter, E. coli (EHEC & EIEC), Salmonella and amoebiasis. Non-
infectious causes include inflammatory bowel disease, pseudomembranous
colitis, colonic polyps and colorectal carcinoma. Also ask about symptoms of
anaemia.
o Abdominal pain. Small bowel abdominal pain is peri-umbilical and is
persistent even after defecation. Large bowel abdominal pain is usually
pelvic/suprapubic and it is relieved by passing stool. It is also associated with
tenesmus & urgency and may be associated with blood stool.
o Signs of fat malabsorption. These include flatulence, explosive stool, foul-
smelling and floats in the toilet. This suggests steatorrhoea. This is common
with cholera, Giardia, Yersinia and rotavirus.
• Systemic symptoms. These include fever, vomiting and anorexia. Weight loss is
important to ask, and is common in HIV-infected individuals with chronic diarrhoea.
It may also indicate any other chronic condition such as thyrotoxicosis or malignancy.
• Food history. What was the last thing the patient ate before their first episode of
diarrhoea? It is important in determining whether there was a food source involved.
In chronic diarrhoea, try identify if there is any meal (e.g. breakfast) that is usually
eaten before onset of diarrhoea, and ask if diarrhoea occurs when that meal is
skipped. Ask about individuals elements of that meal, e.g. milk, to try and isolate the
probable causative agent for the diarrhoea.
• Travel history. The time difference between the time of travel & onset of diarrhoea
is important in determining the possible source of diarrhoea. ETEC is the leading
cause of traveller’s diarrhoea. Campylobacter also causes travellers’ diarrhoea.
• Comorbid conditions. Ask about the patient’s HIV status, and if they are being
managed for any other conditions. Ask about the medications they are taking.
• Other affected family/community members. There may be a common
contaminated food or water source.
• Signs & symptoms of dehydration. These include dry mucus membranes, reduced
skin turgor, sunken eyes (children), prolonged capillary refill and hypotension
(shock). Also check for level of consciousness.
• Examine for masses. You should do a rectal examination to check for masses or
impacted faeces.

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Investigations
The investigations done for diarrhoea are:

• Stool investigations. You need to do microscopy, culture and sensitivity to identify

any causative organisms in excess. You may identify bacterial pathogens or
ova/cysts. You may also identify white cells3 in entero-invasive diarrhoea, and red
cells in stool when there is blood stool. In the presence of white cells or clinical
features of colitis, always culture for Salmonella, Shigella, Campylobacter4 and
Yersinia. Also look for C. difficle if there is a history of antibiotic use. For viruses, you
can do enzyme immunoassay or latex agglutination on the stool specimens. You may
do a stool anion gap to determine whether it is osmotic or secretory. If it is greater
than 100mOsm/L, it is osmotic. If it is less than 100mOsm/L, it is secretory. You can
also do a faecal fat excretion test to check for malabsorptive diarrhoea.
• Blood investigations. You need to do:
o FBC. This is done to check for anaemia. The MCV is decreased in chronic
blood loss, but it is elevated in patients with alcohol abuse or vitamin B12
deficiency5. If there is thrombocytopaenia, consider EHEC infection or a TTP.
There may be eosinophilia in parasitic infections.
o U&Es. This is to check the potassium level. Hypokalaemia can occur with
severe diarrhoea & vomiting.
• Imaging. You need to do an abdominal X-ray series to ensure that there is no
perforation of bowel (seen as free air in the abdomen). Sigmoidoscopy/colonoscopy
can be done for chronic diarrhoea, or in cases where stool cultures are negative. If a
colonoscopy is done, there needs to be a biopsy taken to rule out microscopic colitis.
Avoid a colonoscopy in acute diarrhoea as you can perforate the friable bowel.

Management of diarrhoea
Management of diarrhoea is as follows:

1. Fluid resuscitation. Oral rehydration is better than intravenous therapy, but

intravenous rehydration is often needed for dehydrated patients. Oral rehydration
can be done using ORS. For intravenous rehydration, give normal saline.
2. Electrolyte replacement. You add 20mmol of KCL (potassium chloride) to each litre
of normal saline.
3. Antidiarrhoeal agents. These can be used in patients with excessive stool motions.
You can give codeine phosphate 30mg 3-4 times daily or loperamide 2mg after each
loose stool (maximum of 16mg per day). They should be used with caution in

3
Presence of white cells excludes ETEC, Vibrio and viruses.
4
Campylobacter does not grow on traditional culture media. It requires Skirrow media.
5
This may be a consequence of malabsorption syndromes.

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 patients with fever, as using antidiarrhoeal agents reduces colonic motility which
precipitates toxic megacolon.
4. Antibiotics. These are usually avoided and only used when there is an invasive
bacterial infection causing systemic upset. Prompt specific treatment may be needed
before sensitivities are known, particularly in the case of Salmonella, Shigella and
cholera. You can give ciprofloxacin 500mg twice daily for 6 days. You can also
empirically add metronidazole 400mg 3-times daily to cover giardiasis & anaerobic
bacteria (including C. difficile6).
5. Treat the cause. This is indicated for other non-infectious diarrhoea.

6
In severe disease, use vancomycin 125mg 6-hourly orally.

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 Inflammatory bowel disease
(IBD)
This is an inflammatory disease consisting of 2 major disease entities: ulcerative colitis and
Crohn’s disease. These 2 diseases have both distinct & overlapping characteristics (clinical
features, histological features, radiological abnormalities). In 10% of inflammatory bowel
disease, a definitive diagnosis of ulcerative colitis or Crohn’s disease cannot be made. In this
case, the diagnosis given is colitis of undetermined type & etiology (CUTE). Another form of
colitis is related to microscopic inflammation and is termed microscopic colitis.

Although both conditions have a worldwide prevalence, the highest rates have been
reported in Europe & North America. The prevalence of Crohn’s disease is 25-100 cases per
100 000 population. The incidence is 4-10 cases per 100 000 population. The prevalence of
Crohn’s disease is lower in Hispanics & Asians compared to white people. Prevalence rates
in populations also change after migration. About 25% of patients are diagnosed before they
turn 18, and there is increasing evidence that disease commencing in youth is more
extensive & aggressive that adult onset disease. The prevalence of ulcerative colitis is 6-15
cases per 100 000 population. This prevalence has remained static over time.

Risk factors
The precise aetiology of IBD is unknown. However, it is known to be the result of
interactions between several factors:

• Genetic factors. Inflammatory bowel disease is a complex polygenetic phenomenon,

and having a positive family history is the single strongest risk factor for
development of the disease. 1 in 5 patients with Crohn’s disease and 1 in 6 patients
with ulcerative colitis have a 1st-degree relative with the disease. The major genetic
factors implicated are the NOD2 gene (also known as CARD15), autophagy genes
(ATG16L1 & IRGM1 genes) and the Th17 pathway (IL-23-type Th17 cells). HLA genes
on chromosome 6 also appear to have a role in susceptibility & disease modification.
Ulcerative colitis is associated with HLA-DR2 while Crohn’s disease is associated with
HLA-A2, HLA-DR1 and HLA-DQw51.
• Genetic syndrome. Inflammatory bowel disease is more likely in patients with
Turner’s syndrome, Hermansky-Pudlak syndrome and glycogen storage disease type
1b.

1
This, however, is associated with extra-intestinal manifestations of Crohn’s disease.

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 • Age & gender. The mean age of onset of inflammatory bowel disease is 15-40 years.
Many studies suggest a bimodal distribution, with a 2nd peak at age 50-80 years.
There is a slight female predominance in Crohn’s disease, which may suggest some
hormonal factors may play a role in disease expression.
• Race & ethnicity. Inflammatory bowel disease is more common in Ashkenazi Jews. It
is lower in black & Hispanic populations than in white people. These differences,
however, may be related to the differences in environmental & lifestyle factors.
• Smoking. Smoking is associated with an increased risk of Crohn’s disease, as well as
an increased risk of recurrence. Smoking is protective for ulcerative colitis.
• Diet. A “western diet” is associated with increased risk of developing Crohn’s
disease, and possibly ulcerative colitis. Breastfeeding is protective, as it stimulates
growth & maturation of the infant’s GIT mucosa.
• Hygiene. Good hygiene has been shown to be a risk factor for Crohn’s disease, but
not for ulcerative colitis. Poor & large families living in crowded conditions have a
lower risk of developing Crohn’s disease.
• Intestinal microbiota. There is intestinal dysbiosis in patients with Crohn’s disease.
There are higher concentrations of Bacteroides & E. coli and lower concentrations of
bifidobacteria and F. prausnitzii. There is also increased adherence of pathogenic
bacteria, such as E. coli.
• Psychological factors. Chronic stress & depression increase relapse rates of disease.
• Appendicectomy. This is protective for ulcerative colitis, but the mechanism is
unknown.

Pathogenesis
Inflammatory bowel disease occurs when there is an inappropriate immune response
mounted against luminal antigens, such as bacteria. Bacterial ligands interact with the
innate & acquired mucosal immune system via Toll-like receptors. There are deficiencies in
the clearance of invading bacteria. This may allow inappropriate activation of the acquired
immune system.

In addition, special bacteria have distinct immunologic effects mediated by dendritic cells
which sample bacteria from the intestinal lumen and direct the differentiation of naïve T-
cells into effector & regulator populations. There is an imbalance in the relative numbers of
intestinal homing effectors (Th1 & Th17) and regulatory T-cell populations. This disturbs the
normal tolerance to the luminal antigenic load.

Pro-inflammatory cytokines released by these activated effector T cells stimulate

macrophages to release more pro-inflammatory cytokines, such as TNF-α, IL-1 and IL-6 in
large quantities. This leads to increased adhesion molecule expression on the intestinal
vascular endothelium, which facilitates recruitment of leukocytes from the circulation and

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the release of chemokines. All these lead to tissue damage, which stimulates activation of
macrophages & release of cytokines. Therefore, a vicious cycle is set up.

Pathology
The pathologic features of the 2 conditions differ:

Crohn’s disease

Crohn’s disease may affect any part of the GIT, from the mouth to the anus. It does,
however, have a particular tendency to affect the ileum & ascending colon (ileocolonic
disease; 50% of cases). It can involve one small area in the gut, or it can involve multiple
isolated areas, with regions or normal gut mucosa in between lesions (called skip lesions). It
can also involve the whole colon (total colitis) without involving small bowel, thus mimicking
ulcerative colitis.

Macroscopically, the involved bowel is usually thickened & narrowed. Deep ulcers & fissures
produce a cobblestone appearance on endoscopy. Fistulae & abscesses may develop, and
these represent penetrating disease. An early feature seen is aphthoid ulceration, which
later progresses into larger deeper ulcers. Microscopically, the inflammation extends
throughout all layers of the mucosa. There is an increase in chronic inflammatory cells and
lymphoid hyperplasia. In 50-60% of patients, there are granulomas which are non-caseating
epithelioid cell aggregates with Langhan’s giant cells.

Ulcerative colitis

Ulcerative colitis is mainly limited to the colon & rectum. It can involve the rectum alone
(proctitis) or it can extend proximally to involve the colon. Unlike Crohn’s disease, ulcerative
colitis forms one single extensive lesion which always begins in the rectum and ascends
proximally. It can therefore simply be a proctitis (in the rectum), extend to the descending
colon (left colitis) or involve the whole large intestine (total colitis). In a few patients, there
is also inflammation of the distal ileum, a phenomenon called backwash ileitis.

Macroscopically, the mucosa looks reddened & inflamed, and it bleeds easily. In severe
disease, there is extensive ulceration with the adjacent mucosa appearing as an
inflammatory polyp (pseudopolyp). Microscopically, the inflammatory infiltrate & the
ulceration are limited to the lamina propria. There are also crypt abscesses & goblet cells
depletion. Granulomas are rare.

Extra-GI manifestations

The extra-gastrointestinal manifestations can be seen with both diseases, but they are more
likely in Crohn’s disease than in ulcerative colitis:

System affected Crohn’s disease Ulcerative colitis

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Dermatologic:
• Erythema nodosum. 15% 10%
• Pyoderma gangrenosum. 10% Less common
• Perianal skin tags. 75-80% Rare
• Oral mucosal lesions. Common Rare
• Psoriasis Present in 5-10% of patients but not an extra-intestinal
manifestation.
Rheumatologic:
• Peripheral arthritis. 15-20% (CD>UC)
• Ankylosing spondylitis. 10% (CD>UC)
• Sacroiliitis. CD=UC
Ocular (about 10% of IBD): 3-4% of IBD patients
• Uveitis (vision
threatening).
• Episcleritis (benign).
Hepatobiliary:
• Cholelithiasis. 15-35% of patients with ileal Crohn’s disease.
• Primary sclerosing 1-5% of IBD cases involving colon.
cholangitis.
• Fatty liver.
Urologic:
• Calculi. Most common in Crohn’s disease, especially following ileal
resection
• Ureteric obstruction.
• Fistulae. Characteristic of Crohn’s disease
Other: • Thromboembolism.
• Vasculitis.
• Osteoporosis.
• Vitamin deficiencies, especially B12 & ADEK.
• Cardiopulmonary disorders.
• Pancreatitis (rare)

Clinical features
The clinical features of inflammatory bowel disease depend on the actual disease present:

Crohn’s disease

The clinical features of Crohn’s disease are as follows:

• History. Crohn’s disease most commonly presents with recurrent episodes of

abdominal cramps, weight loss and diarrhoea (bloody in colonic disease). There may
be systemic symptoms during attacks: low-grade fever, malaise, lethargy, anorexia,
nausea and vomiting. Some patients are able to proceed with their normal lives,
while others with extensive disease have frequent recurrences and progress from

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 inflammatory disease to stricturing & perforation. Other possible symptoms include:
steatorrhoea, acute right iliac fossa pain (acute abdomen; mimics appendicitis).
• Examination. There are a few physical signs suggestive of Crohn’s disease. On
general examination, you may see wasting & signs of malnutrition. Aphthous
ulceration of the mouth is often seen. Abdominal examination may reveal
tenderness ± a right iliac fossa mass, which may be due to matted inflamed loops of
bowel or an abscess2. You may also see perianal fissures, skin tags, fistulae and anal
strictures.

Ulcerative colitis

The clinical features of ulcerative colitis are:

• History. The main presenting complaint of ulcerative colitis is bloody mucoid

diarrhoea, which may be episodic or chronic. Bowel frequency relates to severity of
disease. The presence of urgency & tenesmus suggests rectal involvement. During
attacks, systemic symptoms are present: fever, malaise, anorexia and weight loss 3.
• Examination. There may also be no signs suggestive of ulcerative colitis. Aphthous
ulceration may also be seen. In severe cases, the patient may have fever, tachycardia
and a tender distended abdomen. The patient may also be clubbed.

Complications
The complications of Crohn’s disease are:

• Anal strictures.
• Anal fistulae.
• Perianal disease, leading to formation of tags.

The complications of ulcerative colitis are:

• Toxic megacolon. On a plain abdominal X-ray, the patient will have dilated thin-
walled colon loops with mucosal islands. It is a serious disease, with impending
perforation & mortality reaching 15-25%. Urgent surgery is required in these
patients.
• Venous thrombosis.
• Colonic cancer.

Investigations
The investigations done for inflammatory bowel disease are:

2
This may also cause psoas irritation.
3
These are less than with Crohn’s disease.

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 • FBC. Patients with Crohn’s get anaemia for different reasons. They can get
normocytic normochromic anaemia of chronic disease. They can also get iron
deficiency & megaloblastic anaemia from malabsorption of the ions. They can also
get iron deficiency anaemia from occult blood loss. There may also be a raised white
cell count & platelet count.
• Liver function tests. This is reduced due to albumin being a negative acute phase
reactant. This can be confirmed by a raised CRP & ESR. Liver biochemistries may be
abnormal.
• Serology. In Crohn’s disease, ANCA is negative while in ulcerative colitis is positive.
• Stool tests. Stool should be cultured for Clostridium dificile to rule out
pseudomembranous colitis if diarrhoea is present. Microscopy for parasites should
be done if there is a recent travel history. Faecal calprotectin & lactoferrin are raised
in active colonic disease.
• Endoscopy. Colonoscopy is done in patients in whom colonic involvement is
suspected, except in patients presenting with severe disease (in whom limited
unprepared sigmoidoscopy should be performed). Upper GI endoscopy is done to
rule out upper GI disease. Endoscopy allows the mucosa to be directly visualised and
biopsies to be taken.
• Imaging. You can do bareal meal & follow through, barium enema, CT scan with oral
contrast, small bowel ultrasound and MRI enteroclysis. An abdominal series should
be done in patients presenting with acute abdomen.

Management of Crohn’s disease

The aim of treatment of Crohn’s disease is to induce & maintain clinical remission, as well as
promote mucosal healing. Signs of severity include: pyrexia, tachycardia, raised ESR & CRP,
leukocytosis and hypoalbuminaemia. These require admission. Alternative causes of the
symptoms must be excluded before commencing therapy. Cigarette smoking should be
stopped.

Management of Crohn’s disease is divided into medical and surgical management:

Medical management

Induction of remission can be done by:

• Glucocorticoids. For mild-to-moderate disease, you can use controlled-release

budesonide. For moderate/severe disease, you use oral prednisolone. For critical
patients you give intravenous prednisolone or hydrocortisone, with intravenous fluid
support. Overall response rate is 60-90% depending on the site, type and extent of
disease. Steroids should be avoided in patients with penetrating intestinal/perianal
sepsis.

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 • Aminosalicylates. These are used but there is little evidence to support their
efficacy.
• Immunosuppressants. These are used in patients with refractory disease. TNF-α
inhibitors (e.g. infliximab) can be used to decrease disease activity. They work by
clearing the cells driving the immune response. The response may be short-lived, but
it may be repeated every at 8 weeks. They are contraindicated in sepsis,
transaminitis, concurrent ciclosporin & tacrolimus, malignancy. You can also try
methotrexate, at a dose of 25mg IM weekly.
• Enteral nutrition. This is standard practice in paediatric patients, but is not used as
liberally in adults due to difficulties with compliance. Enteral diets with low fat (1.3%
of total caloric intake) and low linoleic acid content can induce remission at rates
similar to when steroids are used alone.
• Antibiotics. Ciprofloxacin & metronidazole can be used to prevent development of
complications such as abscesses & perianal disease. rifaximin has been shown to
induce remission in some patients.

Patients with good prognosis disease – older age at diagnosis, no perianal disease, limited
ulceration at index investigation, non-smoker – may not require maintenance therapy.
Those with poor prognosis disease or those that have a flare after withdrawal of induction
therapy require maintenance therapy. This can be achieved with long-term
immunosuppressive therapy:

• Non-biological immunosuppressive agents. The agents used are azathioprine,

mercaptopurine and methotrexate. Long-term treatment with these drugs is
necessary because the rate of relapse with these drugs is high. Careful monitoring is
required as leukopaenia can occur.
• Biological immunosuppressive agents. TNF-α inhibitors can be used for
maintenance as well. They are used as 2nd-line agents. They should be used for a
defined period because they induce anti-drug antibodies if used episodically.

The goals of maintenance are to prevent progression to stricturing or penetrating

phenotype and reduce the need for corticosteroids. These require careful monitoring to
ensure optimal disease control and prevent side effects.

Surgical management

Approximately 80% of patients will require surgery at some point in their lives. Nonetheless,
surgery should be avoided as much as possible. Minimal resections should be done, as
recurrences are common if prophylactic maintenance therapy is not used. The indications
for surgery are:

• Failure of medical therapy, with acute/chronic symptoms producing ill-health.

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 • Complications – toxic dilatation, obstruction, perforation, abscesses,
enterocutaneous fistulas.
• Failure to grow in children despite treatment.
• Perianal sepsis. The patient is examined under anaesthesia, the sepsis is drained and
a seton is inserted to ensure on-going drainage.

The procedures that can be done include:

• In patients with small bowel disease, the stricture can be widened, while others
require resectioning & anastomosis.
• When Crohn’s disease involves the entire colon and the rectum is spared, a subtotal
colectomy with ileorectal anastomosis is conducted. An eventual recurrence rate of
2
60-70% is expected, although 3s of these patients retain functional rectum for at
least 10 years.
• If the whole colon & rectum are involved, a panproctocolectomy is done (whole
colon + rectum) with end ileostomy. The patient then needs to have an ileostomy
bag attached. Patients with Crohn’s disease are not suitable for a pouch operation.

Management of ulcerative colitis

The severity of ulcerative colitis is assessed by using the modified Truelove & Witts criteria:

Variable Mild Moderate Severe

Motions per day <4 4-6 >6
Rectal bleeding Small Moderate Large
Temperature (°C) at 0600h Apyrexial 37.1-37.8 >37.8
Resting pulse <70 70-90 >90
Haemoglobin (g/dL) >11 10.5-11 <10.5
ESR (CRP) <30 >30 (or CRP > 45mg/L)

Medical management

For inducing remission, you can use the following:

• Mild ulcerative colitis. Aminosalicylates acting topically in the colonic mucosa form
the mainstay of treatment. The active moiety is 5-aminosalicylic acid (5-ASA), and for
it to be delivered effectively, it is combined with sulfapyridine (to form sulfasalazine),
4-aminobenzol-β-alanine (balsalazide) or to 5-ASA itself (olsalazine) it can also be
given as it is (mesalazine). The mode of action of 5-ASA is unknown, although it may
involve modification of PPAR-γ signalling. Steroids may help with induction of
remission, and these can be tapered down if improvement is seen within the first 2
weeks.

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 • Moderate ulcerative colitis. If the patient is otherwise well, you can try inducing
remission using oral steroids. If there is improvement, you taper down steroids
slowly. If there is no improvement, treat as severe ulcerative colitis.
• Severe ulcerative colitis. These patients should be admitted with nil per oral and
treated with intravenous hydrocortisone. Nutritional support & IV fluids are also
necessary. Thromboembolism can be prevented by giving low molecular weight
heparin. Patients should be tested for C. dificile, as the incidence of concurrent
ulcerative & pseudomembranous colitis is increasing. If the patient is improving,
transfer to oral prednisolone with aminosalicylic acid. If the patient has not
responded by day 3, salvage therapy or surgery is indicated.
o Salvage medical therapy. This is indicated if there are still 6 or more bowel
motions per day after 3 days of treatment. Salvage therapy involves adding
intravenous cyclosporin or infliximab to prednisolone. This should be done as
part of an MDT with experienced colorectal surgeons. If patients do not
respond, surgery is indicated.

Surgical management

Surgery is required at some stage in about 20% of patients. The indications for surgery are:

Fulminant attack: Chronic disease:

• Failure on medical treatment. • Incomplete response to medical

• Toxic megacolon. treatment.
• Haemorrhage. • Steroid dependence.
• Imminent perforation. • Dysplasia on surveillance
colonoscopy.
In acute disease, subtotal colectomy with end-ileostomy and preservation of the rectum is
the procedure of choice. At a later date, a more definitive procedure can be done. The
options include:

• Proctectomy with permanent ileostomy.

• Ileoanal anastomosis. This involves construction of an ileoanal pouch4.

4
This can complicate with “pouchitis”, which is characterised by diarrhoea, bleeding, fever, and exacerbation
of extra-colonic manifestations. It is treated with antibiotics.

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 Cirrhosis
Cirrhosis is a diffuse hepatic process that is characterised by fibrosis, with replacement of
the normal cellular hepatic architecture with a predominantly fibrotic one. As is typical of all
forms of fibrosis, cirrhosis is the result of chronic inflammation. Cirrhosis is irreversible. It is
the 9th leading cause of death in the US, and it is the 14th leading cause of death across the
rest of the world.

Pathogenesis
Cirrhosis is a result of necrosis of hepatocytes. Necrosis initiates repair, which is initially
through primary intention with reconstitution of hepatocytes. However, conditions leading
to repeated inflammation of the liver, or chronic low-grade smouldering inflammation,
result in healing by secondary intention.

Fibrosis is initiated by activation of stellate cells, which are also known as Ito cells and are a
store of vitamin A (retinoids). In the early stages, stellate cells are activated to transform by
growth factors such as PDGF & TGF-β1. These growth factors are secreted by inflammatory
cells, hepatocytes, Kupffer cells and the sinusoidal epithelium. The stellate cells are
transformed into collagen-forming cells, which form collagen I & III fibres which are then
deposited in the space of Disse. These fibres are normally metabolised by matrix
metalloproteases (MMPs), but are inhibited by tissue inhibitors of metalloproteases
(TIMPs). Deposition of collagen in the space of Disse leads to loss of fenestrations in the
sinusoidal capillaries in the liver, leading to capillarisation of hepatic sinusoids. The fibrosis
in the space of Disse cause constriction of hepatic sinusoids, and this contributes to portal
hypertension.

Within the increasingly fibrous extracellular matrix, islands of regenerating cells form. The
cellular islands are separated by fibrous septa. There is loss of the classical lobular
architecture in these cellular islands. The regenerating islands of cells form nodules, which
can be macronodules or micronodules. Macronodular cirrhosis (>3mm) occurs in chronic
viral hepatitis, and is typified by large nodules of variable size with some normal acini in the
larger nodules. Micronodular cirrhosis (<3mm) is seen with chronic alcoholism and biliary
tract disease.

Cirrhosis causes a gradual reduction in hepatic function which is normally well-tolerated by

the body, i.e. the body adjusts to the reduction. This is a compensated state. However,
when exposed to an appropriate stressor, the body decompensates, resulting in
development of symptoms of acute hepatic failure. Decompensation occurs as a result of:

• Dehydration.

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 • Constipation.
• Covert alcohol use.
• Infections, such as spontaneous peritonitis.
• Opiate over use.
• Occult GIT bleed.
• Portal vein thrombosis.

Aetiology
The main causes of cirrhosis are:

• Viral hepatitis. HBV & HCV chronic hepatitis are the viral causes of cirrhosis. Cirrhosis
is more likely to develop in HBV & HCV co-infection, as well as HBV & HDV co-
infection. Viral hepatitis is the leading cause of cirrhosis in the developing world
where the prevalence of these viruses is high.
• Alcohol. Chronic alcoholism leads to repeated hepatocyte damage, which leads to
chronic inflammation. Chronic alcoholism is the leading cause of cirrhosis in
developed countries where the prevalence of viral hepatitis is low.
• Non-alcoholic fatty liver disease. 1% of cases of non-alcoholic fatty liver disease
eventually evolve to cirrhosis. In non-alcoholic fatty liver disease, oxidative stress
leads to lipid accumulation in the liver. Fatty infiltration leads to inflammation, which
leads to fibrosis & cirrhosis. Non-alcoholic fatty liver disease affects 3-6% of the
population in the US.

Other uncommon causes of cirrhosis include:

• Genetic disorders, e.g. α1-antitrypsin deficiency, cystic fibrosis, glycogen storage

diseases, Wilson’s disease, haemochromatosis, galactosaemia.
• Biliary cirrhosis, whether primary or secondary.
• Autoimmune disease, e.g. autoimmune hepatitis, primary biliary cirrhosis (PBC),
primary sclerosing cholangitis (PSC).
• Vascular defects, e.g. Budd-Chiari syndrome, hepatic venous congestion.
• Drugs, e.g. amiodarone, methyldopa, methotrexate.
• Idiopathic.

Clinical presentation
The majority of patients are asymptomatic and have no complaints. The ones that do,
however, either have signs of chronic liver disease or have features of decompensated liver
disease.

Compensated liver disease

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Patients with cirrhosis will present with symptoms of chronic liver disease:

• Right upper quadrant pain in early stages

• GIT haemorrhage – oesophageal varices or haemorrhoids.
• Gynaecomastia (in men) due to endocrine dysfunction.
• Loss of libido & amenorrhoea.

On examination, you can find:

• General examination: clubbing, palmar erythema, Dupuytren’s contracture,

xanthomas, scratch marks, testicular atrophy.
• Abdominal examination: leuconychyia, Terry’s nails, spider naevi, loss of body hair.
Hepatomegaly in early stages, but becomes shrunken in later stages.

Decompensated liver disease

In decompensated disease, patients with either of 3 symptoms, or any of them in

combination:

• Jaundice.
• Abdominal swelling due to ascites. Patients may also develop ankle swelling.
• Confusion (due to encephalopathy).

On examination, you will find:

• Confusion, coma, depressed GCS. This is supported by a hepatic flap.

• Hepatic flap & fetor hepaticus.
• Loss of proximal muscle bulk.
• Abdomen: ascites and dilated abdominal veins.
• Peripheral oedema.

Complications of cirrhosis
The complications of liver cirrhosis are:

Portal hypertension

Portal hypertension is an elevation of the blood pressure within the portal vein. The normal
portal venous pressure is 5-8mm Hg, with only a small gradient across the liver to the portal
vein. When there is blockage of outflow through the portal vein, the portal pressure rises. If
it rises above 10-12mm Hg, collaterals occur within the systemic venous circulation. The
main sites of collaterals are: the lower oesophagus, the rectum, the left renal vein,
diaphragm, retroperitoneum and the anterior umbilical wall. The causes of portal
hypertension can be classified into pre-hepatic, hepatic and post-hepatic.

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 • Pre-hepatic. This is caused by portal venous thrombosis or splenic venous
thrombosis.
• Intrahepatic. The majority of cases of portal hypertension are intrahepatic, the
majority of which are attributable to cirrhosis. Cirrhosis is an intrasinusoidal cause of
portal hypertension. Pre-sinusoidal causes include Schistosomiasis1 (which causes
periportal fibrosis). Post-sinusoidal causes are mostly veno-occlusive diseases. This
happens with high-dose chemotherapy or ingestion of pyrrolizidine alkaloids.
• Post-hepatic. These include chronic right-sided heart failure, Budd-Chiari syndrome,
tumours invading inferior vena cava, etc.

Portal pressure can be measured using trans-jugular intrahepatic portosystemic shunts

(TIPS). You insert a catheter and then you place it at the hepatic vein, to measure the
wedged hepatic venous pressure. This helps provide an estimate of the portal pressure.

Variceal haemorrhage

Variceal haemorrhage occurs as a complication of portal hypertension. 90% of cirrhotic

patients will develop varices in 10 years, regardless of whether they will bleed or not.
Bleeding is likely to occur in large varices, severe liver disease and red signs on varices.

Ascites

Ascites is the accumulation of fluid in the peritoneum. It is a common complication of portal

hypertension. Ascites develops secondary to renal sodium & water retention. The factors
involved include:

• Sodium & water retention results from peripheral vasodilation and consequent
reduction in the effective blood volume. This activates the RAAS system, thus
promoting sodium & water retention. Urinary sodium excretion rarely exceeds
5mmol/24h.
• Portal hypertension exerts a local hydrostatic pressure that leads to increased
production of lymph by the liver & blood vessels and increased transudation of fluid
with little protein into the peritoneum.
• Low serum albumin results from chronic liver disease. This reduces the oncotic
pressure.

The abdominal swelling develops over many weeks or days. It can be precipitated by a high
salt diet, splanchnic vein thrombosis or a new hepatocellular carcinoma. Abdominal pain &
discomfort are common (if abdominal pain is more severe, suspect spontaneous bacterial
peritonitis). On examination, you can demonstrate shifting dullness & a fluid thrill.

To investigate ascites, you aspirate ascitic fluid (through an ascitic tap) and conduct
investigations on it. You do the following:
1
Schistosomiasis is the most common underlying cause of non-cirrhotic variceal bleeding in the world.

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 • Comment on its appearance. Straw coloured ascitic fluid could be: malignancy,
cirrhosis, infection, hepatic vein thrombosis, chronic pancreatitis, congestive cardiac
failure, constrictive pericarditis, Meig’s syndrome and hypoalbuminaemia. Chylous
ascitic fluid is caused by cirrhosis or obstruction of the main lymphatic duct.
Haemorrhagic ascitic fluid is caused by malignancy, ruptured ectopic pregnancy,
abdominal trauma and acute pancreatitis.
• Cell count. A neutrophil count above 250cells/mm3 is indicative of a bacterial (usually
spontaneous) peritonitis.
• Microscopy, culture and sensitivity. This is done to check for bacteria in the fluid. You
do microscopy & culture for bacteria and TB.
• Protein. Protein levels in ascitic fluid are usually low in portal hypertension. The
serum-ascitic albumin gradient (SAAG) is the difference between serum protein and
ascitic protein. If it is greater than 11g/L, it is caused by portal hypertension. If it is
less than 11g/L, suspect other causes such as peritoneal carcinomatosis, peritoneal
TB, pancreatitis and nephrotic syndrome.
• Cytology. This is done to check for malignant cells in the peritoneal fluid.

Spontaneous bacterial peritonitis

This is a serious complication of ascites with cirrhosis, occurring in approximately 8% of

these patients. The infectious organisms gain access to the peritoneum through
haematogenous spread. The most common causative organisms are E. coli, Klebsiella and
enterococci. This condition must be considered in patients with ascites who deteriorate
quickly. Features such as pain & fever are usually absent. Elevated neutrophil count alone is
enough to initiate treatment.

Porto-systemic/hepatic encephalopathy

This is a chronic neuro-psychiatric syndrome that results from diversion of blood from the
liver and directly into the systemic circulation. It is thought that the toxic metabolites in
portal blood that are normally processed by the liver enter the systemic circulation and
reach the brain. The causative toxins include ammonia, free fatty acids, mercaptans and
false neurotransmitters. Another theory is that GABA produced by the GIT crosses the extra-
permeable blood vessels of individuals with cirrhosis, leading to generation of IPSPs
(inhibitory post-synaptic potentials).

The grades of hepatic encephalopathy are:

• Grade 0 – subclinical: normal mental status but minimal changes in memory,

concentration, intellectual function and coordination.
• Grade 1 – mild symptoms: mild confusion, euphoria/depression, decreased
attention, inverted sleep cycle.

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 • Grade 2 – drowsiness, lethargy, gross deficits in performance of mental tasks,
obvious personality changes, and inappropriate behaviour.
• Grade 3 – somnolent but arousable state, unable to perform mental tasks,
disoriented, marked confusion, amnesia, occasional fits of rage.
• Grade 4 – coma with/without response to pain stimuli.

Patients typically have elevated free venous ammonia. CT/MRI of the brain is important in
ruling out intracranial lesions.

Hepatorenal syndrome

Hepatorenal syndrome is a condition in which there is cirrhosis, ascites and renal failure. It is
the result of massive splanchnic & systemic vasodilation but with renal vasoconstriction. The
initiating factor is production of nitric oxide which leads to hypotension. This activates the
RAAS system and leads to elevated levels of angiotensin II, which vasoconstricts the renal
vasculature. There is increased pre-glomerular resistance, leading to shunting of blood away
from the renal cortex. This reduces the GFR, with salt & water retention. This leads to
reduced urine output with a low sodium concentration. Hepatorenal syndrome is
precipitated by over-vigorous diuretic therapy, NSAIDs, diarrhoea, paracentesis and
infection.

There are 2 types of hepatorenal syndrome:

• Type 1 HRS. This is a rapidly progressive deterioration in circulatory & renal function,
with a median survival of 2 weeks. It is often triggered by other pathology.
• Type 2 HRS. This is a more steady deterioration in circulatory & renal function.
Trans-jugular intrahepatic porto-systemic shunting is the best option for most.

Other renal disease

In cirrhosis, there is reduced hepatic clearance of immune complexes. This leads to

increased trapping of immune complexes in the glomeruli, thus predisposing to
glomerulopathies. Examples include IgA nephropathy with/without hepatic
glomerulosclerosis. HBV may cause membranous/membranoproliferative
glomerulonephritis, with/without Polyarteritis nodosa. HCV can cause cryoglobulinaemia
with membranoproliferative nephropathy.

Hepatocellular carcinoma

This is a major cause of mortality amongst patients with cirrhosis. It evolves faster in
patients with viral hepatitis involve multiple viruses (HBV, HCV and HDV). HCC develops in
10-25% of patients with cirrhosis. It occurs in about 3% of patients per year.
Cholangiosarcoma occurs in 10% of patients with primary sclerosing cholangitis.

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Investigations
Investigations in cirrhosis are done to assess the type of liver disease and the severity of
cirrhosis. The investigations done for a person with cirrhosis to determine severity are:

• Serum albumin & prothrombin time. The best indicators of liver function are serum
albumin & prothrombin time. The outlook is poor when serum albumin drops below
28g/L. Prothrombin time increases as the severity of liver dysfunction progresses.
• Liver biochemistry. Bilirubin levels are normal or slightly increased. There is a slight
elevation in serum transaminases & ALP levels. These are grossly elevated in
decompensated cirrhosis.
• Urea & electrolytes. A true hyponatraemia develops because of a defect in free
water clearance or excessive diuretic therapy. An elevated creatinine level above
130µM is a bad prognostic indicator.

The investigations done to determine the type of cirrhosis are:

• Viral markers. For HBV, you can test for the presence of HBsAg. For HCV, you do RT-
PCR.
• Serum auto-antibodies. This is done when autoimmune diseases are suspected.
• Iron indices & ferritin. This is done to check for haemochromatosis.
• Copper & ceruloplasmin2. This is done to check for Wilson’s disease.
• A1-antitrypsin1.

Other investigations done for cirrhosis are:

• Liver ultrasound. This will demonstrate either hepatomegaly or a small shrunken

liver which is usually nodular. It will also demonstrate focal hepatic lesions,
splenomegaly, hepatic vein thrombus, reversed flow in the portal vein, and ascites. It
can also be used to identify fatty changes and any neoplasms.
• CT scan. This shows hepatosplenomegaly with dilation of collaterals. Detection of
hepatocellular carcinoma can be made using a triple-phase contrast CT scan.
• Endoscopy. Endoscopy is done for identification & treatment of varices & portal
hypertensive gastropathy. Colonoscopy is occasionally done for colopathy.
• MRI scan. This is used to diagnose both benign & malignant tumours.
• Liver biopsy. This is usually necessary to perform to determine the type & severity of
liver disease. However, you need to make sure that you have ruled out
hepatocellular carcinoma. Biopsy is done to diagnose haemochromatosis or Wilson’s
disease.

Grading of cirrhosis
2
These should always be measured if the cirrhotic patients are young.

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Cirrhosis is graded using the modified Child-Pugh classification. The score is as follows:

Clinical variable 1 point 2 points 3 points

Ascites None Mild Moderate/severe
Encephalopathy None Mild Marked
Bilirubin (µM) <34 34-50 >50
OR OR OR
<68 in PBC or PSC 68-170 in PBC or PSC >170 in PBC or PSC
Albumin (g/L) >35 35-28 <28
Prothrombin time <4 4-6 >6

You then add the score that the patient has in each parameter. Patients are then stratified
according to their Child scores.

Grade Score % survival

1 year 5 years 10 years
Child’s A <7 82 45 25
Child’s B 7-9 62 20 7
Child’s C ≥10 42 20 0
Variceal bleeding is more likely if the Child’s score is above 8.

Management
Cirrhosis is irreversible, and management of cirrhosis is mainly to prevent progression of
fibrosis and to manage complications.

Long-term management

Management of long-term complications includes:

• Lifestyle modification. Patients should abstain from alcohol. Patients should also
take a balanced diet and restrict salt intake. Patients should avoid NSAIDs, opioids
and sedatives. Regular exercise is encouraged.
• Pharmacologic management. Colestyramine may help with pruritus. You can use
ursodeoxycholic acid for patients with primary biliary cirrhosis, which normalises
LFTs but does not alter progression of condition. You can treat autoimmune hepatitis
using azathioprine & prednisolone. Supplementation of vitamin D is important for
patients at risk of osteoporosis. Vaccination against hepatitis A is also important.
• Liver transplant. This is the only definitive treatment for cirrhosis. It significantly
increases 5-year survival from 20% to 70%. For acute hepatitis, liver transplantation
is indicated for patients with fulminant hepatic failure of any cause, including acute
viral hepatitis. For chronic liver disease, it is indicated for cirrhosis that is no longer

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 responsive to therapy and for complications. It is also indicated for all patients with a
Child’s grade C. Chronic hepatitis C is the most common indication for
transplantation.
o Absolute contraindications include sepsis outside the biliary tree, malignancy
outside the biliary tree, non-neuroendocrine liver metastases, and patients
that are not psychologically committed.
o Relative contraindications are mainly anatomical, such as extensive
splanchnic venous plexus thrombosis, patients aged 70 years & above. In
hepatocellular carcinoma, recurrence rates are high.
• Monitoring. Monitoring is done for variceal bleeding & hepatocellular carcinoma, as
these represent the 2 biggest threats to life. On diagnosis, endoscopy is done to rule
out varices, and if they are absent you repeat every 2 years. If varices are present,
you give prophylactic non-selective β-blockers to reduce heart rate by 25% and
prevent bleeding. Large varices may be ligated. Patients should have an ultrasound
conducted every 6 months to screen for early development of hepatocellular
carcinoma. Patients with suspicious lesions on ultrasound should have a 4-phase CT
scan done. If the CT is suggestive of hepatocellular carcinoma with no evidence of
intrahepatic disease, the patient should receive curative therapy.

Treating complications

The management of complications is as follows:

• Variceal haemorrhage. Management is divided into prophylactic measures to

prevent the first bleed, management of the acute bleeding episode and prevention
of subsequent bleeding episodes.
o Preventing the first bleed. You can prescribe non-selective β-blockers to
reduce the chances of upper GI bleeding. These agents do not prevent
development of varices; they simply help prevent bleeding. If these agents
are contraindicated, variceal banding is an option.
o Initial management of bleeding. Initial management entails stopping a
bleeding diathesis, which can kill the patient at that moment. A bleeding
varice is a medical emergency. You first resuscitate the bleeding as you do
with all bleeding patients. You then perform urgent endoscopy with the
intention of ablating the bleeding varix through banding, cauterisation or
injection sclerotherapy. You can also give vasoconstrictor therapy
(terlipressin & somatostatin) or balloon tamponade.
o Definitive management of an acute bleed. Rebleeds occur in 15-20% of
patients within 5 days. To correct the bleeding, you can place a trans-hepatic
porto-caval shunt, which relieves the portal hypertension and helps relieve
the tension in the varices. There is, however, an increased risk of portal-
systemic encephalopathy. You can also do emergency oesophageal surgery if

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 rebleeding is from a gastric fundal varice. You do oesophageal transection &
ligation.
o Prevention of recurrence. You can give β-blockers, repeated banding at 2-
weekly intervals and a transjugular portosystemic shunt (endoscopic or
surgical). You can also do a liver transplant.
• Ascites. The aim of treatment of ascites is to reduce sodium intake and increase
renal excretion of sodium. The maximum rate at which ascites can be mobilised is
500-750ml per 24 hours. Take baseline U&Es and eGFR and take them every other
day for monitoring. Also take baseline weight and take daily urine output
measurements. Institute sodium restrictions and fluid restriction. Start aldosterone
antagonists (such as spironolactone) as 1st choice agents, as this drug counters the
RAAS abnormalities. The aim of diuretic therapy is to produce a loss of weight of
0.7kg or 700ml per day. If response is poor, add furosemide. Paracentesis is used to
relieve tense ascites or when diuretic therapy is insufficient.
• Spontaneous bacterial peritonitis. Give empirical antibiotics, usually a 3rd-
generation cephalosporin, and modify the antibiotic used based on culture results.
An oral fluoroquinolone is given for prophylaxis against recurrence. Prophylactic
treatment is given for patients with: hypoalbuminaemia, raised PT or INR, those with
low ascitic albumin and those with a previous episode.
• Porto-systemic encephalopathy. Identify & remove the possible precipitating cause,
such as cerebro-depressant drugs, constipation or electrolyte imbalances. Give
purgatives such as lactulose to empty bowel. Maintain nutrition with adequate
calories. Give antibiotics and intravenous antibiotics.
• Hepatorenal syndrome. You must stop nephrotoxic drugs, including
aminoglycosides. Patients may be salvaged by aggressive expansion of intravascular
volume using plasma expanders (colloids, e.g. albumin or FFP). You can try
vasoconstrictors, either systemic ones such as terlipressin or splanchnic ones such as
octriotide. For more advanced disease, however, liver transplant is required.

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 Portal hypertension
Portal hypertension is a condition in which the mean venous pressure of the portal venous
system is elevated. The average pressure in the portal vein is 5-7mm Hg (or 8-12cm water),
and portal hypertension is present when the portal pressure exceeds 12mm Hg.

Portal hypertension is usually a result of 2 factors:

1. An increase in vascular resistance. This is consistent with Poiseuille’s law, which

states that the resistance in a blood vessel is directly proportional to the length of
the vessel and the viscosity and inversely proportional to the fourth power of the
radius:
8𝜂𝐿
𝑅=
𝜋𝑟 4
The length of the portal vein does not change, and the viscosity of blood usually does
not change much within its normal physiological range. Therefore, the major
determinant of vascular resistance is the portal system’s diameter.
2. An increase in portal blood flow. Blood flow to the portal system can be increased by
arteriolar vasodilation resulting from the excessive release of endogenous
vasodilators. These can be endothelial, humoral or neural.

Causes of portal hypertension

The causes of portal hypertension can be classified into their location with relation to the
liver. They can be pre-hepatic, intrahepatic or post hepatic.

Pre-hepatic Intrahepatic Post-hepatic

Pre-sinusoidal Sinusoidal Post-
sinusoidal
• Congenital portal vein • Schistosomi • Hepatic • Post- • Budd-Chiari
atresia. asis. cirrhosis. sinusoidal syndrome.
• Stenosis of the portal • Primary • Alcoholic obstructi • Veno-occlusive
vein. biliary hepatitis. on disease.
• Thrombosis of the cirrhosis. • Schistosomias syndrome • Cardiac
portal vein. • Hepatic is. . diseases
• thrombosis of the metastases. • Budd-Chiari • veno- (constrictive
splenic vein. • Myeloprolife syndrome1. occlusive pericarditis,
• extrinsic compression rative disease of valvular heart
of the portal vein diseases. the liver. disease, right
(tumours) heart failure)

1
Budd-Chiari syndrome is a condition in which the hepatic vein is blocked. This syndrome is independent of
the cause of the blockage, although most blockages are a result of thrombosis. It causes prominent ascites,
hepatomegaly and abdominal pain.

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Sequelae of portal hypertension
The most common & clinically relevant symptoms of portal hypertension are as follows:

• Engorgement of portal-systemic collaterals. The portal-systemic collaterals are sites

at which veins draining directly into the inferior vena cava (systemic veins)
anastomose with those ultimately draining into the portal vein. there are 4 sites at
which these are found:
1
1. The lower 3 of the oesophagus, where the left gastric vein (portal element)
1
anastomoses with the oesophageal veins draining the middle 3 of the
oesophagus (systemic element; drains into the azygos veins). In portal
hypertension, these form oesophageal varices.
2. The anus, where the superior rectal veins (portal element) anastomoses with
the middle & inferior rectal veins (systemic element; drain into the internal
iliac & internal pudendal veins respectively). In portal hypertension, they
form haemorrhoids.
3. The umbilical region, where the paraumbilical veins (portal element)
anastomose with the superior & inferior epigastric veins (systemic
component; drain into the internal thoracic & femoral veins respectively). In
portal hypertension, they form caput medusae.
4. The back region, where the colic veins (portal component) anastomose with
the retroperitoneal veins (systemic component; drain into azygos veins)
Under normal conditions, these collateral pathways are collapsed. However, in
portal hypertension, these pathways are sequestered and the veins become
engorged. This serves to divert blood away from the portal circulation. By far the
most significant complication is oesophageal varices. These may develop into
variceal bleeding which may be massive and life threatening. It presents as
haematemesis & melena (even haematochezia if it is profuse enough). Another
complication that may develop is hepatic encephalopathy. This develops because the
ammonia formed by the intestines is no longer going to be processed by the liver.
Instead, it is directly entering the systemic circulation and reaching the brain, causing
damage.
• Splenomegaly. This is the most constant physical finding of portal hypertension. It
occurs in 80% of patients regardless of the cause of the expansion, although in
schistosomiasis the expansion is partly due to an intense inflammatory reaction. The
spleen enlarges because of congestion of the splenic circulation. This causes the
spleen to sequester the formed elements of blood. As a result, if you do a blood
count, you will discover that the patient will have anaemia, leukopenia and
thrombocytopenia, and eventually they will begin to have bleeding disorders.
• Ascites. These are multifactorial and are not merely caused by the portal
hypertension alone. They are caused by other factors including hypoalbuminaemia

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 (below 30g/L), salt & water retention due to high levels of aldosterone, oestrogen
and ADH, and increased lymphatic transudation from liver surface.

Diagnosis of portal hypertension

As the patient presents to you, you first take a history of the patient. After identifying that
the patient suffers from portal hypertension, you will want to determine the cause of the
portal hypertension. Look for a history of jaundice, blood transfusion, alcohol &
schistosomiasis. All these are risk factors for portal hypertension. Also assess for risk factors
of upper GIT bleeding (UGB): bleeding diathesis, alcohol/NSAIDs, documented cirrhosis and
previous UGB. You should also enquire about symptoms of liver disease, such as malaise,
anorexia, vomiting, pruritis, loss of weight and jaundice. Also ask about haematemesis,
melena, mental state changes, abdominal swelling, abdominal pain and fever 2.

On examination, you will want to look for:

1. Portal systemic collateral formation – caput medusae, haemorrhoids.

2. Signs of chronic liver disease – ascites, jaundice, gynecomastia, dupuytren’s
contracture, liver flap.
3. Signs of a hyper-dynamic circulation – bounding pulse, arterial hypotension and
warm peripheries.
4. Other signs include venous hums and tarry stool.

Lab studies include the following:

• Full blood count (FBC). This is to identify any anaemia, thrombocytopenia and
leukopenia.
• Liver function tests (LFTs). The liver is the only site of albumin synthesis, and
therefore hypoalbuminaemia can serve as an indicator of liver dysfunction. However,
this is not a reliable test as albumin levels in circulation fluctuate naturally in
response to other non-hepatic causes. Prothrombin time, rather, is used to assess
liver function as it is more sensitive to liver function.
• Other tests assessing the cause of cirrhosis include hepatitis serology and ferritin &
ceruloplasmin levels.

Imaging techniques that are applicable include:

• Ultrasound. These reveal features suggestive of cirrhosis & portal hypertension such
as a nodular liver, splenomegaly and collateral circulation.
• CT scanning & MRI scans. These are useful when the ultrasound evaluation is
inconclusive.

2
All these are complications of portal hypertension.

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 • Upper GI endoscopy. This is now an essential diagnostic tool. It is conducted on
every patient suspected of having portal hypertension. It is done to screen for
oesophageal varices. It allows the investigator to view the size of the varices, their
location and the amount of bleeding stigmata on the lesion. It allows a person to get
prompt therapeutic intervention.

Treatment of portal hypertension

Portal hypertension is a complex manifestation of an underlying disease. Therefore,
ultimate treatment of portal hypertension is treatment of the underlying disease. Bleeding
oesophageal varices are the most lethal manifestation of oesophageal varices and therefore
they need to be treated even before the underlying condition has been discovered.
Treatment of oesophageal varices includes sclerotherapy and vasoactive drugs that stop
bleeding.

Treatment of the portal hypertension itself can be achieved by using β-blockers to lower the
portal pressure.

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 Blood transfusions
Blood transfusion is the transfer of blood or blood products to a person. Usually, the source
of blood product is another person who previously donated a pint of blood. The world over
blood is a scarce resource that needs to be used appropriately & judiciously. Blood
therefore needs to be used appropriately. The appropriate use of blood products means the
transfusion of safe blood products only to treat a condition that cannot be prevented or
managed effected by any other means.

The safety & effectiveness of blood transfusion depends on 2 key factors:

1. A supply of blood/blood products that is safe, accessible, at a reasonable cost and

adequate to meet the national needs.
2. The appropriate clinical use of blood & blood productions.

Physiology of anaemia
The major physiologic mechanisms relevant to anaemic patients are: the degree to which
oxygen delivery to tissues is adequate, and compensatory mechanisms for maintaining
oxygen delivery that will not become overwhelmed or deleterious. Oxygen delivery is
determined by the product of cardiac output & arterial oxygen content:

𝐷𝑂2 = 𝐶𝑂 × 𝑎𝑟𝑡𝑒𝑟𝑖𝑎𝑙 𝑜𝑥𝑦𝑔𝑒𝑛 𝑐𝑜𝑛𝑡𝑒𝑛𝑡

Arterial oxygen content consists of haemoglobin-bound oxygen & dissolved oxygen to a

much lesser extent:

𝐷𝑂2 = 𝐶𝑂 × (1.39[𝐻𝑏][𝑆𝑝𝑂2 ] + [0.0031][𝑃𝑎𝑂2 ])

In critically ill patients, oxygen utilisation becomes pathologically dependent on oxygen

delivery.

Some indicators of poor tissue perfusion Attempts to increase oxygen delivery

include: include:
• Elevated arterial lactate levels. • Improvements in haemoglobin
• Oxygen extraction ratio of greater saturation.
than 0.3. • Augmentation of cardiac output
• Oxygen delivery of less than 10- (mainly by increasing heart rate).
12ml/kg/min. • Red cell transfusion.
In a normal individual, there is a large redundancy of oxygen delivery, since delivery exceeds
consumption by a factor of 4 (4.6ml/dL of oxygen extracted in tissues from 19.8ml/dL of
oxygen in arterial blood). Therefore, if intravascular volume is maintained during bleeding

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and cardiovascular status is not impaired, oxygen delivery will be theoretically adequate
until haematocrit falls below 10%, since greater cardiac output, right shift of the oxygen
dissociation curve and increased oxygen extraction can compensate.

Anaemia in the postoperative setting has effects on the overall mortality of patients. Based
on a study on postoperative mortality in relation to haemoglobin levels, the mortality rates
were as follows:

Haemoglobin level (g/dL) Mortality (%)

7.1-8.0 0
5.1-7.0 9
3.1-5.0 30
≤3.0 64

Indications for blood transfusion

The indications for blood transfusion are:

• Blood loss. Transfusions should be considered when there has been a massive acute
bleed. It is usually indicated when there has been blood loss of more than 15% of
total blood volume in an otherwise healthy individual. This can be secondary to
trauma or major surgery. It can also be given prophylactically.
• Bone marrow failure. Causes include post-chemotherapy, some drugs, leukaemias
and chronic illnesses (e.g. CKD).
• Red blood cell disorders. These may be inherited (e.g. homozygous β-thalassemia,
red cell aplasia, sickle cell anaemia) or acquired (myelofibrosis, myelodysplasia,
selected use in renal disease).
• Neonates. Exchange transfusions are usually done for neonates. The indications
include: haemolytic disease of the new-born, neonatal jaundice, meningococcal
septicaemia, malaria.

Historically, the target for transfusion was 10g/dL. However, this has since been associated
with higher levels of morbidity & mortality. Transfusion is usually necessary when the
haemoglobin level falls below 7g/dL.

Blood & blood products

There is a variety of blood products that can be given to patients.

• Whole blood. Whole blood contains blood that is physiologic, i.e. with quantities
that are in the same proportions as in normally-occurring blood. It is blood that is
taken as is and is delivered un-separated. It is now rarely available in civilian practice

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 because it is ineffective in limited settings. Nonetheless, when compared to packed
cells, it has significant advantages in that it is rich in coagulation factors, is fresh and
is more metabolically active. An average pint contains 510ml (450ml blood + 63ml
anticoagulant preservative solution – usually citrate phosphate dextrose, CPD). It has
a haemoglobin level of approximately 12g/dL and haematocrit of 35-45%. There are
no functional platelets (after 24 hours), white cells are destroyed rapidly and there
are no labile coagulation factors (factors V & VIII). It is also of high infection risk as it
is not sterilised. Whole blood is stored at 2-6°C, and during storage changes occur in
the composition due to red cell metabolism. The patient receiving blood must be
ABO & Rhesus D compatible. Never add medication to a unit of blood and
transfusion must be completed within 4 hours of commencement.
Indications Contraindications
• Red cell replacement in acute blood There is a risk of fluid overload in:
loss with hypovolaemia. • Chronic anaemia.
• Exchange transfusion. • Incipient heart failure.
• Patients needing transfusion where red
cell concentrates are unavailable.
• Packed cells. This is also known as red cell concentrate or plasma-reduced blood.
Packed cells are obtained by centrifuging whole blood at 2000-2300G for 15 minutes
and removing the sediment. The volume of packed cells is 280ml ±20ml. They have a
haemoglobin level of about 20g/dL (no less than 45g per unit) and a haematocrit of
55-75%. They are stored in the same way as red cells. The recipient must be ABO &
rhesus D compatible and medication should never be added to a unit of blood.
However, you can add normal saline using a Y-pattern infusion set to improve
transfusion flow. Packed cells have a shelf life of 2-3 weeks.
• Red cell suspension. This is a variant of packed cells in which plasma is removed and
replaced by SAG-M (normal saline, adenine, glucose, mannitol solution). This
increases the shelf life to 5 weeks. The haemoglobin level is approximately 15g/dL,
although there is no less than 45g per unit. Haematocrit levels are 55-70%. It has the
same indications as for packed cells. However, it is not advised for exchange
transfusions. It is administered the same way as whole blood, but achieves better
flow rates than whole blood & packed cells.
• Plasma. Plasma is obtained from the supernatant of centrifuged blood and is what is
separated from packed cells. it can be fractionalised into different fragments:
o Fresh frozen plasma (FFP). FFP is prepared by removing plasma from the
blood of a single donor by centrifugation within 8h of collection. The plasma
is then rapidly frozen to -25°C or colder. It is then stored at that temperature
for up to a year. It contains the normal plasma levels of stable clotting
factors, albumin and immunoglobulins. The usual volume of the pack is 200-
300ml. FFP can be untreated, in which case it poses an infection risk, or it can
be treated with methylene blue or ultraviolet inactivation. Before use, it

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 should be thawed in a water bath at 30-37°C1, and once thawed it should be
stored in a fridge at 2-6°C. The initial dose of FFP is 15ml/kg body weight.
Indications
1st-line therapy in treatment of coagulopathic haemorrhage.
• Warfarin overdose.
• DIC (from obstetric haemorrhage, trauma, postoperative
complications, severe infection & septic shock, and acute blood loss).
• Liver disease & biopsy.
• Massive blood transfusion.
• Isolated coagulation deficiencies where no specific concentrate is
readily available.
• TTP & HUS.
• Non-specific haemostatic failure in a bleeding patient.
Hypovolaemia alone is not an indication.
Key notes
• Despite having clotting factors, these factors have half-lives (ranging
from less than 12 hours to more than 48 hours) when infused. It is
important to note these when treating a patient with coagulopathy.
• Administer FFP as soon as possible after thawing. Do it within 1 hour
through a filter needle.
• The donor & recipient must be group compatible. If blood group not
known, give “all groups”.
• If a woman of child-bearing age is Rhesus D-negative, you can give
Rhesus D-positive FFP but you also give anti-D immunoglobulins
250IU.
• Check PT & aPTT before and 5 minutes after administration to assess
response.
• Note the clinical response in the patient and repeat administration if
necessary.
Acute allergic reactions are not uncommon, especially with rapid infusions.
Severe anaphylactic reactions can occur.
o Cryoprecipitate. Cryoprecipitate is a precipitate that forms from the slow
thawing of FFP at 4°C. The cryoprecipitate is then re-suspended in 10-20ml of
plasma and stored at -30°C for up to 1 year2. Cryoprecipitate is rich in factors
II, VIII, XIII, von Willebrand factor and fibronectin. It does not contain any
other coagulation factors, but may contain anti-A/anti-B blood group
antibodies.

1
You can also thaw it at room temperature, but it takes longer. Higher temperatures will destroy clotting
factors & proteins.
2
Usually 6 packs of cryoprecipitate are required per patient. The packs may be separate or pooled into 1 large
pack.

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 Indications
Low-fibrinogen states:
• DIC.
• Liver disease/transplantation.
• Massive transfusion.
Inherited deficiencies:
• Factor VIII deficiency (Haemophilia A)
• Factor XIII deficiency.
• Von Willebrand’s disease.
Key notes:
• Keep frozen until required.
• Thaw at room temperature or at 37°C and use immediately.
• ABO compatibility not required although if possible use ABO-
compatible blood.
• Target fibrinogen level is 150mg/dL.
• Dose for hypofibrinogenaemia: 2-4 packs/10kg for severe cases; 1-2
packs/10kg for less severe cases. The dose depends on indication for
use & desired increment.
All donations are screened for HIV, HBV and HCV.
• Platelet preparations. Platelet preparations can be:
o Platelet-rich plasma. This is obtained from centrifugation of freshly-donated
blood. Platelet-rich plasma contains 55 × 109 platelets, with a much lower red
& white cell content. A single donor unit has a volume of 50-60ml. Platelet-
rich plasma can be stored for up to 72h at 20-24°C3. Longer storage periods
increase the risk of bacterial proliferation. It is often administered at a dose
of 1 unit/10kg body weight: in an adult, 4-6 units are required, and they raise
the platelet count by 20-40 × 109 cells/L. The rise is lower if there is
splenomegaly, DIC and septicaemia. The platelets should be infused within 4
hours of collection and infused over 30 minutes.
o Platelet concentrate. Platelet concentrate is obtained from plasmapheresis.
This one contains 150-500 × 109 platelets, and it has a volume of 150-300ml.
it is also stored for up to 72h at 20-24°C.
The indications for platelet preparations are as follows:
Indications: Contra-indications:
Patients who are actively bleeding with: • Prophylaxis of bleeding in surgical
• Thrombocytopaenia patients (unless there is significant
(quantitative defects). pre-operative platelet deficiency).
• Platelet function defects • TTP.
(qualitative defects). • Untreated DIC.

3
Do not store it at 2-6°C.

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 They are also used for prevention of • Septicaemia (unless treatment has
bleeding due to thrombocytopaenia, commenced or when there is
such as in bone marrow failure. concurrent hyposplenism).
• Autologous blood. Autologous transfusion can be employed for some surgical
patients, and thus avoid problems associated with allogenic transfusion. This is done
for patients who do not wish to receive allogenic blood or who have difficult
antibodies that make cross matching difficult. It can be pre-deposit or intra-
operative red cell salvage.
o Pre-deposit. This is collection of blood prior to surgery. The first unit of blood
is collected about 2 weeks prior to surgery while the next one is collected 7-
10 days prior to surgery.
Advantages: Disadvantages:
• Can store red blood cells • Requires Hb ≥ 11g/dL.
for up to 5 weeks at 4°C. • Patient must live near the
• May donate 2-4 weeks transfusion centre and be fit to
pre-op. donate 2-4 units pre-op.
• Avoids many problems • Requires close coordination
associated with allo- between the surgeon, patient and
infusion. transfusion lab.
o Immunologic • No reduction in workload –
incompatibility. screened in the same way as
o Risk of allogenic blood.
transmission of • Expensive.
infection. • Patient may still require additional
o Transfusion allogenic units.
reactions. • Patients with epilepsy excluded.
o Intraoperative red cell salvage. This is when blood lost intra-operatively is re-
infused into the patient using suction catheters & filtration systems. It is
particularly used in cardiac surgery, but it can be used for any surgical
procedure provided there is no faecal contamination. Its use is limited by its
high cost. You can use single-use disposable canisters such as Solcotrans™
where a patient is heparinised and anticoagulated blood is collected into an
anticoagulant in the canister. You can also use an automated/semi-
automated salvage such as Haemonetics Cell Saver™ in which blood is
collected, washed centrifugally, filtered and held for re-infusion.

Clinical procedures of blood transfusion

When blood is required for transfusion, the following needs to be done:

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 1. Assess the patient’s need for transfusion and record it in the patient’s notes. There
are different needs for blood:
a. It may be required for possible need for blood, such as in obstetric cases or in
preparation for elective surgery.
b. It may be required for a definite need for blood, such as in an anaemic case
(Hb < 7g/dL) where blood is required but is not an emergency.
c. It may be required for emergency purposes, in which blood is required within
1 hour or less.
2. Select the blood product & quantity required. It is important to inform the patient,
where possible, of the reason for transfusion.
3. Complete the blood request form, also indicating the reason for transfusion. If blood
is needed urgently, order blood via telephone. It is important to indicate on the
request form how quickly you need the blood.
4. Obtain & correctly label the blood sample for compatibility testing (cross-matching or
group & retain). Send both the blood request form & blood sample to the blood
bank.
5. The laboratory performs pre-transfusion antibody screening, compatibility testing
and selecting compatible units. This is done to prevent transfusion reactions.
6. Store blood products in the correct storage units if it is not to be transfused
immediately. Following delivery of blood, whole blood, packed cells and thawed FFP
should be administered within 30 minutes. If the blood cannot be used within this
period, you can store it in a fridge at 2-6°C. Platelet concentrates should be issued
from the blood bank in a cold box or insulated & maintained at 20-24°C4.
7. When the blood product comes, check the patient’s identity, the patient’s notes for
the blood product ordered, and the blood product that has come. Often the blood
1
bank sends group O blood to prevent errors. 3 of unmatched transfusions will lead to
transfusion reactions, and 10% of these will be severe or fatal5. Also check the blood
pack for any sign of haemolysis in the plasma6, any sign of contamination in the pack,
any clots or any leak in the pack (indicating that it has been tampered with or has
been opened.
8. Record in the patient’s notes the blood product (including blood group) & the volume
received and the unique serial number of the blood pack. This is done at the bedside.
Do not discard the pack following transfusion so that you can refer to the pack
details in the case of a transfusion reaction.
9. Administer the blood pack. This is usually done using a filter needle. The cannula
must be sterile and never reused. For whole blood, packed cells, FFP and

4
Platelets should never be placed in the fridge.
5
When non-group-specific blood is being transfused, red cell concentrates (packed cells) are preferred
because plasma has been removed.
6
This may indicate that the blood has been contaminated, allowed to freeze or has become warm.

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 cryoprecipitate, you use a set containing a 170-200 micron filter7. During blood
component transfusion, change the set at least 12 hourly. There is no evidence
suggesting that warming blood has any benefit if infusion is slow, although keeping
the patient warm is more important8. Do not add drugs to the blood pack.
10. You should monitor the patient before, during and after completion of the
transfusion. Check for transfusion reactions. These are usually due to ABO
mismatches. The patient must be monitored before administering the blood, as soon
as the transfusion is started, 15 minutes after starting the transfusions, hourly during
the transfusion, on completion of the transfusion and for 4 hours after completion.
Each time, check for:
a. The patient’s general appearance.
b. Temperature.
c. Pulse.
d. Blood pressure.
e. Respiratory rate.
f. Fluid balance – oral & IV fluid intake (input) versus urine output (output)
The patient should be monitored for shivering, flushing, pain, anxiety or shortness of
breath.

Complications of transfusions
The complications of transfusions are:

• Febrile reactions. This is the most complication of transfusions. It is due to impurities

in blood such as pyrogens which come from blood or from the infusion set. The
features include headache, fever & chills, nausea & vomiting and tachycardia.
Transfusion is temporarily stopped or flow is slowed down. Antipyretic drugs (e.g.
paracetamol) can be administered to reduce the fever. Transfusion of that unit often
needs to be discontinued.
• Allergic reactions. These are often reactions to donor proteins, and can manifest as
urticaria. It is often mild and is treated with steroids & antihistamines. However,
serious anaphylactic reactions can occur, and the unit is discarded, new washed
packed cells are given and platelets are administered. In severe anaphylactic
reactions (which manifest as dyspnoea, bronchospasm, angioedema and
hypotension), you must discontinue the transfusion and administer epinephrine &
methylprednisolone.
• Acute haemolytic transfusion reactions (AHTR). These are the most serious
reactions. They are immunological and are due to incompatibility between donor

7
The filter removes clots and small clumps of platelets & white cells that develop during blood collection &
storage.
8
Blood is only to be warmed in a blood warmer and not in a water bath.

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 cells & the recipient’s antibodies. In the majority of cases, it is due to ABO
incompatibility (which is usually severe), although it may also be due to Rhesus
incompatibility (which is milder). There are a number of things that happen during
an acute haemolytic transfusion reactions:
o There is antibody- & complement-mediated red cell destruction due to the
presence of foreign antigens on the red blood cells.
o The antibodies & complement activate factor XII, leading to the production of
bradykinin. This leads to increased capillary permeability & hypotension.
o The complement system releases histamine & serotonin from mast cells. This
causes bronchospasms.
o Haemolysis releases haemoglobin, which binds to haptoglobulin & albumin.
When haptoglobulin saturates, haemoglobin remains free and is filtered
freely through the kidneys. In kidneys, it is changed to the acid haematin and
this toxic to the renal tubules.
o There may be hypertension secondary to renal vasoconstriction.
o Antigen-antibody complexes may deposit in the glomeruli, inducing damage
in the process.
The signs & symptoms of AHTR include fever & chills, nausea & vomiting, diarrhoea,
hypotension, tachycardia, dyspnoea, chest & back pain and a headache. AHTR is
mostly due to either a clerical or a technical error. AHTR is treated by preserving
systemic blood pressure, preserving renal perfusion & urine output and preventing
DIC. Hydrocortisone/dexamethasone is given IV immediately. Mannitol 20g in 100ml
is given over 5 minutes. Furosemide 120mg is then injected intravenously.
• Transfusion-related acute lung injury (TRALI). This is a non-cardiogenic form of
pulmonary oedema which occurs after administration of a blood product. This occurs
when antibodies present in the plasma of the donor pack react with leukocyte
antigens in the recipient. The activated leukocytes are sequestered in the lungs
where they release mediators that increase capillary permeability and cause
endothelial damage. The features include: breathlessness, a drop in saturation, fever
and hypotension. The features include:
o Acute onset of hypoxaemia.
o Bilateral chest infiltrates on chest X-ray.
o Absence of evidence of left atrial hypertension.
o Absence of temporarily related cause of ALI.

Massive blood transfusion

A massive blood transfusion is defined as replacement of blood equivalent to the patient’s
blood volume (in relation to the patient’s age9) in less than 24 hours. Massive blood

9
In adults, this is 5-6 litres (or 70ml/kg). In infants, it is 85ml/kg.

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transfusion is used in severe trauma associated with liver, major vessel, cardiac, pulmonary
and pelvic injuries. It is also required for surgical bleeding during major surgeries. Morbidity
& mortality tend to be high in these patients (mainly due to the initial trauma & subsequent
hypovolaemia, not due to the transfusion itself).

The complications of a massive transfusion are:

• Coagulopathy. Plasma undergoes progressive loss of clotting factors (especially

factors V & VIII) during storage. Packed cells usually contain little coagulation factors.
Therefore during massive transfusion, there is dilution of the recipient’s clotting
factors such that disorders of coagulation occur. Platelet function is also lost during
storage of whole blood. If there is prolonged PT, give ABO-compatible FFP. If aPTT is
prolonged, you give factor VIII/fibrinogen in combination with FFP10. Give platelets
only if there are clinical signs of microvascular bleeding (bleeding from mucous
membranes, wounds, raw surfaces, catheter sites) and platelet count falls below 50
× 109 cells/L, or when platelet count falls below 20 × 109 cells/L in an asymptomatic
patient.
• Metabolic acidosis. This is more likely the result of inadequate treatment of
hypovolaemia than due to the effects of transfusion. Under normal circumstances,
the body can easily neutralise the extra acid load from transfusion. The routine use
of neutralising agents such as bicarbonate may be unnecessary.
• Citrate toxicity. Citrate is used as an anticoagulant in stored blood11. Use of multiple
packs may result in accumulation of citrate in the circulation. However, this is a rare
complication because citrate is rapidly metabolised to bicarbonate.
• Hypocalcaemia. Hypocalcaemia can result in a reduction in cardiac output,
bradycardia and other arrhythmias.
• Hyper- & hypokalaemia. Storage of blood will lead to a small increase in
extracellular potassium concentration which increases when the blood pack is stored
longer. This is rise is more significant in neonatal exchange transfusions.
Hypokalaemia can occur as well.
• Infections.
• Hypothermia. This occurs when there is rapid infusion of blood products coming
straight from the fridge. Care should be taken during administration of blood
products to prevent hypothermia.
• Iron overload. Iron overload can occur in patients who receive repeated transfusions
over a long time. Each unit of blood contains about 250mg of elemental iron.

10
If none of these is available, give cryoprecipitate instead. It also contains factor VIII & fibrinogen.
11
There is little citrate in red cell concentrates & red cell suspensions.

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 Vitamin B12 deficiency
Vitamin B12 – also known as cobalamin – is an essential vitamin require by the body. Vitamin
B12 deficiency is not very common, but it can occur in patients with certain conditions.

Physiology of vitamin B12

Cobalamin is a macromolecular complex consisting of a tetrapyrole ring with a cobalt ion in
its centre. The cobalt ion forms 6 coordinate bonds, 4 of which it forms with the tetrapyrole
ring. The 5th bond is formed with a benzimidazole nitrogen. 6th ligand can vary, and this
gives the molecule its identity. There are different types: methylcobalamin,
deoxyadenosylcobalamin, cyanocobalamin and hydroxycobalamin. In food, you get
methylcobalamin & deoxyadenosylcobalamin, while in supplements you get
cyanocobalamin & hydroxycobalamin. Vitamin B12 is mainly found in animal products, such
as meat (especially liver meat), fish and dairy products, but not in plants.

Vitamin B12 is released from food by acid & pepsin, and then becomes complexed to an R-
binder in the stomach1. In the duodenum, B12 is released from the R-binder pancreatic
enzymes and binds to intrinsic factor (IF) released from gastric parietal cells. The IF-B12
complex is then carried down to the terminal ileum where it is absorbed. This complex binds
to a complex called cubillin, and the new complex binds to another protein called
amnionless which facilitates the uptake of the IF-B12-cu complex into the enterocytes.
Successful absorption of vitamin B12 therefore depends on the presence of:

• Adequate dietary intake.

• Acid-pepsin in the stomach.
• Pancreatic proteases.
• Gastric secretion of a functional intrinsic factor.
• An ileum with functional IF-B12 receptors.

The complex is then broken down and B12 is released into the circulation. In the circulation,
it is transported bound to plasma transcobalamin II (TCII) [70-90%] & haptocorrin. It is then
transported to the liver & bone marrow, where it is stored. On an average diet, a human
being will absorb 5-25µg of vitamin B12 every day. However, only 1-5µg is used daily by the
body. The rest of it is stored in the liver & bone marrow. The body has total stores of 2-5mg
of vitamin B12.

Vitamin B12 has 2 main functions in the body:

1
This protein is related to plasma transcobalamin I (TCI), a salivary protein.

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 1. Methylcobalamin takes part in folic acid metabolism. It is a cofactor for the enzyme
homocysteine-methionine methyltransferase. This enzyme catalyses the
demethylation of dietary N5-methyltetrahydrofolate to form tetrahydrofolate. This
increases tetrahydrofolate levels required for the synthesis of dTMP synthesis.
Cobalamin only works as a cofactor; the methyl group is transferred to homocysteine
to form methionine. This helps reduce homocysteine levels2.
2. Deoxycobalamin is a cofactor for methylmalonyl coA mutase. This enzyme catalyses
the isomerisation of methylmalonyl coA to succinyl coA. This reaction is useful for
incorporating odd-chain fatty acids, some amino acids, cholesterol and thymine into
the Krebs cycle. The significance of this reaction is unknown. However, considering
that this is the only major difference in function between B12 & folate and that folate
deficiency lacks neurological symptoms, it is possible that it is important in myelin
formation.

Pathophysiology
The major consequence of vitamin B12 deficiency is megaloblastic erythropoiesis. Vitamin
B12 deficiency leads to a rate of DNA synthesis that is too slow to keep with cell growth &
division. Megaloblasts are erythroblasts with delayed nuclear maturation because of
defective DNA synthesis. Megaloblasts are large and have large immature nuclei. The
nuclear chromatin is more dispersed than normal. On occasion, giant metamyelocytes are
also seen in megaloblastic anaemia. It is also suggested that methionine deficiency may
contribute to the slowing of DNA synthesis.

The cause of anaemia can be addressed by the kinetic (quantitative) & morphological
(qualitative) approach. There is ineffective erythropoiesis, and that contributes to ultimately
reduced red cell output (largely by increased apoptosis), as reflected by the reduced
reticulocyte count. There is also increased intramedullary haemolysis of red cells before
they are released into the circulation. Therefore, there is intense erythroid hyperplasia but
relative reticulocytopenia. Megakaryocytosis is also affected: there is an increased number
of megakaryocytes, but they have diminished ploidy and therefore they have a reduced
capacity to produce adequate platelets.

For anaemia to develop in B12 deficiency, there needs to be either depletion of body stores
or inhibition of the utilisation of the vitamin. The body has 2-5mg of cobalamin stores, but
uses 1-5µg per day. Therefore, it takes years for a person who stops taking vitamin B 12 to
develop vitamin B12 deficiency symptoms simply from not eating enough.

Aetiology

2
Homocysteine levels will accumulate because methionine is used to form SAM (S-adenosine methionine),
which acts as a methyl donor for many other reactions, such as methylation of cytosine.

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The causes of vitamin B12 deficiency are as follows:

• Low dietary intake. This is more common in vegans & vegetarians who preferentially
do not eat meat. It is uncommon in people who skip meat every now and then.
• Pernicious anaemia. This is an autoimmune condition that is caused by a reaction to
intrinsic factor. This leads to the inhibition of absorption of vitamin B 12 in the gut. It
is a form of atrophic gastritis. There are many mechanisms as to how the antibodies
inhibit the interaction.
o There could be production of anti-parietal antibodies that attack parietal cells
of the gastric glands, leading to atrophy of the gastric mucosa. These are
found in 90% of patients.
o There could be production of blocking antibodies that interfere with the
interaction between intrinsic factor and vitamin B12.
o There could be production of binding antibodies that bind to the IF-B12
complex and interfere with the absorption of the complex.
It occurs in 1 in 8000 individuals in the UK. It is more common amongst women, and
it usually presents in the elderly. It also has an association with other autoimmune
disorders.
• Previous gastric surgery. This reduces the available gastric glands for the secretion
of acid and production of intrinsic factor. This reduces the body’s capacity to absorb
vitamin B12.
• Ilial surgery. Vitamin B12 is absorbed in the terminal ileum. Therefore, if you get ileal
resection surgery, you are likely to impair the capacity for absorption by reducing its
surface area. This forms part of the short bowel syndrome.
• Pancreatic insufficiency. Pancreatic insufficiency means that the pancreatic enzymes
that normally cleave the complex between vitamin B12 & R-binder cannot be cleaved.
• Crohn’s disease. Crohn’s disease also affects the terminal ileum and impairs its
absorptive capabilities.
• Drugs. Prolonged use of proton pump inhibitors leads to vitamin B12 deficiency. This
is due to inhibition of production of acid, which is vital for the liberation of B12 from
food and is subsequent binding to intrinsic factor. Cancer drugs such as
methotrexate, mercaptopurine and cytosine arabinoside impair the absorption of
the vitamin.
• Fish tapeworm. The fish tapeworm Diphyllobothrium latum is known to cause
vitamin B12 deficiency. This infection, however, is not common.
• Malabsorption syndromes. Tropical sprue & coeliac disease3 can cause vitamin B12
deficiency.
• Bacterial overgrowth in small intestine. Any condition leading to bacterial
overgrowth in the small intestine can cause vitamin B12 deficiency.

3
Coeliac disease often does not cause vitamin B12 deficiency because often the terminal ileum is spared.

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Clinical features
The patient will present with a combination of anaemia symptoms and neurologic
symptoms. The patient will be pale and jaundiced due to anaemia & haemolysis
respectively. Patients will a beefy red tongue secondary to glossitis, as well as angular
stomatitis.

The neurologic features of disease can occur without anaemia. They include:

• Neuropsychiatric symptoms. These include irritability, depression, confusion,

delirium and dementia. These changes respond to treatment.
• Cranial nerve involvement. This is rare in vitamin B12 deficiency. If present, you can
develop optic atrophy, leading to reduced vision. There may also be retinal
haemorrhage.
• Spinal cord. Spinal cord leads to a syndrome called sub-acute combined
degeneration of the spinal cord. In this syndrome, there is a combination of
symmetrical dorsal column loss (causing sensory & lower motor neuron signs) and
symmetrical corticospinal tract loss (causing motor & upper motor neuron signs).
The features of sub-acute combined degeneration of the spinal cord include:
o Joint position (proprioception) and vibration are affected first, leading to
ataxia.
o This is followed by weakness & stiffness if not treated.
o The classic triad is: brisk knee jerk, absent ankle jerk and extensor plantar
response (up-going Babinski sign).
The legs are affected more than the arms. The spinothalamic tracts are preserved,
and therefore pain & temperature sensation are preserved. The spinal changes are
not reversible with treatment. The condition can progress to cause faecal & urinary
incontinence.
• Peripheral neuropathy. This is one of the initial features of vitamin B12 deficiency.
Initially, there is numbness & tingling of the fingers & toes. There is also distal
sensory loss (especially vibration & proprioception). These changes are variably
reversible.

Patients with vitamin B12 deficiency are at increased risk of osteoporosis.

Investigations
The investigations that are done in vitamin B12 deficiency include:

• FBC. This will reveal a macrocytic anaemia with an Hb of less than 12.5g/dL and MCV
greater than 100fL (unless there is a concurrent cause of microcytosis). The red cells
demonstrate an increased red cell distribution width (RDW), which shows the
significant difference in size between red cells. In severe cases, there is a

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 pancytopaenia, with thrombocytopaenia & leukocytopaenia. The reticulocyte count
will be reduced as well.
• Peripheral smear. On a peripheral smear you will see large oval-shaped red blood
cells called macro-ovalocytes. There is also anisopoikilocytosis (red cells with
different size and shape). There are also hypersegmented neutrophils, which is
reflected by more than 5% of neutrophils with more than 5 lobes and more than 1%
of neutrophils with more than 6 lobes. The combination of macrocytosis with
hypersegmented neutrophils is pathognomonic of vitamin B12 deficiency, although
either of macrocytosis or hypersegmented neutrophils on their own are found in
other disorders.
• Bone marrow aspirate. This will show hypercellularity of the bone marrow coupled
with megaloblasts. Megaloblasts are erythrocytes with delayed nuclear maturation
because of defective DNA synthesis. Megaloblasts are large and have immature
nuclei. The nuclear chromatin is more finely dispersed and has a stippled
appearance. You will also see giant metamyelocytes. Bone marrow aspirate is usually
not done because of its cost, its invasiveness and because often the diagnosis will
have been made based on clinical features and other lab investigations.
• Serum vitamin B12 levels. The vitamin B12 levels are usually low – below 200ng/L for
definite deficiency. If the levels are between 200 & 300ng/L, the result is not
conclusive and therefore requires other tests.
• Other serum studies. Serum iron, unconjugated bilirubin and LDH are raised, while
haptoglobulin is low due to the haemolysis.
• Metabolites. You can measure the levels of homocysteine & methylmalonic acid.
These metabolites accumulate in the setting of vitamin B12 deficiency. In folic acid
deficiency, you only get accumulation of homocysteine and not methylmalonic acid,
so this is another way of differentiating the 2. These metabolites are only measured
if the vitamin B12 & folate levels are not conclusive (borderline).
• Tests for pernicious anaemia. Because pernicious anaemia is a common cause
vitamin B12 deficiency (especially in the West), it should be tested for in patients
presenting with vitamin B12 deficiency. The tests include:
o Anti-IF antibodies. The presence of anti-IF antibodies is useful in diagnosing
pernicious anaemia. This test, however, has a low sensitivity (50-70%) but a
high specificity (almost 100%).
o Anti-parietal cell antibodies. This test is more sensitive (90%) but has lower
specificity than anti-IF antibodies.
o Schilling test. This test is a 2-stage test used for diagnosing pernicious
anaemia.
In the first stage, you give a tracer dose (1µg) of radio-labelled vitamin B124
orally, then giving a flushing dose (1mg) of normal unlabelled vitamin B12

4
This vitamin B12 contains 58Co.

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 intramuscularly 1 hour later to clear all the radio-labelled vitamin B12. This
allows the radio-labelled vitamin B12 to be excreted in urine. You then
measure the 24-hour radio-labelled vitamin B12 levels. A normal excretion
level is one that is greater than 5%, and this is only seen if the vitamin B 12 is
absorbed properly, i.e. the deficiency was due to dietary deficiency alone &
not an absorption problem.
In the second stage, you repeat the same thing, but you also give oral
intrinsic factor (and this is only done if the first stage was abnormal). If the
radio-labelled vitamin B12 excretion normalises, then it is most likely the
deficiency was due to pernicious anaemia or gastrectomy. If it does not, it is
likely due to a malabsorption syndrome from whatever cause.
The Schilling is useful in evaluating other causes of vitamin B12 deficiency.
Other ways of evaluating the Schilling test are as follows:
Test Gastrectomy, Coeliac Bacterial Ileal disease Pancreatic
pernicious disease overgrowth or resection insufficiency
anaemia
1st stage Low Low Low Low/normal Low
1st & 2nd Normal Low Low Low/normal Low
stages
1st & 2nd Low Normal Low/normal Low
stages after
antibiotic
1st & 2nd Normal Low/normal Low
stages after
gluten-free
diet
1st & 2nd Low/normal Normal
stages after
pancreatic
enzymes

Management
The treatment of vitamin B12 deficiency requires 2 things: treating the cause, and replacing
vitamin B12. The cause of vitamin B12 deficiency needs to be treated if possible – many of the
causes can be treated in some way.

Vitamin B12 levels also need to be replaced. This can be done in a number of ways:

• Parenteral cobalamin. Hydroxycobalamin is the formulation used for parenteral

treatment. You give 1mg daily for 1 week, then 1mg weekly for 4 weeks. If the cause
is reversible, you can stop treatment when the deficiency has fully reversed and the
cause has been eliminated. If the cause is a permanent one, you give 1mg 3-monthly

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 for the rest of the patient’s life. Cobalamin is generally a non-toxic substance. You
can also use cyanocobalamin in place of hydroxycobalamin.
• Oral cobalamin. Oral cobalamin can be used for nutritional deficiency as well as for
absorption problems in some cases. The rational is that at high oral doses, 1-2% of
the drug is absorbed through diffusion without the need for intrinsic factor. You can
give 2mg daily. The only issue one may have is compliance with an oral regimen for
the rest of the patient’s life.

Patients with vitamin B12 deficiency probably need folate supplementation.

Clinical improvement may occur within 48hours. Reticulocytosis can be seen in 2-3 days.
Maximum improvement of polyneuropathy & other neurologic features can take 6-12
months. Longstanding spinal cord damage is mostly irreversible. Iron deficiency often
develops in the first few months following therapy and if this happens supplements should
be given. Hypokalaemia can develop during the first few months due to rapid utilisation
during production of new red cells. It may be profound in those that are severely anaemic at
the beginning of treatment.

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 Anaphylaxis
Anaphylaxis refers to an acute potentially lethal multi-systemic syndrome resulting from an
allergic reaction. It is a medical emergency and it requires prompt recognition and
treatment. It is, however, a rare event.

Aetiology
Anaphylaxis is the result of widespread mast cell degranulation. This can be caused by an
immunologic reaction or non-immunologic reaction.

Immunologic anaphylaxis

Immunologic pathways are those in which an allergen generates an immune reaction in a

sensitised individual. They include:

• IgE-mediated reactions. This is the classical mechanism associated with anaphylaxis.

Anaphylaxis is the result of the interaction between an allergen and mast
cell/basophil-bound IgE immunoglobulin. This initiates intracellular signalling and if
the signalling is sufficiently robust, the mast cell becomes activated and degranulates
to release preformed mediators. The mediators either interact with tissues directly
or activate other immune cells, leading to the propagation of a fulminant chain
reaction of allergic inflammation.
• IgG-mediated reactions. These have only been studied in animal models. They may,
however, be used to explain why some individuals receiving IgG anti-IgE antibodies
develop anaphylactic reactions.
• Immune complex/complement mediated reactions. Some allergens produce life-
threatening reactions that are clinically-similar to allergic reactions but without
demonstrable IgE anibtodies.

Non-immunologic anaphylaxis

This has been implicated for various drugs. Some of the potential mechanisms include:

• Direct activation of complement. Direct activation of complement in the absence of

immune complex formation has been proposed for some drugs such as propofol &
paclitaxel which were dissolved in Cremophor®1. Cremophor forms large micelles
with lipids which activate complement. In susceptible patients, C3a & C5a are
anaphylatoxins which bind to receptors on mast cells and lead to degranulation.

1
Cremophor EL (now known as Kolliphor EL) is a solvent formed from mixing castor oil with ethylene oxide. It
is usually mixed with many drugs, such as paclitaxel, propofol, miconazole, diazepam, vitamin K and nelfinavir
(protease inhibitor).

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 • Direct activation of mast cells. This has been implicated in the “red man” syndrome
resulting from vancomycin. It can involve hypotension and present similarly to
anaphylaxis in up to 15% of individuals. Opiate medications can also cause direct
mast cell degranulation.
• Cold urticaria. This is characterised by rapid onset of erythema, pruritus and oedema
after exposure to cold. There may be associated cryoglobulinaemia.
• Direct activation of kallikrein-kinin pathway. Oversulphate chondroitin sulphate
(which contaminated heparin in 2007-2008) caused anaphylaxis by directly activating
the kinin-kallikrein pathway. This generates bradykinin, C3a and C5a. These
reactions, however, consistently lacked urticaria. ACE inhibitors can also cause
angioedema ± anaphylaxis due to direct activation of bradykinin.

Pathophysiology
Anaphylaxis occurs as a result of widespread systemic degranulation of mast cells &
basophils, releasing histamine into the circulation. The mediators of anaphylaxis include:

• Mast cells & basophils. Mast cells and basophils degranulate release a number of
mediators, which include:
o Histamine. Histamine is a known vasodilator, and it also mediates other effects
similar to those of an allergic reaction. Localised release is associated with
urticaria. Widespread histamine release leads to increased vascular permeability
& vasodilation and is not associated with urticaria. Histamine acts on H1 & H2
receptors alike. H1 actions include tachycardia, pruritus, rhinorrhoea and
bronchospasm. Combined H1 & H2 actions include flushing, hypotension and
headache. The binding of histamine to H1-receptors leads to PLC-mediated
calcium mobilisation, leading to increased nitric oxide synthase and increased
nitric oxide levels. This mediates increased vascular permeability & vasodilation.
o Tryptase. Tryptase is a protease that is relatively specific to mast cells, but
basophils & myeloid precursors contain a small amount. Tryptase can activate
complement & coagulation pathways, as well as the kallikrein-kinin contact
system. Potential consequences include hypotension, angioedema, clotting and
clot lysis (with possible DIC). Orally-ingested allergens trigger release of lower
levels of tryptase than parenterally-administered allergens2, and apart from food
allergies, tryptase levels correlate with disease severity.
o Platelet-activating factor (PAF). Serum PAF correlates directly with the severity
of anaphylaxis. Serum PAF hydroxylase, however, correlates inversely with the
severity of anaphylaxis.

2
The opposite, however, is true about antigen-specific IgE antibodies: IgE antibody release is higher with
orally-ingested allergens.

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 o Arachidonic acid metabolites. LTB4 is a chemotactic agent and can lead to
biphasic & protracted reactions. LTC4 increases mast cell degranulation when
produced in large quantities. LTD4 & LTE4 increase microvascular permeability
and are potent bronchoconstrictors.
• Serum factors & other inflammatory pathways. During severe anaphylaxis, there is
activation of:
o Complement. There are decreased levels of C3 & C4 in anaphylaxis, with
increased levels of C3a.
o Coagulation. There are decreased levels of factor V, factor VIII and fibrinogen,
and in some cases fatal DIC3.
o Kallikrein-kinin contact system. Contact system activation is indicated by
decreased high molecular weight kininogen and the formation of kallikrein-C1
inhibitor & factor XIIa-C1 inhibitor complexes. Kallikrein generates bradykinin and
also activates factor XII, leading to clotting & clot lysis.

Organ effects
In humans, the predominant shock organs are the heart, vasculature and the lungs.
Fatalities are divided between cardiovascular collapse and respiratory arrest.

• Cardiovascular system. Anaphylaxis can lead to myocardial depression due to

ischemia, and there may also be conduction defects. It is unclear whether these
effects are due to the direct action of released mediators on the myocardium,
exacerbation of pre-existing myocardial insufficiency, endogenous epinephrine
release from the adrenal medulla or exogenous epinephrine injected during
treatment. Histamine mediates coronary vasoconstriction & possible vasospasm and
increases vascular permeability via H1 receptors. It also leads to coronary artery
vasodilation via H2-receptors, and through these same receptors it also has positive
inotropic & chronotropic effects. There is an increased occurrence of acute coronary
events.
• Circulatory system. Widespread histamine release can lead to systemic vasodilation
which causes hypotension due to massive expansion of the vascular space. Massive
fluid shifts occur due to increased vascular permeability. Up to 35% of the
intravascular fluid can shift out of the vascular space within 10 minutes. This can
produce a picture of hypovolaemic shock. Compensatory mechanisms include the
release of catecholamines, angiotensin II and endothelins, and these induce
vasoconstriction. However, there may still be shock despite maximal
vasoconstriction, and in some cases there is limited vasoconstriction despite
elevated catecholamines.

3
DIC accounts for 8% of deaths from anaphylaxis.

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 • Respiratory system. Anaphylaxis can affect any part of the respiratory system. Upper
airway symptoms include sneezing, rhinorrhoea, dysphonia, laryngeal oedema &
obstruction and oropharyngeal angioedema. Lower airway manifestations include
cough, wheeze, pulmonary hyperinflation, oedema, haemorrhage, petechiae, mucus
plugging, respiratory failure and respiratory arrest.

Clinical presentation
The classic presentation of anaphylaxis comprises of the following:

1. Rapid onset & progression of symptoms.

2. Life-threatening compromise of one or more of airway (breathing & swallowing
difficulty, stridor, voice change), breathing (shortness of breath, hypoxaemia,
wheezing and respiratory arrest) and circulation (tachycardia, hypotension/shock,
confusion, decreased urine output and chest pain). Respiratory symptoms are
experienced in 70% of cases while cardiovascular symptoms are experienced in 45%
of cases.
3. Skin/mucosal involvement (itching, erythema, warmness, angioedema, intestinal
obstruction, nausea & vomiting, diarrhoea and crampy abdominal pain). This,
however, is not always present.

Anaphylaxis should be suspected if airway, breathing or circulation is compromised after

ingestion of a known allergen.

The diagnostic criteria for anaphylaxis include:

Criterion 1: Acute onset of illness (minutes to hours) involving skin & mucosal tissue (e.g.
generalised hives, pruritus or flushing, swollen lips, tongue and uvula) AND:
1. Respiratory compromise – dyspnoea, wheezing, stridor, reduced PEF (in older
children & adults), hypoxaemia.
2. Reduced blood pressure or associated symptoms of end organ dysfunction, e.g.
hypotonia, collapse, syncope, incontinence.
Criterion 2: 2 or more of the following that occur rapidly (minutes to hours) following
exposure to a likely allergen for that patient.
1. Involvement of skin or mucosal tissues – generalised hives, itchiness, and swollen
lips, tongue and uvula.
2. Respiratory compromise – dyspnoea, wheeze, stridor, reduced PEF in older children
& adults, hypoxaemia.
3. Reduced BP or associated symptoms – hypotonia, collapse, syncope, incontinence.
4. Persistent GIT symptoms – crampy abdominal pain, nausea & vomiting.
Criterion 3: Reduced BP after exposure to a known allergen for that patient.
• Infants & children: age-specific low systolic BP, or >30% decrease in systolic BP.
o 1-12 months: 70mm Hg.

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 o 1-10 years: (70 + [2×age])mm Hg.
o 11-17 years: 90mm Hg.
• Adults: systolic BP of less than 90mm Hg or >30% decrease in systolic BP from that
patient’s baseline.

Anaphylaxis is often defined by a defined exposure to a potential trigger followed by rapid

onset, evolution and resolution of symptoms & signs within minutes/hours. Anaphylaxis can
be biphasic in which a recurrence of symptoms occurs after the initial episode resolves with
no additional exposure to the trigger. This occurs in 23% of episodes in adults and 11% of
cases in children. Anaphylaxis can also be protracted, in which the attack persists for long.

Differentials
The differential diagnoses for anaphylaxis include:

• Vasovagal reactions. • Carcinoid syndrome.

• Septic shock. • Phaeochromocytoma.
• Seizures. • Systemic mastocytosis.
• Cardiogenic shock. • Hereditary angioedema.
• Benign flushing.

Management
Anaphylaxis is a medical emergency and management should be initiated immediately
before tests are conducted.

Emergency management

It is managed as follows:

1. Airway support. You must secure the airway by giving 100% oxygen at 6-8L/min and
intubating the patient if respiratory obstruction is imminent. Before, administering
oxygen, ensure that the airway is free. Cricothyrotomy may be necessary.
2. Epinephrine. You must give 0.5mg of epinephrine (or 0.5ml of 1:1000)
intramuscularly into the mid-anterolateral thigh. Also establish venous access. If
symptoms are severe, an intravenous infusion should be prepared. Repeat every 5
minutes if shock persists (as guided by BP, pulse and respiratory function).
3. Remove allergen. At times, this is a drug that is being infused; you can stop infusion.
You must raise the legs to help restore circulation.
4. Intravenous fluids. Give a bolus of 1-2L in adults (20ml/kg in children) of normal
saline as a rapid infusion. Titrate against blood pressure. Be wary of massive

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 intravascular shifts.
5. Other medications. Other medications to consider include:
a. Salbutamol. This is done for patients that are persistently wheezing
(bronchospasm). You give 2.5-3.5mg in 3mL normal saline via nebulisation.
Repeat as needed.
b. Anti-histamine. You can give chlorphenamine 100mg intravenously,
diphenhydramine 25-50mg intravenously4 or ranitidine 50mg intravenously.
c. Glucocorticoids. Administer hydrocortisone 100mg intravenously.

Post-emergency intervention

After stabilising the patient, you do the following:

• Admit the patient into the ward.

• Carry out continuous haemodynamic monitoring: blood pressure, ECG, pulse
oximetry. Also monitor urine output in patients receiving intravenous fluids.
• Continue chlorphenamine 4mg every 6h orally if itching.
• Do lab tests:
o Tryptase levels 1-6h after anaphylactic attack (acute) and an additional
sample should be taken at least 24 hours after resolution of symptoms
(baseline). In normal individuals it is undetectable, although baseline levels
can be 1-11.4ng/mL. This test indicates that mast cell degranulation has
occurred and is useful in distinguishing anaphylaxis from other differentials.
The ratio of mature to immature tryptase is used to differentiate it from
other causes of elevated tryptase (systemic mastocytosis5, AML,
myelodysplastic syndrome). For an anaphylactic reaction, the acute sample
must be elevated higher than the baseline sample.
o Skin prick test for identification of allergen.
• Monitor the patient for 4-6 hours

Discharge information & long-term management

On discharge, inform the patient as follows:

1. The patient needs to be reviewed by a family physician after 24-48 hours.

2. The patient may have a second phase of reaction (biphasic reaction) up to 48 hours
later.
3. Give the patient a 3-day course of anti-histamines & corticosteroids.

4
This is administered only for urticaria & itching alone.
5
The ratio of total-to-mature tryptase in anaphylaxis is typically <10 and it is lower with higher tryptase levels.
in other conditions, the ratio is often greater than 20.

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For long-term management, the following can be advised:

• Suggest a MedicAlert® bracelet suggesting the inciting allergen.

• Teach about self-infected adrenaline. In most cases, patients may know about self-
injection but may not have filled the prescription, did not have the auto-injector
available or had it available but failed to use it. These must be discussed repeatedly.
• Manage comorbidities. Asthma is one of the most important risk factors for
anaphylaxis. Cardiovascular disease & COPD are risk factors for death from
anaphylaxis and must be managed. The medications to watch out for include:
o B-blockers may be associated with severe anaphylaxis. They cause
unopposed α-adrenergic action (vasoconstriction leading to hypertension)
and reducing the effect of bronchodilators.
o A-blockers may antagonise epinephrine effects.
o ACE inhibitors may interfere with endogenous compensatory mechanisms,
resulting in more severe & prolonged symptoms.
o CNS-active medications such as psychotropics, anxiolytics and insomnia
remedies can impair cognitive function and can affect the patient’s ability to
recognise the anaphylactic triggers.
• Avoidance of specific triggers.

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 Sarcoidosis
Sarcoidosis is a multisystem granulomatous disease of unknown aetiology. It has a
prevalence of 10-20 per 100 000 population, and its prevalence is highest in Northern
Europe. Black people are affected more frequently (lifetime risk of 2.4%) & more severely
than white people (lifetime risk of 0.85%), particularly by extra-pulmonary disease. it
commonly affects young adults (in their 20s & 30s) and is more common in females.

Pathogenesis
The majority of patients present with pulmonary manifestations, and it is thought this is the
initial lesion. The initial lesion is a CD4+ T-cell alveolitis, followed by development of a non-
caseating granuloma. The granuloma has a tightly-packed central area composed of
macrophages, epithelioid cells and multinucleated giant cells, and these are surrounded by
lymphocytes, monocytes, mast cells and fibroblasts. The sarcoid granuloma can resolve
without sequelae or undergo fibrosis and lead to interstitial fibrosis.

There is depressed cell-mediated immunity and reduced reactivity to tuberculin skin test.
There is also an overall lymphopaenia: circulating T-cells are decreased, but there is an
increase in circulating B-cells. Bronchoalveolar lavage (BAL) shows a great increase in the
number of cells. Lymphocytes & alveolar macrophages are increased, but the percentage of
alveolar macrophages in the BAL is decreased. All these changes (decreased circulating
lymphocytes, changes in delayed-type hypersensitivity and increased lymphocytes on BAL)
reflect sequestration of lymphocytes in the lung. There is no evidence suggesting that these
patients suffer from an overall decrease in immunity.

Possible aetiology
The exact antigenic stimulus that causes sarcoidosis is unknown. However, several
associations have been made:

• Occupational exposures. Beryllium & its salts have been shown to produces
granulomata similar to those produced by sarcoidosis.
• Infections. M. tuberculosis has been isolated in many patients with sarcoidosis. Other
implicated infections include fungi and EBV.
• Family history. The risk of developing sarcoidosis is higher if you have a 1st-degree
relative who is suffering from sarcoidosis. The risk is higher if you’re Caucasian than
if you’re black (OR 18.0 vs. 2.8).
• HLA. Sarcoidosis is associated with HLA-DRB1 & HLA-DQB1 alleles.

Clinical manifestations

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In 20-40% of cases, the disease is asymptomatic and detected incidentally on routine chest
X-ray. The proportion of symptomatic cases is higher in children, and symptomatic
sarcoidosis is rare in children. The disease involves a number of systems.

• Pulmonary manifestations. Pulmonary disease is present in up to 90% of patients.

The pulmonary symptoms include: dry cough, progressive dyspnoea, chest pain and
decreased exercise tolerance. Symptoms progress in 10-20% of patients, and there is
concurrent deterioration in lung function. Crackles & rales are not commonly heard
on examination, although wheezes may be present.
• Extra-pulmonary manifestations. These present in up to 30% of patients. they may
be the only presenting manifestations in young children. The extra-pulmonary
features include:
o Skin manifestations. These are present in up to 10% of cases. The most
common skin manifestation is a maculopapular eruption involving the alar
nares, lips, eyelids, forehead, rear of neck and previous trauma sites.
Sarcoidosis is the most common cause of erythema nodosum, which is a
condition characterised by painful tender dusky blue/red nodules that
commonly present over the shins or lower limbs and fade of 2-3 weeks1.
Sarcoidosis is the only cause of erythema nodosum associated with bilateral
hilar lymphadenopathy. You can also get lupus pernio, which is a chilblain-like
reaction2 that develops in chronic sarcoidosis.
o Eye manifestations. This is present in up to 20% of patients and is the
presenting feature in 5%. The lesions include anterior uveitis (presents with
misting of vision, red eye and pain), posterior uveitis (progressive loss of
vision), conjunctivitis & keratoconjunctivitis sicca and uveoparotid fever3.
Secondary glaucoma, cataract formation and blindness.
o Upper respiratory tract disease. Sarcoidosis can affect the larynx, pharynx,
nares and/or sinuses. it should be suspected in all patients with sarcoidosis &
upper respiratory tract symptoms (stridor, nasal obstruction, anosmia,
epistaxis and nasal polyps).
o Reticuloendothelial manifestations. These include: peripheral
lymphadenopathy (up to 40% of patients), hepatomegaly (20%), non-
caseating granulomas on liver biopsy (75%), and splenomegaly (25%).
o Musculoskeletal manifestations. Arthralgia without erythema nodosum is
seen in 5%. Other manifestations include: acute polyarthritis (especially
around the ankle joints, usually associated with erythema nodosum and
1
Other causes of erythema nodosum include: streptococcal infections, drugs (sulphonamides & oral
contraceptives), bacterial gastroenteritis (Salmonella, Shigella, and Yersinia), fungi (Histoplasmosis,
blastomycosis), TB, leprosy, IBD, and chlamydia.
2
Chilblain is a painful itching swelling on the hand/foot caused by poor circulation in the skin when exposed to
cold.
3
This is a combination of bilateral uveitis and parotid enlargement associated with sarcoidosis, with occasional
development of facial nerve palsy.

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 sometimes with acute uveitis), chronic arthritis with periosteal bone
resorption, and diffuse granulomatous myositis. You can also get phalangeal
bone cysts.
o Metabolic manifestations. Sarcoidosis can cause disorders in calcium
metabolism. Hypercalcaemia is rarely a presenting complaint, but is present
in 10% of established cases. Hypercalcaemia & calciuria can lead to the
development of renal calculi & nephrocalcinosis. The hypercalcaemia is due
to excessive levels of calcitriol due to added 1α-hydroxylation being done by
alveolar macrophages. If left untreated, the patient may develop chronic
kidney disease & renal failure.
o Cardiac manifestations. Cardiac involvement is rare, occurring in 3% of cases.
However, when present it is severe. Granuloma formation in the ventricular
septum & conducting system can lead to ventricular arrhythmias & sudden
cardiac death. Chronic hypertension & cor pulmonale can result from severe
scarring of the pulmonary parenchyma & vasculature. In this setting, death
often occurs due to right heart failure.
o CNS manifestations. This occurs in 2% of cases and they usually present
early. Granulomatous basal meningitis with infiltration/compression of
surrounding structures accounts for most of the CNS manifestations. They
include: hypothalamic-hypopituitarism, central diabetes insipidus,
hydrocephalus, lymphocytic meningitis and cranial nerve palsies (particular
facial nerve palsy).
o Other manifestations. This includes: GIT involvement (stomach most
common. others include oesophagus, appendix, colon and rectum),
reproductive (endometrium, ovaries, uterus – causes abnormal menstrual
bleeding)4, thyroid (diffuse goitre, solitary thyroid nodule), fatigue (very
common, occurs in 5% of patients).
• Acute sarcoid syndromes. There are 2 acute sarcoid syndromes:
o Lofgren’s syndrome. This is an acute presentation consisting of 4 things:
fever, erythema nodosum, bilateral hilar lymphadenopathy and migratory
polyarthralgias. It is primarily seen in women, although in men it presents
pirmarily with bilateral ankle arthritis but without erythema nodosum. It has
a good prognosis as remits spontaneously.
o Heerfordt-Waldenstrom syndrome. This acute presentation consists of fever,
parotid enlargement, anterior uveitis and facial nerve palsy.

Investigations
The investigations done for sarcoidosis include:

4
There is no effect on fertility.

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 • Chest X-ray. This is the first test that should be done if sarcoidosis is being
suspected. The chest X-ray is abnormal in 90% of patients with sarcoidosis. 2
features are prominent on chest X-ray:
o Bilateral hilar lymphadenopathy. This is usually not associated with
symptoms, although it may be accompanied by a dull ache in the chest,
malaise and a mild fever. The differentials include:
Tuberculosis (usually unilateral hilar enlargement).
Lymphoma (it is rarely confined to the hilar lymph nodes).
Carcinoma bronchus (this is also rarely symmetrical).
Others include pneumoconiosis, metastatic disease,
o Pulmonary infiltration. Pulmonary infiltrates appear as mottling in the mid-
zones that evolve over time to generalised fine nodular shadows. Eventually,
linear shadows appear, which resemble underlying fibrosis. You can
occasionally get a honeycomb appearance. The combination of pulmonary
infiltrates with normal lung function tests is suggestive of sarcoidosis. The
differentials include:
TB
Pneumoconiosis
Idiopathic pulmonary fibrosis
Alveolar cell carcinoma
There are 4 stages of pulmonary involvement based on chest X-ray findings, and this
is helpful in prognosis:
Stage Description 2-year remission
Stage 1 Bilateral hilar lymphadenopathy alone. >60%
Stage 2 Bilateral hilar lymphadenopathy with pulmonary infiltrates. 50%
Stage 3 Pulmonary infiltrates alone. ≈33%
Stage 4 Fibrosis.
• Full blood count. There may be a mild normocytic normochromic anaemia
consistent with anaemia of chronic disease. Other causes of anaemia include bone
marrow involvement and AIHA (autoimmune haemolytic anaemia). Hypersplenism
can cause pancytopaenia. Leukopaenia is seen in 5-10% of cases, and there is a
lymphopaenia with an increase in circulating B-cells. Eosinophilia is seen in 25% of
cases. Thrombocytopaenia is rare.
• ESR. ESR is raised frequently, but is a poor marker of disease activity.
• Serum biochemistries. There are elevated ALP levels due to diffuse granulomatous
hepatic involvement. Serum CAMP may reveal elevated calcium levels. There is also
hypergammagobulinaemia. Serum ACE levels are elevated by 2SDs above the mean
level in 75% of patients. This test is not very specific for diagnosis, as this is also
elevated in patients with TB, lymphoma, asbestosis and silicosis. However, it is useful
in assessing response to treatment.

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 • Lung function tests. These are usually normal in patients with early stages of
sarcoidosis. You can get a restrictive picture in patients with pulmonary infiltration
or fibrosis. There is a decrease in TLC, FEV1 and FVC. There is also a decrease in gas
transfer. You can get an obstructive pattern if there is upper airway disease.
• Bone X-rays. These show punched out lesions in the terminal phalanges. You can
also see bone cysts.
• Bronchoalveolar lavage (BAL). BAL shows an increase in lymphocytes in active
disease, with a decrease in the percentage of alveolar macrophages, reduced
number of CD8+ cells and decreased CD4+/CD8+ ratio. There is an increase in
neutrophils where there is pulmonary fibrosis.
• Other tests. Other tests are to look for complications. A slit lamp eye exam is used to
check for uveitis and an ECG to check for arrhythmias.

Management
Patients with stage 1 disease do not require treatment as most (85%) resolve on their own.
50% of patients with stage 2 disease also resolve spontaneously on their own. Persisting
infiltration visible on chest X-ray with normal lung function tests requires close follow-up.
Patients with acute sarcoid syndromes generally have a good prognosis and simply require
bed rest and NSAIDs.

Treatment is mainly immunosuppressive. It is indicated for:

• Parenchymal lung disease (pulmonary infiltrates/fibrosis) that is symptomatic, static

(≥6 months) or progressive (declining lung function tests).
• Hypercalcaemia.
• Extra-pulmonary manifestations, particularly uveitis, cardiac and/or neurologic
involvement.

The treatment options include:

• Corticosteroids. You start with high-dose prednisolone (30-40mg po od) for 4-6
weeks, then decrease to 15mg for 6-12 months according to clinical status. A few
patients relapse and may require another course or long-term therapy. Severe
persistent erythema nodosum or uveoparotid fever will respond rapidly to a 2-week
course of prednisolone 5-15mg po od. In more severe disease, intravenous
methylprednisolone can be used.
• Immunosuppressant therapy. You can use methotrexate, hydroxychloroquine,
cyclophosphamide or ciclosporin. You can try anti-TNF-α agents, such as infliximab,
adalimumab or etanercept.

In refractory cases (advanced pulmonary fibrosis with associated pulmonary hypertension),

lung transplantation may be an option.

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Progression of disease is best monitored by doing lung function tests.

Prognosis
Prognosis is poorer in black patients, where death rates up to 10% are recorded. Causes of
death include respiratory failure, cor pulmonale, myocardial sarcoidosis and renal damage.
Patients can also die from secondary aspergillomas developing in damaged lung tissue (also
aggravated by long-term immunosuppressant therapy). 20% of patients on steroid therapy
respond. The rest are unlikely to respond to steroids.

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Systemic lupus erythematosus
(SLE)
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterised by
alternating exacerbations & remissions. There is usually multi-organ involvement during
exacerbations. SLE is fairly common, affecting 1 in 2000 people. It is primarily a disease of
the young to middle aged (the modal age range is 14-50 years). Females outnumber males
(as in most autoimmune diseases) by 10:1, and this is believed to be related to oestrogen
being a triggering factor. People on exogenous oestrogen & male patients with Klinefelter’s
syndrome are also at risk of developing SLE. In America, SLE affects black & Hispanic people
more than white people, but it is rare amongst black people living in Africa. There is less
than 100% concordance in monozygotic twins.

Aetiology
Systemic lupus erythematosus is an autoimmune disease resulting from development of
antibodies against self-antigens. The implicated antigens in the disease are nuclear antigens,
and this is why the disease is mostly not organ specific. The trigger initiating development of
autoantibodies in SLE is unknown. The proposed triggers are:

• Heredity. There is 40-60% concordance in identical twins. 1st-degree relatives are at

increased risk of developing disease (3% chance), although autoantibodies are
present in up to 20% of these relatives. The implicated HLA molecules are HLA-DR2-5
and HLA-B8. HLA-DR2 molecules are associated with the production of anti-dsDNA
antibodies and are therefore associated more with SLE than the rest. HLA-DR3 is
associated with the production of anti-SS antibodies A & B. HLA-DR4 & HLA-DR5 is
associated with the production of Smith antibodies & anti-ribonucleoprotein
antibodies (anti-RNP).
• UV light. UV light induces apoptosis of keratinocytes, thus increasing the risk of
expression of lupus autoantigens. This triggers skin & systemic manifestations.
Dendritic cells, however, are implicated more in this disease.
• Drugs & toxins. These conjugate with host antigens in predisposed patients and
cause lupus-like reactions. Examples of such drugs are hydralazine, phenytoin and
isoniazid. Slow acetylators are at increased risk. These diseases do not have
antibodies against double-stranded DNA. The lupus-like symptoms stop after
cessation of the drug.
• Hormones. This causes increased incidence of the disease in premenopausal women
and in individuals receiving hormonal replacement therapy. It is also most common
during the patients’ reproductive age. It is thought that oestrogens enhance

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 antinuclear antibody formation. Women are prone to getting SLE if they use oral
contraceptives.
• Complement deficiency. This is not particularly a trigger, but it is associated with a
100% chance of SLE with anti-dsDNA antibodies. The implicated complement genes
include C1q, C2 and C4.
• Polyclonal B-cell stimulation. leading to defective apoptosis. There is also reduction
in suppressor T-cells.
• Specific autoantibody production. These are directed at transcription & translation
molecules and nucleosomes. Affinity to self-antigens increases as the disease
progresses.
• Exposure to EBV. This is thought to be a possible trigger.

Pathogenesis
There are many proposed mechanisms of development of these antibodies:

1. Defective apoptosis leads to display of cellular antigens on the surface of blebs.

2. Dysregulated lymphocytes target normally-protected intracellular antigens.
3. Disruption of lymphocyte signalling.

Ultimately, the disease is caused by a breakdown of tolerance.

The disease can be a type II hypersensitivity disease (resulting from immunoglobulins

binding to antigens in tissues) or a type III hypersensitivity disease (resulting from
immunoglobulins binding to soluble antigens in serum, with the resulting immune
complexes being deposited in tissues). Localisation of the disease depends on the size of the
antigen, the charge of the molecule, the nature of the antigen and the local concentration of
complement. There is widespread tissue damage due to complement activation in tissues in
which immune complexes have been deposited. The antibodies are formed are against
many antigens. The antigens that are specific for SLE are antibodies against double-stranded
DNA (anti-dsDNA). Non-nucleic acid antibodies are also present. These include anti-
erythrocyte antibodies (causing haemolytic anaemia) and anti-platelet antibodies (causing
thrombocytopenia).

Effects of SLE in various systems

The onset of SLE may be acute or insidious. Patients may have constitutional signs during
exacerbations: fever, weight loss, malaise and lethargy. Patients typically present with multi-
organ dysfunction during remissions. Organ-specific features of SLE are:

• Joints & muscles. 90% of patients have polyarthralgia or arthritis that is symmetrical
and mainly affects the small joints. There is usually no joint erosion or deformity1 in

1
In rare cases, you can get major joint deformity – a phenomenon called Jaccoud’s arthropathy. This,
however, is not associated with joint erosion.

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 SLE, and this helps differentiate it from rheumatoid arthritis. SLE may lead to
avascular necrosis of the head of the femur.
Myalgia is seen in up to 50% of cases, but true myositis is seen in less than 5% of
patients.
• Skin. Skin manifestations, together with joint problems, are the commonest
manifestation of SLE; skin manifestations account for 85% of cases. In some cases it
simply affects the skin. In these cases it is called discoid lupus erythematosus
(although this is no longer SLE – just LE). Patients develop an erythematous rash in
sun-exposed areas, particularly those with anti-Ro antibodies. When it is on the face,
it is called a butterfly rash as it is symmetrical. Patients may also develop alopecia
(hair loss) which is diffuse, patchy & circumscribed. Patients can get scarring alopecia
which may be distressing.
• Kidneys. 75% of patients have nephritis on autopsy, although less than 30% manifest
symptoms. Because the disease is an immunological disease, it mostly causes
glomerulonephritis. SLE causes mesangial glomerulonephritis, focal
glomerulonephritis (which affects less than 50% of glomeruli in the kidney), diffuse
proliferative glomerulonephritis (which leads to excessive cellular proliferation in
more than 50% of glomeruli), membranous glomerulonephritis and sclerosing
glomerulonephritis. SLE may also cause tubulointerstitial disease (that has a poor
prognosis) and kidney failure. All patients should have urinalysis done, and the
presence of proteinuria or haematuria must prompt treatment as there is a risk of
progression. Renal vein thrombosis can also occur.
• Heart. 25% of SLE patients develop heart problems. SLE causes verrucous
endocarditis, also known as Libman-Sachs endocarditis. The heart valves develop
large 1-4mm ovoid vegetations along the lines of closure. They mainly affect the
mitral valve, and they rarely cause clinical disease – they are seen on autopsy.
Myocarditis in SLE is rare. Patients may develop congestive cardiac failure (CCF) and
presents with tachycardia, cardiomegaly and a gallop rhythm. Coronary artery
disease develops secondary to the use of corticosteroids.
• Central nervous system. In the CNS, SLE causes neuropsychiatric disorders. This
manifests as psychosis, depression, seizures, aseptic meningitis, cerebrovascular
accidents and migraine headaches. Most patients experience mild fluctuating
symptoms and some patients improve spontaneously. Other patients, on the other
hand, have irreversible changes. Cerebral thrombosis is not uncommon and is more
common with antibodies to clotting factors & phospholipids. CNS involvement
occurs in up to 60% of patients and is a clinical diagnosis. It may be the presenting
feature in a patient. The pathogenesis of the features is complex and may involve
vasculitis or immune complex deposition.
• Lungs. The lungs are affected in 30% of patients. In the lungs, SLE causes pleural
effusions with pleuritic chest pain (due to pleurisy). It also causes vasculitis which
affects the pulmonary vessels and may cause pulmonary haemorrhage, which is a

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 medical emergency. It may also cause a pulmonary infiltrate (pneumonitis) that may
predispose to infection. There can also be a restrictive lung disease which leads to
loss of lung volumes & a raised diaphragm. This called a shrinking lung syndrome.
• Eyes. 20% of SLE patients have eye manifestations. Patients may develop a fluffy
white exudative lesion that follows focal degeneration of nerve fibres. Patients may
also be affected by Sjögren’s syndrome, which causes kerato-conjunctivitis sicca (dry
cornea & conjunctiva) & xerostomia (dry mouth). There may also be infarcts which
present as hard exudates and haemorrhages.
• Spleen. On microscopic examination, onion skin lesions may be seen. These are
formed by peri-arterial concentric fibrosis.
• Polyserositis. SLE leads to pericarditis, pleurisy and peritonitis.
• GIT. Patients with SLE develop oro-genital mucosal ulceration. This ulceration may be
secondary to vasculitis. SLE patients also develop pancreatitis, cholecystitis and
hepatitis. Mesenteric vasculitis can produce inflammatory lesions involving small
bowel which may eventually lead to infarction or perforation.
• Blood vessels. SLE causes small- & medium-vessel vasculitides. Small vessel
vasculitides cause splinter haemorrhages, finger pulp infarcts and glove & stocking
peripheral neuropathy. Medium-vessel vasculitides cause bowel infarcts &
cerebrovascular accidents. SLE-related vasculitides also cause Raynaud’s
phenomenon.

The pathognomonic features of systemic lupus erythematosus are haematoxylin bodies,

which are homogenous nuclear material of injured cells. They stain blue – hence the name.
Lymphocytes that ingest particles are known as LE cells. These features appear in several
tissues, including the heart, lungs & kidneys.

Differential diagnoses for SLE

The differentials for SLE are:

• Polyarthritis – viral infections, infective endocarditis, rheumatoid arthritis &

rheumatic fever.
• Raynaud’s phenomenon – systemic sclerosis.
• Myositis – polymyositis & dermatomyositis.
• Felty’s syndrome.
• Discoid lupus erythematosus.

Investigations done for systemic lupus erythematosus

The diagnostic tests that are done are:

• Proteins & complement. 80% of patients have high levels of α2-microglobulin & γ-
globulins (particularly IgG). Patients may also have hypoalbuminemia. There are low

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 serum C3 & C4 levels in active disease, and this is due to complex utilisation, immune
complex fixation and reduced synthesis.
• Detection of autoantibodies. More than 95% of patients with SLE have antinuclear
antibodies (ANA). These are detected using indirect immunofluorescence in which
you place labelled antibodies against ANAs in your test sample and they bind to
immune complexes in the nuclei of your sample. There are different
immunofluorescence patterns produced in the nuclei and these indicate different
diseases:
o A homogenous pattern indicates the presence of antibodies against the DNA-
histone complex. It is present in SLE, drug-induced lupus erythematosus and
other connective tissue diseases.
o A speckled pattern indicates the presence of antibodies to Smith antigens
(SLE), RNP (ribonucleoprotein; SLE), SS-A/anti-Ro (SLE & Sjogren’s syndrome)
or SS-B/anti-La (SLE & Sjogren’s syndrome).
o A peripheral pattern indicates antibodies against double-stranded DNA and is
therefore more specific for active SLE.
o A nucleolar pattern indicates antibodies against nucleolar-specific RNA. It is
associated with scleroderma, polymyositis and dermatomyositis.
DNA antibodies are mostly IgG, but may be IgM as well. The antibodies that are
detectable in SLE are dsDNA & ssDNA antibodies. DsDNA, however, is more specific
to SLE than ssDNA – anti-ssDNA is also present in rheumatoid arthritis and drug-
induced lupus erythematosus. Other positive antibodies include antiphospholipid
antibodies (in 25-40% of cases) and anti-histone antibodies (found in almost all cases
of drug-induced lupus). About 40% of patients have positive rheumatic factor
antibodies. DNA antibodies are detected by ELISA (enzyme-linked immunosorbent
assay) or RIA (radio-immunoassay). Erythrocyte antibodies can also be detected, and
they are present in 10-65% of patients.
• Tissue immunofluorescence. This is direct immunofluorescence that is done to
detect the presence of immune complexes in tissues. It is done on tissue biopsies to
confirm organ involvement. It can be done on kidney specimens, in which there is
accumulation of immunoglobulins in the glomerular basement membrane &
mesangial cells. Tissue immunofluorescence can be used to detect immunoglobulin
& complement deposition in skin.
• Other blood investigations. FBC may show a pancytopaenia. The anaemia is due to
anaemia of chronic disease or AIHA (autoimmune haemolytic anaemia). U&E may
show derangements when renal disease is advanced; early indicators are
hypoalbuminaemia and high urine albumin/creatinine ratio. ESR is raised in relation
to disease activity, but CRP is normal.
• Imaging. CT scan of the brain may show old and/or new infarcts or haemorrhage.
There may be evidence of brain atrophy. MRI can be used to detect white matter
lesions that cannot be identified on CT.

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The presence of high anti-dsDNA, high ESR and low C3 may indicate an acute flare.

Management
SLE management needs to be discussed with the patient. You need to explain to the patient
that they have the disease for life, and that it is a chronic disease with remissions &
relapses. The aims of treatment are to avoid stimuli that may trigger exacerbation, to
control autoantibody production by immunosuppression and to limit organ damage, all with
the aim of optimising quality of life in the patient. You do need to advise the patient on the
effects of the disease on his/her appearance and debility due to fatigue. Flare-up of activity
often follows: exposure to sunlight, infections, pregnancy, surgery and stress. Therefore,
patients need to avoid exposure.

SLE is a relapsing & remitting disease and therefore immunosuppressive therapy is variable.
In mild disease, corticosteroids form the basis of treatment. Mild disease mainly comprises
of skin & joint symptoms. High dose aspirin (or any other NSAID) is used to treat arthralgia,
while skin/mucosal involvement is treated with topical steroids & chloroquine2.

In severe SLE, cytotoxic agents are used. Azathioprine is used in persistent disease to spare
the use of corticosteroids. Most patients can be controlled on a combination of
azathioprine, steroids & antimalarial agents. Cyclophosphamide used to be used to treat
vasculitis, cerebral SLE and severe lupus nephritis. Nowadays, cyclophosphamide is being
replaced by mycophenolate mofetil. Newer agents include rituximab (anti-CD20 monoclonal
antibody).

The activity of the disease is monitored by measuring the DNA antibody level, serum C3 &
C4 and CRP levels3.

Prognosis
The effects of the disease may be due to the disease process itself or from the complications
of the disease. SLE has a range of outcomes, from mild to fatal. If left untreated, it is likely to
cause renal failure & CNS lupus. As a result of corticosteroid use, patients may develop
atherosclerosis, infection and cancer. Overall, the 10-year survival rate for SLE is good –
90%.

In pregnancy, SLE raises the risk of spontaneous abortions, intrauterine death, pre-
eclampsia, IUGR and preterm birth. Fertility is usually normal except in severe disease.
Patients with anti-ss A or B have a 2% risk of giving birth of babies with neonatal lupus
syndrome. This presents with rash, hepatitis and foetal heart block. Women with SLE are
advised not to fall pregnant until the disease has been quiescent for at least 6 months.

2
Chloroquine is associated with renal toxicity and therefore low doses should be used
3
CRP level indicate infection, as it rarely rises due to SLE alone.

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 Diabetes mellitus
Diabetes mellitus is an endocrine disorder that is a result of chronic hyperglycaemia. The
chronic hyperglycaemia is a single aspect of a far-reaching metabolic derangement. The
majority of complications are related to secondary vascular disease, which may be
microvascular or macrovascular. You can also get neuropathy & immunopathy as the
mechanisms behind complications. It affects 220 million people worldwide. Diabetes is
generally incurable, but glycaemic control can be maintained for a long period of time.

Insulin & glucose metabolism

Insulin is produced by the β-cells of the islet of Langerhans. It is a peptide hormone
consisting of 2 chains: an α-chain with 21 amino acids and a β-chain with 30 amino acids,
and the chains are linked by disulphide bonds. The hormone is initially translated as a single
chain pre-proinsulin, which is then cleaved to proinsulin. Insulin is then formed by removal
of the connecting peptide – called the C-peptide1 – between the 2 chains. After synthesis
insulin is stored in vesicles. The majority of insulin secreted into the body is secreted via the
regulated pathway. Insulin is secreted in response to elevated glucose levels. Glucose enters
β-cells via GLUT2 transporters, and after metabolism it leads to elevated ATP levels. The
elevated ATP stimulates closure of ATP-sensitive potassium channels, which causes
depolarisation of the membrane. This allows opening of voltage-gated calcium channels,
allowing entry of calcium ions which stimulate exocytosis of preformed insulin. A small
amount of insulin is secreted via the constitutive pathway regardless of any stimulus.

The majority of insulin produced by the pancreas is carried to the liver, which is the prime
target organ. 50% of circulating insulin is extracted by the liver, with the C-peptide levels
being left relatively constant. The remainder of the insulin “survives” the liver and circulates
to the rest of the organs, and is extracted by the kidneys. In the liver, insulin binds to insulin
receptors, which are receptors linked to the tyrosine kinase signalling pathway. In the liver
and in many other tissues, insulin stimulates the insertion of vesicles containing GLUT4
channels and allows entry of glucose into the cell. It also stimulates glycolysis & glycogenesis
and inhibits glycogenolysis & gluconeogenesis.

Blood glucose levels are usually kept within the range of 3.5-8.0mM in normal people
despite the varying demands of food, fasting and exercise. The majority of carbohydrate
homeostasis is maintained in the liver, which stores excess glucose as glycogen and breaks
down glycogen whenever glucose is needed. The liver can also synthesis glucose from amino
acids and other 3-carbon compounds e.g. glycerol. About 200g of glucose is produced each
day: 90% from the liver through glycogen breakdown & hepatic gluconeogenesis, and 10%
from renal gluconeogenesis. The brain is the major consumer of glucose. It has negligible

1
The C-peptide can be measured to estimate the endogenous insulin production.

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carbohydrate stores and therefore relies on a steady supply of glucose in the circulation. It
consumes 1mg/kg/minute, which comes down to about 100g daily (half the glucose
demand) in a 70kg man. Glucose uptake by the brain, however, is obligatory and not
dependent on insulin. Uptake of glucose in other tissues (e.g. muscle & adipose) is
facultative, and is under the influence of insulin. Insulin levels usually increase after meals
so as to lower the threshold of glucose entry into cells (since the body is in a hyperglycaemic
state). Glucose can be stored in muscle as glycogen, while adipose converts glucose into
triglycerides. The actions of insulin on glucose regulation are countered by diabetogenic
hormones such as glucagon, growth hormone, cortisol, thyroid hormones and epinephrine,
and these are more numerous because they are designed to protect the brain against
hypoglycaemia, which is more deadly to the body & brain than hyperglycaemia.

Classification of diabetes mellitus

Diabetes is classified into primary and secondary diabetes mellitus.

Primary diabetes mellitus

Primary diabetes mellitus is a result of a defect in glucose homeostasis that is not a result of
other disease states. It is a result of either decreased insulin production or increased insulin
resistance. Ultimately, there is some degree of β-cell dysfunction. There are 2 main types of
primary diabetes mellitus.

• Type I diabetes mellitus. This is a disease caused by absolute insulin deficiency which
usually involves destruction of β-cells. It is also called insulin-dependent diabetes
mellitus. Diabetes manifests when there is less than 20% of β-islet cells left. The
highest incidence of type I diabetes is in Finland & other Northern European
countries. There are many possible causes, and there are 2 main sub-classifications
of the disease.
o Type Ia. This is an autoimmune disease in which there is immune-mediated
destruction of β-cells. Many antigenic targets have been identified: GAD
(glutamic acid decarboxylase)2; 1A2 (tyrosine phosphatase); ZnT8 (zinc
transporter 8); and insulin. There is a strong genetic link with this condition,
but concordance in monozygotic twins is only about 45%. It is also associated
with other autoimmune diseases, such as autoimmune thyroid disease &
coeliac disease.
o Type Ib. This is an idiopathic disease in which the cause of islet cell
destruction is unknown. The disease has no associated autoantibodies.
There is increased genetic susceptibility, but the condition is not inherited. Genetic
susceptibility to type I diabetes mellitus is polygenic, and the greatest contribution
comes from HLA region. More than 90% of patients carry HLA-DR3-DQ2, -DR4-DQ8
or both. Other implicated genes include: the insulin gene itself (INS; chromosome

2
Antibodies against this antigen are associated with Stiffman syndrome.

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 11), CTLA4 (cytotoxic T-lymphocyte-associated protein 4) gene, PTPN22 (protein
tyrosine phosphatase) gene and IL2RA gene. In addition, the risk of developing type I
diabetes is higher if you have a diabetic father than if you have a diabetic mother.
There may also be environmental factors implicated in the development of type I
diabetes, although the exact causative agents are not known.
The majority of type I diabetic patients are diagnosed in their adolescence, although
the disease can occur at any age. There is, however, a slow-burning variant that
develops later in adulthood called latent autoimmune diabetes in adults (LADA),
which may be difficult to distinguish from type II diabetes mellitus.
• Type II diabetes mellitus. This is a disease characterised by peripheral insulin
resistance which cannot be overcome by increased insulin production. It is also
characterised by a relative insulin deficiency, which is “necessary” for diabetes to
develop in these patients. the pathophysiology of type II diabetes can be
summarised by the De Fronzo’s Ominous octate3:
De Fronzo’s ominous octate
1. Increased hepatic glucose production.
2. Decreased glucose uptake in muscle.
3. Increased lipolysis in adipose & other fat-containing tissue.
4. Decreased incretin (GLP-1 & GIP) effects.
5. Increased glucagon secretion.
6. Increased glucose reabsorption by the kidneys.
7. Neurotransmitter dysfunction, leading to defecting appetite regulation.
8. Decreased insulin secretion.
It is found in societies that mainly enjoy an affluent lifestyle4. The 4 main
determinants are age, obesity, ethnicity and family history. In the UK, the overall
prevalence is 4-6%, making it much more common than type I diabetes. It is also
associated with other diseases such as hypertension, dyslipidaemia
(hypercholesterolaemia, hypertriglyceridemia and low HDL-cholesterol) and central
obesity. These conditions constitute the metabolic syndrome5, which is a result of
insulin resistance. Diabetes often develops from a preliminary phase of impaired
glucose tolerance or impaired fasting glucose. The genetic influence in type II
diabetes is greater than in type I. There are also elevated CRP levels consistent with
sub-clinical inflammation which may elevate the cardiovascular risk of the patients. A
high proportion of patients have alcoholic fatty liver disease. Type II diabetes
typically affects individuals over 40 years of age, although younger individuals are
developing the condition due to increasing childhood obesity.

3
This octate is important because the efficacy of oral hypoglycaemic treatment is measured by the number of
elements of the octate that the agent in question corrects.
4
In poor countries, diabetes is a disease of the rich, while in rich countries it is a disease of the poor (mainly
associated with obesity).
5
Usually, there also needs to be impaired glucose tolerance.

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 • Monogenic diabetes mellitus. This is a type of diabetes mellitus that develops as a
result of a defect of a single gene encoding one of the elements involved in
glycaemic control. It is therefore different from traditional type I & type II diabetes in
which the genetic element is polygenic. It should be suspected in infants that
develop diabetes before the age of 6 months, excluding transient neonatal diabetes
which develops soon after birth and resolves at 12 weeks. Often, there is defective
insulin release rather than β-cell destruction. Neurologic features are common and
are found in up to 20%. The most commonly implicated genes are: HNF-1a (accounts
for 70%) & HNF-1b (accounts for 2%), HNF-4a, glucokinase and IPF-1.
• Gestational diabetes. This is a special entity that involves new-onset diabetes that
develops or is diagnosed during pregnancy, or a woman with pre-existing diabetes
who falls pregnant. 4% of pregnancies are complicated by diabetes mellitus, and the
majority comprise of new-onset diabetes in pregnancy. Gestational diabetes carries
risks to the mother (miscarriage, pre-term labour, pre-eclampsia and worsening of
diabetic conditions such as retinopathy & nephropathy) and foetus (low birth
weight, macrosomia, congenital malformations, intra-uterine death). 50% of women
with gestational diabetes will go on to develop full-blown diabetes mellitus.

Secondary diabetes mellitus

Secondary diabetes mellitus develops from another disease process that causes chronic
hyperglycaemia in a person with normal β-cells and without intrinsic insulin resistance. The
conditions are divided into:

• Pancreatic causes. These include pancreatitis, pancreatic surgery (involving removal

of more than 90% of the pancreas), trauma, pancreatic destruction
(haemochromatosis, cystic fibrosis), pancreatic cancer and fibrocalculous
pancreatopathy.
• Drugs. The common causes are steroids, ARVs (protease inhibitors), newer
antipsychotic agents and thiazide diuretics. Other drugs include niacin, pentamidine,
thyroid hormones, β-blockers, β-agonists and interferon-α. Immunosuppressive
agents such cyclosporine, tacrolimus and sirolimus can also cause secondary
diabetes mellitus.
• Endocrine causes. These include Cushing’s syndrome/disease (cortisol excess),
acromegaly (GH excess), phaeochromocytoma (adrenaline-producing tumour),
hyperthyroidism and pregnancy (increased production of diabetogenic hormones,
e.g. progesterone).
• Genetic syndromes. These include Down’s syndrome, Friedreich’s ataxia,
Huntington’s chorea, Klinefelter’s syndrome, mycotic dystrophy, porphyria, Prada-
Willi syndrome, Turner’s syndrome and Wolfram’s syndrome.

Risk factors for diabetes

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These include:

• Family history. A large proportion of people living with diabetes report a positive
family history of diabetes. There is 45% concordance in monozygotic twins for type I
diabetes, and if one child has diabetes the chances of developing type I diabetes is
about 6%. With type II diabetes, however, the chances are higher: there is greater
than 50% concordance in monozygotic twins, and the risk to non-identical twins &
siblings is around 25%.
• Obesity. Obesity (BMI of greater than 30kg/m2) is a key risk factor particularly for
type II diabetes. Obesity leads to increased levels of free fatty acids, and this is
believed to induce insulin resistance all over the body. Obesity increases the
incidence of type II diabetes mellitus by 80-100 times. The inhabitants of affluent
countries gain 1g of body weight every day between the ages 25-55 years, and this is
because of a more sedentary lifestyle with little exercise rather than increased food
intake.
• Ethnicity. The incidence of diabetes is highest amongst black people, South-East
Asians and people from the Pacific islands.
• Pre-existing disease. The diseases associated with diabetes are hypertension,
coronary heart disease and dyslipidaemias.

Clinical presentations
The presentation of diabetes mellitus depends on the type of diabetes mellitus. There are
different features of the disease & patients that should make the clinician wary of the type
of diabetes being dealt with:

Features Type I Type II

Age of onset Young (<30 years) Older (>30 years)
Weight Lean Overweight/Obese
Symptom Weeks Months/years
duration
High-risk ethnicity Northern Europeans Blacks, South-East Asians,
Polynesians
Seasonal onset Yes No
Hereditary links HLA-DR3 & -DR4 in greater than –
90% of cases
Pathogenesis Autoimmune Non-autoimmune
Ketonuria Yes No
Clinical features Absolute insulin deficiency Relative insulin deficiency
Ketonuria Hyperosmolar state
Always need insulin Will eventual need insulin when β-
cells fail

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Biochemical C-peptide disappears C-persists until β-cells fail
features

Patients will present as follows:

• Asymptomatic. This is often the case in type II diabetes, and it is detected as a high
blood sugar on routine medical check-up or after hospitalisation for some other
condition unrelated to diabetes.
• Symptoms of insulin deficiency. Patients typically present with polydipsia, polyuria,
polyphagia and weight loss. Polyuria develops due to the osmotic diuresis induced by
glucose excess in blood. Polyphagia develops largely due to the insulin deficiency,
which relieves insulin’s satiety effects. Polydipsia is a result of hypovolaemia caused
by polyuria. Weight loss results from the fluid depletion and the accelerated
breakdown of fat & muscle due to insulin deficiency. These symptoms are mainly
found in type I diabetics, and they usually develop within days or weeks of onset of
insulin deficiency. In type II diabetics, the symptoms are usually not as prominent,
especially weight loss. Patients may also present with ketones in their urine.
• Symptoms of complications. At times patients present with complications of
diabetes. This occurs either because patients overlook their initial symptoms, or
because there are no initial symptoms for the patient to pay attention to. This is
often the case for patients with type II diabetes. Patients may present with diabetic
ketoacidosis or hyperosmolar hyperglycaemic coma, which are direct complications
of hyperglycaemia. Other complications involve end-organ damage, and include
retinopathy, nephropathy (chronic kidney disease), polyneuropathy, erectile
dysfunction, etc.

Diagnosis of diabetes mellitus

The tests done for patients with diabetes mellitus include:

• Random blood sugar (RBS) and Fasting blood sugar (FBS). These are point-of-care
tests that directly measure glucose tests. They are conducted using a small
automated glucometer device, and the test can be done in any setting. The nature of
the test and the interpretation of the results is what is important. In an RBS, you can
conduct the test at any time, although the test is less reliable because it does not
standardise the condition of the patient when the test is taken. It is therefore not
advised to be taken alone. An FBS is conducted after a patient has fasted for at least
12 hours, so it can be taken in the morning after the patient is advised to not eat
anything after 8pm. It is more standard as everyone in whom an FBS is done has
been fasted for that period. It requires, however, compliance with instructions. If the
FBS is too high, the patient has impaired fasting glucose.

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 • Oral glucose tolerance test (OGTT). This is a test that assesses the patient’s
glycaemic control. It is conducted in a clinical setting under supervision from a
trained clinician and is therefore more reliable. You ensure that the patient is fasted
for at least 6 hours, and you take the patient’s FBS. You them give them a 75g
glucose load just afterwards and take serial glucometer readings after every 2 hours.
The blood sugar readings are taken and recorded. If the blood sugar reading is too
high after 2 hours, the patient has impaired glucose tolerance.
• HbA1C (glycated haemoglobin). This is a test that measures the proportion of
haemoglobin that has glucose attached to each. Normally in blood, haemoglobin
(and other proteins) undergoes spontaneous glycosylation with glucose through a
non-enzymatic process. The rate at which this happens is proportional to the
concentration of glucose in the plasma. Therefore, the proportion of glycosylated
haemoglobin molecules demonstrates the general glucose level in the circulation.
Furthermore, because haemoglobin has a long half-life (life span of red cells = 120
days), glycated haemoglobin shows the long-term glycaemic control of patients.

The criteria required to diagnose diabetes according to WHO are:

• 2 raised venous glucose (FBS > 7.0mM, RBS > 11.1mM or OGTT-2h value > 7.8mM) in
an asymptomatic patient on 2 separate occasions that are 2 weeks apart.
• A single raised venous glucose (RBS > 11.1mM or FBS > 5.6mM) in a patient
presenting with symptoms.
• HbA1C value greater than 6.5% (or 48mM). A negative result, however, does not
exclude diabetes mellitus. The test is not conducted in pregnant women, patients
with type I diabetes and children.

Complications
The complications of diabetes can be divided into acute and chronic. Acute complications of
diabetes are:

Acute Chronic
• Diabetic Vascular:
ketoacidosis. • Macrovascular complications, e.g. atherosclerosis, leading
• Hyperglycaemic to coronary heart disease, stroke, renal artery stenosis,
hyperosmolar etc.
coma. • Microvascular complications, e.g. diabetic foot, diabetic
retinopathy.
Non-vascular:
• Dermopathy.
• Infections.
• Complications of dental procedures.

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 • Foot complications.
• Rheumatologic complications. These include frozen
shoulder, Dupuytren’s contracture and prayer sign)

Diabetic ketoacidosis (DKA)

This is an emergency resulting from absolute insulin deficiency. It is a hallmark of type I

diabetes, but in rare cases it can be found in type II diabetes. It occurs in: previously
undiagnosed patients (10%), patients with interrupted insulin therapy (15%), and patients
with inter-current illness (30%). Other triggers include: surgery, MI, pancreatitis,
chemotherapy and antipsychotics.

• Pathogenesis. Ketoacidosis occurs as a result of uncontrolled catabolism. There is

ketogenesis which occurs due to the body being unable to utilise glucose. Ketone
bodies (mainly β-hydroxybutyrate, acetoacetate and acetone) are normally
produced in the liver in the setting of starvation, whether real or functional (as in
diabetes), so as to provide a source of energy to the cells. Normally, even low levels
of insulin can inhibit hepatic ketogenesis, so the condition requires 0 insulin activity.
The accumulation of ketone bodies leads to metabolic acidosis. In the absence of
insulin, hepatic gluconeogenesis takes place coupled with reduced uptake of glucose
by tissues. This leads to excessive amounts of glucose, leading to osmotic diuresis,
loss of electrolytes and dehydration. Plasma osmolality rises & renal perfusion falls.
Dehydration & electrolyte imbalances also results from vomiting induced by acidosis
resulting from ketone bodies. Renal hypoperfusion impairs the excretion of ketones,
further worsening the acidosis and therefore creating a vicious cycle. Respiratory
compensation results in hyperventilation. The combination of severe hyperglycaemia
& ketoacidosis can be fatal.
• Clinical presentation. The patients appear drowsy, and dehydrated. The clinical
features include: vomiting, abdominal pain, polyuria, polydipsia, anorexia and
hyperventilation. In more severe cases, confusion & stupor can develop – up to 5%
present in a coma. On examination, the patient is ill, appears dehydrated (with
sunken eyes even) and has a ketotic smell. The patient is tachycardic/bradycardic
and may be hypotensive. They may be in respiratory failure (oxygen saturation <
92% on air where respiratory function was normal). The body temperature is often
low even in the presence of infection. The patient also demonstrates Kussmaul
breathing.
• Investigations. The investigations done are:
o FBC. A high white cell count usually indicates infection, but it may be seen in
the absence of infection. The haematocrit may be elevated due to
dehydration.
o Arterial blood gases.

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 o Blood glucose & ketones.
o Blood culture.
o U&Es. Plasma creatinine may not reflect true renal function because some
ketone bodies cross-react with creatinine assays. Hyponatraemia is common
due to osmolar compensation for the hyperglycaemia. Therefore,
hypernatraemia/normal sodium levels indicate severe water loss.
o Urine dipstick and MSU (mid-stream urine). Ketonuria does not always equal
ketoacidosis.
o ECG.
Diabetic ketoacidosis can complicate with cerebral oedema, aspiration pneumonia,
hypokalaemia, hypomagnesaemia, hypophosphataemia and thromboembolism.
• Diagnostic criteria. DKA is diagnosed by the presence of:
o Acidaemia (pH < 7.3).
o Hyperglycaemia.
o Ketonaemia. This can be demonstrated by either taking a blood test or by
finding ketones in urine.
Severe ketonaemia should be suspected if you find one or more of:
o Blood ketones > 6mM.
o Venous bicarbonate < 5mM.
o pH < 7.1 (venous or arterial).
o Hypokalaemia (K < 3.5mM) on admission.
o Glasgow coma scale < 12.
o Oxygen saturation < 92% on air in the absence of respiratory disease.
o Hypotension (systolic blood pressure < 90mm Hg).
o Tachycardia (pulse > 100bpm) or bradycardia (pulse < 60bpm).
o Anion gap > 16mM.
• Treatment. Diabetic ketoacidosis is a medical emergency. You do the following:
1. Initial management. The initial management involves taking bloods for lab
studies and setting up the patient for fluid replacement. The baseline studies
taken are FBC, U&Es, blood sugar and ABGs. If the patient’s systolic BP is
below 90mm Hg, give a bolus of 500ml saline. If the patient responds, start
fluids as below. If the patient does not respond, give another bolus and get
ICU advice.
2. Insulin administration. Give soluble insulin intravenously at a dose of
0.1U/kg/h by infusion (50U actrapid in 50mL normal saline). Alternatively,
you can give 20U im stat followed by 6U im hourly. Measure blood glucose 7
ketones hourly. Aim for a fall in blood ketones of 0.5mM/h and a fall in
glucose of 3-6mM/h. if this is not being achieved, increase insulin rates by

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 1U/h until target rates are achieved. Continue insulin until blood ketones are
less than 0.3mM6, venous pH > 7.3 and venous bicarbonate > 18mM.
3. Fluid replacement. Give 0.9% sodium chloride as the fluid of choice initially.
The typical fluid deficit is 100ml/kg body weight. Therefore, for a 70kg man,
you want to give a total of 7000ml (7L). You give the first 1L in 30 minutes,
then another 1L over 1h, then 1L over 2h, then 1L over 4h, then 1L over 8h.
You can adjust KCl concentration. When blood glucose reaches 10-12mM,
change infusion fluid to 5% dextrose 6-hourly while continuing insulin
adjusted to hourly glucometer readings.
4. Electrolyte replacement. The potassium deficit is 3-5mmol/kg, which can
reach about 350mmol in a 70kg man. This may not necessarily be reflected by
the plasma potassium. Potassium (KCl) should be given as soon as insulin is
started as insulin drives potassium into cells. Don’t add potassium to the first
bag – wait until urine output is above 30ml/h. The amount of potassium
given depends on the serum potassium level:
Serum K+/mM Amount of KCl per litre of fluid
administered
> 5.5 None
3.5-5.5 40mmol
< 3.5 Seek help from HDU/ICU
Check U&E hourly initially, and then replace potassium as required.
If pH is below 7.0, give sodium bicarbonate 1.26% + KCl 10mmol. Repeat
when necessary until pH is above 7.0.
5. Other interventions. Insert a catheter if urine is not being passed after 1h.
Consider an NGT if the patient is drowsy and/or vomiting. Start all patients on
low molecular weight heparin. If an infection is present, find it and treat it.
Find and treat the cause of the ketoacidosis.
• Complications. The complications of management include:
1. Hypotension. This may lead to renal shutdown. Plasma expanders (colloids)
are therefore given if the systolic BP falls below 80mm Hg. A bladder catheter
is inserted if no urine is produced in 2 hours.
2. Coma. In this case, you pass a nasogastric tube to prevent aspiration.
3. Cerebral oedema. This is a rare but serious complication. It usually occurs
with rapid fluid replacement or use of hypertonic fluids. It is common in
children & young adults, and mortality from it is high.
4. Hypothermia. This can be overlooked unless rectal (core) temperature is
taken.
5. Late complications. These include: DVT and pneumonia.

Hyperglycaemic hyperosmolar state

6
Do not rely on urinary ketones. They stay positive even after DKA has resolved.

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This complication mainly affects patients with type II diabetes in which there is some insulin
function. It is characterised by severe hyperglycaemia without ketoacidosis. It is a result of
chronic uncontrolled diabetes or undiagnosed diabetes mellitus.

• Pathogenesis. Hyperglycaemic hyperosmolar state can result from consumption of

glucose-rich foods, concurrent medications (e.g. thiazides diuretics or steroids) and
intercurrent illness. There is marked dehydration from the excessive osmotic diuresis
as a result of the very high glucose levels (usually in excess of 35mM). This produced
a hyperosmolar state (osmolality is usually greater than 340mOsm/kg) without
ketosis because there is some insulin in the circulation7. The disorder is advanced by
old age because elderly patients experience thirst less, and mild renal impairment
associated with age results in increased fluid & electrolyte losses.
• Clinical presentation. Patients characteristically present with stupor & coma.
Impairment of consciousness is directly related to degree of hyper-osmolality.
Evidence of underlying illness (e.g. pyelonephritis or pneumonia) may be present.
The hyperosmolar state may predispose to occlusive diseases such as stroke, MI or
arterial insufficiency.
• Investigations. The investigations are:
o Plasma osmolality. This is usually very high. It can be measured directly or
calculated from the sodium, potassium, glucose and urea concentrations 8.
• Management. The patients are managed as follows:
1. Rehydration. This is done slowly using intravenous normal saline over 48
hours. The typical fluid deficit is 110-220ml/kg, which comes to about 8-10L
in an adult. Add potassium when the patient’s urine starts to flow.
2. DVT prophylaxis. Give all patients (without contraindications) with this
condition.
3. Insulin. Insulin is not to be given unless blood glucose is not falling by more
than 5mM/h, or ketosis develops. The infusion is slow, as rapid infusion may
cause a sudden plummet in glucose concentration which may cause cerebral
oedema. The infusion is given at a rate of 0.05U/kg/h (or 3U/h for a 70kg
man). Increase to 6U/h if glucose level is not falling satisfactorily.

7
This little insulin is sufficient to inhibit ketone body production.
8
These are obtained from U&Es.

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 Management of diabetes
The goals of treatment in diabetes are: to maintain blood sugar levels within an acceptable
range for management (since obsession with normal glucose levels may be dangerous for
the patient); to prevent development of complications due to diabetes; to prevent
complications due to treatment; and to improve overall quality of life. Management of
diabetes mellitus is therefore a multidisciplinary approach. The care of diabetes is largely
dependent on patient self-management based on professional advice.

Management of diabetes consists of the following:

• Dietary modification.
• Lifestyle changes.
• Pharmacotherapy.
• Monitoring, follow-up & review.
• Screening for complications.
• Psychosocial aspects of diabetes.

Dietary modification
The diet recommended for diabetic patients is no different from that considered healthy for
everyone. The dietary requirements for diabetic patients are:

• Carbohydrate. Carbohydrate should constitute 40-60% of total energy intake.

Complex carbohydrates are preferred to simple sugars. Sucrose should make up no
more than 10% of total energy intake as long as it is taken in the context of a healthy
diet. Encourage artificial sweeteners instead of sugar, and limit fruit juices,
confectionaries, cakes and biscuits. In selecting the foods you need to eat, you also
need to take into account the glycaemic index1, which the glucose peak produced
after eating compared to the baseline. Foods with a low glycaemic index are
generally advised for diabetic patients as they prevent rapid swings in blood glucose
level. Factors that increase the glycaemic index include: ripeness, increased cooking
time/overcooking, and processing.
• Protein. 1g per kg ideal body weight is recommended for these patients.
• Fat. Fat should constitute no more than 35% of total energy intake. Limit the amount
of fat/oils in cooking, fried foods, processed meats and high-fat snacks. Encourage
low-fat dairy productions and lean meat. Saturated & trans-unsaturated fats should

1
The glycaemic index is defined as the AUC (area under the curve) of the 2-hour blood glucose response curve
after eating a particular test food following a 12-hour fast. The AUC of the test food is divided by the AUC
produced of a standard food item (glucose or white bread, thus producing 2 different definitions) and then
multiplied by 100. Foods with carbohydrates that break down easily an are readily released have a high
glycaemic index, while those that are more complex & break down slowly have a low glycaemic index.

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 constitute no more than 10% of the total energy intake. Omega-6 fatty acids should
constitute no more than 10% of total energy intake. There is no recommended limit
on the amount of omega-3 fatty acids (eat fish).
• Vitamins. These are best taken as fruits & vegetables in a mixed diet. Fruits &
vegetables should be found in at least 5 portions per day.
• Salt. You should take no more than 6g a day in total. The amount should be lower in
patients with comorbid hypertension.
• Fibre. There is no absolute quantity of fibre recommended. Soluble fibre benefits
glucose & lipid metabolism. Insoluble fibre lacks such effects, but it benefits satiety &
GIT health.

When prescribing a diet, you need to look at the patient’s pre-existing diet and prescribe a
diet with the least possible interference with the patient’s lifestyle. Meals must not be
missed.

Lifestyle changes
The lifestyle changes the patient must employ are:

• Weight control. This is important for ensuring that you do not worsen any pre-
existing insulin resistance.
• Smoking cessation.
• Exercise. This is encouraged for all patients. Any increase in exercise is welcome, but
participation in a more formal exercise regimen is advised. Both aerobic & resistance
training improves insulin sensitivity & metabolic control in type I & type II diabetes.
They should be wary of the risk of hypoglycaemia 6-12 hours after exertion, though.
Always take a snack before & after sports.
• Alcohol. Alcohol is not recommended for diabetic patients.

Pharmacologic intervention
The drugs used for diabetes are divided into definitive medication and supportive. Definitive
medication aims at reducing blood glucose levels. There are 2 broad groups: injectable
insulin agents and oral antidiabetic agents.

Injectable insulin

This a broad group of insulin analogues used for insulin replacement therapy. There are 4
main classes of insulin drugs:

• Rapid-acting insulin. These include insulin lispro, insulin aspart and insulin glulisine.
This type of insulin is mainly used in continuous infusion insulin pumps. They are
taken just before meals.

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 • Short-acting insulin. This includes soluble insulin (actrapid). It is usually taken 30-45
minutes before meals because if it is taken later, it causes post-prandial
hyperglycaemia because it works later than rapid insulin (this is because it
aggregates and forms hexamers which dissociate slowly). Soluble insulin is used
widely by patients for long-term therapy and is particularly useful when mixed with
NPH. Furthermore, it is used in the hospital setting where insulin per sliding scale is
required.
• Intermediate-acting insulin. This mainly includes isophane insulin, also known as
NPH (neutral protamine Hagedon). Mixing the insulin with protamine prolongs its
actions (given as protaphane). Furthermore, it can be mixed with soluble insulin for
better control over the day. NPH is widely used in most patients on insulin therapy.
• Long-acting insulin. These include insulin glargine (Lantus) & insulin detemir.
Glargine is soluble at acidic pH but when it enters an alkaline pH (which is
characteristic of most body tissues) it precipitates, and this prolongs its duration of
action. Detemir has a fatty acid tail that allows it to bind to albumin. These are not
regularly used in most patients, although they can be used in patients failing on NPH
or those with troublesome hypoglycaemia.

Insulin is administered as a subcutaneous injection. It is given in a syringe, or as a pen

injection device. You can also use continuous subcutaneous insulin infusion (CSII) devices,
which are small pumps strapped around the waist. The CSII devices can be set to deliver
boluses during mealtime.

Oral antidiabetic agents

The oral agents used for diabetes are:

• Biguanides. The main biguanide used for diabetes is metformin. Metformin acts
mainly in the liver to reduce insulin resistance. It is known to activate AMP kinase,
but its precise mechanism of action is not clear. It reduces hepatic glucose output
and increases insulin sensitivity. It does not affect insulin secretion or induce
hypoglycaemia, and it does not cause weight gain. It is therefore safe to use in
overweight patients. It also reduces cardiovascular risk. Metformin, however, causes
severe lactic acidosis in patients with renal or hepatic disease. It also causes
anorexia, diarrhoea and epigastric discomfort.
• Sulfonylureas. The drugs in this class include glibenclamide, tolbutamide, glipizide
and chlorpropramide. The drugs act as insulin secretagogues, and they close ATP-
sensitive potassium channels, thus increasing insulin release from the pancreas.
Their glucose-lowering effects are good during the first 1-3 years. However, their
function declines as β-cell mass declines. Glibenclamide is the one that is mostly
used, although tolbutamide is preferred in the elderly due to its short half-life.
Sulfonylureas predispose to hypoglycaemia. They should also be used with care in
patients with liver disease.

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 • Thiazolidinediones (TZDs). These drugs act on PPAR-γ, thus reducing insulin
resistance. PPAR-γ is a nuclear receptor mainly found in adipose tissue and it is
involved in lipid metabolism. It is believed to work by inhibiting lipolysis and thus
reducing free fatty acid levels in the circulation, thereby stimulating peripheral
uptake of glucose particularly by muscles. They also reduce hepatic glucose
production. The main TZD used is pioglitazone. They do, however, cause weight gain,
fluid retention, heart failure, mild anaemia and osteoporosis.
• DPP-4 inhibitors. These drugs inhibit breakdown of GLP-1, which is an incretin
secreted under the influence of insulin. This therefore potentiates insulin’s incretin
effects. Examples include saxagliptin, linagliptin, vidagliptin and sitagliptin. They are
most effective in the early stages of diabetes when insulin secretion is preserved.
• GLP-1 agonists. These include exenatide and liraglutide. They mimic the incretin
effect induced by GLP-1. The drugs, however, are administered subcutaneously.

Treatment regimens for diabetes

Generally, pharmacologic treatment of diabetes is pointless if diet & lifestyle modification
has not taken place. When a person has been diagnosed with diabetes, you need to employ
these changes for 4-6 months before assessing the need for pharmacologic management.

The treatment regimens depend on the type of diabetes the patient has:

Type 1 diabetes

For type 1 diabetes, insulin is the mainstay of therapy. It is always indicated for patients who
have had ketoacidosis. It is vital to educate the patient on how to self-inject insulin and to
self-adjust doses in the light of exercise, finger-prick glucose (glucometer) and caloric intake.
Finger-prick glucose before meals helps determine the long-acting insulin doses, while
finger-prick glucose after meals determines the short-acting insulin doses. Target glucose
levels are 4-7mM before meals and 4-10mM after meals.

Patients are advised to take a multiple injection dosing regimen containing a short-acting
and intermediate/long-acting insulin. It allows the insulin & food to go in at roughly the
same time. Examples of regimens include:

• Biphasic insulin therapy. In Zimbabwe we used premixed soluble insulin (Actrapid)

with isophane insulin (Protaphane) – called actraphane. The two are mixed at a
2
actrapid:protaphane ratio of 30%:70%, and 3s of the dose is given in the morning
1
while the remaining 3 is given in the evening. The doses are taken 30 minutes before
meals.
• QDS (basal/bolus) regimen. This entails 3 rapid-acting insulin doses before meals + 1
long-acting insulin dose before bed. This regimen is flexible as it allows the dose of
soluble insulin to be adjusted according to the meal anticipated.

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A physiologic insulin regimen should have:

1. Basal insulin. This is covered by administering a long-acting insulin once-daily before

bed/in the morning, or administering intermediate-acting insulin twice daily at a
morning: evening dose ratio of 1:1 or 2:1.
2. Nutritional/prandial/meal/bolus insulin. For this you can use rapid-acting or short-
acting insulin. You give it before breakfast, lunch and dinner. Rapid-acting insulin can
be given just before meals, while short-acting insulin has to be given 30-45 minutes
before.
3. Supplementary insulin/corrected dose. Based on the TDD, the patient is classified
into low-dose (<40IU per day), medium dose (40-80IU per day) and high dose (>81IU
per day). The supplementary insulin depends on the pre-meal blood glucose levels.
Pre-meal glucose Dose of additional rapid/short-acting insulin (IU) to be added
to prandial insulin.
Low-dose Medium dose High dose
8.5-11.1 1 2 3
11.2-14 2 4 6
14.1-17 3 6 9
17.1-22 4 8 12
The sum of these 3 components makes up the patient’s total daily dose (TDD). 50% of the
TDD should be basal insulin, while the remaining 50% should be prandial insulin. TDD is
estimated by calculating the dose based on the weight & body habitus. The normal initiation
dose is 0.1IU/kg per day. This may need to be reduced over the first few days, as there is
some transient recovery of endogenous insulin secretion – the honeymoon period. If the
patient is of standard weight with normal body habitus, you give 0.4U/kg. You give 0.3U/kg
if: the patient is on dialysis; very lean; has hypoglycaemia risk factors (e.g. old age). If BMI is
25-30kg/m2, give 0.5U/kg, and if the BMI is above 30kg/m2 give 0.6U/kg2.

Type II diabetes

For type II diabetes, oral agents form the mainstay of treatment. However, in certain
situations, insulin therapy is added or substituted for oral agents. The indications for starting
insulin in type II diabetes are:

• Very high glucose level.

• Symptomatic for hyperosmolar symptoms.
• Patient preference.
• Very high HbA1c – >10%.
• Catabolic states.

If the patient is obese, you do the following:

2
Also give this dose if the patient is on high-dose corticosteroids or has a known high degree of insulin
resistance.

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 1. You usually start with metformin 500mg twice daily after food. The maximum dose
of metformin that can be given is 2g per day. Do not use metformin if the patient has
renal failure, severe heart failure and liver failure.
2. If the blood sugars are poorly controlled with strict adherence to medication & diet,
add a sulfonylurea – either glibenclamide 5-10mg once/twice daily or gliclazide 80-
160mg once/twice daily.
3. If the blood sugars are still poorly controlled, you replace the sulfonylureas with
insulin. The total daily dose of insulin is 0.2IU/kg per day, and you give an
intermediate-acting insulin once-daily.

If the patient is of normal weight, you give a combination of metformin (500-850mg 2-3
times daily) and glibenclamide (2.5mg once/twice daily). If poorly controlled despite strict
adherence to diet, you either change to insulin therapy, or you add it to the current therapy.

Monitoring
Diabetic patients are monitored as follows:

• Home-based glucometer reading. Diabetic patients should be taught how to take

their own glucometer readings before & after meals. Patients should aim to keep
their glucose levels at 5-7mM. Regular profiles (4 daily samples on at least 2 days of
the week) are needed for those on intensive therapy and these should be recorded
in a book or electronically.
• Glycated haemoglobin. The normal range for glycated haemoglobin is 4-6.1% or 20-
44mmol/mol. It demonstrates the long-term glycaemic control (over about 8 weeks)
and therefore gives better indication of likelihood of complications developing. The
ideal target is usually 7% or less. A reasonable but not ideal level is 8%. Greater
control may be required in at-risk patients such as patients with past MI or strokes.
Less tight control may be required for patients at risk of hypoglycaemia. Glycosylated
haemoglobin may be misleading in patients with reduced red cell life spans.
• Fructosamine. Fructosamine is glycated albumin, and it gives an impression of
intermediate glycaemic control. Albumin has a half-life of 20 days, and therefore
fructosamine responds earlier to changes in glycaemic control. It is useful in patients
with anaemia or haemoglobinopathies, and in pregnancy.

Other things that need to be monitored & screened include:

• Blood pressure. Diabetic patients are at risk of developing hypertension, and

concurrent diabetes & hypertension carries a poor prognosis as it increases
cardiovascular risk and increases mortality. Blood pressure is therefore constantly
140
monitored. Blood pressure should be kept below mm Hg, and if the patient has
80
130
diabetic nephropathy, the blood pressure must be maintained below 80
mm Hg.

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 • Urine tests. Urine needs to be tested for proteinuria & albumin/creatinine ratio.
Microalbuminuria is when urine dipstick tests negative for proteins but the
albumin/creatinine ratio is greater than 3mg/mol3. This reflects early renal disease
and increased cardiovascular risk. If urine albumin/creatinine ratio is above
3mg/mol, give ACE inhibitors or AT1-receptor antagonists even if blood pressure is
normal. This test needs to be conducted at least once every year.
• Plasma lipids. Plasma lipid control is also important for reducing mortality. The
targets are as follows:
Total cholesterol <4.0mM
LDL <2.0mM
HDL >1.1mM in males & >1.3mM in females
Triglycerides <1.7mm
Plasma lipids need to be measured annually.
• Annual eye checks. Diabetic retinopathy is a common complication of diabetes
which can be treated if detected early. If pre-proliferative changes appear in
patients, patients should be referred to ophthalmologists. Cataracts also warrant
referral to ophthalmologists.
• Foot care. Patients are at risk of developing diabetic foot, and this condition is
responsible for a considerable amount of mortality in these patients. Patients need
to have their feet checked for general condition (rule out ulcers, calluses, and
deformities), pulses and sensation. They should be referred to a podiatrist. The
things they should informed include:
o Keeping the foot warm & dry at all times.
o Keep your nails short at all times.
o Check the foot daily for cuts, bruises, calluses, blisters or any changes to the
skin or nails.
o Not moving around barefoot or with uncovered shoes.
o Not to wear tight-fitting shoes or square toe shoes. They should wear at least
1 size greater than their normal shoe size.
o Get regular foot examinations.

33
The minimum level detected on urine dipstick is 10-20mg/mol.

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 Thyroid disease
Thyroid gland disease is common, particularly in women. Endocrine disease occurs mostly in
women, as the majority of cases are autoimmune in origin. Dietary deficiencies also cause
disease, although these are now very few due to salt fortification with iodine. Thyroid
dysfunction may or may not be associated with structural disease of the thyroid.

Thyroid hormone physiology

The thyroid gland is located in the visceral compartment of the neck anterior to the trachea
and just below the thyroid cartilage. The thyroid gland consists of numerous follicles that
enclose a colloid containing thyroglobulin. The follicles are lined by thyrocytes which range
between being squamous, cuboidal and columnar depending on the activity of the gland.
The follicles are separated by a thin interstitium containing blood vessels and parafollicular
cells which release calcitonin.

Thyroid hormones are synthesised from thyroglobulin stored in the follicles. The protein
undergoes iodination of tyrosine residues whilst in the colloid, and a large amount of the
protein is iodinated when iodine in the circulation is plentiful. Secretion is stimulated by TSH
(thyroid-stimulating hormone), which is an anterior pituitary hormone that is secreted
under the influence of TRH (thyrotropin-releasing hormone) released by the hypothalamus.
The thyroid hormones exert negative feedback on TSH & TRH secretion. TSH binds to
receptors on thyrocytes which stimulate the cleavage of iodothyronine residues from
thyroglobulin, and these are further processed to form triodothyronine (T3) &
tetraiodothyronine/thyroxine (T4). 90-93% of thyroid hormones in the circulation are T4
while 7-10% is T3.

Thyroid hormones travel bound mainly to thyroid-binding globulin (TBG). Other plasma
proteins involved in thyroid hormone transport are transthyretin (thyroid-binding pre-
albumin) and albumin. T4 has a higher affinity for plasma proteins than T3, and therefore T3
has higher free plasma levels. They have a very long half-life: T3 has a half-life of 1 day, while
T4 has a half-life of 6 days.

Thyroid hormones act in virtually all tissues of the body. They act on nuclear receptors. T 3 is
the active form and T4 is converted to T3 for the hormone to act properly. A considerable
amount of T4 is converted to reverse T3 (rT3), which is metabolically inert.

Thyroid hormones have many functions:

• Increasing basal metabolic rate (BMR). This is reflected by an increase in oxygen

consumption. It is a result of redundant burning of energy.
• Increased carbohydrate metabolism, leading to increased glycolysis. There is also an
increase in plasma glucose levels – thyroid hormones are diabetogenic.

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 • Increased fat catabolism, leading to elevated free fatty acids. However, they
decrease circulating cholesterol, phospholipids and triglyceride levels.
• Increased vitamin requirement.
• Increased cardiac activity: increased cardiac output, increased heart rate, increased
contractility,
• Stimulation of the GIT. This leads to increased appetite & food intake, increased
motility and increased secretions.
• Increased cerebration of the brain. The cerebral blood flow and oxygen & glucose
consumption remain the same, though.
• Growth. This is more marked in children before the age of puberty. Growth
retardation occurs in deficiency, but hormone excess does not cause gigantism.
• Increased muscle activity. Thyroid hormones have a stimulatory effect on muscles,
although excessive amounts cause muscle weakness due to destruction of muscle
protein.
• Increased endocrine activity. Thyroid hormones increase the demand for other
hormones in the circulation, such as insulin.

Thyroid function tests

The tests for thyroid function are:

• T3 & T4 levels. This measures the amounts of each hormone in the circulation. You
can measure either free or total thyroid hormone levels in the circulation. The free
hormone measurement is more reliable as total hormone levels are affected by the
concentration of plasma proteins, particularly TBG1. The normal free T3
concentration is 3.5-7.5pmol/L, and the normal free T4 concentration is 10-25pmol/L.
thyroid hormone levels are elevated in primary hyperthyroidism, and decreased in
primary hypothyroidism.
• TSH. TSH measurement provides the single most specific, sensitive and reliable test
of thyroid status in clinically overt & subclinical thyroid dysfunction. It helps
distinguish the source of dysfunction when there are symptoms. In primary
hyperthyroidism, TSH levels are decreased while in primary hypothyroidism, TSH is
raised. In disease secondary to pituitary or hypothalamic dysfunction, TSH levels
alone are inadequate for diagnosis. The normal TSH level is 0.3-3.5mU/L.
• Thyroid antibodies. These are usually measured when autoimmune disease is
suspected. You can measure anti-thyroid peroxidase antibodies, anti-thyroglobulin
antibodies and anti-TRH/TSH receptor antibodies.

Usually, free T4 & TSH levels are the only ones required to diagnose thyroid disease.

Free T4 TSH

1
The affinities of albumin & transthyretin have little effect on the binding of T4.

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 levels Low Normal High
High Overt hyperthyroidism Thyrotroph adenoma Thyrotroph adenoma or
(rare) or thyroid thyroid hormone
hormone resistance resistance, otherwise
(rare) assay interference.
Normal Subclinical Euthyroid Subclinical hypothyroidism
hyperthyroidism or T3 or recovering from non-
hyperthyroidism or non- thyroidal illness
thyroidal illness
Low Non-thyroidal illness or Non-thyroidal illness or Overt hypothyroidism or
hypopituitarism hypopituitarism recovery from non-
thyroidal illness

They are some problems with interpretation of thyroid hormone levels in some patients.
They include:

1. Pregnancy. Pregnancy leads to increased TBG levels, thus distorting total T3 & T4
levels. Furthermore, the normal ranges for free T4 & TBG change over the course of
pregnancy. These are oestrogen-mediated changes.
2. Oral contraceptives. Combined oral contraceptives contain oestrogen, which lead to
changes similar to pregnancy: elevated TBG & total T4.
3. Serious acute & chronic illness. Illness can cause: reduced concentration & altered
affinity of binding proteins; decreased peripheral conversion of T4 to T3, with
increased rT3; and reduced TSH production. Systemically ill patients can therefore
have low total & free thyroid hormone levels with normal or low basal TSH levels.
This is called the sick euthyroid syndrome. The changes are mediated by IL-1 & IL-6.
4. Drugs. Amiodarone reduces conversion of T4 to T3, and therefore T4 levels can be
above normal in euthyroid patients. Amiodarone can also cause overt hyper- &
hypothyroidism. Many other drugs interfere with thyroid function.

Hyperthyroidism
Hyperthyroidism is an excess of thyroid hormones. It may or may not have clinical
manifestations, and when clinical manifestations are present it is called thyrotoxicosis.
Hyperthyroidism is very common, affecting 2-5% of all women during their lifetime. It is 5-
times more common in females than males and is most common between the ages of 20 &
40 years.

Aetiology

Nearly all cases are primary (>99%) – pituitary causes are very rare. The causes of
hyperthyroidism are:

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 • Grave’s disease. This is the most common cause of hyperthyroidism, accounting for
2
s of cases. It is 9-times more common in females, and typically affects women aged
3
40-60 years. Grave’s disease arises from circulating TSH-receptor antibodies that
bind to TSH-receptors on thyrocytes and stimulate them, resulting in increased
thyroid hormone levels (especially T3) and smooth thyroid enlargement. Patients are
often hyperthyroid, but may become euthyroid or hypothyroid. It is associated with
other autoimmune diseases, such as vitiligo, type I diabetes mellitus and Addison’s
disease. There is an associated between this disease and HLA-B8, -DR3 and –DR2.
There is a 40% concordance rate between monozygotic twins and 5% concordance
between dizygotic twins. Graves’ disease is associated with an antibody reaction
with orbital auto-antigens, and this leads to thyroid eye disease. Other associations
include thyroid dermopathy. Patients demonstrate a fluctuating pattern of relapse &
remission.
• Toxic multi-nodular goitre. Toxic nodular goitre accounts for about 11% of cases of
hyperthyroidism. This disease is seen in iodine-deficient areas and in the elderly. It is
characterised by the presence of multiple nodules in the thyroid that secrete thyroid
hormones. The condition is rarely brought into remission by anti-thyroid drugs,
although they help control the hyperthyroidism. Surgical intervention is indicated for
compressive symptoms (dysphagia & dyspnoea).
• Toxic nodule/adenoma. This accounts for about 5% of cases of hyperthyroidism.
They are solitary nodules belonging to the class of follicular adenomas that secrete
thyroid hormones2, thus making them hot nodules. They are a result of mutations in
the GNAS1 gene. They are not forerunners of thyroid malignancies, although 10% of
cold nodules can become malignant. Toxic nodules are well-demarcated lesions with
an intact capsule. On an isotope scan, the nodule takes up radioactive iodine, while
the rest of the gland is suppressed.
• Subacute thyroiditis (also known as de Quervain’s thyroiditis). This is a transient
hyperthyroidism resulting from an acute inflammatory process. It could occur as a
result of an acute viral infection. Apart from thyrotoxicosis, patients develop fever,
malaise, neck pain, tachycardia and local thyroid tenderness. There are elevated
thyroid hormones with raised blood viscosity & ESR and there is low uptake on a
radioisotope scan. It may then follow with hypothyroidism. It is treated with aspirin
in the acute phase and prednisolone for more severe cases.
• Amiodarone-induced thyrotoxicosis (AIT). Amiodarone is a type III anti-arrhythmic
drug. It causes 2 types of thyrotoxicosis:
o Type 1 AIT. This is associated with pre-existing Graves’ disease or
multinodular goitre. The hyperthyroidism is probably triggered by the high
iodine content of the drug.

2
The majority of follicular adenomas are cold – i.e. they do not secrete thyroid hormones.

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 o Type 2 AIT. This is not associated with pre-existing thyroid disease and results
from the direct effects of the drug itself on thyrocytes. This leads to
destructive thyroiditis and release of T3 & T4. It may be associated with a
hypothyroid state several months after presentation.
• Other causes of primary hyperthyroidism. These include: neonatal thyrotoxicosis,
exogenous iodine, postpartum thyroiditis, post-radiation thyroiditis, thyrotoxicosis
factitia and TB infection.

Causes of secondary hyperthyroidism include:

• TSH-secreting pituitary tumours.

• Metastatic differentiated thyroid carcinoma.
• hCG-producing tumours.
• Hyper-functioning ovarian teratoma (also known as struma ovarii).

Clinical features

The symptoms of hyperthyroidism are:

• Weight loss despite an increased appetite.

• Diarrhoea.
• Over-activity & irritability.
• Sweaty.
• Heat intolerance.
• Muscle weakness.
• Resting tremor.
• Vomiting.
• Thirst.
• Eye complaints. This is seen only in Graves’ disease.
• Loss of libido.
• Oligomenorrhoea.
• Onycholysis (chipping nails).

The signs of hyperthyroidism are:

• General: tremor, wasting, tachycardia, full-volume pulse, warm dilated peripheries,

goitre with bruit.
• CVS: atrial fibrillation, cardiac failure, systemic hypertension.
• Eye examination: exophthalmos, lid lag, conjunctival oedema, ophthalmoplegia,
periorbital oedema.
• Musculoskeletal: proximal myopathy, proximal muscle wasting, palmar erythema.
• Skin examination: Graves’ dermopathy, pretibial myxoedema, thyroid acropachy
(clubbing).

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Complications

Some thyroid situations include:

• Thyroid storm. This is an acute deterioration of hyperthyroidism. It has a mortality of

10%. Patients present with hyper-pyrexia, severe tachycardia, extreme restlessness,
cardiac failure and liver dysfunction. It is usually precipitated by stress, infection and
surgery in an unprepared patient (one who is not euthyroid at the time of surgery).
Treatment is urgent:
1. Propranolol started immediately.
2. Potassium iodide.
3. Anti-thyroid drugs.
4. Corticosteroids.
5. Full supportive measures.
Control of cardiac failure & tachycardia is also necessary.

Investigations

The diagnostic investigations for hyperthyroidism are:

• TSH. This is low in primary hyperthyroidism (<0.05mU/L), but may be high if

hyperthyroidism is due to a pituitary adenoma.
• Free T3 & T4. T4 is almost always raised, but T3 is more sensitive as there are some
cases of isolated raised T3.
• Antibodies. Anti-TPO and anti-thyroglobulin antibodies are usually present in Graves’
disease. TSH-receptor antibodies are not routinely measured but are commonly
present.

Other supportive tests include:

• FBC. There may be a mild normocytic anaemia and mild neutropenia in Graves’
disease.
• Elevated LFTs.
• Raised ESR.
• Hypercalcaemia.
• Radio-isotope scan. This can be used for a thyroid mass.

Management

There are 3 definitive treatment options available:

1. Anti-thyroid drugs. The most common anti-thyroid medications used are

carbimazole and propylthiouracil. They inhibit the formation of thyroid hormones.
Carbimazole also has immunosuppressive effects. However, because of the long half-
life of thyroid hormones, there is residual thyroid function after starting medication

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 for about 10-20 days. Therefore, you give β-blockers for rapid control of symptoms3.
There are 2 treatment regimens you can employ:
a. Gradual dose titration. You start a high dose of carbimazole, e.g. 20-40mg
daily, and then review after 4-6 weeks for dose reduction. You also start a β-
blocker. Dose reduction depends on free thyroid hormone levels taken every
1-2 months. TSH levels remain suppressed for several months and are
therefore useless at this stage. When the patient is clinically & biochemically
euthyroid, stop the β-blockers and review thyroid function regularly during
the planned course of treatment (6-24 months). Reduce the dose of
carbimazole if free T4 levels fall or TSH rises, as well as when you’re now
approaching the end of treatment. Increase carbimazole if free T4 rises or TSH
falls.
b. “Block & replace” regimen. With this regimen, full doses of antithyroid drugs
(carbimazole 40mg) are given to suppress thyroid function completely while
replacing thyroid activity with levothyroxine (100µg) once the patient is
euthyroid. This is continued for 18 months. This regime is used so as to
manipulate the immunosuppressant effects of the drugs; prolonged use of
carbimazole inhibits the autoimmune effects of the disease processes. It is
also used to avoid over- & undertreatment. This regime is contraindicated in
pregnancy as carbimazole cross the placenta more than T4.
About 50% of patients will relapse with symptoms and require radio-iodine or
surgery. Due to the agranulocytosis it causes, carbimazole can cause dangerous
sepsis. If a patient develops a fever, sore throat or mouth ulcers, stop the drug and
get an urgent FBC.
2. Radioactive iodine. This is a form of radio-ablation of the thyroid gland using radio-
active iodine, which is preferentially taken up by the thyroid gland. Iodine is given at
an empirical dose of 200-500MBq. It usually takes several months to be effective.
Patients, however, must be rendered euthyroid before treatment. They should stop
anti-thyroid drugs 4 days prior to treatment and then recommence them 3 days after
treatment. Early discomfort of the neck & hypothyroidism are seen with radioactive
iodine treatment. If worsening occurs, the patient must receive propranolol and
carbimazole can be restarted. Hypothyroidism usually persists in patients.
3. Surgery. Thyroidectomy is only conducted in patients previously rendered euthyroid.
You should stop anti-thyroid drugs 10-14 days before operating. You should also give
potassium iodide to reduce vascularity to the gland. Common complications include
haematoma formation (which causes tracheal compression), recurrent laryngeal
nerve damage, and transient/permanent hypoparathyroidism.

Hypothyroidism

3
B-blockers can be used alone if the hyperthyroidism is self-limiting, e.g. sub-acute thyroiditis.

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Hypothyroidism is a deficiency in thyroid hormones. It may be clinical where there are
obvious symptoms, or subclinical where there are no symptoms. It is often insidious, so the
doctor must have a high index of suspicion.

Hypothyroidism can be primary or secondary. Primary hypothyroidism is one of the most

common endocrine diseases, affecting over 2% of women & 0.1% of men4. The worldwide
prevalence of subclinical hypothyroidism is 1-10%. Secondary hypothyroidism results from
defective pituitary or hypothalamic dysfunction.

Aetiology

The causes of primary hypothyroidism are:

• Iodine deficiency. This is the leading cause of deficiency worldwide. It manifests as

an endemic goitre, and is commonly found around Gokwe in Zimbabwe. Patients
may be euthyroid or hypothyroid depending on the severity of disease. The goitre is
thought to develop because of increased stimulation by the elevated TSH levels
leading to hyperplasia. The incidence of iodine deficiency is declining worldwide due
to the fortification of salt.
• Hashimoto’s thyroiditis. This is an autoimmune disorder that is a result of auto-
antibodies against various antigens in the thyroid. In the majority of cases, the
antibodies found are anti-thyroid peroxidase antibodies (anti-TPO). The disease is
more common in middle-aged women and produces atrophic changes with
regeneration, leading to development of goitre. The gland is usually firm & rubbery,
but may range from soft to hard. Patients may be hypothyroid or euthyroid and they
may enter an initial hyperthyroid state called Hashi-toxicity. The goitre resolves
spontaneously after administration of levothyroxine.
• Atrophic hypothyroidism. This is one of the most common causes of
hypothyroidism, and is also a result of an autoimmune disorder. This disorder is
characterised by an atrophic & fibrotic thyroid gland due to lymphoid infiltration.
The thyroid is therefore small, as opposed to Hashimoto’s thyroiditis. It is 6-times
more common in females. It is associated with other autoimmune disorders such as
pernicious anaemia & vitiligo. Patients often manifest with intermittent
hypothyroidism with subsequent recovery. Anti-TSH antibodies are sometimes
involved in the aetiology.
• Post-partum thyroiditis. This is usually a transient phenomenon observed following
pregnancy. It causes hyperthyroidism and/or hypothyroidism. It is a lymphocytic
thyroiditis that results from the modifications to the immune system that occur
during pregnancy. The condition is usually self-limiting, but when conventional
antibodies are found, the condition can change to permanent hypothyroidism. This
condition can be misdiagnosed for post-partum depression.

4
Hypothyroidism mostly affects women 6-times more than males.

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 • Dyshormonogenesis. This is due to genetic defects in the synthesis of thyroid
hormones. Patients develop hypothyroidism with goitre. Once form presents with
sensorineural deafness and is due to deletion of chromosome 7, causing a defect in
the transporter pendrin. This is called Pendred syndrome.
• Congenital. Congenital hypothyroidism occurs in 1 in 4000 births. Untreated severe
hypothyroidism causes severe neurological & intellectual damage in the future.
Often the babies are born normal because maternal thyroid hormones can cross the
placenta and carry out thyroid function in the foetus. Routine screening of new-born
using a blood spot to detect a high TSH level (Guthrie test) is efficient & cost-
effective. Cretinism is prevented when T4 is started early in life.
• Iatrogenic. Hypothyroidism can develop secondary to a thyroidectomy or radio-
iodine treatment. Certain drugs such as amiodarone also cause hypothyroidism.

Clinical features

The symptoms of hypothyroidism are:

• CNS: tiredness, sleepiness, lethargy, decreased mood (depression), reduced memory

& cognition, dementia and psychosis.
• General: weight gain, cold-intolerance, hoarse voice, dry unmanageable hair &
coarse brittle skin.
• GIT: anorexia (reduced appetite), constipation.
• GUT: menorrhagia or oligomenorrhoea, poor libido, subfertility.
• Musculoskeletal: arthralgia, myalgia, cramps, weakness.

The clinical signs of hypothyroidism can be abbreviated by the acronym BRADYCARDIC:

• B – Bradycardia.
• R – Reflexes: slow-relaxing reflexes.
• A – Ataxia, which is cerebellar.
• D – Dry thin skin & hair.
• Y – Yawning & drowsiness. Even coma.
• C – Cold hands, hypothermia.
• A – Ascites. This may be associated with non-pitting oedema (myxoedema5) on the
lips, hands and feet. There may also be a pericardial and/or pleural effusion.
• R – Round puffy face. There may also be a double chin & obesity.
• D – Defeated demeanour (depression).
• I – Immobile with/without bowel ileus.
• C – Congestive cardiac failure.

Other features include: neuropathy, myopathy and goitre. Young children with cretinism
demonstrate growth retardation.

5
Myxoedema is caused by accumulation of mucopolysaccharides in subcutaneous tissues.

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Complications

The complications of hypothyroidism are:

• Myxoedemic coma. This is when patients with hypothyroidism present with a coma.
It is a very rare phenomenon and the affected patients are often elderly patients.
Hypothermia is often present and patients often have cardiac failure, pericardial
effusion, hypoventilation, hypoglycaemia and hyponatraemia. Treatment is as
follows:
1. Most physicians would advise treating the condition with oral T 3 given at a
dose of 2.5-5µg, and then increasing the dose gradually. Large doses should
not be used.
2. Oxygen per face mask. Ventilation can be given if necessary.
3. Gradual rewarming.
4. Hydrocortisone 100mg intravenously every 8 hours.
5. Glucose infusion.
• Myxoedemic madness. Depression is common in hypothyroidism, and in the elderly
patients may become frankly demented or psychotic. It may be associated with
striking delusions. This may occur shortly after commencing T4 treatment.
• Pregnancy. In pregnancy, hypothyroidism can cause eclampsia, anaemia,
prematurity, low birth weight, still birth and postpartum haemorrhage.

Diagnosis

The diagnostic investigations are:

• Serum TSH. This is usually high in primary hypothyroidism.

• Free T4. A low free T4 confirms the hypothyroid state.
• Thyroid antibodies may be present as well, depending on the aetiology. Other organ-
specific antibodies may be present as well.

Supporting tests include:

• FBC, which demonstrates normocytic normochromic anaemia. It can also be

macrocytic anaemia due to associated pernicious anaemia, or microcytic anaemia
due to associated menorrhagia.
• LFTs, which demonstrate elevated AST levels from muscle or liver.
• U&Es which will show hyponatraemia due to increased ADH & impaired free water
clearance.
• Lipid profile, which will show hypercholesterolaemia & hypertriglyceridemia.
• Creatine kinase will be elevated.

Management

Patients are managed as follows:

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 1. Thyroid hormone replacement therapy. Thyroid hormones are replaced with
levothyroxine, which you give for life in permanent cases. We often start with 50-
100µg once daily. In elderly patients or patients with ischemic heart disease, you
start with a dose of 25µg once daily and perform serial ECGs.
2. Monitoring. The first review is done at 12 weeks – you measure free T4 & TSH levels.
Thyroxine has a half-life of 7 days, and therefore any change in dose should be
reviewed 6-weekly. Once free T4 levels are normal, check TSH levels yearly.
If TSH levels remain high, the levothyroxine level should be increased by 25-
50µg. Tests should be repeated at 6 week intervals until TSH levels are
normal. In elderly patients & patients with ischemic heart disease, you make
25µg increments to the dose.
Complete suppression of TSH is not advised as this poses a risk of atrial fibrillation &
osteoporosis.
3. Pregnancy. During pregnancy, an increment of 25-50µg is required due to the
greater circulating thyroid hormone pool.

Clinical improvement is not seen until at least 2 weeks of treatment. Full resolution of
symptoms may take 6 months. Also screen for the development of other autoimmune
disorders.

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 Cushing’s syndrome
Cushing’s syndrome is a state of chronic glucocorticoid excess (hypercortisolism). There is
loss of normal feedback inhibition on the hypothalamus-pituitary-adrenal axis, which
normally maintains the glucocorticoid levels within normal limits. There is also loss of the
normal circadian rhythm of cortisol secretion.

Causes
The causes of Cushing’s syndrome are classified in two ways. One way of classifying the
causes is to classify them into ACTH-dependent and ACTH-independent causes.

• ACTH-dependent causes. These are:

o Cushing’s disease. This is a secondary hypercortisolism resulting from
excessive production of ACTH by the anterior pituitary gland – it is also
known as Cushing’s disease. This is commonly caused by an ACTH-secreting
pituitary adenoma. It accounts for 70% of cases of endogenous (arising from
within the body) hypercortisolism. The majority of pituitary adenomas are
microadenomas (smaller than 1cm), although some are macroadenomas. It is
4-times more common in females, and the peak age is 30-60 years. There is a
variable degree of bilateral cortical nodular hyperplasia, with raised ACTH &
cortisol levels.
o Ectopic ACTH production. At times ACTH comes from another site that is not
the pituitary gland. This happens with some malignancies, such as small cell
carcinoma (most common cause), carcinoid tumours, thyroid medullary
carcinomas and pancreatic neuroendocrine tumours. The excessive ACTH
leads to nodular hyperplasia of the adrenal gland.
o Ectopic CRH production. This happens with some thyroid medullary &
prostatic carcinomas.
o ACTH administration. Exogenous ACTH can cause Cushing’s syndrome.
• ACTH-independent causes. These are:
o Iatrogenic administration of corticosteroids. This is the leading cause of
Cushing’s syndrome. There may not be a direct increase in cortisol levels, but
there is an increase in glucocorticoid activity and suppression of ACTH
secretion due to negative feedback effects. The suppression of ACTH leads to
adrenal gland atrophy1.
o Adrenal adenoma & adenocarcinoma. The majority of adrenal neoplasms are
non-functional and do not produce hormone excess. They account for 15-
20% of cases of endogenous primary hypercortisolism. The pituitary gland

1
The zona glomerulosa is preserved as its function is not entirely dependent on ACTH production.

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 undergoes what is called Crooke hyaline change in which the granular
basophilic cytoplasm of corticotrophs changes to a light basophilic cytoplasm
due to accumulation of intermediate keratin filaments.
o Other rare causes. Other rare causes include Carney complex and McCune-
Albright syndrome.

Clinical features
The clinical features of hypercortisolism are:

• History. In the history, you want to find the following:

o Weight gain.
o Mood change (depression, lethargy, irritability, psychosis).
o Proximal weakness.
o Gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction).
o Virilisation in females.
o Easy bruising.
o Growth arrest in children.
o Polyuria & polydipsia (glucose excess).
• Examination. The signs on examination are:
o General: the patient appears depressed or psychotic, and has a plethoric
face. There may be acne, frontal balding in females and hirsutism (beard).
The blood pressure is elevated.
o Skin examination: hyperpigmentation2, numerous poorly-healed bruises on
the skin, purple/red striae, buffalo rump & moon face. The skin may be
infected.
o Musculoskeletal: rib fractures, pathological long bone fractures, osteoporosis,
proximal muscle wasting, kyphosis.

Investigations
The investigations for hypercortisolism are divided into diagnostic & supportive
investigations. Random cortisol level measurements are of no value as they are affected by
the time of day, illness and stress (even from venepuncture) all influence cortisol levels. The
diagnostic investigations are:

• Overnight dexamethasone suppression test. This is the initial test done in

outpatient settings and is done for screening. The logic is that when you administer a
glucocorticoid, you exert negative feedback effects on the pituitary, which leads to
suppression of ACTH secretion and subsequently cortisol production. Because
Cushing’s syndrome is a result of unresponsive excess of cortisol levels – whether
secondary to ACTH or not – hypercortisolism results in absence of suppression when
2
This is due to stimulation of melanocytes by ACTH.

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 dexamethasone is administered. You give the patient 1mg dexamethasone at
midnight, and then measure plasma cortisol levels at 8am. In normal people plasma
cortisol comes down to below 50nmol/L. However, this test gives false negatives in
2% and false positives in 2% of normal people, 13% of obese individuals and 26% of
in-patients. False positives are also seen in depression, alcohol excess and in patients
taking liver enzyme inducers.
• 48-hour low-dose dexamethasone suppression test. This test is done in patients
with abnormal overnight dexamethasone suppression test results. You give low-dose
dexamethasone (0.5mg 6-hourly – a total of 8 doses) and you measure the cortisol
level exactly 48 hours after. In normal people, cortisol levels fall to below 50nmol/L.
Patients with Cushing’s syndrome fail to suppress cortisol levels to below this.
• 24-hour urinary free cortisol. This test is easy to conduct, but is less reliable as some
patients with Cushing’s syndrome (about 10%) have normal values.
• Plasma ACTH level. Low ACTH levels (<10ng/L) indicate ACTH-independent disease.
• Imaging. Adrenal CT or MRI may be used to detect functional adrenal adenomas or
adenocarcinomas, which are usually fairly large. Carcinomas are distinguished by the
large size, irregular outline and signs of infiltration & metastasis. A chest X-ray may
reveal a bronchial carcinoid tumour which may be the source of ACTH.

Supportive tests include:

• U&Es. This may reveal hypokalaemia due to mineralocorticoid actions. In this case,
all diuretics must be stopped.

Treatment
Cushing’s syndrome can lead to death from hypertension, MI, infection and heart failure.
Management of Cushing’s syndrome therefore relies on both lowering the cortisol levels
and offering definitive management of symptoms.

The management is as follows:

1. Stop all corticosteroids. Since majority of cases are due to iatrogenic use of steroids,
stopping them should be the first step in treatment.
2. Reduce cortisol production. Cortisol levels can be lowered using medical
management. This, however, is not curative. Rather, it is used to prevent the
continued effects of high cortisol levels. You can use metyrapone (an 11β-
hydroxylase inhibitor) at a dose of 750-4000g daily divided into 3-4 doses. You can
also use ketoconazole 200mg 3-times daily – it is synergistic to metyrapone. Other
drugs include aminoglutethimide (blocks conversion of cholesterol to pregnenolone)
1g daily, and trilostane (3β-17-hydroxysteroid dehydrogenase inhibitor).
3. Surgical intervention. Surgical intervention can be employed on the pituitary gland
or the adrenal gland for pituitary or adrenal adenomas & carcinomas respectively.
The surgical interventions for pituitary adenomas are:

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 • Trans-sphenoidal resection of the pituitary adenoma. This is the treatment of
choice for pituitary adenomas. This usually leaves the patient ACTH-deficient
after surgery, and this is a good prognostic sign. Pituitary surgery results in
remission in 75-80% of cases.
The surgical interventions for adrenal masses are:
• Adenoma resection. This can be done for small adenomas. It cures ACTH-
independent hypercortisolism.
• Adrenalectomy. Adrenalectomy can be conducted for large adenomas and for
some adenocarcinomas. It cures adenomas, but not always
adenocarcinomas. Bilateral adrenalectomy can be used in pituitary adenomas
when all other pituitary interventions have failed. In about 20% of cases,
bilateral adrenalectomy complicates with Nelson’s syndrome, which is a
syndrome of hyperpigmentation following removal of the adrenal glands.
This results in the lifting of negative feedback exerted by cortisol on the
pituitary gland and therefore leads to accumulation of ACTH. The excessive
ACTH leads to hyperpigmentation. It is often associated with an enlarging
pituitary adenoma, which may be treated with surgery or radiotherapy.
All surgery should be conducted only after cortisol hyper-secretion has been
controlled.
4. Radiotherapy. Radiotherapy can be used both for pituitary and adrenal masses.
External pituitary radiation on its own is slow-acting and it is only effective in 50-60%
of patients after follow-up. It is mainly used for failed surgery. Radiotherapy can be
used for adrenal adenocarcinomas after surgical resection of the main tumour
(which is done when there are no metastases). You can also follow-up with medical
therapy using mitotane, which inhibits growth of the tumour.

The prognosis of Cushing’s syndrome after treatment is generally good, although many of
the effects remain. These include myopathy, diabetes mellitus, obesity, hypertension,
menstrual irregularity, osteoporosis and subtle mood changes.

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 Adrenocortical insufficiency
Adrenocortical insufficiency is a condition in which there is glucocorticoid &
mineralocorticoid deficiency. Unlike in Cushing’s syndrome, the mineralocorticoid layer is
often destroyed as well. Adrenocortical insufficiency occurs as a result of destruction of 90%
of the adrenal cortex.

Pathophysiology
Adrenocortical insufficiency can be divided into primary and secondary. Primary
adrenocortical insufficiency is when the cause of insufficiency is due to a primary disease
process arising from the adrenal cortex. This is further divided into acute and chronic.

• Primary acute adrenocortical insufficiency. These are conditions that cause a

sudden decline in adrenocortical function. They include:
o Waterhouse-Friderichsen syndrome. This is a condition that arises as a
complication of sepsis. It results from the widespread release of toxins by
bacteria, which lead to DIC (disseminated intravascular coagulation) in the
adrenals. The implicated organisms are N. meningitidis1, Pseudomonas and H.
influenzae.
o Stress in a patient with pre-existing chronic adrenocortical insufficiency.
Sudden stress can result from.
o Adrenalectomy. This can be done for patients with either refractory pituitary
adenomas or adrenal adenomas/adenocarcinomas leading to Cushing’s
syndrome.
• Primary chronic adrenocortical insufficiency (also known as Addison’s disease).
These conditions result from chronic destruction of the adrenal gland. The causes
include:
o Autoimmune adrenalitis. This is the leading cause of Addison’s disease in
developed countries (60-70%) with low incidences of HIV. it is also more
common in females. Autoimmune adrenalitis occurs as a result of organ-
specific autoantibodies which are sensitive to a particular antigen. In most
cases, the inciting antigen is 21-hydroxylase. There are associations with
other autoimmune conditions in the autoimmune polyendocrine syndromes
(APS) types I (autoimmune adrenalitis, hypoparathyroidism, pernicious
anaemia and premature ovarian failure) & type II (autoimmune adrenalitis,
type I diabetes mellitus, and thyroiditis). The adrenal glands are shrunken &
irregular and they have a lymphocytic infiltrate.

1
Neisseria-mediated sepsis is caused by an endotoxin.

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 o Tuberculosis (TB). This is the commonest cause in developing countries and in
countries where HIV prevalence is very high. In such countries, it accounts for
more than 90% of cases. In developed countries, however, it accounts for less
than 10%. TB produces numerous granulomatous reactions in the adrenal
cortex.
o Opportunistic infections. These are mainly related to HIV. They include:
disseminated fungal infections such as Histoplasma capsulatum &
Coccidioides immitis.
o Degenerative diseases. These include amyloidosis and Schilder’s disease
(adrenal leukodystrophy). Antiphospholipid syndrome & SLE also cause
Addison’s disease, as well as Waterhouse-Friderichsen syndrome.
o Metastatic malignancies. Metastasis to the adrenal gland accounts for the
majority of adrenocortical malignancies. In the majority of cases,
adrenocortical function is preserved. However, as the malignancies continue,
they destroy surrounding normal adrenal tissue. The sources of malignancy
are: breast, lung, GIT tumours, malignant melanomas and lymphomas.
Addison’s disease is very rare, with an incidence of 3-4 per million per year and a
prevalence of 40-60 per million.
• Secondary adrenocortical insufficiency. This results from under-stimulation of the
adrenal gland by malfunctioning of the hypothalamus and/or pituitary gland. The
causes include: metastatic cancer, infections, infarcts and irradiation. They are very
rare causes of adrenocortical insufficiency. Secondary adrenocortical insufficiency
also results from chronic use of corticosteroid medication. Prolonged corticosteroid
therapy leads to chronic secretion of subnormal amounts of ACTH2, which results in
atrophy of the adrenal cortex. When corticosteroid therapy is suddenly removed in
such a case, the remaining adrenal gland is too atrophic to produce adequate
amounts of steroids on its own. It is for this reason that chronic administration of
corticosteroids requires that you taper down the dose instead of abruptly removing
the drug.

Clinical features
The symptomatology of Addison’s disease is often vague & non-specific – it is called “the
unforgiving master of non-specificity & disguise”. For this reason, it is often diagnosed late.

• History. The symptoms of adrenocortical insufficiency are:

o General: fever, malaise, syncope (from postural hypotension).
o Skin: hyperpigmentation in palmar creases, buccal mucosa, new scars.
o GIT: weight loss & anorexia, abdominal pain, vomiting, constipation or
diarrhoea.
o GUT: impotence & amenorrhoea.
2
ACTH has a trophic effect on the adrenal gland.

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 o Musculoskeletal: progressive weakness, myalgia, joint & back pain.
o CNS: depression, confusion.
• Examination. On examination you may find:
o Hyperpigmentation, particularly on new scars & palmar creases.
o Postural hypotension3.
o General wasting.
o Dehydration3.
o Loss of body hair.
o Possible vitiligo.
Patients may also be hypotensive and dehydrated.

Investigations
Investigations into adrenocortical insufficiency are urgent. If the patient is seriously
hypotensive, he/she must get hydrocortisone 100mg intravenously followed by intravenous
normal saline. This must be done, however, after taking a blood sample for cortisol
measurement. Single cortisol measurements, however, are of no use. Nonetheless, when
done you should suspect Addison’s disease when the cortisol level is below 100nmol/L
during the day. A cortisol level above 550nmol/L makes the diagnosis unlikely.

The investigations done in adrenocortical insufficiency are:

• Short ACTH stimulation tests. In this test, you try to assess the patient’s response to
tetracosactide (synthetic ACTH). You measure the baseline plasma cortisol, and then
you measure it again 2 hours after administering tetracosactide 250µg
intramuscularly. In normal individuals, the resulting cortisol level is usually above
550nmol/L. An absent or impaired cortisol response is diagnostic of adrenocortical
insufficiency. However, this test does not distinguish between Addison’s disease and
ACTH deficiency and iatrogenic suppression by steroids. Steroid drugs interfere with
the assay.
• 9am plasma ACTH level. This is usually high in primary adrenocortical suppression
(above 80ng/L). It is low in secondary causes.
• Antibodies. You can measure antibodies against 21-hydroxylase. These are positive
in autoimmune adrenalitis in 80% of cases.
• U&Es. These are used to assess for electrolyte imbalances. The classical picture is a
hyponatraemia, hyperkalaemia and a high urea level. However, these can be normal.
• Blood glucose. This may be low.
• Chest & abdominal X-ray. This is done to detect any evidence of past TB, such as
cavities, upper zone fibrosis and adrenal calcifications.

3
Postural hypotension & dehydration are spared in secondary adrenocortical insufficiency because ACTH
deficiency does not cause mineralocorticoid deficiency.

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Treatment
The management will depend on whether the presentation is acute or chronic.

Management of acute adrenocortical insufficiency

The main deficiencies are of salt, steroid and glucose. For management, you do the
following:

1. Give 1L normal saline over 30-60 minutes with 100mg intravenous hydrocortisone
bolus.
2. The patient will subsequently require several litres of normal saline over the
following 24 hours, coupled with 100mg of hydrocortisone intramuscularly every 6-
hours.
3. Glucose must be infused if there is hypoglycaemia.
4. Oral replacement medication is then started, unless the patient is unable to take oral
medication. Initially, you give hydrocortisone 20mg 8-hourly, and then reduce to 20-
40mg in divided doses over a few days.

Fludrocortisone is not necessary in the acute phase – it can be introduced later.

Management of chronic adrenocortical insufficiency

Long-term treatment of adrenocortical insufficiency requires glucocorticoid &

mineralocorticoid replacement. If TB is suspected/diagnosed, it needs to be treated.

1. Glucocorticoid – hydrocortisone 15-30mg daily in divided doses (e.g. 10mg on

waking up, 5mg at lunchtime and 5mg at 1800h4), or prednisolone 7.5mg daily (5mg
on waking up, 2.5mg at 1800h) or dexamethasone 0.75mg (0.5mg on waking up,
0.25mg at 1800h)
2. Mineralocorticoid – fludrocortisone 50-300µg daily. Mineralocorticoids are given to
correct the postural hypotension, hyponatraemia and hyperkalaemia.

Adequacy of glucocorticoid treatment is judged by: clinical wellbeing & restoration to

normal and normal cortisol levels during the day while on hydrocortisone (this cannot be
done with synthetic steroids). Adequacy of mineralocorticoid treatment is judged by:
correction of electrolyte derangements; blood pressure response to posture (should not fall
by more than 10mm Hg after 2 minutes of standing) and suppression of plasma renin
activity to normal.

The majority of patients are going to require treatment for life. Therefore, their education
requires the following:

• Know how to increase steroid replacement dose for intercurrent illness.

• Carry a steroid card.
4
Avoid giving in the evening as hydrocortisone causes insomnia.

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 • Wear a Medic-Alert bracelet.
• Keep an ampoule of hydrocortisone at home in case oral therapy is impossible for
administration by self, family or doctor.

Patients must come for annual follow-up for BP & U&E measurement. You should screen for
the development of other autoimmune diseases.

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 Management of HIV
HIV affects 37 million people worldwide, and the prevalence of the infection continues to
rise. However, the incidence is falling as a result of increased awareness of the disease and
increased use of protection during sexual intercourse. Furthermore, the mortality rate of
the infection has fallen mainly due to the use of ARVs. This means that HIV is turning into a
chronic disease rather than a terminal illness. Its management therefore requires long-term
maintenance of immunological function and routine screening of opportunistic infections.

Diagnosis of HIV
HIV diagnosis is included under HIV testing services (HTS), which encompass HIV testing,
counselling, and linkage to appropriate HIV prevention, treatment and care services. HTS is
guided by 6 core principles: consent, confidentiality, counselling, correct results, comfort for
the mother in labour and connection-linkage to care & prevention services. Delivery of HTS
can be done in facilities (clinics, hospitals, etc.), in the community (home-based testing) and
self-testing. Self-testing is now encouraged for first-time testers as some form of “screening
test”. Once a person tests positive, they need to be linked to a formal health facility, and if
they test positive there they can be linked to treatment & care.

Routine testing for HIV in children above 18 months, adolescents and adults makes use of
antibody tests which are both rapid tests. The 1st test that is conducted makes use of HIV
Determine® or SD Bioline®. The 2nd test is conducted using the Chembio or the First
Response test. The way in which HIV is confirmed is as follows:

• If the 1st test comes out negative, the patient is reported negative but encouraged to
return after 3 months for a retest.
• If the 1st test comes out positive, you conduct the 2nd test.
o If the 2nd test comes out positive, the patient is reported positive and
directed to treatment & care.
o If the 2nd test comes out negative, the results are discordant and then you
repeat the tests concurrently.
• if after repeating the 2 tests:
o The tests come out negative – you report the patient as negative.
o The tests come out positive – you report the patient as positive.
o The tests are discordant – you do a 3rd test (INSTI)
• If after doing the 3rd test:
o The result is negative, you report the patient HIV negative.
o The result is positive, the test is inconclusive – the patient is to return after
14 days for a retest.

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All patients diagnosed with HIV need to be linkage to prevention, treatment and care
services.

Antiretroviral therapy (ART)

ART has allowed people living with HIV to live for much longer than before with good
disease control. The regimens we use include:

• NRTIs (nucleoside reverse transcriptase inhibitors). They include zidovudine

(3TC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and
didanosine (ddl). Tenofovir (TDF) is a nucleotide reverse transcriptase inhibitor,
which has a better resistance profile.
• NNRTIs. They include efavirenz (EFV), nevirapine (NVP),
• Protease inhibitors. These include ritonavir (RTV/r), lopinavir (LPV), atazanavir
(ATV), indinavir, and many more. Usually, these agents are boosted with ritonavir
which is an enzyme inhibitor and thus allows lower doses to be used.
• Integrase inhibitors. These include raltegravir (RAL) & dolutegravir (DTG).
• Fusion inhibitors. These include maraviroc.

The common side effects to expect are:

• Tenofovir – renal disease (AKI & CKD), osteoporosis.

• Lamivudine is generally devoid of adverse effects.
• Efavirenz – neuropsychiatric side effects. These are more pronounced in patients
with pre-existing psychiatric conditions and a history of seizures. It can also cause
hepatotoxicity & gynaecomastia.
• Zidovudine – agranulocytosis with a pancytopaenia.
• Nevirapine – rash (Stephens Johnson syndrome), hepatitis.
• Abacavir – hypersensitivity reaction. This starts as a vague abdominal pain with
nausea & vomiting and progression to a rash. This condition has a 50% mortality
rate. You should stop abacavir and never recalling the patient.
• Protease inhibitors – GI side effects1. Atazanavir causes hyperbilirubinaemia, which
presents as a benign tinge of jaundice.
• Dolutegravir – minimal side effects, although research has proven them to be
teratogenic.

The effectiveness of ART relies on the efficacy of the regimen and adherence on the part of
the patient. The efficacy of ART depends on: potency of regimen chosen, minimal adverse
events, reduced pill burden, and accessibility & affordability of the medicines. Adherence
ensures that the medication is maintained at effective concentrations in the body so as to
suppress viral replication.

1
These are more pronounced with lopinavir.

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First-line regimen

The old regimen comprised of 2 NRTIs and 1 NNRTI, as having at least 2 drugs from different
classes improves efficacy of treatment. The common regimen used was tenofovir 300mg,
lamivudine 300mg and efavirenz 600mg (TDF/3TC/EFV), and efavirenz was now being rolled
out at 400mg due to the dose having less side effects. However, efavirenz is being replaced
by dolutegravir (DTG) 50mg due to the superior side effect profile. Tenofovir can be
exchanged for zidovudine, but zidovudine can cause fatal agranulocytosis as a side effect.
Tenofovir itself can cause renal disease (acute & chronic) and therefore it is replaced when
this happens. Efavirenz can be exchanged for nevirapine (particularly in the case of
neuropsychiatric side effects), although nevirapine causes rash and hepatotoxicity
particularly in individuals with higher CD4+ counts (>200 in men, >250 in women).

In patients starting on nevirapine in place of efavirenz, you start with a starter pack for 2
weeks. In the starter pack, tenofovir 300mg & lamivudine 300mg are given in the morning
while nevirapine 200mg is taken in the evening. After the starter pack is taken and no
adverse events develop, you step up to the maintenance dose. You then give tenofovir
300mg & lamivudine 300mg in the morning, and then give 2 dose of nevirapine; one 200mg
dose in the morning and another 200mg in the evening. If the patient had been on efavirenz
before, there is no need for the starter pack – you can start with the maintenance dose.

When you give zidovudine (300mg) in place of tenofovir, you give lamivudine at a dose of
150mg instead of 300mg. furthermore, zidolam (AZT/3TC) is given as a twice daily dose.

Second-line regimen

Second-line treatment should be considered only after assessing for adherence & failure,
and in consultation with a specialist team. There is no need for resistance testing because
NNRTIs have a low barrier to resistance and so the virus can easily become resistant to them
with single mutations. The barrier to resistance with PIs, however, is much lower.

Second-line treatment consists of 2 NRTIs and 1 PI standing in for the NNRTI. The usual PIs
used are ritonavir-boosted (with 100mg) lopinavir (LPV/r) 400mg or atazanavir (ATV/r). If
tenofovir was used in the 1st-line regimen, you replace it with zidovudine or abacavir 600mg.
When there is HIV & TB co-infection and the patient is receiving rifampicin, you can either
replace rifampicin with rifabutin, or you can double the dose of the PI. If patients have co-
infection with HBV, you need to always include tenofovir & lamivudine. ATV/r is taken once
daily while LPV/r is taken twice daily.

Third-line regimen

Those who require third-line treatment need confirmation of virus resistance prior to
initiation, because PIs have a high barrier to resistance and therefore if there is treatment
failure, it is more likely due to adherence issues or inappropriate dosing rather than
resistance.

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For PI-experienced patients, the third-line regimen requires dolutegravir 50mg and
darunavir(600mg)/ritonavir(100mg) twice daily. Raltegravir 400mg twice daily can be used
where dolutegravir is unavailable.

Initiation of ART
ART is initiated in patients with conclusive positive test results for HIV. ART initiation is a
cooperative process that also involves the patient, and it requires the patient to be in a
sound state of mind. Simply rolling out medication will not achieve the desired effects for
both parties. There are many aims of ART:

• Suppressing replication of the virus.

• Restoring & preserving immune function.
• Reducing morbidity & mortality from disease, including reducing incidence of OIs.
• Improve quality of life.
• Preventing vertical transmission through PMTCT.
• Preventing transmission by suppressing the virus in the patient – “treatment as
prevention”.

Early treatment initiation is associated with clinical & HIV prevention benefits and early
initiation is associated with lower morbidity & mortality from opportunistic infections even
in patients with apparently good virological control. Untreated HIV also increases risk of
non-communicable diseases such as cardiovascular disease, cancer, renal disease, hepatic
disease and neurocognitive disorders. Prior to initiation of ART, however, it is important to
retest patients, even those with prior confirmed HIV tests.

ART initiation entails the following:

1. History & examination. These need to be taken in full, and should include a detailed
social history.
2. Assessing readiness for ART. You need to discuss many issues with the patient.
These issues include:
a. The ARV regimen. The patient needs to be informed of the regimen they are
starting on. In the majority of cases, patients start on TDF/3TC/EFV, and this
can come as a fixed dose combination with all 3 medications taken once a
day.
b. The side effects of treatment. tenofovir
c. The requirement for monitoring.
d. The importance of adherence. Adherence is important, and patients must
continue taking ART for them to remain well. This is, however, improved
giving enough information about HIV, medications, expected adverse events,
3. Medical criteria for starting ART. All patients with confirmed HIV infection are
eligible for commencement of ART regardless of the WHO clinical stage.

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 a. As a priority, however, ART should be commenced in individuals with HIV
clinical disease (WHO clinical stage 3 or 4) or CD4+ ≤ 350 cells/mm3, or
individuals with active TB disease, pregnant/breastfeeding women,
individuals in discordant couples and HIV co-infection with chronic liver
disease.
b. Patients with CD4+ counts less than 100 cells/mm3 should be fast-tracked for
treatment initiation. They should be screened for symptomatic TB &
Cryptococcal meningitis and receive cotrimoxazole & isoniazid prophylaxis.
They should also be screened for TB or Cryptococcal IRIS (immune
reconstitution inflammatory syndrome). They should be encouraged to
report to healthcare facilities if they fall ill while their CD4+ count is still below
100.
4. Psychosocial criteria. The psychosocial criteria are as follows:
a. The patient should be adequately counselled & informed about ARVs.
b. The patient should have a treatment partner, and disclosure should be made
to the treatment partner.
c. There should be an easy way of following up on the patient.
d. The patient should be ready to take medications indefinitely.
5. Blood tests. The tests taken for patients when you initiate ART are:
a. CD4+. CD4+ count is important for 2 things. It helps ascertain the patient’s risk
of developing PCP, which can be avoided by giving cotrimoxazole prophylaxis.
It also helps predict the possibility of having subclinical TB or Cryptococcal
infection, which may then convert into an IRIS as the CD4+ count improves.
b. Full blood count. This is particularly important where zidovudine is to be
used.
c. Creatinine. This is done for patients in whom tenofovir is being started.
Tenofovir is known to cause renal impairment. Therefore, measuring
creatinine can be used to calculate the estimated GFR of the patient using the
Cockcroft-Gault equation.
𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑖𝑛 𝑘𝑔𝑠)
𝑒𝐺𝐹𝑅 = 𝑘 × (140 − 𝑎𝑔𝑒) ×
𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝜇𝑀)
Where k = 1.23 in males & 1.04 in females
Do not initiate tenofovir in a patient with an eGFR of less than 50mls/min.
Also avoid using tenofovir in patients with diabetes, uncontrolled
hypertension and chronic renal failure.
d. Blood pressure measurement.
e. ALT.
f. Screening for TB. A GeneXpert or a chest X-ray should be done for all patients
with a suspected cough. TB confirmed on sputum is more likely to be active
and is associated more with extra-pulmonary complications. A Mantoux test
can be done in children.

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 g. Pregnancy test.
h. Syphilis serology test.
i. Hepatitis B & C screen. HBV & HCV have got increased morbidity & mortality
in patients with HIV. They are more likely to cause chronic liver disease which
can evolve to cirrhosis and hepatocellular carcinoma. Furthermore,
concurrent HBV infection is going to affect the regimen2.
6. Initial monitoring visits. The patient should return every 2 weeks for the first 2
months, followed by once monthly for 3 months, followed by every 2 months
thereafter. After the first 6 months, the patient can be seen less frequently
depending on how stable they are.

A patient may defer ART if:

• The patient has Cryptococcal meningitis. In this case, ART is deferred for a month.
• The patient needs further psychosocial counselling.
• The patient has TB. In this case, ART is deferred for at least 2 weeks.
• The patient needs further information on HIV & AIDS.
• The patient is terminally ill and unable to swallow oral medication. Palliative care is
then offered to this patient.

Monitoring of treatment
The components of monitoring of treatment include:

• Treatment adherence. At every visit you need to ensure that the patient is taking
their medication. There needs to be a 95% adherence rate, which comes to a
defaulting rate of about 1 in every 30 days. You need to ask about adherence the
right way, i.e. ask how often they miss medication, and this is more likely to get you
more detail. Adherence is improved by providing accurate & adequate information
on the disease and possible side effects of medication. Also encourage them to bring
medication containers to each visit.
• Frequency of visits. Patients can be seen once every 2-3 months. If a patient is
stable, they do not need to be seen by a clinician. A stable patient is one in whom
the viral load is suppressed (<1000 copies/mL), there are no OIs and the patient has
been on ART for at least 6 months. If viral load is unavailable, the last CD4+ must
have been greater than 200cells/mm3. There are 3 types of visits:
o Clinical visit. This is a scheduled visit where the clinician makes a thorough
assessment and reviews monitoring blood tests. A stable patient should have
1 clinical visit every 6 months.
o Refill visit. This is a visit for collection of prescription medication (ARVs). This
does not require the presence of a clinician.

2
In HBV confection, tenofovir & lamivudine are to be included at all times.

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 o Unscheduled visits. This is a visit in-between refill or clinical visits made when
the patient does not feel well.
• Adverse medical events & medicine side effects. Patients should be monitored for
adverse effects of treatment. A thorough examination is required with each visit to
ensure there are no side effects developing. Screen for:
o Neuropsychiatric effects with efavirenz – hallucinations, abnormal dreams,
confusion, depression, convulsions. These tend to occur within the first
month. If symptoms do not settle, change to nevirapine.
o Metabolic abnormalities. Hyperglycaemia (diabetes) & hyperlipidaemia
should be anticipated with long-term use of ARVs. Check blood sugar levels &
lipid profiles with every CD4+ check or when clinically indicated.
o Anaemia. This is more marked with use of zidovudine. Check FBC after first
month using zidovudine.
o Lactic acidosis. This is common with most NRTIs. It is characterised by non-
specific symptoms, such as SOB, weight loss, hyperventilation, fatigue,
abdominal pain, vomiting and tachycardia. To screen for lactic acidosis, you
use bicarbonate as a surrogate marker. To treat it, stop ARVs and rehydrate
the patient, then restart ART with a tenofovir-based regimen.
o Lipodystrophy. This presents a cosmetic problem with long-term use of NRTIs.
• Screening for IRIS. IRIS (immune reconstitution inflammatory syndrome) is clinical
deterioration after commencing ART. It is due to the recovering immune system
interacting with latent infections. It is common in patients with very low (<50) CD4 +
counts on ART initiation. Common IRIS infections in Zimbabwe are TB, Cryptococcal
meningitis and recurrent herpes simplex infection. IRIS is not an indication for
stopping ART. Rather, the OI must be managed.
• Monitoring effectiveness of ART. This comprises of virological, immunological and
clinical. ART used to be monitored by routinely taking CD4+ count every 3 months.
This has since been superseded by routine viral load monitoring. In places where
viral load is unavailable, CD4+ counts are taken every 6 months.
o Clinical monitoring. This can be done subjectively at every clinical visit by
looking at how the patient has improved if they were ill. Infections to look at
include oral thrush, hairy leukoplakia, genital herpes, skin rash, molluscum,
chronic diarrhoea, KS, etc. It also includes other indices like a sensation of
well-being, gaining weight. In children, growth & development monitoring
are important. You should also check for neurologic symptoms, particularly
depression.
o Virological monitoring. Viral load testing is now the gold standard for
monitoring response to ARVs. It provides an earlier & more accurate
indicator of treatment failure when compared to clinical & immunological
monitoring. In a patient who is 95% adherent to treatment, viral load should
decrease by log10 after every month. Generally as a rule, after initiation of

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 ART the viral load should decrease to undetectable levels in 6 months. Viral
load should be done every 6 months after ART initiation for the first year and
then every 12 months afterwards. 70% of patients that are adherent to ART
should have virological suppression on 1st-line.
o Immunological monitoring. The rate of increase in CD4+ count depends on
the initial CD4+ count. This was the major drawback of using CD4+ to assess
clinical status, because it does not reflect how well the patient is responding
to ART. CD4+ count, however, predicts the likelihood of developing certain
OIs. Persistently declining CD4+ counts are suggestive of clinical failure.
• Sexual partners. Ask if the patient has a sexual partner. If they do, ask if they know
about the patient’s HIV status, if they know their own HIV status and if they use
condoms.

Treatment failure
Treatment failure is defined clinically, virologically and immunologically.

• Clinical failure is the appearance of a new or recurrent condition indicating severe

immunodeficiency (WHO clinical stage 4 diseases) after 6 months of effective
treatment. In children, WHO clinical stage 3 diseases (except TB) are included.
• Immunologic failure is when CD4+ count falls to below baseline or persists below
100cells/mm3 in children above 5 years, adolescents and adults. In children below 5,
you use CD4+ percentage – if it is below 10% (or 200cells/mm3), it is immunologic
failure.
• Virological failure is a viral load reading above 1000 copies/ml on 2 consecutive
readings taken more than 3 months apart in a patient who has been on ART for at
least 6 months and has had been adherent to therapy.

Before switching ART regimens, you need to ensure that the patient has been adherent to
medication. Adherence is affected by:

• Failure of adherence, which occurs in 90% of cases. This must be probed, as it may
be due to certain stresses in the patient’s life. Adolescents are the ones who are
more likely to experience this.
• Inadequate dosing. This is common in patients on TDF/3TC who switch to AZT/3TC
who are not informed that they are changing from a once-daily dosing regimen to a
twice-daily dosing regimen.
• Hyperemesis following dosing. This may be the case in pregnant women, and
therefore pregnant women need to be asked about hyperemesis. Hyperemesis
reduces the effective dose that is working in the patient.
• Sexual reinfection. This happens when 2 HIV-infected individuals have unprotected
intercourse. There is a high likelihood of a resistant strain being transmitted to the
patient which then fails to respond to treatment.

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• Drug-drug interactions. This happens particularly in patients on TB treatment and is
more pronounced with protease inhibitors.

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 Malaria
Malaria is a tropical disease caused by infection by Plasmodium parasites, which belong to
the group of coccidian/sporozoan parasites of blood cells. About 400 million across the
world are infected with malaria annually, and about 1 million of these patients die. 85% of
cases of malaria occur in sub-Saharan Africa, and this is where the majority of deaths occur
too. In most developed countries, malaria has been eradicated, and infection now comes
from migrants to these countries. In Zimbabwe, the majority of cases are found in
Manicaland, Mashonaland East and Mashonaland Central. The estimated incidence of
malaria in Zimbabwe was 675 000 in 2016, and the number of deaths was estimated to be 1
700. 79% of the population is exposed to malaria, with 29% living in high-transmission areas.
The groups at risk of developing malaria are children & pregnant women.

Parasitology
There are 5 Plasmodium species – P. falciparum, P. vivax, P. ovale, P. malariae and P.
knowlesi. The most virulent organism amongst these is P. falciparum, and it is also the most
common cause of death from malaria (the others rarely cause severe malaria). P. falciparum
is most commonly found in sub-Saharan Africa, while P. vivax is the most common form
found in Asia1. Plasmodium species are spread by female mosquitoes. Depending on the
region in question, there are different mosquito species that spread the infection. In
Zimbabwe, female Anopheles mosquitoes are the most common cause of spread of
infection. 2 species of Anopheles mosquito found in Zimbabwe are A. gambiae & A.
fenustus.
The life cycle of malaria consists of 3 phases – the sporogonic cycle, the exo-erythrocytic
cycle and the erythrocytic cycle:
The exo-erythrocytic cycle occurs in the liver.
1. Human infection occurs after a mosquito has deposited the infectious agents (called
sporozoites) into the circulation through its saliva.
2. The sporozoites are carried to the parenchymal cells of the liver, which they infect. In
the liver, the sporozoites can follow one of 2 routes:
a. They can reproduce asexually as merozoites and form what is called a
schizont. All malaria species can do this.
b. They can enter a dormant phase and form what is called a hypnozoite. P.
vivax & P. ovale can enter these forms. These can cause relapse of infection
months or years later.
3. The schizonts rupture, releasing merozoites into the circulation, thus allowing the
erythrocytic phase to occur.
The erythrocytic phase occurs in red blood cells.

1
P. vivax is the most prevalent parasite on the globe.

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 4. The merozoites enter red blood cells using specific membrane receptors. P.
falciparum & P. knowlesi infect reds cells at any stage of development. P. vivax & P.
ovale attack reticulocytes & young cells. P. malariae tends to attack older cells.
5. They then enter a series of replicative cycles and go through numerous stages – the
ring stage, the trophozoites stage and the schizont stage. This allows the formation
of a schizont with up to 24 merozoites in it. On a peripheral film, P. falciparum
schizonts & trophozoites are only seen in heavy parasitaemia, as the majority are
sequestered in the liver & spleen.
6. Rupture of the red cell leads to release of these merozoites, which then enter the
circulation and initiate the erythrocytic stage again.
The sporogonic stage is the process by which gametes are formed which are then taken up
by the mosquito for spread elsewhere.
7. Some merozoites develop into male & female gametes within red cells instead of
replicating.
8. After a mosquito blood meal, these gametes are taken up into the mosquito and
within the mosquito’s salivary glands they fuse to form a zygote.
9. The zygote then develops into an oocyst which contains numerous sporozoites.
These are then released into another host in the next blood meal when the oocyst
ruptures.

Pathophysiology
The clinical effects of malaria infection are a result of haemolysis, cytokine release and
impairment of the microcirculation.

• Anaemia. Anaemia in malaria is multifactorial:

1. Haemolysis occurs as a result of bursting of red cells. The haemolysis is
multifactorial. Infection with Plasmodium organisms makes the red blood cell
membranes more rigid, thus making them easier to lyse. Furthermore, non-
infected red cells can also be haemolysed, and this gives rise to black water
fever.
2. Red cells are sequestered in the liver & spleen.
3. Folate depletion in red cells.
4. Dys-erythropoiesis.
• Cytokine release. Cytokine release is a result of toxin release from ruptured red cells.
Cytokine release is responsible for the systemic effects of infection such as fever. The
implicated toxin is haemozoin, which is a product of digested haem (free haem is
toxic to the parasite) and is crystallised to form a pigment. This pigment leads to
overproduction of TNF-α, IFN-γ and IL-1. Cytokine release coincides with schizogony,
where there is widespread rupture of schizonts & release of haemozoin. This
accounts for the cyclical fever characteristic of malaria.
• Impairment of the microcirculation. The parasites digest membrane protein
elements and this leads to the creation of knobs on the membrane. These knobs
cause infected red cells to attach to non-infected red cells, leading to stacking of

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 these red cells (called rosetting). Rosetting leads to clogging up of capillaries and
therefore impairment of the microcirculation. This is the major mechanism
associated with organ damage. The antigens thought to be processed by the parasite
include blood group antigens A & B2, CD36, complement receptor 1, and HS-like
GAGs.
Patients can develop antibodies against the parasite after exposure. However, the
hypergammaglobulinaemia that follows infection is polyclonal and only a small percentage
of the antibodies are directed against the parasite. Patients living in endemic areas will have
high anybody levels in their circulation, but will not necessarily be immune to infection. T-
cells are also vital in defence against the parasite, and this is why pre-existing HIV infection
predisposes to progression to severe malaria. There is a considerable increase in
macrophage phagocytic activity when the parasites begin to decrease in number. With each
infection, some memory is retained such that with each subsequent infection with the
parasite, the clinical course of disease is shorter and less severe. This is called premunition.
Premonition, however, is affected by repeated re-exposure.

Risk factors of infection

The risk factors for infection with malaria are:

• Travel to an endemic area. People who live in non-endemic areas are not protected
against malaria infection because of lack of immunity, and therefore are more likely
to develop infection when exposed.
• Age. In endemic areas, infections are more common in children aged 2-5 years, and
these are more likely to be severe. This does not go to say that adults from these
areas do not develop severe disease.
• Pregnant women. Pregnant women are prone to severe disease. many factors
contribute, such as sequestering of parasites in the placenta, hypoglycaemia,
anaemia, etc. The major consequences are severe anaemia in the mother and low
birth weight infants.
• Lacking the Duffy antigen. Lacking the Duffy antigen on the membrane of red cells
has been shown to be protective against developing P. vivax malaria infection.
• Haemoglobinopathies. Patients with sickle cell anaemia are protected from
developing malaria. Furthermore, patients with the sickle cell trait (heterozygous for
the sickle cell allele) are less likely to develop malaria than patients without the trait
(homozygous normal)3.
• HIV. HIV decreases T-cell mediated immunity to infection. Therefore, in patients who
are immunocompromised, malaria is more likely to progress to becoming a severe
infection. Malaria has also been shown to enhance the course of HIV infection
(enhanced viral replication & high viraemia).
• Splenic sequestration. The size of the spleen has been seen to correlate to the
number of antibodies produced. This means that children with larger spleens are
2
Rosettes formed in blood groups A & B are larger, tighter and stronger than those formed in blood group O.
3
This accounts for the persistence of these alleles in West Africa and other sickle cell & malaria endemic areas.

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 protected more against malaria. Patients with splenectomise are at risk of
developing severe/overwhelming infection.

Clinical features of malaria

The clinical features of malaria are:
History
Patients present with the following symptoms:

• Fever. The fever may be continuous or erratic, but it later becomes cyclical, occurring
every 48 hours (tertian fever) or 72 hours (quartan fever). There are generally 3
phases of the fever paroxysm: shivering, hot stage (temperature about 41°C
associated with rigors) and sweating stage.
• General malaise.
• Headache.
• Nausea & vomiting.
• diarrhoea
Other things to look for in the history:

• Recent history of travel (within 1 month) to endemic area.

• HIV status.
• Pregnancy status.
• Haemoglobinopathies.
• Previous treatment for malaria.
Examination
On examination, you will find:

• General: febrile patient, who is pale, but with no rash and no lymphadenopathy.
• Abdomen: hepatosplenomegaly. This may be tender.
• Nutritional status. This is important for children.

Clinical syndromes
The clinical syndromes produced by different Plasmodium infections are:

• P. falciparum malaria. This often produces a malignant tertian fever. Patients

present with paroxysms of fever, headache, nausea & vomiting, general malaise and
diarrhoea that occur every 48 hours. This infection is also called malignant tertian
fever, because P. falciparum often becomes sever when it is left untreated. Most
deaths from malaria are from P. falciparum. P. falciparum also has a short incubation
period of 7-10 days. Cerebral involvement is more common with P. falciparum.
• P. vivax & P. ovale malaria. These produce similar infections. They cause benign
tertian fever, with a longish incubation period (10-17 days). The infection is mostly
limited to fever paroxysms that remain relatively mild. Severe attacks entail hours of

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 exhaustion, high fever, sweating, chills and shaking. Relapses & recurrences of
infection can occur many months & years later.
• P. malariae malaria. P. malariae has the longest incubation period (18-40 days). It
produces quartan malaria which comes every 72 hours. The infection is generally
mild, and it can persist for up to 20 years without intervention.
• P. knowlesi malaria. This infection is common in Old World monkeys and has also
been termed simian/quotidian malaria. The parasite has a short life cycle of 24
hours, and therefore produces quotidian symptoms. It presents with the typical
symptoms. However, 7% of cases can progress to severe infection, and the most
common complication is respiratory distress.

Complications of malaria
The complications of malaria are mostly related to its microvascular occlusive phenomena
secondary to rosetting of red blood cells. Other mechanisms include direct toxic effects of
haemoglobin (particularly with renal disease). The complications of malaria are:

• Cerebral malaria. Cerebral malaria is a result of occlusion of the cerebral

microvasculature by red blood cell rosettes. Cerebral malaria is marked by the
presence of a confusion/coma with seizures. There is often confusion as a preceding
feature. The neurological sequelae of cerebral malaria are usually reversible in
adults, but they persist in 5-30% of children. However, prolonged seizures (more
than 3 convulsions in 24 hours) carry a poor prognosis. Patients may develop
posturing, such as opisthotonos or decorticate/decerebrate rigidity. This is also
common in children.
• Renal injury. Haemoglobinuria can occur when there is overwhelming free
haemoglobin in the circulation. Haemoglobin is toxic to the renal tubules and
therefore malaria can cause acute tubular necrosis. Patients develop uraemia with
accumulation of creatinine (>250µM). Renal injury should be suspected in black
water fever (where a patient presents with Coca Cola coloured urine).
• Severe anaemia. This results from excessive haemolysis caused by a high
parasitaemia. Excessive haemolysis also leads to clinical jaundice, and jaundice is
more common in adults. Dys-erythropoiesis also contributes to the anaemia.
• Thrombocytopaenia. Thrombocytopaenia results from disseminated intravascular
coagulation. This leads to consumption of platelets, which predisposes to mucosal
bleeding such as epistaxis & abnormal uterine bleeding. Retinal haemorrhages can
also occur. Bleeding & clotting disturbances are more common in adults and are rare
in children.
• Hypoglycaemia. This comes from consumption of body sugar by the parasite.
Hypoglycaemia is more likely in children.
• Acute respiratory distress syndrome. Patients with malaria may present with
acidotic breathing and/or acute pulmonary oedema.
• Metabolic acidosis.

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 • Shock. Shock can be hypovolaemic, which comes from excessive vomiting &
diarrhoea. it can also be due to superimposed Gram-negative sepsis.
Complications of malaria warrant its classification as severe malaria and are a medical
emergency.

Investigations
The diagnostic investigations done for malaria are:

• Rapid diagnostic test (RDT). This is a quick easy-to-conduct point-of-care test that
tests for malaria antigens. The antigen detected by RDTs is the histidine-rich protein
2 (HRP2), although some tests can also detect Plasmodial lactate dehydrogenase
(PLDH) and aldolase. The only drawback of the RDT is that it can only detect
falciparum malaria and not the other species.
• Peripheral smear microscopy. This is the gold standard for diagnosis of malaria, and
it makes use of Giemsa staining of a thick & thin smear. It is often done in tertiary
institutions. However, it requires expertise in determining aetiology, and it is time
consuming when case loads are high. The thick smear is used for determining
parasitaemia (quantitative/sensitivity testing) while the thin smear is used for
speciation (qualitative/specificity testing). At least 3 films should be examined before
malaria is declared likely. Parasitaemia above 10% in adults suggests severe
infection. In children, it is above 5% in non-endemic areas and 7% in endemic areas.
Generally, RDTs are done as first line for all suspected malaria cases. However, microscopy is
used for: all patients admitted for malaria (to improve follow-up); confirming co-infections;
those with a recent travel history to areas where other species are reported; suspected
treatment failure; and patients who have received treatment within the preceding 2 weeks.
Other optimisation tests conducted include:

• Full blood count. This is to check for anaemia and thrombocytopaenia. Anaemia is
diagnosed by a haemoglobin level below 5.5g/dL for patients coming from endemic
areas or below 7.5g/dL for patients coming from non-endemic areas. Leukocytosis
can also be suggestive of superimposed infection.
• Urea & electrolytes. This is used to screen for renal impairment. Renal impairment
can also be screened for using urinalysis.
• Liver function tests. You first want to check for bilirubin levels, and if there is
hyperbilirubinaemia, establish whether it is conjugated or unconjugated
hyperbilirubinaemia. Patients with hepatic injury can also get a transaminitis.
• Arterial blood gases. This is used to check for metabolic acidosis. Acidosis is defined
by a pH of less than 7.25 with a plasma bicarbonate below 15mM.
• Chest radiography. Pulmonary oedema can be seen on a chest radiograph.
• Blood glucose measurement. This can be done using POCT glucometer strips.
Hypoglycaemia is indicated by a glucometer reading below 3.4mM.
• Blood culture. This is done to rule out septicaemia.

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Management
Firstly, you want to stabilise the patient, and in the process establish whether the patient
has severe malaria or uncomplicated malaria. Severe malaria is malaria confirmed on
RDT/peripheral smear with complications. Management of malaria is divided into treatment
of complicated (severe) and uncomplicated malaria.
Treatment of uncomplicated P. falciparum malaria
Artemisinin-based therapy is used for P. falciparum as there is widespread chloroquine
resistance in the country.

• The 1st-line agent used is coartemether, which is a combination of artemether &

lumefantrine. Each tablet of coartemether contains 20mg of artemether and 120mg
of lumefantrine. Adults take 4 tablets stat on the first day4, followed by 4 tablets 8
hours later. They then take 4 tablets twice daily for the following 2 days. The patient
must improve. If there is no improvement after 48 hours, do a peripheral film and
screen for treatment failure before giving 2nd-line treatment.
• The 2nd-line regimen used is ASAQ, which is a combination of artesunate and
amodiaquine. Each tablet contains 25mg of artesunate and 67.5mg of amodiaquine
base (or 50mg artesunate + 135mg amodiaquine, or 100mg artesunate + 270mg
amodiaquine). In adults, you give 2 tablets of 100mg artesunate & 270mg
amodiaquine twice daily for 3 days. If there is a weight-age disparity, the weight
should be used. If there is no improvement after 48 hours, the patient vomits
repeatedly or symptoms progress, treat as severe malaria. Do not co-administer
ASAQ with efavirenz5, and should be administered with caution in patients taking
zidovudine as they both pancytopaenia.
• The alternative 2nd-line regimen is oral quinine with doxycycline/clindamycin.
Quinine is given at a dose of 600mg 3-times daily for 7 days. Doxycycline is given at a
dose of 100mg once daily for 7 days. Clindamycin is given at a dose of 300mg 3-times
daily for 7 days. Clindamycin is used in place of doxycycline for children below 8
years of age and pregnant women.
• Uncomplicated malaria in elimination areas (where malaria is close to eradication) is
treated by adding a gametocidal agent such as primaquine to the artemisinin-based
regimen. However, primaquine should be used with caution in patients with G6PD
deficiency. To avoid significant haemolysis, you give 0.25mg/kg stat for one day to:
children above 1 year, children above 10kg and women who are not pregnant. The
standard dose of primaquine is 0.75mg/kg body weight as a stat dose. Primaquine is
contraindicated in: patients with severe malaria, pregnant & breastfeeding women,
patients with G6PD deficiency, pallor or existing anaemia (<8g/dL), patients on
haemolytic medication, patients that are on medications that suppress the bone
marrow, and patients on zidovudine.

4
If the stat dose is vomited out, repeat it. If vomiting persists, treat as severe malaria.
5
The combination therapy, not artesunate alone.

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The artesunate-based regimens should not be used in the 1st trimester of pregnancy.
Treatment of uncomplicated non-falciparum malaria
The treatment of uncomplicated non-falciparum malaria includes cure of the disease as well
as eradication of latent infection (for P. vivax & P. ovale). P. malariae & P. knowlesi are
treated as P. falciparum. For patients with P. vivax & P. ovale, you give artemisinin
combination therapy as with P. falciparum, but you combine it with primaquine 0.25mg/kg
taken with food once daily for 14 days in patients without G6PD deficiency. If patients have
G6PD deficiency, you give primaquine 0.75mg/kg once weekly for 8 weeks. If the G6PD
deficiency is severe, do not use primaquine.
Treatment of severe malaria
Severe malaria is a medical emergency. Patients require a rapid assessment:
1. Check that the airway is patent. Provide manual/assisted ventilation in the case of
inadequate breathing.
2. Provide oxygen for children with suspected hypoxia or saturation below 90%.
3. Patient must be nursed in the left lateral position with frequent turns and
catheterisation (to prevent retention & bed wetting).
4. Correct hypoglycaemia – 200-500mg per kg of glucose followed by 5% or 10%
dextrose solution through a peripheral line.
5. Convulsions are treated using diazepam 0.3mg/kg as a slow bolus over 2 minutes or
0.5mg/kg rectally. Diazepam is repeated if seizure does not stop after 10 minutes. If
after 2 doses seizures persist, the patient is in status epilepticus: give phenytoin
18mg/kg loading dose followed by 5mg/kg/day for 48 hours. Alternatively, you can
give phenobarbitone 15mg/kg im/slow iv stat followed by 5mg/kg/day for 48 hours6.
6. To maintain fluid balance in patients unable to take fluids orally, give fluids
intravenously at a rate of 3-4ml/kg/h.
7. Transfuse blood to correct severe anaemia.
8. To deal with the fever, give an antipyretic – paracetamol 15mg/kg every 4 hours to
keep rectal temperature below 39°C.
After the initial management, you treat the severe malaria:

• The 1st-line management is injectable artesunate given at a dose of 2.4mg/kg (or

3mg/kg if body weight is 30kg or less). This can be given intravenously or
intramuscularly, and the intramuscular formulation is usually more concentrated
than the intravenous formulation. You give 3 doses: the 1st one as you meet the
patient (hour 0), the 2nd one at hour 12 and the 3rd one at hour 24 (24 hours after 1st
dose). When the patient can take oral medication, give them a full 3-day course of
coartemether. The first dose of coartemether should be taken 8-12 hours after the
last dose of artesunate. If after 3 dose the patient is unable to take oral medication,
continue with artesunate injections, and give once daily for a maximum of 7 days.

6
Phenobarbitone requires monitoring for respiratory depression, which may require ventilator support.

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 • Intravenous quinine can be used if artesunate is unavailable. It is also the first choice
in children under 5 and pregnant women. Give a loading dose of 20mg/kg diluted in
500ml of 5% dextrose/normal saline over 4 hours, and then after 8 hours give
10mg/kg diluted in 500ml of 5% dextrose7/normal saline over 4 hours. Ensure that
you monitor glucometer readings every 4 hours. If blood sugar is less than 3.4mg,
give 20ml of 50% dextrose diluted with water for injection at a ratio of 1:1 and give
2ml/kg. once the patient can take oral medication, give doxycycline 100mg once
daily or clindamycin 300mg 3-times a day for 7 days.

7
10% dextrose is preferred to ameliorate hypoglycaemia.

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 Viral hepatitis
Viral hepatitis is one of the commonest causes of liver disease in the world. The leading
causes of viral hepatitis are traditionally known as the hepatitis viruses (hepatitis A-E). These
viruses are not genetically similar, but are grouped together due to their primary tropism
for the liver. The 5 viruses that constitute viral hepatitis are divided into the enteral &
parenteral viruses. The enteral viruses are hepatitis A & E, while the parenteral ones are
hepatitis B, C and D.

Hepatitis A
Hepatitis A is caused by the hepatitis A virus (HAV). It is the most common viral hepatitis
occurring worldwide, often occurring in epidemics. It causes about 40% of cases of acute
hepatitis. In western countries, however, its incidence is declining. It is mainly spread
through the faecal-oral route, and it. The disease mainly affects children & young adults.

The risk factors for acquiring hepatitis A virus are:

• Close contact with person with similar symptoms.

• Institutionalisation.
• Occupation (particularly in a day-care centre).
• Living in overcrowded areas with poor water & sanitation.
• Intravenous drug users.
• Foreign travel.
• Homosexuality.
• Patients with chronic liver disease.

Hepatitis A virus (HAV)

HAV belongs to the family of Picornaviridae viruses, to which enteroviruses, rhinovirus and
cardiovirus belong – they are all spread by the faecal-oral route. HAV belongs to the
hepatovirus genus. HAV is a small unenveloped positive-sense single-strand RNA virus, and
it has a diameter of 27nm. It is taken up by the GIT and then transported to the liver, where
it replicates slowly.

Pathogenesis

The viral infection itself does not produce cytological changes that are toxic to cells. Rather,
it is the immune reaction that causes disease. IgM antibodies can be detected with the
onset of symptoms. Histologically, there is a portal & periportal lymphocytic infiltrate, with
periportal necrosis.

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The virus has an incubation period of 2-6 weeks. The period of greatest shedding of the virus
is during the anicteric prodrome phase (0-2 weeks), during which there are no symptoms.
During this period as well, the virus appears in faeces. Liver transaminase levels rise just
before symptoms begin.

Clinical features

Patients initially present with non-specific features such as nausea & vomiting, anorexia and
develop distaste for cigarettes. This is the prodromal phase. Jaundice usually develops later
after 1-2 weeks (it is common in adults but is rare in children) and it is usually preceded by
dark urine and pale stool1. This is called the icteric phase. In the icteric phase, there may
also be abdominal pain, itching, arthralgia and a skin rash. If nausea, vomiting or any mental
confusion persists, the patient requires assessment at a hospital.

On examination, patients will be jaundiced once they are in the icteric phase. Hepatomegaly
is common, and splenomegaly occurs in 10% of cases. You should always remember to look
for features of chronic liver disease and rule out features of decompensation.

Majority of infections are self-limiting. A small proportion of individuals develop fulminant

hepatitis

Complications

The complications of acute HAV infection include arthritis, vasculitis, myocarditis and AKI.
Chronic liver disease does not occur.

Investigations

The investigations done in suspected HAV infection are:

• Liver function tests (LFTs). There is a transaminitis which begins prior to the
appearance of jaundice, but still occurs 22-40 days after exposure. Nonetheless, AST
levels peak 1-2 days after onset of jaundice and may rise above 500U/L.
Transaminase levels return to normal after 5-20 weeks.
• Serological tests. IgM rises from day 25 post infection, and indicates recent
infection. IgG persists for life.
• Faecal tests. You can do direct RT-PCR on faeces, and this tests positive sooner than
serological tests.
• Other blood tests. FBC will reveal a relative lymphocytosis. There may also be
anaemia (rare) from either Coombs’ test-positive haemolytic anaemia or from
aplastic anaemia. PT is prolonged in severe cases, and ESR is raised.

1
This is due to intrahepatic cholestasis.

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 • Ultrasound. This is done when an alternative diagnosis is suspected, to assess vessel
patency and to assess for underlying chronic liver disease. It is also essential in
patients with fulminant hepatic failure.

Management

Treatment of acute HAV hepatitis is supportive. Admission is usually not necessary, unless in
fulminant cases in which you administer interferon-α.

You can immunise susceptible patients using Havrix Monodose®, which is an inactive
protein derived from HAV. You give 1ml intramuscularly, and this give immunity for 1 year
unless a booster is given at 6 months (which prolongs immunity to 20 years). You can give
Havrix Monodose Junior® to children aged 1-15 years. The vaccine is administered to people
travelling to endemic regions, patients with chronic liver disease, haemophilia patients and
workers who frequently contact hepatitis cases. If exposure will be in less than 2 weeks, you
give normal human immunoglobulins (0.02ml/kg intramuscularly).

Hepatitis D
Hepatitis D is caused by the hepatitis D virus (HDV). Due to defects in HDV, it requires HBV
for its infection, replication and spread and therefore exists as co-infection. About 15 million
people worldwide are living with HDV. HDV is spread through blood, semen and vaginal
secretions. However, it can only establish infection and replicate in individuals with
concurrent HBV infection.

Hepatitis D virus

HDV belongs to the Deltaviridae family of viruses. It is a negative-sense single-stranded

enveloped RNA virus. However, the virus is defective in that its genome does not encode for
its own envelop antigens. Rather, it requires the HBV surface antigens. Therefore, it cannot
replicate in the absence of HBV, and it travels together with HBV. It contains a delta antigen
which surrounds its genome, and this is surrounded by the viral coat.

The virion infects hepatocytes using the envelop HBsAg. HDV is peculiar, however, in that it
utilises the host cell’s RNA polymerase II to make its mRNA. Replication of the delta agent
results in cytotoxicity & liver damage. It is the direct cytopathic effect of HDV that leads to
damage.

Clinical syndromes

HDV infection can occur in 2 situations:

• Co-infection. Patients can get infected with both HDV & HBV at the same time. This
is clinically indistinguishable at the time. However, a biphasic transaminitis may be

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 seen. IgM anti-HDV antibodies are seen at 1 week and disappear after 5-6 weeks
after the IgG antibodies appear.
• Super-infection. Infection with HDV in a patient with chronic HBV without previous
exposure to HDV may produce an acute flare up of hepatitis.

HDV leads to a more complicated HBV infection: it hastens the progression to cirrhosis,
increases the incidence of fulminant hepatitis and increases development of hepatocellular
carcinoma.

Diagnosis

HDV can be detected by measuring HDV-RNA in serum, the delta antigen and anti-HDV
antibodies. You can order HDV tests in a patient who is HBsAg positive.

Treatment

There is no definitive treatment available for HDV. There is no enzyme in HDV that can be
blocked by drugs, as HDV predominantly depends on the host enzyme machinery to
replicate. You can try to control the HBV, and pegylated interferon-αs been shown to have
some anti-HDV activity. Liver transplantation may be needed in some cases.

Hepatitis E
Hepatitis E is caused by Hepatitis E virus, which is an enteral virus. It is common in
developing countries, and it occurs in epidemics in India, China, Pakistan, Nepal, Burma,
North Africa and Mexico. It is more common in men than women. In the UK, it is commoner
than hepatitis A.

Hepatitis E is its own unique virus, although it resembles caliciviruses in its size (27-34nm)
and structure. It is an RNA virus. It is transmitted through the faeco-oral route, and 30% of
dogs, pigs and rodents are carriers of the virus. Epidemics can occur in developing countries.
In developed countries, it occurs in sporadic cases, especially in individuals with a travel
history to a developing country or those in contact with farm animals.

It follows a course similar to that of hepatitis A: it has an incubation period of 15-50 days
and usually causes mild disease with an abrupt onset. However, symptoms appear later
than in hepatitis A. It has a mortality of 1-2% from fulminant hepatitis2. However, it can be
severe during pregnancy – its mortality in these patients is 20%. It can be diagnosed using
ELISA for IgG & IgM antibodies. It is treated by supportive treatment.

2
Hepatitis A has a mortality of less than 0.5%.

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 Hepatitis B
Hepatitis B is caused by hepatitis B virus (HBV). Hepatitis B is one of the leading causes of
mortality around the world. 350-400 million people worldwide are carriers of the HBV virus,
and 0.5% of carriers spontaneously seroconvert worldwide (this is higher in countries where
HIV is a problem). The incidence of HBV is highest in sub-Saharan Africa, South-east Asia and
South America, where prevalence rates are higher than 8%.

HBV is a very contagious virus. It is spread by sexual transmission, contact with body fluids,
blood products and intravenous drug use. The risk factors for development of hepatitis B
infection are:

• Having multiple sexual partners.

• Concurrent HIV infection. This increases the risk of seroconversion and it hastens
development of complications.
• Having multiple transfusions. These are usually screened for hepatitis B, but the
patient is still at risk of contracting infection.
• Intravenous drug abuse. The methods used are not exactly “sterile”.
• Occupation. Healthcare workers are at risk of contracting HBV, since they come into
contact with fluids at multiple occasions.
• Vertical transmission. The risk is therefore increased in children whose mothers are
infected with HBV. Mothers living with HIV should also be screened for virus. This is
the leading cause of infection in highly-endemic areas.

Hepatitis B virus
HBV is a double-stranded enveloped DNA1 virus belonging to the Hepadnaviridae family. It
has an average diameter of 42nm. There are 8 serotypes, and each serotype is distributed in
a distinct geographical region. These serotypes have differences in their rate of
seroconversion as well as chronicity. The virion (also called a Dane particle) has a viral
envelope, which contains a surface antigen (HBsAg), and a capsid formed by the core
antigen (HBcAg). Within the capsid there is also an e antigen (HBeAg) which is sequentially
similar to HBcAg but is processed differently by the cell. The virion includes a protein kinase
and a reverse transcriptase.

The replication of HBV is special in that it replicates through an RNA intermediate and it
release HBsAg particles as decoy particles. The mechanism through which it infects
hepatocytes is not well understood. The viral DNA genome is delivered to the nucleus. The
viral genome does not incorporate into the hepatocyte DNA during replication because it

1
This is the only hepatitis virus that has a DNA genome.

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lacks integrase activity (unlike HIV)2. It is then transcribed into different overlapping mRNA
molecules, producing 3 major classes (comprising of 2100, 2400 and 3500 base pairs) and 2
minor classes (900 base pairs each). The larger 3500bp molecule is transcribed into HBcAg &
HBeAg, the polymerase and a protein primer for DNA replication. The 3500bp molecule is
larger than the genome and it is used to form the genome. It is used as a template, and a
negative-sense single-strand DNA molecule is formed. The viral genome is then assembled
with the nucleocapsid & envelop and released from the cell by exocytosis rather than lysis.

Pathogenesis
Replication of HBV within hepatocytes leads to expression of the different HBV antigens.

• The surface antigen HBsAg is released into the serum of infected people, most as
HbsAg-rich particles that are not complete virions. These particles are more
numerous than the actual virion particles. These particles are also very
immunogenic. Antibodies developed against HBsAg (called anti-HBs) imply the
patient has been exposed either to HBV or to the vaccine.
• The core antigen HBcAg is incorporated into the viral capsid. Antibodies developed
against HBcAg (called anti-HBc) imply that there is minute persistence of the virus in
the circulation. The IgM anti-HBc implies acute infection or reactivation, whereas IgG
anti-HBc implies chronic infection. The activity of disease cannot be understood
using this antibody alone, however.
• The e antigen HBeAg is released during active replication of the virus. It therefore
indicates active infection that is replicating. The presence of this antigen also
indicates high infectivity. Antibodies to HBeAg (called anti-HBe) indicate
seroconversion with HBV, or a non-replicative state in a patient with negative HBV-
DNA.

The disease is not a result of any destructive effects of the virus, which itself is not
destructive. Rather, it is the resulting inflammatory reaction that causes disease. HBV-
specific cytotoxic T-cells recognise the viral antigen via MHC class I molecules expressed on
infected cells. Regulatory T-cells, however, limit the inflammatory reaction, and this allows
the HBV genome to persist and develop into a chronic infection.

Chronic HBV infection goes through 2 stages:

• Replicative phase. The replicative phase is characterised by active viral replication &
hepatic inflammation. Both HBsAg & HBeAg are present in the circulation and the
patient is HBV-DNA positive. During this stage, the patient is very infectious, and
there is significant hepatocyte damage leading to a transaminitis.

2
However, it can be integrated into the host genome, and this has been found in hepatocellular carcinoma.

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 • Integrated phase. During this phase, the viral DNA integrates into the host genome.
Viral genes are then transcribed alongside those of the host. At this stage, HBeAg &
DNA levels in serum are low. There is no inflammatory reaction mounted and
therefore there is no hepatocyte damage. This stage can lead to development of
cirrhosis. Hepatocellular carcinoma is more likely in these individuals, whether or not
cirrhosis develops.

Clinical course
The course of infection is as follows:

• Immune-tolerant phase. This stage is the initial stage and it lasts 2-4 weeks (or 3-45
days)3. During this stage, slow active replication continues but seroconversion has
not occurred, and there is no hepatocellular damage. Active replication is indicated
by the presence of HBsAg & HBeAg, and the absence of seroconversion is indicated
by the absence of anti-HBe. HBV-DNA levels are very high (above 200 000IU/mL).
The absence of hepatocellular damage is indicated by normal ALT levels and minimal
histological disease.
• Immune active/clearance. It is during this stage that active disease occurs. There is
widespread destruction of hepatocytes. Patients develop positive HBeAg & HBsAg
due to widespread replication of the virus. Hepatocellular damage is signified by
elevated ALT levels and necro-inflammatory activity on histology. The duration of
this stage is usually 3-4 weeks in acute infection. In patients with chronic infection,
this stage may persist for as long as 10 years. This stage can resolve completely, or
progress to chronic infection. Seroconversion can occur at this stage.
• Inactive chronic hepatitis/immune-control phase. In these patients, there is chronic
infection leading to chronic liver disease. Patients seroconverted in this stage, and
therefore have positive anti-HBe in their blood. HBeAg clears slowly, and once it
clears it can remit. The host targets infected hepatocytes and HBV. HBV-DNA is low
or undetectable. ALT levels are within normal range. HBsAg & anti-HBc can be
detected in serum. This is associated with a low risk of complications, such as
cirrhosis & hepatocellular carcinoma.
• Chronic HBeAg-negative hepatitis/immune-escape mutant. In this stage, there is
negative HBeAg without anti-HBe. It results from a mutation in the pre-core or basal
core promoter gene, resulting in the production of virions without HBeAg. ALT levels
are abnormal, and this indicates background destruction of hepatocytes. HBV-DNA
levels are abnormal or fluctuating. Older patients are at risk of progressive disease,
with rapid progression to cirrhosis.
• Occult hepatitis B. In this form, only HBcAb can be detected. HBsAg and HBeAg are
both undetectable. This indicates hidden infection that reactivates when the patient

3
In neonates born with HBV, this stage lasts very long.

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 is immunosuppressed, as with immunotherapy (rather than HIV). HBV-DNA persists
in the liver, albeit being undetectable in serum.
• Recovery. During this stage, HBV-DNA & HBsAg are undetectable, and antibodies to
various antigens are produced. Recovery is spontaneous in 99% of
immunocompetent patients.

Phase HBsAg HBeAg HBcAg Anti-HBeAg ALT HBV-DNA

Immune-tolerant + + - - ↔ ↑↑
Immune-active + + - - ↑↑ ↑↑
Immune-control (chronic) + + + + ↔ ↔
Chronic HBe-negative + - + - ↑ ↑ (fluctuating)
Occult hepatitis - - + - ↔ ↔

Clinical features
HBV hepatitis can be acute or chronic. Acute infection ranges from subclinical infection to
fulminant hepatitis. Acute hepatitis does not occur in individuals with congenital HBV
infection. Chronic hepatitis occurs in 5-10% of patients.

• History. The symptoms are of insidious onset in the majority of cases. Symptoms
include fever, malaise and anorexia followed by nausea, vomiting, abdominal pain &
discomfort and chills. The classical icteric symptoms of liver damage – jaundice, dark
urine and pale stools – follow thereafter. In fulminant hepatitis, patients have more
severe symptoms, such as ascites & bleeding. Patients may present with more
serious features, such as encephalopathy (confusion, coma,) and coagulopathy.
Chronic hepatitis is often asymptomatic and is detected when there is
decompensation. When they decompensate, they develop symptoms similar to
those of acute hepatitis, but with other features of portal hypertension.
In addition to symptoms, other questions need to be asked, such as history of
hepatitis, HBV vaccination status, HIV status, family history of HCC, and substance
use (especially alcohol and IV drugs).
• Examination. The features on examination are:
o General: low-grade fever, jaundice, palmar erythema, signs of chronic liver
disease (muscle wasting, Dupuytren’s contracture, spider naevi, palmar
erythema, peripheral oedema, gynaecomastia), signs of liver failure (liver
flap, fetor hepaticus, confusion).
o Abdomen: distended abdominal veins (caput medusa), ascites, tender
hepatomegaly (liver smooth in acute hepatitis, nodular in hepatocellular
carcinoma)4, splenomegaly.

4
In cirrhosis, it is small & shrunken.

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Complications
The complications of HBV infection and/or hepatitis include:

• Cirrhosis. Cirrhosis is a manifestation of chronic inflammation. There is an 8-20%

cumulative risk of developing cirrhosis in patients with chronic HBV hepatitis.
Cirrhosis results in progressive decline in hepatic function, with an increase in the
portal pressure. Patients develop portal hypertension & hypoalbuminaemia. On
examination, patients will have features of portal hypertension, such as ascites,
peripheral oedema and distended abdominal veins, and they will have a shrunken
liver.
• Hepatocellular carcinoma. Over 80% of cases of hepatocellular carcinoma are
attributable to HBV infection. About 650 000 patients with chronic HBV infection die
of HCC every year worldwide. The mechanism by which this happens is not fully
understood. However, HCC resulting from HBV infection may or may not be
preceded by cirrhosis. HCC develops after 9-35 years following infection. It is more
likely to develop in patients with congenital HBV infection.
• Glomerulonephritis. This is more likely in patients with congenital HBV infection. The
most common pattern of glomerulonephritis seen is membranous
glomerulonephritis in children and membranoproliferative glomerulonephritis in
adults, which both manifest as nephrotic syndrome. Glomerulonephritis is believed
to develop in a variety of ways. It is believed that the antigens (HBsAg & HBeAg) act
as triggers that elicit formation of immune complexes with deposition of these
complexes on the GBM. There is also activation of complement, which is seen with
reduced complement levels in serum.
• Polyarteritis nodosa (PAN). This is supported by the high prevalence of HBsAg
amongst patients with PAN. PAN is a form of vasculitis affecting medium-sized
vessels across the body, forming small aneurysms in affected organs that look like a
string of beads. The clinical manifestations of PAN are:
o Cardiovascular – hypertension, pericarditis, heart failure.
o Renal – haematuria, proteinuria, renal insufficiency.
o GI – abdominal pain, mesenteric vasculitis.
o Musculoskeletal – arthralgia, arthritis.
o Neurologic – mononeuritis.
o skin– rashes.

Investigations
Prior to doing other tests, you first test for HBsAg & anti-HBs. If this is positive, you do:

• Hepatitis B profile. A hepatitis B profile includes: HBsAg, HBcAg and HBeAg. In acute
infection, where HBsAg can be cleared quickly, IgM anti-HBc is diagnostic.

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 o The presence of HBsAg for longer than 6 months signifies chronic infection.
o The presence of HBeAg needs to be determined to see if the patient is in the
HBeAg-positive or HBeAg-negative phase. HBeAg can be used to monitor
treatment response.
• Nucleic acid assays. HBV-DNA is the most sensitive index of viral replication. It is
used to differentiate HBeAg-negative disease from inactive chronic infection. This is
used to guide treatment and subsequent monitoring. Serial measurements over a
few months are preferable, but there is no consensus over which level is desirable.
Serum HBV-DNA levels should be expressed in IU/ml5.
• Liver biochemistry. This is used to assess degree of liver damage. You can measure:
o AST & ALT. AST & ALT levels are elevated in active acute disease. ALT levels
are usually higher than AST levels and are therefore more sensitive. However,
with progression to cirrhosis, AST may become higher.
o ALP & GGT. These may be elevated, but are usually no more than 3-times the
upper limit of normal.
o Serum albumin. Serum albumin decreases as decompensated cirrhosis
develops.
o Bilirubin. Elevated bilirubin typically reflects the jaundice that develops. It
also rises in decompensated cirrhosis.
o Prothrombin time. This test reflects the synthetic function of the liver, as the
vitamin K-dependent clotting factors are synthesised in the liver. It increases
in decompensated chronic liver disease.
• Liver biopsy. This has been used to ascertain the degree of necro-inflammation &
fibrosis. Biopsy is only done once hepatocellular carcinoma has been excluded, as
biopsy can lead to massive bleeding. In acute hepatitis B, there are scattered
individual clusters of dying cells, with a diffuse lymphocytic infiltrate. The necrotic
pattern is predominantly centrilobular. In chronic infection, there is a lymphocytic
infiltrate primarily surrounding the portal tracts. Ground-glass cells are seen in 50-
75% of cells. In some livers, there is widespread fibrosis with bridging of the portal
tracts, leading to cirrhosis.
Several biopsy scoring systems have been developed. The METAVIR system, Knodell
and Ishak scores are the most widely used ones. The METAVIR system is as follows:
METAVIR F0 F1 F2 F3 F4
stage
Definition No Portal fibrosis Portal Numerous septa Cirrhosis.
fibrosis. without fibrosis with without cirrhosis.
septa. septa.
• Non-invasive tests. You can use computed markers of fibrosis, such as FIB4 and
APRI. These are computed from the age, liver enzyme levels, platelet count.

5
If they are in copies per mL, you divide this value by 5 to get the corresponding value in IU/ml. for example,
200 000 copies/ml = 40 000IU/ml.

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 o APRI (AST platelet ratio index). This is calculated as follows:
𝑠𝑒𝑟𝑢𝑚 𝐴𝑆𝑇 𝑙𝑒𝑣𝑒𝑙 × 100
𝐴𝑃𝑅𝐼 =
𝑈𝐿𝑁 (𝑢𝑝𝑝𝑒𝑟 𝑙𝑖𝑚𝑖𝑡 𝑜𝑓 𝑛𝑜𝑟𝑚𝑎𝑙) × 𝑝𝑙𝑎𝑡𝑒𝑙𝑒𝑡 𝑐𝑜𝑢𝑛𝑡
A score of 0.5 or 1.5 indicates significant fibrosis (F2) while a score of 1 or 2
indicates cirrhosis (F4). Patients falling within intermediate range require
further evaluation using fibrotest or transient elastography.
o FIB-4 (fibroblast-4). This is calculated as follows:
𝑎𝑔𝑒 × 𝐴𝑆𝑇
𝐹𝐼𝐵4 =
𝑝𝑙𝑎𝑡𝑒𝑙𝑒𝑡 × √𝐴𝐿𝑇
A FIB-4 score of above 1.45 (low cut-off) or 3.25 (high cut-off) indicates
significant fibrosis.

Other non-specific tests conducted for patients with hepatitis are:

• Blood tests. You should also do an FBC and U&E to rule out anaemia of chronic
disease and renal impairment.
• HCV screening. You also need to screen for HCV, as HBV-HCV co-infection carriers a
poorer prognosis and has a more rapid progression.
• Imaging. You need to do an ultrasound of the liver to rule out malignancy as the
primary priority prior to biopsy. Once a lesion is suspicious of HCC, you take a triple-
phase high-resolution CT scan with contrast of the liver.

Management
Treatment of confirmed HBV depends on the stage of disease. Patients that require
treatment are those in the immune-reactive stage and those with chronic hepatitis. Those
with occult hepatitis only require treatment when they are undergoing immunosuppressive
therapy. The majority of patients recover completely, with fulminant hepatitis occurring in
1% of patients. The goals of treatment are to prevent progression to cirrhosis, liver failure
and hepatocellular carcinoma.

For acute hepatitis, treatment is mainly symptomatic, as most people will clear the
infection. Patients should, however, have their HBV markers monitored. If HBsAg persists
for more than 12 weeks, the patient should take antivirals. For chronic hepatitis, treatment
is indicated when there is chronic active infection, e.g. abnormal ALT levels and abnormal
HBV-DNA levels with/without positive HBeAg. Therefore, treatment is indicated for patients
with reactivation (decompensated chronic disease) or chronic HBeAg-negative disease.

The options are:

• Pharmacological therapy. The pharmacological agents in use are:

o Conventional interferon-α. Interferons have antiviral, antiproliferative and
immunomodulatory effects. They induce intracellular signals that help the

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 cells to inhibit viral entry, translation, transcription, protein processing,
maturation and release. They also increase host expression of MHC
molecules, macrophage phagocytic activity and proliferation & survival of
cytotoxic T-cells. Through these actions, they initially cause a flare in the
hepatitis which is followed by resolution of the infection6. Good prognostic
factors for treatment with interferon-α include high transaminase levels, low
viral load and infection with the wild type virus. It is also used for treatment
of glomerulonephritis and is used in conjunction with adenine arabinoside to
treat PAN.
o Pegylated interferon-α. This has an enhanced half-life compared to
conventional interferon-α. Pegylation lowers the rate of absorption from
subcutaneous injection. It also reduces renal clearance and decreases
immunogenicity. Pegylated interferon-α is also used to treat hepatitis C,
alone or in combination with ribavirin.
o Nucleoside & nucleotide reverse transcriptase inhibitors. The NRTIs used in
the treatment of HBV hepatitis include tenofovir, entecavir, adefovir,
lamivudine and telbivudine. Entecavir is used as a 1st-line agent in many
countries due to its high potency and low resistance rate. However, use of
tenofovir & lamivudine is beneficial in countries where HIV prevalence is high
and these agents are used as 1st-line ARV agents. The mechanisms by which
these drugs differ. Adefovir inhibits priming of reverse transcription.
Tenofovir, lamivudine and emtricitabine inhibit synthesis of the negative-
sense single-stranded viral DNA. Entecavir inhibits all 3 stages of synthesis,
thus accounting for its potency.
Discontinuation of pharmacological therapy is considered in: patients without
evidence of cirrhosis; patients who can be followed up carefully for reactivation;
evidence of HBeAg loss and seroconversion to anti-HBe; and persistently normal ALT
& undetectable HBV-DNA.
• Surgical intervention. Surgical intervention is done for patients with fulminant
hepatic failure who do not recover. It is also indicated for patients with end-stage
liver disease due to HBV disease. You can do orthotropic liver transplantation (OLT)7.
Hepatitis recurrence rates reduce if you administer hepatitis B immunoglobulin
during & after the OLT period. You can also administer adefovir/lamivudine during
the pre- & post-op periods.
• Hepatitis B & pregnancy. All pregnant women require screening for HBsAg
regardless of previous test results or vaccinations. Neonates born to mothers with
chronic HBV should receive hepatitis B immunoglobulins as well as hepatitis B

6
In patients with decompensated cirrhosis, this flare can lead to further deterioration.
7
Orthotopic liver transplantation is the removal of the native liver and its replacement with a donor liver in the
exact same anatomic position as the original liver.

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 vaccine8. Thereafter, the children should receive the hepatitis vaccines as per routine
ZEPI schedule at birth, at 6, 10 and 14 months as part of pentavalent. Breastfeeding
is not contraindicated in children chronically infected with HBV if the child receives
immunoglobulins & vaccine active prophylaxis.
• HBV-HCV confection. In these patients, HBV-DNA levels are usually low, and the
majority of chronic hepatitis progression is due to HCV. They should receive initial
treatment for HCV. If there is no access to measurement of viral loads for both
viruses, you treat both infections.

Monitoring treatment
Monitoring treatment of HBV comprises of: monitoring of treatment response, monitoring
of disease progression, monitoring for tenofovir & entecavir toxicity, and monitoring for
hepatocellular carcinoma.

Monitoring is as follows:

• Annual monitoring. You should do HBV-DNA, HBeAg9, HBsAg and ALT levels. These
are done for patients that do not meet the criteria for treatment. In those without
cirrhosis at baseline, you need to do non-invasive tests to assess for likelihood of
development of cirrhosis.
• More frequent monitoring. this depends on whether patients are on treatment or
not:
o Patients who do not meet the criteria for treatment: you monitor more
frequently if patients have intermittently abnormal ALT or HBV-DNA levels.
More frequent monitoring is also indicated in patients co-infected with HIV.
In these patients, the aim is to identify a change in clinical status, such as an
APRI score > 2, development of HCC, and a rise in ALT or HBV-DNA.
o Patients on treatment or following treatment discontinuation: you monitor in:
patients with more advanced disease (compensated/decompensated
cirrhosis); first year of treatment to assess adherence & treatment response;
patients in whom adherence is an issue; HIV-positive patients; patients after
discontinuation of treatment.
• Monitoring for tenofovir & entecavir toxicity. Tenofovir causes proximal tubular
dysfunction, which ranges in severity from mild renal tubular dysfunction &
hyperphosphataemia to classical Fanconi syndrome & impaired GFR. It also causes
osteoporosis, severe hepatomegaly with steatosis and lactic acidosis. Risk factors for
tenofovir toxicity include low CD4 count, low body weight and underlying renal
dysfunction. To monitor for tenofovir toxicity, you need to measure baseline renal
function and assess for baseline risk of renal dysfunction, and then monitor renal

8
The majority of vertical infections occur perinatally.
9
If the patients initially tested HBeAg, you must conduct anti-HBe.

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 function annually. You also need to monitor growth in children. Baseline renal
function is assessed by measuring eGFR using the Cockcroft-Gault formula. If the
eGFR falls below 50, reduce the dose of tenofovir or switch to entecavir. The dose of
entecavir should also be reduced if there is declining renal function, as entecavir is
primarily excreted by the kidneys. Also monitor renal function by doing regular urine
dipsticks, paying particular attention to proteinuria & glycosuria. You should take
serum creatinine, eGFR decline, serum phosphate, and urine protein-to-creatinine
ratio.
• Monitoring for hepatocellular carcinoma (HCC). You monitor for hepatocellular
carcinoma by taking a hepatobiliary ultrasound and measuring AFP levels every 6
months. This is indicated for patients with cirrhosis, patients with a family history of
HCC, patients above 40 years of age without evidence of cirrhosis and HBV-DNA
above 2000IU/ml.

Prevention of HBV
HBV can be prevented by:

• Vaccination. Vaccination is offered for infants & neonates, particularly in areas

where the virus is endemic. The vaccine is concentrated HBsAg, which is
immunogenic and will generate antibodies for the infant. Vaccination is encouraged
for: people in endemic areas, and high-risk groups (e.g. healthcare workers, sex
workers, prisoners, household contacts of infected individuals).
• PMTCT for hepatitis. This is achieved by giving a tenofovir-based regimen for
hepatitis. This can substantially reduce the chances of spread of infection to as little
as 1-2%. You give tenofovir, lamivudine and efavirenz.

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 Hepatitis C
Hepatitis C is a viral infection caused by the hepatitis C virus. The virus is a recently-
discovered virus that was discovered in 1989. It is a major cause of both acute & chronic
hepatitis. It is estimated that 71 million people globally have chronic hepatitis C. The highest
prevalences of hepatitis C are in Eastern Mediterranean and Europe. In Egypt, the rate is
about 22% due to parenteral antimony treatment for Schistosomiasis. 339 000 people die
every year as a result of complications of hepatitis C infection, particularly cirrhosis &
hepatocellular carcinoma. Hepatitis C is one of the leading causes of chronic liver disease1,
together with alcohol. 75% of patients with acute hepatitis C develop chronic hepatitis.

Hepatitis C virus
Hepatitis C virus (HCV) belongs to the Flaviviridae family of viruses, to which yellow fever
virus, Dengue virus, West Nile virus, etc. belong to. These viruses are enveloped viruses that
have a positive-sense single-stranded RNA genome. It has a diameter of 50nm. The viral
envelop consists of glycoproteins, with one E protein (E1) folding over another (E2). The
viruses infect hepatocytes, but can also infect B-lymphocytes.

The virus enters cells by means of receptor-mediated endocytosis. The receptor it binds on
is CD-81 (tetraspanin), through which it interacts using E2. The virions can also coat
themselves with LDLs or VLDLs and uses these lipoproteins’ receptors to enter hepatocytes.
The viral envelop then fuses with that of the endosome upon acidification and it releases
the virus into the cytosol. The viral genome is then translated into a polyprotein which is
then cleaved to form non-structural early proteins (NS2, NS3, NS4, NS5A and NS5B) and
structural proteins. The non-structural proteins work as helicase (NS3), protease (NS2 &
NS3) and RNA-dependent RNA polymerase (NS5B) enzymes. The structural proteins include
the C- (core protein) and the E-proteins (envelop proteins E1 & E2). After virion assembly,
the virus assembles and buds into the endoplasmic reticulum and becomes associated with
the cell.

Pathogenesis
HCV proteins inhibit apoptosis & IFN-α action by binding to the TNF receptor and to protein
kinase R. These actions prevent death of hepatocytes. The ability of HCV to remain cell
associated & prevent host cell death both help the virus persist in the body.

Cell-mediated immunity accounts for both resolution of infection and tissue damage. The
inflammatory reaction can exhaust CD8+ cytotoxic T-cells to prevent resolution of infection.

1
More than hepatitis B.

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The extent of lymphocytic infiltration, inflammation, portal & periportal fibrosis and lobular
necrosis – identified on liver biopsy – can be used to grade severity of disease.

The inflammatory response may be of a TH1-type or a TH2-type. A predominantly TH2-

response is pro-fibrotic, and if the TH1-response & IFN-γ are weak the cytokine profile of this
response will lead to fibrosis & eventual cirrhosis. A predominant TH1-response with IFN-γ is
anti-fibrotic and is therefore associated with less fibrosis. Viral load & viral genotype has
been shown not to affect the rate of progression to fibrosis.

Aetiology
The majority of infections are acquired through infected blood. The risk factors & methods
of spread are:

• Transfusion of infected blood. This was once the leading mode of spread of the virus
prior to identification of the virus and screening of blood products.
• Use of non-sterile needles. This is currently the leading mode of spread in developed
1
countries. It is thought that 3 of young IV drug users in America are infected with
HCV.
• Occupational exposure. Healthcare workers are particularly prone to contracting HCV
through needle stick injuries. Needle stick injuries pose a 3% risk of transmission of
the virus.
• Sexual transmission. This mode of transmission, however, is very rare and
contributes to a very small number of new cases. A higher rate of transmission,
however, occurs in homosexual men.
• HIV. HIV increases the likelihood of contracting HIV. More than 90% of HIV-positive
people who are also intravenous drug users are also infected with HCV. In contrast,
only 4% of those that acquire HIV through sexual intercourse also have HCV.

HCV is not effectively transmitted vertically, through breastfeeding, through household

contact with infected persons or through contact with saliva.

Other associated risk factors that speed progression to fibrosis include:

• Male gender.
• Alcohol intake.
• Non-alcoholic fatty liver disease.
• Concurrent HBV infection.
• Diabetes.

Clinical features
The clinical features of HCV are:

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History

Hepatitis C causes 3 kinds of clinical presentations.

• Acute viral hepatitis. These patients are mostly asymptomatic, with about 10%
presenting with a mild flu-like illness with jaundice and a transaminitis. There are
also prominent extra-hepatic features, such as arthralgia & arthritis, paraesthesia,
myalgia, pruritus, sicca syndrome (Sjögren’s syndrome) and sensory neuropathy.
15% of patients clear the infection within 6 months.
• Chronic persistent infection. This occurs in the majority (70%) of patients. Chronic
active hepatitis develops within 10-15 years, and cirrhosis develops in 20% of chronic
cases after 20 years. This may be exacerbated by alcohol, certain medications and
other hepatitis viruses. This syndrome is often asymptomatic and is detected
through routine biochemical testing. If symptomatic, the commonest presentation is
fatigue, and it may be accompanied by nausea, vomiting, weight loss and anorexia.
These symptoms do not correlate with disease activity.
Patients with cirrhosis can present with decompensation, which causes synthetic
dysfunction & portal hypertension. They can present with ankle swelling, abdominal
distension, melena, hematemesis and mental status changes.
• Rapid onset cirrhosis. In 15% of patients, hepatitis C rapidly progresses to cirrhosis.

Examination

Most patients with HCV infection have no findings on physical examination. Patients with
extra-hepatic features, however, may have signs such as porphyria cutanea tarda or
necrotising vasculitis. The findings of acute/acute-on-chronic hepatitis are:

• General: jaundice, pallor (due to upper GI bleeding), asterixis, petechiae,

excoriations due to pruritus, ankle oedema, fetor hepaticus.
• Abdomen: ascites, caput medusa, hepatosplenomegaly

The findings of chronic hepatitis are:

• General: palmar erythema, Dupuytren’s contracture, leukonychia, clubbing, thenar

& temporal wasting, parotid enlargement, lichen planus.
• Abdomen: gynaecomastia, spider naevi, scant abdominal hair, small testes,
hepatosplenomegaly.

Complications
The complications of HCV infection are:

• Cirrhosis. The risk of cirrhosis after 20 years of infection is 15-30%. This is initially
compensated, with decompensation occurring later leading to variceal

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 haemorrhage, ascites and encephalopathy. Factors contributing to progression to
cirrhosis include alcohol abuse, HBV & HIV co-infection, and immunosuppression of
any cause.
• Hepatocellular carcinoma. 1-3% of patients with cirrhosis progress to hepatocellular
carcinoma every year2. Contributing factors to hepatocellular carcinoma include
alcohol abuse, HBV & HIV co-infection, and immunosuppression of any cause.
• Depression. This occurs in 24% of patients. There are also associated changes in
mood, cognition and personality. HCV is thought to cause a surge in inflammatory
cytokines that affect the brain. Depression & other neuropsychiatric manifestations
are also thought to be the result of interferon treatment.
• Diabetes mellitus. This occurs in 15% of cases. HCV interferes with the insulin
modulating pathway by modulation of cell gene expression. HCV is known to induce
insulin resistance.
• Chronic renal disease. This occurs in 10% of cases. HCV causes cryoglobulinaemia &
vasculitis, which can complicate with chronic renal disease.

Investigations
The investigations done for hepatitis C are:

• Liver function tests. In acute infection, the LFTs are usually deranged. ALT levels are
usually elevated more than AST levels such that AST:ALT ration is less than 1.
However, this ratio is reversed in the setting of cirrhosis. In chronic infection, ALT
levels are normal unless there is decompensation.
• Antibody tests. Testing for anti-HCV antibodies confirms previous exposure. These
antibodies are not very useful in an acute infection as antibodies appear about 8
weeks after infection. The test is very useful in patients with chronic infection. False-
negative tests, however, can occur in patients with compromised immune systems
such as those with HIV, renal failure or HCV-induced cryoglobulinaemia. There is also
a rapid antibody test called the OraQuick HCV Rapid Antibody Test, which is used for
patients at risk for hepatitis.
• HCV-RNA assays. This is the gold standard for detecting HCV in an infected
individual. You can use RT-PCR, branched-chain DNA assay (a signal amplification
technique) and other related techniques. HCV-RNA assays are divided into
quantitative assays and qualitative assays:
o Qualitative assay. This is used to detect the presence of HCV in the
circulation.
o Quantitative assay. This is used to determine the amount of HCV in blood. It
makes use of RT-PCR & branched-chain DNA assay. The quantitative assay
2
HCC from HCV infection is associated more with cirrhosis than HBV because HBV is integrates with the host
genome and is more likely to cause carcinogenesis without preceding fibrosis. HCV, however, first causes
fibrosis which leads to chronic regenerative activity which eventually leads to HCC.

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 helps predict the response to treatment, and the change in HCV-RNA level is
used to monitor response to treatment.
• HCV genotyping. HCV genotyping is important for predicting the likelihood of
response to treatment. The genotype of HCV should be differentiated between
genotypes 1, 1a, 1b, 2, 3, 4 and 5.
• Liver biopsy. Liver biopsy is considered for patients that are HCV-PCR positive,
particularly those with genotypes 1 & 4. This is done to assess liver damage & the
need for treatment. However, it is not mandatory for treatment to be commenced. It
is often taken when:
o The diagnosis is uncertain.
o Other co-infections/diseases are present.
o The patient being considered for treatment has normal LFTs and no
extrahepatic manifestations.
o The patient is immunocompromised.
On histology, what you’re looking for is:
o Features of inflammation: lymphocytic infiltration, moderate degrees of
inflammation & necrosis, periportal bridging and fibrosis.
o Features of cirrhosis: widespread fibrosis with bridging of portal tracts and
islands of regenerating cells.
• Imaging. A liver stiffness test called a FibroScan is available as a non-invasive
method of staging liver disease in a patient with chronic viral hepatitis. An
ultrasound can be done to assess the size of the liver and for the presence of any
malignancies. You can also do a CT scan to assess the degree of fibrosis or screen for
hepatocellular carcinoma.

Management of hepatitis C infection

Treatment is appropriate for every patient with hepatitis C infection. Active acute infection
is demonstrated by the presence of HCV-RNA in blood with negative antibodies, or the
presence of liver changes with no antibodies. For acute infection, the goal of infection is to
eradicate it and prevent its progression to chronic infection. For established chronic
infection, the goal is to cure it, stop progression of liver disease and prevent the
development of hepatocellular carcinoma. The presence of cirrhosis is no contraindication
to treatment, but it affects the responses to treatment.

Cure is defined as a sustained virological response, which is a negative HCV-RNA 6 months

after completion of treatment.

The treatment options are:

Pharmacological intervention

The pharmacological options for HCV are:

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 • Direct-acting antiviral agents (DAA). These are fairly recent drugs, and their use has
increased since 2014 (when the HCV guidelines were first published). The drugs are
often given in combination and they achieve high cure rates within weeks. The
agents act on 3 different targets depending on the target protein in question:
o NS3/NS4 inhibitors – bocepevir, telaprevir, simeprevir, voxilapevir,
paritapevir, grazopevir and glecaprevir. These drugs target the viral protease.
o NS5A inhibitors – daclatasvir, velpatasvir, ledipasvir, ombitasvir, pibrentasvir
and elbasvir.
o NS5B inhibitors – sofosbuvir (nucleotide inhibitor) & dasabuvir (non-
nucleotide inhibitor). These drugs target the viral polymerase.
The WHO guidelines recommend the use of pangenotypic regimens that will target
all genotypes of HCV. Examples of the pangenotypic regimens include:
o Sofosbuvir/velpatasvir. This regimen is associated with good efficacy in
infections with genotypes 1-6. It is also effective in patients with HIV/HCV co-
infection, opioid substitution therapy3 and cirrhosis (compensated or not).
o Sofosbuvir/velpatasvir/voxilapevir. This is used for re-treatment of a patient
who was on a DAA regimen before.
o Glecaprevir/pibrentasvir. This regimen has good efficacy in patients with
genotypes 1-6, compensated cirrhosis and in patients with renal insufficiency
& ESRD. It is contra-indicated in patients with cirrhosis & Child-Pugh class C.
o Sofosbuvir/daclatasvir. This has been shown to be effective against
genotypes 1-4, people with decompensated liver disease, liver transplant
recipients and those with HIV/HCV co-infection.
WHO recommends starting treatment in all infected individuals above the age of 12
years irrespective of disease stage. The FDCs have been shown to have sustained
virological responses of more than 90% except for patients infected with genotype 3
and those with cirrhosis. There is also improvement of extrahepatic complications.
The regimens are as follows:
Patient Sofosbuvir/velpatas Sofosbuvir/daclatas Glecaprevir/pibrentas
subset vir vir vir
Patients 12 weeks 12 weeks 8 weeks
without
cirrhosis
Patients 12 weeks 24 weeks 12 weeks
with OR OR
compensat 12 weeks in 16 weeks in patients
e cirrhosis countries where who have genotype 3
genotype 3 who have received
prevalence is known interferon/ribavirin in
and is lower than the past.

3
Opioid substitution therapy is supplying illicit drug users with a replacement drug for opioid drug users.
Examples include methadone & buprenorphine.

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 5%.
• Interferons. Interferons work by inhibiting viral replication in host cells and
increasing expression of MHC class-I molecules, thus increasing immunologic
clearance of virally-infected cells. These drugs are generally used to treat both acute
& chronic infection. Pegylation (addition of propylene glycol, PEG) of the Interferons
has led to the development of longer-lasting interferons with longer bioavailability.
Interferon therapy led to cure, but only cured 10% of patients. It is generally no
longer recommended in combination therapy.
• Ribavirin. Ribavirin is a nucleoside analogue of guanosine. Its mechanism of action is
not fully understood, but it is believed to interfere with synthesis of GTP required for
capping of viral mRNA. Ribavirin is effective when combined with conventional
interferons for 6-12 months, the treatment had cure rates of 30-40%. Ribavirin
continues to be used with sofosbuvir alone or with other DAAs.

Management of decompensated HCV cirrhosis

Decompensated cirrhosis is managed using a combination of ribavirin and a DAA

combination. You can use:

• Sofosbuvir/ledipasvir with low dose ribavirin for 12 weeks.

• Sofosbuvir/velpatasvir with weight-based ribavirin for 12 weeks.
• Daclatasvir and sofosbuvir with a low initial dose of ribavirin for 12 weeks. This is
used only for genotypes 1 & 4.

If the patient is ineligible for ribavirin therapy, you can use:

• Ledipasvir/sofosbuvir for 24 weeks.

• Sofosbuvir/velpatasvir for 24 weeks.
• Daclatasvir/sofosbuvir for 24 weeks. This is used for genotypes 1 & 4 only.

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 Cryptococcosis
Cryptococcosis is a systemic mycosis caused by organisms belonging to the Cryptococcus
species. The infection ranges from harmless asymptomatic colonisation of the airways to
serious meningitis. The organisms responsible for infection include C. neoformans & C. gatti.
C. neoformans has a worldwide distribution. The infection mainly affects individuals that
have pre-existing immunosuppression (with no neutropaenia or immunoglobulin
deficiency). C. gatti1 is commonly found in tropical & subtropical climates, and it usually
affects immunocompetent people, responds slowly to treatment and produces intracerebral
mass lesions (and therefore more serious neurological sequelae).

Mycology
Microscopically, Cryptococcus organisms are spherical encapsulated yeast-like organisms
that multiply by budding. Gem tubes, hyphae and pseudo-hyphae are usually absent from
these organisms. The capsule is made out of polysaccharide, and it may be up to 5-times the
diameter of the yeast cell.

There are many serotypes of Cryptococcus: C. neoformans includes A (C. neoformans var
grubii), D (C. neoformans var neoformans), AD and C, while C. gatti includes B & C. The
majority of infections are caused by C. neoformans serotype A (var grubii), which typically
affects immunocompromised individuals. C. neoformans is found as a ubiquitous saprophyte
of the soil, particularly that which is enriched by bird droppings. The organism is found in
high concentrations in pigeon droppings, although the birds themselves do not get infected
by the fungus. In moist excreta, the fungus can persist for up to 2 years. However, in a
saprobic environment (rich in organic matter but lacking oxygen), the fungus can remain un-
encapsulated and is generally non-virulent.

C. gatti is generally associated with Eucalyptus trees. It is mostly found in subtropical

regions, such as South America, South-East Asia, sub-Saharan Africa and Australia. It has
recently been discovered in Vancouver Island in Canada and in Washington & Oregon.

Cryptococcus organisms are mainly spread by inhaling aerosolised cells from the
environment. This accounts for the initial colonisation of the respiratory system.
Subsequent dissemination of infection from there can occur in certain situations.

Pathophysiology
When the aerosolised Cryptococcus fungi are inhaled, they travel to the alveoli, where they
must survive the neutral/alkaline pH here. An enzyme called glucosylceramide synthase

1
The most common C. gatti strain that causes meningitis is C. tetragatti.

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(GCS)/ceramide glucosyltransferase facilitates growth & survival of the organism in this
alkaline pH by helping it transition through the cell cycle. Without this enzyme, the organism
cannot grow in the extracellular environment. The cryptococcus organisms are then
engulfed by alveolar macrophages, and therefore enter an acidic environment. Here, they
can grow without the aid of GCS. Unencapsulated yeast cells are easily engulfed &
destroyed while encapsulated yeast cells are resistant to phagocytosis. The capsule may also
mediate immunosuppression.

The host response to Cryptococcal infection includes both cellular & humoral components.
NK cells participate in the early killing of Cryptococcal cells and in ADCC (antibody-
dependent cell-mediated cytotoxicity). Anti-Cryptococcal antibodies & soluble anti-
Cryptococcal factors also play a role in macrophage- & lymphocyte-mediated immune
response.

C. neoformans can cause pneumonia and meningitis. Patients with pneumonia can develop
poorly-defined lung masses, pulmonary nodules and pleural effusions in rare cases. The
majority of these patients are immunocompetent. Meningitis is common in the setting of
AIDS. It can also cause limited cutaneous disease, although this is rare. Infection causes
little/no necrosis in other organs except in advanced disease. This is primarily due to organ
distortion secondary to increasing fungal burden.

Risk factors
The risk factors for Cryptococcal infection are:

• HIV/AIDS. This is the most common risk factor in countries where HIV prevalence
rates are very high. In these patients, infection usually develops when the CD4 + is
very low (below 100 cell/mm3). C. neoformans is the most commonly isolated
organism in these patients. In immunocompetent patients, C. gatti is isolated in 70-
80% of cases.
Cryptococcal meningitis accounts for 15% of deaths from HIV. There were 223 100
cases of crytpococcal meningitis amongst HIV-infected individuals in 2014, and 181
100 of those patients died.
• Immunocompromise from other conditions. This can be due to steroid use and use of
immunosuppressing agents for cancer therapy or other conditions.
• Age. Cryptococcal infection can occur in individuals of any age, and the mean age of
incidence is younger in HIV-infected individuals.
• Sex. Cryptococcal meningitis is more common.
• Underlying pulmonary disease. This may promote the initial colonisation & infection
by the fungus.
• Malignancies. Malignancies can also lead to immunosuppression, which predisposes
to Cryptococcal infection.

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Clinical presentation
The clinical presentation of cryptococcosis depends on the location of the infection:
whether it is meningitis, pneumonia or skin infection.

Pulmonary cryptococcosis

Pulmonary cryptococcosis ranges from asymptomatic colonisation of the airway to acute

respiratory distress syndrome. It can also become a slow-growing mass that can compress
thoracic structures such as the superior vena cava.

In pulmonary cryptococcosis, you will see the following:

• History. Patients present with fever, malaise, cough with scant sputum and pleuritic
chest pain. Haemoptysis is rare. The history is often a chronic rather than acute one.
• Examination. Less than 15% of patients show a picture of pneumonia. Cryptococcus
isolated from sputum is often due to colonisation rather than true infection,
especially in patients with COPD or bronchiectasis.

Cryptococcal meningitis

This is the most common manifestation of Cryptococcal infection. Without treatment it

inevitably leads to death.

• History. The most common symptoms are a chronic history of headache, nausea &
vomiting, altered mental status (personality changes, confusion, lethargy and coma).
Fever & neck stiffness are less common since they are due to an aggressive
inflammatory response (typically found in patients with high CD4 + counts).
• Examination. Patients will be ill-looking, have altered mental status and neck
stiffness. Patients with cryptococcosis present with focal neurologic defects.

Cutaneous manifestations

Cutaneous cryptococcosis is a feature of disseminated cryptococcosis. Cutaneous

manifestations occur in 10-15% of patients with the infection. Patients may develop
papules, pustules, nodules, ulcers and draining sinuses. Umbilicated papules may resemble
those from molluscum contagiosum.

Investigations
The investigations done in cryptococcosis are:

• CSF studies. CSF should be taken to screen for Cryptococcal meningitis. You need to
test for the Cryptococcal antigen (CrAg). High opening pressures above 25cm H2O
have poor prognosis and serial CSF taps need to be done to maintain opening

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 pressure below 20cm H2O2. There is usually a high leukocyte count (above 20
cells/µL) with a lymphocyte predominance. You should also view CSF under the
microscope using India ink staining. You can also culture the CSF on standard
mycological media, such as Sabouraud dextrose agar. C. neoformans grows at 37°C,
assimilates inositol and tests positive for phenoloxidase activity. The tests with the
highest sensitivity are CSF CrAg testing & culture. India Ink staining has a low
sensitivity, but it can be done in settings where CrAg testing is unavailable.
• Blood tests. Blood culture can be done to identify active infection. Serum CrAg is not
very sensitive for diagnosing active infection. However, it is used in patients with HIV
being initiated on ART to determine the risk of developing Cryptococcal meningitis.
• Bronchoalveolar lavage. This can be used for microscopy to diagnose infection
/colonisation in the chest.
• Chest X-ray. The chest X-ray findings of pulmonary Cryptococcal infection include:
nodular infiltrates, which are more diffuse in severe disease. Cavitation & hilar
lymphadenopathy are rare.
• CT/MRI scan. These are done prior to taking a lumbar puncture to rule out a space-
occupying lesion.

Management
The management of Cryptococcal infection is as follows:

Cryptococcal meningitis

Cryptococcal meningitis leads to death within 2 years in all untreated cases. It is treated as
follows:

• Induction phase. This is done in first 2 weeks. You can start with a combination of
amphotericin B deoxycholate 1mg/kg/d intravenously and fluconazole 1200mg (or
12mg/kg for children & adolescents up to a maximum of 800mg) once daily orally.
Alternatively, you can start with high dose fluconazole (1200mg orally daily or
12mg/kg for children & adolescents) and flucytosine 100mg/kg/day divided into 4
doses for 2 weeks. You can also give amphotericin B 1mg/kg/day & flucytosine
100mg/kg/day divided into 4 doses for 1 week, followed by 1 week of fluconazole
1200mg daily for adults and 12mg/kg/day up to a maximum of 800mg for children &
adolescents.
• Consolidation phase. This is administered for 8 weeks. You give fluconazole 800mg
once daily orally for adults and 6-12mg/kg/day up to a maximum of 800mg.
• Maintenance phase. This is administered until the CD4+ count is above 200
cells/mm3 for 6 months. It is only indicated in patients living with HIV and not

2
Prior to tapping, however, you need to take a CT/MRI scan of the head to exclude space-occupying lesions.

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 immunocompetent patients. You give fluconazole 200mg orally once daily in adults
or 6mg/kg/day in children & adolescents.

Prior to administration of amphotericin B deoxycholate, prehydration & electrolyte

replacement is indicated. Prehydration is done using normal saline – give 1L of normal saline
over 2 hours. Potassium chloride (KCl) is given as replacement electrolyte: you add 20mmol
to the prehydration fluid.

Other therapeutic interventions for patients with Cryptococcal meningitis include:

• Therapeutic CSF tapping (keeping CSF opening pressure below 20cm H2O – you
remove 10-30ml of CSF). There is no need to take a CSF tap at the end of the
induction phase.
• Immediate initiation of ART is not recommended. It should be deferred for 4-6 weeks
after initiation of antifungal treatment.

Pulmonary cryptococcosis

Most of these patients are not immunocompromised or immunosuppressed, and therefore

they do not need antifungal therapy as long as CSF parameters are normal. For mild-to-
moderate disease, you can give fluconazole or itraconazole for 6-12 months, or you can give
amphotericin B. For severe disease, you give amphotericin B with flucytosine for 6-10
weeks, or you treat as for meningitis.

Cryptococcoma

A cryptococcoma is a localised brain lesion containing localised Cryptococcal organisms wall

off into an abscess. C. gatti is the more commonly implicated organism. You treat as for
Cryptococcal meningitis. Surgical resection is not always required. However, it can be done
for lesions in certain locations and for lesions causing neurologic symptoms. Prolonged
fluconazole therapy with 400mg orally may be required for 1-2 years.

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 Kaposi sarcoma
Kaposi sarcoma (KS) is an angio-proliferative tumour that arises from vascular & lymphatic
endothelial cells. It mainly affects skin & mucus membranes, but it can affect the mucosa of
any tissue.

Classification
Kaposi sarcoma is classified into 4 types:

• Classic/sporadic KS. This is an indolent form and is most common in men (by 10-15
times) in the eastern Mediterranean & Jewish communities. It is usually limited to
skin. As many as 30% of patients eventually develop secondary malignancy,
particularly non-Hodgkin’s lymphoma.
• Endemic KS. This form is more common in sub-Saharan Africa amongst men. This
form shows extensive cutaneous lesions with lymph node involvement. Oedema is a
prominent feature. Visceral involvement is rare. The risk of developing endemic KS is
increased by rarely/never wearing shoes in areas with volcanic clay soils (linked to
chronic lymphatic obstruction by fine soil particles).
• Epidemic/AIDS-related KS. This is the most common form found in the world due to
the AIDS pandemic. KS is 500-times more common in HIV-positive people than in the
general population. It is also more common in gay men. KS usually manifests in
individuals with a low CD4+ count and is one of the AIDS-defining illnesses. Survival is
also improved with ARVs. Epidemic KS is very aggressive, and usually has visceral
involvement.
• Immunosuppression-related/iatrogenic KS. This form is found amongst patients on
immunosuppressive therapy, such as organ transplant patients or patients with
autoimmune disease. Just like the epidemic form, it follows an aggressive course
with visceral involvement. The average time for development of KS in these men is
15-30 months. Sirolimus, used to prevent transplant rejection, appears to be
protective against development of KS.

Cigarette smoking is protective against KS. Relative affluence is also associated with
increased risk endemic & epidemic KS.

Pathogenesis
95-98% of cases of KS have been associated with infection by HHV-8 (also known as the
Kaposi sarcoma virus, KSV). It underlies all types of KS. The virus is thought to be spread via
saliva, not sexual contact – intercourse is thought to be a mere surrogate for other close
contact. The virus can also be transmitted through solid organ donation. The HHV-8 genome
has also been identified in Castleman’s disease, some lymphomas and leiomyosarcomas. A

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lot of cytokines are associated with development of KS: IL-1β, FGF (basic & acidic forms),
EGF and VEGF.

The cell of origin is still unknown, although a pluripotent mesenchymal progenitor cell has
been suggested. The cells develop into spindle cells, which proliferate on a background of
reticular fibres, collagen and mononuclear cells including macrophages, lymphocytes and
plasma cells. The lesions may only involve the reticular dermis (patch stage) or involve the
whole dermis (plaque & nodular stages). The tumour nodules are also believed to arise from
multiple independent foci rather than being metastatic from a single focus. This, however, is
applicable to less aggressive cutaneous KS and not the aggressive visceral forms.

Clinical presentation
History

The pathognomonic feature of KS is the presence of multiple purple macules, plaques,

papules and nodules present on skin and mucosal surfaces. The lesions are usually
hyperpigmented and assume a brown, red, purple or pink colour. The colour comes from
deposition of red cells or haemosiderin. The lesions can involve any system. The commonest
sites are:

• Cutaneous KS. Cutaneous KS is the commonest form of KS that is common in almost

all individuals. It is also usually the first to present. The lesions are multiple,
multicentric and they may be confluent. Patients may also develop swelling of legs,
which is due to lymphoedema caused by obstruction of subdermal lymphatic
channels.
• GIT KS. Visceral KS in the GIT can develop anywhere along the GIT, from the mouth
to the anus. It can manifest with nausea & vomiting, abdominal pain, dysphagia &
odynophagia, GI bleeding (haematemesis, haematochezia and melena) and bowel
obstruction.
• Pulmonary KS. Patients with visceral pulmonary KS may develop symptoms which
are difficult to distinguish from other opportunistic infections. They present with
cough, chest pain, dyspnoea and haemoptysis. Patients may also present
asymptomatically with a radiologic findings suggestive of KS.
• Other systems. KS can involve other systems, such as the liver, larynx, CNS, eye,
other glands, heart, breast, wounds and biopsy sites.

Physical examination

Examination findings include:

• General: ill-looking depending on extent of disease. The patient will have often
bilateral oedema which may be pitting or non-pitting. Areas where lymphoedema
once developed will become hyperpigmented & woody hard. In active KS, the woody
hard areas are usually warm to touch. Patients often have lymphadenopathy, and all

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 groups must be inspected. The conjunctivae & hard palate must be inspected for KS
lesions, and palatal lesions suggest visceral involvement. Patients may also be pale
due to anaemia.
• Skin: inspect the lesions on all skin surfaces. The lesions often start as macules, but
can progress to plaques, papules and nodules. Often lesions can become confluent,
particularly in the lower limbs. The lesions can develop on the fingers, ears and nose,
and can ulcerate. It is important to document the lesions on the skin.
• Respiratory system: Patients can be present with reduced chest movement on one
side, with reduced chest expansion and stony dull percussion note (due to an
effusion). There are often reduced breath sounds with crackles.
• Abdominal examination: there may be hepatosplenomegaly in the abdomen.

Investigations

The investigations done for KS are:

• Biopsy. The major differential for KS is bacillary angiomatosis, which produces

lesions that appear similar to KS. A biopsy of the skin or mucous membrane with a
lesion must be taken to confirm diagnosis. On histology, bacillary angiomatosis
shows capillary proliferation with neutrophils inflammation. KS, on the other hand,
contains slit-like vascular spaces with lympho-plasmacytic infiltrates, spindle cells
and extravasated red cells.
• Imaging. You can do bronchoscopy or upper GI endoscopy to look for lesions in
patients with suspected lesions.
• Chest X-ray. This is used to demonstrate pulmonary involvement. Chest radiograph
features include diffuse reticulonodular infiltrates, interstitial infiltrates, pleural
effusions, hilar/mediastinal lymphadenopathy and an isolated pulmonary nodule.
• Sputum studies. Patients with KS should be screened for TB, as the 2 can co-exist.

Staging of KS
No precise staging system has been accepted universally. Nonetheless, there are many
classifications that are used for KS:

AIDS clinical trials group (ACTG) system

This is also known as the TIS staging which is based on 3 parameters: tumour, immunologic
status and systemic illness:

T – tumour
T0 (good Confined to skin and/or lymph nodes, and demonstrates minimal oral disease
risk) (with flat rather than raised lesions).
T1 (poor Widespread KS, as evidenced by:
risk) • Oedema due to tumour.

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 • Extensive oral KS with nodular lesions or lesions elsewhere other than
hard palate.
• Visceral organ involvement.
I – immunologic status
I0 (good CD4+ greater than 200cells/µL
risk)
I1 (poor CD4+ less than 200cells/µL
risk)
S – systemic illness
S0 (good No systemic illness present:
risk) • No history of opportunistic infections or thrush.
• No B symptoms or chronic (>2 weeks) diarrhoea.
• Karnofsky performance score ≥ 70 (patient up & about at most times
and able to take care of self).
S1 (poor Systemic illness present:
risk) • History of opportunistic infection or thrush.
• B symptoms or chronic diarrhoea present.
• Karnofsky performance score < 70.
• Other HIV-related illness (HIV neurologic disease, lymphoma) present.

Mitsuyasu classification

This stages KS into 4 stages:

Stage 1 Localised nodular KS.

Stage 2 Localised invasive aggressive KS.
Stage 3 Disseminated mucocutaneous KS.
Stage 4 Stage 3 with visceral involvement.

Treatment of KS
There is no treatment that is able to eradicate HHV-8 and therefore there is no cure for KS.
The purpose of therapy is to alleviate symptoms, slow disease progression and prevent
relapses.

Medical therapy

Medical therapy for KS is as follows:

• ART. ARV therapy can be tried in HIV-infected individuals with cutaneous disease
only. The response to ART ranges from 30-80% depending on the stage of disease
and the amount of treatment. However, poor-risk patients on ART may not respond

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 to ART alone. In addition, approximately 6-39% of patients develop KS-IRIS within 3-6
months after re-initiating ART – it is associated with decreasing viraemia & improving
CD4+ count. Risk factors for KS-IRIS include: pulmonary disease, concurrent use of
glucocorticoids, advanced immunosuppression.
• Chemotherapy. Chemotherapy is preferred therapy for relapsed cutaneous disease
or as 1st-line for advanced disease. The agents used are bleomycin, vincristine,
doxorubicin (or pegylated liposomal doxorubicin, PLD), paclitaxel and etoposide. The
choice of chemotherapeutic agent is governed by many things, such as cost and
comorbidities. Doxorubicin is cardiotoxic and therefore an echocardiogram needs to
be taken prior to commencement, with serial echocardiograms being taken in
subsequent visits.

Local therapy

This is preferred for patients requiring palliation or locally advanced disease.

• Radiotherapy. KS is very radio-sensitive. Radiotherapy can be used as palliative

therapy for bleeding, pain and unsightly lesions. The type & dose varies with site,
depth and diameter of lesions. You can use low-voltage photons or EBRT. However,
patients with HIV are more prone to develop radiation-associated mucositis.
• Surgical excision. This is of benefit to patients with small superficial lesions. The
major problem with surgical excision is local recurrence. Surgery is also indicated for
patients with a visceral crisis, such as intestinal obstruction or deep bleeding.
• Intralesional chemotherapy. You can use low-dose vincristine, vinblastine or
bleomycin, usually for the classic form. Responses occur in 60-90% of patients. Side
effects include changes in pigmentation, swelling, blistering, ulceration, pain on
injection and transient neuropathic symptoms. Another problem is recurrence in
another site.
• Cryotherapy. You topically apply liquid nitrogen to the lesion, particularly small
(<1cm) facial lesions. It has the advantage of short duration, minimal discomfort and
ability to use repeatedly in combination with other forms of treatment. It has little
penetration and therefore should not be used for large deep lesions.
• Laser therapy. Laser photocoagulation can shrink smaller lesions. It is used for
palliative treatment of bleeding & pain in larger lesions. It has limited use in large
deep lesions.

Monitoring

Since no cure for KS is available, patients require life-long monitoring. Patients are at risk of
relapse even if they achieve remission. Patients should have routine physical examination
every 3-4 months to check for any new lesions, oedema and signs & symptoms suggestive of
visceral involvement. Patients living with HIV should also be monitored using an FBC,
metabolic profile, CD4+ count and viral load. HIV control is important in minimising relapse

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& progression, although patients can still relapse with good virological & immunologic
control. Compliance with ART should be emphasised at each encounter.

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 Schistosomiasis
Schistosomiasis (also known as bilharzia/bilharziasis) is a tropical helminthic infection
caused by Schistosoma species. There are 6 species known to cause human disease: S.
haematobium, S. mansoni, S. intercalatum, S. japonicum, S. mekongi and S. guineensis.
However, the species that cause the most disease are S. haematobium, S. mansoni and S.
japonicum. The disease can cause serious morbidity & mortality. It is estimated that over
200 million individuals are infected worldwide (1 in 30 individuals), and the disease is
responsible for over 200 000 deaths annually. 90% of infections are found in sub-Saharan
Africa. In Zimbabwe, 22.7% of the population is infected with schistosomiasis, but it does
not have a uniform distribution – it has a low prevalence in dry areas such as Matebeleland
North & South and parts of the Midlands.

The distribution of Schistosomiasis depends on the species in question, and this is due to the
distribution of snail species in the world:

• S. haematobium is mostly found in North Africa, sub-Saharan Africa, the Middle East,
Turkey and India.
• S. mansoni is the most widely distributed Schistosoma species. It is found in some
parts of tropical & subtropical sub-Saharan African, the Middle East, Saudi Arabia,
South America (Brazil, Suriname, and Venezuela) and the Caribbean.
• S. japonicum is regarded as an Oriental blood fluke: it is found in China, Japan, the
Phillipines, Thailand and Sulawesi (Indonesia)
• S. intercalatum is found in Central & West Africa.
• S. mekongi is restricted to Laos & Cambodia.
• S. guineensis is found the rainforests north of Congo.

In Zimbabwe, S. haematobium is the most frequently encountered species.

In endemic areas, the infection is acquired in childhood and the prevalence peaks at 15-20
years. In adults, the prevalence does not change significantly, but the parasite intensity
decreases drastically.

Life cycle of Schistosoma species

Schistosoma species belong to the family of trematodes/flukes. They are also known as
blood flukes. The life cycle of the Schistosoma species involves 2 hosts:

1. Humans, who serve as the definitive host, in which sexual reproduction takes place.
2. Snails, which serve as the intermediate host, in which asexual reproduction takes
place.

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The life cycle is as follows:

1. The eggs of the schistosomes are laid in either urine or faeces (depending on the
species)1. The eggs are round with spines. S. haematobium has a terminal spine
while S. mansoni has a lateral spine.
2. In water, the eggs hatch and release larvae called miracidia (sing. miracidium).
3. The miracidia penetrate snails and turn into sporocysts. These multiply in the snail,
and this is the asexual reproduction stage.
4. The snail then release mature larvae called cercariae (sing. cercaria). Cercariae have
a head connected to a forked tail, which allows them to swim in water.
5. Cercariae penetrate human skin and enter the circulation. Here, they lose their tails
and become schistosomulae (sing. schistosomula).
6. After developing, the schistosomulae travel in the circulation until they get to the
portal vein. In the portal vein, the schistosomulae develop into adult schistosomes.
Adult schistosomes have an elongate cylindrical structure, and like other flukes they
have an oral sucker (opens into an incomplete digestive system) and a ventral sucker
(for attachment). They are not hermaphroditic, and they have definitive sexes. The
males are wider than the females and have a slit called the gynaecophoric canal, in
which the female enters. This is where copulation takes place.
7. After development, the adult schistosomulae then travel to their final destinations.
They can travel against the flow of blood to the mesenteric veins (small intestines for
S. japonium & S. mekongi; large intestines for S. mansoni & S. intercalatum). They
can also travel to the vesical plexus (S. haematobium). In their definitive positions,
the females can lay as many as 300-3000 eggs per day for 4-35 years. The eggs travel
in the circulation to other sites. They can also traverse the intestinal/bladder mucosa
and reach the lumen (through release of enzymes by larvae inside the eggs), where
they are excreted in urine or faeces.

Pathogenesis
Adult worms develop an elaborate defence system against host resistance. They coat
themselves with substances that the host recognises as self and consequently they do very
little damage to the host. Only when they migrate to the spinal cord or the brain do they
cause damage.

The eggs, however, are responsible for causing disease. The disease is the result of the
mounting of an immune response to the eggs laid by the females. Eggs invade local tissues
and release toxins & enzymes which mediate a TH2-mediated immune response.
Inflammation & granuloma formation occurs around these eggs, and if the reaction is
chronic enough can lead to fibrosis & scarring of the affected tissue. The eggs of S. mansoni,
S. japonicum, S. intercalatum and S. mekongi tend to penetrate the intestinal wall or travel

1
Urine for S.haematobium; faeces for the other species.

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to the liver via the portal vein. The eggs of S. haematobium predominantly travel to the
walls of the bladder.

The reaction to infection will depend on where the patient comes from. People from
endemic areas are more likely to develop chronic infection associated with high burden of
infection. People from non-endemic areas generally have acute infection.

Clinical syndromes
Most people infected with Schistosomiasis are asymptomatic. Symptoms are more common
in travellers from non-endemic areas, particularly the acute symptoms. The clinical
syndromes of bilharzia can be divided into 3 stages:

1. 1st stage: Swimmer’s itch. The first stage coincides with the invasion of the human
host by fresh water cercariae. It causes a Swimmer’s itch, which is a localised
dermatitis that can lead to pruritic popular or urticarial rash. It usually occurs within
1 day of exposure and can last up to a week. The reaction is mediated by a
hypersensitivity immune reaction and prior exposure results in a more rapid
response and more severe symptoms. This is more with S. japonicum.
2. 2nd stage: Katayama fever. The second stage coincides with the first 2 weeks of egg-
laying. Katayama fever is a systemic hypersensitivity reaction to the migrating
parasites. This occurs within 2-8 weeks of exposure. It is more common with S.
mansoni & S. japonicum infections. These are also more common with patients from
non-endemic areas. The symptoms of Katayama fever are a sudden onset of fever &
chills, myalgia, arthralgias, dry cough, diarrhoea and headache. In children,
symptoms of encephalitis & cardiac involvement may be present. It often mimics
serum sickness. Lymphadenopathy & hepatosplenomegaly are prominent features
on examination. There is also leukocytosis with eosinophilia. Symptoms usually
resolve over a few weeks, but neck stiffness & coma can occur; it may even be fatal.
The diagnosis relies upon clinical findings & identifying potential exposure. Proper
diagnostic tests, such as egg detection & antibody tests are usually negative, and this
complicates the situation.
3. 3rd stage: Chronic infection. The third stage coincides with the host’s reaction to
eggs deposited in various tissues. The host responds to eggs laid by an intense
inflammatory reaction, with granuloma formation & fibrosis. Chronic infection is
more common in individuals coming from endemic areas in whom the acute stages
of disease are usually not seen. The severity of disease depends on the number of
eggs deposited in the tissues. The precise reaction depends on the tissue affected as
well as the species involved. The clinical syndromes are:
a. Urinary schistosomiasis. Urinary schistosomiasis is caused by S. haematobium
infections. The adult worms are usually located in the vesical plexus. The
worms lay eggs which go and lodge in the distal ureters and bladder, inducing

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 granulomas & fibrosis. It can be asymptomatic, but otherwise the most
common symptom when present is painless terminal haematuria
(microscopic or macroscopic). In severe cases, haematuria may be present
throughout voiding. Symptoms related to iron deficiency anaemia may be
present as well. Other symptoms include dysuria, frequency and
incontinence. With progressive involvement, fibrosis & calcification of the
bladder & ureters leads to obstructive uropathy (which manifests as
hydronephrosis & hydroureter and vesicoureteric reflux). These symptoms
usually resolve with treatment. Obstruction may lead to chronic bacterial
pyelonephritis, and this ultimately leads to renal failure. Chronic
inflammation of the bladder leads to increased risk of developing squamous
cell carcinoma.
b. Bilharzial nephrotic syndrome. Any species of Schistosoma can be associated
with immune complex deposition, which leads to nephrotic syndrome.
c. Intestinal schistosomiasis. Intestinal schistosomiasis is seen with the other
Schistosoma species that are not S. haematobium (most of the time, at least).
The adult worms are located in the mesenteric veins, and the eggs are laid
and migrate to the intestinal wall. The most common symptom is
chronic/intermittent abdominal pain, poor appetite, and diarrhoea with
dysenteric stool. Chronic ulceration may be present, leading to secondary
iron deficiency anaemia. Intestinal polyps may also develop secondary to
granulomatous reactions to egg deposition in the intestinal wall. These
mostly develop in the lower colon & the recto-sigmoid junction. Bowel ulcers
& strictures can develop as a complication. These ulcers can cause protein
loss, which leads to oedema & ascites. Rarely, an inflammatory mass can lead
to obstruction. You can also get acute appendicitis.
d. Hepatic & hepato-splenic schistosomiasis. Liver schistosomiasis is caused by S.
mansoni, S. japonicum and S. mekongi. Hepatic involvement usually results
from massive or repeated infections which cause a large burden of
Schistosoma eggs. These penetrate the liver via the portal vein. Infection can
lead to 2 distinct syndromes. You can get inflammatory hepatic
schistosomiasis, which is the main cause of hepatomegaly & severe
splenomegaly in children. You can also get chronic hepatic schistosomiasis,
which develops years later in young & middle-aged adults with a long
duration of intense infection. Fibrosis in the periportal space leads to the
pathognomonic periportal/Symmer’s pipestem fibrosis, with accompanying
splenomegaly & portal hypertension. Hepatocellular function in this scenario,
however, remains normal. Morbidity & mortality is mainly due to ascites and
bleeding from oesophageal varices.
e. Genital involvement. Genital involvement can occur in S. haematobium
infection. Symptoms in female patients include hypertrophic & ulcerative

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 lesions of the vulva, vagina or cervix. Involvement of the ovaries or fallopian
tubes leads to infertility. In males, it can affect the prostate, spermatic cord,
epididymis or testis. Women with genitourinary involvement are at increased
risk of contracting HIV due to the lesions in their sexual organs.
f. Pulmonary complications. Pulmonary complications are more common in
cases with heavy disease burden, and are mostly seen in patients with
hepatosplenic disease. Pre-sinusoidal portal hypertension fosters the
development of porto-systemic collateral vessels, leading to eggs embolising
to the pulmonary circulation. This leads granulomatous pulmonary
endarteritis, leading to pulmonary hypertension, aneurysmal dilatation of the
pulmonary artery and cor pulmonale2. These late cardiac changes are often
irreversible. Dyspnoea is the principal symptom. The chest X-ray shows fine
military nodules. Initiation of anti-bilharzial therapy can lead to embolization
of adult worms to the lungs which can present with coughing & wheezing.
g. Neurologic complications. Schistosomiasis can sometimes be associated with
serious neurologic complications. Neurologic complications can occur even in
individuals that are lightly infected. The syndromes can occur in 2 ways. 1
way is that eggs may enter the vertebral plexus and go to the spinal cord or
brain. The other way is that adult worms can aberrantly enter the brain or
spinal cord. The 2 main syndromes are spinal cord neuro-schistosomiasis and
localised cerebral/cerebellar neuro-schistosomiasis. Spinal cord neuro-
schistosomiasis manifests as acute or sub-acute myelopathy. Transverse
myelitis occurs with S. haematobium & S. mansoni infection: patients usually
present with rapidly progressing symptoms of myelitis (lower limb pain,
weakness, bowel dysfunction). Localised cerebral/cerebellar schistosomiasis
manifests as focal CNS impairment, seizures and increased intracranial
pressure. It has been described more commonly with S. japonicum.

When symptoms are present, enquire about where the patient comes from and exposure to
fresh water (in patients from endemic areas). Also ask about recent travel history in patients
from non-endemic areas, particularly when they present with acute presentations.

Investigations for schistosomiasis

The investigations done for schistosomiasis are divided into routine tests and diagnostic
tests. Diagnostic tests include:

• Microscopy. Detection of eggs in a urine or stool specimen is usually required to

demonstrate infection. Microscopy is usually used for this. For S. haematobium, a
urine sample is ideal for diagnosis. To improve the sensitivity, the urine sample
should be taken between 10am & 2pm, which is when maximal excretion occurs. The

2
Heart failure in bilharzia can result from rare myocardial granulomatous involvement.

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 diagnostic yield can be improved by sedimentation or filtration of the urine (as well
as the formol ether technique). Eggs of S. mansoni, S. japonicum, S. intercalatum and
S. mekongi are found in stool. You can use concentration techniques to improve the
sensitivity of the test. the infectious species depends on the morphology of the egg:
o S. haematobium measures 115-175µm and has a prominent terminal spine.
o S. mansoni measures 110-170µm and has a prominent lateral spine.
o S. japonicum measures 70-100µm and has a small inconspicuous spine.
o S. mekongi resembles S. japonicum, but has smaller eggs that measure 50-
80µm.
o S. intercalatum measures up 240µm (larger than S. haematobium) and it has
a terminal spine.
Eggs can also be detected in other biopsy specimens, such as rectal, bladder,
intestinal and liver biopsies. It is also important to assess disease intensity. For stool,
you can use the Kato Katz method in which you do quantitative sampling of defined
amounts of stool. You can use syringe filtration for urine samples. These methods
are used for determining disease burden in order to predict the likelihood of
developing complications.
• Serologic testing. Advances in serological testing have increased their usefulness in
diagnosing schistosomiasis. You can use ELISA, which has high sensitivity &
specificity. The tests, however, cannot distinguish between a current infection and a
past infection. They are therefore not useful for post-treatment follow-up, and they
are not as beneficial in endemic areas. They are useful, however, in diagnosing
travellers from non-endemic areas. Antibody tests are usually negative when the
patients have Katayama fever, but they become positive before eggs are detectable.
• Antigen detection. Antigen detection tests measure circulating antigens regurgitated
by schistosomes in the circulation. The tests measure 2 gut-associated antigens:
circulating cathodic/cationic antigen (CCA) and circulating anionic/anodic antigen
(CAA). These antigens are present in the circulation during active infection. Antigen
detection techniques have equal sensitivity to urine/stool concentration techniques.
Antigen titres correlate with severity of disease. They are more useful in assessing
treatment efficacy since they disappear after cure (after 5-10 days post-treatment).

Other routine tests include:

• FBC. A routine FBC may reveal eosinophilia in infected patients (>0.4 × 109 cells/L).
The degree of eosinophilia correlates with stage, duration and intensity of infection.
1 2
- s of infected patients have peripheral eosinophilia, and this is frequently marked
3 3
early during infection. Eosinophilia is also a prominent feature in Katayama fever.
Features of iron deficiency anaemia may be present in patients who have had
chronic blood loss. Thrombocytopaenia may be a feature in patients with
hepatosplenic schistosomiasis, and this is a result of splenic sequestration.

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 • LFTs. LFT levels are usually normal since fibrosis occurs within hepatic blood vessels
instead of within the liver parenchyma itself. A mild increase in ALP & GGT may be
present.
• Imaging. Imaging is used to detect complications of schistosomiasis. Chest X-rays are
used to detect pulmonary involvement or to investigate cough & wheezing post-
treatment. A plain KUB X-ray may show urinary tract calculi – a characteristic “foetal
head” appearance – and a CT-IVU may demonstrate ureteric strictures, as well as
other abnormalities such as hydronephrosis. Cystoscopy may show bladder
irregularities such as bladder polyps or a bladder mass. Ultrasound can be used to
image the liver, and this may show periportal fibrosis in late S. japonicum & S.
mansoni infections. It can also detect splenomegaly, portal vein dimensions and the
presence of collateral vessels. Echocardiography is required in all patients with
hepatosplenic schistosomiasis, particularly when there are pulmonary complications
to detect/exclude aneurysmal pulmonary artery dilatation & cor pulmonale. CT/MRI
is required for all patients with suspected neurological complications.

Treatment
All patients with evidence of infection should be treated, since adult worms can live for
years and cause complications. The aim of treatment in endemic areas is to decrease the
worm load and therefore minimise the chronic effects of egg deposition. It may not always
be possible to completely eradicate adult worms, and re-infection is common. Nonetheless,
a 90% reduction in egg output has been achieved in mass treatment programmes, and in
light infections with no risk of re-exposure the drugs are usually curative. Treatment of
schistosomiasis leads to reversal of chronic effects. Reversal of periportal fibrosis & portal
vein thickening has been documented. However, late-stage fibrosis & associated
complications (oesophageal varices & cor pulmonale) are irreversible.

The treatment options for schistosomiasis include:

• Praziquantel. Praziquantel is the drug of choice in treatment of schistosomiasis and

is effective against all types. It induces ultrastructure changes in the tegument of
mature adult worms that increase permeability to calcium channels, which allow
calcium to enter the worm. Increased cytosolic calcium concentrations lead to
paralysis of the worm. It also causes exposure of schistosomal antigens to host
defences, which assist in destroying & clearing worms3. For infections with S.
haematobium, S. mansoni and S. intercalatum, the recommended dose is 40mg/kg
taken as a single or in divided doses. For S. japonicum & S. mekongi, the
recommended dose is 60mg/kg taken in 2-3 divided doses that are at least 3 hours
apart. Praziquantel has cure rates of 85% in endemic areas, as well as reducing

3
Treatment therefore partly relies on the strength of the host immune system.

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 intensity of infection by more than 90%. Praziquantel has no effect on immature
worms or eggs, and therefore is not useful in early infection (1st & 2nd stages).
Pregnant & lactating women should not be excluded from praziquantel treatment
regimens.
• Glucocorticoids. Glucocorticoids are used in 2 scenarios:
o Katayama fever. The optimal treatment regimen for Katayama fever is not
known (because of lack of clinical trials). Praziquantel is ineffective, and
therefore treatment is often supportive. Glucocorticoids are used to
ameliorate symptoms. You can give high-dose prednisolone (40mg daily for 5
days). However, glucocorticoids will not do anything about attacking worms.
Ultimately praziquantel therapy will need to be initiated. Praziquantel is
initiated 6-10 weeks following presentation, after the adult worms have
matured. Starting praziquantel straight after diagnosis, however, is an
alternative, and it reduces worm load and reduces the risk of ectopic
localisation. When the second approach is used, glucocorticoids should be
started as well.
o Neurologic disease. Glucocorticoids are used as an adjunct to praziquantel in
treatment of neurologic disease. Praziquantel therapy evokes an
inflammatory response, and if this happens in neurologic disease it can cause
neurologic worsening. Anticonvulsant therapy may also be needed if there
are seizures.

Patients are monitored by:

• Measuring eosinophil count, if they had eosinophilia.

• Examination of stool or urine for eggs.
• Antigen testing.

Patients with oesophageal varices benefit from propranolol and from sclerotherapy or shunt
procedures.

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 Gonorrhoea
Gonorrhoea is a sexually-transmitted infection caused by Neisseria gonorrhoeae.
Gonorrhoea occurs naturally only in humans. It is the second most common sexually-
transmitted disease after chlamydia. Infection rates are higher in males & females, and its
incidence is higher amongst black people than amongst white or Hispanic people. The peak
incidence of disease is 15-24 years of age. More than 300 000 cases are diagnosed every
year in the United States.

Neisseria gonorrhoeae
N. gonorrhoeae belongs to the Neisseria genus, which is an aerobic Gram-negative coccus
typically arranged in pairs (diplococcic). The outer surface of N. gonorrhoeae is not covered
with a polysaccharide capsule, but has a negative charge. The organism has fastidious
growth requirements (grows at 35-37°C in carbon dioxide-enriched air), and therefore
cannot be cultured in just any culture medium. The organism is an intracellular organism.

N. gonorrhoeae has multiple antigens on its outer surface. It has pilli, which extend from the
cytoplasmic membrane through the outer membrane. These pilli mediate a number of
functions, such as attachment to the host cells, transfer of genetic material and motility.
These pilli contain pilli proteins (called pilins). There are also porin proteins, which are
integral outer membrane proteins that form pores & channels for transport of nutrients into
cells and waste products out of cells. One important porin protein (PorB) is important as it
interferes with neutrophil degranulation and thus protects the bacterium from destruction
within the phagosome. PorB also facilitates epithelial invasion, as well as resistance to
complement-mediated serum killing. Iron is also important for the survival of Neisseria
organisms. They can compete & bind host cell transferrin. There are also Opa proteins
(opacity proteins), which are proteins that facilitate binding to epithelial cells as well as cell-
to-cell signalling. They are responsible for producing opaque colonies when grown in
culture1. A major antigen in the cell wall is the LOS (lipo-oligosaccharide) protein, which
possesses endotoxin activity (through a lipid A moiety).

Pathogenesis
N. gonorrhoeae is primarily spread by sexual contact (oral or genital; also includes
homosexuals). It can also be spread vertically from mother to child during vaginal delivery.
The risk of contracting infection is higher in women who have sex with infected men (50%)

1
Opaque colonies are predominantly found in local disease, while translucent colonies are found in PID &
disseminated disease.

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than in men who have sex with infected women (20%). Asymptomatic carriage is higher
amongst women.

N. gonorrhoeae can infect any columnar epithelium, such as the urethra, cervix, rectum,
pharynx and conjunctiva. The organisms attach & penetrate mucosal cells through the use
of their pilli. Following attachment, the organism is phagocytosed by a process called
parasite-directed endocytosis. Here, they multiply and then pass into the sub-epithelial
space where infection is established. In this sub-epithelial space, the gonococci are
phagocytised and internalised in phagosomes. Gonococcal LOS stimulates release of TNF-α
which is responsible for most of the symptoms. Antibodies are formed against pilin, Opa and
LOS proteins.

Normal human beings are able to evade infection through activation of complement and
deposition of terminal complement complexes on the cell surface. However, some strains
are serum-resistant and dissemination is therefore possible.

Risk factors
The risk factors of gonorrhoea infection are those that increase acquisition (through sexual
contact) as well as those that increase progression. They include:

• Recently changed sexual partner.

• Multiple sexual partners.
• Being unmarried.
• Young age (15-24 years).
• Minority ethnicity.
• Low educational & socioeconomic status.
• Substance abuse.
• Previous gonorrhoea.
• Concurrent HIV infection.

Clinical manifestations
Up to 50% of women & 10% of men are asymptomatic. The clinical manifestations depend
on the location of the infection:

• Local infection. In the majority of cases, patients present with the clinical disease
gonorrhoea, which is a genital disease.
o Gonorrhoea in men. In men, the infection is commonly restricted to the
urethra. The most common syndrome is that of anterior urethritis causing
dysuria & discharge. This comes after a 2-5 day incubation period.
Complications include epididymitis, prostatitis and peri-urethral abscess.

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 Rectal infection can occur in homosexual males, and presents with proctitis,
discharge and itch.
o Gonorrhoea in women. In women, the primary site of infection is the
endocervix, because the organism cannot infect the squamous epithelium of
the vagina. Symptomatic women typically experience vaginal discharge,
dysuria, abdominal pain and intermenstrual bleeding. Ascending genital
infections can occur, including salpingitis, tubo-ovarian abscess and PID2. This
is observed in 10-20% of women, and may be the presenting feature. They
can also get a Bartholin’s abscess. Gonorrhoea is one of the leading causes of
tubal infertility. Rectal infection occurs due to local spread.
Pharyngitis can occur in patients who engage in oral sex.
• Systemic/disseminated infection. Dissemination occurs secondary to
gonococcaemia. It can complicate with:
o Arthritis. Gonococcus can cause septic arthritis, which is usually
monoarticular or pauci-articular.
o Skin infections. Disseminated gonorrhoea produces a characteristic
papular/pustular rash. The lesion is a necrotic greyish central lesion on an
erythematous base associated with fever & malaise. Skin infections are
thought to arise from bacterial embolization. The skin lesions are self-
limiting, and last for 3-4 days without treatment.
o Reiter’s syndrome. This is a reactive arthritis, and it involves a triad of
polyarthritis, uveitis and urethritis. It may be associated with mucocutaneous
lesions.
o Endocarditis. Gonoccocal infection can cause subacute bacterial infective
endocarditis.
Dissemination is more common amongst females (1-3%) than men (much lower).
This is because of the greater proportion of untreated infection found in women.
• Neonatal infection. Gonococcal infection amongst pregnant women was estimated
to be at least 1% in developed countries and 3-15% in developing countries. The
majority of infected children develop ophthalmia neonatorum, which is
characterised by a purulent conjunctivitis, a profuse exudate and swelling of the
eyelids. Without treatment, it can spread from superficial epithelial layers to
subconjunctival tissues and cornea, leading to ulceration, scarring and eventual
visual impairment. You can also get localised infection in the pharynx, vagina,
urethra and anus, and you can get a scalp abscess (from use of a foetal scalp
electrode). Dissemination can also occur, and septic arthritis is the most common
manifestation. Gonococcal bacteraemia & meningitis can also occur.

Diagnosis of gonorrhoea

2
PID is associated with development of peri-hepatic adhesions, called Fitz-Hugh-Curtis syndrome.

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The diagnosis of gonorrhoea can be made clinically. Nonetheless, lab diagnosis can be
conducted as follows:

• Microscopy. You can view your specimen under the microscope using a Gram-stain.
You will see Gram-negative diplococci. Microscopy is very sensitive (90%) and
specific (96%) for identification of organisms on clinical specimens from symptomatic
men. From asymptomatic men, however, the sensitivity is ≤60%. It is also relatively
insensitive to detection of gonococcal cervicitis, both symptomatic & asymptomatic
forms. Microscopy is also useful for examining for gonococcal infection in joint
aspirates, but not from skin lesions, anorectal infections or pharyngitis. Microscopy
can be used to examine CSF.
• Culture. Culture on selective media has a sensitivity of 95%. N. gonorrhoeae grows
on chocolate agar in an atmosphere enriched with 5% carbon dioxide. An example of
a modified medium is the Thayer-Martin medium. For collection of the specimen,
the endocervix must be properly exposed, although you can also use rectal
specimens.
• Nucleic acid amplification tests. These have been developed for direct detection of
N. gonorrhoea organisms in clinical specimens. They are sensitive & specific, and
they are rapid. They also have the advantage of being able to be combined with
Chlamydia nucleic acid amplification tests.
• Antigen detection. Antigen testing is less sensitive than nucleic acid amplification
tests & culture.
• Blood culture. In patients with disseminated disease, blood cultures are positive
during the first week of disease. In addition, special handling is required, as some
supplements present in the blood culture medium are toxic to Neisseria.

Treatment
Treatment of gonorrhoea is divided into pharmacologic & no-pharmacologic:

Pharmacologic treatment

This is indicated for:

• Patients who have a positive test result for gonorrhoea on microscopy, culture or
NAAT.
• People who recently had sexual contact with an infected person.

For uncomplicated cases, you can treat using single dose ceftriaxone 500mg IM. You can
also give single-dose amoxicillin 3g together with probenecid 1g, ciprofloxacin 500mg or
ofloxacin 400mg. Longer courses of antibiotics are indicated for complicated infections

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(disseminated disease) – for arthritis, treatment may need to be extended for 7-14 days3. If
chlamydia has not been excluded, treatment is combined with azithromycin 1g stat, or
doxycycline 100mg bd for 7 days.

After treatment is complete, a follow-up assessment & culture should be done after 72
hours.

Non-pharmacologic treatment

You need to trace contacts of the patient so that the sexual contacts may be treated for
infection as well. You also need to encourage the patient to engage in safe sexual practices:
promote sexual negotiation skills and purge abusive relationships.

Neonatal gonorrhoea

Infants with ophthalmia neonatorum should be hospitalised and observed for response to
therapy and for disseminated disease. Treatment includes a single dose of ceftriaxone 25-
50mg/kg (not to exceed 125mg) IV/IM. Treatment is also indicated for infants of
symptomatic mothers. Topical antibiotic therapy alone is inadequate, and unnecessary
when systemic antibiotics are being given. The eyes should be irrigated frequently with
saline until the discharge clears. Septic arthritis is treated with ceftriaxone 25-50mg/kg for 7
days, and the duration should be extended to 10-14 days if meningitis is present.

The most effective way of preventing new-born infections is to diagnose & treat these
infections in pregnant women. Prophylactic eye antibiotic therapy can be given to at-risk
babies: you can use 1% silver nitrate, 1% tetracycline or 0.5% erythromycin eye ointment.

3
There may be need for joint drainage.

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 Syphilis
Syphilis is a chronic infectious disease caused by Treponema pallidum. In its early stages, it is
easy to treat, but if left untreated it can cause complex sequelae in many organs and
eventually lead to death. In the West, it is the 3rd most common infection after gonorrhoea
& chlamydia. Many of these infections in the developed world occur in homosexual males,
and many are co-infected with HIV.

Treponema pallidum
T. pallidum belongs to the bacterial order of Spirochaetales, which is a group of thin, helical
Gram-negative bacteria. The organism has pointed straight ends, and has 3 periplasmic
flagella. T. pallidum cannot be cultured extracellularly, because it is an intracellular
organism. T. pallidum lacks the TCA cycle, and therefore relies on the host cell for synthesis
of all purines, pyrimidines and most amino acids. The bacteria are micro-
aerophilic/anaerobic and are therefore extremely sensitive to oxygen toxicity.

The bacterium has lipoproteins anchored to the inner surface of the cell membrane and
none of them are exposed to the outer membrane. It therefore lacks any system-specific
antigens and therefore successfully evades the immune system. The bacteria are able to
resist phagocytosis by coating themselves with host fibronectin, allowing interaction with
host cells. Most investigators believe that the tissue destruction & lesions found in syphilis
are due to the host immune response. The bacterium contains hyaluronidase which
facilitates perivascular infiltration.

Human beings are the only natural host. T. pallidum in its acquired form is spread through
close sexual contact with an unprotected person. It can also be acquired through vertical
transmission from mother to child (congenital form). The organism enters the host through
breaches in the squamous or columnar epithelium. Primary infection of non-genital sites is
rare. The bacterium is not highly contagious: the risk of acquiring infection after a single
sexual contact is estimated to be 30%. However, this only occurs during the early stages of
disease.

Clinical course
Acquired syphilis follows a course of 3 stages:

• Primary syphilis. This is the earliest stage of the disease. The bacterium has a latency
period of 10-90 days (21 days on average), after which a papule develops on the site
of inoculation. This papule ulcerates, leaving a hard/firm painless ulcer with elevated
borders. Histologically, the lesion reveals an endarteritis & periarteritis, and the ulcer

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 is infiltrated with numerous neutrophils & macrophages. The spirochaetes are often
engulfed by phagocytes but they survive. In most patients, a painless regional
lymphadenopathy appears 1-2 weeks after the appearance of the ulcer. The ulcer
usually heals spontaneously after 2-3 weeks.
• Secondary syphilis. The bacterium is disseminated in blood early during infection.
The infection spreads throughout the body, and there are prominent skin lesions
dispersed all over the body surface (including the palms & soles but excluding the
face in 75% of cases). The rash is a red-brown maculopapular rash that is non-itchy
and may be scaly, and the lesions are infectious. This stage appears 6 weeks to 6
months after infection. Constitutional symptoms appear (fever, night sweats, weight
loss), accompanied by sore throat, malaise and arthralgia. The patient may also
develop condylomata lata (sing. condyloma latum; raised warty-like plaque lesions)
in the perianal area and many other wet surfaces of the body. They also get
superficial confluent ulcers on mucosal surfaces (mouth & genitalia) called snail-
1
track ulcers. Other features include alopecia, hepatitis (in up to 3 of patients,
particularly if infected with HIV), hepatosplenomegaly, glomerulonephritis,
periosteitis and acute neurological features (uveitis, aseptic meningitis and optic
neuritis). The disease then progresses to either latency or late stage syphilis.
During the latent phase, the symptoms ablate over 3-12 weeks. Symptoms may
return after many years. The patient remains with positive syphilis serology but with
no symptoms. During latency, the patient is not infectious.
1
• Tertiary (late) syphilis. Approximately 3 of patients progress from secondary syphilis
straight to tertiary syphilis. Tertiary syphilis can be divided into late benign1 syphilis
and syphilis with end-organ damage (or quartenary syphilis). The main characteristic
of tertiary syphilis is the diffuse chronic inflammatory reaction to the spirochaetes,
with subsequent destruction of many organs. The chronic inflammatory reaction is
characterised by the presence of numerous granulomata (called gummas). In late
benign syphilis, the gummas are found anywhere on skin & mucosae and in bones,
joints and in viscera such as the lungs, liver (hepar lobatum) and testes. Gummas are
commonly found in the skull, tibia, fibula and clavicle, although any bone can be
affected. When end organs are involved (quartenary syphilis), the manifestations
include:
o Cardiovascular (cardiovascular syphilis). There can be ascending aortic
aneurysm, aortic valve regurgitation, aortitis and stenosis of the coronary
ostia.
o Neurologic (neurosyphilis). Subacute meningitis, cranial nerve palsies,
strokes, tabes dorsalis2 (ataxia, numbness of legs, chest and bridge of nose,
lightning pains, gastric crises, loss of reflexes, up-going plantar reflexes, Argyl

1
This stage is benign in terms of response to treatment rather than clinical manifestations.
2
Tabes dorsalis is due to demyelination of dorsal roots leading to a complex de-afferentiation syndrome.

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 Robertson pupil, ptosis, optic atrophy, Charcot’s joints), general paresis of
the insane (GPI) [dementia, psychosis, seizures, tremor]3. There may also be
an expanding intracranial mass (gumma) and paraparesis from spinal
meningovasculitis.

All stages are due to an endarteritis obliterans.

Diagnosis of syphilis
The diagnosis of syphilis is made as follows:

• Microscopy. Microscopy is the most sensitive & specific method of identification of

T. palladium organisms. They are identified in chancre fluid or in the mucous patches
of secondary lesions. T. pallidum is too thin to be identified by light microscopy.
Therefore, you use dark field microscopy or you use special fluorescent stains. The
diagnosis is reliable when an experienced microscopist examines the specimen soon
after collection because the organisms do not survive transport to the laboratory
and tissue debris can be mistaken for non-viable spirochaetes. These limitations can
be circumvented using the direct fluorescent antibody test on the microscopy
specimen. This will identify even the dead organisms.
• Serologic tests. Despite microscopy being the gold standard for diagnosis, the
majority of patients are diagnosed on the basis of a serologic test. The serologic tests
are divided into treponeme-specific & treponeme-nonspecific tests. Treponeme-
specific tests detect antibodies produced against T. pallidum itself and are therefore
more specific & more diagnostic. They become positive earlier than treponeme-
nonspecific tests and they remain positive even after treatment. Therefore, being
more specific & confirmatory, they are used after a positive treponeme-nonspecific
test has been done. However, they will not differentiate between syphilis and other
treponemal diseases such as yaws, bejel and pinta4. The treponeme-specific test are:
o T. pallidum haemagglutination assay (TPHA)/ T. pallidum particle
agglutination (TP-PA) test. This is a microtitre agglutination test. Gelatin
particles sensitised with T. pallidum antigens are mixed with the patient’s
serum. If the antibody is present, the particles agglutinate.
o Fluorescent treponemal antibody absorption (FTA-Abs) test. This was the
most commonly used treponeme-specific test historically. The organism is
immobilised on a glass slide and the slide is overlaid with the patient’s serum.
Fluorescein-labelled antihuman antibodies are then added to detect the
antibodies from the patient’s serum that attach to the organisms. This test is
technically difficult to conduct & difficult to interpret.

3
This is fatal within 3 years if left untreated.
4
Yaws is caused by T. pallidum pertenue, bejel is caused by T. pallidum endemicum and pinta is caused by T.
carateum. Syphilis is caused T. pallidum pallidum.

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 o Enzyme-linked immunosorbent assay (ELISA). You can conduct syphilis ELISA
tests for IgG & IgM.
Treponeme-nonspecific tests measure the antibodies against lipids (particularly
cardiolipin) released from damaged cells during T. pallidum infection. They are rapid
& inexpensive, and they are useful as screening tests for at-risk patients (such as
pregnant women). They have a sensitivity of 70-75% during primary infection and
100% for secondary disease, but their detection wanes off in late disease and after
treatment. They produce false positives during pregnancy, recent immunisation,
pneumonia, malaria, SLE, TB, leprosy, rheumatoid arthritis and after multiple blood
transfusions. The treponeme-nonspecific tests are:
o Rapid plasma reagin (RPR) & Venereal Disease Research Laboratory (VDRL)
tests. Both tests measure the flocculation of cardiolipin antigen by the
patient’s serum. For VDRL to be conducted, however, complement needs to
be inactivated 30 minutes before. Furthermore, only VDRL should be
conducted on CSF specimens.
o Unheated serum reagin (USR).
o Toluidine red unheated serum test (TRUST).

Neurosyphilis is diagnosed by the presence of high antibody titres & neurologic signs. The
antibody test is troublesome. VDRL is highly specific for detection of T. pallidum in CSF
specimens, but is not sensitive. Therefore, a positive test result is diagnostic but a negative
test result does not rule out the disease. In contrast, FTA-Abs has high sensitivity but low
specificity (because treponemal antibodies passively cross from blood to CSF). A positive
FTA-Abs result is not particularly diagnostic, but a negative result rules out infection. T.
pallidum is not amenable to in vitro culture.

Treatment
Syphilis is treated medically using antibiotics. You use long-acting benzathine penicillin (X-
pen or penicillin G) 600mg im od, and you can use doxycycline 100mg b.d. or erythromycin
500mg q.i.d. (or azithromycin) as alternatives. The duration of treatment depends on the
stage of disease.

• Early stage disease (primary & secondary syphilis) should be treated for 10 days.
• Late stage disease should be treated for 2 weeks. Established neurologic disease is
arrested but not reversed by penicillin. If the patient is HIV positive, neurosyphilis
may not be reversed by penicillin alone.

Beware of Jansen-Herxheimer reaction with penicillin. It is commonest in secondary disease

and more severe in tertiary disease5. It is caused by release of bacterial endotoxins after

5
It can be, however, found in other diseases caused by spirochaetes such as Lyme disease, leptospirosis and
relapsing fever.

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destruction by antibiotics. Patients presents with fever, tachycardia and vasodilation hours
after the first dose of antibiotic. If a patient develops this, consider giving steroids.

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 Chlamydia
Chlamydia is the commonest bacterial STI in the world. In the UK, up to 14% of individuals
under the age of 25 are infected with the disease. It often found together with other
organisms: up to 20% of men & 40% of women with gonorrhoea also have concurrent
chlamydia infection. Chlamydia is often asymptomatic and therefore many infections go
unrecognised.

Chlamydia trachomatis
Genital chlamydia is caused by Chlamydia trachomatis. There are 2 other organisms in the
species that cause human disease: C. pneumoniae, which is responsible for respiratory
infections, and C. psittaci, which mainly causes pneumonia.

Chlamydia species are small Gram-negative bacilli which are obligate intracellular organism.
The organisms lack the rigid peptidoglycan found in the cell walls of many other bacteria,
but they have a central dense core surrounded by a cytoplasmic membrane and a double-
layered outer membrane. The cell wall contains a lipopolysaccharide which has weak
endotoxin activity. Chlamydia organisms have a unique developmental cycle, alternating
between metabolically-inactive but infectious forms (called elementary bodies, EB) and
metabolically-active non-infectious forms (called reticulate bodies, RB). The EBs bind to
host cells & enter them, where they transform into RBs within 6-8 hours. They utilise host
ATP for their energy requirements & replication. After replication, the RBs then reorganise
into small EBs which are released after the cell ruptures.

In the outer membrane, there is a protein called the major outer membrane protein
(MOMP), which is a major structural component that is unique for each species. Variable
regions in the gene encoding this protein are found in C. trachomatis and are responsible for
the 18 variants – called serovars – of the organism. C. trachomatis is divided into 2 biovars
(trachoma and lymphogranuloma venereum, LGV) into which all the serovars are grouped.

Serovars Disease
A, B, Ba, C Trachoma
D-K Urogenital disease
L1, L2, L2a, L2b, L3 Lymphogranuloma venereum
The range of cells that C. trachomatis can infect is limited to non-ciliated columnar, cuboidal
and transitional epithelium. This is found on the mucous membranes of the urethra,
endocervix, endometrium, fallopian tubes, anorectum, respiratory tract and conjunctivae.
The LGV serovars are more invasive as they replicate in mononuclear phagocytes.

C. trachomatis gains access to the body through minute abrasions or lacerations in the
mucosal barrier involved. This is mainly through:

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 • Unprotected sexual intercourse with an infected individual.
• Perinatal infection by passage of child through infected genital tract.
• Respiratory droplets.
• Faecal contamination.
• Contaminated hands or clothing.

Studies of the natural history of chlamydia are scarce. The incubation period of the disease
is 7-14 days. From a study done, spontaneous resolution of infection was seen in only 18%.
The majority of patients persist as asymptomatic carriers.

Clinical syndromes
The clinical syndromes associated with chlamydia are:

• Trachoma. This is caused by serovars A, B, Ba and C. Initially patients have a follicular

conjunctivitis with diffuse inflammation that involves the entire conjunctiva. Scarring
of the conjunctiva causes entropion of the eyelids. This entropion leads to abrasion
of the cornea, corneal ulceration, scarring and pannus formation (invasion of vessels
into the cornea), with subsequent loss of vision. Chlamydia is the leading cause of
preventable blindness in the world.
• Adult inclusion conjunctivitis. This is caused by the serovars responsible for genital
infections. It is characterised by mucopurulent discharge, keratitis, corneal infiltrates
and some corneal vascularisation. Chronic infection leads to corneal scarring.
• Neonatal conjunctivitis. This occurs in neonates exposed to Chlamydia at birth. After
an incubation period of 5-12 days, the infant’s eyelids swell, hyperaemia occurs and
a copious purulent discharge occurs. The disease can run a course of 12 months,
during which conjunctival scarring & corneal vascularisation occur. Infants who are
left untreated or treated with topical therapy only are at risk of atypical pneumonia
with C. trachomatis.
• Infant pneumonia. The onset of infantile pneumonia is often 2-3 weeks after birth
(during which the baby was infected). Rhinitis is initially observed, after which a
distinctive staccato cough develops. The child remains afebrile throughout the
illness. Radiologic signs of infection can persist for months.
• Urogenital chlamydia. Most genital tract infections in women are asymptomatic
(close to 80%). The clinical manifestations are: Bartholinitis, cervicitis (most
common), endometritis, perihepatitis, salpingitis and urethritis. A mucopurulent
discharge is often seen in symptomatic infections. In women, chlamydia complicates
with PID in 30% of cases. It often presents with a vaginal discharge, post-coital or
intermenstrual bleeding and lower abdominal pain. In men, however, the majority of
infections are symptomatic, and only 25% of patients will have unapparent

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 infections. This presents as non-gonococcal urethritis1, which is a urethral discharge
and/or dysuria coupled with documented urethral inflammation (as identified by a
mucopurulent discharge or leukocytes on Gram stain). Chlamydial infection is also
thought to be the initiating event of Reiter syndrome (urethritis, conjunctivitis,
polyarthritis and mucocutaneous lesions).
• Lymphogranuloma venereum (LGV). This is a different form of chlamydia with a
more chronic course. It caused by serotypes L1, L2, L2a, L2b and L3. Unlike mucosal
chlamydia infections, LVG is predominantly a lymphoproliferative disease. There has
been an upsurge in the number of cases occurring in male homosexuals. LGV follows
a 3-stage course:
o The primary lesion is a painless ulcerating papule on the genitalia occurring
7-21 days following infection. This is frequently unnoticed as it heals rapidly.
The patient may also experience fever, headache and myalgia.
o The secondary stage follows days to weeks after the painless papule heals. It
is characterised by regional lymphadenopathy (the inguinal syndrome). This is
often painful & fixed, and the overlying skin develops a dusky erythematous
appearance. The nodes become fluctuant, producing buboes, and rupture to
form draining fistulas. Systemic manifestations include fever, chills, anorexia,
headache, meningism, myalgia and arthralgia. Patients can also develop
proctitis (the anorectal syndrome). It results from lymphatic spread of the
infection from the cervix or vagina. In men it results from spread from the
urethra, or from anal intercourse. The patient can develop perianal abscesses
that resemble Crohn’s disease.
o The third stage is characterised by progression to a chronic ulcer, fistula or
stricture. Destruction of local lymph nodes can result in lymphoedema, which
complicates with elephantiasis. You can also get frozen pelvis2 and infertility
from LGV.
An ocular form exists which has been implicated in Parinaud oculoglandular
conjunctivitis. This is a conjunctivitis associated with pre-auricular, submandibular
and cervical lymphadenopathy.
• Other manifestations. These include
o Epididymitis. In epididymitis, patients present with unilateral testicular pain
& tenderness, hydrocele and palpable swelling of the epididymis. On
ultrasound, you can find epididymal hyperaemia & swelling, although a
normal ultrasound does not rule out infection. Asymptomatic urethritis often
accompanies epididymitis.
o Prostatitis. Chlamydia can cause chronic prostatitis. Symptoms include
dysuria, urinary dysfunction, pain on ejaculation and pelvic pain.

1
Chlamydia accounts for 19-31% of cases of non-gonococcal urethritis (NGU) – it is the commonest cause.
2
Frozen pelvis is a condition in which the pelvic organs are distorted & tethered to each other due to
adhesions.

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 1
o Reactive arthritis. 1% of men with urethritis develops reactive arthritis, and
3
of these patients develop the complete reactive arthritis triad (RAT; formerly
known as Reiter syndrome): arthritis, uveitis and urethritis.

Diagnosis of chlamydia
The diagnosis of chlamydia is made on the basis of a characteristic clinical picture, positive
screening test or when another indication suggests presence of chlamydia (e.g. PID). It can
be diagnosed: based on cytologic, serologic or culture findings; direct detection of the
antigen in clinical specimens; and use of nucleic acid-based tests. Specimens must be taken
from involved sites rather than just pus or a vaginal exudate3; high vaginal or endocervical
swabs should be taken in women. In men, you take first-catch urine4. In those that engage in
receptive anal intercourse, you do a rectal swab. You can also do a conjunctival swab.

The testing modalities include:

• Nucleic acid-based tests. You can use a nucleic acid probe test or a nucleic acid
amplification test (NAAT). This is now the diagnostic test of choice for Chlamydia
infection. Care must be taken to monitor for the presence of inhibitors to the
amplification reaction (e.g. urine). The drawbacks of using NAAT are: same-day
results cannot be obtained; and it is too expensive to use in resource-limited
settings.
• Culture. This remains the most specific method of detecting chlamydia, but is still
insensitive when compared to NAAT (70-85% when a single endocervical smear is
taken). The culture medium includes in-vitro cell lines that normal Chlamydia
organisms infect. The culture is then stained with iodine- or specific fluorescin-
labelled antibodies targeted against inclusion bodies. The sensitivity of culture is
affected if inadequate specimen is taken or if viability is lost during transport.
Culture is the gold standard of isolation of chlamydia in neonatal infection.
• Serologic tests. This is of limited value in urogenital chlamydia as it cannot
differentiate between current & past infection5. Demonstration of a significant
increase in antibody levels can be used, albeit the increase not being demonstrable
for a month or longer. Antibody tests can be used for LGV, however, and this can be
through complement fixation (CF), micro-immunofluorescence (MIF) and enzyme
immunoassay (EIA). CF is directed against species-specific LPS (lipopolysaccharide)
and therefore a 4-fold increase/single titre ≥ 1:256 is highly suggestive of LGV.
• Antigen detection. You can use direct immunofluorescence staining, or you can use
ELISA. The tests target either chlamydial MOMP or LPS. However, because antigenic

3
Pus & exudates usually contain a small number of living cells in which C. trachomatis organisms can be found.
4
The patient must not have voided within the last 2 hours.
5
IgM antibodies may not be detected in adolescents & young adults with active infection, and this limits their
usefulness. They can be measured, however, in infants with chlamydia pneumonitis.

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 determinants of LPS may be shared with other bacteria, the tests that detect LPS are
less specific.

Treatment
The goals of treatment of chlamydia are:

• Attain resolution of symptoms.

• Preventing the development of complications related to chlamydia.
• Decrease the risk of transmission of infection to others. This entails management of
sexual partners.

Treatment of chlamydia

The bacterial EBs are generally resistant to antibiotics, while the active MBs are not.
Therefore, the antibiotic chosen should have good intracellular penetration and a relatively
long half-life. In general, chlamydia is sensitive to tetracyclines & macrolides – doxycycline &
azithromycin are used. You can also use long-acting fluoroquinolones (ofloxacin &
levofloxacin) but they require a full week’s therapy and they are relatively more expensive.

• Uncomplicated infection. You can give doxycycline 100mg po bd for 7 days or

azithromycin 1g as a single dose. You can also give: erythromycin 500mg qid for 7
days; levofloxacin 500mg po od for 7 days; ofloxacin 300mg po bd for 7 days.
• Co-infection with gonorrhoea. In co-infection, you give ceftriaxone 1g as a stat dose.
This is safe to use in pregnancy. This may be empirical in females, as Gram-staining
will reveal a number of non-pathogenic commensals when you do a vaginal swab.
• Pregnant women. Treatment of chlamydia in pregnant women prevents
transmission of the bacterium during delivery. You can give: azithromycin 1g as a
single dose; erythromycin 500mg po qid for 7 days (or 250mg po qid for 14 days);
amoxicillin 500mg po tds for 7 days. Cure rates in pregnant women are lower than in
the general population, particularly with amoxicillin.
• Lymphogranuloma venereum. Medical therapy cures infection and helps prevent
further damage to pelvic structures. For LGV, you can give: doxycycline 100mg po bd
for 14 days; erythromycin 500mg po qid for 21 days; azithromycin 1g po weekly for 3
weeks. Buboes may require needle aspiration or incision & drainage. Pregnant
mothers should be treated with azithromycin.
• Neonatal chlamydia. Chlamydia conjunctivitis must be treated on the basis of a
positive diagnostic test. However, chlamydial pneumonia must be treated on a
presumptive diagnosis. You give erythromycin 50mg/kg orally per day in 4 divided
doses for 14 days6. Topical therapy is not indicated and there is a high failure rate.

6
Administration of erythromycin to neonates predisposes to development of infantile hypertrophic pyloric
stenosis.

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 You can also give systemic azithromycin 20mg/kg orally for 3 days to treat
conjunctivitis.

Counselling

The following counselling points must be stressed:

• Medication adherence. Treatment adherence must be encouraged, particularly if

doxycycline is prescribed.
• Sexual activity. Patients should avoid sexual activity until 7 days after initiating
treatment. Persistence of symptoms may indicate infection with another pathogen,
e.g. Trichomonas vaginalis.
• Sexual contacts. All sexual contacts that the patient had in the last 60 days must be
contacted and informed of the STI. They should also receive standard chlamydia
therapy, unless any symptoms suggest otherwise (e.g. for LGV).
• HIV testing. All patients must be tested for HIV.

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 Sepsis
Sepsis is defined as the presence of infection and SIRS. It is the leading cause of death in the
non-coronary ICU setting. Any infection can potentially lead to sepsis. Mortality rates are
high – in the range of 20-60%.

Pathogenesis
Sepsis is thought to arise from triggering of the innate immune response & inflammatory
cascade due to recognition of pathogen-associated molecular patterns (PAMPs) on
pathogens. These molecular patterns are seen on pathogens, and for septicaemia to occur,
there needs to be systemic dissemination of either an endotoxin or an exotoxin. An
endotoxin is a lipopolysaccharide derived from the cell wall of a Gram-negative bacterium.
Gram-positive organisms also have molecules similar to lipopolysaccharide on their cell
walls, but they act in a different way to activate inflammation. An exotoxin is an antigenic
protein produced & secreted by bacteria. Exotoxins are predominantly produced by Gram-
positive organisms such as Staphylococcus & Streptococcus, but Pseudomonas organisms
also produce exotoxins. Accordingly, gram-positive organisms generally cause sepsis by
release of exotoxins, creating toxaemia. Gram-negative organisms, however, usually
produce sepsis by causing bacteraemia. At times, there is no haematogenous spread of the
infectious agent. In this case, the immune response to the localised infection spreads
beyond the confines of the infection and causes a systemic inflammatory response.

Sepsis & other complications are the result of release of inflammatory mediators such as IL-
6, TNF-α and other substances from inflammatory cells. The processes involved include:

• Cytokine cascade. Pro-inflammatory cytokines such as IL & TNF are released in

response to the triggering factors. TNF release mediates many of the responses to
endotoxins, such as induction of COX (cyclooxygenase), PAF (platelet activating
factor) and NOS (nitric oxide synthase). IL-6 mediates hepatic synthesis of acute
phase proteins, and IL-8 is a chemo-attractant.
• Complement activation. Fragments of C3 act as opsonins for bacteria & bacterial
components (such as toxins). They also act as co-stimulatory molecules that assist
lymphocytes with the adaptive immune system.
• Free radical release. There is uncontrolled release of free radicals due to
overwhelming infection & inflammation activation. There is increased consumption
of iron and oxygen in the circulation, and the system-wide activation of neutrophils
leads to widespread production of free radicals such as superoxide, hydrol radicals,
hydrogen peroxide and peroxynitrite ions. This causes many things, such as lipid &

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 protein peroxidation, damage to cell membranes, increased capillary permeability,
impaired mitochondrial respiration, DNA strand breakage and apoptosis.
• Release of vasoactive mediators. These vasoactive mediators come from the
endothelium. They include nitric oxide (NO) and prostacyclin (PGI2). These agents
lead to vasodilation, which leads to haemodynamic changes.

Stages of sepsis
The spectrum of conditions that sepsis goes through is as follows:

1. Sepsis.
2. Severe sepsis.
3. Septic shock.
4. Multi-organ dysfunction syndrome.

Sepsis

Sepsis is defined by the presence of SIRS and a concurrent infection. SIRS (systemic
inflammatory response syndrome) is a condition of disseminated inflammation that is
characterised by any 2 of:

• Temperature >38°C or <35.5°C.

• Tachycardia >90bpm.
• Respiratory rate >20 breaths/min or paCO2 <4.3kPa/32mm hg.
• White cell count >12 × 109 cells/L, <4 × 109 cells/L, or >10% bands (left shift).

Severe sepsis

Severe sepsis is defined by sepsis (infection + SIRS) in the presence of organ hypoperfusion,
dysfunction or hypotension. The features suggestive of severe sepsis include:

• Oliguria (urine output <0.5ml/kg/h).

• Hypoxaemia (paO2/FiO2 <300mm Hg1).
• Lactic acidosis (>1 mM)2.
• Altered cerebral function.
• AKI (creatinine increase >0.5mg/dL used as sarrogate).
• Coagulation abnormalities (INR >1.5 or aPTT >60s).
• Ileus (absent bowel sounds).
• Thrombocytopaenia (platelet count <100 × 109 cells/L).
• Hyperbilirubinaemia (total bilirubin >70mM).

1
The paO2/FiO2 is also called the Horowitz index. In normal individuals, this index yields a value of 350-450mm
Hg.
2
This is a tissue perfusion variable rather than a sign of organ dysfunction.

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 • Leukocytosis (WCC >12 × 109 cells/L).

Septic shock

This is sepsis with arterial hypotension despite adequate fluid resuscitation, or the
requirement of inotropes/vasopressors to maintain blood pressure. This is often the result
of an inflammation-related fall in peripheral vascular resistance, but it may also be related in
part to cardiogenic dysfunction. It is a form of distributive shock. The hypoxia induced by the
shock may be further worsened by reduced mitochondrial respiration at tissue level.

Shock can also be classified as refractory shock, in which the shock does not respond to
conventional therapy – IV fluids or inotropes – within an hour.

Multi-organ dysfunction syndrome (MODS)

MODS is a complication of SIRS3 in which there is dysfunction in 2 or more organ systems

such that homeostasis cannot be maintained without intervention. It occurs in 5-15% of
patients requiring ICU admission. It is characterised by progressive organ impairment. Organ
failure is defined either by measures of physiologic derangements or by treatment methods.
MODS usually follows 2 clinical courses. The short-course/acute type usually follows a direct
pulmonary insult, such as trauma or aspiration, and is relatively short, with MODS becoming
evident just before death. The longer chronic type is the one seen with severe sepsis, in
which MODS is present early doing the course of illness and progresses after a 7-10 day
delay.

The classic form of MODS progresses through 4 stages:

1. Shock. Periods of relative/total ischemia are common to all inciting events of MODS.
Ischemia can be due to regional or global perfusion deficits. The path of organ
dysfunction to organ failure depends on the severity of perfusion deficits, the
passage of time to adequate resuscitation, and the functional reserve capacity of the
organ involved.
2. Period of active resuscitation. If resuscitation is rapid & effective, the sequence of
events precipitating MODS may not occur. However, in many cases despite adequate
management, the syndrome progresses4.
3. Systemic inflammatory response. If resuscitation fails, there is widespread cellular
damage with pan-endothelial dysfunction. This is seen with increased microvascular
permeability with exudative oedema. This period is a period of hyper-metabolism
and widespread activation of the immune response, thus causing SIRS. When
associated with infection, this is called sepsis. Mortality at this stage rises to 25-40%.
4. Organ failure. During this stage, there’s increasing organ dysfunction, failure and
death. The appearance of organ dysfunction causes the mortality chances to leap to
3
Sepsis is therefore just one of the causes.
4
This suggests a genetic component.

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 40-60%, with the mortality rising to 90-100% as hepatic & renal dysfunction ensues.
Definitions of organ failure use 2 types of criteria based on either the measures of
physiologic derangements or the types of interventions used.

The organs involved in MODS are:

• Respiratory system (lungs). In the majority of patients, the lungs are the first organs
to fail. The lungs are pivotal in the development of MODS, as they appear to
generate inflammatory mediators and/or allow inflammatory mediators to persist in
the circulation (through decreased capacity to clear them). This leads to persistent
endothelial dysfunction. Lung dysfunction occurs on a spectrum, from minor
pathology (designated acute lung injury. ALI) to massive alterations in the lung
(adult respiratory distress syndrome, ARDS). ARDS is defined by:
o Respiratory distress.
o Stiff lungs.
o Hypoxia despite high levels of supplemental oxygen (paO2/FiO2
<40KpA/300mm Hg for ALI and paO2/FiO2 <26.6kPa/200mm Hg for ARDS).
o Bilateral infiltrates on chest X-ray.
o Pulmonary capillary wedge pressure of less than 18mm Hg (or no clinical
evidence of increased left atrial pressure)5.
In ARSD, there is widespread endothelial damage to pulmonary capillaries. These
become leaky and cause interstitial oedema & fibrosis.
• Gastrointestinal system. The gut is particularly vulnerable to the processes occurring
in MODS. It is believed that sepsis in the absence of a focus of infection is due to
colonisation of the normally sterile upper GIT, with translocation of bacteria & toxins
from the gut into the circulation. The gut wall is also involved in the systemic disease
process, particularly due to redistribution of blood from the splanchnic circulation to
muscles. This predisposes the gut to ischemia & membrane reperfusion injury. This
allows translocation of bacteria & toxins into the portal circulation. For this reason,
the gut has been termed the motor of multiple organ failure. GIT complications
include GI failure (inability to tolerate enteral feeding; paralytic ileus), ischaemic
colitis, acalculous cholecystitis, pancreatitis and GIT haemorrhage.
• Liver. Normally, the hepatic reticuloendothelial system is supposed to be able to
clear overspill of gut luminal toxic products into the portal circulation. In MODS,
however, there is reduced clearance and therefore the spillage of toxins is washed
into the pulmonary microcirculation. This leads to activation of pulmonary
macrophages, leading to increased destruction of pulmonary architecture.
• Cardiovascular system. Normally, when the body is subjected to an insult or stress,
the cells of the body adjust by extracting more oxygen from blood. However, in SIRS
leading up to MODS, the tissues are unable to extract more oxygen from blood and

5
This means the pulmonary oedema is non-cardiac in origin.

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 therefore rely on increased oxygen delivery (i.e. increased cardiac output),
experienced as a tachycardia. This is called the pathological oxygen supply/flow
dependency. The tachycardia coupled by the systemi-wide vasodilation leads to a
hyperdynamic state characteristic of SIRS. In patients with pre-existing cardiac
conditions, there may be an oxygen supply-utilisation disequilibrium. Examples of
such patients include those with coronary artery disease and heart failure.
• Kidneys. The presence of renal dysfunction in MODS heralds a substantial rise in
mortality risk. It is thought that perhaps the kidneys act as an extra source of
inflammatory mediators that fuel the inflammatory process. The loss of intravascular
volume control may exacerbate ARDS & heart failure, with potential for volume
overload. In addition, instituting renal support may exacerbate activation of
reticuloendothelial cells by bio-incompatibility of the extra-corporeal unit &
haemodialyser.
• Haematological system. Massive transfusion/fluid replacement (replacement of 1
circulating volume/5L/10 units of blood in less than 24 hours; usually following major
trauma) may result in diffuse microvascular bleeding from surgical wounds, cannula
sites and areas of minor trauma. This causes a coagulopathy as there is increasing
consumption of clotting factors. Furthermore, the dilution of clotting factors brought
about by fluid replacement with fluids deficient in clotting factors, such as packed
red cells, crystalloids and colloids. There is thrombocytopaenia, reduced fibrinogen
levels and elevated PT time. Severe injury can also result in DIC (disseminated
intravascular coagulation), which leads to microvascular occlusion that complicates
with infarcts & tissue necrosis. There is also coagulopathy induced by DIC, and this
leads to deficient haemostasis. DIC can be identified by restlessness, confusion,
neurological dysfunction, skin infarcts, oliguria and renal failure.
• Central nervous system. Features of CNS dysfunction include impaired
consciousness, disorientation followed by coma.

Presentation
The presentation of a patient with sepsis is as follows:

• History. The patient will present with fever, chills, dyspnoea, cool extremities,
fatigue, malaise and anxiety. The patient may also be confused.
• Examination. The vitals will be abnormal: fever, tachypnoea, tachycardia and
hypotension. The patient may have local signs of infection.
• Investigations. These are mainly blood investigations.
o FBC will show anaemia and/or leucocytosis. Thrombocytopaenia can occur in
DIC.
o U&Es to check for renal dysfunction and to use as a baseline to assess for
development of AKI.
o Liver enzymes to rule out liver injury.

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 o Clotting profiles – PT, aPTT and FDPs (fibrin degradation products).
o Blood culture.
Other investigations include a urine culture & sensitivity as well as chest X-ray.

Management of sepsis
Sepsis is a medical emergency and should be treated in an ICU/HDU. Management of sepsis
is divided into treatment of infection and supportive therapy.

1. Oxygen. Supportive oxygen should be given, and this may require intubation &
ventilation. Oxygen must be increased to a point where oxygen consumption no
longer rises or to levels where serum markers of anaerobic respiration (e.g. lactate)
start falling. Ventilation is instituted using a lung-protective regimen – low tidal
volume (6mL/kg) & limited plateau pressure (<30cm H2O). this reduces mortality.
2. Cardiovascular support. You need to monitor, restore and maintain haemodynamic
function. Insert a central venous & arterial catheter. Maintain central venous
pressure at 8-12mm Hg with crystalloids or colloids. Vasoactive agents should be
used to maintain mean arterial pressure at 65-90mm Hg. You can use inotropes,
such as norepinephrine.
3. Treat the infection. The infection is treated by identifying the focus of infection,
testing for the appropriate microorganism & its sensitivity and instituting empirical
antibiotic therapy until sensitivity results return. Start with a broad-spectrum
antibiotic, with additional drugs depending on patient risk factors (e.g.
immunosuppression), suspected aetiology and local microbial susceptibilities.
4. Corticosteroids. Start IV hydrocortisone in septic shock patients who are
unresponsive to fluids & vasopressors.
5. Controlling hyperglycaemia. Hyperglycaemia is controlled by giving insulin. This
reduces infectious complications.
6. Nutrition. Early enteral feeding is indicated to preserve the function of the intestinal
mucosal barrier. There is a significant increase in amino acid oxidation. There is need
to supply metabolic support by providing adequate calories to maintain nitrogen
balance. Excessive glucose may cause fatty liver, hyperosmolality, hyperglycaemia
and increased CO2 production (which increases the excretory load to the liver and
may exacerbate the lung injury). The requirements are as follows:

Calories (non-protein) 25-30kcal/kg/day

Glucose 4-5mg/kg/min
Lipids 0.5g/kg/day
Proteins 1-2mg/kg/day
7. DVT prophylaxis. You can start the patient on prophylactic heparin (5000IU). Have a
high index of suspicion in these patients.

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 Acute kidney injury (AKI)
AKI is a rapid deterioration in renal function over hours to days, as measured by urea &
creatinine, and leading to failure to maintain fluid, electrolyte and acid-base homeostasis.
The KDIGO (Kidney Diseases: Improving Global Outcomes) guidelines suggest use of the
following criteria:

• Rise in serum creatinine of more than 26µM in 48 hours.

• Rise in serum creatinine of more than 1.5-times baseline (best figure in the last 3
months).
• Urine output of less than 0.5ml/kg/h in 6 consecutive hours.

Acute kidney injury is a medical emergency. It affects 18% of all hospital admissions and is
an independent risk factor for mortality.

Classification of AKI
AKI is classified using the RIFLE criteria, in an attempt to distinguish between AKI and CKD
(chronic kidney disease). The Acute Kidney Injury Network (AKIN) proposed a modification
to the original RIFLE criteria proposed by the Acute Dialysis Quality Initiative group. The
AKIN modification has been adopted by KDIGO.

Stage Serum creatinine criteria Urine output criteria

1 Increase in serum creatinine of more than Less than 0.5ml/kg/h for more than 6
26.4µM in 48 hours. consecutive hours.
OR
Increase of more than 1.5-times baseline.
2 Increase in serum creatinine of 2-3 times Less than 0.5ml/kg/h for more than
baseline. 12 consecutive hours.
3 Increase in serum creatinine of more than 3- Less than 0.3ml/kg/h for more than
times baseline. 24 consecutive hours.
OR OR
Increase of more than 354µM. Anuria for 12 hours.
OR
Commencement of renal replacement
therapy regardless of stage.

Causes of AKI
The causes of AKI are classified into pre-renal, intrinsic and post-renal.

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Pre-renal causes

Pre-renal causes account for 40-70% of causes and are therefore the most common. AKI in
these cases results from hypoperfusion of the kidneys. This is caused by:

• Hypovolaemia/hypovolaemic shock.
• Hypotension from other causes, particularly sepsis.
• Cardiogenic shock & cardiorenal syndrome.
• Vascular disease, e.g. renal artery stenosis. This is made worse by concurrent
administration of ACE-inhibitors and NSAIDs1.

A drop in renal perfusion leads to pre-renal uraemia and parenchymal kidney damage.
These are better established by evidence of blood/fluid loss, sepsis or cardiac disease. It
corrected by re-establishing perfusion to the kidney. On examination, you may find postural
hypotension, a low jugular venous pressure and a low-volume tachycardia.

Intrinsic causes

Intrinsic causes result from intra-renal pathology. They account for 10-50% of cases. The
causes of intrinsic renal disease are classified into:

• Glomerular. Glomerular diseases are mainly classified into primary and secondary
glomerulopathies. The primary glomerulopathies are divided into nephrotic
syndrome and nephritic syndrome. Nephrotic syndrome results from increased
leakiness of the glomerular basement membrane, leading to increased protein loss.
The clinical syndromes include: minimal change disease, focal sclerosing
glomerulosclerosis (FSGS), membranous glomerulonephritis and membrano-
proliferative glomerulonephritis. Nephritic syndrome is a result of damage to the
glomerular endothelium & mesangium, resulting in haematuria, increased leakiness,
reduced filtration function, uraemia and hypertension. The clinical syndromes
include post-streptococcal acute glomerulonephritis and IgA nephropathy.
Secondary causes of glomerular disease include autoimmune diseases (such as SLE),
drugs, and infections.
• Tubular. Acute tubular necrosis (ATN) is the leading cause of intrinsic AKI. It can
result from renal ischemia, or from direct toxic effects of drugs and toxins (e.g.
contrast, haemoglobin and myoglobin). ATN is thought to develop through:
o Intra-renal microvascular vasoconstriction. This occurs as a result of
vasoconstrictive agents such as endothelin, adenosine, thromboxane A2 and
leukotrienes. Sympathetic nerves also induce vasoconstriction. There is also
reduced response to nitric oxide, prostaglandin E2, acetylcholine and
bradykinin.

1
ACE inhibitors & NSAIDs impair renal autoregulation, meaning that the kidneys cannot maintain GFR when
there is reduced renal blood flow due to renal artery stenosis.

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 o Tubular cell injury. Ischemic injury results in rapid depletion of intracellular
ATP, leading to death by apoptosis or necrosis.
ATN contributes to reduced glomerular filtration by glomerular contraction, back-
leak of filtrate and obstruction of tubules.
In ATN, oliguria is common in the early phase (the oliguric phase), unless the insult is
less severe. Recovery occurs in 7-21 days unless sepsis continues. In the recovery
phase, GFR remains low while urine output increases (the polyuric phase). This is due
to defective tubular reabsorption of filtrate. ATN is usually a self-limiting process.
• Interstitial. Causes of interstitial disease (acute interstitial nephritis) include drugs,
lymphoma, infection and tumour lysis syndrome (following chemotherapy).
• Vascular. Vascular causes include vasculitis, malignant hypertension, thrombi,
cholesterol emboli, HUS & TTP and large vessel occlusion (e.g. by thrombi or
dissection).

Postrenal causes

Postrenal causes are a result of obstruction of the urinary tract. Obstruction can occur at
any point along the urinary tract, from the calyces to the urethral meatus. Obstruction
accounts for 10-25% of cases of AKI. The causes of obstruction are classified into:

• Luminal. These are causes that enter the lumen and occlude it form here. Examples
include renal stones, blood clots and sloughed papillae.
• Mural. These are things that develop within the walls of the urinary tract and cause
the wall to collapse and obliterate the lumen. They include strictures, BPH, and
primary malignancies (of the ureter, bladder and prostate).
• Extramural. These are things that do not form the urinary tract that grow and cause
collapse of the lumen through pressure effects. They include other pelvic
malignancies (especially cervical) and retroperitoneal fibrosis.

Risk factors for developing AKI

The risk factors for developing AKI are:

• Poor fluid intake or increased losses.

• Age above 75 years.
• Chronic kidney disease.
• Cardiac failure.
• Peripheral vascular disease.
• Chronic liver disease.
• Diabetes.
• Sepsis.
• HIV infection.

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 • Drugs, especially newly-started ones.
• History of urinary symptoms.
• Severe trauma.

Assessment of patient with AKI

The assessment of AKI includes:

History

From the history, check for:

• Risk factors, e.g. comorbid conditions (e.g CKD), previous renal disease, recent fluid
intake & losses (most important), new drugs and chemotherapy.
• Systemic symptoms, such as rash, joint pain and fever.
• Other system-specific symptoms, such as cough & haemoptysis, GI symptoms or
urinary symptoms.

Examination

You should do a full system examination. Look for signs of dehydration, palpable kidneys
and/or bladder, renal angle tenderness, abdominal & pelvic masses, renal bruits and rashes.

Investigations

One of the aims of investigation is to distinguish between pre-renal and intrinsic renal AKI.
This is done by using:

• Fractional excretion of sodium (FENa). In pre-renal AKI, renal tubular function is

retained, and so the kidney aims to reabsorb as much fluid & electrolyte as it can.
Therefore, in pre-renal AKI, the fractional excretion of sodium is low (<1%). In
intrinsic renal AKI, there is impaired reabsorptive function by the tubules and
therefore the fractional excretion is often high (>1%). However, it can be low in
some intrinsic diseases, such as contrast nephropathy, myoglobinuria, AIN. It is also
falsely elevated in some pre-renal causes, such as cardiorenal & hepatorenal
syndromes and diuretic use. Therefore, a more reliable indicator is the fractional
excretion of urea (FEU).
• Urine osmolality & specific gravity. These are both elevated in pre-renal AKI and
reduced in intrinsic renal disease. However, these parameters are unreliable in the
presence of glycosuria & other osmotically active substances in urine. In pre-renal
AKI, urine osmolality is above 500mOsm/kg while specific gravity is above 1.020. In
intrinsic kidney disease, the urine osmolality is below 350mOsm/kg while specific
gravity is below 1.010.
• Urine-serum creatinine ratio. This is reduced in pre-renal AKI.

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Other investigations done in AKI include:

• Blood tests. You can measure FBC (normocytic normochromic anaemia suggests
CKD), U&Es (hyponatraemia may be present in fluid overload; hyperkalaemia
common in oliguric phase of ATN while hypokalaemia common in polyuric phase),
arterial blood gases (acidosis common unless there is concurrent vomiting), clotting
profile, and inflammatory markers (CRP & ESR).
• Urinalysis. Presence of red cells & red cell casts is suggestive of nephritic syndrome.
Massive proteinuria (>3.5g in 24 hours) is suggestive of nephrotic syndrome. The
presence of glucose, phosphates, bicarbonate and hyaline casts is suggestive of
acute tubular necrosis. The presence of white cell casts is suggestive of acute
interstitial nephritis.
• Imaging. A renal ultrasound is indicated in suspected obstruction, and when stones
are suspected, it is necessary to do a CT-IVU. In elderly men, suspect prostatic
enlargement and therefore do a transrectal ultrasound. Chronic kidney disease
should be suspected if the kidneys are small.

Management of AKI
The management of AKI is as follows:

1. Assess volume status. Look for signs of either fluid overload (hypertension, raised
JVP, lung crepitations, peripheral oedema and gallop rhythm) or hypovolaemia
(reduced urine output, reduced JVP, hypotension, tachycardia and reduced tissue
turgor).
2. Aim for euvolaemia. If there is a difficult balance between overload &
hypovolaemia, consider titrating fluid input hourly by matching the previous hour’s
fluid output + 25ml/h (insensible losses). This usually requires intensive care nursing
and is difficult to do outside the HDU setting. If euvolaemic, review balance daily –
match the input to the output + 500ml (for insensible losses). Avoid potassium-
containing fluids, unless the patient is hypokalaemic.
3. Stop nephrotoxic drugs. These include NSAIDs2, ACE inhibitors2, aminoglycosides and
amphotericin B. If the patient is on metformin, stop metformin if serum creatinine
goes above 150µM. Adjust the dose of renally-excreted drugs.
4. Nutritional adjustment. Dietary sodium & potassium restrictions should be made.
Aim for normal caloric intake, and increase in catabolic states such as sepsis & burns.
Dietary protein restriction is controversial. In order to avoid haemodialysis, dietary
protein restriction is placed at 0.5mg/kg/day or 40mg/day. This poses the risk of
negative nitrogen balance, despite efforts to avoid nitrogen metabolism by a high
calorie diet. Catabolic patients require more protein. Enteral food is preferred to
parenteral food. Vitamin supplements are usually supplied.
2
This is if the patient has renal artery stenosis.

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5. Treating the underlying cause. The underlying cause is treated as follows:
a. Pre-renal. Correct volume depletion, treat sepsis and consider transfer to ICU
if there are signs of shock (particularly from cardiac causes).
b. Intrinsic renal. Rehydrate the patient and then wait for the condition to
resolve. Refer to a nephrologist if there is concern for
glomerular/tubulointerstitial disease, there are signs of systemic disease,
multi-organ involvement or indications for dialysis.
c. Post renal. Relieve the obstruction as far as possible. If necessary, do urinary
diversion.
6. Monitoring. Check the blood pressure, pulse, JVP and urine output hourly. If the
patient is in ICU or HDU, consider inserting a central venous line. U&Es should be
taken daily, and there should be a daily fluid balance chart, with daily weights.
7. Manage complications. The complications of AKI are:
a. Hyperkalaemia. Give calcium gluconate followed by insulin & glucose. Give
salbutamol nebulisers at high doses. If venous bicarbonate is low, give
sodium bicarbonate, but it may be inappropriate if the patient is fluid
overloaded. You can also consider potassium-binding resins. If all these do
not work, consider dialysis.
b. Pulmonary oedema. In patients with pulmonary oedema, sit the patient up
and give high-flow oxygen. Give a venous vasodilator such as diamorphine
2.5mg IV together with an antiemetic. Then give high-dose furosemide 80-
250mg intravenously over an hour or in boluses titrated to response. If there
is no response, urgent haemodialysis is indicated. Consider CPAP.
c. Sepsis. Sepsis needs to be treated urgently. However, avoid nephrotoxic
drugs.
d. Uraemia. This may require haemodialysis if it results in complications, such as
pericarditis & encephalopathy. You must contact the nephrologist.
e. Acidaemia. This may also require dialysis.

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 Chronic kidney disease (CKD)
Chronic kidney disease is progressive impairment of renal function for 3 months or more.
The renal impairment is based on abnormal structure or abnormal function (GFR less than
60ml/min/1.73m2 with or without evidence of kidney damage). CKD is usually progressive
and in most cases the primary disease process cannot be reversed. Exceptions include relief
of urinary tract obstruction, immunosuppressive therapy for vasculitis & Goodpasture’s
syndrome, treatment of accelerated hypertension and correction of critical narrowing of
renal arteries.

Aetiology
20% of cases of CKD are idiopathic and they present late with small shrunken kidneys and an
uninformative biopsy. Otherwise, the causes of CKD can be classified into:

• Congenital & inherited diseases. These include both structural diseases and
metabolic disorders. Structural disorders include polycystic kidney diseases,
medullary cystic disease, tuberous sclerosis and congenital obstructive nephropathy.
The metabolic disorders include oxalosis and cystinosis.
• Glomerulonephritis. These can be classified into primary or secondary depending on
whether they are result of systemic disease or not. The primary causes include focal
segmental glomerulosclerosis (FSGS) and IgA nephropathy. Secondary glomerular
diseases include SLE, amyloidosis, Wegener’s granulomatosis, haemolytic uraemic
syndrome and systemic sclerosis. CKD can also be caused by malaria.
• Vascular diseases. Vascular diseases such as renovascular diseases and small- &
medium-vessel vasculitides cause chronic kidney diseases. Atherosclerosis can also
cause chronic kidney disease.
• Tubulointerstitial diseases. These can be due to drugs or immunological process.
Patients can also have reflux nephropathy, tuberculosis, nephrocalcinosis, multiple
myeloma and renal papillary necrosis
• Urinary tract obstruction. This can be due to calculus disease, prostatic disease,
pelvic tumours, retroperitoneal fibrosis and schistosomiasis.
• Other chronic disease. Diabetes is the leading cause of CKD in the developed world –
it causes diabetic glomerulosclerosis. Other causes include hypertension
(hypertensive nephrosclerosis) and malignancies.

Pathophysiology
Each kidney has about 1 million nephrons in it, and the kidney has a very large functional
reserve. This means that it can maintain normal renal function even when it loses 50% of its

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nephrons. The plasma level of creatinine will double once GFR has reduced to 50%,
regardless of whether the creatinine levels are within normal range or not.

The remaining healthy nephrons undergo compensatory hypertrophy and hyperfiltration.

This is a way of compensating for the reduced number of nephrons in order to maintain
filtration. The hyperfiltration & hypertrophy is believed to represent progressive renal
dysfunction. The increased glomerular capillary pressure may damage capillaries, leading
initially to focal segmental glomerulosclerosis (FSGS) and then to global glomerulosclerosis.

Other contributory conditions include:

• Pre-existing systemic hypertension.

• Poor-controlled diabetes mellitus.
• Nephrotoxins, such as NSAIDs.
• Decreased profusion, from either shock or renal artery stenosis.
• Proteinuria.
• Hyperlipidaemia.
• Hyperphosphataemia.
• Smoking.

Furthermore, developing AKI (acute kidney injury) is a risk factor for developing chronic
kidney disease in the future.

Most cases of CKD are acquired rather than genetic. However, some genetic syndromes are
associated with CKD. These include polycystic kidney disease, Alport syndrome and atypical
HUS (haemolytic uremic syndrome).

Classification of CKD
CKD is broadly divided into 5 stages that are described by the GFR and the pathological
process in the kidney. This is the KDIGO (Kidney Disease: Improving Global Outcomes)
classification.

Stage GFR(mL/min/1.73m2) Description

1 ≥90 Normal or increased GFR with evidence of renal damage
2 60-89 Slightly decreased GFR with other evidence of renal
damage.
3A 45-59 Moderate decrease in GFR with or without evidence of
3B 30-44 renal damage.
4 15-29 Severe decrease in GFR with or without evidence of
renal damage.
5 <15 End-stage renal disease
The evidence of renal damage being looked for is:

1. proteinuria (>30g/24hr).

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 2. Haematuria.
3. Electrolyte abnormalities.
4. Evidence of abnormal anatomy or systemic disease.
5. History of kidney transplant should be included.

The suffix P can be added to the stage of renal disease if there is significant proteinuria
defined as an albumin-creatinine ratio of more than 65mg/mmol or protein-creatinine ratio
of more than 100mg/mmol.

Complications of CKD
The complications of CKD are:

• Anaemia. The anaemia of chronic kidney disease is normocytic normochromic.

Several factors have been implicated in the development of anaemia in kidney
disease.
o The most significant factor is the decrease in production of erythropoietin.
o Increased bone marrow toxins (uraemia).
o Bone marrow fibrosis.
o Nutritional deficiencies – iron, folate or vitamin B12.
o Abnormal red cell membranes & increased destruction.
o Increased blood losses from the GIT.
o Blood sampling (venepuncture).
o Blood loss during dialysis.
o Platelet dysfunction.
o ACE inhibitors. These lead to increased consumption of erythropoietin.
Anaemia starts early in the course of disease and progressively becomes more
severe. The prevalence of anaemia becomes higher as the stage of disease increases.
• Bone disease. Renal bone disease is a common complication of chronic kidney
disease. The condition is called chronic kidney disease – mineral & bone disease
(CKD-MBD)/renal osteodystrophy. It results in skeletal complications, such as
abnormalities in bone turnover, mineralisation and linear growth. There are also
extra-skeletal complications such as vascular & soft tissue calcification. It is believed
to start as phosphate retention, and this results from reduction in kidney function. It
is one of the early events in CKD. Hyperphosphataemia results in release of FGF-23
(fibroblast growth factor-23), which aims to induce phosphaturia and reduce the
phosphate levels. However, at some point, the FGF-23 fails to compensate for the
elevated phosphate levels. In addition, FGF-23 also downregulates expression of 1α-
hydroxylase, which is responsible for forming calcitriol (vitamin D3) from calcidiol.
Increased phosphate levels & reduced vitamin D3 levels (as well as concurrent
hypocalcaemia) stimulate secretion of PTH from the parathyroid glands – secondary
hypeparathyroidism. PTH promotes bone resorption and renal calcium reabsorption

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 & phosphate excretion. This is mediated by osteoclastic activity, and this leads to
cyst formation & bone marrow fibrosis. You can also get a tertiary
hyperparathyroidism, in which there is gland hypertrophy as a progressive stage
from secondary hyperparathyroidism, resulting in autonomous production of PTH.
There is therefore resultant hypercalcaemia. Vitamin D3 deficiency & hypocalcaemia
both lead to osteomalacia. Osteoporosis is also commonly found in CKD, often after
transplantation and the use of corticosteroids.
• Electrolyte abnormalities. The electrolyte abnormalities found in CKD are:
o Hyperkalaemia. Potassium levels are generally maintained within normal
ranges in the early stages, due to aldosterone secretion being normal and
distal flow being maintained. There is also increased potassium excretion in
the GIT as a result of aldosterone. Hyperkalaemia usually develops when the
GFR falls to 20-25ml/min/1.73m2. It also develops in patients with low
aldosterone levels, such as those taking ACE inhibitors, NSAIDs and β-
blockers. Hyperkalaemia can also be aggravated by an extracellular shift of
potassium, as is the case in acidosis or in insulin deficiency.
o Uraemia & azotaemia. Azotaemia is merely an accumulation of urea in blood,
while in uraemia there is accumulation of urea accompanied by signs &
symptoms. The symptoms range from lethargy to pericarditis &
encephalopathy. There are 3 main manifestations of excessive uraemia:
uraemic frost (due to crystalisation of urea found in sweat after a patient has
perspired), uraemic flap (due to uraemic encephalopathy) and uraemic feto
(which is a uraemic stench). Uraemia also results in retention of nitrogenous
waste products in skin, resulting in pruritus1. It is correctable with dialysis.
o Hypocalcaemia. This is a result of many things. Firstly, there is vitamin D3
deficiency, which leads to reduced calcium absorption in the GIT and reduced
calcium reabsorption in the kidneys. There is also resistance to the calcaemic
action of PTH. Despite the hypocalcaemia, however, secondary (and tertiary)
hyperparathyroidism leads to renal osteodystrophy and extra-skeletal
calcification, which mainly leads to vascular calcification. An extreme
consequence is calciphylaxis, in which there is calcification of the small
vessels of the skin & subcutaneous fat layer, leading to ischemia & infarction
of areas of skin. It results in chronic non-healing ulcers.
o Hyperphosphataemia. This is due to reduced GFR. This independently
increases the cardiovascular risk as it stimulates vascular calcification.
Furthermore, elevated FGF-23 levels also lead to left ventricular hypertrophy.
o Metabolic acidosis. There may be a normal anion gap or an increased one
(particularly in stage 5 disease, although no higher 20mEq/L). Metabolic
acidosis is due to the kidneys being unable to produce ammonia in the

1
Pruritus is also a result of hyperphosphataemia & hyperparathyroidism.

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 proximal tubules to excrete endogenous acids into urine in the form of
ammonium. Metabolic acidosis leads to negative nitrogen balance, increased
protein degradation, increased essential amino acid oxidation, reduced
albumin synthesis and lack of adaptation to a low-protein diet. Metabolic
acidosis is therefore linked to protein-energy malnutrition. Metabolic acidosis
also leads to increased fibrosis & rapid progression of CKD, and it promotes
development of renal osteodystrophy (since bone is a buffer for excess acid2)
• Salt- & water-handling abnormalities. In CKD, there is a failure of filtration of excess
sodium & water. This becomes clinically significant when GFR falls to below 10-
15ml/min/1.73m2. There is increasing sodium retention and expansion of ECF
volume. This leads to peripheral oedema, pulmonary oedema and hypertension.
Tubulointerstitial disease, however, results in fluid loss rather than overload and can
manifest as polyuria & volume depletion with inability to concentrate urine.
• Metabolic abnormalities. Patients with CKD suffer from the following:
o Gout. Urate retention is a common feature because of the kidney’s
decreasing GFR leading to increased reabsorption of uric acid. The treatment
of clinical gout is complicated by the nephrotoxic potential of NSAIDs.
Colchicine is therefore used for acute attacks.
o Insulin. Insulin is catabolised by the kidneys, and this catabolic action reduces
in individuals with CKD. Therefore, insulin requirements in individuals with
concurrent diabetes & CKD should be reduced.
o Lipid abnormalities. In CKD, there is impairment in the clearance of
triglyceride-rich lipoproteins and hypercholesterolaemia, particularly in
advanced cases. Furthermore, the lipid abnormalities may be worsened by
regular heparinisation (during dialysis), excessive glucose absorption and
immunosuppressive drugs
• Endocrine abnormalities. These include hyperprolactinaemia (galactorrhoea), raised
LH levels & abnormal pulsatility of release, low serum testosterone and abnormal
thyroid hormone levels due to altered protein binding.
• Cardiovascular disease. There is a greatly increased incidence of cardiovascular
disease amongst individuals with CKD. Comorbid hypertension & diabetes are
possible exacerbating factors in the evolution of heart disease. Left ventricular
hypertrophy is common, as is systolic & diastolic dysfunction. Left ventricular
hypertrophy is a risk factor for early death. Coronary artery calcification is more
common in patients with end-stage failure, and this happens in blood vessels of all
sizes. In addition to atherosclerosis, there are other factors that contribute to blood
vessel calcification. These include a raised calcium × phosphate product,
hyperparathyroidism, hyperphosphataemia and inflammation. Vascular calcification
leads to reduced vascular compliance, which leads to increased pulse pressure and

2
Therefore, patients who are persistently acidotic are more likely to have osteomalacia and low-turnover
disease.

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 increased pulse wave velocity. Increased afterload also contributes to left ventricular
hypertrophy.
• Pericarditis in CKD. This occurs in 2 settings. Firstly, pericarditis can occur as a
complication of uraemia – uraemic pericarditis. Uraemic pericarditis is an indication
for haemodialysis. It is associated with a haemorrhagic pericardial effusion and atrial
arrhythmias. There is a danger of pericardial tamponade, and anticoagulants should
be used with caution in these patients. Pericarditis can also occur in a patient on
dialysis – dialysis pericarditis. It occurs as a result of undercurrent illness or surgery
in a patient who was receiving adequate dialysis.

Clinical presentation of a patient with CKD

Patients in their early stages are often asymptomatic, apart from the accumulation of
metabolites. Symptoms appear when serum urea rises above 40mmol/L. Serum urea &
creatinine can be measured, and their levels appear to correlate with the symptoms that
present. The nature of metabolites that are involved in the symptoms is not very clear.

• History. Ask about any history of hypertension, diabetes, ischemic heart disease or
other systemic disease such as SLE. Also ask about previous UTIs and lower urinary
tract symptoms. Check for a drug history (particularly nephrotoxic drugs) and family
history. Also screen for malignancies in the patient.
• Symptoms. The symptoms are:
o Anorexia.
o Malaise.
o Polyuria & nocturia, in earlier stages and in tubulointerstitial disease.
o Itching.
o Nausea, vomiting & diarrhoea.
o Paraesthesia (due to poly-neuropathy. This may also be due to
hypocalcaemia).
o Restless leg syndrome.
o Bone pain (due to metabolic bone disease).
o Tetany, due to hypocalcaemia.
o Anasarca (generalised body oedema, including pulmonary oedema).
o Anaemic symptoms.
o Amenorrhoea in women; erectile dysfunction in men.
• Examination. The features on examination are either suggestive of uraemia, fluid
overload, aetiology or complications.
o Short stature due to stunting (if CKD was in childhood).
o Elevated blood pressures.
o Pallor. This results from anaemia.
o Increased photosensitive pigmentation.
o Scratch marks (uraemic pruritus).

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 o Signs of fluid overload – pitting oedema, distended neck veins, bibasal
crackles, raised blood pressure.
o Pericardial friction rub and flow murmurs.
o Glove & stocking peripheral sensory loss.
o The kidneys are usually not palpable unless there is polycystic kidney disease,
obstruction or tumour. In most cases they are shrunken.
Always remember to screen for depression in these patients. 45% of CKD patients
have depression upon initiation of dialysis

In more advanced CKD with severe uraemia, you can get:

• Mental slowing, clouding of consciousness and seizures.

• Myoclonic twitching.

Severe depression of GFR can cause oliguria. Always ask about it.

Investigations
The laboratory investigations done for a patient suspected to have CKD include:

• Blood tests. Patients may present with a normochromic normocytic anaemia. They
also have decreased/increased calcium levels, raised phosphate levels, raised ALP
(due to renal osteodystrophy) and raised PTH in stage 3 or higher CKD.
• Urine tests. Urinalysis is done to look for haematuria and proteinuria, which may
indicate glomerular disease. Urine microscopy is used to look for white cells
(infections) and casts (tubular cells – active disease; red cells – glomerulonephritis).
You can also measure urine electrolytes (this is not very helpful) & urine osmolality,
and you can conduct urine electrophoresis.
• Serology. Serological tests can be done to screen for numerous diseases, such as
autoimmune diseases (SLE, scleroderma, Wegener’s granulomatosis and
Goodpasture’s syndrome) and infections (post-streptococcus, hepatitis B & C and
HIV).
• Imaging. Ultrasound scans can be done to check the size, anatomy &
corticomedullary differentiation of the kidney. The kidneys are usually small in CKD.
CT scans can be done to diagnose retroperitoneal fibrosis and some causes of urinary
tract obstruction. It may also demonstrate cortical scarring. MRI scans are indicated
in renovascular disease.
• Renal biopsy. This is indicated in patients with unexplained CKD and normal sized
kidneys. If rapidly progressive glomerulonephritis is suspected, you should do the
biopsy as soon as possible.

Management

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Management of CKD patients can be done by general practitioners or physicians managing
other conditions. The indications for referral of a CKD patient to a nephrologist are as
follows:

• Stages 4 & 5 CKD.

• Moderate proteinuria, unless the proteinuria is due to diabetes mellitus and the
patient has already been appropriately treated.
• The patient develops proteinuria with haematuria.
• The patient has a rapidly falling GFR – more than 5ml/min/1.73m2 in 1 year or more
than 10ml/min/1.73m2 in 5 years.
• The patient has poorly-controlled hypertension despite 4 or more anti-hypertensive
agents being given at therapeutic doses.
• The patient has known or suspected rare or genetic causes of CKD.
• The clinician suspects renal artery stenosis.

Management of CKD follows a 4-step process:

1. Investigation. It is important to investigate & treat underlying causes if they are

correctable. This includes relieving urinary obstruction, stopping nephrotoxic drugs,
dealing with low/high serum calcium, reducing cardiovascular risk factors (such as
smoking, obesity) and tight glucose control in diabetes mellitus.
2. Limiting progression & complications. Various parameters need control in order to
limit progression of CKD:
a. Blood pressure. A small drop in blood pressure may save renal function. The
target blood pressure is 130/80, and in diabetic patients it is 125/75. In
diabetic patients, the drugs used are ACE-inhibitors and α-receptor blockers.
b. Renal bone disease. To limit the development of bone diseases, check for
raised PTH levels. Restrict dietary phosphate and give phosphate binders
such as calcium carbonate (Calcichew®) to reduce absorption in the GIT. Give
vitamin D analogues together with calcium supplements – these relieve bone
disease & hyperparathyroidism.
c. Cardiovascular modification. Risk of dying of cardiac failure is higher in stage
1 & 2 than the risk of developing end-stage disease. Give statins to relieve
hypercholesterolaemia and give low-dose aspirin (aspirin acts as an
antiplatelet agent to prevent thrombosis).
d. Diet. All patients should be reviewed by a dietician for advice on a healthy
moderate protein diet with potassium & phosphate restriction.
3. Symptom control. This is done to treat the symptoms patients present with. The
interventions are as follows:
a. Anaemia. Replace iron, B12 and/or folate if necessary. The target
haemoglobin levels are 10-12g/dL, as levels above this could lead to
intravenous access thrombosis, hypertension and myocardial infarction. If the

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 patient still remains anaemic consider giving recombinant human
erythropoietin. If the haemoglobin levels still fall despite these interventions
and there is no infection, haemolysis or blood loss, suspect red cell aplasia
and refer to haematologists.
b. Acidosis. Sodium bicarbonate is given to patients with low serum
bicarbonate. However, in hypertensive patients, the sodium load may raise
the blood pressure.
c. Oedema. High doses of loop diuretics (e.g. furosemide) may be needed to
treat oedema. The patient needs to restrict their fluid & sodium intake.
d. Restless legs & cramp. One should check ferritin levels, as low ferritin levels
worsen symptoms. Clonazepam and gabapentin may help treat restless legs.
Quinine sulphate may help reduce cramps.
4. Preparation for renal replacement therapy. Renal replacement therapy aims to
mimic the normal excretory & regulatory functions of the kidney. It involves passing
blood against a membrane separating it from dialysis fluid containing a substance
called dialysate. Dialysate extracts toxins from the blood down a concentration
gradient. The interventions available are:
a. Haemodialysis. In haemodialysis, blood is passed over a semi-permeable
membrane against dialysis fluid flowing in the opposite direction. Adequate
dialysis requires a blood flow of at least 200ml/min and therefore an
arteriovenous fistula is constructed so that this blood flow is achieved. Blood
is therefore always meeting a solution containing wastes in lower
concentrations and therefore diffusion of waste substances always occurs
down the concentration gradient. The major problems with haemodialysis
include disequilibration syndrome, hypotension, venous access problems,
infection, blockage and time.
b. Haemoflitration. In this procedure, blood is filtered across a highly
permeable membrane that allows large & small particles to move across the
membrane at the same time. The dialysis fluid moves in the same direction as
the blood, so there is less haemodynamic instability. For this reason, it is used
in critically ill patients. However, it takes much longer than haemodialysis to
achieve the same clearance.
c. Peritoneal dialysis. This method uses the peritoneum as the permeable
membrane. A Tenckhoff catheter is placed in the peritoneum and fluid is
infused into it. Solutes diffuse slowly across the vascular space and into the
peritoneum, and then the dialysate is exchanged regularly. Ultrafiltration is
achieved by addition of osmotic agents to the dialysis fluid, such as glucose.
This method allows the patient more freedom. However, it leads to
peritonitis and exit site infections, and there may be loss of membrane
function over time, leading to technical failure.

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 The complications of renal replacement therapy are: infections, cardiovascular
disease (which are the leading cause of death in dialysis patients), protein caloric
malnutrition, renal bone disease, renal amyloidosis, adult cystic kidney disease and
malignancy.
5. Kidney transplantation.

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 Renal replacement therapy
Renal replacement therapy refers to interventions designed to replace function of the
kidney: excretory functions (including excretion of nitrogenous wastes), maintenance of
normal electrolyte concentrations and maintenance of normal ECF volume. It includes
dialysis (haemodialysis & peritoneal dialysis) and renal transplantation. Preparation of
patients for renal replacement is vital, and it often requires a multidisciplinary approach.

Renal replacement therapy is mainly indicated for end-stage kidney disease, in which the
GFR falls below 15ml/min/1.73m2. This is a chronic indication. For acute indications, dialysis
is usually used for certain indications, and the indications for dialysis can be abbreviated
using AEIOU:

A – Acidosis: refractory metabolic acidosis.

E – Electrolyte imbalances: refractory hyperkalaemia.

I – Ingestion: dialyzable toxins, such as toxic alcohols (methane, ethylene glycol),

salicylate, lithium, sodium valproate, carbamazepine.

O – Overload: refractory fluid overload.

U – Uraemia: symptomatic uraemia; pericarditis, encephalopathy, coagulopathy.

Haemodialysis
Haemodialysis involves pumping blood through an array of semi-permeable membranes
which bring blood in close contact with the dialysis fluid (called the dialysate) and allow
exchange of substances between the 2 fluids. It is the most effective way of achieving
biochemical improvement, and hence it is used even in acute emergencies.

Basic principles

The apparatus consists of:

• A dialyser. The dialyser is composed of a polyurethane capsule within which hollow

fibres or parallel membrane plates are suspended in dialysate. The surface area for
dialysis is important in determining the degree of biochemical change.
• Dialysis solution (dialysate). The dialysate is prepared using a proportionating unit
which mixes specially purified water with concentrate.
Sodium 130-1451
Potassium 0.0-4.0

1
High sodium causes thirst & hypertension.

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 Calcium 1.0-1.62
Magnesium 0.25-0.85
Chloride 99-108
Bicarbonate 35-40
Glucose 0-10
The dialysate uses acetate or bicarbonate as a buffer.
• Tubing for transport of blood & dialysis solution.
• A machine to power and mechanically monitor the procedure. The machine is an
external machine. Blood is supposed to flow at a rate of 200-300ml/min, while the
dialysate should flow at a rate of 500ml/min.

The dialysate flows in a countercurrent fashion (similar to that found in the loop of Henle).
This countercurrent allows blood solutes to always be at a higher concentration than those
of the dialysate and therefore allow constant diffusion from blood to the dialysate
throughout the interaction between the 2 solutions.

Vascular access for dialysis can be achieved in a number of ways:

• AV fistula. This is the reconstruction of a high-flow vessel by joining a major artery

and a major vein. In most cases, this is reconstructed by joining the brachial/radial
artery with the cephalic vein. This leads to distension of the vein and thickening of its
wall (arterialisation) such that after 6-8 weeks large bore cannulas can be inserted
for dialysis. AV fistulas are prone to thrombosis when compressed, and they cannot
be used in patients with poor quality vessels (such as those with diabetes).
• AV grafts. These are usually made of plastic (polytetrafluoroethylene, PTFE) and they
can be used in patients with poor veins or arterial disease. However, they are much
more prone to thrombosis and their 2-year patency is 50-60%. Dipyridamole or fish
oils improve graft patency, but warfarin, aspirin and clopidogrel do not, and
therefore there is a high incidence of complications. PTFE graft stenosis can be
managed with balloon angioplasty with stenting.
• Vascular catheter. This is large bore double-lumen catheter that is normally inserted
into a central vein, usually the subclavian, jugular or femoral vein. This is used when
temporary access is required in emergency settings.
• Permanent catheter. This is also large bore dual-lumen catheter which is inserted
into a central vein. These are becoming increasingly common. They can be inserted
through a skin tunnel to lower the risks of infection. The jugular vein is now
preferred because subclavian stenosis is common. Their main disadvantage is that
they are associated with high rates of infection, hospitalisation and death. They are
also prone to occlusion, which may lead to inadequate dialysis.

Administering dialysis

2
High calcium causes hypercalcaemia, while low calcium (combined with poor compliance to medication with
oral calcium & vitamin D) will lead to hyperparathyroidism.

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Dialysis must be tailored to the patient. Dialysis is usually started when the eGFR is below
15ml/min/1.73m2. The decision to start dialysis, however, should be individualised.

1. Pre-dialysis workup. Prior to dialysis a number of tests are taken, including HIV,
hepatitis B & C viruses, and pre-dialysis haemoglobin concentration. The body
weight must be measured before & after dialysis, and the dry weight is recorded.
The transmembrane pressure in subsequent dialysis sessions is adjusted to achieve
excess fluid removal equal to that by which they exceed their dry weight.
2. Anticoagulation. All patients have to be anticoagulated, usually using heparin.
3. Monitoring. This is done to detect and treat complications. The observations made
include: blood pressure, temperature, ECG, post-dialysis haemoglobin.
4. Frequency & duration. An adult of average size usually receives 4-5 hours of
treatment 3 times a week. Twice weekly dialysis is acceptable if the patient has
adequate residual renal function.

Between sessions, it is important to ensure that the patient is adequately nourished.

Complications

The complications of haemodialysis are:

During dialysis: After dialysis (long-term complications):

• Hypotension. • Anaemia of kidney disease.
• Cramps. • Cardiovascular disease.
• Febrile reactions. • Malnutrition.
• Arrhythmia. • Depression.
• Haemolysis. • Uraemic neuropathy.
• Dis-equilibration syndrome3. • Dialysis-related amyloidosis4.
• Adult cystic kidney disease5.
• Renal cell carcinoma.

Adequacy of dialysis

The only true measure of the adequacy of haemodialysis is patient morbidity & mortality. In
most cases, dialysis is empirical as the size, number and nature of uraemic toxins in
unknown. Symptoms of under-dialysis include: fatigue, itching, insomnia, restless legs and
peripheral neuropathy.

Adequacy can be assessed by computerised calculation of urea kinetics. This requires the
measurement of: residual renal urea clearance, rate of rise of urea concentration between

3
This is a condition caused by over-rapid correction of uraemia. It is characterised by nausea, vomiting,
restless legs, headache, hypertension and myoclonic jerking. In severe cases, seizures & coma result.
4
This is due to reduced clearance of β2-microglobulin. This protein polymerises and forms amyloid deposits
which can compress the median nerve (carpal tunnel syndrome) or cause a dialysis arthropathy.
5
This predisposes to renal cell carcinoma.

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dialysis sessions, and reduction in urea concentration during dialysis sessions. You can
measure:

• Urea reduction ratio (URR). A urea reduction ratio of 65% per dialysis sessions is
deemed adequate.
• Equilibrated urea clearance. This found by:
𝐾𝑡
𝑢𝑟𝑒𝑎 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 =
𝑣
K = dialyser clearance of urea
t = duration of dialysis
v = urea distribution volume estimated as total body water
A Kt/V value of 1.0-1.2 is deemed adequate for a well-nourished patient who is
dialysed 3-times a week.

Haemofiltration
Haemofiltration is the removal of plasma water & dissolved constituents by convective flow
across a high-flux semi-permeable and replacing with a solution of desired biochemical
composition. Large & small solutes move across the barrier at almost the same rate. The
ultra-filtrate is replaced with an equivalent amount of fluid so there is less haemodynamic
instability. Lactate is used as a buffer in this case because rapid infusion of acetate causes
vasodilation, while bicarbonate may cause precipitation of calcium bicarbonate.

Haemofiltration is used for critically ill patients with haemodynamic instability. It can be
used for AKI and CKD. Its major drawback is the need to exchange large amounts to achieve
adequate small molecule removal. It needs 22L exchange 3-times a week for maintenance
therapy and 1L per hour for acute kidney injury. It is therefore unsuitable for long-term
therapy in the majority of patients. The costs are also high.

Peritoneal dialysis
In peritoneal dialysis, the peritoneum is used as the dialysis membrane. It avoids the need
for extra-corporeal circulation. Dialysis is achieved through diffusion (driven by
concentration gradient of solutes) and convection (driven by osmotic & hydrostatic
gradients of water). The filtration barrier in peritoneal dialysis includes the capillary walls &
interstitium6. The mesothelium of the peritoneum is of much less significant as a transport
hindrance.

Procedure

The principles of the procedure are very simple.

6
The capillary wall is a barrier for large solutes & fluid, while the interstitium is a barrier for transport of small
solutes.

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 1. A Tenckhoff peritoneal dialysis catheter is placed into the peritoneal cavity through
the anterior abdominal wall.
2. Dialysate is run into the peritoneal cavity, usually under gravity.
3. Urea, creatinine, phosphate and other uraemic toxins pass into the dialysate down
their concentration gradient. Water passes down its osmotic gradient into the
dialysate. The osmotic gradient of the dialysate is determined by the
glucose/polymer (icodextrin) content of the dialysate. The content of the dialysate
used is as follows:
Sodium 130-134mM
Potassium 0mM
Calcium 1.0-1.75mM
Magnesium 0.25-0.75mM
Chloride 95-104mM
Lactate 35-40mM
Glucose 77-236mM
Total osmolality 356-511mOsm/kg
4. The fluid is changed regularly to repeat the process.

Types of peritoneal dialysis

Peritoneal dialysis can be adapted in a number of ways:

• Continuous Ambulatory Peritoneal Dialysis (CAPD). In this type of dialysis, the

dialysate is present within the peritoneal cavity continuously, except when the
dialysate is being changed. Dialysate exchanges are done 3-5 times daily using a
sterile no-touch technique. You connect 1.5-3L bags of dialysate to the peritoneal
catheter, and each exchange takes 20-40 minutes. This is the technique used most
often for maintenance peritoneal dialysis in ESKD.
• Nightly intermittent peritoneal dialysis (NIPD). This is also called automated
peritoneal dialysis (APD). An automated device is used to perform exchanges each
night while the patient is asleep. Sometimes dialysate is left in the peritoneal cavity
during the day, during which biochemical exchanges are occurring. APD is associated
with fewer complications than CAPD.
• Tidal dialysis. In this technique a residual volume of dialysate is left in the peritoneal
cavity and small volumes are cycled in & out.

Osmotic removal of excess water & solutes is achieved using a hypertonic dialysate.

Complications

The complications of peritoneal dialysis are:

• Peritonitis. This is a common complication. Patients present with generalised

abdominal pain. A culture of effluent dialysate should be ordered prior to empirical

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 treatment. In the majority of cases, the cause is S. epidermidis, but other causes
include E. coli, Klebsiella, Pseudomonas, S. aureus, TB and fungal infections. In
approximately 20% of cases, no bacteria are found. On microscopy, neutrophil count
is often above 100cells/ml.
• Catheter site infection. This is also relatively common. It should be treated
aggressively using systemic/topical antibiotics to prevent spread to the catheter
tunnel & peritoneum. Staphylococci are the most common cause.
• Others. These include:
o Constipation.
o Massive pleural effusion (through a diaphragmatic defect into the pleural
cavity).
o Scrotal swelling (patent processus vaginalis).
o Failure of peritoneal membrane function (thought to be due to excessive use
of hypertonic dialysate).
o Sclerosing peritonitis7.

Adequacy of peritoneal dialysis

No consensus on the optimal degree of removal of urea & other waste products has been
reached. However, there is a general agreement that the minimum dose delivered should
not be less than 1.7. Weekly Kt/v of 2 or more coupled with creatinine clearance of at least
60L per week is recommended.

Renal transplantation
This is the best form of renal replacement therapy, and it offers the potential for almost
complete rehabilitation in ESKD. It has a significant survival advantage as well. However, the
transplant involves major surgery, long-term immunosuppression and a number of potential
complications. The patient must also be physically & psychologically suitable for the
transplant.

The advantages of renal transplantation are:

• Freedom from dietary & fluid restriction.

• Correction of anaemia & infertility.
• Reduced need for parathyroidectomy.
• No need for repeated weekly visits to dialysis.

The supply of donor organs is greatly exceeded by demand and donor organs must
therefore be used optimally. 80% of grafts survive 5-10 years in the best centres, while 50%
survive for 10-30 years. The half-life of renal allografts is still 13-16 years. The 3 commonest

7
This is a potentially fatal complication. If this complication appears, CAPD should be abandoned.

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causes of late graft loss are: death with functioning graft in place, recurrence of renal
disease, and chronic allograft nephropathy. The donor can be:

• Live related donor.

• Live unrelated donor.
• Cadaveric donor. This is divided into donor after cardiac death (DCD) and donor
after brainstem death (DBD).

Procedure

The donor kidney is anastomosed onto the iliac vessels of the recipient, while the donor
ureter is implanted into the bladder. Unless the donor is genetically identical to the
recipient, immunosuppressive therapy is required for as long as the transplant remains in
place (to prevent rejection).

Factors affecting success of graft

The factors affecting success of the graft include:

• ABO compatibility. This is required in the majority of cases, although in some

centres such as Japan ABO-incompatible procedures are being conducted. The
transplants are followed by immune-adsorption (to remove preformed antibodies),
splenectomy, anti-CD20 antibodies (rituximab; removes B-cells) and intravenous
pooled antibodies (for immunomodulation).
• Matching HLA type. HLA typing has the greatest impact on graft survival. Complete
compatibility at A, B and DR loci offer the best chance of success. A donor factor – an
allotype of the C3 complement molecule – may be associated with better long-term
outcomes for cadaveric grafts.
• Adequate immunosuppressive treatment. Long-term immunosuppression is
employed for prevention of rejection in all cases except a living twin. Some degree of
immunologic tolerance does develop, and the risk of rejection is highest in the first 3
months. Conventional induction is with basiliximab (IL-2 receptor monoclonal
antibody; anti-CD25 antibody) or alemtuzumab (anti-CD52 antibody). These agents
provide broad immunosuppression and allow a steroid-free maintenance regimen8.
Maintenance is often achieved on a triple therapy comprising of: a calcineurin
inhibitor (tacrolimus or cyclosporine), an antimetabolite (azathioprine or
mycophenolate) and prednisolone. You must be aware of the side effects:
o Calcineurin inhibitors – nephrotoxicity, hypertension, diabetes, and hirsutism
& virilisation.
o Anti-metabolites – pancytopaenia, deranged LFTs9, diarrhoea, and interaction
with allopurinol9.

8
This is particularly useful in patients with diabetes.
9
Azathioprine

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 o Steroids – osteoporosis, hypertension, diabetes, weight gain, poor wound
healing and lipid abnormalities.

Complications

The complciations of transplantation are:

• Surgical complications. These include bleeding, thrombosis of renal vessels,

infection, urinary leak, lymphocoele, and hernia. If urine output drops, a Doppler
ultrasound, DTPA scan or renal angiography is required. Surgical re-implantation may
be required.
• Delayed graft function. This affects up to 40% of grafts. It is more common in DCD.
Acute tubular necrosis can occur as a result of ischemic-reperfusion injury10. Acute
tubular necrosis is the commonest cause of cadaveric graft dysfunction. This is
associated with worse long-term outcomes. In recipients at high risk of ATN, it is
usual practice to start with induction of antibodies and 50% of the starting dose of
calcineurin inhibitors (since they are nephrotoxic).
• Graft rejection. Graft rejection can be acute or chronic.
o Acute: this is seen in 10-30% of patients. Acute rejection is further divided
into humoral (pre-existing antibody-mediated), vascular or cell-mediated.
Renal biopsy confirms the diagnosis and assesses severity & type of rejection.
It is treated with high-dose IV methylprednisolone with an intensification of
immunosuppression (anti-HLA antibodies & rituximab). Humoral rejection
often requires plasma exchange.
o Chronic (now known as chronic allograft nephropathy): This is thought to be
a combination of chronic de novo low-grade antibody response plus vascular
changes and the effects of calcineurin inhibitors. It generally has no
treatment but can be slowed down by switching from
tacrolimus/cyclosporine to sirolimus.
• Drug toxicity. Drug adverse effects include neurological symptoms (tremor &
confusion: seen with calcineurin inhibitors), new-onset diabetes, gum hypertrophy
(cyclosporine), hirsutism (cyclosporine), agranulocytosis (antimetabolites) and
hepatitis (antimetabolites).
• Infections. In the first few months, infections are mostly bacterial. CMV infections
develop weeks to months after transplantation in 70% of seronegative recipients
receiving a kidney from a seropositive donor, as well as in patients receiving
biological agents. Prophylaxis can be routinely given to patients with PCP & oral
candidiasis. Graft dysfunction can result from Polyomavirus infection, and this
infection mainly causes tubulointerstitial nephritis.
• Malignancy. There is a 5-fold increased risk of malignancy in patients receiving
immunosuppression. The implicated malignancies are skin (SCC & BCC) & virally-
10
This is more prominent if cold ischemia time is more than 24 hours.

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 mediated cancers. Patients should avoid sunlight exposure, and women should go
for regular cervical smears.
• Cardiovascular disease. This is the post-transplant cause of death in 50% of patients.
it is due to increased incidence of hypertension, diabetes, obesity & insulin
resistance and lipid disorders. Statins reduce cardiac endpoints (MI &
revascularisation) but were not associated with increased survival.
• Recurrence. This is common. Primary FSGS commonly recurs and causes early graft
loss.

The absolute contraindications to renal transplantation are: active infection, cancer within
the last 5 years, and severe comorbidity. HIV is no longer an absolute contraindication.

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 Approach to acute
arthropathies
Acute arthropathies are a common presentation in the primary care setting. The majority
are short-lived, self-limiting conditions or they settle with a short course of simple analgesia
& physiotherapy/osteopathy. However, these diseases occur on a spectrum, with other
arthropathies being severe disabling & life-threatening illnesses.

Patient assessment
Rheumatologic patients are assessed as follows:

History

In the history of the patient, you need to find out the following information about the joint:

• Symptoms. The common presenting symptoms that could point towards joint
problems are:
o Pain. This is divided into: usage pain, in which pain worse on use and relieved
by rest; rest pain, which the pain is worsened by rest and improved by
movement; and night/bone pain, which is pain mostly felt at night and poorly
related to movement. Also ask abour diurnal variations.
o Stiffness. This is a subjective feeling of the inability to move freely. Ask about
severity in the morning and after inactivity.
o Swelling. This could be cause fluid, bone or soft tissue
o Loss of function. The joint could have reduced range of movement or be
deformed. This is usually better assessed during examination.
o Warmth and redness. These are signs of inflammation.
Ask about the pattern & progression of joint involvement and symmetry.
Ask about the duration of symptoms and if the patient has had any prior episodes.
• Extra-articular symptoms. These include: rashes, photosensitivity, Raynaud’s
phenomenon (pain, pallor and eventual gangrene of digits), dry eyes/mouth, red
eyes (iritis), diarrhoea, urethritis, nodules, mouth ulcers, genital ulcers,
constitutional symptoms (fever, night sweats and weight loss) and symptoms of
heart failure.
• History of trauma.
• Age & sex. These have an important bearing on disease epidemiology and
likelihoods. Also ask about ethnicity.
• Extent of disability. This can be graded according to WHO as follows:

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 o Impairment: loss/abnormality of physical or psychological structure or
function.
o Disability: restriction or lack of ability to perform an activity in a manner or
within the range considered normal for a human being.
o Handicap: a disadvantage for an individual resulting from an impairment or
disability that limits /prevents fulfilment of a role that is normal for that
individual.
The patient’s own perception/limitation should be taken into account during
assessment.
• Associated medical conditions & drugs. Associated conditions include psoriasis,
inflammatory bowel disease, diabetes, hypertension and HIV. Also ask about their
medications for these conditions or any medication they took just before symptoms
began (e.g. NSAIDs, DMARDs, biological agents).
• Family history.
• Occupational history. Find out what kind of work the patient does – manual labour,
office work (ergonomics, computer-related repetitive strain injury).
• Psychosocial history. Is there any recent stressful event that occurred at home or
work1? Has there been an injury for which a legal case for compensation is pending.
Is the patient a smoker or a heavy drinker?

Examination

You need to be observant as the patient walks in: look at their gait and look for disabilities.
There is a rapid examination of the joints done to look at all joints in general, and there’s a
detailed examination done for all joints.

Gait:
Ask the patient to walk a few steps forwards & backwards:
• Look for smoothness of walking.
• Assess the arm swing: whether it is adequate or not.
• Assess the stride length.
• Normal heel strike & toe off.
Rapid examination of the upper limbs:
• Raise arms sideways right up to the ear (abduct arms slowly) – [screens for shoulder
or rotator cuff problems].
• Hold arms out forwards & straight (elbows extended), fingers spread out, and then
rotate your palms to face up then down – [fixed flexion at the elbows indicates an
elbow problem]. Examine hands for swelling, wasting and deformities.
• Place hands together in prayer position (pray hands) with elbows apart – [flexion

1
Stresses usually cause flair ups of rheumatic diseases.

Page 448 of 455

 deformities at fingers, restricted movement at wrist].
• Make a tight fist – [loss of flexion/grip]. Also squeeze the fingers [joint/tendon
synuvitis].
Rapid examination of the lower limbs:
• Ask the patient to walk a short distance away from you and towards you – [look for
abnormal posture or stance].
• Ask the patient to stand on each leg if they can – [Trendelenburg test].
• Ask the patient to flex & extend each knee – [look for knee deformities].
• Ask the patient to put each foot in turn on the opposite knee with the hip externally
rotated – [painful resistance on the hip or knee].
• Move each ankle up & down. These are examined while standing.
• Look at the toes to assess for signs of uneven wear.
Rapid examination of the back:
• Look at the back from behind – assess for muscle bulk, symmetry, straightness of the
spine (scoliosis), localised swelling or deformities (scoliosis).
• Look at the back from the side for abnormal spinal curves (kyphosis and lordosis).
• Ask the patient to bend forwards (flexion2), backwards (extension) and sideways. Ask
the patient to bend the neck forwards, backwards and sideways as well.
• Ask the patient to lie supine and lift their leg up [restriction in straight leg raising].
• Ask the patient to lie prone and passively flex knee [anterior thigh pain] – the
femoral stretch test.
• Palpate the spine & buttocks for tender areas.

The detailed examinations for the individual joints follow a similar regimen – look, feel and
move.

LOOK

You first need to observe the patient without touching them. At first you look at the
patient’s joint while it is not moving at all (inspection at rest) and then inspect it as the
patient moves the limb (inspection during movement).

• At rest. At rest, you need to not if there is: symmetry & attitude of limbs, swelling,
visible deformity, skin changes, rash, muscle wasting, signs of inflammation (redness)
and scars.
• During movement. You look for:
o Restriction of movement: whether it is restricted in a single plane or in
multiple planes.

2
You can also do the Schober’s test, in which you measure out a line along the spine between a point 5cm
below the level of the posterior iliac spine and 10cm above it. If upon flexion the line does not lengthen by at
least 5cm, there is reduced lumbar flexion, such as in ankylosing spondylitis.

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 o Increased range of movement.
o Pain on usage. This could be stress pain, where there is pain towards the end
of range of movement of a joint.
o Disordered movement. This may indicate deformity.

FEEL

When you palpate the patient, you check for:

• Tenderness: check to see if the limb is tender at rest. Palpate along the joint line as
well as around the joint (peri-articular). Also check for tenderness on passive
movement.
• Swelling: feel the swelling to establish whether it is fluctuant (fluid), soft (soft
tissue), rubbery (synovium) or hard (bone).
• Warmth: this usually signifies inflammation, whether infectious or not.
• Crepitus: this can be coarse or fine, and they may be loud or soft & only heard by
auscultation.
• Stability: this is established by passively moving the joint. Check the ranges of
movement.
• Restriction of movement: check to see if the patient has full ranges of movement.

MOVE

This is assessed by determining features during active movement (carried out by patient) &
passive movement (carried out by examiner). Movements are assessed during looking &
feeling.

Pattern of joint disease

After taking history & examining, it is important to determine whether the joint issue is a
true joint problem or it is a peri-articular problem, as both cases will come with local joint
pain. The differentiating features are:

Joint problem Peri-articular issue

Tenderness Tenderness is over joint line. Tenderness is away from joint line.
Restricted Both active & passive movement Active movement restricted more
movement restricted equally. than passive movement.
Restricted active No pain. Pain in muscle, tendon, ligament or
enthesis.
Stress pain Pain present in several planes of Pain present in single plane of
movement. movement.
Swelling Follows joint capsule. Is localised to extra-capsular
structure.

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Crepitus Coarse or fine, easily felt, readily Fine, localised, best heard on
audible auscultation

To differentiate between synuvitis (inflammatory cause) and joint damage (mechanical

cause), the history & examination features are:

Synuvitis Joint damage

Early morning inactive stiffness +++ ±
Warmth + -
Stress pain + -
Soft tissue swelling + -
Effusion +++ ±
Crepitus - +++
Deformity - +
Instability - +

Different findings of joint disease point to different things. One important thing is the
distribution of affected joints (the number of joint):

Monoarthritis (1 joint Oligoarthritis (2-5 Polyarthritis (>5 joints invovled)

involved) joints involved) Symmetrical Asymmetrical
• Septic arthritis. • Crystal arthritis • Rheumatoid • Reactive
• Crystal arthritis (gout & arthritis. arthritis
(gout & pseudo-gout). • Osteoarthritis. • Psoriatic
pseudo-gout). • Psoriatic • Viral infection arthritis
• Osteoarthritis. arthritis. (hepatitis A, B,
• Trauma (e.g. • Reactive C).
haemarthrosis) arthritis
(Yersinia,
Salmonella, • Connective tissue diseases (SLE,
Campylobacter relapsing polychondritis).
). • Sarcoidosis.
• Ankylosing • Malignancy (leukaemias).
spondylitis. • Endocarditis.
• Osteoarthritis. • Haemochromatosis.
• Sickle cell anaemia.
• Familial Mediterranean fever.
• Behçet’s disease.

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Important investigations
The important investigations in joint pain are:

• Joint tap. This is an important investigation in monoarthritis. The procedure should

be a sterile one as there is risk of introducing infection into the joint. Do not tap
through inflamed or potentially infected skin (such as a psoriatic plaque). When you
take the fluid you need to assess for: colour (clear colourless, straw-coloured clear,
turbid yellow, xanthochromic, bloody), viscosity (normal, increased, decreased),
white cell count, microscopy (Gram-staining, polarised light microscopy) and culture
(to rule out septic arthritis).
Appearance Viscosity WCC Neutrop
(mm ) 3 hils (%)
Normal synovium Clear & colourless ↔ ≤200 None
Osteoarthritis Straw-coloured & ↑ ≤1000 ≤50%
clear
Haemorrhage (trauma, Bloody/xanthochromic Varies ≤10 000 ≤50%
tumour, haemophilia)
Acute inflammation:
• Rheumatoid Turbid, yellow ↓ 1-50 000 Varies
arthritis
• Crystal arthritis Turbid, yellow ↓ 5-50 000 ≈80%
Septic arthritis Turbid, yellow ↓ 10-100 >90%
000
• Blood tests. The blood tests you do for acute arthropathies are:
o FBC with differential. Normocytic anaemia suggests chronic inflammatory or
autoimmune disease. Microcytic hypochromic anaemia suggests iron
deficiency anaemia secondary to blood loss, which may be due to
haemorrhage. Neutrophilia is seen in bacterial infection, while lymphopaenia
occurs with viral illness or active SLE.
o ESR & CRP. ESR & CRP are raised in inflammatory conditions such as
rheumatoid arthritis and infections. These parameters are normal in SLE.
o LFTs. Raised ALP may indicate bone or liver disease.
o Serum uric acid/urate levels. This is not routinely done for gout, but may be
done.
o U&E and urinalysis. This is done to rule out renal disease. You can also check
for proteinuria on urinalysis, after which you measure urinary Bence Jones
proteins to rule out myeloma.
• Serologic tests. The serologic tests that you can do in acute arthropathies include:

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 o Rheumatic factor. This is a non-specific antibody test with high sensitivity in a
number of autoimmune/inflammatory conditions, such as rheumatoid
arthritis, SLE, and in chronic infections.
o Anti-citrullinated peptide antibodies (anti-CCP). These are more specific for
diagnosis of rheumatoid arthritis, although they have low sensitivity (60%).
o Anti-nuclear antibodies (ANA). These are used to screen for SLE, systemic
sclerosis, rheumatoid arthritis and chronic infections. They are not diagnostic.
o Anti-double-stranded DNA (anti-dsDNA). These are diagnostic for SLE. The
levels of this antibody usually rise & fall with disease activity.
• Infection screen. This done if reactive arthritis is suspected, and this is guided by the
history. You can do HBV & HCV serology, HIV test, urine chlamydia PCR and any
other viral serology wherever necessary.
• Imaging. Usually the diagnosis is secured by history, examination and lab
investigations. You can do:
o X-ray. They are usually diagnostic in some conditions and can be used to
confirm typical changes, e.g. in chondrocalcinosis & RA. They are also
valuable in cases of trauma. X-ray can be used to detect:
▪ Joint space narrowing.
▪ Erosions.
▪ Soft tissue calcification.
▪ New bone formation (e.g. osteophyte formation).
▪ Osteopenia or osteosclerosis.
In acute lower back pain, X-rays are indicated when the pain is persistent,
recurrent, associated with neurologic symptoms, worse at night and
associated with constitutional symptoms. In inflammatory conditions they
are not useful in early disease, but can be used as a baseline for detecting
later changes.
o Ultrasonography. This is particularly useful for peri-articular structures, soft
tissue swellings and tendons, and for detecting active synovitis in
inflammatory arthritis. It can be used to examine shoulder movement in
shoulder impingement syndrome. Doppler ultrasound can be used to
measure blood flow.
o CT scan. This is also useful for detecting calcified structures, but the dose
radiation is high.
o MRI. This shows bone changes & intra-articular structures. T1-weighted
images are used for anatomic structures while T2-weighted imaging is used to
detect fluid & STIR (short tau inversion recovery) for the presence of bone
marrow oedema. It is more sensitive than X-ray in detecting articular & peri-
articular disease.

Common conditions

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The common conditions are:

• Septic arthritis. This is an infection of the joint space. It usually arises from
introduction of infection into the joint space by direct injury or through blood-borne
transmission from an infected site. The risk factors for contracting septic arthritis
include:
o Chronically inflamed & damaged joints.
o Immunosuppression – AIDS, immunosuppressive therapy.
o Extremes of age – infants & elderly.
o Alcohol abusers.
o Those with joint prostheses.
In the majority of patients, S. aureus is the cause. Other causes include: N.
gonorrhoeae, H. influenzae, Gram-negative organisms (both aerobic & anaerobic),
Streptococcus species and TB. In young previously fit patients, the joint is red, hot,
swollen and agonisingly painful, and the joint is held immobile by muscle spasm. In
the young & old, immunocompromised and in RA patients, the picture is less
dramatic, and so an index of suspicion should be suspected. Septic arthritis is a
medical emergency because it causes rapid destruction of the joint. You do a joint
tap and take the fluid for MCS (microscopy, culture and sensitivity) and you take
blood samples for culture and for FBC. In the acute setting, X-rays have no role. You
can also take skin & throat swabs and urine samples to identify the source of
infection. In the initial phase of treatment, you immobilise the joint and then start
physiotherapy early. You first administer empirical therapy:
flucloxacillin/erythromycin/clindamycin + gentamycin/fusidic acid. You then change
to definitive therapy when culture & sensitivity results come out. Drainage of the
joint & arthroscopic joint washouts is helpful in relieving pain. In the case of infected
prostheses, you remove the prosthesis and fill the joint with a spacer impregnated
with antibiotics.
Specific types of septic arthritis include:
Infectious At-risk Features of disease Diagnosis Treatment
organism population
N. Most common Fever, characteristic Blood culture in Oral penicillin,
gonorrho cause in young, pustular eruption on early stage. Joint ciprofloxacin
eae previously fit distal limbs, fluid may be or doxycycline
adults: polyarthralgia, sterile with for 2 weeks
commoner in tenosynuvitis positive genital with joint
women & gay tract culture. immobilisatio
men. n & joint rest.
TB 1% of TB cases; in Insidious course; forms Culture & biopsy Treat with
adults usually caseating granulomas of synovium. HRZE for 2
from secondary in cartilage & adjacent Chest X-ray months and

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 pulmonary bone; reactive should be done. HR for 6
source. Primary polyarthritis3. MRI months
disease in Commonly affects hip demonstrates (skeletal TB).
children. & knee, but spine can abnormalities Optimise ART
Commoner in be affected. earlier. where
immunosuppress Accompanied by necessary.
ed individuals. constitutional
symptoms.
• Gout. Gout is a type of crystal arthritis in which there is an inflammatory reaction
mounted against crystals within the joint space that are formed due to super-
saturation of synovial fluid with uric acid. It is common in places of affluence,
particularly in the West. It is characterised by acute attacks in single or a few joints
(oligoarthritis), particularly the big toe(s). The precipitants of acute attacks include:
diuretics, dehydration, alcohol, heavy meat meal, aspirin ingestion, taking a high
concentration of organic acids. The typical patient is a middle-aged male patient4.
Gout attacks can also occur during chemotherapy as a result of tumour lysis
syndrome. Repeated acute attacks of inflammation coupled with low-grade
smouldering inflammation result in formation of tophi, which are large concretions
of uric acid. Other complications include urate uropathy & urate stones. Diagnosis is
mainly by history & examination, and serum urate levels are usually high. U&Es are
monitored for signs of renal impairment. Synovial fluid reveals negatively
birefringent sharp intracellular crystals in neutrophils5. On X-ray in chronic gout you
will see soft tissue calcifications as well as tophi within joint spaces. Untreated
attacks usually last 7 days and the overlying skin desquamates. In acute attacks, you
treat using non-aspirin NSAIDs or coxibs or colchicine. Patients should be
encouraged to reduce alcohol intake, non-dietary carbonated fizzy drinks, offals,
some fish and spinach.
• Osteoarthritis. Osteoarthritis is the commonest type of arthritis.

3
This is known as Poncet’s disease.
4
Gout is less likely in women of reproductive age because oestrogen enhances urate excretion.
5
In pseudo-gout, the crystals are positively birefringent. Pseudo-gout is caused by deposition of calcium
pyrophosphate crystals.

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