THYROTOXICOSIS

Prof Fatima Bello

Objectives

 At the end of this short lecture, I expect you

to be able to fully take medical history,
examine, diagnose, and treat a subject with
thyrotoxicosis.

 Should be able to recognize thyroid storm &

manage accordingly

 Ask questions about any muddy areas

The thyroid gland
ANATOMY, PHYSIOLOGY & BIOCHEMISTRY

 The Germans call the thyroid the "shield

gland" (Schilddrüse), & the English name,
derived from the Greek, means the same
thing.

 It wraps itself abt & bcomes firmly fixed by

fibrous tissue to the ant & lat parts of the
larynx & trachea.
• Anteriorly, it’s convex; posteriorly, it’s
concave. The isthmus lies across the
trachea anteriorly, just below the level of
the cricoid cartilage.

• The thyroid is a fleshy red brown bow tie

shaped gland; located in the neck. It lies on
the thyroid cartilage to which it is attached.

• It is made up of two lobes & joined by an

isthmus, which may have a small pyramidal
lobe sitting on it.
Thyroid Anatomy
Gross Anatomy of the thyroid & surroundings (from: Netter FH, The Ciba
Collection of Medical Illustrations, vol. 4, Endocrine system & selected
metabolic diseases, Ciba, 1965, with permission).
The Thyroid Gland
 Anterior neck on
trachea just
inferior to larynx

 Two lateral lobes &

an isthmus

 Produces two main

hormones
◦ Thyroid hormones
◦ Calcitonin
 The weight of the normal thyroid
gland in an adult is 10-25 g
depending on body size & iodine
supply.

 The lateral lobes from superior to

inferior poles usu measure 4 cm.

 Theirbreadth is 15-20 mm, & their

thickness is 20-39 mm.
Clinical Exam. of Thyroid
 Have patient seated on a stool / chair
 Inspect neck – also while drinking water
 Examine with neck in relaxed position
 Palpate from behind the patient
 Remember the rule of finger tips
 Use the tips of fingers for palpation
 Palpate firmly down to trachea

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Where to look for Thyroid ?

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Clinical Anatomy of Thyroid

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 The thyroid gland is enveloped by a thin,
fibrous, nonstripping capsule, incomplete
lobulation. No true lobulation exists.

 The lateral lobes lie in a bed betwn the

trachea & the larynx medially & betwn the
carotid sheath & the sternomastoid muscles
laterally. In front are the thin, ribbon-like
infrahyoid muscles.

 Itcan usu be felt by careful palpation in

normal humans.
 Theparathyroids, are usu situated on
the posterior surface of the lateral
lobes of the gland within the surgical
capsule

 The recurrent laryngeal nerves, run in

the cleft btwn the trachea & esophagus
just medial to the lateral lobes.

 The relationship to the trachea is

important from the point of view of
pressure symptoms.
 Blood supply is provided from the 4 major
thyroid arteries.

 The superior pair arise from the external

carotid & the inferior pair from the
thyrocervical trunk of the subclavian
arteries & frequently,

 a 5th artery, the thyroidea ima, from the

arch of the aorta, enters the thyroid in
the midline.
 The veins emerge from the interior of the
gland & form a plexus of vessels under the
capsule.→ drain into the internal jugular,
the brachiocephalic, & the anterior jugular
veins.

 The adult thyroid gland is composed of

follicles, or acini whc are the 1o, or
secretory, units of the organ.

 The cells of the follicles are the makers of

hormone; the lumina are the storage
depots.
 Lymphatics

A rich plexus of lymph vessels

is in close proximity to the
individual follicles, but no
unique role in thyroid function
has been assigned to this
system.
 Innervations

 The gland receives fibers from

both sympathetic &
parasympathetic divisions of the
autonomic nervous system.

 The sympathetic fibers are

derived from the cervical ganglia
& enter the gland along the blood
vessels.
The main function of the
thyroid gland is to make
hormones, T4 & T3, which are
essential for the regulation of
metabolic processes
throughout the body.
Thyroid Regulation

HYPOTHALAMUS - TRH

ANT. PITUITARY - TSH

TSH -R
THYROID T4 and T3

PLASMA T4 + FT4
PLASMA T3 + FT3

TISSUES FT4 to FT3, rT3

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THYROID HORMONE METABOLISM IN HUMANS
 Clinical summary
 Thyroid gland produces predominantly the
prohormone T4 together with a small amnt of the
bioactive hormone T3.

 Most T3 is produced by enzymatic deiodination (ORD)

of T4 in peripheral tissues. Alternatively, deiodination
(IRD) of T4 yields the metabolite rT3.

 Normally about ⅓ of T4 is converted by ORD to T3 &

about ⅓ to rT3.

 The remainder of T4 is metabolized by diff pathways,

in particular glucuronidation & sulfation.
 Definitions
 Thyrotoxicosis - clinical state that results
from inappropriately high thyroid hormone
action in tissues generally due to
inappropriately high tissue thyroid hormone
levels
 Hyperthyroidism – a form of

thyrotoxicosis due to inappropriately high

synthesis and secretion of thyroid
hormone(s) by the thyroid

Bahn et al. Hyperthyroidism and Other Causes of Thyrotoxicosis: Management

Guidelines of the American Thyroid Association and American Association of
Clinical Endocrinologists. Thyroid, 2011 Jun;21(6):593-646 & Endocr Pract, 2011
Thyrotoxicosis(Definition & Causes)

 This is a condition where patient has

elevated basal metabolic rate (BMR) due to
over secretion of T3 & T4

 It can be due to :
◦ A) Multinodular toxic goiter

◦ B) Toxic nodule
Thyrotoxicosis causes ctd
◦ C) A diffuse toxic goiter (Graves’
disease, also called, Basedow’s disease)

◦ D) Plummer’s Disease: Toxic

autonomous adenoma.

◦ E) Jodbasedow disease (iodine

induced hyperthyroidism)
Graves’ Disease(GD)
Introduction
• Autoimmune disease of thyroid
• Commonest cause of hyperthyroidism

Features include:
• -dermopathy
• -acropachy,
• -ophthalmopathy,
• -diffuse goiter

• Not all need to be present at the same time

Introduction of GD ctd
 DEFINITION
 Graves' dx is a syndrome xterized by

hyperthyroidism, ophthalmopathy, &

pretibial myxoedema. Rarely thyroid
acropachy is associated.

 Usu thyroid enlargement, goitre, &

excessive thyroid hormone are the
features of the illness.
Introduction conts
Excess thyroid hormone
causes a widespread
disturbance in metabolism,
since thyroid hormone
effectively regulates the
metabolic level in the body.
Introduction conts
 Hyperthyroidism was described by
the Irish physician Robert Graves,
to whom credit is attributed.

 Theeponym Basedow's dx is often

used on the European continent to
recognize the description by Karl A.
von Basedow (1799 - 1854).
CAUSES OF GRAVES' DISEASE
Graves' disease is accepted as
a syndrome induced by
autoimmunity to the thyroid,
due to disordered immunity.

Contemporary understanding
is that the process involves a
variety of factors allowing self-
reactivity to occur.
CAUSES conts
 While our immune sysm is
designed to prevent self-reactivity,
to some extent, very low levels of
self-reactivity re normally present .

 Presumably genetic &

environmental factors interact to
augment this immunity, from a low
& physiologically unimportant level,
to a degree that causes a dx state.
CAUSES conts
 Environmental Factors( )irradiation, cigarette smoking

 Thymic Selection of Lymphocytes

 Molecular Mimicry(A theory on the etiology of autoimmune
dxs is that a persistent exposure to a particular peptide epitope in an environmental
Ag might develop immune reactivity to an amino acid sequence identical to that
present in a human endogenous Ag such as TSH receptor, TPO, or TG - yersinia)

 Thyroid Injury & Antigen Release

 Alterations in immune function
 Genetic Factors (powerful genetic influence on development of the
dx. HLA-B8,HLA-DR3,HLA molecule DQA1)
Aetiology of Graves’
Disease
 Genetic – Gender, Ethnic, Familial, etc

 Environmental – stress, ?iodine

metabolism

 Altered immune response- development

of antibodies to thyroid peroxidase,
thyroglobulin & binding antibodies to
thyroid hormone receptors
 THYROID GLAND FUNCT IN GD

 Thethyroid gland is functioning at an

accelerated rate.

 Cell membrane adenyl cyclase

activity in tissue from Graves' pts is
higher than in normal thyroids, & the
increment coincides with TS-Ab in
the serum, wch acts on TSH
receptors to cause the response.
 THE GLAND FUNCT IN GD conts
 Thus,
the Graves' gland appears to
be unusually sensitive to small
amounts of iodide, as manifested by:

 (1) a block of iodide uptake & binding

 (2) a block of hormone release.

INCIDENCE & DISTR OF GD

 GD is most typically a dx of adult woman

in the age grp 30 & 60, & has an
incidence roughly 8x in women > in
men.

 Aside from the infrequent occurrence of

postnatal thyrotoxicosis due to maternal
Abs, the incidence of spontaneous GD in
children b4 the age of 10 is most
unusual, but the incidence ↑s with each
decade until about age 60
INCIDENCE & DISTR OF GD conts
 It is the most common type of autoimmune
thyroid disease in Africans with prevalence of
1.2-9.9%
 Prevalence in Nigeria 1.5-54% with the peak
age at the 2nd to 4th & 4th – 6th decades of life.

 Its development is attributed to the presence

of autoantibodies against TSH Receptors the
Thyroid Stimulating Antibodies (TSI) as well as
autoantibodies against Thyroid Peroxidase
(TPO).
 Genetic predisposition is as high as 79%
Clinical features
 Symptoms: weight loss, hyperdefecation,
pruritus, hyperpigmentation, palpitation,
hyperhidrosis, itchy eyes, eye protrusion,
etc

 Signs: exophthalmos, agitation, anxiety,

onycholysis, palmar erythema, tremors,
smooth velvety skin, pretibial myxoedema,
diffuse soft goitre
Symptoms
Heat intolerance ↓ in menstrual flow; menstrual irregularity
or amenorrhea
Weight loss with increased appetite ↓ fertility

Prominence of eyes, puffiness of lids Neuromuscular

Pain or irritation of eyes Fatigue , Weakness, Tremulousness

Goitre Occasional bursitis, Rarely periodic

paralysis
Dyspnea Emotional Nervousness, irritability,
Emotional lability

Palpitations or pounding of the heart Insomnia or↓ sleep requirement

Ankle edema (without cardiac disease)

Dermatologic Thinning of hair Loss of curl
in hair
Less frequently, orthopnea, paroxysmal
tachycardia, anginal pain, & CHF Increased perspiration ,Change in texture
of skin & nails
Increased frequency of stools
Increased pigmentation, Vitiligo , Swelling
over out surface of shin
Polyuria Family history of any thyroid disease,
especially Graves‘ disease
SIGNS Tachypnea on exertion

Tachycardia, overactive heart, widened

Weight loss pulse pressure, & bounding pulse

Hyperkinetic behavior, thought, & speech Occasional cardiomegaly, signs of

congestive heart failure, & paroxysmal
tachycardia or fibrillation
Restlessness, Lymphadenopathy & Neuromuscular
occasional splenomegaly
Eyes
Tremulousness
Prominence of eyes, lid lag,
Exophthalmos, Objective muscle wasting & weakness
lid edema, chemosis, extraocular muscle Quickened & hypermetric reflexes
weakness
Decreased visual acuity, scotomata,
papilledema, retinal hemorrhage, and Emotional lability
edema
Goitre

Sometimes enlarged cervical nodes

Bruit
Dermatologic

Hyperpigmentation or vitiligo

Fine, warm, moist skin

Fine & often straight hair

Pretibial myxedema

Acropachy

Oncholysis (Plummer's nails)

Ophthalmopathy of
Graves’ dx
Classic severe Graves' ophthalmopathy demonstrating a widened palpebral
fissure, periorbital oedema, proptosis, chemosis, & conjunctival injection.
SxS & SnS OF GRAVES’ Dx & THYROTOXICOSIS

 In patients with Graves' dx, the ocular

changes, lymphoid hyperplasia, localized
abns of skin & ct (e.g., acropachy) & the
goitre itself represent parts of the
autoimmune syndrome.

 The remainder of the changes appear to be

entirely attributable to an excess of thyroid
hormone.
 THYROID GLAND

The thyroid is smooth diffuse

goitre, lobulated, & rarely
nodular. The size varies from
the barely palpable normal (15
- 25 g) to an enlargement of
six times normal (100 g) or,
rarely, even more, but
averages about 45 g.
Diffuse goitre, more on
right
 The bruit the audible sn of turbulence
associated with an ↑ rate of flow through
rather tortuous vessels.

 Other sxs, include dysphagia & the

sensation of a lump in the neck.
Sometimes the supraclavicular lymph
nodes become enlarged & tender.

 Vocal cord palsy may be seen, but is found

chiefly in cancer of the thyroid,
occasionally in nodular goitre, & only
rarely in GD.
Plummer's nail changes, showing thinning of
the nail & marked posterior erosion of the
hyponychium.
 CLINICAL BOTTOM LINE:
Diagnosis…

 To make diagnosis, use:

 History and physical exam
 Low serum TSH level with elevated serum levels for
free T4, FT4 I, total T3, or free T3

 To identify cause, use:

 Clinical features
 RAIU and thyroid scan
 Additional tests (TRAb, TSI, TPO antibodies,
thyroglobulin, ESR, HCG, color Doppler US, whole-
Tests of thyroid function

Resin T3 (or T4) uptake is an indirect inverse

test of Thyroid binding proteins
• FTI = T4 andT3 resin uptake

• FT4 more accurate

• Screening purposes TSH (sensitive)

are best if free T4 assays not possible

• Thyroid Antibodies = Antibodies to TPO &

TSI
Others (not specific for
GD )
• Hypothyroidism TSH, Anti-thyroglobulin (ATG) and
Anti-thyroid peroxidase and microsomal antibodies
(ATM).
• Hyperthyroidism TSH, T3
• 123I uptake scan
• ATG & ATM antibodies
• TSH receptor antibodies.
• Nodules Fine needle aspiration biopsy.
• 123
I uptake & scan
• 99m Technetium scan to detect vascular tumors.
• Ultrasound Scans. To detect nodules and cysts
HEMATOLOGIC CHANGES
 In most pts the hb & haematocrit re in the
normal or low range. Blood volume is ↑, &
the red cell mass is actually ↑ in some pts.

 In severe thyrotoxicosis, normocytic anaemia

with Hb concentrations as low as 8 - 9 g/dl
may be observed. A relative lymphocytosis is
frequently found.

 GD is often associated with mild

thrombocytopenia, & occasionally with
idiopathic thrombocytopenic purpura.
Treatment
 Goals:

◦Normalize serum TSH levels

◦Reverse\correct clinical signs &

symptoms and metabolic
derangements.
 Treatments:
Antithyroid Drugs
 1) Thionamides:
 Thionamides possess a thiocarbamide
group ( s=c-n).

 They prevent the synthesis of thyroid

hormones by competitively inhibiting the
peroxidase – organification.

 They also block the coupling of iodotyrosine,

especially diiodothyronine formation.
Thionamides conts

 Carbimazole, methimazole&
propylthiouracil block iodide oxidation &
organification.

 Incorporation of iodine into tyrosine

molecule on thyroglobulin colloid to form
monoiodotyrosine (MIT) & di-iodotyrosine
(DIT)
(Process inhibited by carbimazole & propylthiouracil).
Thionamides conts….

◦ Interfere with iodination of tyrosine residues

Inhibit the synthesis of thyroid hormones
◦ Effects seen 1-4 weeks after initiation of therapy.

Methimazole (MMI) – 5-60 mg daily

Propylthiouracil (PTU) – 100-300 mg per day
divided BID/TID

Start with a high dose and then reduce

the dose when the patient is euthyroid
Thionamides conts….

Carbimazole – not for use in 1st trimester

Methimazole – not for use in 1st trimester
Propylthiouracil – high risk of fatal liver failure, used
in 1st trimester of pregnancy

 Side effects:
◦ Rash, arthralgias, nausea
◦ Vasculitis
◦ Liver function tests abnormalities (acute liver
failure with PTU)
◦ Agranulocytosis
◦ Embryopathy Check baseline CBC/diff and LFT’s
2) Potassium iodine :
• Acutely reduces thyroid hormone
release

 Inhibits organification & hormone release.

 Decreases the size & vascularity of the

hyperplastic glands.

 Useful before thyroidectomy in Graves’ disease

 Given in drops orally

 Don’t use before radioactive iodine therapy
3) β-adrenoceptor antagonists:
---Propranolol, atenolol, metoprolol,
nadolol
Beta blockers improve symptoms of
hyperthyroidism including anxiety,
tachycardia & tremors.
They inhibit the conversion of T4 toT3 in
the tissues.
For symptomatic hyperthyroidism of any
cause
Uses of Beta blockers
 1. While awaiting laboratory confirmation of
thyrotoxicosis

 2. During initiation of therapy with

antithyroid drugs

 3. Before treatment with radioiodine,

because they do not interfere with the
uptake of iodine by the gland
Uses of Beta blockers
conts….

 4. In thyroid crisis ( thyroid storm)

 5. With iodine, as a rapid preparation on

a hyperactive thyroid goiter

 6. In neonatal hyperthyroidism due to

thyroid – stimulating – immunoglobulin(TSI)
from the mother ---usually remits within
about 6 weeks as Ig is cleared.
 4) Radioactive iodine:
 An effective oral treatment for thyrotoxicosis
caused by Graves’ disease or toxic nodular goiter.

 It is safe, causes no discomfort to the patient &

has largely replaced surgery.

 The isotope employed is I with t½ of eight days.

131

 Thyroxine replacement is started after 4 to 6

weeks to life.

 Ablates gland
 Radioactive iodine conts….
• Generally, the dose of 131I administered is 75-200
µCi/g of estimated thyroid tissue ÷ by the % of 123I
uptake in 24 hrs

• Contraindicated in pregnancy & nursing mothers.

• Relative contraindication in those with

ophthalmopathy especially if male or smoker

• No increased incidence of leukaemia, thyroid or

other cancers but concern remains regarding its use
in children & women.
Ancillary Drug Therapy
 Lithium
Reduces thyroid hormone release

 Cholestyramine
Binds thyroid hormone in intestines

 Nonsteroidal anti-inflammatory
Treats subacute thyroiditis

 Glucocorticoids
For severe subacute thyroiditis
 Antithyroid Drugs ……..follow up
If Agranulocytosis, liver injury, vasculitis: discontinue
If Fever or pharyngitis: repeat CBC with differential WBC
If Symptoms of liver injury: order liver profile

◦ Once symptoms resolved + results in reference range…

 Discontinue β-adrenergic blocker + reduce antithyroid Rx

 Continue clinical and lab assessments every 3–6 months

◦ After 12-18 months reduced dose + normal TSH: ? remission

 Taper or stop antithyroid Rx

 Measure TRAb: normal = greater likelihood remission

 No remission: consider 131

I or surgery
Surgery (Thyroidectomy)

 Total
 Subtotal (bilateral)
 Lobectomy
 Lobectomy plus Isthmusectomy
Indications for
Thyroidectomy
• Severe hyperthyroidism in children
• Pregnant women who re noncompliant or intolerant of
antithyroid medication

• Patients with very large goitres or severe

ophthalmopathy
• Patients who refuse radioactive iodine therapy

• Refractory amiodarone-induced hyperthyroidism

• Patients who require normalization of thyroid function

quickly, such as pregnant women, women who desire
pregnancy in the next 6 months, or patients with
unstable cardiac conditions
How should clinicians monitor patients who
are being treated for hyperthyroidism?

 At baseline:
Perform CBC w/ differential WBC count, liver
panel
 Once euthyroid:
Assess clinically
Measure serum TSH every 6 to 12 months for
lifetime

 Monitoring differs depending on chosen treatment…

Complications of
thyrotoxicosis
 Thyroid crises(Thyroid Storm)
 Thyrotoxic heart disease
 Erectile dysfunction
 Infertility
 Psychoses
Thyroid Crises( Thyroid
Storm)
Thyroid crises( Thyroid
Storm)
 Acute exacerbation of symptoms of
thyrotoxicosis, often including jaundice, atrial
fibrillation

 Other features include hyperpyrexia, altered

consciousness & or shock

 Treatment requires dexamethasone, beta

blockers, antithyroid drugs, IV fluids & anti
arrhythmics
Treatment of thyroid crises
 Propanolol 40-60mg 6hrly
 Hydrocortisone 100-250mg 6 hrly or
dexamethasone 1-2 mg 8hrly
 Potassium Iodide (Lugol’s Iodine) 5drops
tds(not more than 2wks)
 Prophythiouracil 200-400mg in divided doses
 Carbimazole 20 -45mg in divided doses
 Chlorpromazine 25 -50mg 8hrly
 IV fluids, antibiotics, cooling, oxygen
 Cooling Blanket
Treatment of thyroid crises
1. Decrease thyroid hormone synthesis
◦ Propylthiouracil or methimazole

2. Inhibit thyroid hormone release

◦ Sodium iodide (IV) or potassium iodide (oral)

3. Reduce heart rate

◦ β-blocker (esmolol, metoprolol, propranolol) or diltiazem

4. Support circulation
 Glucocorticoids in stress doses
 Fluids (IV), oxygen, cooling

5. Treat precipitating cause

Summary
 Thyrotoxicosis caused by Graves’ dx may also be produced by
toxic multinodular goiter, toxic adenomas, excessive thyroid
hormone ingestion, or several other rare syndromes.
 Thyrotoxicosis is a common condition encountered in practice

 Subclinical disease is more common than overt thyrotoxicosis

 TSH best for screening and free T4 for confirmation and monitoring
treatment

 Radioiodine uptake and scan preferred imaging modality

 Graves' disease includes thyrotoxicosis, goiter, exophthalmos, &

pretibial myxoedema when fully expressed, but can occur with one
or more of these features.

 Treatment with methimazole or I usually preferred

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Questions?