put together by Alex Yartsev: Sorry if i used your images

or data and forgot to reference you. Tell me who you are.

aleksei.igorevich@gmail.com

Graves’ Autoimmune Thyroiditis

History of Presenting Illness
- Goiter Only Graves
- hypersensitivity to heat
- Tachycardia disease causes - palpitations
- widened pulse pressure ~BILATERAL~ - fatigue
- warm, fine, moist skin ~EXOPHTHALMOS~ - more appetite
- tremor - weight loss
- eye signs (!! EXOPHTHALMOS !!) - insomnia
- atrial fibrillation - weakness
- nervousness and increased activity - frequent bowel movements
- increased sweating (occasionally diarrhea).
Differential Diagnoses
Anxiety Disorders Pituitary Macroadenomas Thyroiditis, Subacute
Hashimoto Thyroiditis Pituitary Microadenomas Cocaine
Hyperemesis Gravidarum Struma Ovarii Wolff-Parkinson-White Syndrome
Pheochromocytoma Thyroid, Papillary Carcinoma
Findings on History
Has there been an ABRUPT ONSET OF FLORID SYMPTOMS??
- Fever - confusion
- Marked weakness and muscle - psychosis
wasting - coma;
- extreme restlessness - hepatomegaly
- wide emotional swings - mild jaundice

~”THYROID STORM” ~
= life threatening !!
Findings on Examination
LOOK
- Weight loss EYES:
- Anxiety - exopthalmos: !! bilateral = always Graves !!
- Frightened thyrotoxic stare - look from the side or from above
- Patient may be pacing and unable to sit still - complications thereof = scleral injection, oedema of the
conjunctiva ( “chemosis”) +corneal ulceration, inferior
HANDS rectus muscle weakness
- Put arms out: fine resting tremor - Lid retraction and lid lag
- Onycholysis – rarely Graves - ?? IS THERE PTOSIS as well ?? there shouldn’t be!
- Acropachy (clubbing)
- Palmar erythema NECK:
- Warmth - Feel the thyroid from behind and from in front; Graves
- Sweaty palms Dz may be enlarged all over and smoothly, while
everything else will be nodular or unilateral.
PULSE - THYROIDECTOMY SCAR
look for Trousseau’s sign
- Sinus tachy (hypoparathyroid)
- !! Could be in atrial fibrillation if elderly !!
- collapsing “bounding” pulse ARMS:
- Raise arms above head, keep em there: proximal
PROXIMAL MYOPATHY myopathy means patient cant do that
- test for weakness
CHEST:
REFLEXES - Gynacomastia, occasionally.
- Brisk but not hyper-reflexive
LEGS:
HEART: - Pretibial myxoedema: spongy swelling of anterior
- Systolic flow murmurs due to massive increase in tibia, elevated dermal nodules and plaques
ONLY
cardiac output GRAVES!
- Atrial fibrillation in the elderly
Congestive heart failure in the elderly
Tests and Investigations: THYROID HORMONE TESTING

Free T4
NSW government is
too poor to let us run INCREASED NORMAL DECREASED
all thyroid function
tests; only TSH and
T4 are allowed

TSH INCREASED Pituitary tumour, Sub-Acute Hashimoto’s

hypothalamus hyperthyroid atrophic thyroidits
tumour…
Secondary
hyperthyroidism

NORMAL RARE EUTHYROID RARE

DISORDERS DISORDERS

DECREASED Graves disease Subacute Pituitary surgery, or

Early thyroidits hypothyroid non-secreting tumour
Abuse of oral (or a tumour that is
thyroxine secreting something
other than TSH

~A note on thyroid drugs~

Propylthiouracil -- inhibits organification of iodine
Early thyroiditis results by thyroid gland. Blocks oxidation of iodine in
in cellular damage and thyroid gland, thereby inhibiting thyroid hormone
hence the release of
great quantities of T4 synthesis; inhibits T4-to-T3 conversion by blocking
and t3; later, thyroiditis type I deiodinase (advantage over other agents).
becomes atrophic and Methimazole (Tapazole) -- Inhibits thyroid
the efflux of hormones hormone by blocking oxidation of iodine in thyroid
stops. gland; however, not known to inhibit peripheral
conversion of thyroid hormone.
Thyroid Auto-Antibodies
The Antithyroid Microsomal Antibodies
are usually elevated in patients with Autoimmune Thyroiditis (Hashimoto’s Thyroiditis)
Antithyroglobulin antibodies may also be elevated in patients with autoimmune
thyroiditis, but this is less frequent and to a lesser degree.
Thyroid Stimulating Immunoglobulins are associated with Grave’s Disease and
are the likely cause of the hyperthyroidism seen in this condition.
Management
Radioactive Iodine: an outpatient treatment (6-8wks)
May end up destroying whole gland;
Thyroxine supplements ever since
OPHTHALMOPATHY: major issue: eyes will dry out, get infected and DIE
I 131

THUS: early Ophthalmopathy = artificial tears ointment, dark sunglasses, eye-patches at night
Late (fibrotic) Ophthalmopathy = orbital radiotherapy (~!! CAREFULLY !!~) + steroids
If that fails
surgery
BEFORE THYROID SURGERY : must ablate thyroid gland, or else!
If the surgeon happens to nick some thyroid tissues, THYROID STORM will
ensue due to massive sudden release of thyroid hormones.
MUST PREPARE FOR THIS POSSIBILITY: “beta-blockade” before getting on the table
Overall: surgery nowadays reserved for only the biggest most obstructive goitres
Epidemiology
- Approx. 30 cases per 100,000 persons per year.
Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases
such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others.
Thyroid storm (an exaggerated state of manifestation of thyrotoxicosis)

with aggressive therapy and early recognition, the mortality rate remains approximately 20%.
GENETICS:

Susceptibility is influenced by genes in the HLA region on chromosome 6 and CTLA-4 on chromosome 2q33.
The gene focus CTLA-4 appears to be an important locus because it contains code for a negative
regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease.
Sex:
• As with most autoimmune diseases, susceptibility is increased in females.
Hyperthyroidism due to Graves disease has a female-to-male ratio of 7-8 : 1
• The female-to-male ratio for pretibial myxedema is 3.5 : 1.
Age:
• Typically, it is a disease of young women, but it may occur at any age.
• The typical age range is 20-40 years.
• Most affected women are aged 30-60 years.

Behavioural science: MANIFESTATIONS OF ANXIETY

SOMATIC SYMPTOMS of anxiety: “fight or flight response”

mediated by CNS, ANS and hypothalamus-pituitary-adrenal axis
- shakiness/trembling WHAT INCREASES IN ANXIETY
- flushes/chills - heart rate
- sweating - respiration rate,
- nausea/"stomach churning" - blood glucose
- palpitations. - triglyceride concentrations
- corticotrophin releasing hormone (CRH)
The heightened alertness, - adrenocorticotrophic hormone (ACTH)
quick reactions - prolactin (from the anterior pituitary)
enhanced muscle function - vasopressin (from the posterior pituitary)
= evolutionary advantage - cortisol and adrenalin

SEQUENCE OF EVENTS:
1. STRESSOR: charging bull, senior staff specialist, etc:
2. CNS: appreciates the level of danger according to limbic system (amygdala, hippocampus)
3. CNS: sends input to HYPOTHALAMUS
4. HYPOTHALAMUS: secretes CRH, activates sympathetic nervous system
Prolactin and vasopressin release seems a collateral effect of
central hypothalamic stimulation
Activates adrenal glands:
5. PITUITARY: in response to CRH secretes ACTH
ADRENALINE released,
6. ADRENAL GLANDS: in response to ACTH,
thus increases heart rate and blood
Secretes CORTISOL
pressure; vasoconstricts selectively
to redistribute blood flow :
FAVOURING MUSCLES,
BOTH COUNTERACT INSULIN: LUNGS, HEART and BRAIN
- increase glycogenolysis
(breakdown of glycogen)
- increase gluconeogenesis WHAT LOOKS LIKE ANXIETY:
(formation of glucose from some amino acids) Catecholamine secreting tumour
- increase hepatic glucose output. (phaeochromocytoma)
As a result, an increased supply of glucose is OR
available for muscle action. Thyrotoxicosis (catecholamine
effects are potentiated but circulating
titres are not increased
 BMR Management and THERMOGENESIS Basal Metabolic Rate
= the idling of the body engine
BMR is primarily dependent on lean body mass (LBM). = the energy expended when
The greater the LBM, the higher the BMR completely at rest but not asleep,
in the absence of muscle movement and
without any sympathetic nervous system
Shivering thermogenesis arousal.
involves muscle contraction and superficial circulatory vasoconstriction to
reduce the loss of normally produced heat energy to the atmosphere. Resting Metabolic Rate
Non- shivering thermogenesis Unlike BMR is ACTUALLY MEASURABLE
is the production of additional heat energy via biochemical reactions. In
rodents heat production occurs in brown adipose tissue whereas in humans
~ 10-15% over the BMR
the main site of this energy production is the skeletal muscle. measured in Kilocarlories / 24 hrs

THERMOGENESIS for the biochem psycho: If ATP is being consumed

without real work being done, then
Basic premises: OBLIGATORY THERMOGENESIS
HEAT is produced as the
is the heat produced at BMR THERE WILL BE
result of exothermic ADAPTIVE THERMOGENESIS HEAT GENERATED
chemical reactions
triggered by exposure to cold, intake of nutrients etc.
It also arises from
is coordinated by the HYPOTHALAMUS
MOLECULAR MOVEMENT (increases SNS activity, triggers TSH release)
SITES OF ADAPTIVE THERMOGENESIS:

Brown Adipose Tissue: SKELETAL MUSCLE

@ neonate or small mammal Thermogenesis here is either shivering or nonshivering
Brown because of all the mitochondria in it
SHIVERING:
HERE, THERMOGENESIS IS DEPENDENTMuscle contraction relies on the breakdown of ATP, which is an
ON “UNCOUPLING” PROTEIN
EXOTHERMIC REACTION
UPREGULATION BY T3 and T4 Non-SHIVERING:
Theres no contraction, but metabolic cycles run back and forth
IN THE MITOCHONDRIA:
FUTILE CYCLES, do nothing except convert a chemical back and forth
VARIOUS eg: gluconeogenesis can run both ways:
Acetyl CoA
NUTRIENTS
GLUCOSE
gluconeogenesis
glycolysis
PYRUVATE
Oxaloacetate
Citrate ALSO: in skeletal muscle:
Its all about taking T3/T4 control a protein by name of SERCA :
the electrons away “smooth endoplasmic reticulum Ca++ -ATPase”
from the nutrients Which cycles in a futile manner:
Ca++ will MOVE BACK AND FORTH
3 NAD + across the reticulum membrane
3NADH recycled Not enough to contract the muscle, but enough to consume ATP
= electron THUS
HEAT ENERGY IS RELEASED
carriers
NORMALLY complex V happily converts ADP into ATP using the H+ gradient
Intra- BUT When the uncoupling protein is activated by T3/T4, or by beta-3 adrenergic
-membrane receptors… IT CONVERTS ATP BACK TO ADP and thus GENERATES HEAT
space;
pH of 3; H+ H+ H+ H+ ADP
lots of (H+)
Membrane

With co- With With reduction of
Uncoupling ATP
complexes enzyme Q cytochrome C Oxygen
H2O
protein
I III IV
V
each complex is also
a proton pump: pumping
-
e -
e e-
H+ out of matrix
H+ H+
Mitochondrial matrix (the inside bit): H+ cycles back into the matrix via Complex V; this drives the synthesis of ATP from ADP
 MECHANISM OF GRAVES DISEASE 7.01
Control of thyroid hormone secretion: TSH binds to a receptor on the follicular cells, thus inducing
HYPOTHALAMUS: commands the Anterior increased iodine uptake, increased thyroid peroxidase activity,
Pituitary via Thyroxin-Releasing Hormone increased proteolysis of thyroglobulin inside the cells, and thus
(TRH); thus stimulated, the anterior pituitary more T3 and T4 in the blood
produces Thyroid-Stimulating Hormone (TSH)

Travelling in blood:
75% bound to
PATHOGENESIS OF GRAVE’S DISEASE: Thyroxine-binding
LOSS OF SELF-TOLERANCE: Globulin
immature self-reactive T-helper cells somehow the rest bound to
escape the thymus without being destroyed Thyroxine-binding
!!OR!! Prealbumin
CROSS-REACTIVITY with a microbial antigen And normal simple
that somehow happens to closely resemble the Albumin
TSH receptor
…either way…
AUTOIMMUNE REACTION TAKES PLACE
T3: 20 times more active than T4

B-Lymphocytes
(stimulated by T-helper cells
via IL-4, IL-5)
The ANTIBODIES cause !! THERE ARENT ANY MORE
Produce TONS OF
peripheral effects, specific to CATECHOLAMINES IN THE BLOOD IN
ANTIBODIES; and they are
Graves disease only; THYROTOXICOSIS !!
high affinity IgG antibodies.
they just have a greater effect on tissues

THYROID-STIMULATING ANTIBODY GRAVES OPHTHALMOPATHY

binds to the TSH receptor Antibody reacts with
something in the retro-orbital This triggers INFLUX of
space; NOBODY knows Fibroblasts and
THYROID GLAND REACTS by exactly what polymorph. Leucocytes
relentlessly secreting T4 and T3 = basically, like chronic
inflammation.
PLUS: fibroblasts deposit
HORRIBLE METABOLIC glycosaminoglycans, and
The Hypothalamus, whose EFFECTS: “FUTILE CYCLES” Retro-orbital oedema
job it is to control the these trap water chokes off the draining
thyroid, senses this excess
Increased = INCREASING veins of the eye; thus;
OEDEMA and
and down-regulates the thermogenesis EXOPHTHALMOS
CHEMOSIS (puffy eyes)
production of TSH and SCLERAL
-Due to T3-induced expression of an extra INJECTION (bloodshot)
protein into the elctron transport chain of
the mitochondria: the “UNCOUPLING Hence, the
PROTEIN” which turns the oxidative “Thyrotoxic Stare”
THUS the thyroid function phosphorylation reaction into a “futile
test will show a massively cycle” where ATP is not produced, but
raised T3, T4 and a totally rather repetitively turned back and forth
into ADP. This generates HEAT. BECAUSE the futile cycles don’t synthesise anything and the beta (3)
absent (or very tiny )TSH
ALSO T3 induces a skeletal muscle receptors on adipose tissue are upregulated and potentiated, the poor
protein “SERCA” to do something similar thyrotoxic patient LOSES WEIGHT
T3 induces the up-regulation of the by pumping Ca++ ions back and forth out (beta-3 receptors mediate lipolysis and the release of free fatty acids)
NUMBER of beta-adrenergic of the sarcoplasmic reticulum
receptors,and enhances the activity of the
Also a net gain of heat and nothing
G-protein to which these receptors are else.
coupled: HENCE the sympathetic effects
THYROID ANATOMY AND PHYSIOLOGY
http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html
The thyroid gland is located in the neck, in close approximation to the first part of the trachea. In humans, the thyroid
gland has a "butterfly" shape, with two lateral lobes that are connected by a narrow section called the isthmus. Most animals,
however, have two separate glands on either side of the trachea. Thyroid glands are brownish-red in color.
Close examination of a thyroid gland will
reveal one or more small, light-colored
nodules on or protruding from its surface -
these are parathyroid glands (meaning
"beside the thyroid"). The image to the right
shows a canine thyroid gland and one attached
parathyroid gland.
The microscopic structure of the thyroid is quite
distinctive. Thyroid epithelial cells - the cells
responsible for synthesis of thyroid
hormones - are arranged in spheres called
thyroid follicles. Follicles are filled with colloid,
a proteinaceous depot of thyroid hormone
precursor (more about that later). In the low (left)
and high-magnification (right) images of a cat
thyroid below, follicles are cut in cross section at
different levels, appearing as roughly circular
forms of varying size. In standard histologic
preparations such as these, colloid stains pink.
In addition to thyroid epithelial cells, the thyroid
gland houses one other important endocrine
cell. Nestled in spaces between thyroid
follicles are parafollicular or C cells, which
secrete the hormone calcitonin.
The structure of a parathyroid gland is distinctly different from a thyroid gland. The cells that synthesize and secrete
parathyroid hormone are arranged in rather dense cords or nests around abundant capillaries. The image below shows a
section of a feline parathyroid gland on the left, associated with thyroid gland (note the follicles) on the right.

Chemistry of Thyroid Hormones

Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to iodine. The two
principal thyroid hormones are:
• thyroxine (known affectionately as T4 or L-3,5,3',5'-tetraiodothyronine)
• triiodotyronine (T3 or L-3,5,3'-triiodothyronine).
As shown in the following diagram, the thyroid hormones are basically two tyrosines linked together
with the critical addition of iodine at three or four positions on the aromatic rings. The number and
position of the iodines is important. Several other iodinated molecules are generated that have little or no
biological activity; so called "reverse T3" (3,3',5'-T3) is such an example.

A large majority of the thyroid hormone

secreted from the thyroid gland is T4, but
T3 is the considerably more active
hormone. Although some T3 is also secreted,
the bulk of the T3 is derived by deiodination of
T4 in peripheral tissues, especially liver and
kidney. Deiodination of T4 also yields reverse
T3, a molecule with no known metabolic
activity.
Thyroid hormones are poorly soluble in
water, and more than 99% of the T3 and T4
circulating in blood is bound to carrier
proteins. The principle carrier of thyroid
hormones is thyroxine-binding globulin, a
glycoprotein synthesized in the liver. Two
other carriers of import are transthyrein and albumin. Carrier proteins allow maintenance of a stable pool of thyroid hormones
from which the active, free hormones are released for uptake by target cells
Fabrication of thyroid hormones is conducted by the enzyme thyroid peroxidase, an
integral membrane protein present in the apical (colloid-facing) plasma membrane of thyroid
epithelial cells. Thyroid peroxidase catalyzes two sequential reactions:
1. Iodination of tyrosines on thyroglobulin (also known as "organification of iodide").
2. Synthesis of thyroxine (or triiodothyronine) from two iodotyrosines.

Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the surface of thyroid
epithelial cells. Remember that hormone is still tied up in molecules of thyroglobulin - the task remaining is to
liberate it from the scaffold and secrete free hormone into blood.
Thyroid hormones are excised from their thyroglobulin scaffold by
digestion in lysosomes of thyroid epithelial cells. This final act in thyroid
hormone synthesis proceeds in the following steps:

- Thyroid epithelial cells ingest colloid by endocytosis from their apical

borders - that colloid contains thyroglobulin decorated with thyroid
hormone.

- Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic

enzymes that digest thyroglobluin, thereby liberating free thyroid
hormones.

- Finally, free thyroid hormones apparently diffuse out of lysosomes,

through the basal plasma membrane of the cell, and into blood where
they quickly bind to carrier proteins for transport to target cells.

ANATOMY OF THE NECK and the structures thereof

Thyroid Gland
• Curves across anterior surface of the trachea just inferior to the thyroid cartilage
• 2 Lobes of the thyroid gland are united by slender connection called the isthmus
CALCIUM HOMEOSTASIS: important but underexplained
The C cells of the Thyroid Gland: Calcitonin

• A 2nd population of endocrine cells lies between the cuboidal follicle cells and their basement membrane. These cells are larger than those of
follicular epithelium
• These C (clear) cells, or parafollicular cells produce the hormone calcitonin (CT). Calcitonin aids in the regulation of Ca2+ concentrations in
body fluids. The net effect of calcitonin release is a drop in the Ca2+ concentrations in body fluids. This leads to the inhibition of osteoclasts
(slows the rate of Ca2+ release from bones), and the stimulation of Ca2+ excretion at the kidneys.
• Control of calcitonin is an example of direct endocrine regulation, because the C cells respond directly to elevations of Ca2+ concentrations of
the blood. ↑ Ca2+ levels → ↑ Calcitonin release
• Calcitonin is most important during childhood, when it stimulates bone growth and mineral deposition in the skeleton. Also important in reducing
the loss of bone mass 1) during prolonged starvation and 2) in the late stages of pregnancy (when maternal skeleton competes with developing
foetus for calcium ions)

The Parathyroid Glands

• 2 pairs of parathyroid glands are embedded in the posterior surface of the thyroid gland (separated by the dense capsular fibres of the thyroid)
• At least 2 different cell populations in the parathyroid. The chief cells produce parathyroid hormone (PTH); the functions of the other cells,
called oxyphils are unknown
• The chief cells monitor the circulating concentration of Ca2+ (like the C cells) When the Ca2+ level ↓’s below normal, the chief cells secrete PTH
→ net result of ↑ Ca2+ concentration in body fluids.
• PTH has 4 major effects
o Stimulates osteoclasts → ↑’d mineral turnover and release of Ca2+ from bone
o Inhibits osteoblasts → ↓’d rate of calcium deposition in the bone
o ↓’s urinary excretion of Ca2+
o Stimulates the formation and secretion of calcitriol at the kidneys (the general effects of calcitriol enhance those of PTH but also
enhances Ca2+ and PO43- absorption by the digestive tract.
• PTH (aided by calcitriol) is likely the 1º regulator of circulating calcium ion concentrations in healthy adults