Thyrotoxicosis

Weight loss DDX

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Energy
Appetite
Absorption
Increased loss
Increased metabolic demand

Anxiety ddx
Palpitations ddx
Tremor
Excessive sweating
Harrisons notes
Why is TSH sufficient for single testing?
Pituitary hormones generally released in pulsatile manner (TSH is). Highest level
occur at night.
TSH can be tested due to its long half life (50mins) thus single measurement
required.
Thryoid hormone synthesis, metabolism and action
Thyroid derived from Tg (thyroglobulin). Tg is iodinated on tyrosine residues.
Reupdate of Tg into thyroid follicular cells for proteolysis.
Iodine metabolism and transport
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Iodide uptake is critical first step. Ingested iodine bound to albumin (serum
proteins) and unbound iodine excreted in urine
Thyroid gland extract the iodine from blood (highly efficient) 10-25% of
radioactive tracer is taken up by normal thyroid gland over 24 hours

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This can be 70-90% in graves disease

Update mediated by NIS. Low iodine increases NIS to stimulate
update and high suppresses NIS. Selective expression of NIS allows
isotopic scanning, treatment and ablation with radioisotpes of iodine
without significant effects on other organs.
Pendrin is another iodine transport on apical surface for iodine efflux
into lumen.

Problems with too little iodine and too much iodine supplementation
Too little = Cretinism = mental and growth retardation often in children in iodine
deficienct regions. Concomitant selenium deficiency can also contribute to cretinism
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Iodine deficiency is the most common preventable mental deficiency.

Mild iodine deficiency can lead to subtle reduction of IQ

Too much = usually through supplements or iodine rich food such as shellfish and
kept. Associated with increased incidence of autoimmune thyroid disease.
Organification and release
Iodide enter thyroid and oxidized into a organification reaction. T4 or T3 produced in
this reaction depending on the number of iodine atoms. After couple, Tg is taken
back into thyroid. Lysosomes release T4 and T3. Uncoupled Mono and
diodotyrosines (MIT and DIT) are deiodinated by dehalogenase = recycling of iodide
that was not converted into thyroid hormones.
TSH action
TSHR interactions with G proteins and also phospholipase C. Mutations of the TSH-R
receptor and how it can cause thyroid size. Recessive mutations causing loss of
function causing thyroid HYPOPLASIA and congenital hypothyroidism. Dominant
gain of function mutations cause sporadic of familial hyperthyroidism. This clinically
shows a goiter, thyroid cell hyperplasia and autonomous function.
TSH is the dominant hormal regulator. But these also have various effects
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IGF1 associated with goiter and multinodular goiter

Epidermal growth factor
TGF-b
Endothelin
Cytokines Autoimmune thyroid disease inducing thyroid growth

Wolff-Chaikoff effect Excess iodide transiently inhibits thyroid iodide organification.

Thyroid hormone transport and metabolism
T4 is secreted from the thyroid gland is 20x more than T3. Both bind to
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Thyroxine binding globulin TBG (carries 80% of bound hormones high

affinity)
Transthyretin TTR
Albumin (lower affinity so around 10% of T4 30% or T3)

Thyroid hormone binding can be abnormal due to inherited or acquired conditions.

1. X linked TBG deficiency = low levels of total T3 and T4. Patients are euthyroid
and TSH are normal due to normal unbound hormone levels.
a. Attempts to noramlise T4 will lead to thyroitoxicosis
2. Oestrogen increases TBG levels and this increases sialylation and delay TBH
clearance
a. Pregnancy and contraceptive (with oestrogen) increases total T4 and
T3 levesl by unbound levels are normal.
3. Salicylates and salsalate medications can displace thyroid hormones from
circulating binding proteins.
a. These increases Free thyroid and TSH is suppressed.
4. Acute illness can displace thyroid hormone (Sick Euthyroid Syndorme)
Thyroid receptors (nuclear)
Thyroid hormone receptor A and B found in most tissues
TRa brain, kidneys, gonads, muscle and heart
TRb pituitary and liver
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TRb2 is selectively expressed in hypothalamus and pituitary and is involved

in the feedback control of thyroid.

Laboratory evaluation of thyroid

Test TSH first = can be suppressed, normal or elevated
If abnormal test for total and free T4 and T3. Unbound T4 levels is sufficienct to
confirm thyrotoxicosis. However T3 is not so much affected, thus, unbound T3
should be measured only in patients with DECREASED TSH but normal fT4.
Testing for autoimmune thyroid antibodies against TPO. Small proporsion of people
with euthyroid have thyroid antibodies and these indivudlas are increased risk of
developing thyroid dysfunction.
80% of those with Graves have TPO antibodies at high levels.
Radioiodine uptake and thyroid scanning
Thyroid gland selectively transport radioisotopes of iodine and thus allowing thyroid
imaging to take place. Nuclear imaging of Graves show enlarged gland and
increased tracer uptake.
What is the role of autoimmunity in thyroid disease?
What is autoimmunity?
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Breakdown of self tolerance leading to immune reactions against self-antigen

Mechanisms of self tolerance
o Thymus deletion of autoreactive T cells (expression of AIRE)
o Peripheral tolerance or anergy where no costimulatory signals leads to
anergy
o Regulatory T cells inhibit auto-reactive T cells

Environmental factors along with genetic factors contribute to autoimmunity

1. Infection viral infection of pancrease can activate presentation of antigen to
self reactive T cells
2. Drugs such as Type I interferon for Hep c can induce autoiimune thyroid
disease
3. Smoking in RA = a-CCP antibodies
Spectrum of autoimmune disease = thyrogastric cluster

Autoimmune thyroid diseases