Thyroid Gland Disorders

Question 1

Basic Physiology of Thyroid: follicles and synthesis of hormones, actions

Answer 1

Thyroid follicles

• follicular cells: synthesise thyroglobulin (Tg)
• colloid: synthesis and storage of thyroid hormones, contains Tg
• parafollicular C cells: calcitonin

Thyroid hormone synthesis

• iodide uptake across apical membrane by NIS
• oxidation of iodide by H2O2 into reactive intermediate by TPO (thyroid peroxidase)
• iodination of tyrosine residues of Tg by TPO –> form MIT or DIT
• coupling of 2 iodotyrosines to form iodothyronine by TPO - still attached to Tg
• endocytosis of colloid/Tg into follicular cells
• proteolysis of Tg in lysosomes to release iodothyronines by 5’ deiodinase (T3 or T4)
• recycling of iodide from MIT and DIT (didn’t couple)

Actions of thyroid hormones

• intranuclear receptors
• BMR – O2 consumption, mitochondrdrial metabolism
• increase sensitivity to catecholamines
• increase protein synthesis (growth)
• synthesis and degradation of cholesterol
• Ca and PO4 metabolism regulation

Question 2

Thyroid hormone transport and metabolism

Answer 2

T4 t1/2 = 5-7 days vs T3 = 1 day

T4 –> T3 via 5’-deiodination by D1/D2

• majority of T3 is converted from T4 in the periphery
• measurement of fT4 gives good indication of T3 (T3 not routinely measured due to short t1/2 and low concentrations)

Plasma transport:

• only 0.03% fT4 and 0.3% fT3
• T4 –> thyroxine binding globulin (TBG), transthyretin (prealbumin) and albumin
• T3 –> TBG and albumin

Question 3

Regulation of thyroid hormone

Answer 3

Hypothalamic-pituitary-thyroid axis

• negative feedback by fT4, fT3 –> major loop at pituitary level
• inverse log-linear relationship between fT4 and TSH –> [TSH] sensitive marker for primary thyroid disorder

Follicular auto-regulation

• to maintain euthyroid state despite iodine variations
• high intrathyroidal iodide = downregulation of NIS (failed = Joe-Basedow effect)
• = inhibits organification of iodide (Wolf-Chaikoff effect)
• -> “escape” after 2-4 wks of continued excess exposure

Question 4

Iodine deficiency

Answer 4

Causes endemic goitre

Occurs during pregnancy, malnutrition (areas of env iodine deficiency e.g. mountainous areas)

==> decrease iodination to T3,T4 = less negative feedback on TSH = increase TSH = hypertrophy of gland

==> non-toxic nodular goitre
- in the absence of hypothyroidism (hypertrophy of follicles compensate for deficiency by increasing uptake), effects of goitre are mainly cosmetic although complications e.g. haemorrhage into nodule, compression effect may occur

Severe iodine deficiency –> primary hypothyroidism

Question 5

Iodine excess

Answer 5

Both hyper/hypothyroidism can occur

Hyperthyroidism due to Joe Basedow effect

• underlying iodine deficiency with re-introduction of iodine
• autonomic thyroid nodule

Hypothyroidism due to failed Wolff-Chaikoff escape

• Hashimoto thyroiditis
• Graves’ previously treated by RAI or subtotal thyroidectomy
• De Quervain thyroiditis

Question 6

Goitre

Answer 6

Enlargement of thyroid gland due to stimulation by TSH
- can exist in hypo/hyper/euthyroid

E.g.
iodine deficiency – nodular, non-toxic
Hashimoto – lymphocytic infiltration
Graves’ – stimulation of TSI, diffuse toxic

Question 7

Lab evaluation of thyroid status: TSH and fT4/fT3

Answer 7

If no suspicion of pituitary disease, first line Ix is TSH followed by reflex fT4 testing (i.e. depending on TSH levels)

1. Suppressed TSH
   - and high fT4 = primary hyperthyroidism

• and normal fT4 –> measure fT3
  if
  fT3 elevated = T3 toxicosis e.g. iodine deficiency or earliest stages of thyroid disease since fT3 increases earlier than fT4 (e.g. Graves’, MNG)
  fT3 normal = subclinical primary hyperthyroidism
• and low fT4 –> measure fT3
  if
  fT3 elevated = T3 toxicosis (easily misdiagnosed as central hypothyroidism!)
  fT3 low = central hypothyroidism

2. Raised TSH
   - and normal fT4 = subclinical primary hypothyroidism

• and low fT4 = primary hypothyroidism
  (TSH usually above 10 mIU/L in frank hypothyroidism; RR 0.27-4.20)

If suspicion of pituitary/hypothalamic disease, simultaneous TSH and fT4 used

• -> inappropriately normal/low TSH, low fT4 = central hypothyroidism
• -> inappropriately normal/high TSH, high fT4 (rare) = TSH secreting adenoma, thyroid hormone resistance, assay interference

Question 8

Lab evaluation of thyroid status: Anti-thyroid antibodies

Answer 8

Anti-Tg Ab
Anti-TPO Ab
TRAb (TSH receptor Ab)

Hashimoto’s thyroiditis –> Anti-Tg and Anti-TPO diagnostic

Graves’ disease –> TRAb +/- Anti-Tg and Anti-TPO

TRAb classified as stimulating, blocking or neutral

• stimulating type (TSI) causes Graves’
• both blocking and stimulating types seen in Graves’
• blocking type may be seen in atrophic Hashimoto’s

TRAb useful for:

• confirm diagnosis of Graves’ where radio iodine scan is not available or contraindicated e.g. nursing mother
• assess likelihood of remission after antithyroid drugs in Graves’
• assess risk of neonatal Graves’

Question 9

Hyperthyroidism clinical presentations

Answer 9

Symptoms

• nervousness, restlessness, irritability
• weight loss, excessive sweating, heat intolerance
• menstrual irregularity
• diarrhea

Signs

• tachycardia, warm/damp skin
• smooth and shiny skin
• increased reflexed
• eyelid retraction

Specific signs for Graves’ – exophthalmos, clubbing, pre-tibial myxoedema, ophthalmoplegia

Question 10

Hyperthyroidism causes

Answer 10

Excessive TSH receptor stimulation

• Graves’ (TRAb)
• Pregnancy associated transient hyperthyroidism (hCG)
• Gestational trophoblastic disease (hCG)
• TSH producing adenoma (rare)

Autonomous thyroid hormone secretion

• Toxic MNG
• Toxic thyroid adenoma
• Toxic CA thyroid (rare)

Destruction of follicles with release of hormones

• subacute de Quervain thyroiditis (viral infection)
• painless thyroiditis (Hashitoxicosis)/postpartum thyroiditis
• acute bacterial thyroiditis
• drug-induced thyroiditis (amiodarone)

Extrathyroidal source

• iatrogenic
• tiratricol (T3 analogue in slimming agent)
• animal thyroid tissue (slimming agent)
• functional CA thyroid metastasis
• struma ovarii (teratoma with thyroid tissue)

Question 11

Lab manifestations of hyperthyroidism

Answer 11

Low TSH, normal/high fT4 (primary hyperT)
Normal/high TSH with high fT4 (TSH adenoma)

Elevated ALP (secondary osteoporosis)
Increased SHBG
HyperCa
Hyperglycaemia (increase glycolysis and gluconeogenesis)
Low RBC zinc
Low total cholesterol and HDL cholesterol
Thyrotoxic periodic paralysis (20-40 yrs old asian men; 2% cases)

Question 12

Radioactive Iodine uptake scan

Answer 12

Increased

• diffuse: graves’ disease
• localised: toxic nodules (solitary or multiple)

Low

• thyroiditis
• iodine excess
• thyrotoxicosis factitia

Question 13

Graves’ disease manifestations, pathogenesis, treatment

Answer 13

Hyperthyroidism (MC cause), diffuse goitre, ophthalmopathy/orbitopathy (30%), dermopathy occasionally (rarely acropachy)

F>M 4x
Graves’ triad = thyroid, eye, skin

Due to autoimmunity against TSH receptor
- TRAb stimulate the thyroid

Treatment: thionamides e.g. carbimazole, PTU – monitor through fT4 and fT3 (TSH not reliable in early treatment as thyrotrophs response are slower)
==> fT4 should return to normal, TSH (pituitary) may take more time to recover after suppression

Question 14

Toxic multinodular goitre

Answer 14

After 50yrs old in patients who have non-toxic MNG for years

F>M 6x

Milder disease than Graves’

May present abruptly due to exposure to increased quantities of iodine e.g. CT contrast media

Question 15

Toxic adenoma

Answer 15

Hyperfunctioning solitary nodule

Occurs at younger age (30-40s)
Milder disease than Graves’

Question 16

Approach to hyperthyroidism

Answer 16

Recent onset (<3mths)
- USG –> tenderness +ve favours thyroiditis; diffuse goitre/nodular suggestive of different aetiologies –> RAI scan
==> low
–> r/o iodide excess (check urinary iodide)
–> r/o exogenous use (if have, check serum Tg –> low in thyrotoxicosis factitia; normal/high in hyperthyroidism)
–> thyroiditis

==> high

• -> diffuse –> Graves’
• -> nodular –> solitary or MNG

Question 17

Hypothyroidism clinical manifestations, complications if untreated

Answer 17

Very common (2-15% population)
F>M

Symptoms

• mental dullness, lethargy, easy fatiguability (SOB, decreased exercise tolerance), depression
• weight gain, cold intolerance
• deepening of voice/hoarseness, hair loss
• menorrhagia, infertility, delayed puberty (in adolescence)
• constipation, muscle weakness

Signs

• bradycardia, cool dry skin, puffy eyes
• loss of lateral 1/3 eyebrow
• delayed relaxation phase of reflexes
• myopathy
• galactorrhea
• delayed bone age in children

Goitre may be present (Hashimoto’s thyroiditis or stimulation of TSH)

In severe, longstanding untreated cases –> congestive heart failure or myxoedema coma

Untreated children/ congenital –> cretinism (mental retardation and growth failure)

Question 18

Lab manifestations of hypothyroidism

Answer 18

Raised TSH, normal/low fT4 (primary)
Normal/low TSH, low fT4 (central)

HypoNa
Macrocytic anaemia
Raised CK 
Low SHBG
Raised cholesterol and LDL and TG
HyperPRL

Question 19

Primary hypothyroidism causes

Answer 19

Acquired:

• Hashimoto
• iodine deficiency
• drugs blocking synthesis/release of T4 e.g. Li, thionamides, acute exposure to iodide
• goitrogens
• post-ablation
• post-thyroidectomy

Transient: post-thyroiditis

Congenital: (have newborn screening)
- thyroid dysgenesis or dyshormonogenesis

Question 20

Hashimoto Thyroiditis cause, clinical features, lab

Answer 20

Also known as chronic lymphocytic thyroiditis/ painless thyroiditis
(MC cause of hypoT in iodine sufficient areas)

F>M 7x
30-50 yrs old

Combination of genetic and env factors
Thyroid gland infiltrated by lymphocytes and plasma cells –> secondary lymphoid follicles develop

Clinical:

• gradual thyroid failure
• some have goitre, some have atrophic glands
• initial phase of inflammation may lead to transient hyperthyroidism
• a/w Graves’

Lab:

• elevated TSH, normal/low fT4
• +ve anti-TPO and anti-Tg

Treatment:
- replacement of T4 if hypothyroid/ symptomatic –> monitor TSH for normalisation

Question 21

Transient Thyrotoxicosis phenomenon, causes

Answer 21

Abrupt onset and short duration –> patient then becomes normal/hypoT after
Due to thyroiditis causing thyroid cell breakdown

Causes:

• autoimmune i.e. Hashitoxicosis
• viral i.e. subacute De Quervain or granulomatous thyroiditis
• acute due to bacterial/fungal infection (rare)
• drug induced thyroiditis e.g. amiodarone and lithium

Question 22

De Quervain thyroiditis cause, clinical features, lab results

Answer 22

Due to viral infection (following URTI)

Gradual or sudden appearance of pain +/- fever
Hoarseness, dysphagia, palpitation, nervousness
**HyperT –> HypoT (usually asymptomatic) –> EuT (each phase 2-8 wks)

Lab:
Elevated ESR (often >100 mm/hr)
+ve anti-TPO transiently in active phase, but usually negative

Question 23

Central HypoT cause, severity, investigations, caution in treatment

Answer 23

Due to pituitary or hypothalamic disease
- usually have decreased secretion of other pituitary hormones

Congenital or acquired

Less severe than primary hypoT as a small but significant fraction of thyroid gland is independent of TSH

Investigations:

• assess other pituitary hormones
• MRI pituitary
• TRH stimulation test if in doubt (no response of TSH in pituitary disease, delayed response in hypothalamic disease)

==> CAUTION: exclude secondary adrenal insufficiency first before starting T4 replacement! – or else may precipitate acute adrenal crisis (increase turnover and depletion of corticosteroids)

Question 24

Approach to hypothyroidism

Answer 24

1. Distinguish primary or central via TSH and fT4 levels

Primary (high TSH, low/normal fT4) –> TPO Ab

• -> present = Hashimoto’s
• -> absent = transient thyroiditis/viral thyroiditis –> give T4 for 4 months and then reduce by 50% for 6 wks –> increased TSH = permanent hypoT

Central (normal/low TSH, low fT4 + no salicylate, phenytoin or recent thyrotoxicosis) –> MRI
–> pituitary or hypothalamic lesion –> check adrenal, PRL, gonads

–> normal –> consider congenital problem, TSH deficiency, infiltrative disease of pituitary –> check adrenal, PRL, gonads

Question 25

Amiodarone effects on thyroid, complications

Answer 25

Class III antiarrhythmic medication Effects on thyroid: - iodine excess - inhibition of D1 and D2 deiodinases - competes with T3 for binding to thyroid hormone receptor - direct cytotoxic effect on thyroid cells - precipitation of autoimmune thyroid disease in susceptible patients (Ab +ve) 80% remain euthyroid --> 30-50% increase in fT4 with unchanged TSH and fT3 Complications: - in iodine sufficient area: thyroiditis and subsequent hypoT - iodine deficient: hyperT may occur (because it is iodide rich) ==> need regular TFT monitoring!

Question 26

Lithium effects

Answer 26

Treatment of psychiatric disorders (bipolar) and also non-first line Tx of hyperT 40-50% goitre 20-30% hypoT ==> regular monitoring of TSH needed!

Question 27

Thionamides examples, actions

Answer 27

Commonly used in treatment of hyperT --> Methimazole (prodrug: carbimazole), propylthiouracil Target TPO --> inhibit oxidation, iodination and coupling --> intrathyroidal iodine deficiency Large doses of PTU also impairs conversion of T4 to T3 by D1 in the thyroid and peripheral tissues --> more rapid alleviation of severe thyrotoxicosis

Question 28

Thyroid neoplasms

Answer 28

MC endocrine neoplasms Mx: surgical resection with medical therapy Epithelial: follicular adenoma/ carcinoma (papillary, follicular, anaplastic), medullary carcinoma Non-epithelial: lymphomas, sarcomas etc

Question 29

Investigations of thyroid malignancies

Answer 29

Thyroglobulin - specific to thyroid cells - measure by immunoassay Factors affecting Tg values: - mass of thyroid tissue present - injury to thyroid e.g. FNA, ablation, surgery - degree of TSH receptor stimulation Caution: always measure with anti-Tg! --> Tg levels may be falsely low if Ab present Uses: - MONITORING for persistence or recurrence after treatment - can be measured while TSH suppressed (i.e. taking T4 doses) or TSH stimulated (withdraw T4/ give rhTSH)

Question 30

Hormone suppressive therapy

Answer 30

After initial thyroidectomy - -> prevent hypoT - -> minimise potential TSH stimulation of tumour growth T4 dosage titrated according to TSH concentrations --> for high risk groups, TSH should be <0.1 mIU/L initially Risks: - accelerated bone loss, AF and cardiac dysfunction

Question 31

Medullary thyroid CA

Answer 31

Neuroendocrine tumour of parafollicular C cells 75% sporadic, 25% part of MENII Genetic testing of RET for MENII causing mutations is available Serum calcitonin as a tumour marker of MTC --> concentrations usually correlated with tumour mass, also reflect tumour differentiation