Thyroid Disorders

High-yield endocrinology cluster spanning hypothyroidism (Hashimoto), hyperthyroidism (Graves, toxic nodule), the life-threatening thyroid storm, drug-induced (amiodarone) thyroid dysfunction, sick euthyroid syndrome and the FNAC-based workup of a thyroid nodule. Master the antibody profiles, the radioiodine uptake (RAIU) patterns and the drug-of-choice decisions — these are the most repeatedly tested points.

Thyroid physiology — the testable skeleton

The hypothalamus secretes TRH → anterior pituitary TSH → thyroid follicular cells → T4 (thyroxine) and T3 (triiodothyronine). Iodide is trapped by the sodium-iodide symporter (NIS), organified onto thyroglobulin by thyroid peroxidase (TPO), and coupled to form T3/T4. The thyroid secretes mostly T4; ~80% of circulating T3 is generated by peripheral 5'-deiodinase (type 1 & 2) conversion of T4 → T3. T3 is the active hormone (binds nuclear receptor with ~10× affinity).

High-yield: The free T4 and TSH have an inverse log-linear relationship — a small fall in T4 causes a large rise in TSH, making TSH the single most sensitive screening test for primary thyroid dysfunction.

Key mechanistic pearls:

• Wolff-Chaikoff effect: acute large iodine load transiently inhibits organification (protects against thyrotoxicosis; basis of Lugol's iodine in storm). Escape occurs in days.
• Jod-Basedow phenomenon: iodine load induces thyrotoxicosis in an autonomous nodular gland (opposite of Wolff-Chaikoff).
• Thyroid-binding globulin (TBG) rises in pregnancy/oestrogen → total T4 rises but free T4 stays normal.

Classification overview

State	TSH	Free T4	Typical cause
Primary hypothyroidism	↑	↓	Hashimoto, iodine deficiency, post-RAI
Subclinical hypothyroidism	↑	Normal	Early Hashimoto
Central (secondary) hypothyroidism	↓ or inappropriately normal	↓	Pituitary/hypothalamic disease
Primary hyperthyroidism	↓	↑	Graves, toxic nodule/MNG
Subclinical hyperthyroidism	↓	Normal	Early toxic nodule, exogenous T4
TSH-secreting adenoma	↑ or normal	↑	Pituitary thyrotroph adenoma

Hypothyroidism

Etiology

Worldwide the commonest cause is iodine deficiency; in iodine-replete regions it is Hashimoto (chronic autoimmune) thyroiditis. Other causes: post-radioiodine/thyroidectomy, drugs (amiodarone, lithium, anti-thyroid drugs), subacute thyroiditis (transient), congenital (thyroid dysgenesis — commonest cause of preventable mental retardation), central causes.

Hashimoto thyroiditis

• Autoimmune lymphocytic infiltration with germinal centres and Hürthle (Askanazy) cells.
• Antibodies: anti-TPO (anti-microsomal) most sensitive and characteristic; anti-thyroglobulin (anti-TG) also positive.
• Associated with other autoimmune disease (T1DM, vitiligo, pernicious anaemia, Addison — autoimmune polyglandular syndrome) and a small increased risk of primary thyroid lymphoma (suspect if rapidly enlarging goitre).

High-yield: Anti-TPO antibody is the marker of Hashimoto; TSH-receptor stimulating antibody (TRAb/TSI) is the marker of Graves.

Clinical features

Fatigue, cold intolerance, weight gain, constipation, bradycardia, dry coarse skin, hair loss (lateral third of eyebrow — Queen Anne sign), menorrhagia, delayed relaxation of ankle jerk, carpal tunnel, hoarseness, non-pitting myxoedema (GAG deposition), pericardial/pleural effusions, hypercholesterolaemia. Children: growth retardation, delayed bone age, cretinism (coarse facies, protruding tongue, umbilical hernia, lethargy).

Investigations

• TSH = screening test of choice. High TSH + low free T4 = primary hypothyroidism.
• Anti-TPO to confirm autoimmune aetiology.
• Other: hyponatraemia, ↑CK, macrocytic anaemia, ↑LDL/cholesterol.

Management

Levothyroxine (L-T4) is the drug of choice.

• Adult replacement dose ≈ 1.6 µg/kg/day, taken on empty stomach, recheck TSH after 6 weeks.
• Elderly/cardiac disease → start low (12.5–25 µg) and go slow to avoid precipitating angina/arrhythmia.
• Pregnancy: requirement increases ~30–50%; aim trimester-specific TSH; do not use combination T3/T4.

High-yield: In a patient with both adrenal insufficiency and hypothyroidism, give glucocorticoids first — starting thyroxine alone can precipitate adrenal crisis.

Myxoedema coma (emergency)

Elderly female, winter, precipitated by infection/sedatives. Triad: hypothermia, altered sensorium, hyponatraemia, plus hypoventilation and bradycardia. Management: IV levothyroxine (loading) ± liothyronine (T3), IV hydrocortisone, supportive warming, treat precipitant. High mortality.

Hyperthyroidism / Thyrotoxicosis

Causes & RAIU pattern

RAIU	Disorder	Clue
High, diffuse	Graves disease	Bruit, ophthalmopathy, TRAb+
High, focal "hot" nodule	Toxic adenoma	Single nodule, cold rest
High, patchy	Toxic multinodular goitre (Plummer)	Elderly, longstanding goitre
Low/absent	Thyroiditis (subacute/silent/postpartum), exogenous T4, struma ovarii, amiodarone type 2	Tender gland or no uptake

High-yield: A low radioiodine uptake thyrotoxicosis = thyroiditis, factitious (exogenous) intake, or iodine-induced — not Graves. This is a classic discriminator MCQ.

Graves disease

• Commonest cause of hyperthyroidism; young women; TSH-receptor antibody (TRAb/TSI) stimulates the gland.
• Triad unique to Graves (not seen in other causes): diffuse goitre with bruit, ophthalmopathy (proptosis), pretibial myxoedema. Also thyroid acropachy.
• Ophthalmopathy (retro-orbital glycosaminoglycans, lymphocytes) is worsened by smoking and radioiodine; severe disease → IV glucocorticoids/orbital decompression.

Clinical features (any thyrotoxicosis)

Heat intolerance, weight loss with increased appetite, palpitations, fine tremor, sinus tachycardia/AF, anxiety, hyperdefaecation, proximal myopathy, lid lag/stare (sympathetic), oligomenorrhoea, warm moist skin, brisk reflexes, osteoporosis. Apathetic thyrotoxicosis in elderly (weight loss, AF, depression — easily missed).

Investigations

• Suppressed TSH + elevated free T4/T3 = primary hyperthyroidism.
• TRAb confirms Graves; RAIU/technetium scan distinguishes Graves (diffuse) vs nodular vs thyroiditis (low uptake).
• RAIU is contraindicated in pregnancy — use clinical features + TRAb.

Management — anti-thyroid drugs (thionamides)

Block TPO-mediated organification.

Feature	Methimazole / Carbimazole	Propylthiouracil (PTU)
Mechanism	Blocks organification	Blocks organification + peripheral T4→T3 conversion
Dosing	Once daily, more potent	Multiple daily doses
Preferred	Most patients, 2nd/3rd trimester	1st trimester pregnancy, thyroid storm, thionamide allergy
Major toxicity	Aplasia cutis, choanal/oesophageal atresia (1st trimester), cholestasis	Hepatotoxicity (fulminant), ANCA vasculitis
Shared toxicity	Agranulocytosis (warn re: fever/sore throat — stop drug, check CBC)	Agranulocytosis

High-yield: PTU in the first trimester (methimazole teratogenic — aplasia cutis/embryopathy), then switch to methimazole. PTU is preferred in thyroid storm because it also blocks peripheral T4→T3 conversion.

Definitive options:

• Radioactive iodine (I-131): definitive, outpatient. Contraindicated in pregnancy, lactation, active moderate-severe ophthalmopathy. Causes hypothyroidism (expected). Pretreat cardiac/elderly with thionamide.
• Surgery (subtotal/total thyroidectomy): for large compressive goitre, suspected malignancy, pregnancy intolerant to drugs, severe ophthalmopathy. Render euthyroid first; give Lugol's iodine 10–14 days pre-op to reduce vascularity. Complications: recurrent laryngeal nerve palsy, hypoparathyroidism (hypocalcaemia).

Symptom control: propranolol (β-blocker) for tremor/tachycardia; also blocks peripheral conversion at high dose.

Thyroid storm (thyrotoxic crisis)

Decompensated thyrotoxicosis with end-organ dysfunction; mortality high. Precipitants: surgery, infection, trauma, RAI, parturition, iodinated contrast, abrupt drug withdrawal.

Diagnosis is clinical — Burch-Wartofsky score (fever, CNS dysfunction, GI-hepatic, tachycardia/AF, CHF, precipitant). Score ≥45 = highly suggestive.

Stepwise management (mnemonic order matters): 1. Propylthiouracil (block synthesis) → 2. Iodine (Lugol's/SSKI) at least 1 hour AFTER thionamide (block release; Wolff-Chaikoff) → 3. Propranolol (block adrenergic + peripheral conversion) → 4. Hydrocortisone/Prednisolone (blocks T4→T3, treats relative adrenal insufficiency) → 5. Paracetamol + cooling (avoid aspirin — displaces T4 from TBG) → 6. Treat precipitant + supportive ICU care.

High-yield: Give the thionamide before iodine — if iodine is given first to an untreated gland it provides substrate (Jod-Basedow) and worsens the storm. Avoid aspirin for fever (use paracetamol).

Mnemonic: "PTU, Iodine, Propranolol, Steroids, Paracetamol" — think "block synthesis → block release → block effect → block conversion."

Amiodarone & the thyroid

Amiodarone is ~37% iodine by weight and is lipophilic (long half-life).

	AIT Type 1	AIT Type 2
Mechanism	Iodine-induced excess synthesis (Jod-Basedow)	Destructive thyroiditis (drug toxicity)
Underlying gland	Abnormal (nodular/Graves)	Normal gland
Colour Doppler vascularity	Increased	Decreased/absent
RAIU	Low–normal	Very low
Treatment	Thionamides (± perchlorate)	Glucocorticoids

• Amiodarone-induced hypothyroidism (AIH) is commoner in iodine-replete areas/Hashimoto patients → treat with levothyroxine, continue amiodarone.
• AIT (hyperthyroidism) commoner in iodine-deficient areas; mixed forms occur.

High-yield: Doppler vascularity separates the two: Type 1 = increased flow → thionamides; Type 2 = absent flow → steroids.

Sick euthyroid syndrome (non-thyroidal illness)

Seen in critically ill/starvation/post-surgery patients. Reduced peripheral T4→T3 conversion with shunting to reverse T3 (rT3).

• Earliest/commonest pattern: low T3, normal/low T4, normal or low-normal TSH, high rT3 ("low T3 syndrome").
• Severe illness → low T4 (poor prognosis); recovery → transient TSH rise.

High-yield: Do NOT treat sick euthyroid with thyroxine and avoid routine thyroid testing in acute illness — it resolves with recovery of the underlying illness. Low T3 + high reverse-T3 is the classic clue.

Thyroid nodule — FNAC workup

Nodules are common; the goal is to identify the ~5% malignant.

Approach: Nodule found → check TSH + ultrasound → if TSH low: thyroid scan ("hot" nodule = benign, observe; "cold" → FNAC). If TSH normal/high → FNAC based on ultrasound risk/size.

• Ultrasound suspicious (TI-RADS) features: hypoechoic, microcalcifications, taller-than-wide, irregular margins, extrathyroidal extension, abnormal nodes.
• FNAC is the investigation of choice for evaluating malignancy. Reported by the Bethesda system:

Bethesda category	Interpretation	Risk of malignancy
I	Nondiagnostic	repeat FNAC
II	Benign	very low (observe)
III (AUS/FLUS)	Atypia of undetermined significance	low-intermediate
IV	Follicular neoplasm	indeterminate
V	Suspicious for malignancy	high
VI	Malignant	very high (surgery)

High-yield: FNAC cannot distinguish follicular adenoma from follicular carcinoma — diagnosis of follicular carcinoma needs histology showing capsular/vascular invasion (hence Bethesda IV → surgery/lobectomy).

Cancer pearls: Papillary carcinoma = commonest, lymphatic spread, Orphan-Annie nuclei + psammoma bodies, best prognosis. Follicular = haematogenous (bone/lung). Medullary = parafollicular C-cells, secretes calcitonin, associated with MEN 2A/2B (RET proto-oncogene). Anaplastic = elderly, worst prognosis. Serum thyroglobulin is a tumour marker for follow-up of differentiated cancers after total thyroidectomy.

Subacute (de Quervain) thyroiditis

Post-viral, painful tender goitre, raised ESR, transient thyrotoxicosis then hypothyroidism then recovery, low RAIU. Self-limiting; treat with NSAIDs/aspirin (± steroids), beta-blocker for symptoms — not thionamides.

Key differentials at a glance

• Thyrotoxicosis with low uptake: thyroiditis vs factitious vs iodine-induced vs struma ovarii.
• Goitre + hyperthyroidism + eye signs: Graves (vs toxic MNG which lacks ophthalmopathy).
• Painful thyroid: subacute (de Quervain) vs suppurative thyroiditis vs haemorrhage into cyst.
• Elevated total T4 but euthyroid: pregnancy/oestrogen (↑TBG) vs familial dysalbuminaemic hyperthyroxinaemia.
• High TSH + high free T4: TSH-oma vs thyroid hormone resistance (vs assay interference).

Recently asked / exam angle

• Drug of choice in first-trimester Graves = PTU; thyroid storm = PTU first, iodine ≥1 h later — perennial favourite.
• Most sensitive screening test = TSH; most specific antibody for Hashimoto = anti-TPO, for Graves = TRAb/TSI.
• Amiodarone thyrotoxicosis: Type 1 (increased Doppler → thionamide) vs Type 2 (absent Doppler → steroid).
• Low RAIU thyrotoxicosis identification (thyroiditis/exogenous) — single-best-answer image/scan question.
• Sick euthyroid: low T3, high reverse T3, do not treat.
• FNAC + Bethesda: follicular neoplasm (Bethesda IV) needs histology; FNAC can't diagnose follicular carcinoma.
• Myxoedema coma: IV levothyroxine + hydrocortisone; steroids before/along with thyroxine when adrenal insufficiency co-exists.
• Wolff-Chaikoff vs Jod-Basedow direct contrast MCQ.
• Pre-operative Lugol's iodine reduces vascularity in Graves surgery; complications RLN palsy + hypoparathyroidism.

Rapid revision

1. TSH is the most sensitive screen; check free T4 to localise the level.
2. Hashimoto → anti-TPO; Graves → TRAb/TSI.
3. Hypothyroidism DOC = levothyroxine 1.6 µg/kg; start low in elderly/cardiac; recheck TSH at 6 weeks.
4. Treat adrenal insufficiency before thyroxine to avoid crisis.
5. Graves triad: goitre + bruit, ophthalmopathy, pretibial myxoedema; eye disease worsened by smoking & RAI.
6. Low RAIU thyrotoxicosis = thyroiditis / exogenous / iodine (not Graves).
7. PTU = first trimester + thyroid storm (blocks peripheral conversion); methimazole teratogenic (aplasia cutis).
8. Thionamide red flag = agranulocytosis (fever/sore throat → stop drug, CBC).
9. Storm order: PTU → iodine (after 1 h) → propranolol → steroids → paracetamol (never aspirin).
10. Amiodarone: Type 1 = ↑Doppler/thionamides; Type 2 = absent Doppler/steroids; hypothyroidism → continue amiodarone + L-T4.
11. Sick euthyroid: low T3, high reverse T3 — do not treat.
12. Nodule: FNAC (Bethesda) is investigation of choice; follicular carcinoma needs histology (capsular/vascular invasion); papillary = commonest with Orphan-Annie nuclei + psammoma bodies.