Thyroid & Parathyroid Pathology — USMLE Step 2 CK Notes

Hypothyroidism vs hyperthyroidism

• Thyroid hormone does two things: it raises the basal metabolic rate (Na/K ATPase activity, oxygen consumption, heat) and it sensitises tissues to catecholamines by upregulating beta-1 receptors. Nearly every clinical sign follows from those two effects.
• Hyperthyroidism: heat intolerance, weight loss with increased appetite, tachycardia/palpitations and atrial fibrillation, anxiety and tremor, hyperreflexia, increased GI motility (diarrhoea), oligomenorrhoea, increased bone resorption (osteoporosis, hypercalcaemia), warm moist skin. Labs: low TSH, high free T4/T3, low cholesterol, sometimes mild hypercalcaemia and a low CK.
• Hypothyroidism: cold intolerance, weight gain with poor appetite, bradycardia, fatigue and depression, delayed relaxation phase of reflexes ("hung-up" reflexes), constipation, menorrhagia, dry coarse skin, hair loss, myxoedema (non-pitting oedema from glycosaminoglycan deposition, which raises tissue oncotic/osmotic pressure and draws in water). Labs: high TSH, low free T4, high cholesterol, high CK, hyponatraemia, anaemia.
• Molecular markers: thyroid hormone upregulates cardiac sarcolemmal Ca-ATPase and SERCA2 and reduces phospholamban (the SERCA inhibitor), so calcium is cycled faster — explaining the increased contractility and rate of relaxation in hyperthyroidism, and the sluggish, bradycardic myocardium in hypothyroidism.
• Libido/fertility: both extremes reduce libido; hypothyroidism raises TRH, which stimulates prolactin → hyperprolactinaemia, galactorrhoea and reduced libido.

Thyroiditis

• Hashimoto thyroiditis: the commonest cause of hypothyroidism where iodine is sufficient. Autoimmune destruction with anti-thyroid peroxidase (TPO) and anti-thyroglobulin antibodies; a mixed type II and type IV hypersensitivity. Histology: lymphocytic infiltrate with germinal centres and Hurthle cells. There may be a brief early thyrotoxic phase ("hashitoxicosis"). Associations: HLA-DR3/DR5, other autoimmune disease, and an increased risk of B-cell (MALT) lymphoma.
• Subacute granulomatous (de Quervain) thyroiditis: follows a viral illness — a painful, tender goitre with fever and a raised ESR. Histology shows granulomatous inflammation. Course: transient hyperthyroidism → hypothyroidism → recovery. Treat with NSAIDs (steroids if severe); it is self-limiting.
• Riedel thyroiditis: dense fibrosis replacing the gland and extending into surrounding tissue — a rock-hard, painless, fixed goitre that mimics anaplastic carcinoma but occurs in younger patients; part of the IgG4-related disease spectrum. May compress the trachea or recurrent laryngeal nerve.
• Drug-induced thyroiditis: amiodarone (iodine load or destructive thyroiditis; can cause either hypo- or hyperthyroidism), lithium (blocks hormone release → hypothyroidism), interferon-alpha, and immune checkpoint inhibitors.
• Congenital hypothyroidism (cretinism): from thyroid dysgenesis (commonest), dyshormonogenesis or maternal iodine deficiency. The classic 6 P's: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protuberant tongue, Poor brain development. Newborn screening is essential because early thyroxine prevents irreversible intellectual disability.

Iodine effects: Wolff-Chaikoff and Jod-Basedow

• Wolff-Chaikoff effect: a large iodine load transiently SHUTS DOWN hormone synthesis (autoregulatory protection). Most people escape within days; those with underlying thyroid disease (or on amiodarone/lithium) may fail to escape and become hypothyroid.
• Jod-Basedow phenomenon: the opposite — giving iodine (contrast, amiodarone) to a patient with iodine deficiency or nodular goitre unleashes autonomous nodules and causes thyrotoxicosis.

Hyperthyroid disorders

• Graves disease: the commonest cause of hyperthyroidism — IgG antibodies stimulate the TSH receptor (a type II hypersensitivity). Gives a diffuse, non-tender goitre with a bruit, plus the findings unique to Graves: ophthalmopathy/proptosis and pretibial myxoedema (both from fibroblast stimulation and glycosaminoglycan deposition behind the eye and in the shin). Uptake scan shows diffusely increased uptake. Associations: HLA-DR3, other autoimmune disease. Treat with thionamides (carbimazole/methimazole, propylthiouracil), radioiodine or surgery; beta-blockers control symptoms.
• Toxic multinodular goitre: autonomous nodules that function independently of TSH (often activating TSH receptor mutations), typically in older patients in iodine-deficient regions; uptake is patchy/heterogeneous. No eye disease.
• Thyroid storm: a life-threatening decompensation precipitated by infection, surgery, trauma or iodine load — fever, tachyarrhythmia, agitation/delirium, vomiting and high-output heart failure. Treat with the 4 B's: Block synthesis (propylthiouracil, which also blocks peripheral T4→T3 conversion), Block release (iodine, given after the thionamide), Block beta effects (propranolol), Block conversion (corticosteroids). Mortality is high without treatment.

Goitre & thyroid nodules

• Causes of goitre: iodine deficiency (commonest worldwide), Hashimoto, Graves, multinodular goitre, subacute thyroiditis, pregnancy, goitrogens and dyshormonogenesis, lithium/amiodarone, and thyroid neoplasm.
• Thyroid adenoma: a benign, usually non-functional solitary follicular nodule with an intact capsule; a minority ("toxic adenoma") autonomously secrete and appear as a "hot" nodule that suppresses the rest of the gland. Hot nodules are almost never malignant; cold nodules carry the higher cancer risk and warrant fine-needle aspiration.

Thyroid carcinoma

• Papillary carcinoma (~80%, best prognosis): spreads lymphatically. Nuclear features are diagnostic — "Orphan Annie eye" empty-looking nuclei, nuclear grooves, intranuclear inclusions, and psammoma bodies. Risk factor: childhood ionising radiation; associations include RET and BRAF mutations.
• Follicular carcinoma (~10%): spreads haematogenously (bone, lung). It cannot be diagnosed by fine-needle aspiration because the diagnosis rests on capsular and vascular invasion — you need the whole lesion. Uniform follicles without papillary nuclear features.
• Medullary carcinoma (~5%): arises from parafollicular C cells, secretes calcitonin, and shows sheets of cells in an amyloid stroma (stains with Congo red). Associated with MEN 2A and 2B (RET proto-oncogene) — screen relatives and consider prophylactic thyroidectomy.
• Anaplastic (undifferentiated) carcinoma: elderly patients; a rapidly enlarging, rock-hard, fixed mass invading local structures with hoarseness, dysphagia and stridor. Very poor prognosis; often arises from dedifferentiation of a pre-existing carcinoma.

Parathyroid: calcium regulation

• PTH raises serum calcium by increasing bone resorption, renal calcium reabsorption and 1-alpha-hydroxylation of vitamin D (making 1,25-(OH)₂ D), while causing renal phosphate wasting. So PTH: calcium up, phosphate down, ALP up (bone turnover).
• Primary hyperparathyroidism: usually a parathyroid adenoma. High calcium, LOW phosphate, high PTH, high ALP, high urine calcium. "Stones, bones, groans and psychiatric overtones"; most cases are now found incidentally. Severe disease gives osteitis fibrosa cystica — subperiosteal resorption, "brown tumours" (haemorrhagic cystic bone lesions) and a salt-and-pepper skull.
• Secondary hyperparathyroidism: a compensatory response, most often to chronic kidney disease — phosphate retention and failure of 1-alpha-hydroxylation lower calcium, driving PTH up. Labs: LOW/normal calcium, HIGH phosphate, high PTH, high ALP, low 1,25-D. Chronic bone disease here is renal osteodystrophy. (In vitamin D deficiency the phosphate is low, which distinguishes it.)
• Tertiary hyperparathyroidism: after prolonged secondary stimulation the glands become autonomous — very high PTH with HIGH calcium (typically in long-standing dialysis patients); treat surgically.
• Hypoparathyroidism: most often post-surgical (thyroid/parathyroid surgery), also autoimmune or DiGeorge. Low calcium, HIGH phosphate, low PTH. Symptoms of hypocalcaemia: perioral tingling, tetany, Chvostek sign (tapping the facial nerve causes facial twitching) and Trousseau sign (inflating a blood-pressure cuff provokes carpal spasm), and a prolonged QT.
• Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy): end-organ resistance to PTH from a defective Gs-alpha protein (maternally inherited imprinting) — low calcium, high phosphate but HIGH PTH, with short stature, round face, shortened 4th/5th metacarpals and developmental delay.
• Pseudopseudohypoparathyroidism: the same physical phenotype (paternally inherited) but normal calcium, phosphate and PTH — the appearance without the biochemistry.
• PTH-independent hypercalcaemia: PTH is suppressed. Causes: malignancy (PTH-related peptide from squamous cell carcinoma, or lytic bone metastases/myeloma), granulomatous disease (sarcoidosis, TB — macrophages 1-alpha-hydroxylate vitamin D), vitamin D toxicity, thyrotoxicosis, immobilisation and thiazides. Malignancy is the commonest cause in hospital, hyperparathyroidism in the community.
• Familial hypocalciuric hypercalcaemia: an autosomal dominant inactivating mutation of the calcium-sensing receptor, so the set point rises — mildly high calcium with normal/mildly high PTH but LOW urinary calcium (a low calcium/creatinine clearance ratio). It is benign and needs no surgery — the key is not to mistake it for primary hyperparathyroidism.

High-yield revision notes; verify against a primary source before clinical use.