Thyroid Physiology & Disorders

Hormone synthesis and action

Trapping iodide. Follicular cells concentrate iodide from the blood with the basolateral Na+/I− symporter, which TSH stimulates through its Gs-coupled receptor. Perchlorate and pertechnetate compete for this symporter.

TPO runs the synthesis line. Thyroid peroxidase (TPO) performs three steps: oxidation of iodide to iodine, organification of iodine onto tyrosines of thyroglobulin (making MIT and DIT), and coupling (DIT + DIT → T4; MIT + DIT → T3). Hormone is stored in the colloid on thyroglobulin until TSH triggers its endocytosis and proteolytic release. Methimazole and propylthiouracil (PTU) block TPO, and TPO is the main autoantigen of Hashimoto thyroiditis.

T4 is the reservoir, T3 is the worker. The gland secretes mostly T4. Peripheral 5′-deiodinase converts it to T3, which is about 3 to 5 times more potent and does the nuclear receptor work; reverse T3 (rT3) is inactive. Most hormone travels bound to thyroxine-binding globulin (TBG), and only free hormone is active. Estrogen (pregnancy, oral contraceptives) raises TBG and therefore total T4, while free T4 and TSH stay normal. PTU, glucocorticoids and propranolol all inhibit peripheral conversion, one reason each is used in thyroid storm.

PTU blocks both TPO and peripheral 5′-deiodinase, making it useful in thyroid storm and in the first trimester of pregnancy, when methimazole is avoided as a teratogen.

What T3 does. It raises the basal metabolic rate (more Na+/K+-ATPase), increases cardiac β1-adrenergic receptors (tachycardia, which β-blockers relieve), promotes lipolysis and gluconeogenesis, and is essential for brain maturation and bone growth in infancy.

Iodine paradoxes. In the Wolff-Chaikoff effect, a large iodine load transiently inhibits hormone synthesis; this is protective, the gland escapes within about 2 weeks, and the effect is exploited to treat thyroid storm. In the Jod-Basedow phenomenon, iodine repletion (supplements, iodinated contrast) in an iodine-deficient or nodular gland with autonomous tissue triggers hyperthyroidism. Amiodarone, which is rich in iodine, can cause either hypo- or hyperthyroidism.

Reading thyroid function tests

TSH first, then free T4. TSH is the most sensitive screen because it changes log-linearly with small changes in free T4, amplifying any disturbance. In central (pituitary or hypothalamic) disease, the TSH is inappropriate for the T4.

Hypothyroidism

Hashimoto thyroiditis. The most common cause of hypothyroidism in iodine-sufficient areas (iodine deficiency leads worldwide). It is autoimmune, with anti-TPO and anti-thyroglobulin antibodies and an HLA-DR3/DR5 association. Histology shows a lymphocytic infiltrate with germinal centers and Hürthle cells (eosinophilic, mitochondria-rich follicular cells). The goiter is firm and nontender. Early follicle destruction can release stored hormone and cause transient hyperthyroidism (hashitoxicosis). Hashimoto raises the risk of thyroid B-cell (MALT) lymphoma, suggested by a rapidly enlarging gland.

Hürthle cells + germinal centers + anti-TPO = Hashimoto.

Cold and slow. Cold intolerance, weight gain, fatigue, constipation, bradycardia, dry skin and delayed relaxation of deep tendon reflexes, plus hypercholesterolemia and myopathy with a raised CK. Myxedema is non-pitting edema from glycosaminoglycan deposition in skin and soft tissue (puffy face, large tongue). Myxedema coma is the decompensated extreme: hypothermia, hypotension, bradycardia and depressed consciousness, often triggered by infection, cold or sedatives, and treated with IV levothyroxine plus stress-dose hydrocortisone.

Cretinism. Congenital hypothyroidism results from iodine deficiency, thyroid dysgenesis (absent, hypoplastic or ectopic gland) or dyshormonogenesis (inherited defects in synthesis such as TPO mutations). The six P's: Pot-bellied, Pale, Puffy face, Protruding umbilicus, Protuberant tongue and Poor brain development (intellectual disability). Newborns are screened because early levothyroxine prevents irreversible cognitive impairment.

Hyperthyroidism and thyroiditis

Hot and wired. Heat intolerance, weight loss despite a good appetite, tremor, anxiety, palpitations and tachycardia (atrial fibrillation in older patients), diarrhea, warm moist skin, hyperreflexia and bone loss. Lid lag from sympathetic overactivity occurs with any cause.

Graves disease. The most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulin (TSI), an IgG against the TSH receptor, mimics TSH indefinitely and drives a diffuse goiter, often with a bruit; follicles are lined by tall, crowded cells with scalloped colloid. It is associated with HLA-DR3 and HLA-B8 and typically affects women aged 20–40, like the 32-year-old with palpitations, weight loss, bulging eyes and a diffuse goiter. Unique to Graves are ophthalmopathy (exophthalmos) and pretibial myxedema, both from stimulation of retro-orbital and dermal fibroblasts that deposit glycosaminoglycans. Treatment options are β-blockers for symptoms plus thionamides, radioactive iodine ablation or thyroidectomy.

Toxic multinodular goiter (Plummer). Autonomous hot nodules, often with activating TSH-receptor mutations, make hormone independent of TSH. There is no eye disease, and hot nodules are rarely malignant.

Thyroid storm. Infection, surgery or other stress precipitates life-threatening thyrotoxicosis in an uncontrolled patient: fever, tachyarrhythmia, agitation or delirium, and vomiting or diarrhea. Treat with a β-blocker (propranolol), PTU, then iodine (Wolff-Chaikoff), plus glucocorticoids.

In storm, give the β-blocker and PTU before iodine; iodine given first could feed new hormone synthesis.

Thyroiditis types. Subacute granulomatous (de Quervain) thyroiditis is post-viral, with a painful tender gland, elevated ESR and granulomas with giant cells; it is self-limited, running hyper → hypo → euthyroid, and needs only NSAIDs (prednisone if severe) and β-blockers. Silent (painless) and postpartum thyroiditis are lymphocytic and follow the same self-limited course. Riedel thyroiditis is hard, "rock-like" fibrosis that extends into neighboring neck structures; it is IgG4-related, causes hypothyroidism in about a third of patients and mimics anaplastic carcinoma.

Thyroid neoplasia

Papillary carcinoma. The most common and most curable thyroid cancer, driven by BRAF mutations and RET/PTC rearrangements, with childhood ionizing radiation as a key risk factor. It spreads via lymphatics, so cervical nodes may be involved at diagnosis without harming the excellent outlook.

Orphan Annie nuclei + psammoma bodies + nuclear grooves = papillary.

Follicular and anaplastic carcinoma. Follicular carcinoma spreads hematogenously, and because cytology looks like a benign adenoma, only capsular or vascular invasion on the resected specimen makes the diagnosis. Anaplastic (undifferentiated) carcinoma appears in the elderly as a rapidly enlarging mass that invades locally, compressing the airway and esophagus, with a dismal prognosis.

Medullary carcinoma and MEN 2. Medullary carcinoma arises from calcitonin-secreting parafollicular C cells, and the amyloid in its stroma is derived from calcitonin; serum calcitonin is a tumor marker. It is part of MEN 2A (medullary carcinoma + pheochromocytoma + parathyroid hyperplasia) and MEN 2B (medullary carcinoma + pheochromocytoma + mucosal neuromas and marfanoid habitus), both from germline RET mutations. Prophylactic thyroidectomy is offered to RET carriers.