Endocrine Crash Course for USMLE Step 1
1. Foundations (Physiology / Functional Anatomy)
Thyroid Anatomy:
The thyroid is a butterfly-shaped gland located in the anterior neck, anterior to the trachea and just inferior to the laryngeal prominence. It is composed of two lobes connected by a narrow isthmus.
The gland is encapsulated and composed of numerous spherical follicles lined by cuboidal epithelial (follicular) cells. These cells synthesize and secrete thyroid hormones (T3 and T4).
The follicular lumen is filled with colloid, a proteinaceous substance rich in thyroglobulin, which serves as a reservoir for thyroid hormone precursors.
Interspersed among the follicles are parafollicular (C) cells, which secrete calcitonin, a hormone involved in calcium homeostasis by opposing parathyroid hormone (PTH).
Blood supply is rich, derived from the superior and inferior thyroid arteries, ensuring efficient hormone release into systemic circulation.
Hormone Synthesis:
Dietary iodine is absorbed in the small intestine and taken up by follicular cells through the sodium-iodide symporter (NIS) located on the basolateral membrane.
Once inside the cell, iodide is transported to the apical surface and oxidized to iodine by the enzyme thyroid peroxidase (TPO).
Iodine is then attached to tyrosine residues within thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT).
TPO also catalyzes the coupling of iodinated tyrosine residues: MIT + DIT = T3, and DIT + DIT = T4.
The iodinated thyroglobulin is stored in colloid until stimulation by TSH prompts endocytosis back into the follicular cell and enzymatic cleavage of T3 and T4 for secretion.
T4 is secreted in greater quantities but is less active; it is converted to T3, the biologically active form, in peripheral tissues by 5’-deiodinase.
Regulation:
The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH).
TSH binds to receptors on thyroid follicular cells, promoting iodine uptake, thyroglobulin synthesis, and enhanced activity of TPO, all leading to increased thyroid hormone synthesis.
T3 and T4 exert negative feedback inhibition on both the hypothalamus (reducing TRH) and pituitary (reducing TSH) to maintain hormone balance.
2. Disease Mechanisms (Pathophysiology)
Hyperthyroidism:
Graves Disease:
Most common cause of hyperthyroidism; autoimmune activation of the TSH receptor by thyroid-stimulating immunoglobulins (TSI).
Presents with diffuse goiter, exophthalmos (due to retro-orbital fibroblast activation), pretibial myxedema, and other systemic symptoms such as heat intolerance, weight loss, palpitations, anxiety, diarrhea, tremors, and menstrual irregularities.
Common in women aged 20–40, with associations to HLA-DR3 and HLA-B8.
Toxic Multinodular Goiter:
Arises from longstanding iodine deficiency or previous goiter; multiple hyperfunctioning nodules autonomously produce T3 and T4.
Lacks extrathyroidal manifestations such as exophthalmos; radioactive iodine scan shows patchy uptake.
Thyroid Storm:
Severe form of thyrotoxicosis precipitated by stressors (e.g., surgery, infection).
Presents with high fever, tachyarrhythmias, agitation, nausea/vomiting, delirium, and potentially fatal cardiovascular collapse.
Treated emergently with beta-blockers, PTU, corticosteroids, and iodide.
Hypothyroidism:
Hashimoto Thyroiditis:
Autoimmune lymphocytic infiltration leads to gradual thyroid failure.
Features include fatigue, cold intolerance, weight gain, dry skin, constipation, hair thinning, memory impairment, and menorrhagia.
Antibodies: Anti-TPO and anti-thyroglobulin. Histology reveals Hurthle cells and lymphoid aggregates with germinal centers.
Associated with HLA-DR5 and increased risk of B-cell (marginal zone) lymphoma.
Congenital Hypothyroidism (Cretinism):
Results from thyroid agenesis, dyshormonogenesis, maternal iodine deficiency, or maternal hypothyroidism.
Symptoms include macroglossia, umbilical hernia, hypotonia, jaundice, and poor brain development if untreated.
Early diagnosis and levothyroxine therapy are critical to prevent intellectual disability.
Subacute Granulomatous (De Quervain) Thyroiditis:
Typically follows viral infection (e.g., coxsackievirus).
Painful, tender thyroid with elevated ESR; initial hyperthyroidism followed by hypothyroidism.
Self-limited; histology shows granulomas and multinucleated giant cells.
Riedel Thyroiditis:
Rare fibrosing disease; dense collagen replaces normal tissue.
Hard, fixed, painless goiter that may cause dysphagia or airway obstruction.
May be part of IgG4-related systemic disease.
3. Pharmacology
Thionamides:
Methimazole and PTU inhibit TPO, reducing organification and coupling of iodine.
PTU additionally inhibits peripheral conversion of T4 to T3.
Methimazole is first-line except in the first trimester of pregnancy (due to teratogenicity) and thyroid storm (where PTU is preferred).
Side effects: Agranulocytosis (monitor CBC), hepatotoxicity (especially with PTU), and skin rash.
Levothyroxine:
Oral synthetic T4; used for primary hypothyroidism.
Administered on an empty stomach in the morning.
Dosing individualized based on TSH monitoring; caution in elderly and cardiac patients to avoid precipitating angina.
Beta-blockers (e.g., propranolol):
Control adrenergic symptoms of hyperthyroidism.
Non-selective beta-blockers also reduce peripheral conversion of T4 to T3.
Iodide (Lugol’s solution):
Blocks hormone release acutely via the Wolff-Chaikoff effect.
Used preoperatively to reduce thyroid vascularity.
Radioactive Iodine (I-131):
Oral administration leads to selective uptake by thyroid tissue, causing ablation.
Indicated for Graves disease, toxic nodules; contraindicated in pregnancy and breastfeeding.
4. Case Vignettes and Clinical Correlations
Vignette 1: A 28-year-old woman with a diffusely enlarged thyroid, exophthalmos, palpitations, and weight loss. Lab work reveals suppressed TSH and elevated free T4. TSI is positive. → Diagnosis: Graves Disease.
Vignette 2: A 55-year-old man presents with fatigue, dry skin, constipation, and weight gain. His TSH is elevated and T4 is low. Anti-TPO antibodies are detected. → Diagnosis: Hashimoto Thyroiditis.
Vignette 3: A middle-aged woman has anterior neck pain and tenderness after a flu-like illness. Lab shows transient hyperthyroidism with elevated ESR. → Diagnosis: Subacute (De Quervain) Thyroiditis.
5. Mnemonics
"Hot nodules = autonomous hormone producers" → show increased uptake.
"Hashimoto = Hurthle cells + Hypothyroid".
"Graves = Goiter, Glare, and Gasp".
"Cretinism = 6 Ps: Pot-bellied, Pale, Puffy-faced, Protruding umbilicus, Protruding tongue, Poor brain development".
6. Cross-System Integration
Cardiovascular:
Hyperthyroidism: ↑β1 activity → palpitations, atrial fibrillation.
Hypothyroidism: ↓cardiac output, pericardial effusion, bradycardia.
Neurological:
Hyperthyroidism: Agitation, insomnia, hyperreflexia.
Hypothyroidism: Lethargy, slow reflexes, depression.
Reproductive:
Hypothyroid women: Menorrhagia, infertility.
Hyperthyroid men: Gynecomastia; women: oligomenorrhea.
Dermatologic:
Graves: Warm skin, pretibial myxedema.
Hashimoto: Dry, coarse skin; non-pitting edema (myxedema).