Hashimoto's Hypothyroidism

Thyroid peroxidase (TPO) is the enzyme on the apical membrane of thyroid follicular cells that oxidizes iodide and couples it to tyrosine residues on thyroglobulin — the rate-limiting step in T3/T4 synthesis. Anti-TPO antibodies are markers of autoimmune thyroid disease rather than the primary destructive agent; the real damage comes from cytotoxic CD8+ T cells, complement-mediated antibody-dependent cellular cytotoxicity (ADCC), and Th17-driven inflammation. Anti-TPO is positive in ~95% of Hashimoto's, ~75% of Graves', and ~10% of the healthy population, so titer trends matter — high titers suggest more aggressive disease. They can also flag risk for postpartum thyroiditis and progression of subclinical disease.

Combine three findings: (1) Elevated TSH — most labs use a cutoff of 4.5-5.0 mIU/L for diagnosis; overt hypothyroidism is TSH plus low free T4. (2) Positive anti-TPO antibodies (positive in ~95% of cases); anti-thyroglobulin antibodies are positive in ~60%, often together. (3) Symptoms or clinical features (cold intolerance, fatigue, weight gain, bradycardia, dry skin). Ultrasound can show heterogeneous, hypoechoic thyroid with pseudonodules, but is not required for diagnosis. Some patients have a normal-sized or atrophic thyroid; others have a firm goiter. Subclinical disease: TSH 4.5-10 with normal T4, no symptoms — treatment is selective.

Levothyroxine is synthetic T4 — a prodrug. The body's deiodinases convert it to active T3 in peripheral tissues (~80% of circulating T3). Half-life of T4 is ~7 days, so once-daily dosing gives stable levels. Starting dose: ~1.6 µg/kg/day in healthy young adults (e.g., 100-125 µg for a 70 kg person); 25-50 µg in elderly or cardiac patients to avoid precipitating angina. Take on empty stomach, 30-60 minutes before food or other medications. Recheck TSH at 6-8 weeks; titrate by 12.5-25 µg increments to target TSH 0.5-2.5 mIU/L. Many drugs and foods reduce absorption — PPIs, calcium, iron, coffee, soy.

Subclinical hypothyroidism is elevated TSH (4.5-10 mIU/L) with normal free T4 — biochemical evidence of failing thyroid but compensated hormone output. Prevalence ~5-10% in adults, higher in women and elderly. Most cases are stable or even resolve. Treatment is indicated when: TSH >10 (high progression risk), TSH 4.5-10 with symptoms attributable to hypothyroidism, pregnancy or pregnancy planning, infertility, positive anti-TPO antibodies, or significant goiter. In elderly with TSH 4.5-7, observation is often preferred — over-treatment risks atrial fibrillation and bone loss without symptomatic benefit. Recheck at 3-6 months before committing to lifelong therapy.

Thyroid hormones regulate basal metabolic rate by binding nuclear receptors and increasing transcription of mitochondrial uncoupling proteins, Na+/K+-ATPase, and metabolic enzymes. Less T4 means less mitochondrial heat generation — body temperature drops, peripheral vasoconstriction follows, hands and feet feel cold. Decreased thermogenesis also lowers calorie burn by 5-20%, contributing to modest weight gain (typically 5-10 lb) — though most weight gain in hypothyroidism is myxedematous fluid retention from hyaluronic acid accumulation in tissues, not adipose. After replacement, water weight resolves quickly; long-term metabolism normalizes within months.

Myxedema coma is decompensated severe hypothyroidism — the rare endocrine emergency at the opposite extreme from thyroid storm. Features: hypothermia (often <35°C), altered mental status (lethargy progressing to coma), hyponatremia, bradycardia, hypoventilation with CO2 retention, hypotension. Usually triggered by infection, cold exposure, surgery, sedatives, or missed levothyroxine in a patient with longstanding untreated disease. Mortality 25-40% even with treatment. ICU management: IV levothyroxine (200-400 µg loading then 50-100 µg daily), IV liothyronine (T3) in severe cases, IV hydrocortisone (until adrenal insufficiency excluded), passive rewarming, fluid and electrolyte correction, mechanical ventilation if needed, treat the trigger.

Maternal thyroid hormone is essential for fetal neurodevelopment, especially before the fetal thyroid begins functioning at ~12 weeks. Even mild maternal hypothyroidism is associated with lower offspring IQ. Pregnancy itself increases thyroid demand by ~30% (estrogen raises TBG, hCG cross-stimulates TSH receptor). Women on levothyroxine should increase dose by ~25-30% at confirmation of pregnancy and check TSH every 4 weeks in first half. Target TSH <2.5 mIU/L in first trimester, <3.0 thereafter. Hashimoto's also raises risk of postpartum thyroiditis (transient thyrotoxicosis then hypothyroidism, ~5% of all women, higher with positive anti-TPO). Screening is recommended in high-risk women (anti-TPO+, prior thyroid disease, T1DM).