Hypothyroidism - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Causes of Hypothyroidism

Primary Hypothyroidism (TABLE 395-1)

• Hashimoto's thyroiditis (goitrous form)
• Atrophic thyroiditis (end-stage autoimmune destruction)

• Radioiodine (¹³¹I) treatment for hyperthyroidism
• Subtotal or total thyroidectomy
• External neck irradiation (for lymphoma or cancer)

• Iodine excess (including iodine-containing contrast media)
• Amiodarone
• Lithium
• Antithyroid drugs
• p-aminosalicylic acid
• Interferon-α and other cytokines
• Aminoglutethimide
• Tyrosine kinase inhibitors (e.g., sunitinib)
• Immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab)

• Thyroid dysgenesis (65%)
• Inborn errors of thyroid hormone synthesis/dyshormonogenesis (30%)
• TSH-R antibody-mediated (5%)

• Silent thyroiditis (including postpartum thyroiditis)
• Subacute thyroiditis
• Withdrawal of thyroxine treatment in a euthyroid patient
• After ¹³¹I treatment or subtotal thyroidectomy for Graves' disease

• Pituitary or hypothalamic disease causing TSH or TRH deficiency

Pathogenesis of Autoimmune Hypothyroidism

Clinical Features / Symptoms (TABLE 395-3)

• Dry skin, decreased sweating, thinning of epidermis
• Nonpitting myxedema (due to glycosaminoglycan accumulation)
• Puffy face with edematous eyelids, pretibial nonpitting edema
• Pallor with yellow tinge (carotene accumulation)
• Dry, brittle hair; diffuse alopecia; thinning of outer third of eyebrows
• Retarded nail growth

• Weight gain (modest, mainly fluid retention)
• Constipation
• Poor appetite

• Bradycardia, reduced stroke volume
• Diastolic hypertension (increased peripheral resistance)
• Pericardial effusion (up to 30% of patients)
• Cool extremities (blood diverted from skin)

• Fatigue, lethargy, slow thinking
• Depression, dementia (in severe/prolonged cases)
• Cerebellar ataxia, peripheral neuropathy
• Delayed deep tendon reflexes ("hung-up" reflexes)
• Carpal tunnel syndrome

• Dyspnea (pleural effusion, impaired respiratory muscles, sleep apnea)

• Oligomenorrhea, amenorrhea, or menorrhagia (early stage)
• Decreased libido, infertility, increased miscarriage risk
• Elevated prolactin - may cause galactorrhea

• Conductive or sensorineural deafness
• Anemia (normocytic or macrocytic)
• Elevated creatine phosphokinase, cholesterol, triglycerides

Laboratory Evaluation

• TSH is the best screening test; elevated TSH confirms primary hypothyroidism
• Free T4 (FT4) confirms clinical hypothyroidism when TSH is elevated
• Free T3 is normal in ~25% - not indicated for diagnosis
• TPO and thyroglobulin (Tg) antibodies present in >95% of autoimmune hypothyroidism
• Other findings: elevated CK, elevated cholesterol/triglycerides, normocytic or macrocytic anemia

Diagnostic Algorithm (Figure 395-2)

Treatment

Clinical (Overt) Hypothyroidism

• Standard replacement: Levothyroxine (LT4) 1.6 μg/kg body weight/day (typically 100-150 μg/day), taken at least 30 minutes before breakfast
• After Graves' disease treatment, autonomous residual function often means lower doses needed (typically 75-125 μg/day)
• Starting dose in adults under 60 without cardiac disease: 50-100 μg/day
• Goal: TSH in the normal range, ideally the lower half of the reference range
• Recheck TSH 6-8 weeks after starting or changing dose
• Adjust in 12.5-25 μg increments (upward if TSH high; downward if TSH suppressed)
• Clinical relief may take several months even after TSH normalizes
• Once stable: annual TSH monitoring

• Poor adherence (most common with TSH >normal on ≥200 μg/day)
• Malabsorption (celiac disease, post-bowel surgery, H. pylori gastritis)
• Oral estrogens or SERMs
• Drug interactions reducing T4 absorption/metabolism: bile acid sequestrants, ferrous sulfate, calcium carbonate, proton pump inhibitors

Subclinical Hypothyroidism

• TSH >10 mIU/L
• Patient is pregnant or wishes to conceive

Special Populations

• Confirm thyroid function immediately after pregnancy is confirmed
• Monitor every 4 weeks during the first half of pregnancy; every 6-8 weeks after 20 weeks
• Target TSH <2.5 mIU/L (lower half of trimester-specific range)
• LT4 dose increases ~45% in athyroic women; less in Hashimoto's with residual function
• As soon as pregnancy is confirmed: increase from once-daily to 9 doses per week
• Return to pre-pregnancy dose after delivery
• Separate LT4 from prenatal vitamins and iron supplements

Myxedema Coma

• IV LT4: 200-400 μg bolus (loading dose), then 1.6 μg/kg/day IV (reduced 25% vs oral)
• Consider adding IV or NG liothyronine: loading dose 5-20 μg, then 2.5-10 μg every 8 hours
• IV hydrocortisone 50 mg every 6 hours (impaired adrenal reserve)
• Ventilatory support; glucose/hypertonic saline if hyponatremia/hypoglycemia
• Broad-spectrum antibiotics (pending exclusion of infection)
• Passive rewarming only (active external warming only if temp <30°C - risk of cardiovascular collapse)
• Avoid sedatives; reduce all medication doses (impaired drug metabolism)

Recent Evidence Note