Hyperthyroidism - Harrison's Principles of Internal Medicine (22nd Ed., 2025)

Definitions

Etiology and Classification

Primary Hyperthyroidism (elevated thyroid production, low TSH)

• Graves' disease (most common, 60-80%)
• Toxic multinodular goiter (MNG)
• Toxic adenoma
• Functioning thyroid carcinoma metastases
• Activating mutation of the TSH receptor
• Activating mutation of Gsa (McCune-Albright syndrome)
• Struma ovarii
• Drugs: iodine excess (Jod-Basedow phenomenon)

Thyrotoxicosis Without Hyperthyroidism (preformed hormone release, low RAI uptake)

• Subacute thyroiditis
• Silent thyroiditis
• Other thyroid destruction: amiodarone, cytokines, tyrosine kinase inhibitors, immune checkpoint inhibitors, radiation, infarction of adenoma
• Ingestion of excess thyroid hormone (thyrotoxicosis factitia)

Secondary Hyperthyroidism (elevated TSH)

• TSH-secreting pituitary adenoma
• Thyroid hormone resistance syndrome
• Chorionic gonadotropin-secreting tumors*
• Gestational thyrotoxicosis*

Graves' Disease

Epidemiology

• Accounts for 60-80% of thyrotoxicosis
• Prevalence up to 2% of women, ~10x less frequent in men
• Typically onset between 20-50 years; also occurs in elderly

Pathogenesis

• Polygenic susceptibility: HLA-DR, CTLA-4, CD25, CD40, PTPN22, FCRL3, CD226, and TSH-R gene polymorphisms
• Concordance in monozygotic twins: 20-30% vs. <5% in dizygotic twins
• Environmental triggers: stress, smoking (moderate risk for Graves', major risk for ophthalmopathy), sudden iodine increase, postpartum (3x increased risk)
• Also triggered during immune reconstitution (HAART, alemtuzumab) and immune checkpoint inhibitor therapy

• Bioassays
• TSH receptor antibodies (TRAb) - the widely available immunoassay

Clinical Manifestations

• Apathetic thyrotoxicosis in the elderly: fatigue and weight loss dominate, classic features may be absent
• Weight gain occurs in 5% (increased food intake overcomes metabolic rate)
• Neurologic: fine tremor, hyperreflexia, proximal myopathy, hypokalemic periodic paralysis (especially Asian males)
• Cardiovascular: sinus tachycardia, widened pulse pressure, bounding pulse; AF more common >50 yrs; treating thyrotoxicosis converts AF to sinus rhythm in 75% without underlying cardiac disease
• Skin: warm, moist; palmar erythema, onycholysis, diffuse alopecia (up to 40%)
• Bone: osteopenia; mild hypercalcemia in up to 20%
• Menstrual: oligomenorrhea/amenorrhea

Graves'-Specific Features

Graves' Ophthalmopathy (Thyroid Eye Disease, TED)

• Occurs in 10% without hyperthyroidism (euthyroid ophthalmopathy)
• About one-third of Graves' patients have clinical ophthalmopathy
• Pathogenesis: T-cell infiltration of extraocular muscles → IFN-γ, TNF, IL-1 → glycosaminoglycan accumulation + fibrosis; TSH-R expressed on orbital fibroblasts; aberrant IGF-1R signaling also implicated
• Symptoms: grittiness, tearing, proptosis (1/3), diplopia (5-10%), corneal exposure, optic nerve compression (most serious)
• Unilateral signs in up to 10%

• 0 = No signs/symptoms
• 1 = Only signs (lid retraction/lag)
• 2 = Soft tissue involvement (periorbital edema)
• 3 = Proptosis (>22 mm)
• 4 = Extraocular muscle involvement (diplopia)
• 5 = Corneal involvement
• 6 = Sight loss

Thyroid Dermopathy

• Pretibial myxedema: raised, hyperpigmented, indurated skin over lower legs
• Caused by glycosaminoglycan deposition

Thyroid Acropachy

• Clubbing + periosteal new bone formation; rare

Laboratory Diagnosis

• Suppressed TSH (often undetectable)
• Elevated free T4 and/or T3
• TRAb positive (implies TSI; also useful for monitoring in pregnancy due to risk of neonatal thyrotoxicosis)

• Low radionuclide uptake (vs. elevated in Graves'/toxic MNG)
• Elevated serum thyroglobulin (Tg) in destructive thyroiditis
• Low Tg in thyrotoxicosis factitia
• Normal ESR + TPO antibodies in silent thyroiditis vs. elevated ESR in subacute

Treatment of Graves' Disease

Three main options: antithyroid drugs, radioiodine (¹³¹I), or thyroidectomy

Antithyroid Drugs (Thionamides)

• Titration regimen: dose gradually reduced as euthyroidism restored (preferred - minimizes drug dose)
• Block-replace regimen: high fixed antithyroid dose + LT4 supplement (avoids iatrogenic hypothyroidism)

Radioiodine (¹³¹I)

• Thyroid will be rendered hypothyroid over months-years (virtually all eventually)
• Contraindicated in pregnancy; avoid pregnancy for 6 months after treatment
• Can worsen Graves' ophthalmopathy (cover with glucocorticoids if ophthalmopathy present)
• Give antithyroid drugs pretreatment in elderly or those with cardiac disease

Surgery (Thyroidectomy)

• Indicated for: large goiters, suspected malignancy, first-trimester pregnancy complications, patient preference
• Should achieve euthyroidism with antithyroid drugs before surgery
• Risks: hypoparathyroidism, recurrent laryngeal nerve damage
• Leads to hypothyroidism (definitive treatment)

Special Situations

• Pregnancy: PTU preferred in 1st trimester (methimazole teratogenic - choanal atresia, aplasia cutis); switch to methimazole in 2nd/3rd trimester (PTU hepatotoxicity risk). Monitor TRAb - if high, risk of neonatal thyrotoxicosis.
• Children: Methimazole/carbimazole (avoid PTU) as titration regimen for ≥3 years; surgery or radioiodine for severe/relapsing disease.
• Breast-feeding: Safe with low antithyroid drug doses.

Thyroid Storm (Thyrotoxic Crisis)

• Features: Fever, delirium, seizures, coma, vomiting, diarrhea, jaundice
• Mortality: 4-17% even with treatment (cardiac failure, arrhythmia, hyperthermia)
• Precipitants: Acute illness (stroke, infection, trauma, DKA), surgery, radioiodine in untreated/partially treated patients

Management of Thyroid Storm:

1. PTU 500-1000 mg loading dose, then 250 mg every 4 h (PO/NG/PR) - preferred for T4→T3 inhibition
2. Stable iodide (SSKI 5 drops q6h) - given 1 hour after the first PTU/methimazole dose (Wolff-Chaikoff effect; the delay prevents iodine from being incorporated into new hormone)
3. Propranolol 60-80 mg PO q4h or 2 mg IV q4h (high doses also inhibit T4→T3 conversion); esmolol IV for rate control if heart failure concern
4. Hydrocortisone 300 mg IV bolus, then 100 mg q8h
5. Antibiotics (if infection present), cholestyramine (sequesters thyroid hormones), cooling, O₂, IV fluids

Thyroiditis

Subacute (De Quervain's) Thyroiditis

• Viral etiology; painful thyroid, elevated ESR, transient thyrotoxicosis followed by hypothyroidism then recovery
• RAI uptake suppressed during thyrotoxic phase
• Treatment: Aspirin 600 mg q4-6h or NSAIDs ± PPI; glucocorticoids (prednisone 15-40 mg) if severe; β-blockers for thyrotoxic symptoms; no antithyroid drugs (not true hyperthyroidism)

Silent (Painless) Thyroiditis

• Autoimmune; brief thyrotoxicosis 2-4 weeks, then hypothyroidism 4-12 weeks, then recovery
• Postpartum thyroiditis: occurs 3-6 months postpartum in up to 5% of women; 3x more common in type 1 DM; TPO antibodies antepartum
• Distinguish from subacute thyroiditis: normal ESR, TPO antibodies present, no pain
• Treatment: short-course propranolol for symptoms; LT4 for hypothyroid phase; withdraw after 6-9 months

Drug-Induced Thyroiditis

• IFN-α (hepatitis, hematologic malignancies): thyroid dysfunction in ~5%
• Immune checkpoint inhibitors (pembrolizumab, nivolumab): thyroiditis in 5-20% of cancer patients
• Treatment: same as silent thyroiditis; routine TFT monitoring recommended (ASCO guidelines)

Ophthalmopathy Treatment

• Mild: Artificial tears, dark glasses, smoking cessation, euthyroid control, selenium 100 mcg bid
• Moderate-to-severe: IV methylprednisolone 500 mg once weekly x6 weeks, then 250 mg once weekly x6 weeks (preferred over oral)
• Teprotumumab: monoclonal antibody IGF-1R inhibitor; improves proptosis and other features
• Surgery (decompression, strabismus correction, lid) after disease stabilizes
• External beam radiotherapy: reserved for those unresponsive to glucocorticoids