Thyrotoxicosis — Harrison's Principles of Internal Medicine, 22e

Definition

Causes of Thyrotoxicosis (Table 396-1)

Hyperthyroidism (increased thyroid function)

• Graves' disease
• Toxic multinodular goiter
• Toxic adenoma
• Functioning thyroid carcinoma metastases
• Activating mutation of the TSH receptor
• Activating mutation of Gαs (McCune-Albright syndrome)
• Struma ovarii
• Drugs: iodine excess (Jod-Basedow phenomenon)

Thyrotoxicosis WITHOUT Hyperthyroidism

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

Secondary Hyperthyroidism

• TSH-secreting pituitary adenoma
• Thyroid hormone resistance syndrome
• Chorionic gonadotropin-secreting tumors
• Gestational thyrotoxicosis (TSH is low in these forms)

Graves' Disease

Epidemiology

• Accounts for 60–80% of thyrotoxicosis
• Prevalence up to 2% of women, one-tenth as frequent in men
• Typically onset age 20–50 years
• High iodine intake → increased prevalence

Pathogenesis

• Genetic factors: HLA-DR, CTLA-4, CD25, CD40, PTPN22, FCRL3, CD226, TSH-R gene polymorphisms
• Concordance: monozygotic twins 20–30% vs dizygotic <5%
• Environmental triggers: stress (neuroendocrine immune effects), smoking (moderate risk for disease, major risk for ophthalmopathy), sudden iodine increase, postpartum period (3× increased risk)
• Also occurs during immune reconstitution: post-HAART, alemtuzumab, immune checkpoint inhibitors (nivolumab, pembrolizumab)
• Thyroid-stimulating immunoglobulins (TSIs) synthesized by lymphocytes → bind TSH-R → stimulate thyroid growth and hormone synthesis

Clinical Features

• Apathetic thyrotoxicosis in the elderly: fatigue + weight loss only, may mimic depression
• Weight gain in 5% (increased appetite overrides metabolic rate)
• Fine tremor: best elicited by stretching fingers, feeling fingertips with palm
• Hypokalemic periodic paralysis: particularly in Asian males
• Cardiovascular: sinus tachycardia, widened pulse pressure, bounding pulse, aortic systolic murmur; AF more common >50 years
• Bone: accelerated resorption → osteoporosis, hypercalciuria, occasionally hypercalcemia
• Reproductive: oligomenorrhea, loss of libido; subfertility and increased fetal loss if untreated in pregnancy
• Eyes: lid retraction and lag (any cause of thyrotoxicosis); proptosis/ophthalmopathy specific to Graves'

Graves' Ophthalmopathy

• Infiltration of extraocular muscles by activated T cells → cytokines (IFN-γ, TNF, IL-1) → fibroblast activation → glycosaminoglycan synthesis → muscle swelling
• Late disease: irreversible fibrosis
• Increased fat adds to retrobulbar expansion
• Raised intraorbital pressure → proptosis, diplopia, optic neuropathy
• TSH-R expressed in orbital tissues; aberrant IGF-1R signaling on orbital fibroblasts also implicated
• New treatment: teprotumumab (anti-IGF-1R monoclonal antibody) — reduces TSH-R/IGF-1R complexes

Graves' Dermopathy (Pretibial Myxedema)

• Deposition of glycosaminoglycans in the dermis
• Occurs in <5% of patients; almost always associated with ophthalmopathy
• Presents as non-pitting edema, plaques on pretibial skin
• Usually asymptomatic; treatment with topical glucocorticoids if needed

Laboratory Diagnosis

• Suppressed TSH — most sensitive screening test
• Elevated free T4 and/or free T3
• In T3 toxicosis: TSH suppressed, normal free T4, elevated free T3
• TRAb (TSH receptor antibodies): positive in Graves' — distinguishes from other causes
• Radioiodine uptake (RAIU):
  • Elevated in Graves', toxic MNG, toxic adenoma
  • Low/absent in thyroiditis, factitious thyrotoxicosis, struma ovarii
• Thyroid scan: diffuse uptake (Graves'), patchy (MNG), focal hot nodule (toxic adenoma)

Treatment of Graves' Disease

Antithyroid Drugs (Thionamides)

• Methimazole (preferred), Carbimazole (not available in USA), Propylthiouracil (PTU)
• Mechanism: inhibit TPO → reduce oxidation and organification of iodide; reduce thyroid antibody levels
• PTU also inhibits peripheral T4 → T3 conversion (minor benefit; useful in thyroid storm)
• PTU hepatotoxicity → FDA restricts use to:
  1. First trimester of pregnancy
  2. Thyroid storm
  3. Minor adverse reactions to methimazole

• Methimazole/Carbimazole: 10–20 mg q12h initially, then once-daily when euthyroid; maintenance 2.5–10 mg/day
• PTU: 100–200 mg q6–8h; maintenance 50–100 mg/day
• Review TFTs at 4–6 weeks; euthyroidism typically achieved in 6–8 weeks
• TSH may remain suppressed for months → free T4 is the better early monitoring index

• Titration regimen: dose gradually reduced as thyrotoxicosis improves (preferred)
• Block-replace regimen: high-dose antithyroid drug + levothyroxine supplementation

• Maximum remission rates 30–60% after 12–18 months
• Predictors of relapse: younger patients, males, smokers, severe hyperthyroidism, large goiter, persistent TRAb
• TRAb undetectable → better remission rates

• Minor (1–5%): rash, urticaria, fever, arthralgia
• Major: agranulocytosis (~0.3%), hepatitis, vasculitis — require immediate drug withdrawal; check WBC if fever/sore throat

Radioiodine (¹³¹I)

• Preferred first-line in North America; antithyroid drugs preferred in Europe, Latin America, Japan
• Destroys thyroid tissue → eventual hypothyroidism (desired outcome)
• Contraindicated in: pregnancy, breastfeeding, moderate-to-severe active ophthalmopathy
• May transiently worsen ophthalmopathy → prophylactic glucocorticoids used in at-risk patients
• Pretreatment with methimazole recommended for elderly or those with cardiac disease

Thyroidectomy

• Option for large goiters, compressive symptoms, coexisting nodule suspicious for malignancy, or patient preference
• Requires preoperative euthyroidism (antithyroid drugs ± iodine — Lugol's solution to reduce vascularity)
• Complications: hypoparathyroidism, recurrent laryngeal nerve injury

Symptomatic Relief

• Beta-blockers (propranolol, atenolol): control tachycardia, tremor, anxiety, heat intolerance
• Propranolol also inhibits T4 → T3 conversion at high doses
• Used in all patients until euthyroid

Other Causes of Thyrotoxicosis

Toxic MNG and Toxic Adenoma

• Autonomously functioning nodule(s) — TSH suppressed, elevated T3/T4
• Low risk of remission with antithyroid drugs → radioiodine or surgery preferred

Subacute (de Quervain's / Granulomatous / Viral) Thyroiditis

• Viruses implicated: mumps, coxsackie, influenza, adenoviruses, echoviruses; also SARS-CoV-2 and COVID vaccine
• Peak incidence: 30–50 years; women affected 3× more than men
• Pathophysiology: virus-induced thyroid follicular destruction → release of preformed thyroid hormone → thyrotoxicosis phase (low RAIU) → hypothyroid phase → recovery
• Diagnosis: elevated ESR, low RAIU, characteristic painful goiter
• Treatment: NSAIDs for pain; glucocorticoids for severe cases; beta-blockers for thyrotoxic symptoms; levothyroxine if hypothyroid phase symptomatic

Silent (Painless) Thyroiditis / Postpartum Thyroiditis

• Autoimmune lymphocytic infiltration; no pain
• Same biphasic course (thyrotoxicosis → hypothyroidism → recovery) as subacute, but painless
• Postpartum thyroiditis: occurs in 5–10% of women in first year postpartum; high TPO-Ab titers
• Low RAIU differentiates from Graves'
• Usually self-limiting; beta-blockers for symptoms; levothyroxine if hypothyroid phase symptomatic

Drug-Induced Thyroiditis

• Amiodarone: iodine-rich drug; causes two types:
  • Type 1 (Jod-Basedow): excess iodine → increased hormone synthesis (underlying thyroid disease)
  • Type 2 (destructive): amiodarone-induced thyroiditis — treat with glucocorticoids
• Cytokines (interferon-α): induces autoimmune or destructive thyroiditis
• Tyrosine kinase inhibitors and immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4)

Thyroid Storm (Thyrotoxic Crisis)

• Life-threatening exacerbation of thyrotoxicosis
• Precipitants: infection, surgery, trauma, radioiodine in poorly prepared patient, discontinuation of antithyroid drugs
• Features: hyperpyrexia (temperature often >40°C), tachycardia (may have AF), hypertension, CNS dysfunction (agitation, delirium, coma), GI dysfunction (nausea, vomiting, diarrhea, jaundice)
• High mortality without treatment

Treatment of Thyroid Storm

1. PTU 500–1000 mg loading, then 250 mg q4h (blocks synthesis + T4→T3 conversion)
2. Inorganic iodide (Lugol's solution or SSKI) — given 1 hour after PTU to block hormone release (Wolff-Chaikoff effect)
3. Dexamethasone 2 mg q6h (blocks T4→T3 conversion, treats relative adrenal insufficiency)
4. Beta-blockers (propranolol IV or oral) for heart rate control
5. Supportive care: cooling, fluids, treat precipitant (antibiotics if infection), ICU monitoring

Thyrotoxicosis in Pregnancy

• Most commonly caused by Graves' disease (also gestational thyrotoxicosis from β-hCG stimulation)
• Uncontrolled thyrotoxicosis → fetal loss, preterm birth, fetal growth restriction
• PTU preferred in first trimester (methimazole associated with embryopathy — aplasia cutis, choanal atresia)
• Switch to methimazole after first trimester (PTU liver risk)
• Radioiodine is absolutely contraindicated
• Maternal TRAb crosses placenta → fetal/neonatal hyperthyroidism (requires monitoring)
• TSH levels may be low in first trimester even without thyrotoxicosis (hCG cross-reactivity) → assess free T4