Hyperthyroidism

Definition

Causes

• Textbook of Family Medicine 9e, Table 35-5

Graves' Disease - Pathogenesis

• Genetic susceptibility: increased in monozygotic twins; associated with specific HLA alleles and CTLA4 polymorphisms.
• Stimulating and blocking TRAbs can coexist in the same patient, explaining intermittent hypothyroid episodes.
• Ophthalmopathy: TSH receptors on orbital fibroblasts/fat cells are activated by CD4+ T cells, increasing extracellular matrix deposition in the retroorbital space.
• Dermopathy (pretibial myxedema): glycosaminoglycan deposition + lymphocyte infiltration in the skin, most commonly over the shins.
• Robbins & Kumar Basic Pathology

Morphology (Histology)

• Symmetric gland enlargement from diffuse follicular cell hypertrophy and hyperplasia
• Follicular cells tall, crowded; form small papillae projecting into lumen (no fibrovascular cores - unlike papillary carcinoma)
• Pale, scalloped colloid
• Lymphoid infiltrates (predominantly T cells) with germinal centers

Clinical Features

Symptoms Common to All Thyrotoxicosis

• Tachycardia, wide pulse pressure, systolic hypertension
• Warm, moist skin; heat intolerance
• Weight loss despite increased appetite
• Tremor, anxiety, hyperactivity, insomnia
• Diarrhea
• Menstrual irregularities, reduced fertility; gynecomastia in men
• Anemia, relative neutropenia, lymphocytosis

Graves'-Specific Features (the "triad")

1. Diffuse goiter - bruit may be audible over the gland
2. Ophthalmopathy - exophthalmos (proptosis), lid lag, stare, periorbital edema, diplopia; scored by the EUGOGO system
3. Dermopathy - present in <5%; nodular, indurated, pink/purple plaques on shins ("orange skin" texture). Acropachy (clubbing) occurs in <1%.

Radioiodine treatment can worsen ophthalmopathy (especially in smokers). Antithyroid drugs and surgery do not adversely affect eye disease. - Harrison's 22e

Laboratory Diagnosis

• TSH is the most sensitive biomarker - suppressed in all primary hyperthyroidism
• Free T4 is elevated in most cases; if normal, check free T3 (T3 toxicosis occurs in 2-5%)
• T4 toxicosis (elevated T4, normal T3) is seen with iodine excess
• TRAb (3rd-generation assay): confirms Graves' disease with high sensitivity and specificity
• If TSH is not suppressed but T4 is high: suspect TSH-secreting pituitary adenoma or thyroid hormone resistance
• Additional: elevated bilirubin, liver enzymes, ferritin; microcytic anemia; thrombocytopenia may all occur

Treatment

Three Main Options for Graves' Disease

"No single approach is optimal and patients may require multiple treatments to achieve remission." - Harrison's 22e

Antithyroid Drugs (Thionamides)

• Methimazole (MMI): preferred agent (half-life 6 h, once-daily dosing possible); initial dose 10-20 mg every 12 h
• Carbimazole: prodrug of methimazole; not available in the US
• Propylthiouracil (PTU): shorter half-life (90 min), requires dosing every 6-8 h at 100-200 mg per dose. PTU also inhibits peripheral T4 → T3 conversion. FDA-restricted indications: first trimester of pregnancy, thyroid storm, and minor MMI side effects. Hepatotoxicity risk requires LFT monitoring.

• Titration: gradually reduce dose as euthyroidism is restored (preferred - minimizes drug exposure)
• Block-replace: high-dose antithyroid drug + levothyroxine supplementation to prevent hypothyroidism

• Minor: rash, urticaria, arthralgia, fever (~5%)
• Major: agranulocytosis (~0.3%) - warn patients to report sore throat/fever urgently
• PTU-specific: hepatotoxicity (rare but severe)

Radioiodine (¹³¹I)

• Ablates thyroid tissue; most patients develop hypothyroidism and require lifelong levothyroxine
• Absolutely contraindicated in pregnancy or possibility of pregnancy
• Pre-treatment with antithyroid drugs for at least 1 month reduces risk of post-radioiodine thyrotoxic crisis
• Can worsen Graves' ophthalmopathy (particularly in smokers) - Tietz 7e
• Preferred for toxic multinodular goiter and toxic adenoma

Beta-Blockers

Thyroid Storm (Thyrotoxic Crisis)

• Occurs in 1-5% of hospitalized thyrotoxic patients
• Usually precipitates on a background of unrecognized Graves' disease
• Precipitants: infection, surgery, trauma, DKA, labor, cardiac disease, radioiodine
• Clinical diagnosis - not defined by TSH/T4/T3 levels

Clinical Features

• Hyperpyrexia (>38.9°C / 102°F)
• Tachycardia disproportionate to fever
• GI dysfunction: nausea, vomiting, diarrhea, jaundice
• CNS dysfunction: severe irritability, confusion, coma
• Pronounced decompensation of organ systems

Treatment

1. Beta-blockers (high-dose propranolol or esmolol IV)
2. PTU (preferred over MMI in storm - blocks T4→T3 conversion) in high doses
3. Iodine (Lugol solution or SSKI) - given only after antithyroid drug loading, to block T4 release
4. Corticosteroids (dexamethasone) - reduce T4→T3 conversion, treat possible adrenal insufficiency
5. Antipyretics (paracetamol - NOT aspirin, which displaces T4 from binding proteins)
6. Aggressive IV fluid resuscitation
7. Identify and treat precipitating cause
8. Lithium or sodium ipodate for refractory cases
9. Manage in medical ICU with endocrinology consultation

• Textbook of Family Medicine 9e, Goodman & Gilman's Pharmacology, Tietz 7e

Special Situations

Pregnancy

• PTU is preferred in the first trimester (MMI associated with embryopathy - choanal atresia, aplasia cutis)
• Switch to MMI after first trimester (lower hepatotoxicity risk)
• ¹³¹I is absolutely contraindicated
• Neonatal Graves' can occur from placental transfer of TRAb
• hCG-mediated gestational thyrotoxicosis is transient and usually does not require treatment

Subclinical Hyperthyroidism

• Suppressed TSH with normal free T4 and T3
• Follow-up in 6-12 weeks; treat if persistent, elderly, at risk for atrial fibrillation or osteoporosis

Cardiovascular Risks