Autoimmune diffuse goiter driven by TSH-receptor stimulating antibodies; most common cause of overt hyperthyroidism.
Also known as: Graves disease, hyperthyroidism, thyrotoxicosis, TSI, diffuse toxic goiter
Overview
Autoimmune hyperthyroidism caused by stimulating antibodies (thyroid-stimulating immunoglobulins, TSI; also called TRAb) that bind and activate the TSH receptor, producing diffuse goiter, sustained thyroid hormone excess, and characteristic extrathyroidal manifestations (orbitopathy, dermopathy).
Epidemiology
Most common cause of hyperthyroidism in the United States. Female-to-male ratio ~5-10:1. Peak onset 30-50 years. Strong familial clustering and association with other autoimmune disease (T1DM, celiac, vitiligo, pernicious anemia, Addison disease).
🔒 Free preview limit reached
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Hyperthyroidism (Graves Disease) outline — plus all 514 diagnoses, 3,500+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Loss of self-tolerance produces IgG antibodies (TRAb/TSI) that bind the TSH receptor and continuously stimulate follicular cells, driving hormone synthesis and gland hyperplasia. The same receptor (or shared antigens) on retro-orbital fibroblasts and pretibial fibroblasts produces orbitopathy and dermopathy. Excess T3/T4 increases beta-adrenergic receptor density and metabolic rate, explaining most clinical features.
TSH-secreting pituitary adenoma — Inappropriately normal/elevated TSH with elevated free T4/T3; pituitary mass on MRI; elevated alpha subunit
Amiodarone-induced thyrotoxicosis — Type 1: iodine-driven excess synthesis (preexisting nodular disease); Type 2: destructive thyroiditis. Color Doppler discriminates
Diagnostic workup
Diagnostic criteria
Suppressed TSH + elevated free T4 and/or T3 + positive TRAb, or diffuse uptake on RAIU scan. Orbitopathy or pretibial myxedema with biochemical thyrotoxicosis is sufficient even without antibody confirmation.
Labs
TSH (suppressed, <0.01 in overt disease) — most sensitive initial test
Free T4 and total T3 (elevated; T3-predominant toxicosis common in Graves)
Pregnancy test in reproductive-age women (alters treatment choice)
Imaging
Radioactive iodine uptake and scan (RAIU/scan) — diffuse, homogeneous, ELEVATED uptake confirms Graves; differentiates from low-uptake thyroiditis and factitious
Thyroid ultrasound with color Doppler — hypervascular (thyroid inferno) in Graves; useful when RAIU contraindicated (pregnancy, lactation, recent iodine)
Orbital CT/MRI without contrast if moderate-to-severe orbitopathy (extraocular muscle enlargement sparing the tendons)
Diagnostic algorithm
Cause
RAIU
Thyroglobulin
TRAb / TSI
Key feature
Graves disease
Elevated, diffuse
Elevated
Positive
Orbitopathy, bruit, diffuse goiter
Toxic multinodular goiter
Patchy, heterogeneous
Elevated
Negative
Older, nodular gland
Toxic adenoma
Focal hot, rest suppressed
Elevated
Negative
Single autonomous nodule
Subacute thyroiditis
Low
Elevated
Negative
Painful, post-viral, elevated ESR
Painless/postpartum thyroiditis
Low
Elevated
Negative
Painless, transient, postpartum
Factitious thyrotoxicosis
Low
LOW
Negative
Exogenous T4 ingestion
Differentiating causes of thyrotoxicosis by RAIU, thyroglobulin, and TRAb.
Treatment
First-line
Beta-blocker for adrenergic symptoms — propranolol 20-40 mg q6h (also blocks peripheral T4→T3 conversion at high dose) or atenolol/metoprolol; use cautiously in HF
Thionamide — methimazole 10-40 mg daily (first-line in non-pregnancy; longer half-life; less hepatotoxicity); propylthiouracil (PTU) preferred in 1st trimester pregnancy and thyroid storm; carbimazole (UK/EU)
Counsel on agranulocytosis (any sore throat or fever → stop drug and check CBC) and hepatotoxicity
Osteoporosis and fracture (especially postmenopausal women)
Severe orbitopathy with vision loss
Thyrotoxic periodic paralysis (Asian male predominance)
Agranulocytosis or hepatotoxicity from thionamides; transient or permanent hypoparathyroidism after surgery
PANCE pearls
TRAb (TSI) is the most specific antibody for Graves disease and helps predict relapse after thionamide withdrawal.
PTU is preferred only in the FIRST trimester of pregnancy and in thyroid storm; methimazole is first-line otherwise because of better hepatic safety.
Avoid radioactive iodine in moderate-to-severe active orbitopathy — it can precipitate flare. Use thyroidectomy or thionamides instead.
Always check beta-hCG before RAI ablation in reproductive-age women.
Thyrotoxic periodic paralysis: sudden hypokalemic paralysis in an Asian man with new hyperthyroidism — treat with potassium and beta-blocker, then definitive thyroid therapy.
References
ATA 2016 — 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (Ross et al., Thyroid 2016)
ATA/AACE Pregnancy 2017 — 2017 Guidelines of the ATA for Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum (Alexander et al., Thyroid 2017)
EUGOGO 2021 — The 2021 European Group on Graves' Orbitopathy (EUGOGO) Clinical Practice Guidelines (Bartalena et al., Eur Thyroid J 2021)
Practice Endocrinology questions on FirstPassPA
Turn this outline into retention. 3,500+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants.