Graves'-associated positive family hx or at least often abnormal suppression tests in family members; pernicious anemia. Female/male = 4-6:1

Sx: Thyrotoxic: palpitations; weight loss; amenorrhea; hyperactivity; hot, sweaty, smooth skin; prominent essential tremor; decreased libido; frequent often diarrheal stools from steatorrhea, polyphagia of fat, and decreased gi transit time (Ann IM 1973;78:669)

In Graves': above, plus goiter; diplopia and eye protrusion (proptosis); vitiligo, esp of extremities, often precedes toxicosis by years (Ann IM 1969;71:935)

Si: Thyrotoxic: P >100 resting; "adrenergic stare," and lid lag; weight loss; apathetic depression, esp in elderly (Ann IM 1970;72:679)

In Graves': above, plus ophthalmoplegias, esp convergence failure; exophthalmus, cornea >18 mm from lateral orbital rim, can be unilateral; goiter (97%) diffuse, firm (Ann IM 1968;69:1022); gynecomastia in men frequently; pretibial myxedema and localized dermopathy (picture—Nejm 2005;352:918); onycholysis (nail separation); Plummer's nails (serrated) and clubbing; increased pigmentation (increased ACTH turnover); lymphadenopathy (10%)

Graves' is cyclic, worse in winter (daylight effects?); usually better in pregnancy from natural immune suppression (Nejm 1985;313:562)

Thyroid storm, esp with surgery or infection (Nejm 1974;291:1396); cardiac (Nejm 1992;327:94) including myocarditis and CHF, atrial fibrillation, and angina precipitation; myopathies, plain, and hypokalemic (Ann IM 1974;81:332), myasthenia syndromes; osteoporosis (Ann IM 2001;134:560; 1999;130:750) incr 3× if TSH <0.1, reversible w rx; newborn thyrotoxicosis from TSI at age 7-10 d when mother has been on suppressive medications prepartum, and fetal thyrotoxicosis in mothers with ablated thyroids (Nejm 1985;313:562)

Thoracic inlet obstruction w positive Pemberton si (Multinodular Goiter (Nontoxic and Toxic))

Lab:

Chem:sensitive TSH low; elevated total T₄, free T₄, serum thyroglobulin (rules out surreptitious ingestion); TRH stimulation test w 250 µgm iv, draw TSH at 0 and 30 min, shows no rise, often the only abnormal test, esp in elderly with atrial fibrillation

Alkaline phosphatase (bony) elevated in 50+% Graves' pts (Ann IM 1979;90:164), parallels thyroid function if no liver disease. Calcium may be increased (in 10-25%) though PTH normal (Ann IM 1976;84:668; Nejm 1976;294:431)

Hem:Atypical lymphs and lymphocytosis

Xray:RAIU elevated and useful to distinguish from I₂-induced and subacute thyroiditis types; usually not necessary, thyroid ¹³¹I, ¹²³I, or technetium scan shows diffusely enhanced uptake

Rx:

(Nejm 1994;330:1731; Ann IM 1994;121:281)

Propranolol 2-10 mg iv, or 20-80 mg po, or atenolol 50-100 mg po qd to control sx; may not fully prevent storm (Nejm 1977;296:263); also will decrease hypercalcemia if symptomatic (Nejm 1976;294:431)

Antithyroid meds (Nejm 2005;352:905): propylthiouracil (PTU) <100-200 mg po tid, or methimazole (Tapezole) 5-20 mg po qd; block iodination of tyrosine by thyroid peroxidase to T ₃T₄; rx × 12-18 mo, then start replacement; PTU preferred in pregnancy and during lactation because methimazole may be teratogenic; 40-50% failure rates, higher if high po iodine intake not controlled (Ann IM 1987;107:510; Nejm 1984;311:426); adverse effects of both: rash, toxic hepatitis, vasculitis (esp w PTU) and agranulocytosis (0.3%), though no point in screening CBCs. Both cost $400/yr

¹³¹I rx may be 1st choice in older pts under ß-blocker protection, or used if fail 1 or more PTU courses; use w prednisone 0.5 mg/kg po qd × 1 mo, then 2 mo taper to prevent transient worsening of opthalmopathy (Nejm 1998;338:73); ß-blockade may help sx and won't interfere w ¹³¹I uptake. 76% become hypothyroid by 11 yr after rx even with most conservative dosing (Nejm 1984;311:426); ok in premenopausal women as long as not pregnant

Surgical thyroidectomy may be 1st choice, or if fail 2 or more PTU courses and judged unreliable to return if become myxedematous after ¹³¹I, although >26% of surgical patients will be hypothyroid at 11 yr (Nejm 1984;311:426)

of storm: 1st ß-blockade, volume repalcement, and dexamethasone (peripheral T₄ to T₃ conversion blockade); then PTU ~1 gm initial dose po or pr, and possibly SSKI loading dose then 10-15 gtts po qid or lithium 300 mg tid

of ophthalmoplegia: stop smoking (Ann IM 1998;129:632); steroids as prednisone 0.5 mg/kg po qd for 1 mo then q3mo taper, clearly helpful, esp with radioactive iodine rx (Nejm 1989;321:1349); surgery; cyclophosphamide (Ann IM 1979;90:921), or cyclosporine (Nejm 1989;321:1353)

of Graves' in pregnancy: low-dose PTU ok (Nejm 2005;352:905), but try to keep free T₄ at upper normal and taper off in 3rd trimester if can, ß-blockers

of pretibial myxedema: topical steroids

of pituitary adenoma type: octreotide (Ann IM 1993;119:236)