Endocrine

Hyperthyroidism: workup and treatment options

Clinical Overview and When to Suspect Hyperthyroidism

— Overt hyperthyroidism prevalence ~0.5–1%; subclinical ~2–3%

— Female:male ratio ~5–10:1

— Graves disease is the leading cause (60–80%) in adults <50; toxic multinodular goiter (TMNG) and toxic adenoma dominate in older adults and iodine-deficient regions

— Unexplained weight loss with preserved/increased appetite, heat intolerance, palpitations, tremor, anxiety, insomnia, frequent stools, oligomenorrhea

— New atrial fibrillation, especially in patients <60 or without typical risk factors — always check TSH

— Unexplained osteoporosis, fragility fracture, or worsening glycemic control in diabetes

— Resting tachycardia, lid lag, fine tremor on routine exam

— Postpartum mood/weight changes (think postpartum thyroiditis)

— Personal/family history of autoimmune disease (T1DM, vitiligo, celiac, Addison)

— Amiodarone, lithium, immune checkpoint inhibitors, interferon-α, recent iodinated contrast

— Pregnancy, postpartum (up to 12 months), perimenopause

Board pearl: In any older adult with new-onset atrial fibrillation, order a TSH before deciding on long-term rate/rhythm strategy — treating hyperthyroidism often resolves the arrhythmia and changes anticoagulation calculus.

Step 3 management: Hyperthyroidism is a longitudinal, outpatient-managed disease for most patients — your job is recognition, accurate etiology, treatment selection aligned with patient preferences, and structured follow-up.

Definition: Hyperthyroidism = excess thyroid hormone production by the gland; thyrotoxicosis = clinical syndrome of excess thyroid hormone from any source (including exogenous or thyroiditis). Step 3 expects you to keep these terms distinct.

Epidemiology:

When to suspect in ambulatory practice:

High-risk populations to screen with low threshold:

Subclinical hyperthyroidism: suppressed TSH with normal free T4/T3 — clinically silent but raises risk of AF, stroke, osteoporosis, and cardiovascular mortality, particularly if TSH <0.1 mIU/L or age ≥65.

Presentation Patterns and Key History

— Palpitations, tremor, anxiety, irritability, insomnia

— Heat intolerance, diaphoresis, warm moist skin

— Hyperdefecation (not diarrhea), increased appetite, weight loss

— Proximal muscle weakness (difficulty rising from chair, climbing stairs)

— Oligomenorrhea/amenorrhea; reduced libido and gynecomastia in men

— Weight loss, atrial fibrillation, depression, weakness, cognitive slowing

— Few adrenergic symptoms — easily missed; check TSH in any older patient with unexplained AF, weight loss, or new heart failure

— Diffuse symmetric painless goiter ± bruit

— Ophthalmopathy: proptosis, diplopia, periorbital edema, lid retraction, grittiness — strongly correlated with smoking

— Pretibial myxedema (thyroid dermopathy) and acropachy — rare but pathognomonic

— Often subacute onset over weeks; family history of autoimmune disease

— Older patient, longstanding goiter, gradual symptom onset

— Cardiovascular manifestations predominate (AF, HF, angina)

— No eye disease, no dermopathy

— Brief thyrotoxic phase (2–8 weeks) → euthyroid → hypothyroid → recovery

— Subacute (de Quervain): tender goiter, post-viral, elevated ESR/CRP

— Postpartum: within 12 months of delivery; 50% have anti-TPO antibodies

Key distinction: Hyperthyroidism (Graves, TMNG, adenoma) has high radioiodine uptake; thyroiditis and exogenous/factitious have low uptake. This single fork drives etiologic workup.

Board pearl: Pruritus, urticaria, and isolated systolic hypertension with wide pulse pressure are underrecognized presentations — particularly in elderly with apathetic disease.

Classic adrenergic syndrome (young/middle-aged adult):

Apathetic hyperthyroidism (elderly):

Graves-specific clues:

Toxic nodular disease (TMNG/adenoma):

Thyroiditis (painful subacute, painless/silent, postpartum):

Drug/iodine-induced: amiodarone (types 1 and 2), iodinated contrast, kelp/supplements, lithium withdrawal, immune checkpoint inhibitors

Factitious: weight-loss/energy supplements, surreptitious levothyroxine — no goiter, suppressed thyroglobulin

Physical Exam Findings and Hemodynamic Assessment

— Sinus tachycardia (often 100–130), atrial fibrillation in 10–25% (rises with age)

— Wide pulse pressure, systolic hypertension, bounding pulses

— Low-grade hyperthermia possible; fever >38.5°C raises concern for thyroid storm

— Lid lag (von Graefe sign) and stare — adrenergic, seen in any cause

— Proptosis, conjunctival injection, chemosis, restricted extraocular motility, optic neuropathy — Graves orbitopathy only

— Use Hertel exophthalmometry; document visual acuity, color vision, RAPD if vision threatened

— Graves: diffuse, symmetric, non-tender goiter ± audible bruit/thrill (hypervascularity)

— TMNG: asymmetric, multinodular gland

— Toxic adenoma: single palpable nodule

— Subacute thyroiditis: exquisitely tender, firm

CCS pearl: On the CCS exam, when a thyrotoxic patient presents with tachyarrhythmia, order vitals, continuous cardiac monitoring, IV access, telemetry admission if unstable, and IV beta-blocker before lab confirmation — symptom control is parallel to workup, not sequential.

Board pearl: A thyroid bruit is highly specific for Graves disease — it reflects increased vascularity from TSH-receptor antibody stimulation and effectively rules in Graves in a thyrotoxic patient at the bedside.

Vital signs:

General: anxious affect, pressured speech, restlessness; cachexia in advanced disease

Skin/hair: warm, moist, velvety; fine hair; onycholysis (Plummer nails); palmar erythema; pretibial myxedema (Graves-specific, non-pitting)

Eyes:

Neck:

Cardiac: tachycardia, hyperdynamic precordium, loud S1, systolic flow murmur, signs of high-output heart failure (JVD, S3, edema) in severe disease

Neuromuscular: fine resting tremor (best seen with paper on outstretched hand), brisk DTRs with quick relaxation, proximal muscle wasting and weakness

Periodic paralysis: Asian males — thyrotoxic periodic paralysis with hypokalemia and acute flaccid weakness

Diagnostic Workup — Initial Labs

— Suppressed TSH (<0.1 mIU/L) → measure free T4 and total or free T3

— Normal TSH → primary hyperthyroidism essentially excluded

— Elevated or inappropriately normal TSH with high free T4 → think TSH-secreting pituitary adenoma or thyroid hormone resistance (rare; order pituitary MRI, alpha-subunit)

— Overt hyperthyroidism: suppressed TSH + elevated free T4 and/or T3

— T3 toxicosis (5%): suppressed TSH, normal T4, elevated T3 — classic for early Graves or toxic adenoma

— Subclinical hyperthyroidism: suppressed TSH, normal free T4 and T3

— TSH-receptor antibody (TRAb) or thyroid-stimulating immunoglobulin (TSI): highly sensitive/specific for Graves; first-line etiology test in many guidelines, especially in pregnancy where RAIU is contraindicated

— Anti-TPO: supportive of autoimmune thyroid disease but nonspecific

— Thyroglobulin: low in factitious thyrotoxicosis, elevated in endogenous causes and thyroiditis

— ESR/CRP: elevated in subacute (de Quervain) thyroiditis

— CBC (mild leukopenia common, baseline before antithyroid drugs)

— CMP (LFTs may be mildly elevated; baseline before methimazole/PTU)

— Glucose/A1c (hyperthyroidism worsens glycemic control)

— Calcium (mild hypercalcemia from increased bone turnover)

Step 3 management: In ambulatory practice, the practical order is TSH → free T4/T3 → TRAb ± RAIU. TRAb-positive Graves often does not require RAI uptake scanning, saving time and cost.

Board pearl: Always check β-hCG before any radioiodine procedure — RAI is absolutely contraindicated in pregnancy and breastfeeding.

Step 1 — TSH (most sensitive single test):

Step 2 — Free T4 and T3:

Step 3 — Etiology testing:

Supportive labs (workup of comorbidities/complications):

ECG: sinus tachycardia, atrial fibrillation, atrial flutter; obtain in all symptomatic patients

Pregnancy test in reproductive-age women — mandatory before RAI uptake/treatment

Diagnostic Workup — Advanced and Confirmatory Studies

— Diffuse, homogeneous, high uptake (>30%) → Graves disease

— Patchy, heterogeneous uptake → toxic multinodular goiter

— Single hot nodule with suppression of surrounding gland → toxic adenoma

— Near-zero uptake (<5%) → thyroiditis, exogenous hormone, iodine load, factitious

— Useful when RAIU is contraindicated (pregnancy, lactation, recent iodine load)

— Graves: diffusely enlarged, hypervascular ("thyroid inferno")

— Distinguishes nodules; characterizes nodules for FNA if indicated (TI-RADS)

— Amiodarone-induced: Type 1 (vascular, preexisting nodular gland) vs Type 2 (avascular, destructive)

— Recent iodinated contrast: RAIU unreliable for 4–8 weeks → use TRAb and ultrasound

— Amiodarone-induced thyrotoxicosis (AIT): color flow Doppler distinguishes Type 1 (treat with thionamide) vs Type 2 (treat with glucocorticoids); often mixed

— Pituitary MRI: if TSH inappropriately normal/elevated with high free T4 (TSHoma)

— 24-hour urine iodine: if iodine excess suspected

Key distinction: Graves vs thyroiditis is the most common fork — both can present with palpitations and weight loss. RAIU high = Graves, RAIU low = thyroiditis. TRAb positive seals Graves; thyroglobulin low + RAIU low seals factitious.

Board pearl: A "cold" nodule on RAI scan in a thyrotoxic patient = must FNA — risk of underlying malignancy in nonfunctioning nodules approaches 10–15%.

Radioactive iodine uptake (RAIU) and scan — gold standard for etiology when TRAb is negative or equivocal:

Thyroid ultrasound with Doppler:

Fine-needle aspiration (FNA): for any suspicious or cold/hypofunctioning nodule on scan — hot nodules essentially never malignant

Orbital imaging: CT or MRI orbits for moderate/severe Graves orbitopathy — assess extraocular muscle enlargement, apical crowding, optic nerve compression

Special situations:

Pre-treatment labs before thionamides: CBC with differential, LFTs (baseline ALT/AST, bilirubin)

Risk Stratification and First-Line Management Logic

— Beta-blocker (propranolol 10–40 mg q6–8h or atenolol 25–100 mg daily) for tachycardia, tremor, anxiety

— Propranolol additionally blocks peripheral T4→T3 conversion at high doses

— Use cautiously in heart failure with reduced EF (start low, monitor); avoid nonselective beta-blockade in severe bronchospasm — use atenolol or metoprolol

— Graves disease: three options — antithyroid drug (ATD), radioactive iodine (RAI), or thyroidectomy

— Toxic adenoma/TMNG: RAI or surgery preferred (autonomous tissue rarely remits with drugs)

— Thyroiditis: symptomatic only — beta-blocker ± NSAIDs/glucocorticoids; no thionamide (no hormone synthesis occurring)

— Factitious: discontinue source, psychiatric evaluation

— Amiodarone-induced: stop amiodarone if possible; Type 1 → methimazole, Type 2 → prednisone

— ATD (methimazole) preferred when: small goiter, mild disease, first episode, active moderate-severe orbitopathy, pregnancy (PTU 1st trimester, MMI thereafter), patient preference for non-permanent option

— RAI preferred when: TMNG/toxic adenoma, ATD failure/relapse, contraindication to surgery, no significant orbitopathy, patient accepts likely permanent hypothyroidism

— Surgery preferred when: large compressive goiter, suspected/coexisting malignancy, severe active orbitopathy, pregnancy with ATD failure/allergy, patient preference for rapid definitive cure

Step 3 management: Counseling on risks, benefits, time course, and long-term sequelae of each option is itself a tested skill — patients must understand that RAI and surgery typically produce lifelong hypothyroidism requiring levothyroxine and annual TSH monitoring.

Board pearl: Active moderate-to-severe Graves orbitopathy contraindicates RAI (can worsen eye disease) — choose ATD or surgery, and strongly counsel smoking cessation.

First, stabilize symptoms regardless of cause:

Then, treat the underlying cause based on etiology:

Choosing among Graves treatment options — shared decision-making factors:

Predictors of low remission with ATD in Graves: large goiter, high TRAb titer, severe biochemical hyperthyroidism, male sex, smoking, young age

Pharmacotherapy — First-Line Drug Regimens

— Methimazole (MMI): first-line outside 1st trimester pregnancy; 10–40 mg/day; once-daily dosing; longer half-life; fewer hepatotoxicity events

— Propylthiouracil (PTU): 100–150 mg q8h; preferred only in 1st-trimester pregnancy, thyroid storm, or MMI intolerance; also blocks peripheral T4→T3 conversion

— Onset: clinical improvement in 2–6 weeks; biochemical euthyroidism in 6–12 weeks

— Monitor: free T4 and T3 every 4–6 weeks initially, then every 2–3 months; TSH lags 2–3 months and should not drive early titration

— Propranolol 10–40 mg PO q6–8h (also inhibits deiodinase at high doses)

— Atenolol 25–100 mg daily (better adherence)

— Continue until biochemically euthyroid, then taper

— Agranulocytosis (0.2–0.5%): abrupt; counsel patients to stop drug and obtain CBC immediately for fever or sore throat

— Hepatotoxicity: PTU → fulminant hepatic necrosis (black box); MMI → cholestatic pattern; check baseline LFTs and recheck with symptoms

— Rash, urticaria, arthralgia: common (5%); often manageable with antihistamines or switching agents

— ANCA-associated vasculitis (more with PTU)

— MMI teratogenicity: aplasia cutis, choanal/esophageal atresia, omphalocele — avoid in 1st trimester

Board pearl: Stop the thionamide and check CBC the moment a patient on MMI/PTU calls with fever or sore throat — this is the single most tested adverse-event vignette.

Thionamides (block thyroid hormone synthesis by inhibiting thyroid peroxidase):

Beta-blockers (symptom control):

Glucocorticoids: indicated in thyroid storm, severe Graves orbitopathy, amiodarone-induced Type 2 thyroiditis (prednisone 40–60 mg/day)

Iodine (Lugol or SSKI): acute preoperative prep (Wolff–Chaikoff effect) and thyroid storm; never give before thionamides in storm — paradoxical worsening

Cholestyramine: adjunct in severe thyrotoxicosis — binds enterohepatically recirculated hormone

Adverse effects to counsel and monitor:

Duration of Graves ATD therapy: 12–18 months, then taper and trial off; remission rate ~50%

Procedures — Radioactive Iodine and Thyroidectomy

— Outpatient oral dose; destroys functioning thyroid tissue over 6–18 weeks

— Pre-treatment: stop MMI 3–5 days prior (continuing reduces RAI efficacy); confirm negative pregnancy test; counsel on radiation precautions (avoid close contact with children/pregnant women for 5–7 days; no pregnancy for 6–12 months; men defer conception 3–4 months)

— Efficacy: >80% cure of hyperthyroidism with single dose; most patients become hypothyroid within 6–12 months — anticipated outcome, not failure

— Contraindications: pregnancy, breastfeeding, active moderate-severe Graves orbitopathy (relative — pretreat with prednisone if used), suspected thyroid cancer, inability to follow radiation precautions

— Adverse effects: transient radiation thyroiditis (treat with NSAIDs), transient worsening of thyrotoxicosis (pretreat high-risk patients — elderly, cardiac disease — with MMI to euthyroidism first), worsening orbitopathy (mitigated with prednisone), sialadenitis, no proven increase in second malignancy at standard doses

— Indications: large compressive goiter, severe orbitopathy, coexisting suspicious nodule, pregnancy with ATD failure/allergy (2nd trimester ideal), patient preference for rapid definitive cure, severe hyperthyroidism unable to tolerate ATD

— Pre-op preparation: render euthyroid with MMI; add potassium iodide (SSKI) 7–10 days preoperatively to decrease gland vascularity; beta-blocker for symptom control

— Complications: hypocalcemia from hypoparathyroidism (transient 7–25%, permanent 1–2%), recurrent laryngeal nerve injury (1–2%, hoarseness), bleeding/hematoma (airway emergency), permanent hypothyroidism (universal — start levothyroxine 1.6 µg/kg/day post-op)

— Refer to high-volume thyroid surgeon (>25 cases/year) — outcomes are volume-dependent

CCS pearl: Post-thyroidectomy, order serum calcium and PTH at 6–12 hours and again the next morning; supplement calcium ± calcitriol if symptomatic or trending low. Discharge with a calcium symptom checklist (perioral numbness, Chvostek/Trousseau).

Board pearl: SSKI 7–10 days preoperatively reduces gland vascularity and intraoperative bleeding — a classic preop board question.

Radioactive iodine (¹³¹I) ablation:

Total or near-total thyroidectomy:

Special Populations — Elderly, Renal and Hepatic Impairment

— Apathetic hyperthyroidism common — weight loss, atrial fibrillation, heart failure, cognitive change without typical adrenergic symptoms

— Lower threshold to treat subclinical hyperthyroidism, especially TSH <0.1 mIU/L or age ≥65, due to increased risk of AF, stroke, osteoporotic fracture, and CV mortality

— RAI is often preferred — avoids long-term ATD monitoring and is well-tolerated; pretreat to euthyroid with MMI to minimize risk of post-RAI thyrotoxic surge and cardiac decompensation

— Beta-blocker selection: prefer atenolol or metoprolol to limit CNS side effects; cautious dosing if HFrEF

— Anticoagulation in AF: CHA₂DS₂-VASc applies; hyperthyroidism alone is not an automatic indication for anticoagulation, but most older patients meet criteria via age/comorbidities

— Bone health: DEXA scan; calcium, vitamin D; consider bisphosphonate if osteoporosis or prior fragility fracture

— Thionamide dosing typically unchanged

— Beta-blocker dose adjustment: atenolol is renally cleared — reduce dose if CrCl <35; metoprolol and propranolol are hepatically metabolized

— Iodinated contrast caution — can precipitate thyrotoxicosis in autonomous nodular disease

— PTU contraindicated in significant liver disease (risk of fulminant hepatic failure)

— MMI preferred but check baseline LFTs; discontinue for ALT >3× ULN or symptomatic hepatitis

— Mild transaminitis is common in untreated hyperthyroidism itself and improves with euthyroidism

— New AF in hyperthyroidism: rate control with beta-blocker (caution in HF); cardioversion often unnecessary as ~60% spontaneously convert with euthyroidism within 4 months

— High-output heart failure improves with euthyroidism — avoid aggressive diuresis

Step 3 management: In an elderly patient with thyrotoxic AF, render euthyroid first before scheduling cardioversion — most will spontaneously revert and avoid the procedure entirely.

Board pearl: Subclinical hyperthyroidism with TSH <0.1 plus age ≥65, AF, or osteoporosis = treat. TSH 0.1–0.4 in asymptomatic younger patients = monitor every 6–12 months.

Elderly patients:

Renal impairment:

Hepatic impairment:

Cardiac comorbidity:

Special Populations — Pregnancy, Pediatrics, and Postpartum

— Gestational transient thyrotoxicosis (GTT): hCG-mediated, peaks 8–14 weeks, often with hyperemesis gravidarum; TRAb negative, no goiter, resolves by 18–20 weeks; no antithyroid drug needed — supportive care, beta-blocker if symptomatic

— Graves disease in pregnancy: TRAb positive; treat with thionamides

— 1st trimester: PTU (MMI teratogenic: aplasia cutis, choanal/esophageal atresia)

— 2nd–3rd trimester: switch to MMI (PTU hepatotoxicity risk accumulates)

— Use lowest dose to keep free T4 at upper limit of normal — fetal hypothyroidism risk if overtreated

— RAI absolutely contraindicated; surgery reserved for ATD failure/allergy (2nd trimester ideal)

— Measure at initial visit and at 18–22 and 30–34 weeks in any woman with current or past Graves (including those previously treated with RAI/surgery)

— High TRAb (>3× ULN) → risk of fetal/neonatal Graves — coordinate with maternal-fetal medicine and neonatology; monitor fetal HR, growth, goiter on ultrasound

— Up to 10% of women within 12 months of delivery; classic triphasic course (thyrotoxic → hypothyroid → recovery)

— Thyrotoxic phase: low RAIU (avoid scan in lactation regardless), treat with beta-blocker only — no thionamide

— Anti-TPO positive in ~50%; ~20% develop permanent hypothyroidism

— ATD (MMI) is first-line; longer treatment courses (often 2–4 years) with lower remission rates than adults

— RAI generally avoided <5 years and used cautiously 5–10 years

— Surgery preferred for definitive treatment in young children if ATD fails

Board pearl: PTU in 1st trimester, MMI thereafter — and never RAI in pregnancy or lactation (radioiodine crosses placenta and concentrates in breast milk).

Key distinction: Hyperemesis with mild thyrotoxicosis and no goiter = GTT (observe). Persistent thyrotoxicosis with goiter, ophthalmopathy, or positive TRAb = Graves (treat with PTU).

Pregnancy — distinguish two key entities:

Thionamide choice in pregnancy:

TRAb monitoring:

Postpartum thyroiditis:

Pediatric Graves disease:

Complications and Adverse Outcomes

— Atrial fibrillation (10–25%; up to 40% in elderly) — increases stroke risk; CHA₂DS₂-VASc–driven anticoagulation

— High-output heart failure — resolves with euthyroidism

— Worsening angina/ischemia from increased myocardial oxygen demand

— Increased cardiovascular mortality even in subclinical disease

— Life-threatening (10–30% mortality); precipitated by infection, surgery, trauma, RAI, contrast load, parturition, abrupt ATD withdrawal

— Burch-Wartofsky score ≥45 highly suggestive; clinical diagnosis (don't wait for labs)

— Features: T >39°C, severe tachycardia/AF, CHF, agitation/delirium/coma, GI dysfunction (vomiting, diarrhea, jaundice)

— 25–50% of Graves patients have eye signs; 5% severe

— Dysthyroid optic neuropathy = vision-threatening emergency → high-dose IV glucocorticoids ± urgent orbital decompression

— Strongly worsened by smoking and RAI without steroid prophylaxis

— ATD: agranulocytosis, hepatotoxicity, vasculitis, rash

— RAI: permanent hypothyroidism (expected), transient radiation thyroiditis, worsened orbitopathy

— Surgery: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, permanent hypothyroidism

Board pearl: Smoking + Graves + RAI = orbitopathy disaster. Counsel cessation aggressively and consider prednisone prophylaxis (0.3–0.5 mg/kg starting day of RAI, tapered over 6–12 weeks) in patients with mild orbitopathy or risk factors.

Step 3 management: Pre-treat all moderate-severe hyperthyroid patients with MMI to euthyroidism before RAI if elderly or cardiac disease — prevents thyrotoxic surge.

Cardiovascular:

Thyroid storm (thyrotoxic crisis):

Bone: accelerated bone turnover → osteoporosis, increased fracture risk, hypercalcemia

Neuromuscular: thyrotoxic myopathy (proximal weakness), thyrotoxic periodic paralysis (Asian males, hypokalemia)

Ophthalmic (Graves orbitopathy):

Dermatologic: pretibial myxedema, thyroid acropachy (rare)

Reproductive: oligomenorrhea, infertility, increased miscarriage, low birth weight, preeclampsia, preterm delivery

Psychiatric: anxiety, mania, psychosis (rare), depression in apathetic form

Hepatic: mild transaminitis (disease itself), cholestasis with MMI, hepatic necrosis with PTU

Treatment-related:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Sequential pharmacotherapy (order matters):

1. Beta-blocker — propranolol 60–80 mg PO q4h or IV 0.5–1 mg slow push, titrate

2. Thionamide — PTU 500–1000 mg load, then 250 mg q4h (blocks synthesis + peripheral T4→T3 conversion)

3. Iodine (≥1 hour after PTU) — SSKI 5 drops PO q6h or Lugol; blocks hormone release (Wolff–Chaikoff)

4. Hydrocortisone 100 mg IV q8h — blocks T4→T3 conversion, treats possible coexisting adrenal insufficiency

5. Cooling (acetaminophen — avoid aspirin, which displaces hormone from TBG), aggressive fluids, treat precipitant (infection, DKA, MI)

— Consider plasmapheresis or emergent thyroidectomy if refractory

— Hemodynamic instability, severe AF with RVR, decompensated heart failure

— Severe thyrotoxicosis in elderly/cardiac patient unable to tolerate oral medications

— Agranulocytosis from ATD (ANC <500 — admit, broad-spectrum antibiotics, hold drug, never rechallenge)

— Severe drug-induced hepatitis

— Pregnant patient with poorly controlled disease

— Endocrinology: all newly diagnosed overt hyperthyroidism; treatment selection; refractory cases; pregnancy

— Ophthalmology: any vision change, diplopia, proptosis >22 mm, periorbital signs of optic nerve compression

— Endocrine surgery: large compressive goiter, suspicion of malignancy, planned thyroidectomy

— Cardiology: thyrotoxic AF with hemodynamic compromise; pre-existing structural heart disease

— Maternal-fetal medicine: pregnant patients, especially with high TRAb

— Psychiatry: factitious disease, severe affective symptoms

CCS pearl: Suspected thyroid storm — do not wait for confirmatory labs. Order continuous monitoring, IV access, ICU bed, and start the beta-blocker → PTU → iodine (≥1 h later) → hydrocortisone sequence simultaneously with workup. Always identify and treat the precipitant (cultures, CXR, ECG, troponin).

Board pearl: Iodine before thionamide in storm = catastrophic — iodine substrate accelerates hormone synthesis. Always PTU/MMI first, iodine ≥1 hour later.

Thyroid storm — ICU admission and treat empirically:

Inpatient admission criteria (non-storm):

Urgent consultations:

Key Differentials — Other Causes of Thyrotoxicosis

— Autoimmune, TRAb/TSI mediated; diffuse goiter, ophthalmopathy, dermopathy

— High, homogeneous RAIU; TRAb positive

— Longstanding nodular goiter in older patient; gradual onset; no eye disease

— Patchy, heterogeneous RAIU; TRAb negative

— Often precipitated by iodine load (contrast, amiodarone) — Jod-Basedow phenomenon

— Single autonomous nodule >3 cm typically; suppression of surrounding parenchyma

— Single hot nodule on RAI scan with cold remaining gland

— Post-viral; painful, tender goiter; elevated ESR/CRP; low RAIU

— Triphasic course; NSAIDs ± prednisone; beta-blocker

— Autoimmune; postpartum or sporadic; painless goiter; anti-TPO often positive; low RAIU

— Within 12 months of delivery; ~10% incidence; triphasic; ~20% become permanently hypothyroid

— Amiodarone (AIT type 1): iodine-induced in nodular gland — high vascularity on Doppler — treat MMI ± perchlorate

— Amiodarone (AIT type 2): destructive thyroiditis — low vascularity — treat prednisone

— Lithium, interferon-α, immune checkpoint inhibitors (nivolumab, pembrolizumab) — usually destructive thyroiditis

— Iodinated contrast — Jod-Basedow in autonomous tissue

— Exogenous levothyroxine/T3; weight loss supplements

— Low RAIU, low thyroglobulin (key clue), no goiter

— Inappropriately normal or elevated TSH with high free T4/T3; elevated alpha-subunit; pituitary mass on MRI

Key distinction: Within the thyrotoxicosis differential, RAIU partitions the entire list: high uptake = endogenous hyperthyroidism (Graves, TMNG, adenoma); low uptake = thyroiditis, exogenous, ectopic, iodine-induced destructive.

Board pearl: Low thyroglobulin in a thyrotoxic patient with low RAIU = factitious until proven otherwise.

Graves disease (60–80%):

Toxic multinodular goiter (Plummer):

Toxic adenoma:

Subacute (de Quervain/granulomatous) thyroiditis:

Painless/silent thyroiditis:

Postpartum thyroiditis:

Drug-induced:

Factitious thyrotoxicosis:

Struma ovarii: ectopic thyroid tissue in ovarian teratoma; neck RAIU low, pelvic uptake on whole-body scan

TSH-secreting pituitary adenoma (TSHoma):

Key Differentials — Non-Thyroid Mimics of Hyperthyroidism

— Palpitations, tremor, diaphoresis, weight changes, insomnia

— Normal TSH rules out hyperthyroidism; do not start SSRIs without checking

— Episodic headache, palpitations, diaphoresis, hypertension (sustained or paroxysmal)

— Plasma free metanephrines or 24-hour urine metanephrines/catecholamines

— Can coexist with thyroid disease in MEN 2 (medullary thyroid cancer + pheo + hyperparathyroidism)

— Cocaine, methamphetamine, MDMA, pseudoephedrine, high-dose caffeine, energy drinks, ADHD medications

— Urine toxicology; history

— Flushing, diarrhea, wheezing, right-sided valvular disease

— 24-hour urine 5-HIAA, chromogranin A

— Hot flashes, palpitations, mood changes — often overlaps with hyperthyroidism in this demographic

— TSH to differentiate; both can coexist

— Weight loss, sweats, tachycardia in lymphoma, leukemia, solid tumors

— Constitutional symptoms with normal TSH; pursue oncologic workup

— Polyuria, polydipsia, weight loss; check glucose/A1c

— Heat intolerance, palpitations, increased appetite; hCG can suppress TSH transiently

— Tremor, tachycardia, diaphoresis, anxiety; history is key

— Palpitations and exercise intolerance; ECG, echo, TSH should always be part of new AF workup

— Cushing syndrome (weight changes, hypertension, mood)

— Acromegaly (sweating, hypertension, soft-tissue overgrowth)

Step 3 management: Anxiety and panic disorders are the most common "false alarms" referred for hyperthyroidism workup — TSH alone resolves 95% of these cases. Reserve free T4/T3 and TRAb for suppressed TSH.

Board pearl: New AF + sweating + episodic hypertension — check TSH and metanephrines. Pheo and hyperthyroidism are the two endocrine causes of new AF you cannot miss.

Anxiety/panic disorder:

Pheochromocytoma:

Stimulant or sympathomimetic use:

Carcinoid syndrome:

Menopause/perimenopause:

Malignancy with paraneoplastic features:

Diabetes (uncontrolled) or new-onset T1DM:

Pregnancy (early):

Alcohol withdrawal:

Heart failure or arrhythmia of other etiology:

Other endocrine:

Medications: levothyroxine overreplacement, decongestants, albuterol, theophylline

Secondary Prevention, Discharge Planning, and Long-Term Care

— Anticipate lifelong hypothyroidism — start levothyroxine 1.6 µg/kg/day (lower doses in elderly/cardiac patients, start 25–50 µg/day)

— Post-thyroidectomy: start levothyroxine on POD 1

— Post-RAI: monitor TSH every 4–6 weeks for first 6 months; initiate levothyroxine when TSH rises or free T4 falls below normal

— Target: lowest dose to maintain euthyroidism; typically 12–18 month course then taper and discontinue trial

— Remission rate ~50%; relapse most common in first 6–12 months after stopping

— TRAb at end of treatment predicts relapse; persistent elevation → consider definitive therapy

— If relapse: offer RAI or surgery (long-term ATD acceptable in pregnancy/refractory cases)

— Atrial fibrillation: anticoagulation per CHA₂DS₂-VASc; rate control until euthyroid then reassess rhythm

— Many patients spontaneously revert to sinus rhythm with euthyroidism — defer cardioversion 3–4 months

— DEXA scan at diagnosis if postmenopausal, prolonged disease, or fragility fracture

— Calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day; bisphosphonate per FRAX/T-score

— Smoking cessation (single most modifiable risk factor)

— Artificial tears, elevation of head of bed, selenium 200 µg/day for mild active disease (6 months)

— IV methylprednisolone for moderate-severe active disease; teprotumumab (IGF-1R inhibitor) for moderate-severe Graves orbitopathy

— Medication adherence and recognition of agranulocytosis symptoms (fever, sore throat)

— Avoid iodine-rich foods/supplements (kelp, high-iodine multivitamins) during ATD therapy

— Contraception counseling (MMI teratogenicity, pregnancy planning after RAI)

Step 3 management: Establish a structured follow-up plan at discharge — labs at 4–6 weeks, endocrinology in 4–6 weeks, primary care in 2 weeks for medication reconciliation, smoking cessation referral, and bone density planning.

Board pearl: Post-RAI hypothyroidism is expected, not a complication — patients must be counseled that they are exchanging hyperthyroidism for a manageable lifelong hypothyroidism.

Post-RAI or post-thyroidectomy patients (most Graves patients eventually):

ATD therapy (Graves):

Cardiovascular secondary prevention:

Bone health:

Ophthalmopathy:

Patient education:

Comorbid screening: screen for other autoimmune disease (T1DM, adrenal insufficiency, celiac, pernicious anemia) in Graves patients with suggestive symptoms

Follow-Up, Monitoring, and Counseling

— Free T4 and total/free T3 every 4–6 weeks during titration (TSH lags 2–3 months — do not use early)

— Once euthyroid: TSH + free T4 every 2–3 months

— Maintenance phase: every 3–6 months for the duration of therapy

— CBC and LFTs at baseline; recheck only if symptomatic (fever, sore throat, jaundice, RUQ pain) — routine surveillance not recommended

— TRAb at 12–18 months to predict remission likelihood before taper

— TSH and free T4 at 4–6 weeks, then every 4–6 weeks for 6 months

— Once hypothyroidism develops and stable on levothyroxine: TSH every 6–12 months

— Persistent hyperthyroidism at 6 months → consider second RAI dose or surgery

— Calcium and PTH within 24 hours postop; ionized calcium if symptomatic

— TSH 6–8 weeks post-op to titrate levothyroxine

— Annual TSH thereafter on stable dose

— Adjust by 12.5–25 µg every 6–8 weeks based on TSH

— TSH goal: 0.5–2.5 mIU/L (general); lower in select cardiac patients to avoid overreplacement

— Take fasting, 30–60 min before food/calcium/iron/PPI; same time daily

— TSH (and free T4 if recent dose change)

— Symptom check (fatigue, weight, mood, palpitations)

— Bone density per age/risk

— Cardiovascular review (rhythm, BP, lipids)

— Adherence and timing of medications

— Recognition of recurrence (palpitations, weight loss, heat intolerance)

— Smoking cessation (orbitopathy and CV risk)

— Pregnancy planning — adjust levothyroxine empirically by ~30% upon confirmed pregnancy, target TSH <2.5 mIU/L

— Calcium/iron/PPI separation from levothyroxine by ≥4 hours

Step 3 management: In pregnant patients on levothyroxine, TSH every 4 weeks until 20 weeks, then once between 26–32 weeks. Increase dose ~30% as soon as pregnancy confirmed.

Board pearl: TSH lags free T4 by 2–3 months — judge early treatment response by free T4/T3, not TSH.

Monitoring on antithyroid drugs:

Post-RAI monitoring:

Post-thyroidectomy monitoring:

Levothyroxine titration:

Annual monitoring of stable patients:

Counseling topics at each visit:

Ethical, Legal, and Patient Safety Considerations

— Disclose realistic outcomes: RAI almost always results in permanent hypothyroidism; surgery carries risks of permanent hypoparathyroidism and recurrent laryngeal nerve injury

— Use shared decision-making frameworks — present ATD, RAI, and surgery with honest risk/benefit profiles; respect patient values (work, fertility, fear of surgery, radiation concerns)

— Document discussion of teratogenicity and contraception duration after RAI (avoid pregnancy 6–12 months; men 3–4 months)

— Written precautions: distance from children and pregnant women, sleeping arrangements, separate utensils, avoiding public transportation initially, breastfeeding cessation

— Pretreatment pregnancy test mandatory — wrong-patient RAI in pregnancy is a sentinel event; institutional protocols typically require documentation

— Black-box warning on PTU for hepatotoxicity — use only when MMI is contraindicated (1st trimester pregnancy, storm, MMI allergy)

— Patient instructions to stop drug and seek CBC immediately for fever/sore throat (agranulocytosis); document this counseling

— Never rechallenge with thionamide after agranulocytosis or severe hepatitis

— Post-thyroidectomy discharge requires: calcium symptom checklist, prescription for calcium ± calcitriol, levothyroxine, follow-up TSH in 6–8 weeks, surgeon visit in 1–2 weeks

— Post-RAI: scheduled TSH at 4–6 weeks; clear instructions on when to call for fatigue/cold intolerance signaling new hypothyroidism

— Medication reconciliation: verify timing relative to iron, calcium, PPIs, biotin (interferes with assays); adjust amiodarone-related decisions with cardiology

— Factitious thyrotoxicosis in a healthcare worker or caregiver (especially affecting a child or dependent adult) → consider mandated reporting for medical child abuse or elder abuse

— Document objective findings (low thyroglobulin, low RAIU, exogenous source) before confrontation

— Hyperthyroidism can cause psychosis, mania, or delirium impairing decisional capacity — assess capacity before consenting to definitive therapy; involve psychiatry and surrogate decision-makers as needed

Board pearl: A pregnancy test the day of RAI is a non-negotiable safety check — failure is a never event.

Informed consent for definitive therapy (RAI vs surgery):

Radiation safety counseling (RAI):

Medication safety:

Transitions of care (high Step 3 yield):

Mandatory reporting and special considerations:

Capacity and adherence:

Health equity: RAI requires home isolation that may be infeasible for patients in shared housing — surgery or extended ATD may be more appropriate.

High-Yield Associations and Rapid-Fire Facts

— Inhibits T4→T3 conversion (transient TSH rise initially)

— AIT type 1: iodine-induced, treat MMI

— AIT type 2: destructive, treat prednisone

Board pearl: When you see "TSH 8.5 with free T4 elevated" — that's not lab error; it's TSHoma or thyroid hormone resistance until proven otherwise. Get pituitary MRI and alpha-subunit.

Graves disease HLA association: HLA-DR3 and HLA-B8

Graves triad: hyperthyroidism + ophthalmopathy + pretibial myxedema

Thyroid acropachy: clubbing + soft tissue swelling — Graves-specific, rare

Jod-Basedow phenomenon: iodine load → hyperthyroidism in autonomous nodular gland

Wolff-Chaikoff effect: high-dose iodine transiently suppresses thyroid hormone synthesis — basis of iodine prep before thyroidectomy and in thyroid storm

Thyrotoxic periodic paralysis: Asian males, hypokalemia, acute flaccid paralysis — treat with K replacement + propranolol; resolves with euthyroidism

Pemberton sign: facial plethora when arms raised — large substernal goiter compressing thoracic inlet

Hashimoto and Graves can coexist or transition: "hashitoxicosis" — transient thyrotoxic phase in Hashimoto thyroiditis

Apathetic hyperthyroidism: elderly with weight loss, AF, depression — check TSH

Postpartum thyroiditis: 10% of women; 20% become permanently hypothyroid; associated with type 1 diabetes

Subacute (de Quervain) thyroiditis: post-viral, painful, elevated ESR, low RAIU, glucocorticoids if severe

Amiodarone effects:

Drugs that interfere with levothyroxine absorption: calcium, iron, PPIs, bile acid sequestrants, soy, coffee — separate dosing by ≥4 hours

Biotin interferes with thyroid assays — falsely low TSH and high free T4 (TSH-immunoassay) — stop biotin 48–72 hours before testing

Universal newborn screening for congenital hypothyroidism (heel stick) — Step 3 may test in postpartum Graves mother with high TRAb (monitor neonate for Graves)

MEN syndromes: MEN 2 → medullary thyroid cancer (not hyperthyroidism); MEN 1 → no thyroid component

Thyroid storm precipitants mnemonic: infection, surgery, trauma, parturition, iodinated contrast, RAI, DKA, MI, ATD withdrawal

Burch-Wartofsky score ≥45 = thyroid storm likely

Teprotumumab (IGF-1R inhibitor) — moderate-severe Graves orbitopathy

Selenium 200 µg/day — mild active Graves orbitopathy

Board Question Stem Patterns

Board pearl: When the stem gives you low RAIU, the differential is thyroiditis, factitious, exogenous, struma ovarii, or iodine-induced destructive — never reach for methimazole.

The classic Graves stem: Young woman with palpitations, weight loss despite increased appetite, heat intolerance, exophthalmos, diffuse goiter with bruit. → TSH suppressed, T4/T3 elevated, TRAb positive. Next step: methimazole + beta-blocker; counsel on RAI vs surgery vs continued ATD. Avoid RAI if active orbitopathy.

The elderly AF stem: 72-year-old with new atrial fibrillation, weight loss, mild apathy. Next step: check TSH before rhythm-vs-rate decision. TSH suppressed → MMI, beta-blocker, anticoagulate by CHA₂DS₂-VASc, defer cardioversion 3–4 months.

The pregnant Graves stem: Pregnant patient at 8 weeks with thyrotoxicosis. Choice: PTU in 1st trimester, switch to MMI in 2nd; never RAI; monitor TRAb at 18–22 and 30–34 weeks.

The hyperemesis stem: 9-week pregnant patient with vomiting, mild thyrotoxicosis, no goiter, TRAb negative. → Gestational transient thyrotoxicosis — supportive care only.

The agranulocytosis stem: Patient on MMI for 6 weeks calls with fever and sore throat. Next step: stop drug, CBC with differential immediately; if ANC <500, admit, broad-spectrum antibiotics, switch definitive therapy to RAI or surgery.

The thyroid storm stem: Post-op or post-infection patient with T 40°C, HR 150, agitation, AF, jaundice. Sequence: beta-blocker → PTU → iodine (≥1 hr later) → hydrocortisone → cooling + treat precipitant. ICU.

The painful thyroid stem: 35-year-old with neck pain after URI, tender goiter, elevated ESR, suppressed TSH, low RAIU. → Subacute thyroiditis — NSAIDs ± prednisone, beta-blocker, no thionamide.

The factitious stem: Weight-loss seeker, thyrotoxic, low RAIU, low thyroglobulin, no goiter. → Exogenous thyroid hormone. Discontinue source, address underlying motivation.

The amiodarone stem: Patient on amiodarone develops thyrotoxicosis. Doppler high vascularity = type 1 → MMI; low vascularity = type 2 → prednisone; mixed → both.

The post-RAI orbitopathy stem: Graves patient with mild eye disease receives RAI without steroid cover and orbitopathy worsens. → Counsel smoking cessation, start prednisone, consider teprotumumab.

The TSHoma stem: Elevated free T4 + non-suppressed TSH + visual field defect → pituitary MRI, alpha-subunit.

One-Line Recap

Hyperthyroidism workup begins with a suppressed TSH and elevated T4/T3, etiology is then resolved by TRAb and RAI uptake/scan (high uptake = Graves/TMNG/adenoma → treat with thionamide, RAI, or surgery; low uptake = thyroiditis/factitious → supportive care), with beta-blockers for symptom control, special handling in pregnancy (PTU 1st trimester, MMI thereafter, never RAI), and lifelong follow-up for the expected hypothyroidism after definitive therapy.

Diagnostic engine: TSH → free T4/T3 → TRAb ± RAIU. RAIU high vs low is the master fork that partitions the entire differential.

Three Graves treatment options — patient-centered choice: ATD (12–18 months, ~50% remission, preferred in mild disease, active orbitopathy, pregnancy), RAI (definitive, contraindicated in pregnancy and active moderate-severe orbitopathy), surgery (definitive, best for large goiter, malignancy concern, severe orbitopathy, ATD failure in pregnancy).

Don't-miss pearls: stop thionamide for fever/sore throat (agranulocytosis); PTU only in 1st-trimester pregnancy and thyroid storm; iodine after thionamide in storm (never before); pre-treat elderly/cardiac patients to euthyroidism before RAI; smoking cessation is the single most modifiable factor for orbitopathy; check TSH in every new AF.

Longitudinal Step 3 thinking: anticipate and treat lifelong hypothyroidism after RAI/surgery; structured TSH follow-up every 4–6 weeks during titration then every 6–12 months on stable replacement; pregnancy requires immediate ~30% levothyroxine dose increase; bone, eye, and cardiovascular surveillance are part of comprehensive long-term care.