Hyperthyroidism / Graves' Disease
Graves' = most common cause of hyperthyroidism. TSI-mediated thyroid stimulation. Treatment: thionamides, RAI, or surgery. Know when each is preferred.
🔍 Overview
Overview
Hyperthyroidism = excessive thyroid hormone production/release. Causes: Graves' disease (70-80% -autoimmune, TSI stimulates TSH receptor), toxic multinodular goiter (elderly, autonomous nodules), toxic adenoma (single hot nodule), thyroiditis (subacute/painless -transient release of preformed hormone, NOT overproduction), exogenous thyroid hormone, iodine-induced (Jod-Basedow). Graves' has unique extra-thyroidal features: Graves' ophthalmopathy (proptosis, lid lag, diplopia -25-50%), pretibial myxedema (localized dermopathy), thyroid acropachy (digital clubbing). Symptoms: anxiety, tremor, weight loss, heat intolerance, palpitations (AF in 10-15%), diarrhea, menstrual irregularity, hyperreflexia.
🧪 Workup
Workup
- TSH -suppressed (< 0.1 mIU/L). Most sensitive initial test.
- Free T4 + Free T3 -both elevated in overt hyperthyroidism. T3 thyrotoxicosis: suppressed TSH + normal FT4 + elevated FT3 (early Graves' or toxic nodule).
- TSI (thyroid-stimulating immunoglobulins) or TRAb (TSH receptor antibodies) -positive in Graves'. Specific. Can be used to confirm diagnosis without RAIU in pregnancy or when RAIU unavailable.
- Radioactive iodine uptake (RAIU) -differentiates causes:
- Diffusely elevated = Graves'
- Focal hot nodule (suppressed rest) = toxic adenoma
- Patchy = toxic multinodular goiter
- Low/absent uptake = thyroiditis (preformed hormone release, not production), exogenous, or iodine excess
- ESR/CRP -elevated in subacute (de Quervain) thyroiditis (painful + elevated inflammatory markers)
- CBC -baseline before starting thionamides (agranulocytosis risk)
- LFTs -baseline before thionamides (PTU → hepatotoxicity)
- ECG -atrial fibrillation (10-15% of hyperthyroid patients). Often rate-controlled with beta-blockers alone.
- Thyroid ultrasound -if nodule palpated or RAIU shows focal uptake. Evaluate for suspicious features.
🚨 Management
Management
- Beta-blocker (ALL patients, symptom control): Propranolol 20-40 mg TID-QID (preferred -also blocks T4→T3 conversion) or atenolol 50-100 mg daily. Continue until euthyroid.
- Graves' disease -3 treatment options:
- Thionamide for 12-18 months -methimazole 10-30 mg daily is first-line (once-daily dosing, more potent, fewer serious adverse effects). PTU 100-200 mg TID only for first-trimester pregnancy, thyroid storm, or methimazole allergy, because PTU carries a risk of fulminant hepatic failure. Remission after a full course is roughly 30-50%, and is most likely with mild disease, a small goiter and a low TRAb titer, so check TRAb before stopping to predict relapse. Warn every patient that fever or sore throat means stop the drug and get an urgent white cell count -agranulocytosis occurs in 0.2-0.5% and routine monitoring does not predict it.
- Radioactive iodine (I-131) -definitive, simple and outpatient. Permanent hypothyroidism is the expected outcome, not a complication, so plan levothyroxine replacement and check thyroid function at 6-8 weeks. Avoid in pregnancy and breastfeeding (fetal thyroid ablation) and in moderate-to-severe orbitopathy, which it can worsen; if it must be used, give steroid cover.
- Surgery (near-total thyroidectomy) -for a large compressive goiter, suspected malignancy, severe orbitopathy, or pregnancy where drugs fail. Fastest and most certain control. Render euthyroid first and give SSKI for 7-10 days pre-op to reduce gland vascularity and bleeding. Risks are recurrent laryngeal nerve injury and hypoparathyroidism, so check calcium post-operatively.
- Thyroiditis: Self-limited (4-8 weeks). Beta-blockers only. NSAIDs or prednisone for pain (subacute). Thionamides are USELESS (no new hormone being made -just release of preformed).
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Methimazole (Tapazole) | 10-30 mg daily → titrate | PO | First-line thionamide. Once daily dosing. Agranulocytosis (0.2-0.5%) -check CBC if fever/sore throat. Teratogenic in 1st trimester. ATA, 2016 |
| PTU (propylthiouracil) | 100-200 mg TID | PO | ONLY for: 1st trimester pregnancy, thyroid storm, methimazole allergy. TID dosing. FDA black box: severe hepatotoxicity (fulminant liver failure). Also blocks T4→T3. |
| Propranolol | 20-40 mg TID-QID | PO | Symptom control. Also blocks peripheral T4→T3 conversion. Use in ALL hyperthyroid patients. |
| Radioactive iodine (I-131) | Per nuclear medicine calculation | PO | Definitive. Causes permanent hypothyroidism (expected outcome). Avoid pregnancy × 6 months after. Worsen ophthalmopathy → prednisone cover. |
| SSKI (saturated KI) | 1-2 drops TID | PO | Wolff-Chaikoff effect -acute iodine load transiently blocks thyroid hormone release. Pre-op preparation for thyroidectomy. Give AFTER thionamide established. |
| Cholestyramine | 4g TID | PO | Adjunct -binds thyroid hormone in gut, reduces enterohepatic recirculation. Used in severe thyrotoxicosis. |
🏥 Rounds
Pimp Questions
❓ Why is methimazole preferred over PTU?
Methimazole advantages: once-daily dosing (vs TID for PTU), lower hepatotoxicity risk, more consistent pharmacokinetics, no FDA black box warning. PTU is preferred ONLY in: (1) first trimester pregnancy (methimazole causes aplasia cutis + choanal atresia), (2) thyroid storm (PTU also blocks T4→T3 conversion), (3) methimazole allergy/intolerance. After first trimester, switch back to methimazole. ATA, 2016
❓ How does RAIU differentiate causes of thyrotoxicosis?
High uptake (diffuse) = Graves'. High uptake (focal) = toxic adenoma or toxic MNG. Low/absent uptake = thyroiditis (preformed hormone leaking from damaged gland -no new synthesis), exogenous thyroid hormone, or iodine excess. This is the key test because treatment differs fundamentally: thionamides work for Graves'/toxic nodules (blocking new synthesis) but are useless in thyroiditis (nothing being synthesized).
❓ Why can RAI worsen Graves' ophthalmopathy?
RAI-induced thyroid destruction releases thyroid antigens that cross-react with orbital tissue (TSH receptor is expressed in orbital fibroblasts). This triggers an immune flare targeting the orbits → worsening inflammation, proptosis, diplopia. Risk is highest in smokers and those with pre-existing active ophthalmopathy. Prevention: prednisone 0.3-0.5 mg/kg starting the day of RAI × 4-6 weeks taper in moderate-risk patients. Avoid RAI entirely in moderate-severe active ophthalmopathy.
❓ What is the most feared side effect of thionamides and how do you screen for it?
Agranulocytosis (ANC < 500) -incidence 0.2-0.5%, usually within first 90 days. Can be fatal if not recognized. DO NOT do routine CBC monitoring (too insensitive, can develop rapidly between checks). Instead: educate the patient to present immediately for fever, sore throat, or mouth sores → get STAT CBC. If ANC < 500 → stop thionamide permanently, admit, broad-spectrum antibiotics, G-CSF, switch to non-thionamide therapy (RAI or surgery).
❓ How do you manage hyperthyroidism in pregnancy?
First trimester: PTU (methimazole is teratogenic). Second/third trimester: switch to methimazole (PTU hepatotoxicity risk). Use the lowest effective dose -aim for FT4 at upper limit of normal (mild maternal hyperthyroidism is safer than fetal hypothyroidism from overtreatment). RAI is absolutely contraindicated in pregnancy (ablates fetal thyroid). Check TSI/TRAb in third trimester -if elevated, neonatal hyperthyroidism possible. ATA, 2016
Sample Presentation
Ms. Patel is a 32-year-old woman with 3 months of 15 lb weight loss despite increased appetite, palpitations, tremor, anxiety, and heat intolerance. Exam: HR 108, diffusely enlarged thyroid with bruit, lid lag, mild proptosis bilateral, fine tremor. Labs: TSH < 0.01, FT4 4.8 (elevated), FT3 12 (elevated), TSI positive. RAIU: diffusely elevated at 65% (normal 10-30%).
Key Points: Classic Graves' disease -suppressed TSH, elevated FT4/FT3, positive TSI, diffusely elevated RAIU. Start propranolol for symptoms. Discuss 3 treatment options. Methimazole 20 mg daily for 12-18 month trial is reasonable first-line (32-year-old who may want pregnancy). Check CBC + LFTs baseline. Ophthalmology referral for proptosis.
- TFTs (TSH + FT4) q4-6 weeks during thionamide titration. TSH may remain suppressed for months -use FT4 to guide dose adjustments initially.
- CBC -if fever or sore throat on thionamides (agranulocytosis: ANC < 500). Get STAT CBC. Incidence 0.2-0.5%, usually within first 90 days.
- LFTs -baseline + periodic on PTU. Discontinue if transaminases > 3× ULN. PTU hepatotoxicity can be fulminant.
- TSI/TRAb -if monitoring for remission after thionamide trial. Persistently elevated = high relapse risk. Check before stopping thionamide at 12-18 months.
- Post-RAI: TFTs q4-6 weeks × 6 months. Hypothyroidism typically develops by 6-12 weeks. Start levothyroxine when TSH rises.
- Post-thyroidectomy: Check calcium q6h × 48h (hypoparathyroidism risk). Start levothyroxine. Check TSH at 6 weeks.
- Ophthalmopathy assessment -active inflammation = orbital CT/MRI, refer ophthalmology. IV methylprednisolone for moderate-severe active orbitopathy [EUGOGO].
📋 Summary
Summary
Confirm the Diagnosis Before Treating
Suppressed TSH with a raised free T4 (and free T3, since T3-predominant disease exists). Graves disease is the commonest cause and is driven by thyroid-stimulating immunoglobulin. Diffuse goiter, orbitopathy and pretibial myxedema make it clinical; otherwise check TSI or TRAb.
Separate Hyperthyroidism From Thyroiditis
Radioactive iodine uptake distinguishes them and it changes the entire treatment. High, diffuse uptake = Graves, the gland is making hormone. Low uptake = thyroiditis or exogenous hormone, the gland is leaking preformed hormone. Thionamides do nothing in thyroiditis, which is self-limited and treated with beta blockade and NSAIDs.
Beta Blockade for Everyone Symptomatic
Propranolol 20 to 40 mg TID to QID. It controls tremor, tachycardia and anxiety immediately, and at higher doses it also blocks peripheral conversion of T4 to T3. It is the fastest-acting part of the regimen, since thionamides take weeks.
Methimazole Is First Line, With Two Exceptions
Methimazole 10 to 30 mg daily, once-daily dosing, fewer side effects and more potent. Use propylthiouracil only in the first trimester of pregnancy, in thyroid storm, and in methimazole allergy: methimazole is teratogenic (aplasia cutis, choanal atresia) in early pregnancy, and PTU blocks peripheral conversion which helps in storm. PTU otherwise carries a risk of fulminant hepatic failure, which is why it is no longer the default.
Warn About Agranulocytosis Explicitly
Agranulocytosis occurs in 0.2 to 0.5% and it presents as fever and sore throat. Tell the patient to stop the drug and get an urgent white cell count if that happens; treating it as a viral pharyngitis is how these patients die. Routine serial counts do not predict it, so the instruction matters more than the monitoring.
Choose the Definitive Treatment
Radioactive iodine is definitive and simple, and permanent hypothyroidism is the expected outcome, not a complication. Avoid it in pregnancy, breastfeeding and moderate to severe orbitopathy, which it can worsen. Surgery for a large compressive goiter, suspected malignancy, severe orbitopathy or pregnancy where drugs fail. Continued thionamide therapy for 12 to 18 months gives remission in a minority, mostly those with small goiters and low antibody titers.
Orbitopathy Runs Its Own Course
It does not track the thyroid function tests and it does not resolve when the biochemistry is corrected. Smoking is the strongest modifiable risk factor, so cessation is a therapeutic intervention here. Severe active disease is treated with IV steroids or teprotumumab; radioactive iodine can be given with steroid cover if it must be used.
Do Not Miss Storm
Fever, tachycardia out of proportion, agitation or delirium, heart failure and GI symptoms in a hyperthyroid patient. Order is essential: thionamide first, then iodine at least 1 hour later, because giving iodine first supplies substrate for hormone synthesis. Add a beta blocker, steroids, and treat the precipitant, usually infection or surgery.
📄 One Pager
Text version
One-Pager
Hyperthyroidism
Graves', Toxic Nodule, Thyroiditis
RAIU Pattern
Diffuse high = Graves'. Focal hot = toxic adenoma. Patchy = MNG. Low = thyroiditis/exogenous/iodine.
Treatment Choice
Methimazole first-line (12-18 mo). RAI if definitive needed (causes hypothyroidism). Surgery for large goiter/nodule/ophthalmopathy. Thyroiditis: beta-blockers only.
Trials
ATA Hyperthyroidism Guidelines 2016 · EUGOGO (ophthalmopathy management)
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