In a patient receiving checkpoint inhibitor immunotherapy (e.g., pembrolizumab, nivolumab, ipilimumab, atezolizumab) who develops thyroiditis with an initial thyrotoxic phase followed by hypothyroidism, what are the recommended baseline and serial thyroid function monitoring, first‑line treatment for the thyrotoxic and hypothyroid phases, criteria for holding or continuing immunotherapy, and when should endocrinology referral be considered?

Management of Checkpoint Inhibitor-Induced Thyroiditis

Baseline and Serial Thyroid Monitoring

All patients starting checkpoint inhibitor therapy require baseline TSH and free T4 measurement before the first dose, followed by TSH and free T4 testing before each treatment cycle. 1

• Measure TSH and free T4 at baseline (before starting immunotherapy) to establish a reference point 1
• Repeat TSH and free T4 before each treatment cycle during the first 6 months 1
• After 6 months, continue monitoring every 3 months for an additional 6 months, then every 6 months for 1 year 1
• For patients on anti-PD-1/PD-L1 monotherapy, check TSH (with optional free T4) every 4–6 weeks as part of routine monitoring 1
• More frequent monitoring (every 2–3 weeks) is warranted once thyroid dysfunction is detected to catch the transition from thyrotoxicosis to hypothyroidism 1

The rationale for this intensive monitoring is that thyroid dysfunction occurs in 6–20% of patients on anti-PD-1/PD-L1 therapy and up to 20% with combination ipilimumab/nivolumab, with thyrotoxicosis typically appearing within 1 month (median 5.3 weeks) after starting therapy. 1, 2

Management of the Thyrotoxic Phase

For the initial thyrotoxic phase, conservative management with symptom control is sufficient—corticosteroids are NOT required and do not shorten the duration of thyrotoxicosis. 1

Grade 1 (Asymptomatic or Mild Symptoms)

• Continue checkpoint inhibitor therapy without interruption 1
• Monitor TSH and free T4 every 2–3 weeks to detect transition to hypothyroidism 1
• Most patients (67%) remain asymptomatic during thyrotoxicosis 2

Grade 2 (Moderate Symptoms—Palpitations, Tremor, Heat Intolerance)

• Consider holding checkpoint inhibitor therapy until symptoms return to baseline 1
• Initiate non-selective beta-blocker (propranolol or atenolol) for symptomatic relief 1
• Provide hydration and supportive care 1
• Consider endocrinology consultation 1
• Do NOT use corticosteroids—they are ineffective for checkpoint inhibitor-induced thyroiditis 1

Grade 3–4 (Severe Symptoms or Thyroid Storm)

• Hold checkpoint inhibitor therapy until symptoms resolve to baseline 1
• Hospitalize the patient immediately 1
• Initiate beta-blocker (propranolol or atenolol) for symptomatic control 1
• For severe symptoms or concern for thyroid storm, initiate prednisone 1–2 mg/kg/day or equivalent, tapered over 1–2 weeks 1
• Consider SSKI (saturated solution of potassium iodide) or thionamide (methimazole or PTU) for severe cases 1
• Obtain endocrinology consultation 1

Distinguishing Thyroiditis from Graves' Disease

Additional testing is needed only if Graves' disease is suspected (persistent hyperthyroidism >6 weeks, ophthalmopathy, or thyroid bruit): 1

• Measure TSH receptor antibodies (TRAb) or thyroid-stimulating immunoglobulin (TSI) 1
• Measure thyroid peroxidase (TPO) antibodies 1
• Obtain radioactive iodine uptake scan (RAIUS) or Technetium-99m pertechnetate thyroid scan if recent iodinated contrast was used 1
• Thyroiditis shows low/absent uptake; Graves' disease shows increased uptake 1
• If Graves' disease is confirmed, refer to endocrinology and consider thionamide therapy (methimazole or PTU) 1

The thyrotoxic phase is self-limiting and lasts a median of 6 weeks (range 2.6–39.7 weeks), followed by progression to hypothyroidism in 84% of patients. 2

Management of the Hypothyroid Phase

Hypothyroidism develops at a median of 10.4 weeks after starting checkpoint inhibitor therapy (range 3.4–48.7 weeks) and typically requires lifelong levothyroxine replacement. 2

Initiating Levothyroxine Therapy

• Start levothyroxine immediately when TSH becomes elevated with low or low-normal free T4 1
• For patients <70 years without cardiac disease, initiate levothyroxine at approximately 1.6 mcg/kg/day 1
• For patients >70 years or with cardiac disease/multiple comorbidities, start with 25–50 mcg/day and titrate gradually 1
• CRITICAL: Before starting levothyroxine, rule out concurrent adrenal insufficiency (especially in suspected hypophysitis), as thyroid hormone can precipitate adrenal crisis—if adrenal insufficiency is present, start corticosteroids at least 1 week before levothyroxine 1

Monitoring and Dose Adjustment

• Recheck TSH and free T4 every 6–8 weeks while titrating levothyroxine to achieve target TSH of 0.5–4.5 mIU/L 1
• Adjust levothyroxine dose by 12.5–25 mcg increments based on TSH response 1
• Once TSH is stable in the target range, monitor every 6–12 months or if symptoms change 1

Most patients (84%) who develop hypothyroidism after checkpoint inhibitor-induced thyroiditis require permanent levothyroxine replacement, though 16% may recover thyroid function spontaneously. 2

Criteria for Holding or Continuing Immunotherapy

Checkpoint inhibitor therapy can be continued in most cases of thyroid dysfunction, as thyroiditis rarely requires treatment interruption. 1

Continue Immunotherapy:

• Grade 1 thyrotoxicosis (asymptomatic or mild symptoms)—continue without interruption 1
• Any grade of hypothyroidism—continue immunotherapy while initiating levothyroxine replacement 1
• Thyroid dysfunction is managed with supportive care and hormone replacement, not by stopping cancer therapy 1

Consider Holding Immunotherapy:

• Grade 2 thyrotoxicosis (moderate symptoms)—consider holding until symptoms return to baseline 1
• Grade 3–4 thyrotoxicosis (severe symptoms or thyroid storm)—hold until symptoms resolve to baseline with appropriate therapy 1

Resume Immunotherapy:

• Once thyrotoxic symptoms are controlled with beta-blockers or resolve spontaneously 1
• Hypothyroidism on stable levothyroxine replacement is NOT a contraindication to continuing immunotherapy 1

High-dose corticosteroids are rarely required for thyroid dysfunction, unlike other immune-related adverse events, so immunotherapy interruption is uncommon. 1

When to Refer to Endocrinology

Endocrinology consultation is recommended in ALL cases of suspected or confirmed hypophysitis, primary hypothyroidism, hyperthyroidism, thyroiditis, and type 1 diabetes mellitus. 1

Mandatory Endocrinology Referral:

• All cases of suspected or confirmed thyroiditis (both thyrotoxic and hypothyroid phases) 1
• Grade 2 thyrotoxicosis (moderate symptoms)—consider endocrinology consultation 1
• Grade 3–4 thyrotoxicosis (severe symptoms)—obtain endocrinology consultation 1
• Persistent hyperthyroidism >6 weeks or clinical suspicion of Graves' disease 1
• Suspected hypophysitis (low TSH with low free T4, suggesting central hypothyroidism) 1
• Any patient requiring complex management or unclear diagnosis 1

Timing of Referral:

• Early referral (within days) for Grade 2–4 thyrotoxicosis or suspected hypophysitis 1
• Routine referral (within 1–2 weeks) for Grade 1 thyrotoxicosis or newly diagnosed hypothyroidism 1
• Urgent referral for suspected thyroid storm or severe symptoms 1

Critical Pitfalls to Avoid

Do NOT use corticosteroids for checkpoint inhibitor-induced thyroiditis—they are ineffective and do not shorten the duration of thyrotoxicosis. 1

Do NOT assume thyroid dysfunction is permanent without reassessment—16% of patients recover spontaneously, though most (84%) require lifelong levothyroxine. 2

Do NOT start levothyroxine before ruling out adrenal insufficiency in suspected central hypothyroidism or hypophysitis, as this can precipitate life-threatening adrenal crisis. 1

Do NOT stop checkpoint inhibitor therapy for thyroid dysfunction alone—thyroiditis is managed with supportive care and hormone replacement, allowing cancer therapy to continue. 1

Do NOT miss the transition from thyrotoxicosis to hypothyroidism—monitor TSH and free T4 every 2–3 weeks after thyrotoxicosis is detected to catch this transition early. 1