What is the appropriate workup and management for a patient receiving nivolumab who develops hyperthyroidism?

Nivolumab-Induced Hyperthyroidism: Workup and Management

For patients on nivolumab who develop hyperthyroidism, initiate beta-blockers for symptomatic relief and continue immunotherapy in most cases, as this thyroid dysfunction is typically transient and often precedes hypothyroidism requiring long-term hormone replacement. 1

Understanding the Clinical Pattern

Nivolumab-induced thyroid dysfunction occurs in 5-10% of patients receiving anti-PD-1 monotherapy, with rates increasing to 20% with combination ipilimumab therapy. 1 The hyperthyroid phase is characteristically transient and often precedes hypothyroidism—this biphasic pattern is critical to recognize. 1, 2

Key Temporal Features:

• Hyperthyroidism typically appears earlier (median onset 51 days or approximately 8 weeks after starting nivolumab) 2, 3
• Transition to hypothyroidism occurs rapidly, often within 16-32 days of documented hyperthyroidism 4
• One-third of patients with initial thyrotoxicosis will progress to hypothyroidism 2

Diagnostic Workup

Baseline and Ongoing Monitoring:

• Check TSH and free T4 before every infusion for the first 3 months, then every second cycle thereafter (for 2-weekly schedules) 1
• Measure thyroid antibodies (anti-TPO and anti-thyroglobulin) when thyroid dysfunction is detected—approximately 80% of patients who develop clinically significant thyroid dysfunction will have positive antibodies 1
• Check 9 AM cortisol if TSH is falling across two measurements with normal or low T4, as this may suggest hypophysitis rather than primary thyroid disease 1

High-Risk Features to Identify:

• Pre-existing anti-thyroglobulin antibodies confer a 26.5-fold increased risk of developing thyroid dysfunction 5
• Elevated baseline TSH increases risk 7.4-fold 5
• Patients with thyroid autoimmunity at baseline have a 40% incidence of developing thyroid dysfunction versus 7% without 5

Management Algorithm

For Symptomatic Hyperthyroidism:

Initiate beta-blocker therapy immediately (propranolol or atenolol) for symptom control. 1

• Continue nivolumab in most cases—thyroid dysfunction rarely requires treatment interruption 1
• Withhold nivolumab only if patient is unwell with severe symptomatic hyperthyroidism 1
• Restart nivolumab when symptoms are controlled—among patients who had nivolumab withheld for hyperthyroidism, 73-82% successfully reinitiated therapy 6

Antithyroid Medications—Use Sparingly:

• Carbimazole or methimazole are rarely required (used in only 16-26% of cases) 1, 6
• Consider antithyroid drugs only if anti-TSH receptor antibodies are positive, suggesting true Graves' disease rather than destructive thyroiditis 1
• Steroids are rarely needed (required in only 9-20% of hyperthyroid cases) 1, 6

For Painful Thyroiditis:

Consider prednisolone 0.5 mg/kg with taper if the patient develops painful thyroid inflammation. 1

Anticipating the Transition to Hypothyroidism

Monitor closely for hypothyroidism development, as this is the most common long-term outcome:

• Check TSH every 2-4 weeks after initial hyperthyroidism is detected 4
• Subclinical hyperthyroidism (low TSH, normal free T4) often precedes overt hypothyroidism—this is a warning sign 1
• Hypothyroidism develops in approximately 35-76% of patients after initial thyrotoxicosis 6, 2
• Initiate levothyroxine promptly when TSH becomes elevated, as hypothyroidism is usually permanent and requires lifelong replacement 1

Hypothyroidism Management:

• Start levothyroxine 0.5-1.5 μg/kg (start lower in elderly or those with cardiac history) 1
• Continue immunotherapy—even subclinical hypothyroidism should be treated if fatigue or other symptoms are present, but nivolumab can continue 1
• Long-term hormone replacement is usually required in most patients 1

Critical Pitfalls to Avoid

Don't Mistake Hypophysitis for Primary Thyroid Disease:

A falling TSH across two measurements with normal or lowered T4 suggests pituitary dysfunction, not primary hyperthyroidism. 1 This requires weekly cortisol measurements and different management (corticosteroids, not beta-blockers). 1

Don't Overtreat Transient Thyrotoxicosis:

The hyperthyroid phase is typically self-limited destructive thyroiditis, not Graves' disease. 2, 3 Aggressive antithyroid medication is usually unnecessary and may complicate the transition to hypothyroidism.

Don't Delay Monitoring:

Thyroid dysfunction can evolve rapidly—TSH can rise from normal to >50 mIU/L within 18-28 days. 4 Waiting for symptoms before checking labs risks severe, symptomatic hypothyroidism.

Don't Discontinue Immunotherapy Unnecessarily:

Thyroid dysfunction led to permanent discontinuation in 0% of patients in FDA trials. 6 The development of thyroid dysfunction may actually correlate with better overall survival in some tumor types (particularly NSCLC). 2, 3

Prognostic Implications

The occurrence of immune-related thyroid dysfunction may reflect antitumor efficacy. 7, 2 In patients with NSCLC, nivolumab-induced thyroid dysfunction was associated with better overall survival (HR 0.4,95% CI 0.17-0.94, p=0.035). 2 This suggests that thyroid dysfunction should not be viewed solely as a toxicity but potentially as a biomarker of immune activation.

Special Considerations

Iodine Exposure:

Recent CT contrast can transiently affect thyroid function tests—consider timing of imaging when interpreting results. 1

Unique Presentations:

Hyperthyroidism may present with atypical symptoms such as myalgia with high fever (>39.5°C), which can abruptly worsen quality of life and may require temporary discontinuation of nivolumab. 7