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irAEMost common endocrineICD-10 E05 / E03

ICI-related thyroid dysfunction

Immune-checkpoint inhibitor thyroiditis · ICI thyroid irAE

Thyroid dysfunction is the most common endocrine immune-related adverse event of immune-checkpoint inhibitors (ICIs), affecting 5-20% of patients on anti-PD-1 monotherapy and up to 30% on combination ICI. The classical course is biphasic — transient destructive thyrotoxicosis (weeks to ~6-8 weeks) followed by primary hypothyroidism, which is usually permanent. ESMO immune-toxicity guidance and endocrine irAE literature underpin structured TFT monitoring. Most patients can continue ICI with thyroid hormone replacement.

CurrentLast reviewed 16 May 2026

Epidemiology

  • Most common endocrine irAE.
  • Incidence:
    • Anti-PD-1 monotherapy (pembrolizumab, nivolumab, cemiplimab): 5-20%.
    • Anti-CTLA-4 monotherapy (ipilimumab): <5%.
    • Combination anti-PD-1 + anti-CTLA-4: 15-30%.
  • Onset: 2-12 weeks (median ~6 weeks).
  • Higher risk: female, pre-existing thyroid autoantibodies (TPO / Tg), Hashimoto / Graves history.

Clinical phenotypes

  • Destructive thyroiditis / transient thyrotoxicosis:
    • Suppressed TSH, raised T4 / T3.
    • Symptoms: palpitations, tremor, weight loss, heat intolerance, anxiety.
    • Lasts 4-8 weeks.
    • Anti-thyroid antibodies usually negative; technetium / iodine uptake low.
  • Primary hypothyroidism:
    • Raised TSH, low or normal T4.
    • Symptoms: fatigue, cold intolerance, constipation, weight gain, depression, dry skin.
    • Usually permanent (~80-90%); persists after ICI discontinuation.
    • Antibodies (TPO, Tg) may be positive.
  • Graves-like disease: rare; persistent hyperthyroidism with TSH-receptor antibodies, ophthalmopathy.
  • Thyroid storm / myxoedema coma: very rare but reported emergencies.

Monitoring and grading

  • Baseline: TSH, T4, T3 before ICI start; consider TPO antibodies.
  • On-treatment: TSH + T4 every 4-6 weeks for first 6 months; then every 12 weeks.
  • Continue beyond ICI cessation as late-onset reported.
  • CTCAE grading:
    • G1: asymptomatic / mild; biochemical only.
    • G2: moderate; symptomatic; ADL preserved.
    • G3: severe; limits ADLs; hospitalisation.
    • G4: life-threatening (thyroid storm / myxoedema coma).

Management

  • Thyrotoxic phase:
    • Usually self-limiting; symptomatic management.
    • Beta-blocker (propranolol 20-40 mg TDS / atenolol) for symptom control.
    • Anti-thyroid drugs (carbimazole) rarely needed; reserve for persistent hyperthyroidism with raised uptake (true Graves-like).
    • Continue ICI.
  • Hypothyroidism:
    • Levothyroxine 1.6 µg/kg/day starting dose (lower in elderly / cardiac).
    • Titrate to TSH 0.5-2.5 mIU/L every 6-8 weeks.
    • Continue ICI.
    • Most patients require lifelong replacement.
  • Hold ICI: rarely required for thyroid irAE alone; reserve for thyroid storm / myxoedema (G4).
  • Steroids: not routinely indicated for thyroid irAE; reserved for thyroid eye disease.
  • Endocrinology referral for atypical / G3+ / persistent hyperthyroidism.
  • Counsel: ICI rechallenge can usually proceed once euthyroid; permanent hypothyroidism does not contraindicate further treatment.

References

  1. Haanen J et al. ESMO Clinical Practice Guideline for immune-related adverse events. Ann Oncol. 2022;33:1217-1238.
  2. Brahmer JR et al. NCCN guidelines on management of immunotherapy-related toxicities. J Natl Compr Canc Netw. 2024;22:e1-e60.
  3. de Filette J et al. Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019;181:363-374.
  4. Percik R, Criseno S, Adam S, Young K, Morganstein DL. Diagnostic criteria and proposed management of immune-related endocrinopathies following immune checkpoint inhibitor therapy for cancer. Endocr Connect. 2023;12(5):e220513.
  5. NICE TA766 / TA837. Pembrolizumab — adjuvant melanoma indications. London: NICE; 2022 / 2023.

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