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Immune checkpoint inhibitor-associated hypopituitarism causing secondary adrenal crisis and central hypothyroi

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HardEndocrine MedicineImmune checkpoint inhibitor-associated hypopituitarism causing secondary adrenal crisis and central hypothyroidismSCE Geriatric Medicine

A 79-year-old man receiving pembrolizumab for metastatic melanoma presents with 3 weeks of anorexia, nausea, profound fatigue and recurrent falls. He is now confused and clammy. His blood pressure is 78/46 mmHg, pulse 96 beats/min and temperature 36.4°C. He has no hyperpigmentation or focal neurological deficit. He has stable coronary artery disease. Blood samples obtained at 08:15 before treatment show: Sodium 121 mmol/L Potassium 4.3 mmol/L Glucose 3.2 mmol/L Cortisol 38 nmol/L ACTH below the reference range Free T4 5.6 pmol/L TSH 1.3 mIU/L Which is the most appropriate immediate endocrine management?

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Correct answer: D — Give intravenous hydrocortisone 100 mg and 1 litre of 0.9% sodium chloride, continue hydrocortisone 200 mg over 24 hours, then introduce levothyroxine 25 micrograms daily after glucocorticoid cover

The hypotension, confusion, hypoglycaemia and profound hyponatraemia indicate adrenal crisis. A very low morning cortisol with suppressed ACTH identifies secondary adrenal insufficiency, while low free T4 with an inappropriately normal TSH indicates central hypothyroidism. In this context, pembrolizumab-associated pituitary dysfunction is the likely unifying diagnosis. Normal potassium and absent hyperpigmentation are consistent with preservation of aldosterone in secondary adrenal insufficiency. Suspected adrenal crisis requires immediate parenteral hydrocortisone and rapid 0.9% sodium chloride administration; treatment must not await dynamic testing or pituitary imaging. Hydrocortisone should then continue at stress dosage. Levothyroxine is required, but glucocorticoid cover must be established first because thyroid hormone increases metabolic demand and cortisol clearance and can precipitate or worsen adrenal crisis. His age and coronary disease favour an initial levothyroxine dose of 25 micrograms. A gives levothyroxine before glucocorticoids and delays life-saving steroid treatment. B correctly treats the crisis initially, but fludrocortisone is not indicated in secondary adrenal insufficiency, and thyroid replacement need not be deferred until discharge. C misclassifies cortisol-deficiency hyponatraemia as SIADH; fluid restriction would worsen his hypovolaemia. D inappropriately delays hydrocortisone for MRI and Synacthen testing and then starts both hormones simultaneously rather than establishing glucocorticoid cover first.

Reference: Adrenal insufficiency: identification and management — Recommendations (Published 28 August 2024; updated October 2025) — https://www.nice.org.uk/guidance/NG243/chapter/recommendations Adrenal insufficiency: identification and management — Context (Published 28 August 2024) — https://www.nice.org.uk/guidance/ng243/chapter/Context Levothyroxine 50 micrograms Tablets — Summary of Product Characteristics (Updated 8 July 2025) — https://www.medicines.org.uk/emc/product/12780/smpc