Ciara Maye Andal Morales, MD: No financial relationships to disclose
Case Summary A 63-year-old Filipino male physician with stage II clear cell renal cell carcinoma underwent left nephrectomy in May 2023 and began adjuvant pembrolizumab in July 2023. Baseline laboratory evaluation, including thyroid function tests, was normal. After the sixth cycle in January 2024, he developed overt primary hypothyroidism (TSH 72.06 uIU/mL) and was started on levothyroxine 150 mcg daily; however, TSH levels remained persistently elevated.
Prior to his 13th pembrolizumab cycle in May 2024, he reported progressive weakness, arthralgia, and poor appetite. Vital signs and physical examination were unremarkable. Laboratory studies showed normal sodium (138 meq/L) and potassium (4.02 meq/L), elevated TSH (12.513 uIU/mL) with normal FT4 (14.32 pmol/L), and a markedly low morning cortisol ( < 2.21 nmol/L) with inappropriately low ACTH (1.75 pmol/L). Cosyntropin stimulation testing confirmed secondary adrenal insufficiency, with an inadequate cortisol response (17.93nmol/L at baseline; 66.49nmol/L at 30 minutes).
He was started on physiologic glucocorticoid replacement with prednisone 5 mg in the morning and 2.5 mg in the evening, while levothyroxine was continued at the same dose. His symptoms improved, and on follow-up, TSH levels normalized allowing continuation of pembrolizumab.
Discussion Pembrolizumab, a PD-1 inhibitor, may disrupt immune tolerance and trigger autoimmune injury of endocrine organs. Thyroid dysfunction is the most common immune-related adverse events and was the earliest manifestation in this patient. Persistently elevated TSH despite normalized FT4, combined with worsening systemic symptoms, raised concern for an additional endocrinopathy. This case highlights the principle that adrenal insufficiency must be excluded before adjusting thyroid hormone therapy, as cortisol deficiency can contribute to inappropriate TSH elevation and unrecognized adrenal insufficiency may precipitate adrenal crisis.
The combination of low cortisol, suppressed ACTH, normal electrolytes, and inadequate cosyntropin response alongside with patient’s clinical symptoms supports a diagnosis of secondary adrenal insufficiency from isolated ACTH deficiency. This presentation is a recognized immune-related adverse effect of PD-1 inhibitors resulting from immune-mediated pituitary dysfunction (hypophysitis) that may selectively impair corticotroph function. Endocrine irAEs are generally manageable with hormone replacement and rarely require discontinuation of immunotherapy
In conclusion, this case highlights the need for continued vigilance for multiple endocrine irAEs in patients receiving ICIs. Early recognition and appropriate hormone replacement prevent serious complications and allow uninterrupted, life-saving cancer therapy.
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