Endocrine Abstracts

Background: Anti-PD-1 immune checkpoint inhibitor, Pembrolizumab, boosts T-cell activity against cancer cells and treats various solid tumours². It can cause immune-related side-effects including multiple endocrinopathies (thyroid dysfunction, hypophysitis, adrenal insufficiency, and immune-mediated type-1-diabetes)¹. The case below demonstrated multiple endocrinological toxicities, with transient gonadal axis dysfunction.

Case: A 57-year-old man, known type-2-diabetes and metastatic renal cell carcinoma developed diabetic ketoacidosis (DKA) two weeks after pembrolizumab. His diabetes has been reclassified as immune-mediated type-1 evidenced by impaired β-cell function: insulinpenia (<7μIU/mL), suppressed C-peptide(<50pmol/l), and positive anti-GAD antibodies. Endocrinology evaluation showed hypogonadotropic hypogonadism, but other anterior pituitary hormones were normal. MRI(Pituitary) showed mild stalk thickening. DKA resolved on insulin therapy. Spontaneous recovery of the gonadal axis was observed in two weeks. Four weeks later, he developed severe diarrhoea with elevated faecal calprotectin (>2000μg/g), endoscopic evidence of immune-mediated mild colitis, prompted pembrolizumab. discontinuation. His symptoms resolved without treatment. Over next two months, he presented with recurrent hypoglycaemia despite reducing insulin doses, and hyponatraemia (Na125mmol/l). His endocrinology evaluation revealed low cortisol (76nmol/l), high TSH (47mIU/l) with undetectable free T4 (<3 .2pmol/l). He was diagnosed as adrenal insufficiency with primary hypothyroidism. Hypoglycaemia resolved with steroid replacement followed by levothyroxine. However, he developed moderate pericardial effusion which also resolved with thyroid hormone optimisation. Repeat tests showed ACTH deficiency (ACTH 3ng/l, cortisol 59nmol/l). He showed good clinical response on Hydrocortisone, levothyroxine, and insulin therapy.

Conclusion: This case illustrates complex and evolving pattern of multisystem immune-related adverse events following pembrolizumab, including new-onset type1 diabetes, immune-mediated colitis, delayed isolated ACTH deficiency, and severe primary hypothyroidism. Despite breadth of toxicity, he achieved good clinical stabilisation with appropriate immunotherapy cessation and targeted hormonal replacement.

References: 1. Wright JJ, et al. Endocrine Toxicities of Immune Checkpoint Inhibitors. Frontiers in Endocrinology. 2. 2022. Castinetti, F., et.al (2022). Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition:An ESE clinical practice guideline.