Endocrine Abstracts

Background: Immune-Checkpoint-Inhibitors (ICIs) are novel, ground-breaking cancer agents that mediate T-cell activation via targeting surface “check-point” proteins. An undesirable side-effect is autoimmunity against native tissues, with endocrine organs being affected in 10% of patients receiving this treatment. ICIs can trigger abrupt-onset autoimmune diabetes, typically within 6–25 weeks of treatment initiation, although this remains uncommon (≤1%). Many patients present with Diabetic Ketoacidosis (DKA) (59–86%) and pancreatic autoantibodies may be absent (50%). Early recognition is important due to the severity of the metabolic disturbance.

Case: A 41-year-old man with renal-cell carcinoma received adjuvant pembrolizumab following a left nephrectomy. Within weeks, he presented with osmotic symptoms and hyperglycaemia, leading to a diagnosis of severe DKA and immune-mediated diabetes secondary to pembrolizumab. There was no previous history of diabetes. Standard diabetes autoantibodies, commonly present in Type-1 Diabetes (T1DM), were negative. He was managed as per standard DKA treatment protocol and was established on a basal-bolus insulin regimen.

Discussion: ICIs utilise the innate immune system to identify and attack cancer cells by activating CD8+ T-cells. Endocrine organs can be involved, with the thyroid and pituitary being the commonest and the adrenals and pancreas the least common. PD-1 inhibitors are the most prevalent in reported cases of ICI-induced diabetes. PD-1 is expressed on effector T-cells in peripheral tissues and dampens their activation against self-antigens. PD-L1 is expressed in islet cells and PD-1 expression is reduced in T-cells of patients with T1DM. HLA-DR4 is the commonest genotype in ICI-induced diabetes. Approximately 50% of patients are positive for ≥1 autoantibody, and most have a raised HbA1c on presentation with acute hyperglycaemia. Guidelines (ESMO 2022) suggest random glucose monitoring before each immunotherapy cycle, but real-world data indicate this is not always implemented, highlighting the need to maintain a high index of suspicion for new hyperglycaemia during immunotherapy.