Case Presentation: We present a 31-year-old female patient with a medical history significant for Stage II Breast cancer on Chemo and Immunotherapy (Pembrolizumab) who presents to the Emergency Department for the evaluation of nausea, vomiting, and generalized abdominal pain for 1 day. On arrival, the vital signs were within normal limits. On physical examination, generalized abdominal tenderness was noted without any evidence of rebound tenderness. Laboratory studies showed a blood glucose level of 356 mg/dl; reference range 70-110 mg/dl, elevated Anion gap (18 meq/L; reference range 8-16 meq/L), and beta-hydroxybutyrate (46mg/dl; reference range 1-4.16mg/dl). The patient was treated for diabetic ketoacidosis (DKA) with insulin. Further testing revealed low C-peptide levels (< 0.10 ng/ml reference range 0.8-3.85 ng/ml) along with elevated thyroid peroxidase levels (38 IU/L; reference range < 9), HgbA1C (7.1 % reference range 4.5-6.4 %), and TSH levels (36 mcIU/ml reference range 1-4.16 mcIU/ml) eventually leading to a diagnosis of type one diabetes mellitus and Hypothyroidism. Immunotherapy was held after the diagnosis and the patient was discharged home on Insulin and Levothyroxine with close outpatient follow-up. The patient endorsed increased fatigue for the past few weeks on regular outpatient follow-ups. Cortisol level was sent which came out to be very low (< 0.5 mcg/dl reference range 1-75.0 mcg/dl). The patient was eventually started on oral Hydrocortisone with significant improvement in symptoms.
Discussion: Immune Checkpoint inhibitors (ICIs) such as nivolumab, pembrolizumab, and Ipilimumab are monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. Due to its anti-cancer properties, it has been approved for the treatment of numerous cancer types. Agents targeting PD1 such as pembrolizumab have shown widespread efficacy in the recent past and their response rates range from 15-90% depending upon the cancer type. The increased immune responses induced by these agents can result in immune-related adverse events (irAEs) that vary from mild to fatal endocrine toxicities including Hypothyroidism, Hypophysitis, Adrenal Insufficiency, and Pancreatic insufficiency resulting in Type 1 Diabetes Mellitus (DM). In about 50% of cases, the irAEs are irreversible. Data from clinical trials of immune checkpoint inhibitors confirm hypothyroidism/hyperthyroidism and hypophysitis as the most frequently occurring endocrinopathies. Adrenal insufficiency is a very rare side effect of pembrolizumab. Our patient developed polyendocrinopathy, including type 1 diabetes mellitus, thyroiditis, and adrenal insufficiency. The interesting point is that our patient developed adrenal insufficiency a few weeks after we stopped pembrolizumab, which suggests that there might be persistent effects.
Conclusions: From our case presentation, we conclude that Endocrine adverse events must be sought even after discontinuation of immunotherapy. Although it is difficult to predict which patients are at increased risk for the side effects, it seems important to closely monitor those patients who have already had an endocrine-related adverse event.