Abstract
Background: Immune checkpoint inhibitors have become an integral part of oncologic treatment, and their role is rapidly evolving. Nivolumab is an immune checkpoint inhibitor to anti-programmed cell death protein-1 (PD-1), which blocks PD-L1 from binding to PD-1, allowing the T cell to activate. While nivolumab has been shown to improve outcomes in certain malignancies, anti-PD-1 therapy can cause multiple endocrinopathies, including autoimmune diabetes (AD). Case: Here we present a 60-year-old male with a past medical history of end-stage liver disease secondary to hepatitis C and hepatocellular carcinoma (HCC). After undergoing transarterial chemoembolization for HCC, nivolumab was initiated. The patient initially tolerated the immunotherapy well. However, after three cycles, the patient acutely developed nausea, vomiting, lethargy and confusion. On presentation, he was afebrile, blood pressure of 85/46 mmHg, and a heart rate of 92 bpm. Exam was significant for abnormal mentation, and diffuse guarding of the abdomen. Laboratory workup showed hyperglycemia (1,178 mg/dL), positive serum ketones (beta-hydroxybutyrate 11.4 mmol/L), anion gap metabolic acidosis (AG 31, CO2 7 mmol/L), anemia, thrombocytopenia, acute kidney injury, leukocytosis, and elevated lipase. He was admitted to the intensive care unit, and further workup for acute pancreatitis was unrevealing. C-peptide was low (0.8 ng/mL) with corresponding hyperglycemia (1,055 mg/dL). GAD-65, islet cell, and insulin antibodies were undetectable. Hemoglobin A1c was 8.0%. Blood sugars from the previous one and a half years were in normal range. The patient was ultimately diagnosed with DKA and AD secondary to anti-PD-1 therapy. Discussion: This case is representative of AD secondary to nivolumab. While there have been many cases of AD reported after nivolumab, this is the fifth case that has been reported in a patient being treated for HCC. Our patient presented acutely in DKA with no prior diagnosis of diabetes. His antibody testing was undetectable, C-peptide was low in the context of hyperglycemia, and he continued to require insulin therapy until his passing. Prior case reports have demonstrated that the majority of patients with AD related to anti-PD-1 therapy present in DKA, while less than half have detectable diabetes autoantibodies. Specific haplotypes and diabetes autoantibodies have been postulated as risk factors for AD secondary to anti-PD-1 therapy. However, this does not explain the pathology behind a number of patients who have neither of these risk factors. While AD is a rare complication of nivolumab (<1%), this case identifies the need for patients and clinicians to be aware of and discuss the risk of AD after starting nivolumab. Future research is needed to identify risk factors for patients at highest risk of developing AD related to anti-PD-1 therapy and reporting every case encountered is the first step.
Autoimmune Diabetes After Initiation of Nivolumab in a Patient With Hepatocellular Carcinoma