Marked Hypoleptinemia precedes Overt Fat Loss in Immune Checkpoint Inhibitor-induced Acquired Generalized Lipodystrophy

Abstract

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> The development of immune checkpoint inhibitors (ICIs) targeting cancer cells that evade immune T-cell regulation has revolutionized the treatment of metastatic carcinomas. Unfortunately, secondary endocrinopathies associated with ICI use, including adrenal insufficiency, primary hypothyroidism, autoimmune diabetes, and rarely hypoparathyroidism, are increasing. Lipodystrophy, presumably due to autoimmune destruction of adipocytes, leading to metabolic complications is a less well recognized adverse effect of ICI therapy. <h3>Objective/Purpose</h3> To report the clinical features and evolution of Acquired Generalized Lipodystrophy (AGL) in a patient on ICI therapy. <h3>Methods</h3> Case Report: A 66-year-old woman with metastatic lung adenocarcinoma was started on combination chemo/immunotherapy with programmed cell death-1 (PD-1) inhibitor- pembrolizumab after surgical resection of cerebellar mass and radiation. She had good tumor response but developed primary hypothyroidism and secondary adrenal insufficiency approximately ten months after initiation of ICI. <h3>Results</h3> Approximately 15 months following the treatment, she developed new-onset insulin requiring diabetes mellitus but without autoantibodies associated with type 1 diabetes. At that time, she was also noted to have hypertriglyceridemia (436 mg/dL), and elevated liver enzymes (3-4 X ULN), and a subsequent liver biopsy revealed severe macrovesicular steatosis. Her BMI was 30 kg/m2 and she had mild loss of buccal fat. Skin fold thickness measurements over the trunk and limbs were in the normal range. However, she had an undetectable serum leptin level and whole body fluorodeoxyglucose (FDG)- positron emission tomography (PET) scan, obtained for cancer surveillance, showed mild diffuse FDG activity throughout the subcutaneous tissues. She was advised low fat diet and started on insulin therapy. Over the next three months, she lost about 20 kg weight with generalized loss of subcutaneous fat from face, trunk, and extremities. Pioglitazone was started but discontinued after 4 weeks due to pedal edema and no effect on fat loss. Despite generalized lipodystrophy, she has maintained good glucose control on moderate dose insulin therapy (0.6 â€" 0.8 units/kg) and with normalization of liver enzymes and serum triglycerides. <h3>Conclusions</h3> ICI therapy can be associated with AGL, and the diagnosis must be considered in patients who develop metabolic complications such as diabetes, dyslipidemia, or steatohepatitis. Interestingly, metabolic abnormalities may precede overt fat loss. Hypoleptinemia and diffuse FDG uptake of subcutaneous tissue suggest subclinical panniculitis and adipocyte dysfunction even before clinically evident lipodystrophy.