Acute Liver Failure Unmasking XIAP Deficiency in Very Early-Onset Inflammatory Bowel Disease

Introduction X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity with particularly pleiomorphic spectrum of manifestations. These include hemophagocytic lymphohistiocytosis (HLH) with and without primary EBV infection, inflammatory bowel disease (IBD), uveitis, and episodic fevers. Liver manifestations have been rarely reported. Herein we describe severe acute liver failure (ALF) in a patient with very early-onset IBD found to have XIAP deficiency. Case Presentation The patient presented at 5 years of age with intermittent bloody stools, a perianal skin tag, and a history of intermittent fevers since infancy. Endoscopic evaluation at 6 years of age showed ulcerations and histologic colitis and granulomas. He was initiated on infliximab with good clinical response. Concurrent with his IBD evaluation, he was noted to have elevated liver enzymes. Twenty-one months after diagnosis, he developed fever, right upper quadrant pain, nausea, scleral icterus, liver enzymes to the 2000s, and cholestasis without synthetic dysfunction. EBV serologies were IgM positive. Transaminases improved spontaneously, but five days later, he re-presented with marked transaminitis, worsened cholestasis, and new synthetic dysfunction. He was transferred to a tertiary academic referral center ICU with high fevers and encephalopathy for management of ALF. HLH biomarkers were only modestly elevated: ferritin 290, Hgb 9.2, Plts 177, ANC 1620, fibrinogen 103, sIL-2Ra 1500, IFNg 128, and CXCL9 2959. EBV serologies and serial PCRs were negative. IL-18 was 12079. He was treated with IV glucocorticoids and emapalumab with stabilization. Flow cytometry showed XIAP deficiency, and anakinra was added with gradual resolution of liver dysfunction. Whole-genome sequencing revealed an XIAP frameshift variant (c.1021_1022del, p.(N341Yfs*8)). Emapalumab was replaced with ruxolitinib as the patient was preparing for hematopoietic stem cell transplant. Discussion XIAP-deficiency is remarkable for its range and severity of inflammatory phenotypes, including HLH and refractory IBD. Here we present a rare case of ALF in XIAP-deficiency. Antecedent, transient EBV infection was a likely trigger. His ALF improved with steroids, emapalumab, and IL-1 blockade. A high index of suspicion for immune dysregulation should be employed in all cases of VEO-IBD and/or liver failure. Figure 1. Laboratory trends and therapeutics. Day 0 represents initial hospitalization for acute liver failure.