Immune‐Mediated Hepatitis Induced by Therapy With Alemtuzumab in a Patient With Multiple Sclerosis
Authors: Fabian J. Bolte, Hartmut H.‐J. Schmidt, Bernhard Schlevogt
Journal: Hepatology (2020)

Increased use of immunomodulatory agents has led to emerging forms of drug-induced liver injury. Alemtuzumab is a recombinant, humanized monoclonal antibody against CD52, which is present on T cells, B cells, monocytes, and natural killer cells. A single dose results in a depletion of the entire lymphocyte population followed by varied kinetics in the recovery of each cell type.(1) Alemtuzumab has been approved as an immune reconstitution therapy in relapsing and remitting multiple sclerosis (RRMS). Since its approval, cases of acute hepatitis have been documented,(2, 3) and here we present an unusual case of delayed-onset immune-mediated hepatitis with recurrent episodes of liver failure following treatment with alemtuzumab. A 36-year-old woman was diagnosed with RRMS in 2007 and underwent several treatments, including interferon beta, natalizumab, glatiramer acetate, and dimethyl fumarate. In 2016, alemtuzumab was administered intravenously at 12 mg daily for 5 consecutive days. One week later, mild hepatocellular injury with an alanine aminotransferase (ALT) peak of 599 U/L was diagnosed and resolved spontaneously within 2 weeks (ALT 599 U/L, aspartate aminotransferase [AST] 106 U/L, alkaline phosphatase [AP] 33 U/L, and international normalized ratio [INR] 0.9; Table 1). The patient experienced a relief in RRMS symptoms following treatment with alemtuzumab, and therefore a deliberate rechallenge was performed 12 months later with a dose of 12 mg daily for 3 consecutive days. One week following this rechallenge, the patient presented with nausea, vomiting, and jaundice and was diagnosed with severe hepatocellular injury and acute liver failure (ALT 5,389 U/L, AST 7,088 U/L, AP 86 U/L, and INR 5.43; Table 1). Of note, liver tests were normal before the infusion of alemtuzumab, and there was no history of concomitant liver disease or consumption of alcohol, hepatotoxic drugs, or herbal products. Serologies for viral hepatitis and human immunodeficiency virus were negative. Cytomegalovirus and Epstein-Barr virus infection were ruled out by nucleic-acid amplification testing. The antinuclear antibody titer was <1:80, and liver immunoblotting testing revealed an anti-smooth muscle antibody titer of 1:40. Anti-liver-kidney microsomal-1, anti-liver cytosol-1, and anti-mitochondrial and anti-neutrophil cytoplasmic antibodies were all negative. Moreover, gamma globulins, ceruloplasmin, and iron studies were normal. An ultrasound revealed no evidence of hepatic lesions. A liver biopsy showed severe confluent centrilobular necrosis (zone 3) with granulocytic infiltration. There was mild portal inflammation, including infiltration of lymphocytes, plasma cells, and granulocytes, but no evidence of interface hepatitis and fibrosis (Fig. 1). In the light of severe hepatocellular injury, high-dose prednisone treatment was initiated with a rapid decline in liver enzymes and normalization of coagulation studies. This episode was followed by three additional episodes of acute hepatitis and liver failure within a period of 6 months. Each instance was responsive to treatment with prednisone (Fig. 2). The patient initially declined glucocorticoid maintenance therapy, but eventually agreed upon maintenance therapy with mycophenolate mofetil. After initiation of maintenance therapy, acute hepatitis flares were not observed for almost a year. However, the patient was admitted with another episode of severe liver failure (ALT 8,437 U/L, AST 6,767 U/L, AP 69 U/L, and INR 5.37; Table 1), responded more slowly to steroids, and almost required liver transplantation. At this time, mycophenolate mofetil was discontinued and cyclosporine A was prescribed for maintenance therapy. Relapses were not observed for more than 6 months. Because of the highly active RRMS, a multidisciplinary decision was made to continue the treatment of RRMS with ocrelizumab. Here, we report a case of alemtuzumab-induced liver injury followed by recurrent episodes of immune-mediated hepatitis and liver failure. The histological findings of marked hepatic necrosis without interface hepatitis, the absence of autoantibodies, and normal immunoglobulin levels are not consistent with classic autoimmune hepatitis (AIH). However, the long-lasting effects of alemtuzumab on bone marrow cells, intermittent steroid-responsive episodes of hepatitis, and the requirement of a maintenance therapy are highly suggestive for an immune-mediated pathomechanism similar to AIH. This hypothesis also helps to explain the other secondary, delayed-onset autoimmune conditions, such as Graves' disease, immune thrombocytopenic purpura, Goodpasture's syndrome, and sarcoidosis, that have been reported 6-18 months following treatment with alemtuzumab.(4-6) F.J.B., acquisition, analysis and interpretation of data, drafting, revising and final approval manuscript; H.H.J.S., revision and final approval of manuscript; B.S., interpretation of data, revision and final approval of manuscript.