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Humoral Immune Mechanism of Liver Injury in Giant Cell Hepatitis With Autoimmune Hemolytic Anemia

Whitington, Peter F.*; Vos, Miriam B.; Bass, Lee M.*; Melin-Aldana, Hector*; Romero, Rene; Roy, Claude C.; Alvarez, Fernando

Journal of Pediatric Gastroenterology & Nutrition: January 2014 - Volume 58 - Issue 1 - p 74–80
doi: 10.1097/MPG.0b013e3182a98dbe
Original Articles: Hepatology and Nutrition

Background and Aims: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is presumed to be an autoimmune disease, but the mechanism of liver injury is unknown. We proposed that in CGH-AHA, the humoral limb of autoimmunity is the dominant force driving progressive liver injury.

Methods: We studied 6 cases of GCH-AHA and 6 cases of autoimmune hepatitis (AIH) with early childhood onset (3 type 1 and 3 type 2). Liver biopsies were graded for portal and periportal inflammation and for giant cells. Immunohistochemistry characterized cellular inflammation and complement involvement in injury by showing C5b-9 complex in hepatocytes.

Results: Clinical and biochemical features at presentation were generally similar; however, the absence of autoantibodies and the presence of Coombs positivity did distinguish GCH-AHA from early-onset AIH. Liver biopsy pathology in CGH-AHA showed giant cells and little inflammation, whereas AIH showed the opposite. C5b-9 staining showed high-grade complement-mediated pan-lobular hepatocyte injury in all of the cases with GCH-AHA, whereas little C5b-9 was seen in hepatocytes in cases with AIH. Inflammation in GCH-AHA comprised mainly lobular macrophages and neutrophils, whereas portal and periportal T-cell and B-cell inflammation characterized cases with AIH. Most cases with AIH responded to therapy with prednisone and azathioprine, whereas most cases with GCH-AHA responded only to rituximab.

Conclusions: Widespread complement-mediated hepatocyte injury and typical C3a and C5a complement-driven liver inflammation along with Coombs-positive hemolytic anemia in GCH-AHA provide convincing evidence that systemic B-cell autoimmunity plays a central pathologic mechanism in the disease. Our findings support B-cell–directed immunotherapy as a first-line treatment of GCH-AHA.

*Ann and Robert H. Lurie Children's Hospital of Chicago, IL

Department of Pediatrics, Emory University, Atlanta, GA

Department of Pediatrics, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Miriam B. Vos, MD, MSPH, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Dr, NE, Atlanta, GA 30030 (e-mail: mvos@emory.edu).

Received 27 June, 2013

Accepted 17 August, 2013

The authors report no conflicts of interest.

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,