title: Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia.
abstract: OBJECTIVE
  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.
authors: *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.
authors: Peter F
authors: PF
authors: Whitington
authors: Miriam B
authors: MB
authors: Vos
authors: Lee M
authors: LM
authors: Bass
authors: Hector
authors: H
authors: Melin-Aldana
authors: Rene
authors: R
authors: Romero
authors: Claude C
authors: CC
authors: Roy
authors: Fernando
authors: F
authors: Alvarez
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood; D001379:Azathioprine / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism*; D001706:Biopsy; D002675:Child, Preschool; D015926:Complement C3a / Q000378:metabolism; D050776:Complement C5b / Q000378:metabolism; D003298:Coombs Test; D005260:Female; D015726:Giant Cells; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007167:Immunotherapy; D007223:Infant; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008297:Male; D011241:Prednisone / Q000627:therapeutic use; D000069283:Rituximab
chemical_list: D000893:Anti-Inflammatory Agents; D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D007155:Immunologic Factors; D000069283:Rituximab; D015926:Complement C3a; D050776:Complement C5b; D001379:Azathioprine; D011241:Prednisone