Response to Krejci and Mayer (2010)

We thank Drs. Krejci and Mayer for highlighting the potential value of considering serum aminotransferase enzyme (AST, ALT) concentrations in assessing outcomes of treatment for acute graft-versus-host disease (GVHD) of the liver. Liver GVHD has 3 components [1McDonald GB. Hepatobiliary complications of hematopoietic cell transplant, 40 years on. Hepatology. (in press).Google Scholar]. The first involves a cytokine-mediated effect on hepatocyte transport of conjugated bilirubins into bile, primarily in patients with more severe gut GVHD. These cases present as isolated hyperbilirubinemia (cholestasis) with no histologic findings [2Shulman H.M. Sharma P. Amos D. Fenster L.F. McDonald G.B. A coded histologic study of hepatic graft-versus-host disease after human marrow transplantation.Hepatology. 1988; 8: 463-470Crossref PubMed Scopus (152) Google Scholar]. The second involves T cell-mediated apoptosis of small bile duct epithelial cells [2Shulman H.M. Sharma P. Amos D. Fenster L.F. McDonald G.B. A coded histologic study of hepatic graft-versus-host disease after human marrow transplantation.Hepatology. 1988; 8: 463-470Crossref PubMed Scopus (152) Google Scholar], with hyperbilirubinemia as the principal clinical biomarker. The third involves T cell-mediated hepatocyte necrosis and lobular inflammation, also described as hepatitic GVHD, often occurring together with bile duct injury and hyperbilirubinemia. Serum AST and ALT elevations may presage the development of acute GVHD before day 100, and can dominate the clinical presentation of liver GVHD during withdrawal of cyclosporine or tacrolimus or after donor lymphocyte infusion. Extreme AST or ALT elevation without hyperbilirubinemia before day 100 is rarely, if ever, caused by GVHD [3Sakai M. Strasser S.I. Shulman H.M. McDonald S.J. Schoch H.G. McDonald G.B. Severe hepatocellular necrosis after hematopoietic cell transplant: incidence, etiology, and outcome.Bone Marrow Transplant. 2009; 44: 441-447Crossref PubMed Scopus (33) Google Scholar]. Serum AST and ALT elevation lacks specificity as a marker of liver GVHD, because these abnormalities can have many other causes in transplant recipients, including drug injury, cholangitis lenta, biliary sludge disease, vascular liver injury, infection by herpesviruses and adenovirus, and flares of hepatitis C or B after immune reconstitution [1McDonald GB. Hepatobiliary complications of hematopoietic cell transplant, 40 years on. Hepatology. (in press).Google Scholar]. We acknowledge that similar problems occur with the use of hyperbilirubinemia as a marker of liver GVHD, although we believe that this abnormality has better specificity than AST or ALT elevation, particularly in patients who receive ursodiol to prevent hepatic complications after transplantation [4Fried R.H. Murakami C.S. Fisher L.D. Willson R.A. Sullivan K.M. McDonald G.B. Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver.Ann Internal Med. 1992; 116: 624-629Crossref PubMed Scopus (101) Google Scholar, 5Ruutu T. Eriksson R. Remes K. et al.Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation.Blood. 2002; 100: 1977-1983Crossref PubMed Scopus (198) Google Scholar]. Because GVHD seldom occurs in complete isolation, tests lacking specificity are not well suited to measure treatment responses. Evaluation of Response in Hepatitic Variant of Acute Liver Graft-versus-Host DiseaseBiology of Blood and Marrow TransplantationVol. 16Issue 5PreviewAcute graft-versus-host disease (aGVHD) causes serious morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recently, Martin et al. [1] defined important endpoints for clinical trials testing treatment of aGVHD. Criteria for very good partial response (VGPR) of aGVHD were described for skin, liver, and gut. Correct and objective evaluation of treatment response is very important, and the new category of VGPR can be useful for several reasons discussed by Martin et al. Full-Text PDF Open Archive