GASTROENTEROLOGY
1992;103:1355-1356
EDITORIALS
Hepatitis B After Liver Transplantation: New Names for Unusual Presentations The article by Benner et al. in this issue describes a “unique” histological presentation of recurrent hepatitis B virus (HBV) infection in liver allograft recipients.’ The authors show a correlation between viral antigen expression in the liver allograft, hepatocyte ballooning and degeneration, and fibrosis and clinical deterioration despite a paucity of liver allograft inflammation. An accelerated course of recurrent disease in a second allograft after retransplantation was also described. The authors’ conclusion was that HBV may be directly cytopathic in grafts, in contrast to the widely quoted mechanism of major histocompatibility complex (MHC)-restricted, cytotoxic Tlymphocyte liver cell damage in the general population. Other groups have previously reached similar conclusions.z*3 Benner et al.’ propose the term “fibrosing cytolytic hepatitis” to describe this presentation and suggest it more accurately reflects the pathology than the term “fibrosing cholestatic hepatitis” proposed by Davies et a1.3 They do not mention how their new term would mesh with the proposals coined by Phillips et al.* of “fibroviral hepatitis” and “steatoviral hepatitis” for apparently the same process. Pathologists involved in the interpretation of liver allograft biopsies are now faced with a bewildering lingo to describe what appears to be the same phenomenon-an atypical presentation of HBV hepatitis in the allograft liver. From a practical perspective, one should not lose sight of the fact that HBV does not always present in liver allograft recipients in this unusual fashion.’ The complete spectrum of disease similar to that seen in the general population can be encountered. The crucial caveat made by such studies as that by Benner et al.’ is that the traditional hepatotropic viruses, HBV and hepatitis C virus (unpublished observation), may cause unusual histological lesions in a liver allograft. The term used to describe it is of lesser importance. However, the pathologist must be aware of these variations and able to separate virus-induced changes from those associated with sepsis, hyperalimentation, or ethanol-induced injury and ischemia, all of which can appear similar to the changes attributed to HBV in this study. It should also be remembered that de
novo appearance of HBV after transplantation is uncommon but not rare. There are many possible explanations for the uniqueness of the HBV-induced lesions in hepatic allograft recipients. The most plausible appear to be the combination of immunosuppressive therapy and the lack of MHC identity between the liver and the immune system. It is not unreasonable to suggest that in the general population, HBV-induced liver damage is mediated primarily via MHC-restricted cytotoxic T lymphocytes (CTLs), whereas in allograft recipients viral replication may be unchecked because of immunosuppression and CTL inefficiency. Filippi et al5 and Moriyama et a1.6 have shown in mice that both immunological and direct virus-induced liver cell damage are possible, including the steatotic changes described in humans by Phillips et al.* Furthermore, these unique presentations of HBV have not been widely described in patients with acquired immunodeficiency syndrome, in whom there is profound immune deficiency but MHC identity between the immune system and the liver.7-g Although interesting from a scientific perspective, the almost universal recurrence of severe disease in liver allograft recipients who are hepatitis B surface antigen and e antigen positive at the time of transplantation has forced many centers to exclude such patients from waiting lists. Unless innovative treatment strategies are designed, we are unlikely to see many more cases like those described by Benner et al.’ A novel approach on the horizon is the use of xenogeneic liver donors from species not susceptible to HBV hepatic disease. Last, HBV recurrence in hepatitis B surface antigen-positive and e antigen-negative recipients is less predictable. More detailed pretransplant screening of these patients for viral DNA and/or HBV mutants” may help to predict which patients may benefit from hepatic replacement for end-stage HBVinduced cirrhosis. A. J. DEMETRIS,
M.D.
Pittsburgh Transplant University of Pittsburgh Pittsburgh, Pennsylvania
Institute
1356
GASTROENTEROLOGY Vol. 103, No. 4
EDITORIALS
References 1. Benner KG, Lee RG, Keeffe EB, Lopez RR, Sasaki AW, Pinson
7.
CW. Fibrosing cytolytic liver failure secondary to recurrent hepatitis B after liver transplantation. Gastroenterology 1992;103:1307-1312, 2. Demetris AJ, Todo S, Van Thiel DH, Fung JJ, Iwaki Y, Sysyn G,
Ming W, Trager J, Stars1 TE. Evolution of hepatitis B virus liver disease after hepatic replacement. Am J Pathol 1990;137:667-676. 3. Davies SE, Portmann
BC, O’Grady JG, Aldis PM, Chaggar K, Alexander GJM, Williams R. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatis. Hepatology 1991;13:150-157. 4. Phillips MJ, Camerson R, Flowers MA, Blendis LM, Breif PD, Wanless J, Sherman M, Superina R, Langer B, Levy GA. Posttransplant recurrent hepatitis A viral liver disease, viral burden, steatoviral and fibroviral hepatitis B. Am J Path01 1992;140:1295-1308. 5. Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL, Chisari FV. Overproduction of the hepatitis B virus large envelope polypeptide causes filament storage ground-glass-cell formation, hepatocellular injury, and nodular hyperplasia in transgenic mice. Viral Hepatitis and Liver Disease 1988:632-640. 6. Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA, Palmiter RD. Brinster RL, Kanagawa 0, Chisari FV. Immunobiol-
8.
9.
10.
ogy and pathogenesis of hepatocellular injury in hepatitis B virus trangenic mice. Science 1990;248:361-364. Rector WG, Govindarajan S, Horsburgh CR, Penley KA, Cohn DL, Judson FN. Hepatic inflammation, hepatitis B replication, and cellular immune function in homosexual males with chronic hepatitis B and antibody to human immunodeficiency virus. Am J Gastroenterol 1988;83:262-266. Perrillo RP, Campbell CR, Sanders GE, Regenstein FG, Bodicky CJ. Spontaneous clearance and reactivation of hepatitis B virus infection among male homosexuals with chronic type B hepatitis. Ann Intern Med 1984;100:43-46. Rustgi VK, Hoofnagle JH, Gerin JL, Gelmann EP, Reichert CM, Cooper JN, Macher AM. Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:795-797. Takeda K, Akahane Y, Suzuki H, Okamoto H, Tsuda F, Miyakawa Y, Mayumi M. Defects in the precore region of the HBV genome in patients with chronic hepatitis B after sustained seroconversion from HBeAg to anti-HBe induced spontaneously or with interferon therapy. Hepatology 1990;12:12841289.
Address requests for reprints to: A. J. Demetris, M.D., Department of Surgery, Biomedical Sciences Tower (15th Floor), University of Pittsburgh, Pittsburgh, Pennsylvania 15261. 0 1992 by the American
Gastroenterological
Association
1992;103:1355-1356
EDITORIALS
Hepatitis B After Liver Transplantation: New Names for Unusual Presentations The article by Benner et al. in this issue describes a “unique” histological presentation of recurrent hepatitis B virus (HBV) infection in liver allograft recipients.’ The authors show a correlation between viral antigen expression in the liver allograft, hepatocyte ballooning and degeneration, and fibrosis and clinical deterioration despite a paucity of liver allograft inflammation. An accelerated course of recurrent disease in a second allograft after retransplantation was also described. The authors’ conclusion was that HBV may be directly cytopathic in grafts, in contrast to the widely quoted mechanism of major histocompatibility complex (MHC)-restricted, cytotoxic Tlymphocyte liver cell damage in the general population. Other groups have previously reached similar conclusions.z*3 Benner et al.’ propose the term “fibrosing cytolytic hepatitis” to describe this presentation and suggest it more accurately reflects the pathology than the term “fibrosing cholestatic hepatitis” proposed by Davies et a1.3 They do not mention how their new term would mesh with the proposals coined by Phillips et al.* of “fibroviral hepatitis” and “steatoviral hepatitis” for apparently the same process. Pathologists involved in the interpretation of liver allograft biopsies are now faced with a bewildering lingo to describe what appears to be the same phenomenon-an atypical presentation of HBV hepatitis in the allograft liver. From a practical perspective, one should not lose sight of the fact that HBV does not always present in liver allograft recipients in this unusual fashion.’ The complete spectrum of disease similar to that seen in the general population can be encountered. The crucial caveat made by such studies as that by Benner et al.’ is that the traditional hepatotropic viruses, HBV and hepatitis C virus (unpublished observation), may cause unusual histological lesions in a liver allograft. The term used to describe it is of lesser importance. However, the pathologist must be aware of these variations and able to separate virus-induced changes from those associated with sepsis, hyperalimentation, or ethanol-induced injury and ischemia, all of which can appear similar to the changes attributed to HBV in this study. It should also be remembered that de
novo appearance of HBV after transplantation is uncommon but not rare. There are many possible explanations for the uniqueness of the HBV-induced lesions in hepatic allograft recipients. The most plausible appear to be the combination of immunosuppressive therapy and the lack of MHC identity between the liver and the immune system. It is not unreasonable to suggest that in the general population, HBV-induced liver damage is mediated primarily via MHC-restricted cytotoxic T lymphocytes (CTLs), whereas in allograft recipients viral replication may be unchecked because of immunosuppression and CTL inefficiency. Filippi et al5 and Moriyama et a1.6 have shown in mice that both immunological and direct virus-induced liver cell damage are possible, including the steatotic changes described in humans by Phillips et al.* Furthermore, these unique presentations of HBV have not been widely described in patients with acquired immunodeficiency syndrome, in whom there is profound immune deficiency but MHC identity between the immune system and the liver.7-g Although interesting from a scientific perspective, the almost universal recurrence of severe disease in liver allograft recipients who are hepatitis B surface antigen and e antigen positive at the time of transplantation has forced many centers to exclude such patients from waiting lists. Unless innovative treatment strategies are designed, we are unlikely to see many more cases like those described by Benner et al.’ A novel approach on the horizon is the use of xenogeneic liver donors from species not susceptible to HBV hepatic disease. Last, HBV recurrence in hepatitis B surface antigen-positive and e antigen-negative recipients is less predictable. More detailed pretransplant screening of these patients for viral DNA and/or HBV mutants” may help to predict which patients may benefit from hepatic replacement for end-stage HBVinduced cirrhosis. A. J. DEMETRIS,
M.D.
Pittsburgh Transplant University of Pittsburgh Pittsburgh, Pennsylvania
Institute
1356
GASTROENTEROLOGY Vol. 103, No. 4
EDITORIALS
References 1. Benner KG, Lee RG, Keeffe EB, Lopez RR, Sasaki AW, Pinson
7.
CW. Fibrosing cytolytic liver failure secondary to recurrent hepatitis B after liver transplantation. Gastroenterology 1992;103:1307-1312, 2. Demetris AJ, Todo S, Van Thiel DH, Fung JJ, Iwaki Y, Sysyn G,
Ming W, Trager J, Stars1 TE. Evolution of hepatitis B virus liver disease after hepatic replacement. Am J Pathol 1990;137:667-676. 3. Davies SE, Portmann
BC, O’Grady JG, Aldis PM, Chaggar K, Alexander GJM, Williams R. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatis. Hepatology 1991;13:150-157. 4. Phillips MJ, Camerson R, Flowers MA, Blendis LM, Breif PD, Wanless J, Sherman M, Superina R, Langer B, Levy GA. Posttransplant recurrent hepatitis A viral liver disease, viral burden, steatoviral and fibroviral hepatitis B. Am J Path01 1992;140:1295-1308. 5. Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL, Chisari FV. Overproduction of the hepatitis B virus large envelope polypeptide causes filament storage ground-glass-cell formation, hepatocellular injury, and nodular hyperplasia in transgenic mice. Viral Hepatitis and Liver Disease 1988:632-640. 6. Moriyama T, Guilhot S, Klopchin K, Moss B, Pinkert CA, Palmiter RD. Brinster RL, Kanagawa 0, Chisari FV. Immunobiol-
8.
9.
10.
ogy and pathogenesis of hepatocellular injury in hepatitis B virus trangenic mice. Science 1990;248:361-364. Rector WG, Govindarajan S, Horsburgh CR, Penley KA, Cohn DL, Judson FN. Hepatic inflammation, hepatitis B replication, and cellular immune function in homosexual males with chronic hepatitis B and antibody to human immunodeficiency virus. Am J Gastroenterol 1988;83:262-266. Perrillo RP, Campbell CR, Sanders GE, Regenstein FG, Bodicky CJ. Spontaneous clearance and reactivation of hepatitis B virus infection among male homosexuals with chronic type B hepatitis. Ann Intern Med 1984;100:43-46. Rustgi VK, Hoofnagle JH, Gerin JL, Gelmann EP, Reichert CM, Cooper JN, Macher AM. Hepatitis B virus infection in the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:795-797. Takeda K, Akahane Y, Suzuki H, Okamoto H, Tsuda F, Miyakawa Y, Mayumi M. Defects in the precore region of the HBV genome in patients with chronic hepatitis B after sustained seroconversion from HBeAg to anti-HBe induced spontaneously or with interferon therapy. Hepatology 1990;12:12841289.
Address requests for reprints to: A. J. Demetris, M.D., Department of Surgery, Biomedical Sciences Tower (15th Floor), University of Pittsburgh, Pittsburgh, Pennsylvania 15261. 0 1992 by the American
Gastroenterological
Association
