Recurrent hepatitis C after liver transplantation

Cirrhosis due to hepatitis C is now the commonest indication for liver transplantation in Western Europe and in the United States. Graft reinfection is almost universal. The natural history of recurrent hepatitis C ranges from minimal damage to cirrhosis in a few months or years. Different virus and host immune factors are involved in the pathogenesis of hepatitis and are determinants of the outcome. The association between immunosuppression and severity of HCV recurrence is conflicting and remains to be evaluated fully. The treatment of recurrent HCV disease with IFN or ribavirin, as monotherapy, is ineffective. Preliminary results from combination therapy, however, are encouraging. Currently, a reasonable approach would be to treat patients with histological and clinical disease progression. New approaches for the prophylaxis of recurrent hepatitis C are under evaluation but whether this treatment will influence the severity of liver disease or the outcome of recurrence is still unknown.     

Early decrease in circulating dendritic cells number after liver transplantation could favor hepatitis C virus recurrence

Cirrhosis and hepatocarcinoma related to hepatitis C virus (HCV) lead to more than 30% of liver transplantations. Host- and virus-related mechanisms, involved in the recurrence of HCV infection of the liver graft, are not yet well known. A weak CD4+ T-cell response was shown to be involved in the outcome of re-infection but whether dendritic cell numbers are modified in patients transplanted for HCV-related disease has never been evaluated. Eight transplanted patients for HCV-related disease and eight non-HCV-infected transplanted controls were included. Blood plasmacytoid dendritic cells and myeloid dendritic cells were quantified before transplantation, at day 7 and 1 month after transplantation. Plasma interferon (IFN)-alpha and interleukin (IL)-12 were concomitantly measured. The results showed a significant decrease in the relative (P < 0.0001) and absolute (P = 0.0002) values of blood plasmacytoid dendritic cells at day 7 after transplantation when compared to the values obtained before transplantation, increasing again 1 month later, in both HCV-infected patients and controls. The same tendency was observed for myeloid dendritic cell relative values (P = 0.0004) and plasma IL-12 (P < 0.05). IFN-alpha appeared to be less often detectable for HCV-infected patients. These results obtained on dendritic cell numbers could explain partially the early and systematic recurrence of HCV infection on the liver graft and contribute to better adapted therapeutic strategies.     

Hepatitis C-associated granulomas after liver transplantation: morphologic spectrum and clinical implications

Liver granulomas have been described in biopsy specimens from people with de novo chronic hepatitis C virus (HCV) infection and in allograft biopsy specimens from recipients of transplants for HCV-related liver disease. The latter have not been well studied, and there are no data regarding the prevalence, morphologic spectrum, and clinical significance of HCV-associated granulomas after liver transplantation. We observed granulomas in allograft liver biopsy specimens of 4 (8%) of 53 recipients of transplants for HCV-related end-stage liver disease during a 3-year period. Initial appearance of granulomas ranged from 4 to 41 weeks after transplantation. Lobular and portal nonnecrotizing, epithelioid granulomas and lobular microgranulomas were observed, with the latter predominating. Serum transaminase and alkaline phosphatase levels were significantly higher in patients with granulomas than in age- and sex-matched control subjects, but histologic disease activity, cellular rejection scores, HCV genotypes, viral titers, and retransplantation rate owing to recurrent disease were not significantly different. Our study suggests that a granulomatous response to HCV infection occurs in a subset of patients after transplantation; however, this histologic finding does not portend a worse clinical outcome.     

Assessment of genotype and molecular evolution of hepatitis C virus in formalin-fixed paraffin-embedded liver tissue from patients with chronic hepatitis C virus infection

Drawbacks of hepatitis C virus (HCV) RNA detection in paraffin-embedded liver tissue have satisfactorily been solved by RT-PCR amplification of the 5'non-coding region (5'NCR). However, detection of this highly conserved region does not provide information on epidemiological or pathogenetic aspects of HCV infection. This study explores whether other functionally important genetic regions of HCV, such as the hypervariable region 1 (HVR-1) and the interferon sensitivity-determining region (ISDR), can be retrieved from paraffin-embedded liver specimens by RT-PCR, and whether the amplified material is suitable for further molecular analyses. RT-PCR amplification of 5'NCR, HVR-1, and ISDR was assessed in RNA extracted from 50 formalin-fixed, paraffin-embedded liver specimens, including 23 needle liver biopsies (11 from patients with non-A, non-B chronic hepatitis diagnosed between 1971 and 1985, 8 from subjects with normal liver histology and 4 from sequential biopsies from a patient with HCV recurrence after liver transplantation), and 27 liver explants from patients undergoing transplantation between 1988 and 1996 (16 with HCV-related cirrhosis and 11 with other disorders). The 5'NCR was successfully amplified in 8 of 11 (73%) non-A, non-B chronic hepatitis biopsies and in all of the specimens from patients with serological documentation of HCV infection. There were no false-positive results. HCV genotype was identified by RFLP analysis of the 5'NCR in the 13 cases analyzed. HVR-1 and ISDR were amplified in 24 of 28 (86%) samples, which were positive for the 5'NCR. Efficient amplification was inversely related to the time of storage. The evolutionary changes of HVR-1 and ISDR were successfully analyzed by direct sequencing of amplificates from the explanted liver and from the sequential liver biopsies in a patient with HCV infection recurrence after transplantation. These observations indicate that paraffin-embedded liver tissue, even when stored for more than 20 years, is appropriate for advanced studies on the molecular biology of HCV.     

Liver transplantation for alcoholic liver disease with or without hepatitis C

Alcoholic cirrhosis with or without hepatitis C is a common indication for liver transplantation (LT). Comparative post-LT data for the 2 groups are not available. Our aim is to compare the clinicopathologic features of patients with alcoholic liver disease (ETOH) and ETOH/HCV at the time of and after LT and to determine the impact of concomitant hepatitis C virus (HCV) on ETOH patients undergoing LT. A comparative clinical and pathologic analysis at LT and after LT was performed for 56 patients with ETOH and 32 patients with ETOH/HCV. All 88 had cirrhosis at LT. Other native liver features for ETOH and ETOH/HCV, respectively, were: >2+ inflammation 50/56 and 26/32, Mallory's hyalin 12/56 and 6/32, steatosis 9/56 and 7/32, large cell dysplasia 12/56 and 6/32, hepatoma 4/56 and 4/32, iron deposition 24/56 and 12/32; none was statistically significant. The post-LT findings for ETOH and ETOH/HCV were as follows: 1-year survival 93% and 97%; alive 36/56 (419-4,348 days) and 27/32 (488-5,516 days); deaths 20/56 and 5/32; ETOH recurrence 5/56 (all alive) and 3/32 (1 dead); post-LT HCV 4/56 (acquired) and 22/32 (recurrent). Native liver histology in ETOH and ETOH/HCV patients was similar. Post-LT HCV recurrence was common (69%) in ETOH/HCV patients but resulted in death in only 6%. Post-LT ETOH recurrence was uncommon (9%) and progression to liver failure was rare (1.1%). Post-LT outcome for ETOH was excellent, and concomitant HCV did not affect survival.     

Donor-recipient sharing of HLA class II alleles predicts earlier recurrence and accelerated progression of hepatitis C following liver transplantation

Abstract: Both direct viral cytopathic effects and host immune responses appear to be important in the pathogenesis of hepatitis C virus (HCV) infection. Liver transplantation provides a means to explore the role of the immune system in the development of HCV-related liver damage through comparing the natural history of HCV in patients with different degrees of donor-recipient human leukocyte antigen (HLA) matching. We evaluated 36 patients with recurrent hepatitis C viremia following liver transplantation to determine whether hepatocellular injury or progression to bridging fibrosis occur more rapidly when donor and recipients share HLA alleles. HLA typing for the HLA-A and HLA-B loci was performed by serological techniques and PCR-based oligotyping was used to type alleles of the DRB1, DRB3, DQA1, and DQB1 loci. A median of eight liver biopsies, obtained during a median follow-up of 36 months, were reviewed per patient. Donor-recipient sharing of alleles of HLA-DQB1 or DRB1 was associated with more rapid development of recurrent hepatitis by univariate analysis (χ²=5.7, P =0.02 and χ²=5.54, P =0.02 respectively). However, only sharing of HLA-DRB1 alleles was identified as an independent predictor of reduced time to recurrent histologic injury by multivariate analysis (χ² =5.74, P = 0.02). Furthermore, sharing of HLA-DRB3 and histologic evidence of rejection were associated with more rapid progression to bridging fibrosis both by univariate methods (χ²=4.12, P =0.04 and χ²=4.66, P =0.03 respectively), and by multivariate analysis (χ²= 13.01, P =0.001). These findings suggest that HLA class II-restricted immune responses may contribute to the pathogenesis of HCV-related liver injury in liver transplant recipients.     

Donor-specific hyporesponsiveness in ELISPOT assay is associated with early recurrence of hepatitis C in liver transplant recipients

Recurrence of hepatitis C in liver transplant recipients is a common event that often leads to loss of the allograft. There are no means to prevent, or even predict, those patients who are more prone to early aggressive recurrence. Therefore there is an increased need for tailored immunosuppression protocols specific to this patient population. Fifteen liver transplant recipients (eight hepatitis C virus [HCV]+; 7 HCV-) were followed for 12-24 months after transplantation. The frequency of donor-specific interferon (IFN)-gamma- or interleukin-10-producing lymphocytes was monitored using ELISPOT assays. Of the eight HCV+ recipients, six experienced recurrence within the first year after transplant. All six patients had very low (negligible) frequency of donor-specific IFN-gamma precursors; in most cases not higher than the nonstimulated (spontaneous) secretion rate. The other two patients who did not recur exhibited donor-specific IFN-gamma reactivity. A significant difference in the frequency of alloantigen-specific T cells was observed between HCV+ recipients and patients with other indications for transplantation. The results of this preliminary study suggest that posttransplant monitoring of the frequency of donor-specific IFN-gamma-producing precursors may differentiate a subset of patients at risk for early recurrent hepatitis C and therefore may help to devise treatment strategies for HCV+ liver recipient after transplantation.     

Immunohistochemical assessment of hepatitis C virus antigen in cholestatic hepatitis after liver transplantation

BACKGROUND: Patients with common variable immunodeficiency may exhibit rapidly progressive hepatitis when infected with hepatitis C virus (HCV), leading to cirrhosis and liver failure. Liver transplantation in these patients may result in a cholestatic form of HCV reinfection with exceptionally high virus loads. AIMS: To report an immunohistochemical investigation of the pretransplant and post-transplant liver of one such patient. METHODS/RESULTS: On immunohistochemical staining of frozen sections with anti-HCV core monoclonal antibody or fluorescein labelled human polyclonal anti-HCV IgG, no HCV antigens were demonstrated in the native cirrhotic liver removed at transplant, despite a viral load of 10(6.4) genomes/g. The transplanted liver, collected six weeks post-transplant, exhibited cholestatic recurrent hepatitis, had an HCV virus load of 10(10) genomes/g of liver, and revealed HCV antigen in the cytoplasm of most hepatocytes, with a pronounced periportal distribution. No virus antigen was demonstrable in other cell types. The core antigen was also detected in paraffin wax embedded, formaldehyde fixed tissue of this liver after high temperature antigen retrieval, but not in the native cirrhotic liver or a selection of HCV positive livers collected pretransplant from immunocompetent patients. Attempts to delineate the distribution of E1, NS3, and NS4 antigens were unsuccessful because monoclonal antibodies to these antigens produced "false positive" staining of foci of hepatocytes in the post-transplant livers of HCV seronegative patients with cholestasis. CONCLUSION: This case provided an opportunity to study the natural development of HCV during acute infection in the absence of an immune response, and may help to elucidate the pathogenesis of HCV recurrence in liver allografts.     

Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients

Clinicopathologic trends of recurrent hepatitis C after liver transplantation (LT) in hepatitis C (HCV) patients seem to have changed in recent years. Our aims were to define the current post-LT patterns of HCV recurrence and identify features of diagnostic and/or prognostic significance. Detailed analysis was performed on 92 HCV patients who underwent LT from June 1999 to December 2003 and survived early post-LT period. The study patients were grouped, as follows: no histologic recurrence (n = 31), "typical" recurrent HCV (n = 52), and post-LT autoimmune-like hepatitis ("AIH-like") (n = 9). The typical and AIH-like groups had mostly common features with post-LT progressive fibrosis (stage > or =2) more frequent in the latter. Based on post-LT progressive fibrosis (stage > or =2), the 2 post-LT hepatitis categories were regrouped as progressive (n = 24) and nonprogressive (n = 37). High viral counts, HCV genotype 1, and native liver inflammation grade 2 or higher with plasmacytic periseptitis were more frequent in progressive cases than nonprogressive or nonrecurrent cases. Sex mismatch of male recipient and female donor was more common in nonrecurrent group. Overall, death rate was comparable in all groups; however, post-LT HCV-related deaths were more common in progressive cases. In conclusion (1) two thirds (66.2%) of HCV patients developed histologic hepatitis after LT with either typical or AIH-like features; (2) progressive fibrosis was seen in 39.3% of patients with post-LT hepatitis and 26% of the entire study group and was more frequent in AIH-like cases; (3) inflammation grade 2 or higher with plasmacytic periseptitis in native livers may be a predictor of post-LT progressive fibrosis; and (4) male recipient/female donor combination was more common in nonrecurrent cases.     

Hepatitis C virus recurrence and immunosuppression-free state after liver transplantation

HCV-related disease is the most common indication for liver transplantation (LT). HCV recurrence, which is almost universal, has a significant impact on patient and graft survival after LT and still represents a great unsolved issue for the liver transplant community. Several treatment strategies have been proposed. Since antiviral therapy has limited efficacy and can be administrated only in selected transplant recipients and additionally that immunosuppressive drugs have a negative impact on HCV re-infection, the achievement of an immunosuppression-free state after LT could play a central role in the avoidance of rapid HCV recurrence.     

Treatment of recurrent HCV infection after liver transplantation

End-stage liver disease associated with hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) and accounts for 50% of these procedures in Spain and 42% of OLT performed in the United States. Recurrent infection with HCV after OLT, however, is almost universal and is associated with substantial morbidity, mortality, and graft loss. In contrast to immunocompetent individuals, HCV infection in immunosuppressed transplant recipients usually has an accelerated course. Acute hepatitis develops in approximately 75% of HCV recipients in the first six months following OLT. By the fifth postoperative year, over 80% of HCV-infected liver transplant recipients will develop histologic evidence of chronic allograft injury secondary to hepatitis C, with up to 30% developing cirrhosis. While the choice of calcineurin inhibitor has not been clearly shown to affect the histologic recurrence of hepatitis C or the frequency of rejection in HCV-infected recipients, cumulative exposure to corticosteroids is associated with increased mortality, higher levels of HCV viremia and more severe histologic recurrence. There have been no well-controlled, large, prospective, multicenter and randomized clinical trials to determine the optimal approach to the treatment of recurrent HCV infection following OLT. Most published studies were small, lacked controls, had short follow-up periods, and were devoid of histologic analysis. Furthermore, most of the published studies are largely incomparable due to differences in the definition of recurrent hepatitis C, timing of anti-HCV therapy administration relative to transplantation, the drugs and doses used and regimens employed, and the study end points assessed (i. e. biochemical, virologic and histologic end points have not all been consistently investigated). In lieu of large studies in post-transplant patients, monotherapy with conventional interferon or monotherapy with pegylated interferon should be considered in recipients with histologically confirmed recurrence of HCV infection. The role of hepatitis C immunoglobulin and new imunosuppression agents in the management of post-transplant HCV infection is still evolving.     

IgM anti-hepatitis C virus core antibodies as marker of recurrent hepatitis C after liver transplantation

The differential diagnosis of recurrent hepatitis C following orthotopic liver transplantation (OLT) may be difficult. We evaluated the diagnostic significance of IgM anti-hepatitis C virus (anti-HCV) core antibodies in 27 patients undergoing OLT because of HCV-associated cirrhosis. Serial serum samples collected before and after OLT were tested for the presence of IgM anti-HCV core antibodies. Results were compared with the histological evidence of liver damage, the presence, level, and genotype of serum HCV RNA and the degree of immunosuppression. All patients underwent recurrent HCV infection. Recurrent hepatitis was diagnosed histologically in 21 patients an average of 48 weeks after OLT (range 2–209 weeks): 18 had persistence or (re)appearance of the IgM anti-HCV core after OLT, one lost the IgM anti-HCV core after OLT, and two never secreted IgM anti-HCV core either before or after OLT. The remaining six patients did not develop recurrent hepatitis after a follow-up of 44–241 weeks from OLT; in these patients, IgM anti-HCV core either disappeared (1 case) or decreased (1 case) after OLT or were persistently negative throughout the study (4 cases). Thus, 18/21 patients with recurrent hepatitis, but only one of six without recurrent hepatitis, secreted IgM anti-HCV core after OLT (P < 0.05). The IgM anti-HCV core levels were not correlated with the level or genotype of serum HCV RNA or the degree of immunosuppression. In conclusion, secretion of IgM anti-HCV core antibodies after OLT seems associated with recurrence of HCV-associated liver disease and may have diagnostic significance. J. Med. Virol. 56:224–229, 1998. © 1998 Wiley-Liss, Inc.     

Hepatitis C Virus-Mediated Modulation of Cellular Immunity

The hepatitis C virus (HCV) is a major cause of chronic liver disease globally. A chronic infection can result in liver fibrosis, liver cirrhosis, hepatocellular carcinoma and liver failure in a significant ratio of the patients. About 170 million people are currently infected with HCV. Since 80 % of the infected patients develop a chronic infection, HCV has evolved sophisticated escape strategies to evade both the innate and the adaptive immune system. Thus, chronic hepatitis C is characterized by perturbations in the number, subset composition and/or functionality of natural killer cells, natural killer T cells, dendritic cells, macrophages and T cells. The balance between HCV-induced immune evasion and the antiviral immune response results in chronic liver inflammation and consequent immune-mediated liver injury. This review summarizes our current understanding of the HCV-mediated interference with cellular immunity and of the factors resulting in HCV persistence. A profound knowledge about the intrinsic properties of HCV and its effects on intrahepatic immunity is essential to be able to design effective immunotherapies against HCV such as therapeutic HCV vaccines.     

Frequent overlap of active hepatitis in recurrent primary sclerosing cholangitis after living-donor liver transplantation relates to its rapidly progressive course

Recurrence of primary sclerosing cholangitis after liver transplantation is a challenging issue. Liver pathologies of recurrent primary sclerosing cholangitis after living-donor liver transplantation have not been reported. Here, liver pathologies of explanted grafts and biopsies of 9 patients who underwent retransplantation for recurrent primary sclerosing cholangitis were compared with those of native livers. Recurrence was diagnosed in 13 of 36 patients for primary sclerosing cholangitis post-living-donor liver transplantation, and 9 of them underwent retransplantation. All explanted grafts revealed biliary cirrhosis with sclerosing cholangitis, and 6 patients had additional features of active hepatitis. Liver biopsies showed that 3 had active hepatitis in addition to fibrous cholangitis at recurrence of primary sclerosing cholangitis. Two developed active hepatitis later after the diagnosis of recurrence. In explanted grafts, in addition to extensive hilar lymphoplasmacytic cholangitis, 4 cases showed hilar xanthogranulomatous cholangitis. The latter was not evident in 7 native livers. Ductopenia was extensive in all native livers, although such changes were relatively mild in explanted grafts at retransplantation. Patients with recurrent primary sclerosing cholangitis developed progressive graft failure, and the interval between diagnosis of recurrence and retransplantation (mean, 3.2 years) was shorter than that between diagnosis of primary sclerosing cholangitis and first transplantation (mean, 7.7 years). The rather rapid deterioration of recurrent primary sclerosing cholangitis after liver transplantation may be related to the frequent overlap of active hepatitis.     

‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: A comprehensive review

Autoimmune Hepatitis (AIH) is a chronic progressive inflammatory disease of the liver that responds to immunosuppressive therapy. In patients with AIH who have an acute liver failure presentation or those who develop end stage liver disease despite medical therapy, liver transplantation (LT) may become necessary. Despite good outcomes after LT, AIH can develop/recur in the allograft with an estimated incidence of recurrence between 8 and 12% at 1 year and 36–68% at 5 years. The presence of non-organ specific autoantibodies, elevated serum aminotransferases and immunoglobulin G as well as the characteristic histologic features of interface hepatitis (peri-portal plasma cell infiltration) characterize recurrence of disease. De novo AIH is the development of features of classical AIH in the allograft of patients who have not been transplanted for AIH. There are several reports in the pediatric transplant population, where administering immunosuppressive therapy in the regimen used to treat AIH has stabilized graft function in de novo AIH. In adults, hepatitis C (HCV) is the most common indication for LT and HCV often recurs after LT, requiring treatment with Interferon and Ribavirin. Labeling the graft dysfunction ‘de novo AIH’ can be problematic in this context, particularly if HCV RNA is positive at that time. Some have chosen to give other names like ‘graft dysfunction mimicking AIH’ and ‘plasma cell hepatitis’. Regardless of the nomenclature, autoimmune liver graft dysfunction, if managed appropriately with the treatment regimen used to treat AIH, can save grafts and patients. The mechanism causing recurrent or de novo AIH after LT remains unknown. Several mechanisms have been implicated in this loss of self-tolerance including impaired thymic regulation, impaired activity of T regulatory cells, molecular mimicry, calcineurin inhibitors, glutathione-s transferase and genetic polymorphisms. While the phenotype of de novo AIH in pediatrics has been uniform, it has been more variable in adults, highlighting the need for uniform diagnostic criteria or scoring system post LT. Better understanding of the development of autoimmunity and its difference from classical rejection after LT will allow better therapeutic strategies and improved outcome.     

Hepatocellular carcinoma in chronic hepatitis C: from bench to bedside

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and seventh in women, accounting for 7 % of all cancers, and the third cause of cancer-related death worldwide. Nearly 90 to 95 % of all HCC occur in the context of known and often preventable risk factors, such as chronic viral hepatitis, alcohol abuse, and metabolic disorders. Although several experimental lines of research support a direct role for hepatitis C virus (HCV) in cancer promotion, cirrhosis is the main risk factor for this tumor, whereas other factors like alcohol and tobacco smoking are clearly able to accelerate HCC development. For this reason, cirrhotic patients with chronic HCV infection are subjected to abdominal ultrasound surveillance every 6 months, aimed at an early diagnosis of HCC to allow curative treatment options. Current strategies to positively impact on HCC incidence rates in HCV patients include prevention of cirrhosis development by avoiding metabolic, pharmacological, or social factors associated with accelerated progression of liver disease, or through virus eradication by interferon-based treatments. Moreover, a successful antiviral treatment has the added benefit of positively impacting on the rate of HCC development also in patients who are already cirrhotic.     

Various extrahepatic manifestations caused by hepatitis C virus infection

It has been reported that hepatitis C virus (HCV) causes not only liver disease but also disorders of other organs and tissues. Previously, many HCV-related extrahepatic manifestations have been reported. In this study, we report 2 patients in whom tongue cancer was detected during the treatment of HCV-related liver disease. In one patient, tongue cancer was detected during the treatment of HCV-related liver cirrhosis, and articular rheumatism developed thereafter. The duration of HCV-related liver disease was 10 years. In the other patient, tongue cancer was detected during the treatment of HCV-related hepatocellular carcinoma. This patient had a past history of thyroid disease. The duration of HCV-related liver disease was 6 years. In these patients, the possibility that several conditions incidentally and concurrently developed cannot be denied. However, the conditions described above may be regarded as HCV-related extra-hepatic manifestations. In patients with HCV infection, it is important to examine conditions in organs other than the liver. Careful follow-up is needed.     

Experience of orthotopic liver transplantation in 11 patients with liver cirrhosis from Korea: medical factors affecting outcome.

Orthotopic liver transplantation (OLT) has evolved to become a standard treatment of choice for end-stage liver diseases. The present study was performed to evaluate the peri-operative medical factors affecting transplantation outcome and to determine if patients with type B viral cirrhosis were acceptable for OLT. A total of 11 patients with end-stage cirrhosis, who have received OLT in Kangnam St. Mary''s Hospital since May 1993, included 8 HBV-related cases, 1 Hepatitis C Virus (HCV)-related case, and 2 non-B, non-C cases. One-year cumulative survival rate by Kaplan-Meier method was 43.7%. Factors significantly associated with 1-year survival of the recipients during pre-OLT period were performance status and modified Pugh-Child score (p=0.015 and p=0.015, respectively). Among those 4 patients who lived longer than 1 year, 3 of 4 patients with HBsAg-positive had no HBV re-infection with our protocol. These results suggest that, to improve the outcome of OLT in cirrhosis patients, transplantation should be performed in the stage when patients maintain better performance and hepatic functional reserve during the end-stage of liver cirrhosis. In addition, patients with cirrhosis caused by HBV infection may be indicated for OLT, because HBV re-infection is preventable effectively with a high-dose hepatitis B immunoglobulin protocol.