Clinicopathologic findings of recurrent primary sclerosing cholangitis after orthotopic liver transplantation

Whether primary sclerosing cholangitis (PSC) occurs after orthotopic liver transplantation is controversial, largely because the pre-transplant diagnosis of PSC is based on nonspecific radiological and histological findings. We reviewed clinical, radiological, and histological records of 53 patients who underwent liver transplantation for PSC between 1985 and 1998. Three patients with patent hepatic arteries and no evidence of chronic rejection had radiological and histological findings that may have been due to recurrent PSC. Bile duct stricturing in these patients proved permanent and progressive and affected both the quality of life and graft survival. The first patient, who is 110 months after transplantation, has had repeated episodes of cholangitis for the last year. The second patient underwent excision of a strictured hepatic duct 45 months after transplantation and was ultimately retransplanted 95 months after initial transplantation. The third patient underwent left hemihepatectomy of an atrophied lobe 50 months after transplantation. Although the patient population assessed in this study is limited, putative recurrent PSC in the allografts has led either to graft loss or to clinically significant hepatobiliary complications of the graft.     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.     

Recurrence of primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation in Japan

Although there was some initial controversy, there is now a consensus that primary biliary cirrhosis (PBC) does indeed recur in both cadaveric and living donated allografts. Recurrence rate after deceased donor liver transplantation (LT) was reported to be 10.9–23% at 5 years. In the present study, we reviewed 221 PBC patients who underwent living-donor liver transplantation (LDLT) in Japan. The 5-year overall survival rate was 79%, and the rate of recurrence based on histological findings was 10% (7/70) after a median time of 36 months. Primary immunosuppression, withdrawal of corticosteroids and human leukocyte antigen matches were not associated with the recurrence. Recurrent PBC appears to have little impact on graft function and survival, but this may become a greater problem with longer follow up.
It is noteworthy that the 10-year survival of primary sclerosing cholangitis (PSC) patients who underwent LDLT wasfound to be only 39.1% in Japan, whereas that of PBC was 72.9%. Factors associated with the poor prognosis include biliary strictures, hepatobiliary and colorectal malignancies, and recurrence of PSC. In our study, we reviewed 66 patients with PSC who underwent LDLT in Japan. The 5-year survival rate was 72%, and the rate of recurrence diagnosed on histological and cholangiographic findings was 25% (11/44). Well-defined diagnostic criteria and longer studies are required to characterize the nature of recurrent PSC and its impact on graft survival in more detail.     

Possible benefit of splenectomy in liver transplantation for autoimmune hepatitis

Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.     

Disease recurrence after liver transplantation in Western Australia

BACKGROUND AND AIM: Orthotopic liver transplantation (OLT) is now the accepted therapy for end-stage chronic liver disease. Long-term survival is now expected in the majority of patients and, consequently, disease recurrence has emerged as a major concern. Our aim was to document the rate of disease recurrence after liver transplantation for conditions other than hepatitis C, in patients followed up by the Western Australian Liver Transplant Service (WALTS). METHODS: The case notes of all post-OLT patients followed up by WALTS were reviewed. Patients were excluded if survival was less than 3 months post-OLT; OLT was performed for hepatitis C alone or follow up was unavailable. Detection and definition of disease recurrence depended on pretransplant diagnosis, and were based on patient interview, biochemical, immunological and serological tests. Radiological and histological confirmation were obtained where clinically indicated. RESULTS: Eighty-seven patients were identified (89 OLTs performed). The overall rate of recurrence was 10%. Recurrence rates by disease were: primary sclerosing cholangitis (17%), primary biliary cirrhosis (12%), autoimmune hepatitis (17%), hepatitis B (40%) and alcoholic liver disease (4%). Alcohol use relapse after transplantation occurred in 25%. The overall survival post-OLT was 87%, with a mean follow up of 53 months. Survival in patients with recurrent disease was 89%. CONCLUSIONS: Disease recurrence after OLT does occur, but overall, it is relatively uncommon. Recurrence rates vary significantly and depend, in part, on indication for OLT. With medium-term follow up, recurrent disease does not have an effect on mortality.     

Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation

Viral hepatitis and malignancy frequently recur after transplantation, but recurrence of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis is controversial. Differences in study design, number of patients, immunosuppressive treatment, length of follow-up, and criteria for recurrence account for discrepant results. Most patients with suspected recurrent disease are asymptomatic after transplantation. In patients transplanted for PBC, antimitochondrial antibodies frequently persist and do not correlate with disease recurrence; liver biopsy remains the gold standard for diagnosis. Exclusion of other disorders that can mimic PBC is paramount prior to making a diagnosis of recurrent disease. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies will be necessary to address the impact of disease recurrence on the allograft. Due to lack of a diagnostic gold standard, a diagnosis of recurrent PSC after transplantation is difficult to make. An accurate diagnosis of PSC recurrence requires well-defined cholangiographic and histologic criteria. Other disorders that can produce biliary strictures after transplantation should be excluded. As with PBC, the effects of immunosuppression may modify or delay disease expression within the graft; medium-term patient and graft survival is excellent. Recurrence of autoimmune hepatitis is based on clinical, biochemical, serologic, and histologic criteria. As in patients transplanted for PBC and PSC, other conditions that can mimic autoimmune hepatitis require exclusion prior to making a diagnosis of recurrence. Most adult recipients respond to an increase in immunosuppression, whereas pediatric recipients do not respond as well. A cautious approach to withdrawal of immunosuppression is warranted in all patients transplanted for autoimmune hepatitis and the consequences of recurrent disease within the graft will require prolonged follow-up. Future studies should focus on preventive and therapeutic strategies for recurrent autoimmune diseases after transplantation.     

Clinical relevance of recurrence of primary biliary cirrhosis after liver transplantation.

Review of the literature shows that recurrence of primary biliary cirrhosis occurs in about 10% of patients in the first few years after liver transplantation. The cumulative risk is expected to increase in time. The rate of recurrent disease may be affected by the immunosuppression used. Weaning from immunosuppression may initiate recurrence. Disease progression is slow and no reason for graft loss.     

Treatment of hepatitis B and C following liver transplantation

Advanced liver disease from hepatitis B virus (HBV) and hepatitis C virus (HCV) is the leading indication for orthotopic liver transplantation (OLT) worldwide. Our understanding of recurrent liver disease related to HBV and HCV in the setting of OLT has evolved rapidly in the past decade. Recurrent viral hepatitis may lead to graft failure, death, or the need for retransplantation. Until about a decade ago, HBV was considered a contraindication to OLT due to its frequent recurrence and development of associated liver disease. Medical therapy with hepatitis B immune globulin and nucleoside analogues has diminished the risk of HBV recurrence and led to improvement in patient and graft survival. Consequently, OLT is now considered to be the standard of care in patients with end-stage liver disease related to HBV. HCV recurrence after OLT is almost universal. Although short-term survival in patients undergoing OLT for HCV is similar to survival for those transplanted for other indications, recurrent HCV may have an impact on long-term patient and graft survival. A specific and effective therapy has not been defined for recurrent HCV following transplantation, but the combination of interferon and ribavirin appears promising. Optimal strategies to eradicate these viruses or to slow disease progression are continually being investigated in light of the disparity between supply and demand in a diminishing organ pool for OLT candidates.     

Histological recurrence of autoimmune liver diseases after living-donor liver transplantation

Background:  The effects of living donor liver transplantation (LDLT) on the recurrence of autoimmune liver diseases have not been well documented. Genetic similarities may be beneficial to avoid severe rejection but may facilitate the recurrence of autoimmune diseases. Because familial occurrence of autoimmune liver diseases has been documented, there is a possibility that candidates for living-related donors may have the same disease as that of the recipients.
Method:  Between November 1994 and June 2004, 50 patients with primary biliary cirrhosis (PBC) (16-non-blood-relative donors and 34 blood-relative donors), and 28 patients with primary sclerosing cholangitis (PSC) underwent LDLT in Kyoto University Hospital.
Results:  Among 35 patients with PBC who survived more than 1 year, 10 patients (29%) showed recurrent PBC, and nine of 10 patients with recurrent PBC (90%) were associated with blood-relative donors (mean follow-up period, 30 months; range, 2–68). Two recipients had donors with some clinical or histological characteristics of PBC, and their grafts developedrecurrent PBC. Cirrhosis or graft failure was not observed in any patients with recurrent PBC. For PSC patients who survived more than 1 year after LDLT, 13 of 22 (59%) showed PSC-compatible histology and radiological findings (mean follow-up period, 31 months; range, 22–71), and five died or underwent retransplantation. Human leukocyte antigen-DR15 was positively associated with susceptibility to PSC with ulcerative colitis. One donor was revealed to have retroperitoneal fibrosis without evidence of sclerosing cholangitis.
Conclusions:  Blood-relative donors may be associated with susceptibility to recurrent autoimmune diseases. Recurrence of PSC, but not PBC, adversely affected the outcome of LDLT. Caution should be taken as blood-relative donors can be at risk of autoimmune liver diseases.     

Preliminary clinical experience in liver retransplantation

BACKGROUND: The past several decades have witnessed increasingly successful rates of liver transplantation. However, retransplantation remains the only choice for patients with irreversible graft failure after primary transplantation. This article aimed to summarize our clinical experience in liver retransplantation. METHODS: From June 2002 to December 2005, a total of 185 cases of liver transplantation including 8 cases of retransplantation were performed in our hospital. The clinical data were analyzed retrospectively. RESULTS: The rate of liver retransplantation was 4.32%. Retransplantation was indicated for the following reasons: biliary complication (3 cases), chronic rejection (2), hepatic artery thrombosis (1), uncontrollable acute rejection (1) and hepatitis B recurrence (1). The mean model of end-stage liver disease (MELD) scores before primary transplantation and retransplantation were 15.6 and 23.9, respectively (P<0.05). The MELD score reflected the severity of liver disease more precisely than the Child classification. The mean interval between the first and second transplantation was 316 days (78-725 days). The first three patients, with mean interval of 101 days, died of severe infection combined with multiple organ failure after retransplantation. The patients who underwent retransplantation more than six months after the first transplant had better outcomes. The one-year survival rate for retransplantation in our group was 62.5%. CONCLUSIONS: Liver retransplantation is the only means of saving the patient with hepatic allograft failure. Understanding of the indications for retransplantation,careful selection of operation timing, excellent surgical skills and meticulous postoperative management all contribute to the success of each case of retransplantation.     

Successful living donor liver transplantation using a graft from a hepatitis B surface antigen-positive donor.

BACKGROUND/AIMS: Liver transplantation using a graft from a donor with a positive hepatitis B surface antigen (HBsAg) has been contraindicated owing to the extremely high risk for recurrent disease leading to graft loss. However, the severe shortage of donors often forces the transplant community to utilize suboptimal donors, especially in the setting of living donor liver transplantation (LDLT). METHOD: Here, we report a case of successful LDLT for a patient with hepatitis B-related cirrhosis utilizing a graft from an HBsAg-positive 'healthy carrier' donor using a combination prophylaxis of lamivudine and adefovir dipivoxil. RESULTS: To date, the patient has been doing well with normal liver function tests and liver histological findings at 4 years after the transplantation and the donor has also been doing well. CONCLUSIONS: Although virological recurrence appears to be universal despite prophylaxis, re-evaluation of the use of a graft from a healthy HBsAg-positive donor is warranted in this era of combination prophylaxis.     

“Weighing the risk”: Obesity and outcomes following liver transplantation

Obesity is on the rise worldwide. As a result, unprecedented rates of patients are presenting with end stage liver disease in the setting of non-alcoholic fatty liver disease(NAFLD) and are requiring liver transplantation. There are significant concerns that the risk factors associated with obesity and the metabolic syndrome might have a detrimental effect on the long term outcomes following liver transplantation. In general, short term patient and graft outcomes for both obese and morbidly obese patients are comparable with that of non-obese patients, however, several studies report an increase in peri-operative morbidity and increased length of stay. Continued studies documenting the long-term outcomes from liver transplantation are needed to further examine the risk of recurrent disease(NAFLD) and also further define the role risk factors such cardiovascular disease might play long term. Effective weight reduction in the post liver transplant setting may mitigate the risks associated with the metabolic syndrome long-term.     

Recurrence of diseases following orthotopic liver transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.     

Treatment of recurrent hepatitis C following liver transplantation

Cirrhosis due to hepatitis C virus infection is now the most common indication for liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent hepatitis C virus infection is almost inevitable. Although the natural history and intermediateterm outcome of recurrent infection with hepatitis C virus are now better documented, factors that may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon used as a single agent for the treatment of recurrent infection has proven unsatisfactory. Early intervention for recurrent infection with the combination of interferon and ribavirin appears promising, and this approach may prevent or delay progression of hepatitis C virus-related graft disease after liver transplantation     

原发性胆汁性肝硬化肝移植术后合并多发性肌炎一例并文献复习

目的探讨原发性胆汁性肝硬化合并多发性肌炎的临床特点、鉴别诊断及其治疗。方法报道本院原发性胆汁性肝硬化、肝移植术后合并多发性肌炎一例并复习相关文献。结果患者为49岁女性,确诊原发性胆汁性肝硬化7年,肝移植术后1年出现肌无力、心悸,血清肌酶升高,肌电图、肌活检符合多发性肌炎表现。在排除其他免疫性疾病、药物性肌炎、肿瘤相关肌炎和移植物抗宿主反应后,临床诊断为多发性肌炎。加强免疫抑制治疗后病情好转。结论原发性胆汁性肝硬化肝移植后有可能合并多发性肌炎,但临床上应注意鉴别诊断．除外可能引起多发性肌炎的其他因素;治疗上应加强免疫抑制。     

Hepatitis B and C in the liver transplant recipient

Liver disease related to chronic viral hepatitis is the leading indication for orthotopic liver transplantation (OLT) worldwide. The evolution of our understanding of hepatitis B and C infection in the OLT recipient has been rapid in the last decade. The spontaneous risk for viral recurrence after transplantation is high but has been effectively decreased in hepatitis B infected recipients with the use of HBIG and lamivudine with dramatic improvements in patient and graft survivals. HCV recurrence as defined by histologic injury is almost universal although graft or patient outcomes for the first decade after OLT do not appear to be limited by HCV infection for most patients. However, individual patients do suffer severe graft injury and even graft loss due to recurrent HCV. With longer follow up into the second decade, the prevalence of HCV-related graft failure is likely to increase. In addition, the role of different immunosuppressive protocols on disease recurrence requires further study. Thus, although hepatitis B recurrence has been effectively contained by use of HBIG with or without lamivudine, the more intractable problem of managing recurrent HCV has as yet no obvious solutions. Optimal antiviral strategies for hepatitis C post-OLT have yet to be identified.     

Recurrence of primary sclerosing cholangitis after living donor liver transplantation.

BACKGROUND/AIMS: Cumulative experience in deceased donor liver transplantation for end-stage liver disease due to primary sclerosing cholangitis (PSC) suggests that liver transplantation is the treatment of choice with excellent results. Reports on the outcome of live donor liver transplantation (LDLT) for PSC, however, remain anecdotal. METHODS: The clinical course and genetic disposition of nine patients who underwent LDLT for PSC were analyzed. The median follow-up period was 3.5 years. RESULTS: Cumulated 5-year patient and graft survival rates were 90% and 71%, respectively. Recurrent PSC was diagnosed in four patients. Ratios of freedom from recurrent PSC at 1, 3, and 5 years were 100%, 73%, and 49%, respectively. The mean time to recurrence was 3.3 years. Excluding the one case with a biologically unrelated donor, recurrent PSC was diagnosed in 50% (4/8). None of the patients presented with the human leukocyte antigen-B8DR3 haplotype, which is associated with a higher susceptibility for developing PSC among the Caucasian population. Overall patient survival of LDLT for PSC seems to equal that of deceased donor liver transplantation. CONCLUSIONS: PSC might recur earlier at a higher ratio after LDLT. Further study with protocol cholangiogram and genetic considerations, including high resolution human leukocyte antigen haplotype analysis, is necessary.     

Hepatitis C virus and liver transplantation

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation in North America and Europe. While hepatitis C recurrence is common after transplantation, 5-year graft and patient survival in HCV-infected patients are similar to those of patients transplanted for other chronic liver diseases. With longer periods of follow-up, the proportion of patients with fibrosis or cirrhosis increases and graft loss does occur because of recurrent disease. Both viral and host factors have been linked to risk of disease progression. Specific therapies to eradicate infection or slow down disease progression are under study, and the most promising results to date have been obtained with combined interferon and ribavirin.     

Recurrence of primary biliary cirrhosis after orthotopic liver transplantation

BACKGROUND/AIMS: The incidence of graft failure due to recurrence of primary biliary cirrhosis after liver transplantation and the clinical value of histological and serological parameters indicating a recurrence are still discussed controversially in the literature. METHODOLOGY: In a retrospective study 18 patients who had received orthotopic liver grafts for primary biliary cirrhosis were investigated for recurrence of disease. Histological findings, the appearance of primary biliary cirrhosis associated autoimmune diseases, the course of antimitochondrial antibodies, serological parameters of liver function and HLA status were evaluated. RESULTS: During a median follow-up period of 114 months, 6 of 18 patients developed a recurrence of primary biliary cirrhosis as indicated by liver biopsies, one patient developed clinical graft failure together with histological recurrence. Twelve patients developed autoimmune diseases. Antimitochondrial antibodies were present in all patients within a period of 12 months after transplantation. Serological parameters were elevated in 16 of 18 patients. Histological findings, serological parameters and associated diseases did not correlate with each other and with clinical symptoms of primary biliary cirrhosis recurrence. CONCLUSIONS: Graft failure due to recurrent disease can occur, but, despite a follow-up period of nearly 10 years, it is not possible to define predictive factors on the basis of histology or serology.     

Hepatitis C virus recurrence after liver transplantation

Cirrhosis due to hepatitis C virus (HCV) is now the most common indication of liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent HCV infection is almost inevitable. Though the natural history and intermediate term outcome of recurrent HCV are now better documented, those factors which may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon (IFN) as a sole agent for the treatment of recurrent infection has proved unsatisfactory. Early intervention with a combination of IFN and ribavirin seems promising, and this approach may prevent or delay progression of HCV related graft disease after liver transplantation.