Recurrent Primary Biliary Cirrhosis Research Articles

Impact of human leukocyte antigen mismatching on outcomes of living donor liver transplantation for primary biliary cirrhosis

We read with great interest the recent article from the Kyoto group regarding primary biliary cirrhosis (PBC) patients after living donor liver transplantation (LDLT).1 Of 50 patients, 14 died within 6 months after LDLT, and 9 patients showed recurrence with a median follow-up duration of 36 months. The Kyoto group emphasized that the large number of patients with a human leukocyte antigen (HLA) mismatch was related to the poor survival and high recurrence rates. This finding, however, is in contrast to our experience. HLA, human leukocyte antigen; LDLT, living donor liver transplantation; MELD, model for end-stage liver disease; PBC, primary biliary cirrhosis; UMRS, updated Mayo risk score. From September 1997 to July 2006, 64 patients with PBC underwent LDLT procedures at the University of Tokyo Hospital. We have no exclusion criteria in LDLT for PBC in terms of preoperative conditions expressed by the updated Mayo risk score (UMRS)2 or model for end-stage liver disease (MELD) score.3 There were 9 men and 55 women with a median age of 52 years (range: 35-66 years). The median preoperative UMRS and MELD score were 10 (range: 6-14) and 14 (range: 2-39), respectively. The living donors consisted of 34 men and 30 women with a median age of 35 years (range: 20-66 years). There were 54 blood-relative donors (35 offspring, 14 siblings, 1 parent, 1 aunt, 1 cousin, 1 nephew, and 1 niece) and 10 non–blood-relative donors (10 spouses). The median follow-up period was 45 months (range: 0-109 months). Of the 7 patients that died after LDLT, 5 died within 6 months. The causes of death were pneumonia (n = 2), brain hemorrhage (n = 1), simultaneous thrombosis of the portal vein and hepatic artery (n = 1), and chronic rejection (n = 1). The remaining 2 patients died of pneumonia (n = 1) and virus-associated hemophagocytic syndrome (n = 1). The 1-year, 3-year, and 5-year patient survival rates were 92%, 90%, and 88%, respectively. A total of 84 biopsies were performed in 37 patients. Acute rejection was diagnosed in 24 patients. Biopsy specimens confirmed that there was no recurrence of PBC. The 5-year survival rate for patients receiving grafts from blood-relative donors (n = 54) was 87% and was not statistically different from that for patients receiving grafts from non–blood-relative donors (n = 10, 90%, P = 0.98). A univariate survival analysis revealed no statistical difference in other factors, including the UMRS, MELD score, donor age, and graft weight/standard liver volume ratio. Complete HLA typing information for both the recipient and donor was obtained from 60 patients. Of these, 6 patients died after LDLT. The survival rate was not affected by the number of HLA-type mismatches (Fig. 1). Survival rate stratified by the total number of mismatches in HLA-A, HLA-B, and HLA-DR loci. The cause of death should be determined to be immunologic or nonimmunologic when the impact of the positive graft on survival is considered. It is difficult to determine whether all of these deaths were associated with immunologic mechanisms because the causes of death in the Kyoto group's cohort were not explained in detail. Because the strategy of LDLT for patients with PBC in the Kyoto group is not so different from ours, its findings regarding the impact of HLA mismatching on the outcome of LDLT for PBC cannot be accepted as universal. Takuya Hashimoto*, Yasuhiko Sugawara*, * Masatoshi Makuuchi, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.

New insights from recurrent primary biliary cirrhosis in liver transplantation: The paradox of BEComing a fibroblast?

New insights from recurrent primary biliary cirrhosis in liver transplantation: The paradox of BEComing a fibroblast?

Anti-parietal cell autoantibodies (PCA) as serological marker of recurrent primary biliary cirrhosis after liver transplantation

Liver transplantation (OLT) for primary biliary cirrhosis (PBC) is characterized by disease recurrence of up to one third of patients. The diagnosis of recurrence requires a cholestatic profile and a typical histology representing a challenge for transplant hepatologists. Antimitochondrial antibodies (AMA) establish the initial diagnosis, persist after OLT, and are thus of limited value for the diagnosis of recurrence. Aim of this analysis was to identify serological parameters associated with recurrent PBC.

Lebertransplantation bei primär biliärer Zirrhose: Retrospektive Analyse eines Zentrums

Currently liver transplantation (LTx) is the only effective curative therapy of end-stage primary biliary cirrhosis (PBC). Recent data have shown a recurrence rate of up to 32%. However, many studies are based on only a small number of patients with a marginal follow-up below 10 years. It was the aim of this study to analyse survival and complication rates after LTx among 100 patients in a long-term follow-up of up to 17 years. Between 1989 and 2006 data of 115 patients receiving LTx for PBC at the Charité Campus Virchow were retrospectively analysed. The median age of 89 women (84%) and 17 men (16%) was 54 years (25-67). Actuarial patient survival rate after 10 and 17 years was 88% and 83%. 13 patients (12%) died after a median survival time of 42 months (0.5-136). Two of these patients developed organ dysfunction due to recurrence of PBC. In addition, histological recurrence was found in 17 patients (16%) after a median time of 61 months (36-158). Survival analysis of hospital stay, preoperative Child-Pugh score, rejection episodes, PBC recurrence and retransplantation showed no significant results. Long-term follow-up of up to 17 years after liver transplantation for primary biliary cirrhosis showed excellent survival rates. Both the amount and severity of postoperative complications and the preoperative Child-Pugh score did not affect the long-time survival rate significantly.

Long‐term follow‐up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1,553 liver transplantations were performed in 1,415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n = 54) or tacrolimus (Tac) (n = 46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p < 0.05) and also earlier (p < 0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.

Recurrence of autoimmune liver disease after liver transplantation: A systematic review

Recurrence of autoimmune liver disease in allografts has long been a topic of debate. We conducted a systematic review of the literature to examine the reported incidence of recurrence after liver transplantation of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). The MEDLINE, EMBASE, and Cochrane electronic databases were used to identify articles. The inclusion criteria used were articles on patients with at least 90 days of posttransplantation follow-up, histologic criteria for diagnosis of PBC and AIH recurrence, radiologic or histologic criteria or both for diagnosis of PSC recurrence, and exclusion of other causes of liver disease causing similar histologic findings. Incidence in individual studies was combined to calculate the overall recurrence. Risk factors were analyzed whenever crude data were available. Funnel plots were used to assess publication bias. Out of 90 articles identified, 43 met criteria for systematic review (PBC, 16; PSC, 14; AIH, 13). The calculated weighted recurrence rate was 18% for PBC, 11% for PSC, and 22% for AIH. No difference was found in PBC and AIH recurrence by type of primary immunosuppression. There were not enough data to assess this issue in PSC studies. There was evidence of publication bias among PSC and AIH studies but not among PBC studies. In conclusion, recurrence of autoimmune liver disease after liver transplantation appears to be a real concern. As these patients are followed long-term, recurrence of disease may become the primary cause of morbidity.

Liver biopsy interpretation for causes of late liver allograft dysfunction

Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.

Impact of human leukocyte antigen mismatching on outcomes of living donor liver transplantation for primary biliary cirrhosis

Patient selection criteria of deceased donor liver transplantation for primary biliary cirrhosis (PBC) are almost completely established. The aim of this study was to establish selection criteria for both patients and donors of living donor liver transplantation (LDLT) for PBC. We used univariate and multivariate analyses to examine patient and donor characteristics of our first 50 cases of LDLT for PBC to elucidate factors that significantly impacted patient survival or disease recurrence after LDLT in the univariate and/or multivariate analyses. Multivariate analysis demonstrated that the presence of persistent ascites before LDLT, a higher number of human leukocyte antigen (HLA)-A, -B, and -DR mismatches between donor and recipient, and donor age >or=50 years were factors significantly associated with early posttransplant death. Independent risk factors for PBC recurrence after LDLT were a lower number of HLA mismatches between donor and recipient, and a lower average trough level of tacrolimus within 1 year after LDLT. Specifically, the lower the number of HLA-A, -B, and -DR mismatches or the average trough level of tacrolimus within 1 year after LDLT, the higher the possibility of developing a recurrence of PBC. In conclusion, the absence of persistent ascites before LDLT, a lower number of HLA-A, -B, and -DR mismatches between donor and recipient, and a younger donor (<50 years) are preferred for gaining acceptable survival outcomes for the transplant. However, a lower number of HLA-A, -B, and -DR mismatches between donor and recipient may be a risk factor for PBC recurrence.

Living donor liver transplantation for primary biliary cirrhosis: retrospective analysis of 50 patients in a single center

Summary Although living donor liver transplantation (LDLT) is accepted as an alternative therapy for primary biliary cirrhosis (PBC), the postoperative results are not well known. Fifty patients with PBC underwent LDLT at Tokyo University Hospital. Their clinical records were retrospectively analyzed. Postoperative death occurred in four patients within 2 months (mortality, 8%), while later death occurred in three patients. In the median follow-up period of 35 months (range 4-84 months), the 1, 3, and 5-year overall survival rates were 90%, 88%, and 80%, respectively. The laboratory data indicated that graft function was sufficient. No recurrence of PBC was confirmed. Multivariate analysis indicated that an updated Mayo score of <10 was a significantly favorable factor for short hospitalization (hazard ratio, 9.52; 95% confidence interval, 1.14-79.5; P = 0.03). In conclusion, LDLT provides a satisfactory long-term survival with the PBC patients.

Long-Term Immunosuppression for Prevention of Nonviral Disease Recurrence

The choice of immunosuppressive regime used after liver transplantation depends on many factors, which should include the effect of disease recurrence; recurrence of disease after liver transplantation may be affected by the degree and type of immunosuppression used and recurrent disease may affect patient and graft survival. For autoimmune diseases, recurrence of primary biliary cirrhosis develops sooner and more rapidly in those on tacrolimus compared with cyclosporine, but graft loss from recurrent disease is uncommon; recurrence rates of primary sclerosing cholangitis is unaffected by immunosuppressive regimes and recurrence of autoimmune hepatitis may be reduced by prescription of corticosteroids. Whether the immunosuppressive regime affects the pattern of hepatocellular carcinoma recurrence is uncertain. It is probable that the use of calcineurin inhibitor does not have a significant effect and inhibitors of TOR may have an anti-cancer effect, but this still has to be shown clinically. Most metabolic diseases are not affected by the choice of immunosuppression, although recurrence of sarcoidosis may be prevented by corticosteroids.

Liver Transplantation for Primary Biliary Cirrhosis: Influence of Primary Immunosuppression on Survival

Introduction Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. Patients and methods Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). Results The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly ( P = .001) more side effects. Conclusion Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.

Recurrent primary biliary cirrhosis: Peritransplant factors and ursodeoxycholic acid treatment post-liver transplant

Primary biliary cirrhosis (PBC) recurs after orthotopic liver transplantation (OLT) in up to one-third of patients. These patients are typically asymptomatic, can be identified by abnormal liver biochemistries, and have evidence of histologic recurrence on liver biopsy. The effect of treatment on recurrence has not been determined. This pilot study evaluates the factors associated with recurrent PBC and describes our experience using ursodeoxycholic acid treatment in this patient population. Forty-eight patients with PBC were followed for at least 1 yr post-OLT, and 27 patients (56%) developed abnormal serum alkaline phosphatase. Seventeen patients (35%) had evidence of recurrent PBC by liver biopsy. Patients with recurrent PBC had a trend toward longer warm ischemia times and more episodes of acute cellular rejection in the first year posttransplant, but this was not significant in multivariate analysis. Donor or recipient age, donor and recipient cytomegalovirus status, and dose of immunosuppression did not correlate with recurrence of PBC. Those patients diagnosed with recurrent PBC were placed on ursodeoxycholic acid, 15 mg/kg daily, with improvement in serum alkaline phosphatase in the majority. In conclusion, recurrent PBC is not infrequent post-OLT, and ursodeoxycholic acid can be used with some benefit post-OLT. Treatment effects on long-term survival are not known.

Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation.

Identifying the risk factors associated with recurrence of primary biliary cirrhosis after liver transplantation may affect immunosuppression and increase understanding of the pathogenesis. Four hundred eighty-five patients with PBC were followed for a median of 79 months after transplantation; histological evidence of recurrence was found in 23%. On multivariate analysis, the only risk factor identified with recurrence was the type of calcineurin inhibitor used. The odds ratio for recurrence on tacrolimus was 2.73 (95% confidence interval: 1.84-4.10) compared with cyclosporine. For those receiving cyclosporine, the median time to recurrence was 123 months and for those on tacrolimus 62 months (P <.001). Reasons for this difference between the 2 calcineurin inhibitors are not clear.

The changing clinical presentation of recurrent primary biliary cirrhosis after liver transplantation.

Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years. The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically. Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11). Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.

Recurrence of primary biliary cirrhosis after liver transplantation: Histologic estimate of incidence and natural history

The goals of this study were to determine the rate of recurrent primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT) based on strict morphologic criteria and to evaluate histologic progression of recurrent PBC over time. Strict criteria for PBC recurrence were established as the presence of a florid duct lesion or destructive lymphocytic cholangitis within a dense portal infiltrate. Of the 784 OLTs performed at the Mayo Clinic during the first 12 years of the program, 100 met criteria for the PBC study group, and 35 met criteria for the control group. Strict histologic criteria for recurrent PBC were observed in 17 of 100 (17%) study patients (14 with florid duct lesion, 3 with destructive lymphocytic cholangitis within dense portal infiltrate). Mean follow-up for the PBC group was 4.7 years (range, 1.0 to 13.8). Mean time to recurrence was 3.7 years (median, 3.1; range, 0.3 to 7.9). In those who met strict criteria for recurrent PBC, 2 of 17 progressed to septal fibrosis (stage 3). No florid duct lesions, destructive lymphocytic cholangitis, or septal fibrosis were observed in the control group. Other less specific morphologic features of PBC (portal infiltrates, plasma cells, dense lymphoplasmacytic infiltrates, and lymphocytic cholangitis) were also evaluated in the course of this study. Based on strict criteria, a conservative histologic estimate of the rate of recurrent PBC is 17% with a mean of 4.7 years of follow-up. When criteria for histologic recurrence are expanded to include moderate lymphocytic cholangitis with lymphoplasmacytic portal infiltrate, the recurrence rate of PBC is estimated as 26%. (Liver Transpl 2003;9:1086-1093.)

Anti-CD25 and tacrolimus therapy may not prevent early primary biliary cirrhosis recurrence after liver transplantation: two case reports

Primary biliary cirrhosis (PBC) is an immune-mediated disorder of unknown cause characterized by progressive destruction of intrahepatic bile ducts and the presence of antimitochondrial antibodies. There is no known cure for PBC, and treatment generally includes various combinations of ursodeoxycholic acid and immunosuppressive agents. However, in most patients with end-stage PBC, liver transplantation offers a good quality of life. Recurrent PBC after transplantation is controversial, because most patients with suspected recurrent disease are asymptomatic. Antimitochondrial antibodies frequently persist and do not correlate with disease recurrence. However, most studies support disease recurrence within the graft. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survivals are excellent, but the long-term outcome remains unknown. Many immunosuppressive agents have been studied with regard to their anti-recurrence properties; however, no standard therapy has been established for this group of patients. In this study we present two patients transplanted for PBC who displayed early recurrence of disease confirmed by liver biopsy and elevated serum AMA. Both individuals received the same immunosuppressive regimen. The data suggest that two doses of daclizumab and tacrolimus monotherapy in the early posttransplant period is insufficient to prevent recurrence of PBC. Addition of glucocorticoids may have beneficial effects in these patients.

The effect of immunosuppressive regimens on the recurrence of primary biliary cirrhosis after liver transplantation

Recurrence of primary biliary cirrhosis (PBC) has been described in liver transplant recipients. Type of immunosuppression has been reported to influence the frequency of recurrence. The aim of this study is to evaluate the occurrence and pattern of recurrent PBC in our liver transplant recipients and determine any association of immunosuppressive agents with its recurrence. Patients who underwent orthotopic liver transplantation (OLT) for PBC were identified from the University of Chicago Liver Transplant Database. Recurrent PBC was diagnosed based on specific pathological criteria. Of 46 patients who underwent OLT for PBC between 1984 and 2000, a total of 7 patients (15%) were diagnosed with recurrent PBC at a median of 78 months (range, 27 to 120 months) after OLT. Forty-three percent of patients were administered cyclosporine, whereas 57% were administered tacrolimus before disease recurrence. Rates of recurrence were not different between patients maintained on cyclosporine therapy (16%) compared with those maintained on tacrolimus therapy (18%; P = 1.0). There also was no difference in frequency of rejection episodes or duration of corticosteroid therapy between those who did and did not have recurrent PBC. In conclusion, recurrent PBC developed in a small number of patients 2 years or longer after OLT. In our population, there was no difference in recurrence rates between those administered cyclosporine or tacrolimus for immunosuppression. ( Liver Transpl 2003;9:733-736.)

Recurrent primary biliary cirrhosis

Liver transplantation remains the only effective treatment for end-stage primary biliary cirrhosis (PBC). It appears now well accepted that the disease recurs in the allograft. The diagnosis of recurrent PBC is made on the basis of a consistent history and demonstrating the histologic features of PBC on liver biopsy and exclusion of other causes of bile duct damage. (Liver Transpl 2003;9:539-546.)

Liver Transplantation for Cholestatic Liver Disease.

Liver transplantation is an effective form of therapy for patients with end-stage cholestatic disease that improves both survival and quality of life. Liver transplantation is very effective for the treatment of intractable pruritus but less effective for the treatment of lethargy. Survival rates are good (more than 70% at 5 years); these patients are at greater risk of developing acute and chronic rejection and are more likely to require long-term immunosuppression. Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) recur in the graft. Recurrent PSC may be difficult to differentiate from secondary sclerosing cholangitis, but it recurs in up to 60% of patients at 5 years and may reduce graft survival. PBC recurrence, noted in up to 40% of patients at 10 years, has little effect on graft survival with respect to cancers. Patients with PSC are at greater risk of both colonic cancer (which may be reduced by ursodeoxycholic acid) and cholangiocarcinoma. Diagnosis of cholangiocarcinoma before transplantation usually contraindicates transplantation. The main challenges facing liver transplantation are the need to expand the donor pool and the need to find immunosuppressive regimens with fewer long-term toxicities.

Recurrence of primary biliary cirrhosis after liver transplantation

Recurrence of primary biliary cirrhosis after liver transplantation