tacrolimus and Liver-Cirrhosis--Biliary

Recurrent primary biliary cirrhosis (PBC) is frequently observed in patients with PBC after liver transplantation (LT). We performed a meta-analysis to evaluate the risk factors for PBC recurrence.. We searched the EMBASE, PubMed and the Cochrane Library databases for studies published before August 2020. Studies that identified the risk factors of PBC recurrence were eligible for inclusion. We extracted the hazard ratio (HR) data with 95% confidence intervals (CI) for the risk factors.. Our meta-analysis included 6 studies, which comprised 3184 patients (88.5% females) who underwent liver transplantation from 1982 to 2017, and of these patients, 935 (29.4%) developed PBC recurrence. The use of tacrolimus (HR = 2.62, 95% CI = 1.35, 5.09) and preventive ursodeoxycholic acid (UDCA) (HR = 0.40, 95% CI = 0.28, 0.57) were significantly associated with the risk of PBC recurrence based on the pooled analysis of the results obtained from the multivariate analysis.. The use of tacrolimus is associated with an increased risk of PBC recurrence. Preventive UDCA after LT for PBC can help to prevent disease recurrence.

Topics: Adult; Aged; Cholagogues and Choleretics; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Secondary Prevention; Tacrolimus; Ursodeoxycholic Acid

Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.. A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.. The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD.. Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cholangiocarcinoma; Cholangitis, Sclerosing; Colectomy; Cyclosporine; End Stage Liver Disease; Enzyme Inhibitors; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed.. To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence.. A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence.. Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B).. Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis.

Topics: Adult; Clinical Trials as Topic; Cyclosporine; Female; Graft Survival; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Recurrence; Steroids; Survival Rate; Tacrolimus; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC, primary biliary cirrhosis) is an autoimmune cholestatic liver disease characterized by chronic nonsuppurative destructive cholangitis and the presence of serum antimitochondrial antibodies. Ursodeoxycholic acid is the only drug approved by the US Food and Drug Administration to treat PBC. However, one-third of patients show incomplete responses to ursodeoxycholic acid and a poor prognosis. A number of old and new medications have been used in these patients, such as fibrates, glucocorticoids, immunosuppressants, obeticholic acid, mesenchymal stem cells, biological agents (anti-interleukin-12, cytotoxic T-lymphocyte antigen 4 immunoglobulin, anti-CD20), and antifibrotic drugs. This article reviews the therapeutic advances of these old and new medications in patients with PBC.

Topics: Abatacept; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cyclosporine; Enzyme Inhibitors; Fibric Acids; Glucocorticoids; Humans; Immunosuppressive Agents; Indoles; Liver Cirrhosis, Biliary; Mesenchymal Stem Cell Transplantation; Methotrexate; Mycophenolic Acid; Pyridones; Rituximab; Tacrolimus; Ursodeoxycholic Acid; Ustekinumab

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.

Topics: Azathioprine; Celiac Disease; Cholagogues and Choleretics; Cholangitis, Sclerosing; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Osteoporosis; Prednisolone; Pruritus; Tacrolimus; Ursodeoxycholic Acid

Recurrence of primary biliary cirrhosis in the liver allograft remains controversial.. We have examined the liver allograft biopsies taken at 1 and 2 years after transplantation from patients receiving either FK506 or cyclosporin as part of a multi-centre trial.. Histological features characteristic for primary biliary cirrhosis, including bile duct damage, ductopenia, bile duct proliferation and portal granulomas, were found more commonly and earlier after transplantation in patients receiving FK506 than cyclosporin. During the 2-year period, seven of 16 patients receiving FK506 and only one of 11 on cyclosporin had a graft biopsy suggestive of recurrent primary biliary cirrhosis.. These findings confirm earlier reports that features of primary biliary cirrhosis recur in the liver allograft in some patients and suggest that the rate of recurrence may be affected by the immunosuppression regimen used.

Topics: Adult; Biopsy; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Prospective Studies; Recurrence; Tacrolimus; Transplantation, Homologous

A randomized concentration-controlled clinical trial (RCCCT) is a trial design in which patients are randomized to predefined blood drug concentrations (low, medium, high). If the concentration ranges are sufficiently separated, this study design can reveal important blood concentration-response relations. Tacrolimus is a potent yet "infant" immunosuppressant for the treatment and prevention of graft rejection and has been shown to exhibit significant clinical activity in some immune-mediated disorders. A tacrolimus artificial intelligence modeling system (AIMS) was used to guide patient dosing to achieve target concentrations specified by the study protocols. In the Multiple Sclerosis study group, we were able to define a concentration range (0.3-0.7 ng/ml) that appeared to show efficacy and minimal tacrolimus toxicity. Patients randomized to the high zone (0.6-1.2 ng/ml) in the Primary Biliary Cirrhosis study group showed significant reduction (approximately 50%) in surrogate efficacy markers [aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT)] compared with patients in the low zone (0.1-0.6 ng/ml). Therefore the RCCCT allowed the detection and delineation of clinically significant concentration-response relations in an ethical and efficient manner.

Topics: Artificial Intelligence; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Multiple Sclerosis; Randomized Controlled Trials as Topic; Research Design; Tacrolimus

Primary biliary cholangitis (PBC) frequently recurs after liver transplantation. We evaluated risk factors associated with recurrence of PBC and its effects on patient and graft survival in a multicenter, international cohort (the Global PBC Study Group).. We collected demographic and clinical data from 785 patients (89% female) with PBC who underwent liver transplantation (mean age, 54 ± 9 years) from February 1983 through June 2016, among 13 centers in North America and Europe. Results from biochemical tests performed within 12 months of liver transplantation were analyzed to determine whether markers of cholestasis could identify patients with recurrence of PBC (based on histologic analysis). Patients were followed for a median 6.9 years (interquartile range, 6.1-7.9 years).. PBC recurred in 22% of patients after 5 years and 36% after 10 years. Age at diagnosis <50 years (hazard ratio [HR], 1.79; 95% CI, 1.36-2.36; P < .001), age at liver transplantation <60 years (HR, 1.39; 95% CI, 1.02-1.90; P = .04), use of tacrolimus (HR, 2.31; 95% CI, 1.72-3.10; P < .001), and biochemical markers of severe cholestasis (bilirubin ≥100 μmol or alkaline phosphatase >3-fold the upper limit of normal) at 6 months after liver transplantation (HR, 1.79; 95% CI, 1.16-2.76; P = .008) were associated with higher risk of PBC recurrence, whereas use of cyclosporine reduced risk of PBC recurrence (HR, 0.62; 95% CI, 0.46-0.82; P = .001). In multivariable Cox regression with time-dependent covariate, recurrence of PBC significantly associated with graft loss (HR, 2.01; 95% CI, 1.16-3.51; P = .01) and death (HR, 1.72; 95% CI, 1.11-2.65; P = .02).. Younger age at the time of diagnosis with PBC or at liver transplantation, tacrolimus use, and biochemical markers of cholestasis after liver transplantation are associated with PBC recurrence. PBC recurrence reduces odds of graft and patient survival. Strategies are needed to prevent PBC recurrence or reduce its negative effects.

Topics: Age of Onset; Biomarkers; Biopsy; Europe; Female; Graft Survival; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; North America; Recurrence; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Topics: Cholangitis, Sclerosing; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Recurrence; Tacrolimus

A case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.. Lesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.. There was no recurrence of lesions at 3 months follow-up.. Radiotherapy is an effective form of cutaneous directed treatment for localized PTLD.

Topics: Aged; Antibiotics, Antineoplastic; B-Lymphocytes; Carcinoma, Squamous Cell; Follow-Up Studies; Gamma Rays; Humans; Immunohistochemistry; Liver Cirrhosis, Biliary; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Although the development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults, autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome has rarely been seen in liver transplant recipients. Here, we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 years after LT. Standard autoimmune serological tests were positive for anti-nuclear and anti-mitochondrial antibodies, and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus. Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis, which confirmed the diagnosis of AIH-PBC overlap syndrome. We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome; a novel type of autoimmune overlap syndrome.

Topics: Cholagogues and Choleretics; Cholestasis; Fatty Liver, Alcoholic; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Prednisone; Tacrolimus; Treatment Outcome; Ursodeoxycholic Acid

In living donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC), the majority of donors are genetically related to their recipients, leading to concerns of an earlier recurrence of PBC and a poorer prognosis due to genetic susceptibility. Totally 81 patients who underwent LDLT for PBC were the subjects of the present study. Immunosuppressive agents consisted of tacrolimus and methylprednisolone. In the outpatient clinic, when the aspartate and alanine aminotransferase level exceeded the upper limit of the normal range, the dose of methylprednisolone was increased from 4 to 6 mg/day for several months. Blood was examined every 2 weeks for 3 months and a liver biopsy was performed when aminotransferase levels did not decrease to the upper limit of the normal range after more than 3 months. Five-year survival and recurrence rates were estimated and the prognostic factors were analyzed. The mean observation period was 6.2 years. Five years after LDLT for PBC, the biopsy-proven PBC recurrence rate was 1%. The 5-year patient survival rate was 80%. The nonrelated or blood-related donor factor and number of human leukocyte antigen matches did not correlate with prognosis. PBC recurrence rate after LDLT in our series was lower than that in previous studies.

Topics: Adult; Aged; Biopsy; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Prognosis; Recurrence; Tacrolimus; Treatment Outcome

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Up to one-third of patients with primary biliary cirrhosis (PBC) experience recurrent disease following liver transplantation, which is associated with earlier and more severe recurrence in patients treated with tacrolimus as compared with cyclosporine A (CsA). As the latter has known antiviral activity, we hypothesized that CsA has the ability to inhibit the betaretrovirus characterized from patients with PBC.. We investigated whether CsA, the cyclosporine analogue NIM811, tacrolimus and other compounds can modulate the mouse mammary tumour virus production from Mm5MT cells. Viral load was evaluated in the cell supernatants by quantifying reverse transcriptase (RT) levels and betaretrovirus RNA.. A significant correlation was observed with increasing concentrations of CsA and NIM811, and decreasing of RT levels (rho-0.59, P=0.04 and rho-0.74, P=0.006 respectively), whereas tacrolimus had no significant effect (rho-0.27, P=0.4). At a dose of 3 microg/ml, CsA, NIM811 and the human immunodeficiency virus aspartyl protease inhibitor, lopinavir, were all associated with greater than three-fold reduction in the betaretrovirus RNA production from Mm5MT cells as compared with tacrolimus (P<0.005).. These studies demonstrate that the cyclophilin inhibitors CsA and NIM811 have antiviral activity against betaretrovirus production in vitro.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Cyclosporine; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Lopinavir; Mammary Tumor Virus, Mouse; Mice; Pyrimidinones; Recurrence; RNA-Directed DNA Polymerase; RNA, Viral; Tacrolimus; Viral Load; Virus Replication

Liver transplant recipients are known to be at increased risk for the development of de novo neoplasms or the recurrence of preexisting malignancies, and this is possibly related to the use of immunosuppressive medication. Little is known about the effects of cytotoxic chemotherapy on graft function after transplantation. A retrospective chart and pathology database review was undertaken to identify post-liver transplant patients developing rejection during chemotherapy. All liver biopsies were reviewed by a hepatopathologist. Three patients were identified. All patients were diagnosed with cancer within 7 years of liver transplantation; two-thirds died soon after the diagnosis of malignancy. Rejection occurred soon after chemotherapy was started. All patients were receiving prednisone and tacrolimus (trough levels: 2.1-4.8 ng/mL). One patient developed plasma cell hepatitis (de novo autoimmune hepatitis). There was no histologic evidence of hepatotoxicity due to the chemotherapeutic agents. Cytotoxic chemotherapy should be used in liver transplant recipients with caution, and immunosuppressant doses should be maintained at therapeutic levels, as patients may be at risk for allograft rejection. Treatment of rejection or plasma cell hepatitis in this setting should be undertaken in a timely and aggressive fashion to prevent chronic ductopenic rejection.

Topics: Adult; Antineoplastic Agents; Biopsy; Cholangitis, Sclerosing; Colonic Neoplasms; Cytotoxins; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Risk Factors; Skin Neoplasms; Tacrolimus

A perfect or nearly perfect human leukocyte antigen (HLA) match has been associated with better immediate and long-term survival of diseased donor kidney transplants. However, the effect of HLA matching for hepatic allografts remains poorly defined. Using data from the National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, we investigated the association between HLA mismatches and hepatic allograft survival, disease recurrence, and immunosuppression interactions. A, B, and DR loci were used to calculate total mismatch scores of 0 (no mismatches in any loci) to 6 (mismatches in all loci). Seven hundred ninety-nine adults (male, 55%; female, 45%) underwent 883 liver transplants. The 10-year graft survival according to total mismatch score was as follows: 0-2, 60%; 3-4, 54%; and 5-6, 57%. There was a negative effect of mismatching at the A locus on patient survival, with shorter survival for patients with 1 or 2 mismatches compared with 0 mismatches [P = 0.05, hazard ratio (HR) = 1.6]. Patients on tacrolimus with 1 or 2 mismatches at B or DR loci appeared to have increased rates of patient and graft survival compared to patients with 0 mismatches, with the appearance of a protective effect of tacrolimus (HR = 0.67). The effect of HLA mismatching was more pronounced on certain disease recurrences. DR-locus mismatch increased recurrence of autoimmune hepatitis (P = 0.01, HR = 4.2) and primary biliary cirrhosis (P = 0.04, HR = 2). Mismatch in the A locus was associated with more recurrence of hepatitis C virus (P = 0.01, HR = 1.6) and primary sclerosing cholangitis (P = 0.03, HR = 2.9).. Mismatching at the A locus decreases patient survival in liver transplant recipients, and mismatching at the DR and A loci affects recurrence of autoimmune liver diseases and hepatitis C, respectively.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclosporine; Databases as Topic; Female; Follow-Up Studies; Graft Survival; Hepatitis C; Hepatitis, Autoimmune; HLA Antigens; HLA-A Antigens; HLA-DR Antigens; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; National Institute of Diabetes and Digestive and Kidney Diseases (U.S.); Tacrolimus; Treatment Outcome; United States

Topics: Administration, Topical; Aged; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Pruritus; Tacrolimus; Treatment Outcome

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.. 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).. 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.. 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.

Topics: Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

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.

Topics: Adult; Aged; Calcineurin; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Recurrence; Tacrolimus

Topics: Anti-Inflammatory Agents; Female; Follow-Up Studies; Histocytochemistry; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Lymphoma, B-Cell, Marginal Zone; Middle Aged; Prednisone; Tacrolimus; Time Factors

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.

Topics: Adult; Aged; Bile Ducts; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Recurrence; Tacrolimus

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.

Topics: Adult; Antigens, CD; Female; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Methylprednisolone; Middle Aged; Receptors, Interleukin-2; Recurrence; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Cholangitis, Sclerosing; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti-graft rejection and autoimmune disease therapy, is limited by their hepato- and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti-CYP reactivity in 16% of children on CyA for anti-graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8.5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti-cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.

Topics: Adolescent; Adult; Antibody Specificity; Aryl Hydrocarbon Hydroxylases; Autoantibodies; Autoantigens; Azathioprine; Blotting, Western; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cyclosporine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; Epitopes; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Isoenzymes; Kidney Diseases; Kidney Transplantation; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Mixed Function Oxygenases; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Tacrolimus

Topics: Cyclosporine; Drug Monitoring; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Incidence; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Transplantation; Muromonab-CD3; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.

Topics: Adult; Cholestasis; Female; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Recurrence; Tacrolimus