Systematic review: recurrent autoimmune liver diseases after liver transplantation.

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease.

BACKGROUND: A human betaretrovirus (HBRV) has been linked with primary biliary cirrhosis (PBC) following the detection of viral particles in biliary epithelium by electron microscopy and cloning of the betaretrovirus genome from biliary epithelium and peri-hepatic lymph nodes. Evidence for viral infection was found in the majority of PBC patients' peri-hepatic lymph node samples. However, less than a third of the liver samples had detectable HBRV, whereas others were unable to detect betaretrovirus infection or noted the presence of virus in the liver of patients with other diagnoses. AIMS: To address the hypothesis that the betaretrovirus may be below the limits of detection in the liver, biliary epithelial cells (BEC) were investigated for the evidence of infection. METHODS: Ligation-mediated PCR and next generation sequencing were used to detect proviral integrations in liver, lymph nodes and BEC isolated from liver transplant recipients. Hybridisation-based assays were used to detect betaretroviral RNA in BEC. RESULTS: Unique HBRV integrations and betaretrovirus RNA were detected in the majority of biliary epithelia derived from patients with PBC, autoimmune hepatitis and cryptogenic liver disease but rarely in other liver transplant recipients with primary sclerosing cholangitis and other hepatic disorders. HBRV integrations were commonly found in PBC patients' lymph nodes but rarely in whole liver samples. CONCLUSIONS: Human betaretrovirus infection is frequently observed at the site of disease in patients with primary biliary cirrhosis and also in biliary epithelium of patients with autoimmune hepatitis and cryptogenic liver disease.

Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation.

Primary biliary cirrhosis (PBC) reoccurs in a proportion of patients following liver transplantation (LT). The aims of our study were to evaluate the risk factors associated with PBC recurrence and determine whether recurrent disease constitutes a negative predictor for survival. One hundred and eight patients receiving LT for end-stage PBC were studied. Recurrent disease was diagnosed in 28 patients (26%). Probability of recurrent PBC at 5 years was 13% and 29% at 10 years with an overall incidence of 3.97 cases per 100 patient years. By univariate Cox analysis use of tacrolimus (HR 6.28, 95% CI, 2.44-16.11, p < 0.001) and mycophenolate mofetil (HR 5.21, 95% CI, 1.89-14.33, p = 0.001) were associated with higher risk of recurrence; whereas use of cyclosporine A (CsA) and azathioprine were associated with reduced risk of recurrence (HR 0.13, 95% CI 0.05-0.35, p < 0.001 and HR 0.27, 95% CI 0.11-0.64, p = 0.003, respectively). In the multivariate Cox analysis, only CsA was independently associated with protection against recurrence (HR 0.17, 95% CI 0.06-0.71, p = 0.02). Five-year probability of survival was 83% and 96%, in patients without and with recurrence (log-rank test, p = 0.3). Although PBC transplant recipients receiving CsA have a lower risk of disease recurrence, the development of recurrent PBC did not impact on long-term patient survival.

Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol.

BACKGROUND: A human betaretrovirus has been characterized in patients with primary biliary cirrhosis (PBC). Uncontrolled studies using combination anti-retroviral therapy have reported significant biochemical and histological improvement. AIM: To conduct a double blind, randomized controlled trial as a proof of principal to link infection with PBC. METHODS: Fifty-nine patients with an alkaline phosphatase level>1.5 upper limits of normal stabilized on ursodeoxycholic acid therapy were randomized to either 300 mg zidovudine and 150 mg lamivudine B.I.D. or placebo for 6 months. RESULTS: None of the patients normalized alkaline phosphatase and no significant differences were observed in normalizing serum aminotransferase levels. Significant differences were observed in the antiviral versus placebo arms with improvements in serial alkaline phosphatase (p<0.04), ALT (p<0.03) and AST (p<0.04) as well as clinical score (p<0.02). After 6 months, 25% of patients in the placebo arm and 4% in the antiviral arm had evidence of virus in serum. CONCLUSIONS: The study endpoints for normalizing hepatic biochemistry were too stringent to show efficacy for zidovudine and lamivudine therapy despite the demonstrable impact on clinical and biochemical improvement. Accordingly, more potent anti-viral regimens will be required to confirm the efficacy of antiviral therapy in PBC patients with human betaretrovirus infection.

Reverse transcriptase activity in patients with primary biliary cirrhosis and other autoimmune liver disorders.

BACKGROUND: Patients with biliary disease make retroviral antibodies and the Human Betaretrovirus has been characterized in patients with primary biliary cirrhosis. AIM: To screen patients with autoimmune liver disease for evidence of retroviral infection. METHODS: Real-time reverse transcriptase polymerase chain reaction was used to detect Human Betaretrovirus, and a reverse transcriptase assay to measure reverse transcriptase activity in plasma. RESULTS: Using reverse transcriptase polymerase chain reaction, 24% of primary biliary cirrhosis samples were positive for Human Betaretrovirus when compared to 13% with autoimmune hepatitis, 5% of other liver diseases and 3% of the non-liver disease control subjects. Reverse transcriptase activity was found in 73% of patients with autoimmune hepatitis, 42% with primary biliary cirrhosis, 22% of liver patients without viral or autoimmune disease and 7% of subjects without liver disease. In patients with autoimmune liver disease, detection of reverse transcriptase activity was related to higher ALT levels, whereas others stabilized on immunosuppressive therapy either preliver or postliver transplantation were less likely to be reverse transcriptase-positive. CONCLUSIONS: Most patients with autoimmune hepatitis have detectable reverse transcriptase activity. Investigations will be required to assess whether this represents the expression of endogenous retroviruses and retrotransposable elements in inflamed tissue, or signifies the presence of exogenous retroviral infection.

Vaccinia virus infection disarms the mitochondrion-mediated pathway of the apoptotic cascade by modulating the permeability transition pore.

Many viruses have evolved strategies that target crucial components within the apoptotic cascade. One of the best studied is the caspase 8 inhibitor, crmA/Spi-2, encoded by members of the poxvirus family. Since many proapoptotic stimuli induce apoptosis through a mitochondrion-dependent, caspase 8-independent pathway, we hypothesized that vaccinia virus would encode a mechanism to directly modulate the mitochondrial apoptotic pathway. In support of this, we observed that Jurkat cells, which undergo Fas-mediated apoptosis exclusively through the mitochondrial route, were resistant to Fas-induced death following infection with a crmA/Spi-2-deficient strain of vaccinia virus. In addition, vaccinia virus-infected cells subjected to the proapoptotic stimulus staurosporine exhibited decreased levels of both cytochrome c released from the mitochondria and caspase 3 activation. In all cases we found that the loss of the mitochondrial membrane potential, which occurs as a result of opening the multimeric permeability transition pore complex, was prevented in vaccinia virus-infected cells. Moreover, vaccinia virus infection specifically inhibited opening of the permeability transition pore following treatment with the permeability transition pore ligand atractyloside and t-butylhydroperoxide. These studies indicate that vaccinia virus infection directly impacts the mitochondrial apoptotic cascade by influencing the permeability transition pore.