Expert clinical management of autoimmune hepatitis in the real world.

BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

UNLABELLED: Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). CONCLUSION: These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Waitlist mortality decreases with increased use of extended criteria donor liver grafts at adult liver transplant centers.

Extended criteria donor (ECD) liver allografts are often allocated to less severely ill liver transplant (LT) candidates who are at a relatively lower risk of pretransplant mortality, but it is not clear that the use of ECD allografts will decrease center waitlist mortality (WLM). Individual patient data from the UNOS OPTN database (2002-2005) were aggregated to obtain center-specific data. Deceased donor allografts with any of the following characteristics were defined as ECDs: from a donor with any of the criteria described by the New York State Department of Health Workgroup; or 12+ h of cold ischemia. Multivariate regression was used to examine the relationship between WLM and ECD, non-ECD and LDLT use after adjusting for candidate severity of illness. A total of 3555 ECD transplants, 11,660 standard criteria donor (SCD) transplants, and 717 LDLTs were performed at 100 centers during this period. The model demonstrated that SCD and ECD LTs were inversely correlated with a center's WLM (beta=-0.242 and -0.221, respectively; p

Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent.

BACKGROUND: Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs. METHOD: We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels. CONCLUSION: All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.

Animal models for primary sclerosing cholangitis.

Since the aetiopathogenesis of primary sclerosing cholangitis (PSC) in humans remains undefined, investigators have studied a variety of animal models to gain insights into immunopathogenetic mechanisms associated with obliterative fibrous cholangitis of intra- and extra-hepatic bile ducts. To date, no animal model has been developed that exhibits all of the attributes of PSC. Rodent models instigated by bacterial cell components or colitis are promising because they may help to explain the strong association between PSC and inflammatory bowel disease (IBD). Other models of direct injury to biliary epithelia, peribiliary vascular endothelia or portal venous endothelia indicate that inflammation, chemokines and cytokines can produce diffuse sclerosis of bile ducts. Models of toxic, infectious or intra-luminal injury of the biliary tract also exhibit focal biliary sclerosis mediated by inflammation and cytokines. The histopathology of several models suggests a sequence of events beginning with secretion of proinflammatory cytokines by activated hepatic macrophages followed by peribiliary infiltration with CD4 and CD8 T cells with a T helper 1 phenotype. These results strongly suggest co-ordinated, pathogenetic roles for both the innate and adaptive immune responses. However, the stimuli that initiate and perpetuate peribiliary fibrosis remain unknown. Interestingly, several models are also associated with the development of anti-neutrophil cytoplasmic antibodies that react in a perinuclear and cytoplasmic pattern similar to that observed in patients with ulcerative colitis and/or PSC. Finally, models of extra-hepatic biliary obstruction continue to provide important information about the pathogenesis of portal fibrosis and secondary biliary cirrhosis that occurs in PSC and other diseases with obstruction of bile flow. Future studies in either existing or new animal models should advance our understanding of the pathogenesis of PSC, the major prerequisite for the development of effective therapies.

Transmission of hepatitis B infection from hepatitis B core antibody--positive liver allografts is prevented by lamivudine therapy.

Donor shortage has led to the use of hepatitis B core antibody (anti-HBc)--positive (anti-HBc(+)) liver allografts for patients in need of relatively urgent orthotopic liver transplantation (OLT). Because anti-HBc(+) allografts transmit hepatitis B virus (HBV) infection at a high rate, effective prophylaxis is required. We assessed the effectiveness of lamivudine in preventing HBV transmission by anti-HBc(+) allografts. Between March 1996 and March 2000 at Cedars-Sinai Medical Center (Los Angeles, CA), 15 of 169 patients (8.9%) received liver allografts from anti-HBc(+) donors. Six patients were hepatitis B surface antigen (HBsAg)(+) (group 1), and 9 patients were HBsAg negative (HBsAg(-); group 2) before OLT. All patients were administered lamivudine, 100 or 150 mg/d, orally after OLT. Patients who were HBsAg(+) before OLT also were administered hepatitis B immunoglobulin (HBIG) prophylaxis. Hepatitis B serological tests were performed on all patients, and HBV DNA was determined in liver tissues in 10 patients. All 15 patients remained HBsAg(-) at their last follow-up 2 to 40 months (mean, 17 months) post-OLT. All patients in group 1 had antibody to HBsAg (anti-HBs) titers greater than 250 mIU/mL post-OLT (mean follow-up, 20 months; range, 7 to 40 months). Of the 2 patients in group 1 who underwent liver biopsy after OLT, 1 patient had detectable hepatic HBV DNA despite being anti-HBs(+) and HBsAg(-). Among the patients in group 2, none acquired anti-HBc or HBsAg. Hepatic HBV DNA was undetectable in the 7 patients in group 2 who underwent liver biopsy after OLT. Anti-HBc(+) allografts can be safely used in patients who undergo OLT for chronic hepatitis B and susceptible transplant recipients if prophylaxis with combination HBIG and lamivudine or lamividine alone is administered after OLT, respectively. However, more data are needed to determine the efficacy of lamivudine monotherapy in preventing transmission of HBV infection from anti-HBc(+) liver allografts to susceptible recipients.

Viral, host and interferon-related factors modulating the effect of interferon therapy for hepatitis C virus infection.

The estimated prevalence of hepatitis C virus infection in the US is approximately 1.8%. Although interferon monotherapy and combination therapy of interferon with ribavirin represent mainstay for treating HCV infection, the rate of sustained virologic response remains suboptimal. The growing evidence suggested that the clinical sequence and treatment response of chronic hepatitis C are determined by a dynamic, complex tripartite relationship among HCV infection, the host immune response, and the effect of different interferon regimens. The treatment response is associated with various viral factors including the pretreatment viral level, dynamic change of viral level during treatment, viral genotype quasispecies and nucleotide mutation in nonstructural protein 5A of hepatitis C virus. Host factors that may affect treatment response include age, gender, race, HLA alleles and the host immune responses. Interferon regimens, including type, dose, frequency and duration of treatment and combination of interferon with other anti-HCV agents also alter the therapeutic response. Understanding these complicated interaction may provide better insights into the mechanism(s) of interferon response, leading to more effective clinical application of interferon therapy.

Overview of hepatitis B and transplantation in the hepatitis B patient.

Hepatitis B is a disease that infects 300,000 people in the United States each year, resulting in 15,000-30,000 cases of chronic hepatitis. Outcomes include death; development of chronic carrier state, chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) carriers, especially those with cirrhosis, are at high risk for development of hepatocellular carcinoma. Histologically, chronic carriers of HBsAg may have a range of degree of tissue changes, ranging from normal, to varying degrees of portal or lobular inflammation, to significant cell injury with widespread necrosis, fibrosis and cirrhosis. Current histological grading systems reflect both graded inflammation and stage of fibrosis.

Posttransplantation: future therapies.

Recent advances in prophylaxis and treatment of hepatitis B virus (HBV) infection after liver transplantation have improved the outcome of liver transplantation for hepatitis B. Currently, the long-term use of hepatitis B immune globulin (HBIG) and/or nucleoside analogues are the only effective therapies to prevent or ameliorate HBV recurrence in liver transplant patients. However, they are very expensive, and breakthrough infections due to resistant HBV mutants are not infrequent. New strategies are being sought to decrease the risks of breakthrough infection and to increase the cost-effectiveness of liver transplantation for hepatitis B. Vaccination to prevent de novo infection is strongly recommended before transplantation, despite a decreased response in this immunosuppressed population. Adoptive transfer of immunity with such therapies as bone marrow or cytotoxic T lymphocyte transplants or xenotransplantation of an organ from a donor, which is not susceptible to infection by HBV may be effective in preventing or treating recurrent HBV posttransplantation. In addition, gene therapies and use of nucleoside and nucleotide analogues to disrupt various stages of the HBV life cycle may prevent or slow viral replication or assembly of the virus. Ultimately, the most effective therapy for the prevention of recurrent hepatitis B after liver transplantation will involve a combination of HBIG with one or more of the new antiviral agents.

Case studies of the hepatitis B patient: a panel discussion.

In recent years, there have been significant advances in the treatment of patients with hepatitis B who are candidates for liver transplantation. This includes the prevention and management of hepatitis B posttransplantation. However, there is no established protocol for treating these patients. Ultimately, the goal would be to have patients HBV-DNA negative pretransplantation and then to prevent HBV recurrence posttransplantation to help ensure their quality of life. Several clinical case scenarios are presented and possible treatment solutions have been suggested. The timing of a transplant is critical due to the risk of viral mutation while the patient is on a nucleoside analogue antiviral agent and waiting for an organ. One successful option might be to start therapy pretransplant and continue it posttransplant. Combination therapy appears to provide the most effective course of treatment. This should include a nucleoside analogue and patients should be covered with hepatitis B immune globulin throughout the course of therapy. Several other variations of combination therapy are discussed, but many clinical issues remain to be resolved. Guidelines for future studies designed to answer these questions are proposed.

Immortalized intrahepatic mouse biliary epithelial cells: immunologic characterization and immunogenicity.

Nonsuppurative destructive cholangitis (NSDC), a process of T-cell-mediated destruction of biliary epithelia observed in primary biliary cirrhosis (PBC), graft-versus-host disease (GVHD), and hepatic allograft rejection (HAR), also occurs in the B10. D2-->BALB/c model of GVHD. To advance studies of immunopathogenesis in this murine model, we immortalized 4 BALB/c intrahepatic biliary epithelial cell (BEC) lines as a reliable source of target cells. Freshly isolated BEC, as well as each cell line, expressed cytokeratin-19 (CK-19), epithelial cell adhesion molecule (EPCAM) and cystic fibrosis transmembrane conductance regulator (CFTR). None expressed albumin. Immortalized cells also expressed SV40 large T antigen. Class I major histocompatibility complex (MHC) was expressed by >97% of immortalized cells, while class II MHC and intercellular adhesion molecule-1 (ICAM-1) expression ranged from 0% to 13% and 14% to 74%, respectively. Interferon gamma (IFN-gamma) induced aberrant class II MHC expression and increased expression of ICAM-1. Variable proportions of immortalized cells expressed B7-1/B7-2 molecules and FAS. IFN-gamma significantly reduced B7-1 expression in some lines and significantly increased B7-2 expression in others. Allografts of freshly isolated and immortalized BEC injected into subscapular fat pads spontaneously formed duct-like structures. Inflammation was absent in BALB/c recipients. In contrast, inflammatory lesions in B10.D2 recipients were reminiscent of NSDC. Our results indicate that BALB/c-immortalized intrahepatic biliary cells: 1) retain the phenotype of mouse BEC; 2) can be induced to express aberrant class II MHC and increased ICAM-1; 3) express costimulatory B7-1/B7-2 molecules and FAS; and 4) spontaneously form duct-like structures after in vivo injection that are immunogenic in B10.D2 mice. These cell lines should facilitate future studies of the immunopathogenesis of NSDC in the B10. D2-->BALB/c murine model.

Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis.

Autoimmune hepatitis is a form of chronic liver disease characterized by progressive hepatocellular inflammation, which usually responds to treatment with corticosteroids. However, 10% of patients with autoimmune hepatitis are refractory to corticosteroids and develop progressive liver disease and cirrhosis. We describe five patients with autoimmune hepatitis who did not respond to conventional corticosteroids and azathioprine therapy who were then treated with cyclosporine A. Cyclosporine A was started at 2-3 mg/kg/day and induced biochemical remission in four of five patients within 3 months. One of the four responders relapsed within 1 month of discontinuing cyclosporine on two occasions. Each time, liver tests promptly normalized after reinitiation of cyclosporine. Two responders were managed with cyclosporine alone. The single patient who did not respond to cyclosporine developed progressive liver failure, underwent orthotopic liver transplantation, and subsequently died of disseminated cytomegalovirus infection. Cyclosporine was generally well tolerated and none of the patients developed renal insufficiency. These data and review of 11 cases in the literature show that cyclosporine can induce remission of liver disease in patients with autoimmune hepatitis who are refractory to corticosteroids.

Autoimmune cholangiopathy.

Currently available evidence is insufficient to classify PBC and AIC as separate diseases. The ultimate answer to the question of whether AIC, defined as AMA-negative PBC with ANA or SMA, is a disease distinct from AMA-positive PBC with or without ANA will require a detailed comparison of etiologic factors and pathogenetic mechanisms, once they are elucidated. It is intriguing to consider the suggestion of Heathcote that the term autoimmune cholangitis be adopted to describe PBC with or without detectable AMA. However, it is improbable that the venerable term PBC will be supplanted. Hepatologists will probably continue to use the terms AIC and AMA-negative PBC interchangeably, with little risk of being misunderstood.