Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease

BackgroundSorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.MethodsA total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.ResultsPatients with liver cirrhosis, high…

Budesonide in previously untreated autoimmune hepatitis

Background: Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH. Methods: Between October 1998 and August 1999, 12 patients were treated with 3 mg budesonide thrice daily for 3 months in this open one-arm multicenter phase IIa study. Primary end point was induction of remission indicated by a drop of aspartate aminotransf…

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportiona…

Baseline patient characteristics of the German multicentric prospective real-world NAFLD cohort: The Fatty Liver Assessment in Germany (FLAG) study

Development of cytochrome P450 2D6-specific LKM-autoantibodies following liver transplantation for Wilson's disease -- possible association with a steroid-resistant transplant rejection episode.

Abstract Background/Aims: Antibodies to cytochrome P450 2D6, also knownas LKM1-autoantibodies, are characteristic for a subgroup of patients with autoimmune hepatitis, but can also occasionally be found in hepatitis C. We observed the occurrence of LKM1-autoantibodies 4 months after liver transplantation for Wilson's disease, in close association with a steroid-resistant rejection episode, in the absence of evidence for autoimmune hepatitis or hepatitis C. Methods: Sera from several time points prior to and following transplantation were tested for LKM-reactivity by immunofluorescence, ELISA and Western blotting. Antigen specificity was confirmed by Western blotting analysis on different cy…

Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice

Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Therefore, localization and function of JA…

Identification of cyclin A as a molecular target of antinuclear antibodies (ANA) in hepatic and non-hepatic autoimmune diseases.

Abstract Background/Aims: Antinuclear antibodies (ANA) are a diagnostic of various autoimmune diseases and also of autoimmune hepatitis type 1. The designation ANA describes a heterogeneous group of autoantibodies. In liver diseases, only a few nuclear target antigens have been molecularly identified and characterized. Cyclins play a central role in a cell cycle regulation, DNA transcription, and cell proliferation. Cyclin A was also identified as an integration site of the hepatitis B virus in a patient with hepatocellular carcinoma. In this study we identify cyclin A as a novel nuclear target protein of ANA. Methods: Sera of patients with autoimmune hepatitis (AIH) type 1 ( n =61), type 2…

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

To access publisher's full text version of this article click on the hyperlink at the bottom of the page Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci sh…

Clinical significance of detectable and quantifiable HCV RNA at the end of treatment with ledipasvir/sofosbuvir in GT1 patients

Background & aims AASLD/IDSA treatment guidelines for hepatitis C virus (HCV) infection state that testing for quantitative HCV RNA can be considered at the end of antiviral treatment (EOT) with interferon-free regimens. However, it remains unclear how to respond to a detectable or even quantifiable HCV RNA result. The aim of this study was to analyse the frequency and predictive value of detectable and quantifiable HCV RNA results at the EOT in patients with HCV genotype 1 infection treated with ledipasvir (LDV) and sofosbuvir (SOF) ± ribavirin (RBV) in a large real-world cohort. Methods A retrospective analysis of the DHC-R (Deutsches Hepatitis C-Register, German Hepatitis C-Registry) coh…

102 NOVEL SUSCEPTIBILITY LOCI FOR PRIMARY SCLEROSING CHOLANGITIS IDENTIFIED BY GENOME-WIDE ASSOCIATION AND REPLICATION ANALYSIS

Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, …

Genetically flexible murine organoids for mechanistic and functional modeling of cholangiocarcinoma

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed wi…

Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial.

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alani…

Cost effectiveness of peginterferon α-2b plus ribavirin versus interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C

Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We u…

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy

Background & Aims There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis …

Mutational Characterization of the Bile Acid Receptor TGR5 in Primary Sclerosing Cholangitis

Background: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants.Methodology/Principal Findings: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor mod…

Fighting the bushfire in HCC trials

New Therapeutic Aspects in Fulminant Hepatic Failure

HLA DRw8 and primary biliary cirrhosis

Cytoplasmic autoantigens in autoimmune hepatitis: molecular analysis and clinical relevance.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe

Abstract: Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely silent pandemic, its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The …

The designer cytokine hyper-interleukin-6 is a potent activator of STAT3-dependent gene transcription in vivo and in vitro.

Interleukin-6 (IL-6) triggers pivotal pathways in vivo. The designer protein hyper-IL-6 (H-IL-6) fuses the soluble IL-6 receptor (sIL-6R) through an intermediate linker with IL-6. The intracellular pathways that are triggered by H-IL-6 are not defined yet. Therefore, we studied the molecular mechanisms leading to H-IL-6-dependent gene activation. H-IL-6 stimulates haptoglobin mRNA expression in HepG2 cells, which is transcriptionally mediated as assessed by run-off experiments. The increase in haptoglobin gene transcription correlates with higher nuclear translocation of tyrosine-phosphorylated STAT3 and its DNA binding. As H-IL-6 stimulates STAT3-dependent gene transcription, we compared t…

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 1…

Chromosomal aberrations in patients with primary biliary cirrhosis.

Chromosomal aberrations in untreated lymphocyte cultures, bleomycin (BLM)-induced aberrations and sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of 11 patients suffering from primary biliary cirrhosis (PBC) and 14 matched control individuals were analysed. The lymphocytes of the PBC patients had on average a lower mitotic index (2.3) compared with controls (3.5) in the untreated cultures. The mean baseline rate of aberrations of the cultured lymphocytes of the patients was 5.3 aberrations per 100 metaphases (%); this was significantly different (P = 0.0291) from that of the controls with a mean of 2.3%. In lymphocytes of the patients and controls, most of the aberratio…

Performance of two HCV RNA assays during protease inhibitor-based triple therapy in patients with advanced liver fibrosis and cirrhosis.

Introduction: On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance. Aim: To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis. Methods: We collected on-treatment samples of 1…

Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial

UNLABELLED Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoin…

IMPACT OF DIRECT-ACTING ANTIVIRAL THERAPY ON THE NEED FOR LIVER TRANSPLANTATION RELATED TO HEPATITIS C IN GERMANY

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

Background & Aims We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. Methods A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). Results The strongest associations were detected near HLA-B at chromosome 6p21…

Nature of autoantigens and autoantibodies in autoimmune hepatitis

Autoimmune chronic active hepatitis (AI-CAH) is characterized by young age at onset, predominance of females, hypergammaglobulinemia, response to immunosuppressive treatment and characteristic circulating autoantibodies. This clinical syndrome was first described by Waldenstr6m in 1950 [47]. Later the association of autoimmune hepatitis with antinuclear antibodies (ANA) lead to the term "lupoid hepatitis" [19]. Additional autoantibodies have been described [21]. At least three subgroups of AI-CAH can be distinguished serologically and clinically [28]. As diagnostic tools, autoantibodies help to further differentiate the heterogeneous group of hepatitis B virus (HBV) surface antigen (HBsAg)-…

Extrahepatische Malignome nach Lebertransplantation wegen Primär Sklerosierender Cholangitis – eine multizentrische Langzeit-Beobachtungsstudie

Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients.

Background & Aims GALAD and BALAD-2 are statistical models for estimating the likelihood of the presence of hepatocellular carcinoma (HCC) in individual patients with chronic liver disease and the survival of patients with HCC, respectively. Both models use objective measures, particularly the serum markers α-fetoprotein (AFP), AFP-L3, and des-γ-carboxyprothrombin. We aimed to validate these models in an international cohort of patients with HCC and assess their clinical performance. Methods We collected data on cancer diagnosis and outcomes of 6834 patients (2430 with HCC and 4404 with chronic liver disease) recruited from Germany, Japan, and Hong Kong. We also collected data from 229 pati…

Treatment challenges and investigational opportunities in autoimmune hepatitis.

New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic…

Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany - Limitations of the 'sickest first'-concept

Summary Since the introduction of model for end-stage liver disease (MELD) in 2006, post-orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006–December 2007) were included. Recipient data were analyzed for their influence on 1-year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow-up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis-C (17.1%), Hepatitis-B (9.5%), primary sclerosing cholangitis (5.6%) and late graft-…

Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine.We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, …

Risk estimation for biliary tract cancer: Development and validation of a prognostic score.

Background & Aims Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival. Methods Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Results Median overall survival (OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) a…

Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice

International audience; Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profile. In cholestatic conditions, farnesoid X receptor (FXR) signaling by bile acids (BA) is activated and plasma HDL cholesterol (HDL-C) levels are low. This study tested the hypothesis that FXR-mediated induction of CETP contributes to this phenotype. Patients with cholestasis and high plasma BA had lower HDL-C levels and higher plasma CETP activity and mass compared with matched controls with low plasma BA (each P < 0.01). BA feeding in APOE3*Leiden transgenic mice expressing the human CETP transgene controlled by its endogenous promoter increased cholesterol within apoB-c…

Diagnostik und Management des Rezidivs der Primär Sklerosierenden Cholangitis nach Lebertransplantation – eine multizentrische Langzeit-Beobachtungsstudie der deutschen PSC-Studiengruppe

LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.

LKM-1 autoantibodies, which are associated with autoimmune chronic active hepatitis, recognize P450IID6, a cytochrome P-450 monooxygenase. The reactivities of 26 LKM-1 antisera were tested with a panel of deletion mutants of P450IID6 expressed in Escherichia coli. 22 sera recognize a 33-amino acid segment of P450IID6, and 11 of these recognize a shorter segment, DPAQPPRD. PAQPPR is also found in IE175 of herpes simplex virus type 1 (HSV-1). Antibodies for HSV-1 proteins were detected by ELISA in 17 of 20 LKM-1 sera tested. An immobilized, synthetic peptide, DPAQPPRDC, was used to purify LKM-1 antibodies. Affinity purified LKM-1 autoantibodies react on immunoblots with a protein in BHK cells…

Hepatitis B defective virus with rearrangements in the preS gene during chronic HBV infection.

We have found a defective form of HBV2 in a HBsAg- and anti-HBe-positive patient with liver cancer. Viral deletions were identified in the preS coding region using PCR. The presence of deleted HBV forms was observed in serum, PBMC, and liver samples. After sequencing 12 clones were analyzed (subtype adr). In 9 out of 12 clones a 183-bp in-frame deletion was recorded in the preS1 region (2995 to 3177). Three out of 9 clones also yielded rearrangements of the preS2 N-terminal part. Four out of 9 showed numerous point mutations in the preS1 and preS2 sequence. In addition, 3 out of 12 clones, which did not show the 183-bp preS1 deletion were found to have small deletions and insertions in the …

Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study.

Early treatment of acute hepatitis C with interferon alpha-2b for 24 weeks prevents chronic infection in almost all patients. Because pegylated interferons have replaced conventional interferon in the therapy of chronic hepatitis C, the aim of this study was to analyze the efficacy of an early treatment of acute hepatitis C with peginterferon alpha-2b. Between February 2001 and February 2004, 89 individuals with acute HCV infection were recruited at 53 different centers in Germany. Patients received 1.5 microg/kg peginterferon alpha-2b for 24 weeks; treatment was initiated after a median of 76 days after infection (range 14-150). End-of-treatment response and sustained virological response …

Extrahepatic Morbidity and Mortality of Chronic Hepatitis C

Chronic hepatitis C virus (HCV) infection is associated with several extra-hepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B cell non-Hodgkin’s lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurologic manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extra-hepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extra-hepatic cells, or a heig…

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 x 10(-16) and P = 4.1 x 10(-8), respectively).

Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results: If obesity and…

Cytochrome P450 enzymes as human autoantigens

Management of hepatitis C virus genotype 4: recommendations of an international expert panel.

HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in th…