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Background:  The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (DILIN) determines the attribution of injury to an agent through its structured expert opinion causality assessment process, but without the use of chemical analysis data of HDS. We aimed to determine the impact of chemical analysis of HDS products on prior causality assessment scores., Methods: Obtained samples of HDS consumed by DILIN-enrolled patients were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Chemical analysis data were compared to label accuracy and detect whether the product contained botanical and non-botanical compounds. A comparison of the causality scores reassessed with chemical analysis was compared with the original scores., Results: A total of 54 previously adjudicated cases with chemical analysis available were reassessed for causality with chemical analysis data; reviewers were blinded to original causality scores. Using the chemical analysis data, 37% (n = 20) of the 54 cases were scored with a higher likelihood of DILI compared with the original causality scores; 14 of the 20 (70%) moved from probable to highly likely; 52% had no change in causality score; and 11% of cases were scored as a lower likelihood of DILI., Conclusions:  Our study demonstrates that there is value in using HDS chemical analysis data in the causality assessment process for DILI. In more than a third of cases, chemical analysis of products led to an increased confidence in DILI attribution to HDS. These findings suggest that chemical analysis is an important tool in causality assessment for HDS agents, specifically in challenging situations, and further studies are needed to confirm its applicability in clinical practice., Competing Interests: Declarations. Funding: Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under award nos. U01DK065211 (Indiana University), U01DK065184 (University of Michigan), U01DK065201 (University of North Carolina-Chapel Hill), U01DK083020 (University of Southern California), U01DK083027 (Thomas Jefferson University/Albert Einstein Medical Center), U01DK100928 (Icahn School of Medicine at Mount Sinai), and U24DK065176 (Duke University). Additional support is provided by the intramural programs of the NIDDK and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflicts of interest: Authors have no disclosures related to this publication. Ethics approval: This study was approved by the Advarra Institutional Review Board. Protocol title: A Multi-Center Study of Drug-and HDS-Induced Liver Injury (DILIN). Protocol approval #: Pro00072297. Approval date: 5 January 2024. All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for participation: Informed consent was obtained from all patients who participated in this study. Consent for publication: Not applicable. Availability of data and material data: Available upon reasonable request, following applicable regulations, by contacting the corresponding author. Code availability: Not applicable. Author contributions: All authors read and approved the final version. D.H.D. was responsible for analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content and statistical analysis; V.N. for study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, obtaining funding, and study supervision; A.D. for study concept and design, acquisition of data, and analysis and interpretation of data; B.A. for analysis and interpretation of data, acquisition of data, and critical revision of the manuscript for important intellectual content; H.B. for study concept and design, acquisition of data, analysis and interpretation of data critical revision of the manuscript for important intellectual content, and statistical analysis; A.S.B. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; J.A. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; H.L.B. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; V.L.C. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; G.C. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; R.J.F. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; M.S.G. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; I.A.K. for analysis and interpretation of data and critical revision of the manuscript for important intellectual content; C.K. for analysis and interpretation of data and critical revision of the manuscript for important intellectual content; J.O. for analysis and interpretation of data and critical revision of the manuscript for important intellectual content; H.R. for acquisition of data; J.S. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; A.H.S. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; A.S. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; H.L.D. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content; and R.V. for study concept and design, acquisition of data, and analysis and interpretation of data critical revision of the manuscript for important intellectual content., (© 2024. The Author(s).)

Background and Aim: This study investigates temporal trends in gastrointestinal cancer-related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race., Methods: We investigated the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999-2020) for gastrointestinal cancer-related mortality with a focus on the underlying cause of death., Results: A total of 3 115 243 gastrointestinal cancer-related deaths occurred from 1999 to 2020. The overall age-adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was -0.9% (95% CI: -1.0%, -0.9%, P  < 0.001), with no significant difference in AAPC between the sexes but some difference between races and related to individual cancers. African Americans and Asian Americans, and Pacific Islanders experienced a greater decrease in mortality compared with Whites. Mortality rates for American Indian and Alaskan Native populations also decreased significantly from 1999 to 2020 ( P  < 0.001). There were significant declines in esophageal, stomach, colon, rectal, and gallbladder cancer-related mortality but increases in the small bowel, anal, pancreatic, and hepatic cancer-related mortality ( P  < 0.001), with variation across different sexes and racial groups., Conclusion: While overall gastrointestinal cancer-related mortality declined significantly in the United States from 1999 to 2020, mortality from some cancers increased. Furthermore, differences between sexes and racial groups underscore crucial differences in gastrointestinal cancer mortality, highlighting areas for future research., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation., Methods: We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines., Results: The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively., Conclusions: Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.

An estimated 250 million people are chronically infected with hepatitis B virus (HBV), with more than 800,000 deaths related to HBV. 1 Although the prevalence of HBV has been decreasing, reactivation remains a cause for concern. 2 Reactivation is defined by the resurgence of HBV DNA and/or HBV surface antigen (HBsAg) seroreversion in patients with resolved HBV or an increase in HBV viral load in chronic hepatitis. 3 Anti-tumor necrosis factor (TNF) therapies have been shown to place patients at a risk for HBV reactivation. 4 ., (Copyright © 2023 AGA Institute. All rights reserved.)

Background and Aims: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug., Methods: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets., Results: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated., Conclusions: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial., Methods: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS., Results: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10 -6 )., Conclusions: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury., Clinical Trials: gov number: NCT00345930., (Copyright © 2022. Published by Elsevier Inc.)

Purpose of Review: Drug-induced liver injury (DILI) can be induced by a myriad of drugs. Assessing whether the patient has DILI and assessing which drug is the most likely culprit are challenging. There has been too little attention paid to the concept that certain drugs appear to have unique clinical features or 'phenotypes'., Recent Findings: Several case series of DILI because of various drugs have been published, and analysis of these case series points to the fact that individual drugs have characteristic DILI signatures. These clinical phenotypes can be characterized by latency, biochemical features (R-value), as well as clinical symptoms and signs. Several drugs, including isoniazid, amoxicillin-clavulanic acid, anabolic steroids, β-interferon and others, have highly unique clinical features. Such unique properties may be able to be used to improve adjudication processes., Summary: Individual drugs have unique clinical DILI phenotypes or signatures. Furthermore, these may be able to be used to improve adjudication.

Purpose of Review: There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tools and discuss how to improve the causality assessment process as a whole., Recent Findings: Existing DILI-specific causality assessment tools are surprisingly similar and exhibit only minor differences in point allocation. But difference in threshold for likelihood of being DILI. We reviewed the literature on currently used causality assessment tools, identified areas for future improvement, and herein propose approaches for refinement. Opportunities to improve current models, as well as the assessment process, in general, include in particular provision of more precise clinical detail and to perhaps add new components to scoring systems. For example, the incorporation of drug-specific clinical signature patterns, accounting for a drug's inherent hepatotoxicity potential, and/or incorporation of other drug properties to scoring systems may allow enhancement. Further, more systemic exclusion of competing diagnoses is needed. Finally, causality assessment processes will likely benefit from a data-driven and computer-assisted approach., Summary: Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities is poorly characterized, particularly when fatalities occur >26 weeks after DILI onset. We analyzed patients in the US Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by eight network investigators and categorized as DILI having a primary, a contributory, or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic, or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1,089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%), and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute on chronic, and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy, and severe cutaneous reactions with multiorgan failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis, and thrombocytopenia were independently associated with DILI fatalities. New R ratio Hy's law had a higher positive predictive value for overall fatality (14% versus 10%) and a stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's law (hazard ratio, 6.2, 95% confidence interval 3.4-11.1, versus 2.2, 95% confidence interval 1.3-3.7)., Conclusions: DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these had nonacute liver failure courses. New R ratio Hy's law better identifies risk for death compared to the original Hy's law. (Hepatology 2017;66:1275-1285)., (© 2017 by the American Association for the Study of Liver Diseases.)

miR-122 is the predominant liver miRNA that regulates hepatic lipid metabolism and inflammation. Hepatitis C virus (HCV) modulates host intracellular lipid metabolism. HCV stability and propagation also depend on an interaction between virus and miR-122. Our aims were to examine the associations between miR-122, apolipoproteins, and serum makers of fibrosis in chronic hepatitis C (CHC) patients. We evaluated baseline sera from 36 CHC genotype 1 patients who completed the Phase IIa study of miravirsen (LNA oligonucleotide targeting miR-122). Samples were assessed for liver transaminases, IL 28B genotype, IP-10, and lipid profiles. The noninvasive markers of liver fibrosis, APRI, and FIB-4, were calculated using standard formulae. miR-122 levels were measured using RT-PCR and expressed as fold-change compared to normal healthy controls. CHC patients were mostly male (61%) with mean age 47.5 ± 11.6 years. Patients with higher ApoB (ApoB/ULN ≥ 0.5) has significantly lower miR-122 levels in compared to patients with lower ApoB (ApoB/ULN < 0.5). (8.28 ± 6.23 vs. 16.28 ± 13.71; P = 0.02). There were no similar associations between miR-122 and ApoA-1 or between HCV RNA and lipoproteins. There were no differences in miR-122 levels between patients with different stages of fibrosis determined by APRI or FIB-4. Patients with lower ApoB had higher serum miR-122 levels. However, we cannot identify significant association between miR-122, ApoA-1, or fibrosis markers in this small cohort of CHC genotype 1 patients. The mechanism of HCV dyslipidemia is complex and could partly relate to the effect of miR-122 on lipid metabolism which requires further evaluation in a larger study., (© 2015 Wiley Periodicals, Inc.)

It is estimated that there are 350-400 million individuals with chronic hepatitis B virus infection (HBV) worldwide. The natural course of HBV infection is variable with a number of individuals developing no or only mild disease, while others will die from liver-associated complications if left untreated. It is estimated that 25% of individuals with HBV infection will eventually die from the complications of HBV-associated liver disease. Several viral and host variables including hepatitis B e antigen status, HBV genotype, viral load, hepatitis B surface antigen and transaminase levels, and viral mutations have been identified as determinants of disease outcomes. The personalized approach to the treatment of chronic hepatitis B might include mere monitoring of the disease in some patients but aggressive treatment in others. Individuals who require treatment should have close monitoring to help ensure maximum medication compliance, to watch for adverse events, and to monitor virologic and biochemical responses. Therefore, management of patients with chronic HBV infection requires a practical setting to demonstrate the relevance of personalized medicine, the roles and limitations of genetic and non-genetic factors, and the risks and benefits of individualized patient care. This article provides an overview of the viral and host genetics of chronic HBV and reviews the clinical utility of serum quantitative hepatitis B surface antigen in the management of patients with chronic HBV infection.

Unlabelled: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer., Conclusion: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality., (© 2013 by the American Association for the Study of Liver Diseases.)

Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.

Background & Aims: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression., Methods: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome., Results: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed., Conclusions: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Evaluation of: Rocco A, Compare D, Coccoli P et al. Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. Gut doi:10.1136/gutjnl-2012-302344 (Epub ahead of print) (2012). Vitamin B12 was first mentioned to have a role in HCV treatment approximately a decade ago, but it has not been well translated into clinical medicine. Recently, however, a randomized trial has reported significantly better response at all time-points during therapy with pegylated interferon plus ribavirin, if such therapy was combined with vitamin B12. This correlates with reports on vitamin B12 being able to inhibit HCV in vitro and a report that vitamin B12 levels were related to treatment response. If further validated, vitamin B12 is another vitamin reported to be beneficial for HCV therapy. Vitamin D had repeatedly been reported to be associated with response to HCV therapy. It will be interesting to see whether vitamins such as B12 and D will remain relevant in the light of direct antivirals.

Background: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined., Aim: We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy., Methods: A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR)., Results: IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR., Conclusions: IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.

Despite a decline in cases of acute hepatitis B and the low hepatitis B virus (HBV) chronicity rates in adults, still some patients progress to HBV-related fulminant liver failure. In this review, we discuss treatment options that may prevent the progression of severe acute hepatitis B to fulminant liver failure and death. In severe acute HBV with prolonged prothrombin time and increased bilirubin, interferon failed to be effective while antiviral treatment, particularly with lamivudine, appears to improve survival (mean survival almost 80%). Outcome without antiviral therapy has remained considerably poor, whereas there is no convincing evidence of amelioration of HBV-targeted immunity. Of note, most patients who died or required transplantation despite lamivudine therapy, were started on lamivudine at advanced stages compared with those survived. This suggests that prompt and timely antiviral therapy is crucial. Owing to the abovementioned results the design of randomized placebo-control trials in the setting of severe acute hepatitis B seems unethical. On the contrary, the design of multicentre double-blind randomized trials to compare the efficacy between lamivudine and entecavir or even tenofovir in acute severe HBV cases is ideally needed, but these studies appear to be very difficult to perform considering that these cases are not frequent and therefore, it is almost impossible to have two arms adequately numerous and homogenous for statistical evaluation. Thus, in the absence of solid evidence based data, the hepatologists could treat their patients with severe acute hepatitis B with lamivudine or the most potent antivirals entecavir or tenofovir., (© 2011 John Wiley & Sons A/S.)

Background & Aims: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC., Methods: Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT., Results: CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p=0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p=0.001) of CC patients in the Duke cohort., Conclusions: IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Chronic hepatitis C (CHC) infection is a leading cause of endstage liver disease. Current standard-of-care (SOC) interferon-based therapy results in sustained virological response (SVR) in only one-half of patients, and is associated with significant side effects. Accurate host predictors of virologic response are needed to individualize treatment regimens. We applied a label-free liquid chromatography mass spectrometry (LC-MS)-based proteomics discovery platform to pretreatment sera from a well-characterized and matched training cohort of 55 CHC patients, and an independent validation set of 41 CHC genotype 1 patients with characterized IL28B genotype. Accurate mass and retention time methods aligned samples to generate quantitative peptide data, with predictive modeling using Bayesian sparse latent factor regression. We identified 105 proteins of interest with two or more peptides, and a total of 3,768 peptides. Regression modeling selected three identified metaproteins, vitamin D binding protein, alpha 2 HS glycoprotein, and Complement C5, with a high predictive area under the receiver operator characteristic curve (AUROC) of 0.90 for SVR in the training cohort. A model averaging approach for identified peptides resulted in an AUROC of 0.86 in the validation cohort, and correctly identified virologic response in 71% of patients without the favorable IL28B "responder" genotype., Conclusion: Our preliminary data indicate that a serum-based protein signature can accurately predict treatment response to current SOC in most CHC patients., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10(-6) for rs1127354 and P = 10(-7) for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10(-11) ). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR., Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Background & Aims: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR., Methods: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116)., Results: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001)., Conclusions: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.

Advanced liver disease and interferon-based treatment are both associated with varying degrees of cytopenia in patients with chronic hepatitis C. Growth factors to increase hemoglobin and neutrophils are commonly used in clinical practice, despite the absence of data to indicate benefits in terms of sustained viral response. Thrombocytopenia is observed frequently, is multi-factorial in etiology, and may result in significant limitations on interventional and therapeutic options. A small-molecule thrombopoietin mimetic, eltrombo-pag, has demonstrated a dose-response associated increase in platelet count in a phase 2 study, allowing initiation and completion of a 12-week course of peginterferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg of eltrombopag daily, respectively, compared with 6% in the placebo arm. Phase 3 studies are currently evaluating whether initiating and maintaining antiviral therapy with eltrombopag will lead to an increase in sustained virologic response in chronic hepatitis C infection.

Metabasis Therapeutics Inc (previously Ribapharm Inc) is developing pradefovir, an oral liver-targeting prodrug of adefovir developed using its HepDirect technology, for the potential treatment of HBV infection. Phase II clinical trials of pradefovir have been completed.

Unlabelled: HIV-infected individuals are frequently co-infected with different hepatitis viruses. HCV has been associated with impaired quality of life in non-HIV infected patients. Little is known concerning the quality of life in HIV-infected individuals in relation to the different viral co-infections. -, Patients and Methods: We investigated 250 patients who have answered HIV-SELT and EuroQoL (EQ-5D) questionnaires assessing quality of life. Data on HBsAg, anti-HBc, anti-HCV, and GBV-C-RNA were available for 191, 188, 189, 98 patients, respectively. HCV-RNA was tested in 33 of 35 anti-HCV positive patients. -, Results: There was no difference in quality of life in relation to active or past HBV-infection defined by HBsAg (n = 15) and anti-HBc in the absence of HBsAg (n = 84), respectively, for both overall HIV-SELT (p = 0.66, and p = 0.43, respectively) and visual EQ-5D (p = 0.93 and p = 0.64, respectively). However, anti-HCV positivity (n = 35) was associated with significantly impaired quality of life (HIV-SELT overall p<0.001). Importantly, no difference was found in relation to HCV-viraemia in anti-HCV positive patients (p = 0.77). In multivariate analysis anti-HCV positivity, employment status, HIV viral load and GBV-C were relevant to quality of life, with GBV-C being beneficial and HCV being negative. -, Conclusions: While HBV seems to play no role concerning quality of live in HIV-infected patients, the flavi-viruses HCV and GBV-C display opposing influence on quality of life. As quality of life was similarly impaired in HCV-viraemic and HCV-non-viraemic anti-HCV positive patients but better in GBV-C viraemic patients, this should be taken into account in the indication case of planned interferon therapy.

In a search for new hepatitis viruses, two independent groups identified viruses named GB virus C and Hepatitis G Virus, which turned out to be different strains of the same agent. Despite its initial ascription to hepatitis viruses, this new virus does not cause any hepatitis. Thus, the term GB virus C is preferred. Soon after its discovery, a significantly better clinical course of HIV infection was demonstrated for patients coinfected with the GB virus C in 1998. These results were confirmed in other further studies, but not in all of them. Importantly, studies not confirming a positive influence usually found a neutral effect. The data for most of the studies had been mainly collected in the time prior to the availability of highly effective antiretroviral therapy (HAART). Since HAART has become available, some authors have reported a beneficial effect while others have shown only a neutral influence of GB virus C on HIV, considering either survival or the degree of response to HAART. An explanation for these discrepancies may be that different GB virus C strains exhibit different replication capacities. Understanding the mechanisms by how GB virus C and HIV interact may help find new strategies to fight HIV infection. Some recent in vitro findings have added evidence on how GB virus C might interact with and inhibit HIV replication. In this review, we update the current knowledge on GB virus C, its role in HIV infection in the HAART era, and discuss the potential mechanisms of its beneficial effect.

While HCV was initially believed to uniformly cause liver inflammation with the consequence of liver cirrhosis in most of the infected patients, prospective studies have shown a much lower than expected rate of cirrhosis in patients infected for more than 20 years. However, a new problem associated with hepatitis C virus infection is emerging. This is the development of sometimes disabling fatigue. While many other viruses of the flaviviridae cause encephalitis, the most closely related virus to HCV in humans, the GB Virus C seems not to be associated with fatigue. Thus the mechanism for the development of fatigue in HCV infection seems specific for HCV. Delineating the mechanism will be a first step to develop treatment option for this currently untreatable impairment.

Background and Aim: Circulating autoantibodies are diagnostic markers for a variety of autoimmune diseases including rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, and autoimmune hepatitis. Since only view studies exist on individuals without known diseases, we analyzed the prevalence of frequently determined autoantibodies in "healthy" individuals., Patients and Methods: 111 individuals (43 female, 68 male; mean age 58 +/- 13 years, median 58, range 22-89), in whom either known or actual clinical evidence for autoimmune or internal disease was found, were included. Antinuclear and anti-smooth muscle antibodies (ANA and ASMA, respectively) were detected by immunofluorescence on rat organ sections and Hep 2 cells. Antibodies to liver-kidney-microsomes-1 (anti-LKM-1) and antimitochondrial antibodies (AMA) were detected and semiquantified by immunofluorescence. Additionally, anti-LKM-1 and AMA were determined by ELISA and Western blot. Antibodies against soluble liver antigens (anti-SLA) were quantified by ELISA. Sera with a titer of 1 : 40 or higher were classified as positive., Results and Conclusions: Sera of "healthy" adults displayed high frequencies of ANA and ASMA (28/111, 25%, and 48/111, 43%, respectively). Although no sex differences were found for ASMA, sera of healthy women tested more often positive for ANA (p < 0.01). Since at least one in three or four healthy individuals tested positive for ANA or ASMA, the positive predictive value of these autoantibodies is low, and clinical interpretation should include additional information.

Autoimmunity and high rates of autoantibodies have been implicated in the pathogenesis of porphyria cutanea tarda. These abnormalities could be in part virus-induced, since porphyria cutanea tarda in most geographical regions is highly associated with hepatitis C virus infection. We analyzed the link of autoantibodies, autoimmune hepatitis and systemic lupus erythematosus in 111 patients with porphyria cutanea tarda and sex- and age-matched controls (mean age 58+/-13 years) in Germany, a region with a low prevalence of hepatitis C virus infection. Patients with porphyria cutanea tarda displayed lower rates of anti-nuclear antibodies (16/111, 14% vs 28/111, 25%, p<0,05) and of antibodies against smooth muscle (25/111, 23% vs 48/111, 43%, p<0,01), than controls. The percentage of patients with porphyria cutanea tarda with positive anti-HCV was low but significantly higher than in our controls (9/111, 8% vs 0/111, 0%, respectively), (p<0,05). Two patients with porphyria cutanea tarda (2/111, 2%) fulfilled the criteria for systemic lupus erythematosus and not one of 65 patients was found to have clinical autoimmune hepatitis. In the first controlled study of a large cohort of patients with porphyria cutanea tarda no increased prevalence of selected autoantibodies and autoimmune hepatitis was found. However, a higher prevalence of HCV infection and systemic lupus erythematosus in patients with porphyria cutanea tarda was confirmed.