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Objectives. We sought to identify cross-sectional hepatitis B virus (HBV) and HCV prevalence among Asian Americans at a community health fair and to assess referral rates. Methods. We determined HBV prevalence with hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen (anti-HBc), and antibodies to hepatitis B surface antigen (anti-HBs). We determined HCV prevalence with hepatitis C antibodies. Successful referral occurred when participants with HBV or HCV were contacted, medically evaluated, and given contact information of liver specialists for care. Results. Of 202 people screened, 118 were Asian Americans (65 Chinese and 39 Vietnamese). Twelve had chronic HBV with positive HBsAg. However, chronic HBV prevalence increased from 10.2% to 13.6% by concomitant HBsAg, anti-HBc, and anti-HBs testing. Prevalence of HCV was 6% overall but 15.4% among Vietnamese. Overall, 83% of patients with chronic HBV and 100% of patients with occult HBV or HCV were successfully referred. Conclusions. Concomitant HBsAg, anti-HBc, and anti-HBs testing permits diagnosis of chronic, occult HBV infections missed by testing with HBsAg alone. Persons identified with HBV or HCV at community health fairs can be successfully referred. [ABSTRACT FROM AUTHOR]

Addressing drug-induced liver injury is crucial in drug development, often causing Phase III trial failures and market withdrawals. Traditional animal models fail to predict human liver toxicity accurately. Virtual twins of human organs present a promising solution. We introduce the Virtual Hepatic Lobule, a foundational element of the Living Liver, a multi-scale liver virtual twin. This model integrates blood flow dynamics and an acetaminophen-induced injury model to predict hepatocyte injury patterns specific to patients. By incorporating metabolic zonation, our predictions align with clinical zonal hepatotoxicity observations. This methodology advances the development of a human liver virtual twin, aiding in the prediction and validation of drug-induced liver injuries., Competing Interests: Competing interests: S.M.L. is a Dassault Systemes employee. J.M.V. is a member of IQDILI and the NIH NIDDK Drug-Induced Liver Injury Network Data Safety and Management Board. N.R.G. has served as a consultant for Dassault Systemes. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited, due to inadequate risk stratification and suboptimal performance of current screening modalities., Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance with MRI and applied global untargeted metabolomics to 612 longitudinal serum samples from 203 patients. Among them, 37 developed HCC during follow-up., Results: We identified 150 metabolites with significant abundance changes in samples collected prior to HCC (Cases) compared to samples from patients who did not develop HCC (Controls). Tauro-conjugated bile acids and gamma-glutamyl amino acids were increased, while acyl-cholines and deoxycholate derivatives were decreased. Seven amino acids including serine and alanine had strong associations with HCC risk, while strong protective effects were observed for N-acetylglycine and glycerophosphorylcholine. Machine learning using the 150 metabolites, age, gender, and PNPLA3 and TMS6SF2 single nucleotide polymorphisms, identified 15 variables giving optimal performance. Among them, N-acetylglycine had the highest AUC in discriminating Cases and Controls. When restricting Cases to samples collected within 1 year prior to HCC (Cases-12M), additional metabolites including microbiota-derived metabolites were identified. The combination of the top six variables identified by machine learning (alpha-fetoprotein, 6-bromotryptophan, N-acetylglycine, salicyluric glucuronide, testosterone sulfate and age) had good performance in discriminating Cases-12M from Controls (AUC 0.88, 95% CI 0.83-0.93). Finally, 23 metabolites distinguished Cases with LI-RADS-3 lesions from Controls with LI-RADS-3 lesions, with reduced abundance of acyl-cholines and glycerophosphorylcholine-related lysophospholipids in Cases., Conclusions: This study identified N-acetylglycine, amino acids, bile acids and choline-derived metabolites as biomarkers of HCC risk, and microbiota-derived metabolites as contributors to HCC development., Impact and Implications: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited. There is an urgent need for improvement in risk stratification and new screening modalities, particularly blood biomarkers. Longitudinal collection of paired blood samples and MRI images from patients with cirrhosis is particularly valuable in assessing how early blood and imaging markers become positive during the period when lesions are observed to obtain a diagnosis of HCC. We generated a multicenter prospective cohort of patients with cirrhosis under surveillance with contrast MRI, applied untargeted metabolomics on 612 serum samples from 203 patients and identified metabolites associated with risk of HCC development. Such biomarkers may significantly improve early-stage HCC detection for patients with cirrhosis undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality., (© 2024 The Authors.)

Background: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects., Aims: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC., Methods: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years., Results: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2., Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year., Clinicaltrials: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16., (© 2023 CymaBay Therapeutics, Inc and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-μg dose groups ranged from -10.7 to -16.5 U l -1 versus placebo (-7.8 U l -1 ) and tropifexor 140- and 200-μg groups were -18.0 U l -1 and -23.0 U l -1 , respectively, versus placebo (-8.3 U l -1 )) and % HFF (tropifexor 10-90-μg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-μg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164., (© 2023. The Author(s).)

Background: Hepatitis C virus (HCV) is a common cause of progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma worldwide. Despite the availability of effective direct-acting antivirals, patients often have significant hepatic fibrosis at the time of diagnosis due to delay in diagnosis and comorbidities which promote fibrogenesis. Thus, antifibrotic agents represent an attractive adjunctive therapy. Fuzheng Huayu (FZHY), a traditional Chinese medicine botanical formulation, has been used as an antifibrotic agent in chronic HBV infection. Our aim was to assess FZHY in patients with HCV infection and active viremia., Method: We randomized 118 patients with active viremia from 8 liver centers in the U.S. to receive oral FZHY ( n  = 59) or placebo ( n  = 59) for 48 weeks. Efficacy was assessed by histopathologic changes at the end of therapy. A subset of biopsies was further analyzed using qFibrosis to detect subtle changes in fibrosis in different zones of the hepatic lobules., Results: FZHY was well tolerated and safe. Patients with baseline Ishak fibrosis stages F3 and F4 had better response rates to FZHY than patients with baseline F0-F2 ( p =0.03). qFibrosis zonal analysis showed significant improvement in fibrosis in all zones in patients with regression of the fibrosis stage., Conclusions: FZHY produced antifibrotic effects in patients with baseline Ishak F3 and F4 fibrosis stages. Reduction in fibrosis severity was zonal and correlated with the severity of inflammation. Based on its tolerability, safety, and efficacy, FZHY should be further investigated as a therapy in chronic liver diseases because of its dual anti-inflammatory and antiibrotic properties. Lay Summary . This is the first US-based, multicenter and placebo-controlled clinical trial that shows statistically significant reduction in fibrosis in patients with active HCV using an antifibrotic botanical formula. This has important implications as there is an immediate need for effective antifibrotic agents in treating many chronic diseases including NASH that lead to scarring of the liver. With artificial intelligence-based methodology, qFibrosis, we may provide a more reliable way to assess the FZHY as a therapy in chronic liver diseases because of its dual anti-inflammatory and antifibrotic properties., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Tarek Hassanein et al.)

To reduce the disparity in access to liver transplant (LT), United Network for Organ Sharing implemented an exception policy in May 2019, which capped hepatocellular carcinoma (HCC) exception score to the median Model for End-Stage Liver Disease (MELD) at transplant within the donor service area minus 3 points (MMaT-3) after the 6-mo wait period. We aimed to evaluate how this policy affected HCC waitlist outcomes., Methods: Using United Network for Organ Sharing data, we analyzed waitlist outcomes in HCC patients at the time they received exception points from in the pre-MMaT era (August 15, 2017, to November 15, 2018) and MMaT era (June 1, 2019, to August 30, 2020). Comparisons were made within the HCC group and HCC versus non-HCC (at time of listing) groups in the pre-MMaT and MMaT eras and regions were grouped as low, medium, and high MELD based on MMaT., Results: HCC group: LT probability within HCC patients decreased by 20% (subhazard ratio [sHR], 0.78; 95% confidence interval [CI], 0.74-0.85) between the eras and decreased by 41% in low MELD regions (sHR, 0.59; 95% CI, 0.52-0.66). Waitlist dropout was unchanged. Matched HCC versus non-HCC groups: HCC patients had 80% higher LT probability (sHR, 1.84; 95% CI, 1.71-1.99) than non-HCC patients in the pre-MMaT era; which decreased to a 14% higher LT probability in MMaT era. In low and medium regions, HCC patients had over twofold higher LT probability in the pre-MMaT era, which decreased to a ~20% higher probability (sHR, 1.14; 95% CI, 1.06-1.23) in the MMaT era. After implementation of the acuity circle policy, HCC patients had lower LT probability (sHR, 0.84; 95% CI, 0.74-0.94) than non-HCC patients., Conclusions: The geographic disparity between HCC and non-HCC patients has improved with the MMaT-3 policy. Despite lower LT probability for HCC patients, waitlist dropout was not adversely impacted., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The screening for undiagnosed non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (SUNN) study was a population-based screening study that aimed to provide proof of concept to encourage community-level screening and detection for this non-communicable disease. Current screening guidelines do not recommend the routine screening of nonalcoholic fatty liver disease (NAFLD) for asymptomatic populations, so providers are not encouraged to actively seek disease, even in high-risk patients. This study sought to determine whether a self-selecting cohort of asymptomatic individuals would have scores based on vibration controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) significantly correlated to risk factors to suggest that routine screening for high-risk patients should be recommended. The study recruited 1,070 self-selected participants in Houston and Galveston County, Texas, 940 of which were included in final analysis. A pre-screening survey was used to determine eligibility. VCTE-based scores analyzed steatosis and fibrosis levels. Fifty-seven percent of the study population demonstrated steatosis without fibrosis, suggesting NAFLD, while 16% demonstrated both steatosis and fibrosis, suggesting NASH. Statistically significant risk factors included factors related to metabolic syndrome, race, and age, while statistically significant protective factors included consumption of certain foods and exercise. The findings of this study suggest that high-risk individuals should be screened for NAFLD even in the absence of symptoms and that community-based screenings are an effective tool, particularly in the absence of proactive guidelines for providers., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WE, GAW, MLH, and HEC are employees of FLF, which reports program support and educational grants from Allergan, Amazon, Bristol-Myers Squibb, Celgene, Clinical Care Options, Continuum Clinical, Echosens, Eskridge Family Trust, Fibronostics, First Line Creative, Gilead Sciences, Global Engage, Google, Health Business Solutions, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Meetrix, Merck & Co., Inc. NetNoggin, Prosciento, Pfizer, Terns Pharmaceuticals and various private and philanthropic individual donors. JMV reports relevant research and grant support from Allergan, Alnylam, 89Bio, Bristol-Myers Squibb, Celgene, CymaBay, Exalenz, Galectin, Galmed, Genfit, Gilead, Hanmi, Immuron, Intercept, Madrigal, Merck, Mochida, Molecular Stethoscope, Novartis, NovoNordisk, Pliant, Sagimet, Tobira Therapeutics, and Zydus; advisor or consultant fees from Allergan, Blade Pharmaceuticals, Bristol-Myers Squibb, Conatus, CymaBay, Exalenz, Fractyl, Intercept, Novartis; and is on the Data Safety and Management Boards for NIH NIDDK Drug-Induced Liver Injury Network (DILIN) and Fractyl. WG reports grant support from AbbVie and Gilead Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Canadian Association for the Study of the Liver.)

Background & Aims: Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression., Methods: We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96., Results: Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints)., Conclusions: In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To assess the ability of signature metabolites alone, or in combination with the model for end-stage liver disease-Na (MELD-Na) score to predict mortality in patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis., Materials & Methods: Plasma metabolites were detected using ultrahigh-performance liquid chromatography/tandem mass spectrometry in 39 patients with cirrhosis caused by primary biliary cholangitis or primary sclerosing cholangitis. Mortality was predicted using Cox proportional hazards regression and time-dependent receiver operating characteristic curve analyses., Results: The top five metabolites with significantly greater accuracy than the MELD-Na score (area under the receiver operating characteristic curve [AUROC] = 0.7591) to predict 1-year mortality were myo-inositol (AUROC = 0.9537), N-acetylputrescine (AUROC = 0.9018), trans-aconitate (AUROC = 0.8880), erythronate (AUROC = 0.8345) and N6-carbamoylthreonyladenosine (AUROC = 0.8055). Several combined MELD-Na-metabolite models increased the accuracy of predicted 1-year mortality substantially (AUROC increased from 0.7591 up to 0.9392)., Conclusion: Plasma metabolites have the potential to enhance the accuracy of mortality predictions, minimize underestimates of mortality in patients with cirrhosis and low MELD-Na scores, and promote equitable allocation of donor livers., Competing Interests: Financial & competing interests disclosure AL Mindikoglu was supported by 2017 Roderick D MacDonald Research Award/Baylor St Luke's Medical Center (award number 17RDM005). This project was also supported in part by NIH Public Health Service grant P30DK056338, which funds the Texas Medical Center Digestive Diseases Center and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH. JP Arab and VH Shah were supported by NIH/NIDDK P30DK084567 which funds Mayo Center for Cell Signaling in Gastroenterology and the contents of this project are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH. C Coarfa was partially supported by Cancer Prevention and Research Institute of Texas (CPRIT) awards RP170295 and RP170005, and by the NIH/NIDDK award R01DK111522 and the contents of this project are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH. AR Opekun was partially supported by an unrestricted institutional grant from DR and GP Laws. The laboratory of N Putluri receives grant funding from Agilent Technologies to develop mass spectrometry-based biomarkers in cancer (grant number: 0300016016). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2019 The authors.)

Goals: To examine the role that autoantibodies (auto-abs) play in chronic hepatitis C virus (HCV) regarding demographics, presence of extrahepatic manifestations and long-term outcomes in a large US cohort., Background: Auto-abs have been reported to be prevalent in patients with chronic HCV infection, but data on the natural history of these patients are limited., Study: The study included 1556 consecutive patients with HCV without concurrent HIV and/or HBV who had testing for antinuclear antibody (ANA), antimitochondrial antibody (AMA), antismooth muscle antibody (ASMA) and/or antiliver kidney microsomal antibody (LKM). Primary outcomes included development of cirrhosis, hepatic decompensations, hepatocellular carcinoma (HCC), mortality and/or sustained virological response (SVR) to antiviral therapy., Results: A total of 388 patients tested positive for any auto-ab (ANA 21.8%, ASMA 13.3%, AMA 2.2% and LKM 1.2%). Patients who tested positive versus negative were more likely to be women (29.3% vs 20.9%, p<0.001) and less likely to achieve SVR with most treated patients receiving interferon-based therapies (37.2% vs 47.1%, p=0.031). There was no difference between groups for baseline laboratory data, disease state or rate of extrahepatic manifestations (42.8% vs 45.0%, p=0.44). Kaplan-Meier analysis revealed no statistically significant difference between groups for the 10-year development of cirrhosis, hepatic decompensations, HCC nor survival. Furthermore, auto-ab positivity was only found to be a predictor for a lower rate of SVR on multivariate analysis (adjusted OR=1.61, 95 %  CI 1.00 to 2.58, p=0.048)., Conclusions: In our cohort, auto-ab positivity was common, especially in women, and predicted a lower rate of SVR but otherwise had no impact on the natural history of chronic HCV or presence of extrahepatic manifestations., Competing Interests: Competing interests: MHN has served as a consultant for Bristol-Myers Squibb, Novartis, Intercept Pharmaceuticals, Anylam Pharmaceutical, Gilead Sciences, Janssen Pharmaceuticals, and Dynavax Laboratories and has received grant/research support from Bristol-Myers Squibb, Gilead Sciences and Janssen Pharmaceuticals. JMV has research grant support from AbbVie, Gilead, Merck, Novartis, Sundise and Taiwan J. He participates in scientific advisory boards for AbbVie, Gilead, Merck, Novartis and Sundise.

Telomerase reverse transcriptase ( TERT ) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT mutations can be detected in circulating cell-free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of TERT mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, TERT mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion : TERT mutations are detectable in plasma cfDNA. Long-term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. ( Hepatology Communications 2018;2:718-731).

Background & Aims: The rarity of autoimmune liver disease poses challenges to epidemiology studies. However, waitlists for liver transplantation can be used to study patients with end-stage liver diseases. We used these waitlists to assess trends in numbers and demographics of patients awaiting liver transplant for primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH)., Methods: We collected data from UK and US national registries for all adults on liver transplant waitlists, from January 1, 1995, through December 31, 2014. We analyzed data from patients with PBC (n = 1434 in the United Kingdom and n = 5598 in the United States), PSC (n = 1093 in the United Kingdom and n = 6820 in the United States), and AIH (n = 538 in the United Kingdom and n = 4949 in the United States). Numbers of listings per year were adjusted to the estimated populations during each year. Regression analyses were used to examine trends and comparative statistics were used to evaluate differences in individual characteristics among groups., Results: Over the total study period, listings for PBC were 1.2 and 1.0 per million population per year in the United Kingdom and United States, respectively; for PSC, 0.9 and 1.2 per million population per year; and for AIH, 0.5 and 0.8 per million population per year. Over the period studied, numbers of listings for PBC decreased by 50% in both countries; changes in numbers of listings for PSC and AIH were smaller and not consistent between countries. By 2014, PSC had become the leading indication for liver transplantation among patients with autoimmune liver diseases in both countries. Median patient ages at time of listing were lower than those reported as median age of diagnosis for AIH and PBC. The ratio of women:men with PBC decreased by almost 50% from 1995 through 2014. Men with PSC were placed on the waitlist with higher disease severity scores than women in both countries. Among patients with PBC, those of black race were under-represented on waitlists from both countries. Among patients with PSC, Hispanics were under-represented on waitlists in the United States. Patients of non-white races were placed on waitlists at younger ages for all diseases; age differences in waitlist placement varied by up to 10 years, depending on race, among patients with PBC., Conclusions: In an analysis of data collected from UK and US national liver transplant registries over 20 years, we found that PSC has become the leading indication for liver transplantation among patients with autoimmune liver diseases. Numbers of patients with PBC placed on waitlists, and the ratio of women:men with PBC, each decreased by almost 50%, possibly due to increased treatment with ursodeoxycholic acid. Within groups of patients on the transplant waitlist for PBC, PSC, or AIH, we found differences in age, sex, disease severity scores, and ethnicity between diseases and countries that require further study., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population., Methods: We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%)., Results: With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%)., Conclusions: The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection., Material and Methods: In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate., Results: Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients., Conclusion: SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.

Background and Purpose: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection., Methods: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12)., Results: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV., Conclusion: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.

Background & Aims: There is controversy over the use of measuring blood levels of ammonia (NH3) in the management of patients with overt hepatic encephalopathy (HE)., Methods: We performed a retrospective analysis of data from a randomized, double-blind study of 178 patients with cirrhosis given glycerol phenylbutyrate (an NH3-lowering agent) or placebo for 16 weeks. Blood samples were collected at baseline and on study days 7 and 14 and NH3 levels were measured. The probabilities of having an HE episode, based on ammonia values, were modeled using binary logistic regression. A Cox proportional model was used to determine the risk of HE episodes in patients with baseline fasting NH3 levels ≤1.5-fold the upper limit of normal (ULN) versus patients with fasting NH3 levels >1.5-fold the ULN., Results: The risk and frequency of HE episodes and HE-related hospitalizations correlated with baseline (mean, 51 ± 6 μmol/L; ULN, 35 μmol/L) and on-study fasting levels of NH3, and increased sharply at levels >1.5-fold the ULN. Regardless of baseline level, NH3 exposure and the relative risk of HE episodes were decreased by glycerol phenylbutyrate., Conclusions: In analysis of data from a phase 2 study of the effects of glycerol phenylbutyrate in patients with cirrhosis, we found that fasting levels of NH3 in blood can identify patients at risk for HE-related morbidity. Patients with HE might benefit from NH3-lowering therapy. ClinicalTrials.gov no: NCT 00999167., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (© 2015 John Wiley & Sons Ltd.)

Background & Aims: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis., Methods: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular., Results: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups., Conclusions: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Portopulmonary hypertension (POPH) occurs in 5.3% to 8.5% of patients with advanced liver disease. The rate of survival in the absence of orthotopic liver transplantation (OLT) is reportedly 38% at 3 years and 28% at 5 years. Moderate to severe POPH [mean pulmonary artery pressure (MPAP) ≥ 35 mm Hg] is associated with a perioperative mortality rate of 50%. Single-center series have demonstrated the feasibility and short-term efficacy of OLT after POPH is controlled with vasodilators, but long-term outcomes have not been reported. Our aim was to determine graft and patient survival rates and the effects of OLT on pulmonary hypertension (PHT) in patients undergoing transplantation for POPH at our center. Four hundred eighty-eight adult patients underwent transplantation between June 2004 and January 2011, and 7 underwent transplantation for POPH after their MPAP was reduced to ≤35 mm Hg with vasodilators. These 7 patients included 3 men and 4 women with ages ranging from 39 to 54 years at the time of OLT. All patients received IV EPO or inhaled EPO during the perioperative period, and all were weaned off EPO over the course of 3 days to 8 months. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. One patient had recurrent hepatitis C virus cirrhosis and recurrent POPH and died from multiorgan failure unrelated to PHT. Four of the remaining 6 patients required oral vasodilator therapy for persistent PHT. Only 2 of the 7 patients (4.4 and 8.5 years after OLT) did not have PHT. In conclusion, patients with POPH responsive to vasodilator therapy may have excellent long-term graft and patient survival after OLT. Despite the alleviation of portal hypertension by OLT, most patients have persistent or recurrent PHT that can be controlled with oral vasodilators., (© 2014 American Association for the Study of Liver Diseases.)

Background: Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy., Methods: We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided., Results: Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively)., Conclusions: The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: National organizations recommend screening for hepatitis B virus (HBV) before chemotherapy but differ regarding which patients should be screened. We aimed to determine contemporary screening rates at a cancer center and the possible influence on these rates of publication of national recommendations., Methods: We conducted a retrospective cohort study of HBV screening in cancer patients registered during the period from January 2004 through April 2011. Screening was defined as HBsAg and anti-HBc tests ordered around the time of initial chemotherapy. We compared screening rates for 3 periods: January 1, 2004, through December 18, 2008 (Food and Drug Administration and American Association for the Study of Liver Diseases 2007 recommendations); December 19, 2008, through September 30, 2010 (Centers for Disease Control and Prevention, National Comprehensive Cancer Network, American Association for the Study of Liver Diseases 2009, Institute of Medicine, and American Society of Clinical Oncology recommendations); and October 1, 2010, through April 30, 2011. Logistic regression models were used to identify predictors of screening., Results: Of 141,877 new patients, 18,688 received chemotherapy, and 3020 (16.2%) were screened. HBV screening rates increased over the 3 time periods (14.8%, 18.2%, 19.9%; P <0.0001), but <19% of patients with HBV risk factors were screened. Among patients with hematologic malignancies, over 66% were screened, and odds of screening nearly doubled after publication of the recommendations (P <0.0001). Less than 4% of patients with solid tumors were screened, although odds of screening increased 70% after publication of the recommendations (P =0.003). Other predictors of screening included younger age, planned rituximab therapy, and known risk factors for HBV infection., Conclusions: Most patients with solid tumors or HBV risk factors remained unscreened, although screening rates increased after publication of national recommendations. Efforts are needed to increase awareness of the importance of HBV screening before chemotherapy to identify patients who should start antiviral prophylaxis.

Haemophagocytic lymphohistiocytosis (HLH) is associated with high mortality even after prompt diagnosis. We present a young man with HLH triggered by two common viral diseases, infectious mononucleosis and hepatitis A. This patient presented with fever, rapidly progressive liver failure, anasarca and cholestasis, followed by anaemia and neutropenia. His carbohydrate antigen 19-9 reached over 9000 U/mL. Initial bone marrow and liver biopsies did not show histological features of malignancy or HLH. The patient was finally diagnosed and treated almost 1 year after the initial symptoms started, and had an excellent response with etoposide and dexamethasone. This case is unusual because it was triggered following mononucleosis in a patient with positive total antibodies against hepatitis A, with rapidly developing liver failure, and also because the patient's response was excellent despite the delay in treatment. It underscores the importance of suspecting HLH when severe systemic illness develops after a viral infection, even in the absence of clear histological features.

Background & Aims: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria., Methods: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended., Results: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log(10) decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3))., Conclusions: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Non-suppurative destructive cholangitis (NSDC) is characterized by T-cell infiltration of the biliary epithelia of small-to medium-caliber bile ducts, causing apoptosis of biliary epithelial cells (BEC) and, ultimately, ductopenia. NSDC is the primary histopathologic process in the autoimmune disease known as primary biliary cirrhosis (PBC) and in alloimmune graft-versus-host disease (GVHD) and hepatic allograft rejection. The onset of NSDC in the B10.D2→BALB/c murine model of hepatic GVHD is preceded by hepatic production of pro-inflammatory cytokines, accumulation of lipopolysaccharide (LPS), and expression of chemokine genes. To explain the curious restriction of NSDC to small- and medium-caliber intrahepatic bile ducts, we hypothesized that BEC lining these bile ducts secrete chemokines and cytokines that chemoattract, activate, and polarize the effector T cells mediating NSDC. To test this hypothesis we stimulated BALB/c immortalized BEC (IBEC) in vitro with pro-inflammatory mouse recombinant cytokines with and without LPS and determined the expression of chemokines and cytokines by IBEC using a polymerase chain reaction (PCR), quantitative protein enzyme-linked immunosorbent assays (ELISAs), and microarrays. The capacity of stimulated IBEC to chemoattract activated T cells was assessed in the presence and absence of inhibitors of specific chemokine receptors. We found that pro-inflammatory cytokines, especially the combination of IFNγ and TNFα, induced IBEC gene expression and the secretion of chemokine ligands for the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. Chemokines secreted by IBEC stimulated with IFNγ plus TNFα chemoattracted activated T cells. Inhibition of CCR1, CCR3, CCR5, or CXCR3 significantly reduced the chemoattraction of activated T cells. We conclude that BEC probably play an active role in the immunopathogenesis of NSDC by mediating the chemoattraction and terminal activation of effector T cells responsible for apoptosis of BECs and ductopenia. Selective chemokine expression by BEC lining small- and medium-caliber bile ducts could explain the restriction of NSDC to ducts of this caliber. Inhibition of CCR1, CCR3, CCR5, and CXCR3 to block the chemoattraction and terminal activation of alloreactive T cells represents a potential therapeutic strategy for preventing NSDC after hematopoietic stem-cell transplantation or orthotopic liver transplantation.

Biliary epithelia express high levels of CD44 in hepatobiliary diseases. The role of CD44-hyaluronic acid interaction in biliary pathology, however, is unclear. A rat model of hepatic cholestasis induced by bile duct ligation was employed for characterization of hepatic CD44 expression and extracellular hyaluronan distribution. Cell culture experiments were employed to determine whether hyaluronan can regulate cholangiocyte growth through interacting with adhesion molecule CD44. Biliary epithelial cells were found to express the highest level of CD44 mRNA among four major types of nonparenchymal liver cells, including Kupffer, hepatic stellate, and liver sinusoidal endothelial cells isolated from cholestatic livers. CD44-positive biliary epithelia lining the intrahepatic bile ducts were geographically associated with extracellular hyaluronan accumulated in the portal tracts of the livers, suggesting a role for CD44 and hyaluronan in the development of biliary proliferation. Cellular proliferation assays demonstrated that cholangiocyte propagation was accelerated by hyaluronan treatment and antagonized by small interfering RNA CD44 or anti-CD44 antibody. The study provides compelling evidence to suggest that proliferative biliary epithelia lining the intrahepatic bile ducts are a prime source of hepatic CD44. CD44-hyaluronan interaction, by enhancing biliary proliferation, may play a pathogenic role in the development of cholestatic liver diseases.

Background: Distinguishing those patients with fulminant hepatic failure (FHF) and who require transplantation from those FHF patients who will survive with receiving only intensive medical care remains problematic, and this distinction is important because of the chronic shortage of donor livers., Methods: To assess the applicability of two prognostic scoring systems, referred to as the London and Clichy criteria, we compared using both systems, at the time of admission, for 43 FHF patients (15 M/28 F; age: 3716 yrs). Acetaminophen (ACM) was the etiology for 16 patients, while the remaining 27 had other etiologies. All the patients received intensive care, and 18 (8 ACM/10 non-ACM) had investigational BAL support., Results: For the ACM toxicity, neither the London nor the Clichy criteria exhibited acceptable sensitivity (71 vs 86%, respectively), specificity (78 vs 56%, respectively), a positive predictive value (71 vs 60%, respectively), a negative predictive value (78 vs 83%, respectively) or predictive accuracy (75 vs 69%, respectively) to predict patient survival without transplantation. In contrast, applying the London and Clichy criteria to the FHF patients with non-ACM etiologies showed a sensitivity of 96 vs 80%, respectively, a specificity of 100 vs 100%, respectively, a positive predictive value of 100 vs 100%, respectively a negative predictive value of 67 vs 29%, respectively and a predictive accuracy of 96% vs 82%, respectively., Conclusions: Overall, the London criteria more accurately predicted the need for transplantation, and neither the London criteria nor the Clichy prognostic criteria accurately predicted the outcome of those patients who suffered with FHF due to ACM. BAL support may have contributed to the survival of the patients with ACM toxicity and who didn't undergo transplantation, and this survival exceeded the predictions of both prognostic systems. Additional multicenter studies should be conducted to refine these prognostic scoring systems, and this will help physicians rapidly identify those FHF patients who can survive without undergoing liver transplantation.

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

In the absence of preventative therapy, reinfection of allografts with hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) resulted in dismal allograft and patient survival. Major advances in the management of HBV-infected recipients of OLT during the past 15 years have steadily reduced the rate of reinfection, resulting in improved outcomes. Initially, long-term use of hepatitis B immune globulin (HBIG) as a source of anti-HBs antibodies was effective in preventing or delaying reinfection. Lamivudine monotherapy made it possible to suppress HBV replication prior to OLT, markedly decreasing the risk of reinfection. Although lamivudine monotherapy used before and after OLT could prevent reinfection, its effectiveness was limited by progressive development of lamivudine-resistant mutant infections. Combination therapy with HBIG and lamivudine after OLT reduced both HBV recurrence and the risk of lamivudine resistance even in patients with active HBV replication. Introduction of adefovir provided a safe, alternative oral antiviral able to treat effectively lamivudine-resistant mutants HBV. Available strategies to prevent reinfection have resulted in OLT outcomes for HBV-infected patients comparable to those for patients transplanted for non-HBV indications. In the future, combination therapies of HBIG and both nucleoside and/or nucleotide agents will undoubtedly be optimized. Development of new drugs to treat HBV will increase opportunities to combine agents to enhance safety, efficacy and prevent emergence of HBV escape mutants. New vaccines and adjuvants may make it possible to generate anti-HBs in immunosuppressed patients, eliminating the need for HBIG.

Alpha-naphthylisothiocyanate (ANIT) is a hepatotoxin that causes severe neutrophilic inflammation around portal tracts and bile ducts. The chemotactic signals that provoke this inflammatory response are unknown. In this study, we addressed the possibility that ANIT upregulates CXC chemokines in the liver and that these compounds mediate hepatic inflammation and tissue injury after ANIT treatment. Mice treated with a single dose of ANIT (50 mg/kg) exhibited rapid hepatic induction of the CXC chemokine macrophage inflammatory protein-2 (MIP-2). MIP-2 derived primarily from hepatocytes, with no apparent contribution by biliary cells. In ANIT-treated mice, the induction of MIP-2 coincided with an influx of neutrophils to portal zones; this hepatic neutrophil recruitment was suppressed by 50% in mice that lack the receptor for MIP-2 (CXCR2(-/-)). Interestingly, despite their markedly reduced degree of hepatic inflammation, CXCR2(-/-) mice displayed just as much hepatocellular injury and cholestasis after ANIT treatment as wild-type mice. Moreover, after long-term exposure, ANIT CXCR2(-/-) mice developed liver fibrosis that was indistinguishable from that in wild-type mice. In summary, our data show that CXC chemokines are responsible for some of the hepatic inflammation that occurs in response to ANIT but that these compounds are not essential to the pathogenesis of either acute or chronic ANIT hepatotoxicity.

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.

1. Allograft infection with hepatitis C virus (HCV) in immunosuppressed adults results in decreased allograft and patient survival. 2. Risk factors for accelerated progression of hepatitis C related to immunosuppression include treated episodes of acute cellular rejection (ACR), pulse therapy with methylprednisolone, and use of OKT3. 3. Both interferon alfa (IFN-alpha) and ribavirin (RVN) show antiviral actions against HCV and stimulate innate and adaptive immunity to increase cytolysis and polarize T helper subtype 1 (T(H)1) responses. In addition, IFN-alpha inhibits fibrogenesis in the liver. 4. Both IFN-alpha and RVN have been studied in immunosuppressed liver transplant recipients as prophylaxis or treatment of established hepatitis C to reduce allograft failure and patient mortality. Reported protocols include monotherapies with RVN, standard IFN-alpha, and pegylated IFN-alpha and combination therapies using RVN and either standard IFN-alpha or pegylated IFN-alpha. 5. The clinical impact of using IFN-alpha and RVN in highly selected immunosuppressed patients varied among studies. Combination therapy with standard IFN-alpha and RVN resulted in the greatest sustained biochemical and virological responses. However, no therapy prevented progression of acute cholestatic hepatitis C despite evidence of virological responses. Substantial proportions of patients developed adverse events requiring dose reduction or discontinuation that compromised efficacy. RVN monotherapy was not only virologically ineffective, but may have stimulated hepatic fibrosis. Current data regarding monotherapy or combination therapy with pegylated IFN-alpha are limited, but encouraging. 6. Despite potent immunostimulatory actions of both IFN-alpha and RVN that enhance natural killer, T(H)1, their use did not significantly increase the incidence of ACR. 7. Additional studies are needed to resolve the controversy over prophylaxis versus treatment of established disease and the potential utility of low-dose maintenance IFN-alpha therapy to retard fibrogenesis without clearing HCV. 8. After new, less toxic, and more potent antiviral agents become available, they should be tested immediately in patients with hepatitis C post-liver transplantation.

Background & Aims: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD., Methods: Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities., Results: Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2., Conclusions: NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.

The hepatopulmonary syndrome (HPS), consisting of elevated alveolar-arterial oxygen gradient and intrapulmonary vascular abnormalities in the presence of advanced liver disease, is associated with high mortality. Liver transplantation (LT) has been used for the treatment of HPS; however, the success of LT for the treatment of HPS is not uniformly documented. We reviewed our experience over a 5-year period and identified eight adult patients with incapacitating respiratory symptoms compatible with HPS. Inclusion criteria included hypoxemia, normal lung volumes, reduced oxygen diffusing capacity (D(L)CO), and the presence of intrapulmonary shunting. Underlying liver disease was caused by hepatitis C (2 patients), primary biliary cirrhosis (1 patient), cryptogenic cirrhosis (1 patient), alcohol (2 patients), and hepatitis C with alcohol (2 patients). Six out of eight patients required preoperative oxygen support. Severe hypoxemia was present in seven patients (Pa(O2) 51.5 +/- 8.2 mm Hg). Three patients had complicating pulmonary hypertension. All patients exhibited a severely reduced D(L)CO (44.6 +/- 12.2% of predicted value). Six patients were transplanted, with five requiring oxygen support at the time of discharge. Resolution of oxygen dependency occurred in all patients but was delayed in the two patients exhibiting complicating pulmonary hypertension (288.5 +/- 37.4 v 53.5 +/- 35.7 days). All patients exhibited O2 saturations greater than 98% on room air. Currently, three patients are alive and off oxygen. The current report documents successful resolution of hypoxemia after LT in this pilot cohort. This supports the newly implemented United Network for Organ Sharing (UNOS) criteria, that LT for HPS may be extended to include patients with Pa(O2) < 60 mm Hg.

Background & Aims: Chronic hepatitis B is a leading cause of death worldwide. To identify patients who might require urgent liver transplantation despite antiviral therapy, we investigated the determinants of early mortality in a large cohort of patients with decompensated chronic hepatitis B treated with lamivudine., Methods: One hundred fifty-four North American patients with decompensated chronic hepatitis B received lamivudine for a median of 16 months. Univariate and multivariate Cox regression modeling was used to develop a model of 6-month mortality., Results: A biphasic survival pattern was observed, with most deaths occurring within the first 6 months of treatment (25 of 32, 78%) because of complications of liver failure. The estimated actuarial 3-year survival of patients who survived at least 6 months was 88% on continued treatment. In multivariate modeling, elevated pretreatment serum bilirubin and creatinine levels as well as the presence of detectable hepatitis B virus (HBV) DNA (by the bDNA assay) pretreatment were significantly associated with 6-month mortality. An equation approximating the probability of early mortality was developed from these variables., Conclusions: Our data demonstrate a distinct alteration in the slope of the survival curve after 6 months of lamivudine treatment for decompensated chronic hepatitis B. An equation consisting of 3 widely available pretreatment laboratory parameters was developed that can be used to predict the likelihood of early death in patients receiving lamivudine for decompensated chronic hepatitis B. These observations may help identify patients who can be stabilized with suppressive antiviral therapy vs. those who require urgent liver transplantation.

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.