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JHEP Reports
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  This is an Open Access Journal Open Access journal
ISSN (Online) 2589-5559
Published by Elsevier Homepage  [3184 journals]
  • NONALCOHOLIC FATTY LIVER DISEASE IN LEAN INDIVIDUALS

    • Abstract: Publication date: Available online 30 August 2019Source: JHEP ReportsAuthor(s): Somaya Albhaisi, Abhijit Chowdhury, Arun J. Sanyal
       
  • Is PD-1 blockade a potential therapy for HBV'

    • Abstract: Publication date: Available online 28 August 2019Source: JHEP ReportsAuthor(s): Cyrille Féray, F. Xavier López-Labrador
       
  • Liver homing of clinical grade Treg after therapeutic infusion in patients
           with autoimmune hepatitis

    • Abstract: Publication date: Available online 21 August 2019Source: JHEP ReportsAuthor(s): Ye Htun Oo, Susan Ackrill, Richard Cole, Lee Jenkins, Philip Anderson, Hannah C. Jeffery, Nicholas Jones, Louisa E. Jeffery, Philipp Lutz, Rebecca E. Wawman, Amrita Kaur Athwal, Jacqui Thompson, Joanna Gray, Kathy Guo, Darren Barton, Gideon M Hirschfield, Timothy Wong, Peter Guest, David H. Adams Background & AimsAutoimmune hepatitis (AIH) is an immune-mediated disease with no curative treatment. Regulatory T cell (Treg) therapy is potentially curative in AIH given the critical role of Treg in preventing autoimmunity. To work effectively, adoptively transferred Tregs must migrate to and survive within the inflamed liver. We conducted a proof of concept study aiming to assess the safety and liver-homing properties of good manufacturing practice (GMP)-grade autologous Tregs in patients with AIH.MethodsAutologous polyclonal GMP-grade Tregs were isolated using leukapheresis and CliniMACS, labelled with indium tropolonate and re-infused intravenously to 4 patients with AIH. GMP Treg homing to the liver was investigated with longitudinal gamma camera and SPEC-CT scanning. GMP Treg immune-phenotype, function and immunometabolic state were assessed during the study.ResultsWe observed that the isolated Treg cells were suppressive and express CXCR3, a chemokine receptor involved in recruitment into the inflamed liver, as well as Treg functional markers CD39, CTLA-4 and the transcription factor Foxp3. Serial gamma camera and SPECT–CT imaging demonstrated that 22–44% of infused Tregs homed to and were retained in the autoimmune hepatitis patients' liver for up to 72 h. The infused cells did not localize to any off-target organs other than the spleen and bone marrow. GMP-Treg were metabolically competent and there were no infusion reactions or high-grade adverse effects after Treg infusion.ConclusionOur novel findings suggest the liver is a good target organ for Treg cellular therapy supporting the development of clinical trials to test efficacy in autoimmune hepatitis and other autoimmune liver diseases.Lay summary:1.Autoimmune liver diseases occur when body immune cells target it's own liver cells.2.Regulatory T cells (Treg) prevent autoimmunity, thus they are potential therapy for autoimmune liver diseases.3.In patients with autoimmune hepatitis, Treg infusion is safe, nearly a quarter of infused Treg home to the liver and cells suppress tissue-damaging effector T cells. Thus, Treg are likely future curative immune cell therapy to treat the early autoimmune liver diseases.Graphical abstractUnlabelled Image
       
  • New treatments/targets for primary biliary cholangitis

    • Abstract: Publication date: Available online 9 August 2019Source: JHEP ReportsAuthor(s): Christophe Corpechot, Raoul Poupon, Olivier ChazouillèresSummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.
       
  • Diabetes does not increase infection risk or mortality following an
           infection in patients with cirrhosis and ascites

    • Abstract: Publication date: Available online 8 August 2019Source: JHEP ReportsAuthor(s): Lars Bossen, Gitte A. Dam, Hendrik Vilstrup, Hugh Watson, Peter Jepsen Background & AimsBoth cirrhosis and diabetes are established risk factors for infections. However, it remains uncertain whether diabetes adds to the risk of infections in cirrhosis patients who are already at high risk of infections, or increases the mortality following an infection. To answer these questions, we followed a cohort of trial participants with cirrhosis and ascites for one year to compare the incidence of infections and post-infection mortality between those with or without diabetes.MethodsWe used Cox regression to estimate the hazard ratio of any infection, adjusting for confounding by patient age, gender, MELD score, albumin, use of PPI and lactulose, cirrhosis aetiology, and severity of ascites. Further, we analysed the mortality after infection.ResultsAmong 1198 patients with cirrhosis and ascites, the diabetics (n = 289, 24%) were more likely than the non-diabetics (n = 909, 76%) to be old and male, to have low platelets, and to use lactulose. At inclusion, similar proportions of diabetic and non-diabetic patients were taking a quinolone antibiotic (13% vs. 12%) and they had similar median MELD score (14 vs 15). During the follow-up, 446 patients had an infection. Diabetes did not increase the hazard rate of infections (adjusted HR = 1.08, 95% CI 0.87–1.35). Further, diabetes did not increase the mortality following an infection (adjusted HR = 0.93, 95% CI 0.64–1.35).ConclusionsIn patients with cirrhosis and ascites, diabetes did not increase infection risk or mortality after infection. The immune incompetences of each disease seem not to be additive. In clinical terms, this means that particular attention to infections is not indicated in cirrhosis patients with diabetes.Lay summaryCirrhosis and diabetes are chronic diseases that weaken the immune system and increase the risk of infections, but it is unknown whether their combined effects exceed the effect of cirrhosis alone. We showed that the risk of infections was the same in patients with cirrhosis and ascites and diabetes as in patients with cirrhosis and ascites alone. Thus, their combined effects did not exceed the effect of cirrhosis alone.Graphical abstractUnlabelled Image
       
  • Public Health Policies and Alcohol-related Liver Disease

    • Abstract: Publication date: Available online 8 August 2019Source: JHEP ReportsAuthor(s): Meritxell Ventura-Cots, Maria Pilar Ballester-Ferré, Samhita Ravi, Ramon BatallerSummaryAlcohol-related liver disease (ALD) represents a major public health problem worldwide. According to the World Health Organization, the highest levels of per capita alcohol consumption are observed in countries of the European Region. Alcohol consumption is also alarmingly increasing in emerging countries. ALD is one of the main contributors to the burden of alcohol-attributable deaths and disability. In the United States, severe forms of ALD such alcoholic hepatitis are increasing in the last decade and in the United Kingdom, three-quarters of liver-related mortality results from alcohol consumption. Besides genetic factors, there is strong evidence that the amount of alcohol intake plays a major role in the development of advanced ALD. Establishing effective public health policies is therefore mandatory reduce the burden of ALD. Since the 90’s, major public health institutions and governments had developed a variety of policies in order to reduce the harm produced by excessive drinking. Those policies encompass multiple aspects, from pricing and taxation to advertising regulation. Measures focused on taxation and price regulation have been shown to be the most effective to reduce alcohol-related mortality. However, there are few studies focused on the effect of public policies on ALD. This review article summarizes the factors influencing ALD burden and the role of different public health policies.Lay summaryAlcohol-related liver disease (ALD) is the main cause of mortality in liver patients worldwide. Besides treating individual patients, local public health policies aimed at reducing harmful alcohol consumption in each country is essential to beat ALD. There are few studies on the effect of such policies on ALD. Most available data suggest that price and taxation regulation are the most effective measures.
       
  • Ascites control by TIPS is more successful in patients with a lower
           paracentesis frequency and is associated with improved survival

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Felix Piecha, Ulf K. Radunski, Ann-Kathrin Ozga, David Steins, Andreas Drolz, Thomas Horvatits, Clemens Spink, Harald Ittrich, Daniel Benten, Ansgar W. Lohse, Christoph Sinning, Johannes KluweBackground & AimsRefractory ascites is the main reason for the implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in liver cirrhosis, but ascites control by TIPS fails in a relevant proportion of cases. Here, we investigated whether routine parameters pre-TIPS can predict persistent ascites after TIPS implantation and whether persistent ascites predicts long-term clinical outcome.MethodsA detailed retrospective analysis of 128 patients receiving expanded polytetrafluoroethylene-covered stents for the treatment of refractory ascites was performed. Persistent ascites post-TIPS was defined as the prolonged need for paracentesis>3 months after TIPS. The influence of demographics, laboratory results, pre-TIPS heart and liver ultrasound results, and invasive hemodynamic parameters on persistent ascites was evaluated by univariable and multivariable logistic regression. Predictors of the composite endpoint liver transplantation/death were analyzed using a multivariable Cox regression.ResultsAscites control post-TIPS was achieved in 95/128 patients (74%), whereas ascites remained persistent in 33/128 cases (26%). On multivariable analysis, a lower paracentesis frequency pre-TIPS (odds ratio 1.672; 95% CI 1.253–2.355) and lower baseline creatinine levels (odds ratio 2.640; CI 1.201–6.607) were associated with ascites control. Patients with persistent ascites post-TIPS had and impaired transplant-free survival (median 10.0 vs. 25.8 months), for which persistent ascites was the only independent predictor (hazard ratio 5.654; CI 3.019–10.59).ConclusionTIPS-placement in patients with lower paracentesis frequency and creatinine levels is associated with superior ascites control. Thus, TIPS implantation should be considered in moderate decompensation and not as a last resort. Persistent ascites post-TIPS seems to be the only predictor of liver transplantation and death.Lay summaryThe insertion of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with refractory ascites should be considered in patients with moderate decompensation and not as a last resort, as lower paracentesis frequency and creatinine levels pre-TIPS are associated with superior ascites control. In turn, failure to control ascites seems to be the only predictor of liver transplantation and death.Graphical abstractUnlabelled Image
       
  • Hepatitis B and C screening needs among different ethnic groups: A
           population-based study in Amsterdam, the Netherlands

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Freke Zuure, Janneke Bil, Maartje Visser, Marieke Snijder, Anders Boyd, Petra Blom, Gerard Sonder, Janke Schinkel, Maria PrinsBackground & AimsData on the prevalence of chronic hepatitis B (HBV) and hepatitis C (HCV) virus infections, including the proportion of individuals aware of infection, are scarce among migrants living in Europe. We estimated the prevalence of past and present HBV and HCV infection, along with their determinants and peoples’ awareness of infection status, among different groups of first-generation migrants and Dutch-origin residents of Amsterdam.MethodsCross-sectional data of 998 Surinamese (mostly South-Asian and African-Surinamese), 500 Ghanaian, 497 Turkish, 498 Moroccan and 500 Dutch-origin participants from the observational population-based HELIUS study were used. Blood samples of participants were tested for HBV and HCV infection. Infection awareness was determined using records from participants’ general practitioners.ResultsAge- and gender-adjusted chronic HBV prevalence was highest among Ghanaian participants (5.4%), followed by Turkish (4.1%), African-Surinamese (1.9%), Moroccan (1.2%), South-Asian Surinamese (0.9%) and Dutch (0.4%) participants. A total of 58.1% of the cases were aware of their infection. In multinomial logistic regression analyses, Ghanaian (adjusted odds ratio [aOR] 42.23; 95% confidence interval [CI] 9.29–192.01), African-Surinamese (aOR 6.16; 95% CI 1.27–29.79), and Turkish (aOR 13.44; 95% CI 2.94–61.39) participants were at increased risk of chronic HBV infection compared with those of Dutch origin. Older participants were also at increased risk (aOR 1.02 per year; 95% CI 1.00–1.05), whereas women were at lower risk (aOR 0.49; 95% CI 0.29–0.83). HCV prevalence was 0.4% (95% CI 0.1–1.3%) among Dutch and African-Surinamese and 0% (95% CI 0.0–0.5%) for each of the other groups; all cases with follow-up data were aware of their infection.ConclusionsGhanaian, Turkish and African-Surinamese first-generation migrants are at increased risk of chronic HBV infection and many are unaware of their infection, whereas HCV prevalence was low among all ethnic groups. Screening campaigns are urgently warranted and need to consider specific ethnic groups.Lay summaryFirst-generation migrants of Ghanaian, Turkish and African-Surinamese origin were at increased risk of chronic hepatitis B infection, with most infections occurring in older individuals and males. Since over 40% of people were unaware of their chronic hepatitis B infection, screening of these migrant groups is urgently needed. The proportion of first-generation migrants chronically infected with hepatitis C virus was very low among all groups studied.Graphical abstractUnlabelled Image
       
  • Editorial musings

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Morris Sherman
       
  • Mechanistical insights to the inhibition of NTCP by Myrcludex B

    • Abstract: Publication date: Available online 1 August 2019Source: JHEP ReportsAuthor(s): Joanne M. Donkers, Monique D. Appelman, Stan F.J. van de Graaf Background & aimsThe sodium taurocholate co-transporting polypeptide (NTCP) is the entry receptor for the hepatitis B and delta virus (HBV/HDV) and the main hepatic uptake transporter of conjugated bile acids. Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, blocks HBV/HDV infection and inhibits NTCP-mediated bile acid uptake. In humans this increases systemic bile acid levels, that remain elevated for hours even when Myrcludex B is cleared from the circulation. Here, we investigated the dynamics of Myrcludex B-induced NTCP-mediated bile acid transport inhibition in mice and if/how the duration of this effect relates to NTCP protein turnover.MethodsPlasma bile acids were determined in Myrcludex B-treated OATP1a/1b deficient mice. In vitro, plasma membrane-resident NTCP was labeled with biotin or FITC-labeled Myrcludex B and traced in time using hNTCP overexpressing U2OS cells. Förster resonance energy transfer (FRET) by fluorescent lifetime imaging microscopy (FLIM) was used to investigate whether Myrcludex B can transfer to newly synthesized NTCP.ResultsConjugated bile salt levels in plasma peaked 4 h after subcutaneous Myrcludex B administration. After 24 h, plasma bile salt levels were completely normalized, in line with restored NTCP-mediated bile acid transport in vitro. Biotin-labeled NTCP disappeared faster than Myrcludex B-FITC, with almost 40% of FITC signal remaining after 24 h. FITC fluorescence lifetime was strongly decreased upon expression of DY547-labeled Acyl Carrier Protein-tagged NTCP demonstrating transfer of pre-bound Myrcludex B-FITC to newly formed NTCP.ConclusionsThe dynamics of NTCP protein turnover and Myrcludex B-induced plasma bile salt elevations are similar, suggesting that the Myrcludex-B:NTCP interaction is very long-lived. Nevertheless, Myrcludex B is not completely degraded together with NTCP and can transfer to newly synthesized NTCP.Lay summaryThe experimental drug Myrcludex B binds the sodium taurocholate co-transporting polypeptide (NTCP), the viral entry receptor for the Hepatitis B and D virus (HBV/HDV), and thereby prevents infection, but also inhibits hepatic bile salt uptake leading to transiently elevated bile salt levels. This study describes that while the normalization of plasma bile salt levels likely depends on the protein turnover rate of NTCP, Myrcludex B partly escapes co-degradation with NTCP by transferring from one NTCP molecule to another. This is of importance to the HBV/HDV research field as it provides a potential explanation for the distinct kinetics as well as dose-dependence of Myrcludex B effects on viral infection versus bile salt transport.Graphical abstractUnlabelled Image
       
  • PREDICTION OF NOSOCOMIAL ACUTE-ON-CHRONIC LIVER FAILURE IN PATIENTS WITH
           CIRRHOSIS ADMITTED TO HOSPITAL WITH ACUTE DECOMPENSATION

    • Abstract: Publication date: Available online 1 August 2019Source: JHEP ReportsAuthor(s): Giacomo Zaccherini, Maurizio Baldassarre, Michele Bartoletti, Manuel Tufoni, Sonia Berardi, Mariarosa Tamè, Lucia Napoli, Antonio Siniscalchi, Angela Fabbri, Lorenzo Marconi, Agnese Antognoli, Giulia Iannone, Marco Domenicali, Pierluigi Viale, Franco Trevisani, Mauro Bernardi, Paolo Caraceni Background and AimsNosocomial Acute-on-Chronic Liver Failure (nACLF) develops in at least 10% of patients with cirrhosis hospitalized for acute decompensation (AD), greatly worsening their prognosis. This prospective observational study aimed at identifying rapidly obtainable predictors at admission allowing the early recognition and stratification of patients at risk for nACLF.Methods516 consecutive patients hospitalized for AD of cirrhosis were screened: those who did not present ACLF at admission (410) were enrolled and surveilled for the development of nACLF.Results59 (14%) patients developed nALCF after a median of 7 (IQR 4–18) days. At admission, they presented a more severe disease and higher degrees of systemic inflammation and anemia than those (351; 86%) who remained free from nACLF. Competing risk multivariable regression analysis showed that baseline MELD score (sHR = 1.15 [95%CI: 1.10–1.21]; p 
       
  • Copyright and Information

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s):
       
  • The oncogenic role of hepatitis delta virus in hepatocellular carcinoma

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Marc Puigvehí, Carlos Moctezuma-Velázquez, Augusto Villanueva, Josep M. LlovetSummaryHepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.Graphical abstractUnlabelled Image
       
  • Comparison of the current international guidelines on the management of
           HCC

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Friedrich Foerster, Peter Robert GalleSummaryThe management of hepatocellular carcinoma (HCC) has become ever more demanding. To evaluate the available evidence and to give clinicians the best guidance, all major hepatology societies have developed guidelines for HCC. Recently, updated versions have been published by the American, the Asian Pacific, and the European societies. This article presents a comparison of these three guidelines summarising both common ground and differences. Moreover, it highlights areas of ongoing research which will make yet another round of updates of the guidelines necessary in the near future.
       
  • Continuous terlipressin infusion is associated with improved diet intake
           and muscle strength in patients awaiting liver transplant

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Brooke Chapman, Paul Gow, Marie Sinclair, Timothy Hanrahan, Peter Angus, Tess McClure, Chris Mills, Ryma Terbah, Adam TestroBackground & AimsPortal hypertension contributes to the pathogenesis of malnutrition and sarcopenia in cirrhosis via multiple mechanisms. Terlipressin is a vasopressin analogue that we administer via continuous outpatient infusion, as a bridge to transplantation in patients with hepatorenal syndrome or refractory ascites. We describe, for the first time, the impact of outpatient terlipressin on nutritional and muscle parameters.MethodsNutrition (subjective global assessment), handgrip strength, dietary intake (energy, protein), frequency of paracentesis and severity of liver disease (model for end-stage liver disease score) were prospectively recorded at terlipressin commencement and follow-up (transplantation, cessation or census date).ResultsNineteen patients were included (89% male, median age 59.6 years, median model for end-stage liver disease score 24), of whom 12 had hepatorenal syndrome and 7 had refractory ascites. All patients were malnourished at baseline, 63% (n = 12) had sarcopenic-range grip strength, and mean paracentesis frequency was 2.86 ± 1.62/month. Median duration of terlipressin was 51 days (interquartile range 29–222). Fourteen patients (74%) were transplanted, 2 delisted (10%) and 3 (16%) continued terlipressin. Energy and protein intake improved significantly following terlipressin, from 17.94 ± 5.43 kcal/kg to 27.70 ± 7.48 kcal/kg, and 0.74 ± 0.28 g/kg to 1.16 ± 0.31 g/kg, respectively (both p
       
  • Spleen stiffness to liver stiffness ratio significantly differs between
           ALD and HCV and predicts disease-specific complications

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Omar Elshaarawy, Johannes Mueller, Indra Neil Guha, Jane Chalmers, Rebecca Harris, Aleksander Krag, Bjørn Stæhr Madsen, Horia Stefanescu, Oana Farcau, Andreea Ardelean, Bogdan Procopet, Maja Thiele, Sebastian MuellerBackground & AimsBoth liver stiffness (LS) and spleen stiffness (SS) are widely used to non-invasively assess liver fibrosis and portal hypertension, respectively. We aimed to identify the impact of disease etiology, namely the localization of inflammation (portal vs. lobular), on the SS/LS ratio.MethodsIn this multicenter study, LS and SS were prospectively assessed in 411 patients with alcohol-related liver disease (ALD) or hepatitis C virus (HCV) using FibroScan® (Echosens, Paris); changes in these parameters were also studied in response to treatment (alcohol withdrawal, HCV therapy). LS and spleen length (SL) were further analyzed in a retrospective cohort of 449 patients with long-term data on decompensation/death.ResultsBoth, SS and SL were significantly higher in HCV compared to ALD (42.0 vs. 32.6 kPa, p≪0.0001, 15.6 vs. 11.9 cm, p≪0.0001) despite a lower mean LS in HCV. Consequently, the SS to LS ratio and the SL to LS ratio were significantly higher in HCV (3.8 vs. 1.72 and 1.46 vs. 0.86, p≪0.0001) through all fibrosis stages. Notably, SL linearly increased with SS and the relation between SS and SL was identical in HCV and ALD. In contrast, livers were much larger in ALD at comparable LS. After treatment, LS significantly decreased in both diseases without significant changes to the SS/LS ratio. In the prognostic cohort, patients with ALD had higher LS values (30.5 vs. 21.3 kPa) and predominantly presented with jaundice (65.2%); liver failure was the major cause of death (p≪0.01). In contrast, in HCV, spleens were larger (17.6 vs. 12.1 cm) while variceal bleeding was the major cause of decompensation (73.2%) and death (p≪0.001).ConclusionBoth SS/LS and SL/LS ratios are significantly higher in patients with portal HCV compared to lobular ALD. Thus, combined LS and SS or SL measurements provide additional information about disease etiology and disease-specific complications.Lay summaryHerein, we show that patients with hepatitis C virus infection (HCV) have higher spleen stiffness and portal pressure than patients with alcohol-related liver disease (ALD), within the same fibrosis stage and matched to liver stiffness. Thus, the spleen stiffness to liver stiffness ratio is significantly higher in patients with HCV compared to ALD. Additionally, patients with HCV more commonly progress to portal hypertension-related complications (e.g. variceal bleeding), while patients with ALD more commonly progress to liver failure (e.g. jaundice). The spleen stiffness to liver stiffness ratio is a useful tool to confirm disease etiology and predict disease-specific complications.Graphical abstractUnlabelled Image
       
  • Radiotherapy for HCC: Ready for prime time'

    • Abstract: Publication date: August 2019Source: JHEP Reports, Volume 1, Issue 2Author(s): Andrew Bang, Laura A. DawsonSummaryStereotactic body radiation therapy (SBRT) has an evolving role in the management of hepatocellular carcinoma (HCC), largely due to recent advances in imaging technology. Often utilized in situations where other locoregional therapies are not feasible, SBRT has been demonstrated to be an effective treatment that confers high rates of durable local control. However, there is limited evidence to firmly establish its place in the treatment paradigm for HCC. In this article, we review the current evidence and highlight specific considerations in the multiple settings where SBRT may be used, including for primary HCC treatment and bridging/downstaging, as well as exploring the potential for SBRT in the treatment of extrahepatic oligo-metastatic HCC.
       
  • The role of the gut microbiome in chronic liver disease: the clinical
           evidence revised

    • Abstract: Publication date: Available online 31 July 2019Source: JHEP ReportsAuthor(s): Katherine JP Schwenger, Nayima Clermont-Dejean, Johane P. AllardSummaryRecent research has suggested a role for the intestinal microbiota in the pathogenesis and potential treatment of a wide range of liver diseases. The intestinal microbiota and bacterial products may contribute to the development of liver diseases through multiple mechanisms including increased intestinal permeability, chronic systemic inflammation, production of short-chain fatty acids and changes in metabolism. This suggests a potential role for pre-, pro- and synbiotic products in the prevention or treatment of some liver diseases. In addition, there is emerging evidence on the effects of faecal microbial transplant. Herein, we discuss the relationship between the intestinal microbiota and liver diseases, as well as reviewing intestinal microbiota-based treatment options that are currently being investigated.
       
  • Recent Advances in Liver Transplantation for Cancer: The Future of
           Transplant Oncology

    • Abstract: Publication date: Available online 30 July 2019Source: JHEP ReportsAuthor(s): Phillipe Abreu, Andre Gorgen, Graziano Oldani, Taizo Hibi, Gonzalo SapisochinSummary:Liver transplantation for hepatocellular carcinoma is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with the recent therapeutic advances over the last years, as well as due to efforts to increase the donor pool liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid hemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the most modern indications for liver transplantation with a special focus on the future perspectives based on the recently established concept of Transplant Oncology.
       
  • The current issue of JHEP Reports

    • Abstract: Publication date: Available online 29 July 2019Source: JHEP ReportsAuthor(s): S. Francque
       
  • From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment
           options

    • Abstract: Publication date: Available online 19 July 2019Source: JHEP ReportsAuthor(s): Amalia Gastaldelli, Kenneth Cusi The prevalence of NAFLD is estimated today to reached about 25% or more of adults worldwide. NAFLD is prevalent in obese but also may affect non-obese insulin resistant subjects. NAFLD is associated with a 2- to 3-fold increased risk of developing type 2 diabetes (T2D) and may be higher in some studies with more severe liver disease. NAFLD plus severe fibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review we discuss the altered pathophysiological mechanisms that are at the base of development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that can be potentially useful for the management of NASH.
       
  • Anticoagulation in the cirrhotic patient

    • Abstract: Publication date: Available online 16 July 2019Source: JHEP ReportsAuthor(s): Laura Turco, Emmanuelle de Raucourt, Dominique-Charles Valla, Erica VillaSummaryIn the past, patients with liver cirrhosis were thought to be prone to increased bleeding risk. However, those with compensated liver cirrhosis actually have normal coagulative balance, which can become altered when liver function worsens, or infection, bleeding, or acute kidney insufficiency occur. When this happens, it is now recognized that patients with liver cirrhosis are at higher risk of thrombotic rather than haemorrhagic complications. Anticoagulation plays a favourable role both when used therapeutically or prophylactically. Successful anticoagulation is associated with a lower rate of decompensation and with improved survival. To date, treatment has involved the use of low molecular weight heparins and vitamin K antagonists. Preliminary data suggest that novel non-vitamin K antagonist oral anticoagulants can be used safely in patients with liver cirrhosis.
       
  • Immunobiology of Cholangiocarcinoma

    • Abstract: Publication date: Available online 10 July 2019Source: JHEP ReportsAuthor(s): Emilien Loeuillard, Caitlin Conboy, Gregory Gores, Sumera Rizvi Cholangiocarcinoma represents a heterogeneous group of epithelial tumors that are classified according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA). Although surgical resection and liver transplantation following neoadjuvant therapy are potentially curative options for a subset of patients with early-stage disease, the currently available medical therapies for CCA have limited efficacy. Immunotherapeutic strategies such as immune checkpoint blockade (ICB) harness the host immune system to unleash an effective and durable anti-tumor response in a subset of patients with a variety of malignancies. However, response to ICB monotherapy has been relatively disappointing in CCA. CCAs are desmoplastic tumors with an abundant tumor immune microenvironment (TIME) that contains immunosuppressive innate immune cells such as tumor associated macrophages and myeloid-derived suppressor cells. A subset of CCAs may be classified as immune ‘hot’ tumors with a high density of CD8+ T cells and enhanced expression of immune checkpoint molecules. Immune ‘hot’ tumor types are associated with higher response rates to ICB. However, the suboptimal response rates to ICB monotherapy in human clinical trials of CCA implies that the preponderance of CCAs are immune ‘cold’ tumors with a non-T cell infiltrated TIME. An enhanced comprehension of the immunobiology of CCA, particularly the innate immune response to CCA, is essential in the effort to develop effective combination immunotherapeutic strategies that can target a larger subset of CCAs.
       
  • Comparison between non-alcoholic fatty liver disease screening guidelines
           in children and adolescents

    • Abstract: Publication date: Available online 9 July 2019Source: JHEP ReportsAuthor(s): Yamen Ezaizi, Mohammad Nasser Kabbany, Praveen Kumar Conjeevaram Selvakumar, Muhammed Talal Sarmini, Amandeep Singh, Rocio Lopez, Valerio Nobili, Naim AlkhouriBackground & AimThere is currently no agreement on the screening strategy for non-alcoholic fatty liver disease (NAFLD) in children at risk. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommends screening for NAFLD using alanine aminotransferase (ALT) in obese/overweight children, while the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends using both ALT and abdominal ultrasound. The aim of this study was to assess the prevalence of suspected NAFLD in obese children based on the 2 screening strategies.MethodConsecutive overweight/obese children seen at a weight-management program were included. Each child underwent a liver ultrasound and had ALT level measured at first visit. Two screening strategies were compared: the NASPGHAN strategy using ALT ≫2x the gender specific cut-off and the ESPGHAN strategy using elevated ALT ≫45 IU/L and/or fatty liver on ultrasound. Univariate and multivariate analyses were performed to assess predictors of low ALT in individuals with evidence of suspected NAFLD on ultrasound.ResultsOverweight/obese children were included. NAFLD was suspected as follows: 26% based on the NASPGHAN strategy, and 58% based on the ESPGHAN strategy. Fatty liver was present on ultrasound in 53% of our cohort. ALT was ≫2x the gender specific cut-off in only 26% of children with fatty liver on ultrasound. Univariate and multivariate analyses indicated that children with fatty infiltration on ultrasound and low ALT were less likely to have metabolic syndrome, insulin resistance, or hypertriglyceridemia.ConclusionBy relying on ALT values alone to screen for NAFLD, suspected NAFLD might be missed in many children who are at risk. Children with fatty infiltration on ultrasound and low ALT may be less likely to have metabolic syndrome, insulin resistance or hypertriglyceridemia.Lay summaryUsing the combination of elevated alanine aminotransferase and fatty infiltration on ultrasound increases the detection rate of suspected non-alcoholic fatty liver disease in at-risk children. Notably, a significant percentage of children with fatty infiltration on ultrasound have low alanine aminotransferase (≪52/44). Children with fatty infiltration on ultrasound and low alanine aminotransferase may be less likely to have features of the metabolic syndrome.Graphical abstractPrevalence of suspected NAFLD in overweight and obese children determined by two different NAFLD guidelines.Using the combination of elevated ALT and fatty infiltration on ultrasound (European guidelines) increases the detection rate of suspected NAFLD in at risk children.Unlabelled Image
       
  • Opioid epidemic and liver disease

    • Abstract: Publication date: Available online 9 July 2019Source: JHEP ReportsAuthor(s): Elizabeth C. Verna, Aaron Schluger, Robert S. BrownSummaryOpioid use in the United States and in many parts of the world has reached epidemic proportions. This has led to excess mortality as well as significant changes in the epidemiology of liver disease. Herein, we review the impact of the opioid epidemic on liver disease, focusing on the multifaceted impact this epidemic has had on liver disease and liver transplantation. In particular, the opioid crisis has led to a significant shift in incident hepatitis C virus infection to younger populations and to women, leading to changes in screening recommendations. Less well characterized are the potential direct and indirect hepatotoxic effects of opioids, as well as the changes in the incidence of hepatitis B virus infection and alcohol abuse that are likely rising in this population as well. Finally, the opioid epidemic has led to a significant rise in the proportion of organ donors who died due to overdose. These donors have led to an overall increase in donor numbers, but also to new considerations about the better use of donors with perceived or actual risk of disease transmission, especially hepatitis C. Clearly, additional efforts are needed to combat the opioid epidemic. Moreover, better understanding of the epidemiology and underlying pathophysiology will help to identify and treat liver disease in this high-risk population.
       
  • Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic
           fatty liver disease

    • Abstract: Publication date: Available online 4 July 2019Source: JHEP ReportsAuthor(s): Marie Boyle, Dina Tiniakos, Jorn M. Schattenberg, Vlad Ratziu, Elisabetta Bugianessi, Salvatore Petta, Claudia P. Oliveira, Olivier Govaere, Ramy Younes, Stuart McPherson, Pierre Bedossa, Mette J Nielsen, Morten Karsdal, Diana Leeming, Stuart Kendrick, Quentin M. AnsteeBackground & AimThere is an unmet need for non-invasive biomarkers in non-alcoholic fatty liver disease (NAFLD) that can diagnose advanced disease and identify patients suitable for clinical trials. The PRO-C3 collagen neo-epitope is a putative direct marker of fibrogenesis. We assessed the performance of PRO-C3 in a large, well-characterised international NAFLD cohort and report the development and validation of 2 novel panels for the diagnosis of advanced fibrosis (F≥3) in NAFLD, including a simplified clinical score which eliminates the need for online calculators.MethodsPlasma PRO-C3 levels were determined in a prospectively recruited international cohort of 449 patients with biopsy diagnosed NAFLD across the full disease spectrum (F0: n = 90; F1: 100; F2: 92; F3: 101; F4: 66). The cohort was divided into a discovery group (n = 151) and a validation group (n = 298). Logistic regression was performed to establish complex (FIBC3) and simplified (ABC3D) diagnostic scores that accurately identify advanced fibrosis. Performance for each was compared to established non-invasive fibrosis scoring systems.ResultsPlasma PRO-C3 levels correlated with grade of histological steatohepatitis (rs = 0.367, p ≪0.0001) and stage of fibrosis (rs = 0.462, p ≪0.0001), exhibiting similar performance to current fibrosis scores such as FIB4 for the detection of F≥3 fibrosis. FIBC3 exhibited substantially improved accuracy (AUROC 0.89 and 0.83 in the discovery and validation sets, respectively) and outperformed FIB4 and other similar diagnostic panels. The simplified version, ABC3D, was concurrently developed and had comparable diagnostic accuracy (AUROC 0.88 and 0.81 in the discovery and validation sets, respectively).ConclusionPlasma PRO-C3 levels correlate with severity of steatohepatitis and fibrosis stage. The FIBC3 panel is an accurate tool with a single threshold value that maintains both sensitivity and specificity for the identification of F≥3 fibrosis in NAFLD, eliminating indeterminate results and outperforming commonly used non-invasive tools. A greatly simplified version (ABC3D) that is readily amenable to use in the clinic has been validated and shown to perform with similar accuracy, and may prove a useful tool in routine clinical practice.Lay summaryWe performed a comprehensive, independent evaluation of a collagen biomarker (PRO-C3) to detect and quantify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We report the development of 2 diagnostic panels using PRO-C3 to identify patients with advanced fibrosis, one optimal but more complex to calculate (FIBC3), the other easier to use (ABC3D) whilst still performing well.Graphical abstractUnlabelled Image
       
  • HBeAg seroconversion is associated with a more effective PD-L1 blockade
           during chronic hepatitis B infection

    • Abstract: Publication date: Available online 28 June 2019Source: JHEP ReportsAuthor(s): Sara Ferrando-Martinez, Kelly Huang, Angie Snell Bennett, Patricia Sterba, Li Yu, JoAnn A. Suzich, Harry L.A. Janssen, Scott H. RobbinsBackground & AimsCurrent therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1:PD-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.MethodsExpression patterns of the PD-1:PD-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790).ResultsChronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients’ clinical or treatment status.ConclusionPatients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.Lay summaryHepatitis B virus (HBV)-specific T cell responses during chronic infection are weak due to the upregulation of inhibitor molecules on the immune cells. In this study we show that the inhibitory PD-1:PD-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not restore normal levels of PD-1 and PD-L1 expression. However, in HBV e antigen-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell responses by an average of 2-fold and is a promising new therapy for patients with chronic HBV infection.Graphical abstractUnlabelled Image
       
  • Plasma levels of circulating DNA are associated with outcome, but not with
           activation of coagulation in decompensated cirrhosis and ACLF

    • Abstract: Publication date: Available online 28 June 2019Source: JHEP ReportsAuthor(s): Annabel Blasi, Vishal C. Patel, Jelle Adelmeijer, Sarah Azarian, Fatima Aziz, Javier Fernández, William Bernal, Ton LismanBackground & AimsAcute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.MethodsWe measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.ResultsAll analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.ConclusionsCollectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.Lay summaryAcute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.Graphical abstractUnlabelled Image
       
  • Quantitative digital pathology reveals association of cell-specific PNPLA3
           transcription with NAFLD disease activity

    • Abstract: Publication date: Available online 8 June 2019Source: JHEP ReportsAuthor(s): Bynvant Sandhu, Maria C. Perez Matos, Stephanie Tran, Alexander Zhong, Eva Csizmadia, Misung Kim, Mark A. Herman, Imad Nasser, Michelle Lai, Z. Gordon JiangBackground & AimsThe I148M variant (rs738409) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is by far the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, in the context of NAFLD, the transcriptional regulation of PNPLA3 in human liver cells is not known. In this study, we aimed to define the relationship between PNPLA3 transcription and disease characteristics of human NAFLD.MethodsThe abundance of PNPLA3 and collagen 1α (COL1α) transcripts was quantified in situ at single-cell resolution using RNAscope® in 87 patients with NAFLD. We examined the association of PNPLA3 and COL1α transcript levels with NAFLD disease severity, defined by histology.ResultsWhile the majority of PNPLA3 transcripts were found in hepatocytes, approximately 7% of PNPLA3-positive cells co-express COL1α, representing activated myofibroblasts. There is no association between the rs738409 genotype and the level of PNPLA3 transcript. The overall PNPLA3 transcript abundance is lower in zone 1 hepatocytes, patients with higher body mass index, and those with advanced liver fibrosis. The negative association between the PNPLA3 transcript levels and liver fibrosis is largely driven by COL1α-positive cells. A significant proportion of PNPLA3 mRNA is seen in the nucleus. The cytoplasmic-to-nuclear PNPLA3 mRNA ratio is inversely associated with NAFLD disease activity.ConclusionsPNPLA3 transcript abundance and nuclear-to-cytoplasmic translocation are negatively associated with hepatic steatosis and NAFLD disease activity, while its abundance in activated myofibroblasts is inversely associated with the stage of liver fibrosis.Lay summaryA genetic variant in patatin-like phospholipase domain-containing protein 3 (or PNPLA3) is the most important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, it is not known how transcriptional regulation of the PNPLA3 gene contributes to the disease characteristics of human NAFLD. Herein, we show that the mRNA levels of PNPLA3, particularly in the cytoplasm, are negatively associated with the severity of NAFLD in humans.
       
  • Promoter hypermethylation of the AE2/SLC4A2 gene in PBC

    • Abstract: Publication date: Available online 7 June 2019Source: JHEP ReportsAuthor(s): Fabián Arenas, Isabel Hervías, Elena Sáez, Saida Melero, Jesús Prieto, Albert Parés, Juan F. MedinaBackground & AimsPatients with primary biliary cholangitis (PBC) exhibit reduced AE2/SLC4A2 gene expression in the liver and peripheral blood mononuclear cells (PBMCs). AE2 encodes a Cl–/HCO3– exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Reduced AE2 expression in PBC may be pathogenic, as Ae2-knockout mice reproduce characteristic PBC features. Herein, we aimed to identify CpG-methylation abnormalities in AE2 promoter regions that might contribute to the reduced gene transcription in PBC livers and PBMCs.MethodsCpG-cytosine methylation rates were interrogated at 1-base pair resolution in upstream and alternate AE2 promoter regions through pyrosequencing of bisulphite-modified genomic DNA from liver specimens and PBMCs. AE2a and alternative AE2b1 and AE2b2 mRNA levels were measured by real-time PCR. Human lymphoblastoid-T2 cells were treated with 5-aza-2´-deoxycytidine for demethylation assays.ResultsAE2 promoters were found to be hypermethylated in PBC livers compared to normal and diseased liver specimens. Receiver operating characteristic (ROC) curve analysis showed that minimal CpG-hypermethylation clusters of 3 AE2a-CpG sites and 4 alternate-AE2b2-CpG sites specifically differentiated PBC from normal and diseased controls, with mean methylation rates inversely correlating with respective transcript levels. Additionally, in PBMCs a minimal cluster of 3 hypermethylated AE2a-CpG sites distinguished PBC from controls, and mean methylation rates correlated negatively with AE2a mRNA levels in these immune cells. Alternate AE2b2/AE2b1 promoters in PBMCs were constitutively hypermethylated, in line with absent alternative mRNA expression in diseased and healthy PBMCs. Demethylation assays treating lymphoblastoid-T2 cells with 5-aza-2´-deoxycytidine triggered AE2b2/AE2b1 expression and upregulated AE2a-promoter expression.ConclusionsDisease-specific hypermethylation of AE2 promoter regions and subsequent downregulation of AE2-gene expression in the liver and PBMCs of patients with PBC might be critically involved in the pathogenesis of this complex disease.Lay summaryPrimary biliary cholangitis (PBC) is a chronic immune-associated cholestatic liver disease with unclear complex/multifactorial etiopathogenesis affecting mostly middle-aged women. Patients with PBC exhibit reduced expression of the AE2/SLC4A2 gene. Herein, we found that AE2 promoter regions are hypermethylated in the liver and peripheral blood mononuclear cells of patients with PBC. This increased methylation is associated with downregulated AE2-gene expression, which might contribute to the pathogenesis of PBC. Therefore, novel epigenetic targets may improve treatment in patients with PBC who respond poorly to current pharmacological therapies.Graphical abstractUnlabelled Image
       
  • Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk
           with metabolism

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Sander Lefere, Frank TackeSummaryNon-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and a major cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is intimately linked with other metabolic disorders characterized by insulin resistance. Metabolic diseases are driven by chronic inflammatory processes, in which macrophages perform essential roles. The polarization status of macrophages is itself influenced by metabolic stimuli such as fatty acids, which in turn affect the progression of metabolic dysfunction at multiple disease stages and in various tissues. For instance, adipose tissue macrophages respond to obesity, adipocyte stress and dietary factors by a specific metabolic and inflammatory programme that stimulates disease progression locally and in the liver. Kupffer cells and monocyte-derived macrophages represent ontologically distinct hepatic macrophage populations that perform a range of metabolic functions. These macrophages integrate signals from the gut-liver axis (related to dysbiosis, reduced intestinal barrier integrity, endotoxemia), from overnutrition, from systemic low-grade inflammation and from the local environment of a steatotic liver. This makes them central players in the progression of NAFLD to steatohepatitis (non-alcoholic steatohepatitis or NASH) and fibrosis. Moreover, the particular involvement of Kupffer cells in lipid metabolism, as well as the inflammatory activation of hepatic macrophages, may pathogenically link NAFLD/NASH and cardiovascular disease. In this review, we highlight the polarization, classification and function of macrophage subsets and their interaction with metabolic cues in the pathophysiology of obesity and NAFLD. Evidence from animal and clinical studies suggests that macrophage targeting may improve the course of NAFLD and related metabolic disorders.
       
  • Infliximab for the treatment of refractory immune-related hepatitis
           secondary to checkpoint inhibitors: A case report

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Margaret Corrigan, Geoffrey Haydon, Fiona Thompson, Neil Rajoriya, Claire L Peplow, Stefan G Hubscher, Neil Steven, Gideon M Hirschfield, Matthew J Armstrong
       
  • Approaches for patients with very high MELD scores

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Florent Artru, Didier SamuelSummaryIn the era of the “sickest first” policy, patients with very high model for end-stage liver disease (MELD) scores have been increasingly admitted to the intensive care unit with the expectation that they will receive a liver transplant (LT) in the absence of improvement on supportive therapies. Such patients are often admitted in a context of acute-on-chronic liver failure with extrahepatic failures. Sequential assessment of scores or classification based on organ failures within the first days after admission help to stratify the risk of mortality in this population. Although the prognosis of severely ill cirrhotic patients has recently improved, transplant-free mortality remains high. LT is still the only curative treatment in this population. Yet, the increased relative scarcity of graft resource must be considered alongside the increased risk of losing a graft in the initial postoperative period when performing LT in “too sick to transplant” patients. Variables associated with poor immediate post-LT outcomes have been identified in large studies. Despite this, the performance of scores based on these variables is still insufficient. Consideration of a patient’s comorbidities and frailty is an appealing predictive approach in this population that has proven of great value in many other diseases. So far, local expertise remains the last safeguard to LT. Using this expertise, data are accumulating on favourable post-LT outcomes in very high MELD populations, particularly when LT is performed in a situation of stabilization/improvement of organ failures in selected candidates. The absence of “definitive” contraindications and the control of “dynamic” contraindications allow a “transplantation window” to be defined. This window must be identified swiftly after admission given the poor short-term survival of patients with very high MELD scores. In the absence of any prospect of LT, withdrawal of care could be discussed to ensure respect of patient life, dignity and wishes.
       
  • Acute-on-chronic liver failure: Objective admission and support criteria
           in the intensive care unit

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Victor Dong, Constantine J. KarvellasSummaryCirrhosis is a leading cause of morbidity and mortality throughout the world. Significant complications include variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and infection. When these complications are severe, admission to the intensive care unit (ICU) is often required for organ support and management. Intensive care therapy can also serve as a bridge to liver transplantation. Along with decompensation of cirrhosis, the concept of acute-on-chronic liver failure (ACLF) has emerged. This involves an acute precipitating event, such as the development of infection in a patient with cirrhosis, which leads to acute deterioration of hepatic function and extrahepatic organ failure. Extrahepatic complications often include renal, cardiovascular, and respiratory failures. Patients with significant extrahepatic and hepatic failures need ICU admission for organ support. Again, in patients who are deemed suitable liver transplant candidates, intensive care management may allow bridging to liver transplantation. However, patients with a Chronic Liver Failure Consortium ACLF score greater than 70 at 48 to 72 hours post-ICU admission do not seem to benefit from ongoing intensive support and a palliative approach may be more appropriate.
       
  • Copyright and Information

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s):
       
  • Controversies in the management of hepatocellular carcinoma

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Alejandro Forner, Leonardo G Da Fonseca, Álvaro Díaz-González, Marco Sanduzzi-Zamparelli, María Reig, Jordi BruixSummaryThe management of hepatocellular carcinoma (HCC) has evolved considerably over the last decade. Surveillance of cirrhotic patients and refinements to imaging techniques have enabled a relevant proportion of patients to be diagnosed at an early stage, when effective therapies are feasible. Resection, transplantation and ablation are all options in patients with early stage HCC. Thus, there is some controversy regarding which is the best treatment approach in challenging scenarios. There have also been major developments in locoregional therapies, particularly in intra-arterial approaches. Finally, the systemic treatment for HCC has changed dramatically following the demonstration of a survival benefit with sorafenib; there are currently several first-line (sorafenib and lenvatinib) and second-line (regorafenib, cabozantinib and ramucirumab) treatments that have shown a survival benefit. Expectations for immune checkpoint inhibitors are high, with the results of the ongoing phase III trials eagerly awaited. In this review we discuss some of the controversies in the management of HCC, focussing in particular on systemic therapy.
       
  • Liver steatosis is a strong predictor of mortality and cancer in chronic
           hepatitis B regardless of viral load

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Noam Peleg, Assaf Issachar, Orly Sneh Arbib, Michal Cohen-Naftaly, Marius Braun, Moshe Leshno, Alon Barsheshet, Amir ShlomaiBackground & AimsLiver steatosis may occur concomitantly in patients with chronic hepatitis B infection (CHB) and is implicated in increased morbidity and mortality. Hepatitis B virus (HBV) viral load is a marker for disease progression and long-term outcomes in CHB. We investigated the association between liver steatosis and HBV viral load and their individual effects on all-cause mortality and the development of cancer in patients with CHB and liver steatosis.MethodsThis retrospective study included 524 treatment-naïve patients with CHB, with a mean follow-up of 6 years. Liver biopsy was available for 170 patients and liver steatosis was validated by at least 3 ultrasonographic examinations.ResultsA total of 241/524 (46%) patients with CHB had liver steatosis, with a strong correlation between the degree of liver steatosis as assessed by ultrasonography or by liver biopsy (r = 0.9, p
       
  • HSD17B13 truncated variant is associated with a mild hepatic phenotype in
           Wilson’s Disease

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Peter Ferenci, Jan Pfeiffenberger, Albert Friedrich Stättermayer, Rudolf E. Stauber, Claudia Willheim, Karl H. Weiss, Petra Munda-Steindl, Michael Trauner, Michael Schilsky, Heinz ZollerBackground & AimsHSD17B13 encodes hydroxysteroid 17-β dehydrogenase 13, a novel liver lipid-droplet associated protein that is involved in the regulation of lipid biosynthetic processes. A protein-truncating HSD17B13 variant (rs72613567) was shown to protect individuals from alcoholic and non-alcoholic liver disease. Since steatosis is a common feature in Wilson’s disease (WD), we aimed to assess whether the HSD17B13 variant modulates the phenotypic presentation and progression of WD.MethodsThe HSD17B13:TA (rs72613567) variant was determined by allelic discrimination real-time PCR in 586 patients. The HSD17B13 genotype was correlated with the phenotypic presentation. The age of onset and the type of symptoms at presentation were used as markers of the WD phenotype.ResultsThe overall HSD17B13:TA allele frequency in patients with WD was 23.3% (273/1,172), not significantly different from the reported minor allele frequency. There was a significantly lower HSD17B13:TA allele frequency in patients with fulminant WD compared to all other phenotypic WD groups (11.0% vs. 24.0%, p
       
  • JHEP Reports: A new EASL open access journal

    • Abstract: Publication date: May 2019Source: JHEP Reports, Volume 1, Issue 1Author(s): Jessica Zucman-Rossi
       
 
 
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