Journal of Hepatology

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BACKGROUND&AIMS: Chronic alcohol (EtOH) consumption is a leading risk factor for development of hepatocellular carcinoma (HCC), which is associated with marked increase of hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking was used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC. RESULTS: We demonstrate that global deletion of IL-17RA gene suppressed HCC in alcohol-fed DEN-challenged IL-17RA-/- and Mup-uPA/IL-17RA-/- mice compared to wild type mice...

BACKGROUND & AIMS: Mitochondrial dysfunction and subsequent metabolic deregulation are commonly observed in cancers including hepatocellular carcinoma (HCC). When mitochondrial function is impaired, reductive glutamine metabolism is a major cellular carbon source for de novo lipogenesis to support cancer cell growth. The underlying regulators of reductively metabolized glutamine in mitochondrial dysfunction are not completely understood in tumorigenesis including in HCC. METHODS: We systematically investigated the role of oxoglutarate dehydrogenase-like (OGDHL), one of the rate-limiting components of the key mitochondrial multi-enzyme OGDH complex (OGDHC), in the regulation of lipid metabolism in hepatoma cells and explored the underlying molecular mechanisms...

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BACKGROUND AIMS: Multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS: We combined whole exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T-cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 HCC patients with multifocal lesions...

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1β and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in NASH patients. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH...

BACKGROUND & AIMS: The aim of this study was to compare the performance of MRIs with extracellular contrast agents (ECA-MRI) to HB contrast agents (HBA-MRI) for the non-invasive diagnosis of small HCCs in a head-to-head comparison. METHODS: Between August 2014 and October 2017; 171 cirrhotic patients, each with 1 to 3 nodules measuring 1 to 3 cm, were included across eight centers. All patients had both an ECA-MRI and an HBA-MRI within a month. The non-invasive diagnosis of HCC was made when the nodule was hyper-enhanced at the arterial phase (HA) with wash-out at the portal phase (PP) and/or delayed phase (DP) for the ECA-MRI, or PP and/or HB phase (HBP) for the HBA-MRI...

BACKGROUND AND AIM: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in patients with cirrhosis and portal pressure (assessed by the hepatic venous pressure gradient [HVPG]) ≥12 mmHg. We aimed to confirm these results in a randomized, placebo-controlled, double blind study. METHODS: Multicenter study including 263 patients with cirrhosis due to non-alcoholic steatohepatitis (NASH) and baseline HVPG ≥12 mmHg randomized 1:1:1:1 to emricasan 5 (n=65), 25 (n=65), 50 (n=66) mg or placebo (n=67) orally twice daily for up to 48 weeks...

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BACKGROUND AND AIM: Noncytolytic curing of hepatitis B virus (HBV) infected hepatocytes by cytokines including type I interferons (IFNs) is of importance for resolving acute and chronic infection. However, as IFNs stimulate hundreds of genes those most relevant for HBV suppression remain largely unknown. Amongst them are the large Mx GTPases. Human MX1 (or MxA) is active against many RNA viruses while MX2 (or MxB) was recently found to restrict human immunodeficiency virus 1, hepatitis C virus, and herpesviruses...

BACKGROUND AND AIMS: DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) occurring in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. METHODS: A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome-sequencing...

BACKGROUND AND AIMS: Histological classifications used to diagnose/stage nonalcoholic fatty liver disease (NAFLD) are based on morphology, thus empirical, with undetermined clinical correlates and relevance. We assessed the clinical relevance of the fatty liver inhibition of progression (FLIP) algorithm and the steatosis, activity and fibrosis (SAF) scoring system. METHODS: 140 consecutive patients with suspected NAFLD and a separate validation cohort of 78 patients enrolled in a therapeutic trial, all with central reading of liver biopsy, were included...

BACKGROUND AND AIMS: Hepatitis C virus (HCV) has emerged as a sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). We evaluated HCV-incidence and its risk-factors among HIV-negative MSM using HIV pre-exposure prophylaxis (PrEP). METHODS: Participants of the Amsterdam PrEP project were tested for HCV antibodies or HCV-RNA every 6 months. Participants used daily or event-driven PrEP and could switch regimens during follow-up. We calculated incidence rates (IRs) for overall HCV-infection and separately for primary and re-infection...

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. We aim to investigate the role of β-arrestin1 (ARRB1) in the progression of NASH. METHODS: Human liver tissues from patients with NASH and control subjects were obtained to evaluate ARRB1 expression. NASH models were established in ARRB1 knockout and wild type mice fed high-fat diet (HFD) for 26 weeks or methionine/choline deficient (MCD) diet for 6 weeks...

BACKGROUND & AIMS: PAGE-B and modified PAGE-B (mPAGE-B) scores are developed to predict risk of hepatocellular carcinoma (HCC) in patients on nucleos(t)ide analogue therapy. However, how and when to use these risk scores in clinical practice is uncertain. METHODS: Consecutive adult patients with chronic hepatitis B who had received entecavir or tenofovir for at least 6 months between January 2005 and June 2018 were identified from a territory-wide database in Hong Kong...

BACKGROUND: Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF) though with the limitations of surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbeads transplanted intraperitoneally has been shown in animal models. We report our experience of the use of this therapy in children with ALF on named patient basis under a MHRA Specials Manufacture License...

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