Management of alcoholic hepatitis: A clinical perspective.

Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.

The fecal mycobiome in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis. METHODS: We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B. RESULTS: The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis. CONCLUSIONS: Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH. LAY SUMMARY: Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.

Management of Dyslipidemia in Patients with Non-Alcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: Patients with non-alcoholic fatty liver disease (NAFLD), often considered as the hepatic manifestation of the metabolic syndrome, represent a population at high cardiovascular risk and frequently suffer from atherogenic dyslipidemia. This article reviews the pathogenic interrelationship between NAFLD and dyslipidemia, elucidates underlying pathophysiological mechanisms and focuses on management approaches for dyslipidemic patients with NAFLD. RECENT FINDINGS: Atherogenic dyslipidemia in patients with NAFLD results from hepatic and peripheral insulin resistance along with associated alterations of hepatic glucose and lipoprotein metabolism, gut dysbiosis, and genetic factors. Since atherogenic dyslipidemia and NAFLD share a bi-directional relationship and are both major driving forces of atherosclerotic cardiovascular disease (ASCVD) development, early detection and adequate treatment are warranted. Thus, integrative screening and management programs are urgently needed. A stepwise approach for dyslipidemic patients with NAFLD includes (i) characterization of dyslipidemia phenotype, (ii) individual risk stratification, (iii) definition of treatment targets, (iv) lifestyle modification, and (v) pharmacotherapy if indicated.

Comparison of Pre-Endoscopic C-WATCH Score with Established Risk Assessment Tools in Patients with Upper Gastrointestinal Bleeding.

INTRODUCTION: Use of risk scores for early assessment of patients with upper gastrointestinal bleeding (UGIB) is recommended by various guidelines. We compared Cologne-WATCH (C-WATCH) score with Glasgow-Blatchford score (GBS), Rockall score (RS), and pre-endoscopic RS (p-RS). METHODS: Patients with UGIB between January and December 2017 were retrospectively analyzed for 30-day mortality and composite endpoints risk of complications and need for intervention using areas under the receiver-operating characteristics curve (AUROC). Subgroup analysis was conducted for patients with UGIB on admission and in-hospital UGIB. RESULTS: A total of 252 patients were identified (67.5% men, mean age 63.8 ± 14.9 years). In-hospital UGIB occurred in 49.6%. AUROCs for 30-day mortality, risk of complications, and need for intervention (not applicable to RS) were 0.684 (95% confidence interval [CI]: 0.606-0.763), 0.665 (95% CI: 0.594-0.735), and 0.694 (95% CI: 0.612-0.775) for C-WATCH score, 0.724 (95% CI: 0.653-0.796) and 0.751 (95% CI: 0.687-0.815) for RS, 0.652 (95% CI: 0.57-0.735), 0.653 (95% CI: 0.579-0.727), and 0.673 (95% CI: 0.602-0.745) for p-RS and 0.652 (95% CI: 0.572-0.732), 0.663 (95% CI: 0.592-0.734), and 0.752 (95% CI: 0.683-0.821) for GBS. RS outperformed pre-endoscopic scores in predicting risk of complications, while there were no significant differences between pre-endoscopic scores except GBS outperforming p-RS in predicting need for intervention. The subgroup analysis obtained similar results. Positive predictive values for patients with estimated low risk for all three endpoints (C-WATCH score ≤1, RS ≤2, p-RS <1, and GBS ≤1) were 89%, 69%, 78%, and 92%. CONCLUSION: C-WATCH score performed similar to the established pre-endoscopic risk scores in patients with UGIB regarding relevant patient-related endpoints with no significant differences between both the subgroups.

Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice.

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. METHODS: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. RESULTS: Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. CONCLUSIONS: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.

Combined analysis of gut microbiota, diet and PNPLA3 polymorphism in biopsy-proven non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown. METHODS: In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed. RESULTS: Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m2 : 1.23, 95% CI 1.10-1.37, P < .001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P = .007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account. CONCLUSIONS: BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD.

Hepatocellular carcinoma surveillance with liver imaging is not associated with improved survival.

Objective: International guidelines recommend hepatocellular carcinoma (HCC) surveillance with ultrasound in high-risk patients with chronic liver diseases. However, there is low-strength evidence about the effects on mortality. The aim of our study was to assess the impact of surveillance on the clinical course and survival of HCC patients seen at a tertiary referral center in Germany.Material and methods: We retrospectively evaluated the data of 401 HCC patients, who presented to our clinic between 1997 and 2015. Two groups were compared regarding patient and disease outcomes: one group included patients who received at least two ultrasound examinations for surveillance purposes prior to first diagnosis (n = 111). The other group consisted of patients with HCC at first presentation without foregoing HCC surveillance (n = 290).Results: Median follow-up in the surveillance group was 76 months (range 4-310 months). Patients in the surveillance group had smaller median tumor sizes (3.5 cm vs. 4.5 cm; p < .001), fulfilled more often Milan criteria (64% vs. 42%; p < .001) and received more often liver transplantation (27% vs. 9%, p < .001) when compared with the non-surveillance group. However, HCC surveillance was not associated with an improved survival (14 months in the surveillance group vs. 12 months in the non-surveillance group, p = .375), hazard ratio regarding overall mortality for the surveillance group: 0.80 (95% CI: 0.62-1.04, p = .09).Conclusions: HCC surveillance with ultrasound led to the detection of earlier disease stages but was not significantly associated with improved survival. Further prospective and long-term studies are needed to clarify benefits and harms of HCC surveillance programs on mortality.

Detection rates for adenomas, serrated polyps and clinically relevant serrated polyps can be easily estimated by individually calculated detection rate ratios.

Background and aims: Adenoma detection rate (ADR) is a key quality indicator for colonoscopy; however, it is cumbersome to obtain. We investigated if detection rates (DRs) for adenomas, serrated polyps (SPs) and clinically relevant SP (crSPDR) can be accurately estimated by individualized DR ratios (DRRs) in a multicenter primary colonoscopy screening cohort of average-risk individuals.Methods: DRRs were calculated by dividing DRs for a certain polyp entity by polyp detection rate (PDR) for each endoscopist individually on the basis of his/her first 50 (DRR50) and 100 (DRR100) consecutive colonoscopies. DRs were estimated for each endoscopist by multiplying his/her DRR for a certain polyp entity with his/her PDR of subsequent colonoscopies in groups of 50 (DRR50) and 100 (DRR100) consecutive colonoscopies. Estimated and actual DRs were compared.Results: Estimated DRs showed a strong correlation with actual DRs for adenomas (r = 0.86 and 0.87; each p < .001), SPs (r = 0.85 and 0.91; each p < .001) and crSPs (r = 0.82 and 0.86; each p < .001) using DRRs derived from first 50 and 100 consecutive colonoscopies. Corresponding root mean square error (RMSE) between individual estimated and actual DRs using DRR50 and DRR100 was 5.3(±4.6)% and 4.5(±4.8)% for adenomas, 5.2(±4.1)% and 3.9(±2.8)% for SP, 3.1(±3.1)% and 2.8(±2.5)% for crSP, respectively. RMSE was not significantly different between DRR50 and DRR100 for ADR (p = .445), SPDR (p = .178) and crSP (p = .544).Conclusions: DR for all relevant polyp entities can be accurately estimated by using individual DRRs. This approach may enable endoscopists to easily track their performance measures in daily routine.

Phenotyping non-alcoholic fatty liver disease by the gut microbiota: Ready for prime time?

BACKGROUND AND AIM: Several studies observed alterations in the gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD). However, analyzed patient populations and methods strongly differ among these studies. The aim of this study was to prove the reproducibility of published results and to provide a detailed overview of all findings in our NAFLD cohort using next generation sequencing methods. METHODS: The individual taxonomic microbiota composition of fecal samples from 90 NAFLD patients and 21 healthy controls was analyzed using 16S rRNA gene sequencing. Study participants were grouped according to their disease stage and compared regarding their gut microbiota composition. Studies were identified from PubMed listed publications, and the results were compared with the findings in our cohort. RESULTS: Results from 13 identified studies were compared with our data. A decreased abundance of the Bacteroidetes and Ruminococcaceae as well as an increased abundance of Lactobacillaceae and Veillonellaceae and Dorea were the most frequently reported changes among NAFLD patients in 4/13, 5/13, 4/13, 2/13, and 3/13 studies, respectively. Even though these alterations in the gut microbiota composition were also observed in our patient cohort, the majority of published differences could not be reproduced, neither in our own nor in other NAFLD cohort studies. CONCLUSION: Despite repeatedly reproduced abundance patterns of specific bacteria, the heterogeneous study results did not reveal a consistent disease specific gut microbiota signature. Further prospective studies with homogenous patient cohorts and standardized methods are necessary to phenotype NAFLD by the gut microbiota.

Case report of patient with a Cronkhite-Canada syndrome: sustained remission after treatment with corticosteroids and mesalazine.

BACKGROUND: Cronkhite-Canada syndrome is a rare disease of unknown etiology and the optimal treatment for this syndrome is unknown. CASE PRESENTATION: We present the case of a man who at the age of 66.0 years was diagnosed with Cronkhite-Canada syndrome (CCS). In addition to watery diarrhea, alopecia, and a complete loss of toenails and fingernails, the patient had been suffering from dysgeusia and rapid weight loss of more than 10.0 kg within a few months. The patient had recently incurred a distal radius fracture. During the initial endoscopy an extensive polyposis of the stomach and jejunum was found. The diagnosis of CCS was made and after initiation of a steroid therapy his diarrhea improved immediately. A discontinuation of the steroid therapy was not possible and mesalazine (1000 mg t.i.d.) was added to prednisolone (10.0 mg/d). This therapy led to a remission within 6.0 months with weight gain and normalization of serum albumin levels. The prednisolone dose was reduced to 7.5 mg/d. During the following year, the steroids could be further reduced and nails had regrown again. Within three years, all polyps had disappeared and the steroid therapy was finished while the dosage of mesalazine was reduced in a stepwise fashion. Four years later, the mesalazine was stopped and more than 14.0 years after the initial diagnosis the patient is still in complete remission without any treatment. CONCLUSION: The optimal treatment for CCS is unknown. In our case, the initial combination therapy of corticosteroids plus mesalazine followed by a mesalazine monotherapy has led to a remarkable long-lasting remission with complete resolution of all intestinal polyps.

Hepatitis C virus infection triggers a tumor-like glutamine metabolism.

Chronic infection with hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma. However, the molecular mechanisms linking the infection to cancer development remain poorly understood. Here we used HCV-infected cells and liver biopsies to study how HCV modulates the glutaminolysis pathway, which is known to play an important role in cellular energetics, stress defense, and neoplastic transformation. Transcript levels of glutaminolytic factors were quantified in Huh7.5 cells or primary human hepatocytes infected with the Japanese fulminant hepatitis 1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis, and metabolite quantification were performed with HCV-infected Huh7.5 cells. Furthermore, short hairpin RNA vectors and small molecule inhibitors were used to investigate the dependence of HCV replication on metabolic changes. We show that HCV modulates the transcript levels of key enzymes of glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine use and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. CONCLUSION: Our data suggest that HCV establishes glutamine dependence, which is required for viral replication, and, importantly, that glutamine addiction is a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C. (Hepatology 2017;65:789-803).

Detection of clinically relevant serrated polyps during screening colonoscopy: results from seven cooperating centers within the German colorectal screening program.

BACKGROUND: Serrated polyps have been recognized as precursors of colorectal cancer (CRC) via the serrated pathway. Endoscopic detection and histopathological evaluation of serrated polyps are challenging. The aims of this study were to determine detection rates of the recently proposed entity of clinically relevant serrated polyps (crSPs) and to identify factors that influence their detection in a primary colonoscopy screening cohort. METHODS: We retrospectively analyzed average-risk screening colonoscopies performed at a tertiary academic hospital and six community-based private practices in Germany between 01/01/2012 and 14/12/2016. Exclusion criteria were age < 50 years, conditions with increased risk for CRC (e. g. inflammatory bowel disease, history of CRC, hereditary cancer syndromes), and incomplete procedures. CrSPs were defined as serrated polyps ≥ 10 mm and/or > 5 mm located proximally to the splenic flexure. Conventional adenomas were defined as adenomas excluding serrated polyps. RESULTS: A total of 4161 colonoscopies from average-risk individuals were included (median age 62 years [interquartile range 56 - 69]; 48.6 % male). CrSPs were detected in 6.9 %, with a mean detection rate of 4.7 % (95 % confidence interval 2.3 % - 7.2 %). Detection rates ranged from 0 % to 16.2 %. In multivariate analysis, simultaneous detection of conventional adenomas and an endoscopist adenoma detection rate of ≥ 25 % were significantly associated with increased detection of crSPs, with odds ratios of 1.43 (95 %CI 1.11 - 1.85; P = 0.01) and 7.35 (95 %CI 4.43 - 12.19; P < 0.001). The individual endoscopist's detection rate for conventional adenomas and crSPs were significantly correlated (r = 0.54, P = 0.02). CONCLUSION: Detection rates for crSPs differed between participating endoscopists. However, individual skills to detect polypoid lesions have a relevant bearing on the detection rate of crSPs.

Hyperplastic polyps and nonadvanced adenomas, but not advanced polypoid lesions, are detected more frequently in the presence of colonic diverticula during screening colonoscopies.

HINTERGRUND: Die bisher veröffentlichte Studienlage zur Assoziation von Kolondivertikeln und kolorektalen Polypen einschließlich des kolorektalen Karzinoms (KRK) ist konträr. Ziel der Studie war es, die Assoziation für sämtliche relevanten histologischen Polypensubtypen, d. h. hyperplastische Polypen (HP), sessil und traditionell serratierte Adenome (SSA und TSA), klinisch relevante serratierte Polypen (krSP), tubuläre Adenome und fortgeschrittene Adenome in einer ausschließlichen Vorsorgekoloskopie-Kohorte zu untersuchen. MATERIAL UND METHODEN: Wir führten eine retrospektive Analyse von Personen ≥ 50 Jahre und einem durchschnittlichen Risiko für ein KRK, die eine Vorsorgekoloskopie zwischen dem 01.01.2012 und dem 14.12.2016 in einer Universitätsklinik und 6 gastroenterologischen Schwerpunktpraxen erhalten haben, durch. Ausschlusskriterien waren Erkrankungen mit einem erhöhten KRK-Risiko (z. B. chronisch-entzündliche Darmerkrankungen, KRK in der Vorgeschichte, hereditäre Karzinomsyndrome), eine vorherige Koloskopie und eine unvollständige Untersuchung. ERGEBNISSE: 4196 Koloskopien wurden eingeschlossen (mittleres Alter 63,4 Jahre, Standardabweichung ±â€Š7,6 Jahre, 48,6 %). Bei Vorliegen von Divertikeln zeigten sich nach Adjustierung für Alter und Geschlecht erhöhte Odds-Ratios (OR) für den Nachweis von HP im gesamten (OR 1,340, 95 %-Konfidenzintervall 1,133 - 1,584, p = 0,001) und im distalen Kolon (OR 1,459, 95 %-KI 1,208 - 1,763, p < 0,001) sowie von tubulären Adenomen im distalen Kolon (OR 1,355, 95 %-KI 1,144 - 1,604, p < 0,001). Die mittlere Polypenanzahl pro Untersuchung mit dem Nachweis von mindestens einem Polypensubtypen unterschied sich nicht zwischen beiden Gruppen. SCHLUSSFOLGERUNG: Die Untersucher sollten beim Vorliegen einer Divertikulose wachsam für den Nachweis von vor allem distal gelegenen Adenomen sein.

Insufficient evidence of benefit regarding mortality due to albumin substitution in HCC-free cirrhotic patients undergoing large volume paracentesis.

BACKGROUND: Current guidelines for clinical practice recommend the infusion of human albumin after large volume paracentesis. After inspecting the current evidence behind this recommendation, we decided to conduct a systematic review and meta-analysis in order to address the effect of albumin on mortality and morbidity in the context of large volume paracentesis. METHODS: We performed a comprehensive search of large databases and abstract books of conference proceedings up to March 15th 2016 for randomized controlled trials, testing the infusion of human albumin against alternatives (vs no treatment, vs plasma expanders; vs vasoconstrictors) in HCC-free patients suffering from cirrhosis. We analyzed these trials with regard to mortality, changes in plasma renin activity (PRA), hyponatremia, renal impairment, recurrence of ascites with consequential re-admission into hospital and additional complications. We employed trial sequential analysis in order to calculate the number of patients required in controlled trials to be able to determine a statistically significant advantage of the administration of one agent over another with regard to mortality. RESULTS: We were able to include 21 trials totaling 1277 patients. While the administration of albumin prevents a rise in PRA as well as hyponatremia, no improvement in strong clinical endpoints such as mortality could be demonstrated. Trial sequential analysis showed that at least 1550 additional patients need to be recruited into RCTs and analyzed with regard to this question in order to detect or disprove a 25% mortality effect. CONCLUSIONS: There is insufficient evidence that the infusion of albumin after LVP significantly lowers mortality in HCC-free patients with advanced liver disease.

Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity.

OBJECTIVE: Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed. DESIGN: The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts. RESULTS: A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients. CONCLUSIONS: HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.