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Background & Aims: In clinical practice, the diagnosis of alcohol-associated hepatitis (AH) is mostly based on non-invasive criteria, which were defined at a consensus conference by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). These criteria were recently modified by adding C-reactive protein (CRP) and termed NIAAAm-CRP criteria, which showed superior diagnostic accuracy for presence of alcohol-associated steatohepatitis (ASH) on liver histology. The aim of our study was to validate the diagnostic accuracy of both original NIAAA criteria and NIAAAm-CRP criteria for presence of ASH on liver histology in an independent cohort. Methods: Data from a large multinational cohort of 445 patients with alcohol-associated liver disease (ALD) that served to establish a novel grading and staging system of alcohol-associated liver disease were analyzed retrospectively. Diagnosis of ASH was based on presence of hepatocyte ballooning plus lobular neutrophil infiltration and established in virtual consensus meetings of multiple expert liver pathologists. Results: Complete data including CRP values were available in 346 patients. Overall diagnostic accuracy for prediction of ASH was 73% for NIAAA criteria and 77% for NIAAAm-CRP criteria. In a subgroup with suspected severe AH (MELD >20, n = 123), overall diagnostic accuracy for prediction of ASH was 69% for NIAAA criteria and 74% for NIAAAm-CRP criteria. Conclusion: Our findings confirm recent data on suboptimal diagnostic accuracy of original NIAAA criteria and validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for presence of ASH. Impact and Implications: Alcohol-associated steatohepatitis (ASH) is diagnosed on liver histology but liver biopsy is not always feasible. Non-invasive diagnosis based on clinical findings has been proposed using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria and recently improved using NIAAAm-CRP criteria. Our findings validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for the presence of histological ASH. Clinical trials of novel drugs should focus on histologically proven ASH.

Background & Aims: Infections are frequent in patients with cirrhosis and worsen prognosis. We evaluated the incidence of infections and their impact on decompensation and death in patients with early alcohol-related liver disease (ALD) during long-term follow-up. Methods: We performed a prospective cohort study of patients in secondary care with a history of excess alcohol intake, no prior decompensation, and with liver biopsies along with clinical investigations conducted at baseline. During follow-up, we reviewed the patients’ electronic healthcare records for cases of infections, hospitalizations, transient elastography measurements, decompensations, all-cause mortality, and alcohol intake. Results: We included 461 patients with a mean age of 56±10 years (76% males; fibrosis stage F0-1/F2/F3-4 = 259/107/93 [56%/23%/20%]). During a median follow-up of 4.5 years (IQR 2.9-6.3), 134 patients (29%) developed a total of 312 infections, most frequently pneumonia (106/312, 34%) and urinary tract infections (57/312, 18%). Excessive alcohol intake during follow-up, smoking ≥30 pack years, MELD score and elevated liver stiffness during follow-up were independent predictors of infections. Patients who developed at least one infection had a significantly increased risk of subsequent decompensation (hazard ratio 4.98, 95% CI 2.47-10.03) and death (hazard ratio 8.24, 95% CI 4.65-14.59). Infections increased the risk of decompensation and death independently of baseline fibrosis stage, age, gender, and MELD score. Conclusions: Almost one-third of patients with early ALD develop an infection, which worsens their prognosis by increasing the risk of decompensation and death. The risk of infections increases with liver disease severity and ongoing harmful use of alcohol. Impact and implications: This study reveals that infections significantly worsen the prognosis of patients with early alcohol-related liver disease (ALD), increasing the likelihood of decompensation and death by up to eight times. These findings, pertinent to healthcare providers, researchers, and policymakers, emphasize the importance of early prevention and management of infections in patients with ALD, even those in early stages who may be asymptomatic. It was observed that nearly one-third of patients with early-stage ALD developed infections over 4.5 years, with risk factors including alcohol overuse, smoking, and higher MELD scores. The research underscores the critical need to incorporate these insights into clinical practice and public health policies to improve patient outcomes and mitigate the impact of infections in patients with ALD.

Introduction Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites.Methods and analysis ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis.Ethics and dissemination The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion.Trial registration number NCT05056220 EU CT: 2022-501006-34-01

Abstract Alcohol‐associated liver fibrosis accumulates over decades, driven by hepatic inflammation and cell death. We investigated the diagnostic accuracy of keratin‐18 degradation, measured using serum M30 and M65 levels, and the ActiTest for hepatic inflammatory activity in patients with compensated alcohol‐associated liver disease (ALD). Furthermore, we evaluated the prognostic accuracy of markers for liver‐related events and all‐cause mortality. All findings were compared with routine liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma‐glutamyltransferase. Our prospective, biopsy‐controlled, single‐center study included 265 patients with ongoing or prior excessive alcohol intake, representing the full spectrum of compensated ALD. We defined hepatic inflammatory activity as a combined score of lobular inflammation and ballooning. For severe hepatic inflammatory activity (n = 40), we found excellent diagnostic accuracy for M30 (area under the receiver operating characteristics curve [AUROC] = 0.90), M65 (AUROC = 0.86), and AST (AUROC = 0.86). Elevated M30 (M30 > 240 U/L) had the highest positive predictive value (PPV) and specificity, significantly higher than M65, ActiTest and ALT, but not AST (M30: sensitivity = 83%, specificity = 82%, positive predictive value = 45%, negative predictive value = 95%). Patients were followed up for 1445 patient‐years. All markers, except for ALT, significantly predicted liver‐related events and all‐cause mortality. After adjusting for advanced fibrosis, drinking behavior and body mass index, M30 and M65 remained significant predictors of liver‐related events, whereas M30 and AST were significant predictors of all‐cause mortality. Conclusion: M30 and AST accurately detect severe hepatic inflammatory activity in patients with compensated ALD. M30 was the only significant predictor of both liver‐related events and all‐cause mortality after adjusting for advanced fibrosis, body mass index, and drinking behavior at inclusion.

Abstract Background The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. Methods This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. Discussion This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. Trial registration This study is registered on Clinicaltrials.gov ( NCT03789825 ).

Abstract For years, hepatologists have been seeking non-invasive methods able to detect significant liver fibrosis. However, no previous algorithm using routine blood markers has proven to be clinically appropriate in primary care. We present a novel approach based on artificial intelligence, able to predict significant liver fibrosis in low-prevalence populations using routinely available patient data. We built six ensemble learning models (LiverAID) with different complexities using a prospective screening cohort of 3352 asymptomatic subjects. 463 patients were at a significant risk that justified performing a liver biopsy. Using an unseen hold-out dataset, we conducted a head-to-head comparison with conventional methods: standard blood-based indices (FIB-4, Forns and APRI) and transient elastography (TE). LiverAID models appropriately identified patients with significant liver stiffness (> 8 kPa) (AUC of 0.86, 0.89, 0.91, 0.92, 0.92 and 0.94, and NPV ≥ 0.98), and had a significantly superior discriminative ability (p

The aspartate‐to‐alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver‐related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population‐based health‐examination surveys (FINRISK, 2002‐2012; n = 18,067) with linked registry data for incident liver‐related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver‐related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol‐related liver disease (ALD). The dynamic AAR model predicted liver‐related outcomes both overall (optimism‐corrected C‐statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver‐related outcomes within 10 years. In independent cohorts, the C‐statistic for predicting liver‐related outcomes up to a 10‐year follow‐up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area‐under‐the‐curve (AUC) for detecting prevalent cirrhosis was 0.80‐0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C‐statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.

Pantazopoulou et al. find that AGO2 resides in open-ended tunneling nanotubes and close-ended cytokinetic bridges. At the latter location, AGO2 colocalizes with cell division components and the authors show that AGO2 depletion impairs cell division fidelity.

ABSTRACT Gut viruses are important, yet often neglected, players in the complex human gut microbial ecosystem. Recently, the number of human gut virome studies has been increasing; however, we are still only scratching the surface of the immense viral diversity. In this study, 254 virus-enriched fecal metagenomes from 204 Danish subjects were used to generate the Danish Enteric Virome Catalog (DEVoC) containing 12,986 nonredundant viral scaffolds, of which the majority was previously undescribed, encoding 190,029 viral genes. The DEVoC was used to compare 91 healthy DEVoC gut viromes from children, adolescents, and adults that were used to create the DEVoC. Gut viromes of healthy Danish subjects were dominated by phages. While most phage genomes (PGs) only occurred in a single subject, indicating large virome individuality, 39 PGs were present in more than 10 healthy subjects. Among these 39 PGs, the prevalences of three PGs were associated with age. To further study the prevalence of these 39 prevalent PGs, 1,880 gut virome data sets of 27 studies from across the world were screened, revealing several age-, geography-, and disease-related prevalence patterns. Two PGs also showed a remarkably high prevalence worldwide—a crAss-like phage (20.6% prevalence), belonging to the tentative AlphacrAssvirinae subfamily, and a previously undescribed circular temperate phage infecting Bacteroides dorei (14.4% prevalence), called LoVEphage because it encodes lots of viral elements. Due to the LoVEphage’s high prevalence and novelty, public data sets in which the LoVEphage was detected were de novo assembled, resulting in an additional 18 circular LoVEphage-like genomes (67.9 to 72.4 kb). IMPORTANCE Through generation of the DEVoC, we added numerous previously uncharacterized viral genomes and genes to the ever-increasing worldwide pool of human gut viromes. The DEVoC, the largest human gut virome catalog generated from consistently processed fecal samples, facilitated the analysis of the 91 healthy Danish gut viromes. Characterizing the biggest cohort of healthy gut viromes from children, adolescents, and adults to date confirmed the previously established high interindividual variation in human gut viromes and demonstrated that the effect of age on the gut virome composition was limited to the prevalence of specific phage (groups). The identification of a previously undescribed prevalent phage illustrates the usefulness of developing virome catalogs, and we foresee that the DEVoC will benefit future analysis of the roles of gut viruses in human health and disease.

Background & Aims: In experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication. Methods: We studied 39 participants with 3 distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 min. Hepatic and systemic venous blood was sampled simultaneously at 3 time points: baseline, 60, and 180 min after alcohol intervention. Liver biopsies were sampled 240 min after alcohol intervention. We used ultra-high performance liquid chromatography mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples. Results: After alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased, while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, whereas LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared with systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD. Conclusions: Alcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD. Clinical Trials Registration: The study is registered at Clinicaltrials.gov (NCT03018990). Lay summary: We report that alcohol induces hepatic extraction of free unsaturated fatty acids and lysophosphatidylcholines, hepatotoxic lipids which have not been previously associated with alcohol-induced liver injury. We also found that individuals with non-alcoholic fatty liver disease have reduced lipid turnover during alcohol intoxication when compared with people with alcohol-related fatty liver disease. This may explain why alcohol is particularly more harmful in people with non-alcoholic fatty liver and why elevated BMI and alcohol have a synergistic effect on the risk of liver-related death.

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites. Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models. Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/ml [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (29.7 U/ml) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites. Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models. Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (29.7 U/L) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na

Background & Aims: Both 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. Methods: In 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. Results: Both, 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). Conclusion: Both 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 summary: Herein, 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. Keywords: Cirrhosis, liver decompensation, alcohol detoxification, DAAs, portal hypertension

Feces are the product of our diets and have been linked to diseases of the gut, including Chron’s disease and metabolic diseases such as diabetes. For screening metabolites in heterogeneous samples such as feces, it is necessary to use fast and reproducible analytical methods that maximize metabolite detection. As sample preparation is crucial to obtain high quality data in MS-based clinical metabolomics, we developed a novel, efficient and robust method for preparing fecal samples for analysis with a focus in reducing aliquoting and detecting both polar and non-polar metabolites. Fecal samples (n = 475) from patients with alcohol-related liver disease and healthy controls were prepared according to the proposed method and analyzed in an UHPLC-QQQ targeted platform in order to obtain a quantitative profile of compounds that impact liver-gut axis metabolism. MS analyses of the prepared fecal samples have shown reproducibility and coverage of n = 28 metabolites, mostly comprising bile acids and amino acids. We report metabolite-wise relative standard deviation (RSD) in quality control samples, inter-day repeatability, LOD (limit of detection), LOQ (limit of quantification), range of linearity and method recovery. The average concentrations for 135 healthy participants are reported here for clinical applications. Our high-throughput method provides a novel tool for investigating gut-liver axis metabolism in liver-related diseases using a noninvasive collected sample.

Abstract Background Alcoholic liver disease is the leading cause of cirrhosis worldwide. Due to an increase in alcohol overuse, alcoholic liver disease has become an increased burden on health care systems. Abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment; however, this approach is hampered by frequent relapse and lack of specific therapy for treating advanced cases of liver disease. In the present study, we hypothesized that gut microbiota drive the development of liver fibrosis and that modulation of gut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis. Methods/design Our double-blind, placebo-controlled trial will include 136 participants with biopsy-verified alcoholic fibrosis (Ishak liver fibrosis score of 1–4). Participants are randomized 1:1 to receive placebo or 550 mg of rifaximin twice daily for 18 months. A liver biopsy will be performed at the end of the treatment period to evaluate the effect of drug treatment on liver fibrosis. Stool, urine, and saliva specimens will be collected before treatment begins, at 1 month, and at the end of the treatment period. Fecal samples are used for microbiome deep sequencing. Changes in microbiome composition are compared before and after the trial medication period and linked to changes in liver fibrosis. Discussion This is the first clinical trial to evaluate the effect of gut microbiota on liver fibrosis in humans. If gut microbiota are an important promoter of alcoholic liver disease, current results may open new therapeutic avenues and revolutionize the current understanding of chronic liver diseases. Trial registration EudraCT, 2014–001856-51. Registered on 16 August 2014.

Food intake increases liver stiffness, but it is believed that liver stiffness returns to baseline two hours after a meal. The aim of this study was to investigate the impact of different sized meals on liver stiffness. Liver and spleen stiffness was measured with transient elastography (TE) and real-time 2-dimensional shear wave elastography (2D-SWE). Patients ingested a 625 kcal and a 1250 kcal liquid meal on two consecutive days. We measured liver and spleen elasticity, Controlled attenuation parameter (CAP) and portal flow at baseline and after 20, 40, 60, 120 and 180 minutes. Sixty patients participated, 83% with alcoholic liver disease. Twenty-eight patients had METAVIR fibrosis score F0-3 and 32 patients had cirrhosis. Liver stiffness, spleen stiffness and CAP increased after both meals for all stages of fibrosis. False positive 2D-SWE liver stiffness measurements caused 36% and 52% of patients with F0-3 fibrosis to be misclassified with higher stages of fibrosis after the moderate and high caloric meal. Likewise, 10% and 13% of compensated cirrhosis patients were misclassified with clinically significant portal hypertension after the two meals. We observed similar misclassification rates with TE. After three hours, liver stiffness remained elevated more than 20% from baseline in up to 50% of patients. IN CONCLUSION:Liver stiffness, spleen stiffness and CAP increase after a meal across all stages of fibrosis and across elastography techniques. Up to half of patients may be misclassified with higher stages of fibrosis, if they are assessed after less than three hours fasting period.

The complications to chronic hepatitis B (HBV) include incidence of hepatocellular carcinoma (HCC) and mortality. The risk of these complications may vary in different patient groups.To estimate the incidence and predictors of HCC and in untreated HBV patients.Systematic review with random effects meta-analyses of randomized controlled trials and observational studies. Results are expressed as annual incidence (events per 100 person-years) with 95% confidence intervals. Subgroup and sensitivity analyses of patient and study characteristics were performed to identify common risk factors.We included 68 trials and studies with a total of 27,584 patients (264,919 person-years). In total, 1,285 of 26,687 (5%) patients developed HCC and 730 of 12,511 (6%) patients died. The annual incidence was 0.88 (95% CI, 0.76-0.99) for HCC and 1.26 (95% CI, 1.01-1.51) for mortality. Patients with cirrhosis had a higher risk of HCC (incidence 3.16; 95% CI, 2.58-3.74) than patients without cirrhosis (0.10; 95% CI, 0.02-0.18). The risk of dying was also higher for patients with than patients without cirrhosis (4.89; 95% CI, 3.16-6.63; and 0.11; 95% CI, 0.09-0.14). The risk of developing HCC increased with HCV coinfection, older age and inflammatory activity. The country of origin did not clearly predict HCC or mortality estimates.Cirrhosis was the strongest predictor of HCC incidence and mortality. Patients with HBV cirrhosis have a 31-fold increased risk of HCC and a 44-fold increased mortality compared to non-cirrhotic patients. The low incidence rates should be taken into account when considering HCC screening in non-cirrhotic patients.Prospero CRD42013004764.