Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes: The DIRECT PLUS clinical trial.

BACKGROUND AND AIMS: We demonstrated in the randomized 18-month DIRECT PLUS trial (n = 294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with 2 other healthy diets, reducing NAFLD by half, regardless of similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention. APPROACH AND RESULTS: We calculated IHF% by proton magnetic resonance spectroscopy (normal IHF% <5% and abnormal IHF% ≥5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers.Participants (age = 51.3 ± 10.8 y; 89% men; and body mass index = 31.3 ± 3.9 kg/m 2 ) had an 89.8% 18-month retention rate; 83% had eligible follow-up proteomics measurements, and 78% had follow-up proton magnetic resonance spectroscopy. At baseline, 39 candidate proteins were significantly associated with IHF% (false discovery rate <0.05), mostly related to immune function pathways (eg, hydroxyacid oxidase 1). An IHF% prediction based on the DIRECT PLUS by combined model ( R2 = 0.47, root mean square error = 1.05) successfully predicted IHF% ( R2 = 0.53) during testing and was stronger than separately inputting proteins/traditional markers ( R2 = 0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39 candidate proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular matrix remodeling, and immune function pathways. Thrombospondin-2 protein change was higher in the green-MED compared to the MED group, beyond weight and IHF% loss ( p = 0.01). Protein principal component analysis revealed differences in the third principal component time distinct interactions across abnormal/normal IHF% trajectory combinations; p < 0.05 for all). CONCLUSIONS: Our findings suggest novel proteomic signatures that may indicate MRI-assessed IHF state and changes during lifestyle intervention. Specifically, carbonic anhydrase 5A, hydroxyacid oxidase 1, and thrombospondin-2 protein changes are independently associated with IHF% change, and thrombospondin-2 protein change is greater in the green-MED/high polyphenols diet.

Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial.

BACKGROUND AND AIMS: HDV infection leads to the most aggressive form of human viral hepatitis for which there is no FDA-approved therapy. PEG IFN-lambda-1a (Lambda) has previously demonstrated a good tolerability profile in HBV and HCV patients compared to PEG IFN-alfa. The goal of Phase 2 LIMT-1 trial was to evaluate the safety and efficacy of Lambda monotherapy in patients with HDV. APPROACH AND RESULTS: An open-label study of Lambda 120 or 180 mcg, administered once weekly by subcutaneous injections for 48 weeks, followed by 24 weeks of posttreatment follow-up. Thirty-three patients were allocated to Lambda 180 mcg (n=14) or 120 mcg (n=19). Baseline mean values: HDV RNA 4.1 log10 IU/mL (SD±1.4); ALT 106 IU/L (35-364); and bilirubin 0.5 mg/dL (0.2-1.2). Intention-to-treat rates of virologic response to Lambda 180 mcg and 120 mcg, 24 weeks following treatment cessation were 5 of 14(36%) and 3 of 19 (16%), respectively. The posttreatment response rate of 50% was seen in low BL viral load (≤4 log10) on 180 mcg. Common on-treatment adverse events included flu-like symptoms and elevated transaminase levels. Eight (24%) cases of hyperbilirubinemia with or without liver enzyme elevation, leading to drug discontinuation, were mainly observed in the Pakistani cohort. The clinical course was uneventful, and all responded favorably to dose reduction or discontinuation. CONCLUSIONS: Treatment with Lambda in patients with chronic HDV may result in virologic response during and following treatment cessation. Clinical phase 3 development of Lambda for this rare and serious disease is ongoing.

Circulating isomiRs May Be Superior Biomarkers Compared to Their Corresponding miRNAs: A Pilot Biomarker Study of Using isomiR-Ome to Detect Coronary Calcium-Based Cardiovascular Risk in Patients with NAFLD.

Circulating miRNAs are increasingly being considered as biomarkers in various medical contexts, but the value of analyzing isomiRs (isoforms of canonical miRNA sequences) has not frequently been assessed. Here we hypothesize that an in-depth analysis of the full circulating miRNA landscape could identify specific isomiRs that are stronger biomarkers, compared to their corresponding miRNA, for identifying increased CV risk in patients with non-alcoholic fatty liver disease (NAFLD)-a clinical unmet need. Plasma miRNAs were sequenced with next-generation sequencing (NGS). Liver fat content was measured with magnetic-resonance spectrometry (MRS); CV risk was determined, beyond using traditional biomarkers, by a CT-based measurement of coronary artery calcium (CAC) score and the calculation of a CAC score-based CV-risk percentile (CAC-CV%). This pilot study included n = 13 patients, age > 45 years, with an MRS-measured liver fat content of ≥5% (wt/wt), and free of overt CVD. NGS identified 1103 miRNAs and 404,022 different isomiRs, of which 280 (25%) and 1418 (0.35%), respectively, passed an abundance threshold. Eighteen (sixteen/two) circulating miRNAs correlated positively/negatively, respectively, with CAC-CV%, nine of which also significantly discriminated between high/low CV risk through ROC-AUC analysis. IsomiR-ome analyses uncovered 67 isomiRs highly correlated (R ≥ 0.55) with CAC-CV%. Specific isomiRs of miRNAs 101-3p, 144-3p, 421, and 484 exhibited stronger associations with CAC-CV% compared to their corresponding miRNA. Additionally, while miRNAs 140-3p, 223-3p, 30e-5p, and 342-3p did not correlate with CAC-CV%, specific isomiRs with altered seed sequences exhibited a strong correlation with coronary atherosclerosis burden. Their predicted isomiRs-specific targets were uniquely enriched (compared to their canonical miRNA sequence) in CV Disease (CVD)-related pathways. Two of the isomiRs exhibited discriminative ROC-AUC, and another two showed a correlation with reverse cholesterol transport from cholesterol-loaded macrophages to ApoB-depleted plasma. In summary, we propose a pipeline for exploring circulating isomiR-ome as an approach to uncover novel and strong CVD biomarkers.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD. METHODS: In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model. RESULTS: There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids. CONCLUSIONS: We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.

Non-selective dampening of the host immune response after hepatitis C clearance and its association with circulating chemokine and endotoxin levels.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy has revolutionized treatment for the hepatitis C virus (HCV). While DAA therapy is common, little is known about the intrahepatic immunological changes after sustained virologic response (SVR). We aim to describe transcriptional alterations of the gut microbiome and the liver after SVR. METHODS: Twenty-two HCV patients were evaluated before and 9 months after 12 weeks of sofosbuvir/velpatasvir treatment. All achieved SVR. A liver biopsy, portal blood (direct portal vein cannulation), peripheral blood and stool samples were obtained. RNA-seq and immunofluorescent staining were performed on liver biopsies. RNA-seq and 16S rRNA metagenomics were performed on stool. RESULTS: Differential expression within liver transcription showed 514 downregulated genes (FDR q < .05; foldchange > 2) enriched in inflammatory pathways; of note, GO:0060337, type 1 IFN signalling (p = 8e-23) and GO:0042742, defence response to bacterium (p = 8e-3). Interestingly, microbial products increased in the portal blood and liver after SVR. Due to the increase in microbial products, the gut microbiome was investigated. There was no dysbiosis by Shannon diversity index or Bacteroides/Firmicutes ratio. There was a differential increase in genes responsible for bacterial lipopolysaccharide production after SVR. CONCLUSIONS: The decrease in the antiviral interferon pathway expression was expected after SVR; however, there was an unanticipated decrease in the transcription of genes involved in recognition and response to bacteria, which was associated with increased levels of microbial products. Finally, the alterations in the function of the gut microbiome are a promising avenue for further investigation of the gut-liver axis, especially in the context of the significant immunological changes noted after SVR.

Hepatitis D Virus and HBsAg Dynamics in the era of new Antiviral Treatments.

PURPOSE OF REVIEW: Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis, with no FDA-approved therapy. Progress in the development of effective HDV treatments is accelerating. This review highlights how mathematical modeling is improving understanding of HDV-HBsAg-host dynamics during antiviral therapy and generating insights into the efficacy and modes of action (MOA) of new antiviral agents. RECENT FINDINGS: Clinical trials with pegylated-interferon-λ, bulevertide, nucleic acid polymers, and/or lonafarnib against various steps of the HDV-life cycle have revealed new viral-kinetic patterns that were not observed under standard treatment with pegylated-interferon-α. Modeling indicated that the half-lives of circulating HDV and HBsAg are ~ 1.7 d and ~ 1.3 d, respectively, estimated the relative response of HDV and HBsAg during different antiviral therapies, and provided insights into the efficacy and MOA of drugs in development for treating HDV, which can inform response-guided therapy to individualize treatment duration. Mathematical modeling of HDV and HBsAg kinetics provides a window into the HDV virus lifecycle, HDV-HBsAg-host dynamics during antiviral therapy, and the MOA of new drugs for HDV.

HepQuant SHUNT Detects Portal Hypertension in Early Stages of Clinically Compensated Chronic Liver Disease.

Physicians use portal pressure measurements in clinical practice and research but the methods are invasive, can cause complications, and are resource intensive.1-3 Herein we describe preliminary findings of the minimally invasive HepQuant-SHUNT test in the diagnosis of portal hypertension in precirrhotic and compensated cirrhotic patients.

Liver cirrhosis in elderly patients: clinical characteristics, complications, and survival-analyses from a large retrospective study.

BACKGROUND: Liver cirrhosis (LC) is a common disease diagnosed in all ages. With the increasing population age, LC is noticeable more in the clinics. AIM: To distinguish the clinical characteristics, complications, and survival of patients with liver cirrhosis. METHODS: A retrospective study enrolled patients diagnosed with liver cirrhosis at Soroka University Medical Center. Patients with cirrhosis diagnosed at an age older than 65 years (group 1) were compared with patients diagnosed at an age younger than 65 years (group 2). RESULTS: We included 1046 patients; 411 (39.3%) in group 1 and 635 (60.7%) in group 2. Fatty liver and cryptogenic liver disease were found to cause cirrhosis at a significantly higher rate in the elderly (23.4% vs. 13.9%, p < 0.001, 15.3% vs. 6.3%, p < 0.001, respectively). A higher rate of non-hepatocellular carcinoma cancers and mortality (17.5% vs. 9.1%, p < 0.001, 76.6% vs. 57%, respectively) was found among cirrhotic elderly patients, but a lower rate of oesophageal varices (47.7% vs. 60.1%, p = 0.002). Twenty-year follow-up Kaplan-Meier survival analysis for mortality estimated poor survival in the elderly (log-rank p < 0.001). The adjusted Cox proportional hazards regression model showed an association of age > 65 with an all-cause mortality hazard ratio of 2.26 (95% CI 1.89-2.69). CONCLUSION: Higher rates of fatty liver, cryptogenic cirrhosis, non-HCC cancers, and mortality were found among patients diagnosed with cirrhosis in the elderly.

Modeling-Based Response-Guided Glecaprevir-Pibrentasvir Therapy for Chronic Hepatitis C to Identify Patients for Ultrashort Treatment Duration.

We recently showed in a proof-of-concept study that real-time modeling-based response-guided therapy can shorten hepatitis C virus treatment duration with sofosbuvir-velpatasvir, elbasvir-grazoprevir, and sofosbuvir-ledipasvir without compromising efficacy, confirming our retrospective modeling reports in >200 patients. However, retrospective modeling of pibrentasvir-glecaprevir (P/G) treatment has yet to be evaluated. In the current study, modeling hepatitis C virus kinetics in 44 cirrhotic and noncirrhotic patients predicts that P/G treatment might have been reduced to 4, 6, and 7 weeks in 16%, 34%, and 14% of patients, respectively. These results support the further evaluation of a modeling-based response-guided therapy approach using P/G.

Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

Vibration Controlled Transient Elastography (Fibroscan®) in sickle cell liver disease - could we strike while the liver is hard?

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.

Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS: We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018. RESULTS: We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the nonalcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with a small amount of heterogeneity (I2 = 27%). There were improvements by at least 1 point in steatosis scores of 33% ± 3% of patients, in hepatocyte ballooning scores of 30% ± 3% of patients, in lobular inflammation scores of 32% ± 3% of patients, and in fibrosis scores of 21% ± 3% of patients, with a moderate amount of heterogeneity among trials (I2 range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72 ± 0.19), with a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45% ± 0.54%) with moderate heterogeneity (I2 = 40%), and in magnetic resonance proton density fat fraction (by 2.43 ± 0.89), without heterogeneity (I2 = 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7 ± 3.8 U/L and 5.9 ± 2.1 U/L, respectively; P < .01 for both). CONCLUSIONS: In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.

ASCA and ANCA among Bedouin Arabs with inflammatory bowel disease, the frequency and phenotype correlation.

BACKGROUND: Serological markers used for diagnostic purposes and disease stratification in inflammatory bowel disease. We aimed to investigate the frequency of ASCA and ANCA among Arab Bedouin IBD patients and its relationship to disease phenotype and course. METHODS: From cohort of 68, 25 Crohn's disease (CD) and 25 Ulcerative colitis (UC) patients were recruited (72%). ASCA IgG was determined by ELISA assay. Immunofluorescence analysis of ANCA was performed. RESULTS: The IgG ASCA was detected in 13 (52%) of the CD patients and in three (12%) UC patients. The prevalence of ANCA among UC patients was positive with 76%, sub-grouped, atypical ANCA in 9 patients (36%), pANCA in six patients (24%) and cANCA in 4 patients (16%). The detection of ASCA among CD patients was found not to be a reliable predictor of young age at diagnosis, gender, ileal involvement, anti-TNF treatment or surgery. UC patients with positive ANCA were younger, mean age 40.2 ± 11.9 compared with 57.3 ± 21.2 (p = 0.03), and diagnosed at a younger age, 29.2 ± 11.8 compared with 43.5 ± 15.3 (p = 0.05). CONCLUSION: The frequency of ASCA among Bedouin CD patients and ANCA among UC patients was high, however ASCA was not found to have a predictive value for disease phenotype or course. Positive ANCA in UC patients was predictive for younger age and age at diagnosis.

[FIRST GENERATION PROTEASE INHIBITOR BASED TRIPLE THERAPY FOR HCV GENOTYPE 1--LOOKING BACK WHILE PROCEEDING TO A PROMISING ERA].

BACKGROUND: For the last decade the backbone of hepatitis C (HCV) treatment was the pan-genotyping dual therapy with pegylated interferon alfa in combination with Ribavirin. This regimen was limited in achieving sustained virological response (SVR) and accompanied by serious adverse events. In 2010 there was overwhelming progress in the treatment options for HCV. This change began with the introduction of the first generation specific Direct Antiviral Agents (DAA's) that inhibit the viral protease, agents used in combination with the dual protocol for genotype 1 (triple therapy). In 2014 this revolution continued with the introduction of advanced DAA's targeting different non-structural viral proteins. These DAA's achieve an all oral regimen shorter in duration with outstanding SVR rates and mild side effects. Our liver clinic manages the treatment and follow-up of the vast majority of patients with HCV in southern Israel. As part of the unprecedented advance in the treatment regimen for HCV with the introduction of the first generation DAA's and especially after they were included by the national health care as an option for treatment, we started to treat HCV genotype 1 patients with the triple regimen. Now, in the era of advanced DAA's regimens, we look back, retrospectively, analyze and conclude our experience with a regimen that changed the conception of eradication for HCV by combining immune activation and specific inhibition of functional viral proteins. This was conducted in the hope that it will inspire the development of revolutionary regimens for eradication in other viral diseases. METHODS: During the period between September 2011 to November 2013, 55 patients infected with HCV genotype 1 were treated in our outpatient liver clinic with the triple regimen. These patients finished a 6 month period of post-treatment follow-up allowing the evaluation of their viral PCR status at the latest in May 2014. The data were collected from the patient's computerized file and were statistically analyzed by the SMC clinical research center. RESULTS: Out of the 55 patients, 39 received Telaprevir as the protease inhibitor and 16 were treated with Boceprevir. Of all the treated patients 34 achieved SVR; 47% of patients with genotype 1A reached SVR, whereas 71% of those with genotype 1B reached that endpoint. A total of 63.6% of patients with mild or no fibrosis (F 0-2) achieved SVR compared to 63% in patients with advanced fibrosis (F 3-4]. There were 6 patients with no METAVIR evaluation. A total of 57% of naïve patients, 83.3% of prior relapsers and 57.1% of previous non-responders reached SVR at 6 months in current triple therapy. There was no significant response difference in any sub-group when the two first generation PI's were compared. CONCLUSIONS: In our experience with first generation PI based triple regiment for HCV genotype 1, though more effective than previous dual treatment, it was still limited in its effectiveness, while creating some major safety issues. In light of this new era where much more effective and safe DAA's emerged and are now in routine use, the triple therapy in our view should be reviewed as a transitional phase that changed forever the concept of eradicating HCV and aimed at specific viral sites. This regimen paved the way for advanced DAA protocols achieving cures in overwhelming unprecedented rates.

Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma.

Namodenoson (CF102) is a small, orally available, anti-inflammatory, and anti-cancer drug candidate currently in phase 2B trial for the treatment of metabolic dysfunction-associated steatohepatitis (MASH; formerly known as non-alcoholic steatohepatitis (NASH)) and in phase 3 pivotal clinical trial for the treatment of hepatocellular carcinoma (HCC). In both MASH and HCC, the mechanism-of-action of namodenoson involves targeting the A3 adenosine receptor (A3AR), resulting in deregulation of downstream signaling pathways and leading to inhibition of inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8) and stimulation of positive cytokines (G-CSF and adiponectin). Subsequently, inhibition of liver inflammation, steatosis, and fibrosis were documented in MASH experimental models, and inhibition of HCC growth was observed in vitro, in vivo, and in clinical studies. This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC.

Nonalcoholic Fatty Liver Disease and Ethnicity: Lessons Learned from the Arab Population in Israel.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. We aimed to investigate the potential similarities and differences regarding the disease among Arabs and Jews. Retrospective study included all patients older than 18 years with NAFLD diagnosis according to ICD-10 codes. Data regarding demographics, comorbidities, and outcomes were retrieved using the MdClone platform from "Clalit" in Israel. Data concerning 34,090 Arab patients and 173,500 Jewish patients with NAFLD were included. Arab patients were significantly younger at diagnosis (35.0 ± 13 years vs. 43.6 ± 15 years, p < 0.001) and had higher rates of obesity and diabetes mellitus (69.5% vs. 56.5% and 27.0% vs. 22.7%, p < 0.001, respectively). Arab patients had higher rates of cirrhosis and portal hypertension-related complications (2.5% vs. 2.0%, p < 0.001), esophageal varices (0.9% vs. 0.5%, p < 0.001), spontaneous bacterial peritonitis (0.3% vs. 0.1%, p < 0.001), and hepatorenal syndrome (0.3% vs. 0.1%, p < 0.001). There was no significant difference in the prevalence of hepatocellular carcinoma between study groups (0.4% vs. 0.5%, p = 0.156). Liver transplantation was performed in 0.2% of Arab NAFLD patients compared to 0.07% of Jewish NAFLD patients (p < 0.001). Lower rates of all-cause mortality were found among the Arab NAFLD patients versus Jewish NAFLD patients (7.7% versus 11.5%, p < 0.001). According to the Cox regression model, Arab ethnicity is a risk factor for death with OR of 1.36. Significant differences regarding comorbidities, complications, liver transplantations rates, and all-cause mortality were found among NAFLD patients of different ethnicities, hence specific population need specific consideration in prevention, early diagnosis and follow up.

Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal.

INTRODUCTION: Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS: Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS: At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION: At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.

Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.

BACKGROUND: Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. METHODS: Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. RESULTS: Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). CONCLUSIONS: Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.