Recurrent alcohol-associated hepatitis is common and is associated with increased mortality.

BACKGROUND AND AIMS: Alcohol relapse after surviving an episode of alcohol-associated hepatitis (AH) is common. However, the clinical features, risk factors, and prognostic implications of recurrent alcohol-associated hepatitis (RAH) are not well described. APPROACH AND RESULTS: A registry-based study was done of patients admitted to 28 Spanish hospitals for an episode of AH between 2014 and 2021. Baseline demographics and laboratory variables were collected. Risk factors for RAH were investigated using Cox regression analysis. We analyzed the severity of the index episodes of AH and compared it to that of RAH. Long-term survival was assessed by Kaplan-Meier curves and log-rank tests. A total of 1118 patients were included in the analysis, 125 (11%) of whom developed RAH during follow-up (median: 17 [7-36] months). The incidence of RAH in patients resuming alcohol use was 22%. The median time to recurrence was 14 (8-29) months. Patients with RAH had more psychiatric comorbidities. Risk factors for developing RAH included age <50 years, alcohol use >10 U/d, and history of liver decompensation. RAH was clinically more severe compared to the first AH (higher MELD, more frequent ACLF, and HE). Moreover, alcohol abstinence during follow-up was less common after RAH (18% vs. 45%, p <0.001). Most importantly, long-term mortality was higher in patients who developed RAH (39% vs. 21%, p = 0.026), and presenting with RAH independently predicted high mortality (HR: 1.55 [1.11-2.18]). CONCLUSIONS: RAH is common and has a more aggressive clinical course, including increased mortality. Patients surviving an episode of AH should undergo intense alcohol use disorder therapy to prevent RAH.

Screening and risk of hepatocellular carcinoma in patients with advanced fibrosis after hepatitis C virus eradication.

INTRODUCTION: the risk of hepatocellular carcinoma (HCC) after eradication of the hepatitis C virus (HCV) is highly variable in patients with advanced fibrosis (F3). Long-term surveillance for HCC after sustained virological response (SVR) is controversial in these patients. The objective of this study was to describe the post-SVR follow-up in clinical practice in patients with F3 and determine the predictive factors for the development of HCC. PATIENTS AND METHODS: a multicenter, observational and retrospective study was performed, which included HCV-monoinfected patients with F3 fibrosis determined by transient elastography who achieved SVR between 2015 and 2022, with follow-up until May 2023. Clinical-demographic, laboratory, elastography, and ultrasound variables were recorded before and after treatment. A descriptive and inferential analysis, Cox regression analysis and survival analysis were carried out with the R statistical software. RESULTS: two hundred and nineteen patients were included in the study (65.3 % males, median age 57 years), and 175 (79.9 %) received ultrasound screening after SVR for 62 (6-90) months. The prescribing service was the only independent variable related to performing ultrasound surveillance (p = 0.004). Eight patients developed HCC. In multivariate analysis adjusted for sex, age, presence of diabetes and alcohol consumption, a post-SVR FIB-4 ≥ 3.25 was associated with a 12-fold increase in HCC risk. The cumulative probability of HCC was higher in the group of patients with FIB-4 ≥ 3.25 after SVR (p < 0.001). CONCLUSION: post-SVR follow-up of patients with F3 fibrosis is variable in clinical practice. Using the FIB-4 after SVR allows us to identify those patients with a higher risk of HCC who benefit from biannual ultrasound screening.

CRISPR/Cas9-mediated deletion of adipocyte genes associated with NAFLD alters adipocyte lipid handling and reduces steatosis in hepatocytes in vitro.

Obesity is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD), and the subcutaneous white adipose tissue (scWAT) is the primary lipid storage depot and regulates lipid fluxes to other organs. Our previous work identified genes upregulated in scWAT of patients with NAFLD: SOCS3, DUSP1, and SIK1. Herein, we knocked down (KD) their expression in human adipose-derived mesenchymal stem cells (hADMSCs) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology and characterized their phenotype. We found that SOCS3, DUSP1, and SIK1 expression in hADMSC-derived adipocytes was not critical for adipogenesis. However, the metabolic characterization of the cells suggested that the genes played important roles in lipid metabolism. Reduction of SIK1 expression significantly increased both de novo lipogenesis (DNL) and palmitate-induced lipogenesis (PIL). Editing out SOCS3 reduced DNL while increasing isoproterenol-induced lipolysis and insulin-induced palmitate accumulation. Conversely, DUSP1 reduced PIL and DNL. Moreover, RNA-sequencing analysis of edited cells showed that these genes not only altered lipid metabolism but also other biological pathways related to inflammatory processes, in the case of DUSP1, extracellular matrix remodeling for SOCS3, or cellular transport for SIK1. Finally, to evaluate a possible adipocyte-hepatocyte axis, human hepatoma HepG2 cells were cocultured with edited hADMSCs-derived adipocytes in the presence of [3H]-palmitate. All HepG2 cells cultured with DUSP1-, SIK1-, or SOCS3-KD adipocytes decreased [3H]-palmitate accumulation compared with control adipocytes. These results support our hypotheses that SOCS3, DUSP1, and SIK1 regulate multiple aspects of adipocyte function, which may play a role in the progression of obesity-associated comorbidities, such as NAFLD.NEW & NOTEWORTHY Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology successfully edited genomic DNA of human adipose-derived mesenchymal stem cells (hADMSC). SOCS3, SIK1, and DUSP1 regulate adipocyte lipid handling. Silencing SOCS3, SIK1, and DUSP1 expression in hADMSC-derived adipocytes reduces hepatocyte lipid storage in vitro.

Isthmin-1 (ISM1), a novel adipokine that reflects abdominal adipose tissue distribution in individuals with obesity.

BACKGROUND: The assessment of obesity-related health risks has traditionally relied on the Body Mass Index and waist circumference, but their limitations have propelled the need for a more comprehensive approach. The differentiation between visceral (VIS) and subcutaneous (SC) fat provides a finer-grained understanding of these risks, yet practical assessment methods are lacking. We hypothesized that combining the SC-VIS fat ratio with non-invasive biomarkers could create a valuable tool for obesity-related risk assessment. METHODS AND RESULTS: A clinical study of 125 individuals with obesity revealed significant differences in abdominal fat distribution measured by CT-scan among genders and distinct models of obesity, including visceral, subcutaneous, and the SC/VIS ratio. Stratification based on these models highlighted various metabolic changes. The SC/VIS ratio emerged as an excellent metric to differentiate metabolic status. Gene expression analysis identified candidate biomarkers, with ISM1 showing promise. Subsequent validation demonstrated a correlation between ISM1 levels in SC and plasma, reinforcing its potential as a non-invasive biomarker for fat distribution. Serum adipokine levels also correlated with the SC/VIS ratio. The Receiver Operating Characteristic analysis revealed ISM1's efficacy in discriminating individuals with favorable metabolic profiles based on adipose tissue distribution. Correlation analysis also suggested that ISM1 was involved in glucose regulation pathways. CONCLUSION: The study's results support the hypothesis that the SC-VIS fat ratio and its derived non-invasive biomarkers can comprehensively assess obesity-related health risks. ISM1 could predict abdominal fat partitioning and be a potential biomarker for evaluating obesity-related health risks.

Identification of novel targets in adipose tissue involved in non-alcoholic fatty liver disease progression.

Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA-sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)-derived adipocytes. We observed impaired adipogenesis in hMSC-derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC-derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis.

Percutaneous left atrial appendage closure in patients with gastrointestinal bleeding associated with oral anticoagulants.

INTRODUCTION: Percutaneous left atrial appendage closure (LAAC) has shown non-inferiority compared to oral anticoagulation (OAC) in preventing atrial fibrillation (AF)-related stroke. The objective of this study was to assess whether LAAC reduces the incidence of gastrointestinal bleeding (GIB) and/or chronic anaemia associated with OAC, as well as the consumption of healthcare resources. MATERIALS AND METHODS: Prospective, single-center study from 2016 to 2022, LAAC was performed. Clinical, analytical and healthcare resource consumption data were collected (endoscopies, blood transfusions, hospital admissions) prior and 6 months after LAAC. RESULTS: 43 patients were included, with an average age of 77.6 years. LAAC indication was upper, low and obscure GIB in 7 (16%), 8 (19%) and 28 patients (65%) respectively. GIB source was intestinal angiodysplasias in 27 patients (63%), occult origin in 12 (28%), and others (antral vascular ectasia, portal hypertension gastropathy, etc.) in 4 patients (9%). The mean number of packed red blood cells per patient before LAAC was (mean ± SD) 7.29 ± 5 vs 0.42 ± 1.3 (p < 0.001); endoscopic procedures were 4.34 ± 2.85 vs 0.27 ± 0.76 (p < 0.001); and hospitalizations 2.67 ± 2.14 vs 0.03 ± 0.17 (p < 0.001), with a hospital stay of 21.5 ± 17.3 vs 0.09 ± 0.5 days (p < 0.001) at 6 months post-intervention. Haemoglobin value increased from 8.1 ± 1.2g/dl to 12.4 ± 2.2g/dl (p < 0.001) at 6 months. No thromboembolic events were registered during a median follow-up of 16.6 months (range 6-65). CONCLUSIONS: LAAC could be a safe and effective alternative to OAC in patients with non-valvular AF presenting significant, recurrent or potentially unresolvable GIB. This intervention also leads to important savings in the consumption of healthcare resources.

Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Gastrointestinal and liver immune-related adverse effects induced by immune checkpoint inhibitors: A descriptive observational study. / Efectos adversos inmunomediados gastrointestinales y hepáticos inducidos por los inhibidores del punto de control inmunitario: estudio descriptivo observacional.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are effective agents against several malignancies. However, they are associated with gastrointestinal and liver immune-related adverse events (GI-IrAEs and LI-IrAEs), which can lead to their temporary or permanent discontinuation. AIM: The aim of this study was to evaluate the efficacy and gastrointestinal and liver toxicity of ICIs in oncological treatments in actual clinical practice. MATERIAL AND METHODS: Patients with advanced cancer who received at least 1ICI dose between May 2015 and September 2018 were retrospectively assessed. RESULTS: 132 patients with non-small cell lung cancer (65.15%, n=86); melanoma (22.7%, n=30); renal carcinoma (9.09%, n=12); and other tumours (3%, n=4) were included. The treatments administered were nivolumab (n=82), pembrolizumab (n=28), atezolizumab (n=13), durvalumab (n=2), ipilimumab (n=1) and the antiCTLA-4/PD-1 combination (n=6). In total, 51 patients (38.6%) developed IrAEs, 17 (12.9%) of which experienced GI-IrAEs. Of these, 8 (47%) needed steroids and 1patient required surgery due to intestinal perforation. Grade I Li-IrAEs were observed in 4 patients (3.03%): 2 (50%) required corticosteroids and 1 patient had to discontinue treatment. Four patients (66.6%) who received combination therapy experienced GI-IrAEs. IrAE incidence were not associated with age, gender or drug response. CONCLUSIONS: GI-IrAEs are one of the most common adverse events in patients receiving ICIs. A multidisciplinary approach and a greater understanding of these events could help to reduce morbidity and therapy discontinuation.

Unraveling Adipose Tissue Dysfunction: Molecular Mechanisms, Novel Biomarkers, and Therapeutic Targets for Liver Fat Deposition.

Adipose tissue (AT), once considered a mere fat storage organ, is now recognized as a dynamic and complex entity crucial for regulating human physiology, including metabolic processes, energy balance, and immune responses. It comprises mainly two types: white adipose tissue (WAT) for energy storage and brown adipose tissue (BAT) for thermogenesis, with beige adipocytes demonstrating the plasticity of these cells. WAT, beyond lipid storage, is involved in various metabolic activities, notably lipogenesis and lipolysis, critical for maintaining energy homeostasis. It also functions as an endocrine organ, secreting adipokines that influence metabolic, inflammatory, and immune processes. However, dysfunction in WAT, especially related to obesity, leads to metabolic disturbances, including the inability to properly store excess lipids, resulting in ectopic fat deposition in organs like the liver, contributing to non-alcoholic fatty liver disease (NAFLD). This narrative review delves into the multifaceted roles of WAT, its composition, metabolic functions, and the pathophysiology of WAT dysfunction. It also explores diagnostic approaches for adipose-related disorders, emphasizing the importance of accurately assessing AT distribution and understanding the complex relationships between fat compartments and metabolic health. Furthermore, it discusses various therapeutic strategies, including innovative therapeutics like adipose-derived mesenchymal stem cells (ADMSCs)-based treatments and gene therapy, highlighting the potential of precision medicine in targeting obesity and its associated complications.

Lipid Profile and Cardiovascular Risk Modification after Hepatitis C Virus Eradication.

The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals.

MASLD-Related Hepatocarcinoma: Special Features and Challenges.

Metabolic-associated steatohepatitis liver disease (MASLD) currently impacts a quarter of the global population, and its incidence is expected to increase in the future. As a result, hepatocellular carcinoma associated with MASLD is also on the rise. Notably, this carcinoma does not always develop alongside liver cirrhosis, often leading to a more advanced stage at diagnosis. The challenge lies in accurately identifying patients who are at a higher risk to tailor screening processes effectively. Additionally, several therapeutic approaches are being explored to prevent hepatocellular carcinoma, although there are no universally accepted guidelines yet.

Real-life effectiveness of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients previously treated with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir.

BACKGROUND: Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first-line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). METHODS: Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022. RESULTS: In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non-GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR. CONCLUSION: SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first-line therapy with SOF/VEL were not associated with lower SVRs.

Evaluation and Management of Nutritional Consequences of Chronic Liver Diseases.

Liver diseases are the major predisposing conditions for the development of malnutrition, sarcopenia, and frailty. Recently, the mechanism of the onset of these complications has been better established. Regardless of the etiology of the underlying liver disease, the clinical manifestations are common. The main consequences are impaired dietary intake, altered macro- and micronutrient metabolism, energy metabolism disturbances, an increase in energy expenditure, nutrient malabsorption, sarcopenia, frailty, and osteopathy. These complications have direct effects on clinical outcomes, survival, and quality of life. The nutritional status should be assessed systematically and periodically during follow-up in these patients. Maintaining and preserving an adequate nutritional status is crucial and should be a mainstay of treatment. Although general nutritional interventions have been established, special considerations are needed in specific settings such as decompensated cirrhosis, alcohol-related liver disease, and metabolic-dysfunction-associated fatty liver disease. In this review, we summarize the physiopathology and factors that impact the nutritional status of liver disease. We review how to assess malnutrition and sarcopenia and how to prevent and manage these complications in this setting.

Liver Disease Undernutrition Screening Tool Questionnaire Predicts Decompensation and Mortality in Cirrhotic Outpatients with Portal Hypertension.

BACKGROUND: Numerous scores are designed to predict outcomes of patients with liver cirrhosis. Our study aimed to evaluate the ability of the Liver Disease Undernutrition Screening Tool (LDUST) in predicting mortality and decompensation in outpatients with clinically significant portal hypertension (CSPH). We hypothesized that LDUST could help identify patients in need of nutritional supplementation and intervention. METHODS: A prospective study of 57 CSPH patients (36.8% female, mean age: 63.5 ± 9.9 years) with a median follow-up of 41 months was conducted. Baseline liver function, nutrition, and sarcopenia were assessed, alongside LDUST. During follow-up, the occurrence of liver decompensation, hospital admission, need for emergency care, and mortality were evaluated. RESULTS: A total of 56.1% of patients were Child A, and the most frequent etiology was alcohol (50.9%). Malnutrition risk according to LDUST raised mortality (HR: 25.96 (1.47-456.78)), decompensation (HR 9.78 (2.08-45.89)), and admission (HR 4.86 (1.09-21.61)) risks in multivariate Cox analysis. Combining LDUST with Child and MELD scores improved their decompensation prediction (0.936 vs. 0.811 and 0.866 vs. 0.700). CONCLUSIONS: The LDUST has a solid ability to predict complications in cirrhosis outpatients with CSPH, and its integration with Child and MELD models enhances their predictive power. LDUST implementation could identify individuals necessitating early nutritional support.