BACKGROUND:Dropout is common and affects the statistical power and randomization balance of randomised controlled trials (RCTs). AIMS:To estimate the dropout rate in RCTs of metabolic dysfunction-associated steatohepatitis (MASH) and to examine factors associated with dropout in placebo-treated participants. METHODS:PubMed and Cochrane databases were searched for phase 2-4 MASH RCTs with placebo arms through November 24, 2024. Dropout was defined as the attrition of patients included in the intention-to-treat analysis but did not complete treatment. RCTs were qualitatively reviewed to assess the expected and observed dropouts. Generalised linear mixed model was used to estimate pooled dropout rates. RESULTS:Sixty RCTs with 3230 placebo-treated participants with MASH were analysed. Thirty-three RCTs reported the dropout rate used to estimate the effect size. Of these, 60.6%, 36.4%, and 3.0% had an expected dropout rate that was higher, lower, and similar, respectively, than the observed dropout rate in the placebo arm. Overall, the dropout rate was 11.06% (95% confidence interval [CI] 9.07 to 13.42), with a higher rate in phase 3-4 trials than in phase 2 trials. The corresponding rates due to adverse events, loss to follow-up and patient choice were 2.41% (95% CI 1.67 to 3.48), 1.79% (95% CI 1.06 to 2.99) and 4.06% (95% CI 2.97 to 5.53), respectively. Meta-regression determined that the dropout rate increased with longer treatment duration. CONCLUSION:Placebo dropout in MASH RCTs is significant, mainly due to patient choice. Factors such as trial phase and treatment duration should be considered when calculating sample size in future clinical trials.

Risk stratification tools for the prediction of complications in patients with upper gastrointestinal haemorrhage are crucial for appropriate management. Blood group status has been associated with the risk of bleeding, thrombosis and risk of peptic ulcer disease (PUD). We assessed the influence of blood group status on rebleeding and other complications in 699 patients with PUD bleeding. Blood group B was associated with reduced risk in the composite outcome of rebleeding, need for surgery or embolisation and mortality (OR 0.15, 95% CI 0.04-0.63, p = 0.009). Blood group B was protective against rebleeding compared to non-blood group B (OR 0.20, 95% CI 0.05-0.84, p = 0.028).

BACKGROUND:Many patients diagnosed with gastro-oesophageal reflux disease (GERD) have persistent symptoms despite proton pump inhibitor (PPI) therapy. AIMS:The aim of this consensus is to provide evidence-based statements to guide clinicians caring for patients with refractory reflux-like symptoms (rRLS) or refractory GERD. METHODS:This consensus was developed by the International Working Group for the Classification of Oesophagitis. The steering committee developed specific PICO questions pertaining to the management of PPI rRLS. Methodologists conducted systematic reviews of the literature. The quality of evidence and strength of recommendations were rated using the GRADE approach. RESULTS:Consensus was reached on 13 of 17 statements on diagnosis and management. For rRLS, suggested diagnostic strategies included endoscopy, ambulatory reflux testing and oesophageal manometry. The group did not reach consensus on the role of oesophageal biopsies or the use of reflux-symptom association in patients undergoing reflux testing. The group suggested against increasing the PPI dose in patients who had received 8 weeks of a twice-daily PPI. Adjunctive alginate or antacid therapy was suggested. There was no consensus on the role of adjunctive prokinetics. There was little role for adjunctive transient lower oesophageal sphincter relaxation (TLESR) inhibitors or bile acid sequestrants. Endoscopic or surgical anti-reflux procedures should not be performed in patients with rRLS in the absence of objectively confirmed GERD. CONCLUSIONS:The management of rRLS should be personalised, based on shared decision-making regarding the role of diagnostic testing to confirm or rule out GERD as a basis for treatment optimisation. Anti-reflux procedures should not be performed without objective confirmation of GERD.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide, with alarming prevalence reaching epidemic proportions. AIMS AND METHODS:The objective of this study is to provide a comprehensive review of the latest blood proteomics studies on MASLD and metabolic dysfunction-associated steatohepatitis (MASH), with emphasis on fibrosis. Furthermore, our objective is to conduct an analysis of protein pathways and interactions by integrating proteomics data using functional enrichment analysis of the deregulated proteins. RESULTS:Notwithstanding the considerable discrepancies in the methodology and the number of proteins examined in the circulation, the analysis reveals a consistent pattern among the list of proteins that are decreased or increased in the blood of the affected patients. The relevant biological processes (BP) associated with down- and upregulated proteins are high-density lipoprotein remodelling and complement activation, respectively. The protein families identified include not only those expected to be involved in the immune system and cell adhesion and migration but also ligands of glycoproteins expressed in cells that have been subjected to stress and proteins containing the Sushi domain. CONCLUSIONS:The application of cutting-edge methodologies to investigate the blood proteome in MASH is yielding insights that facilitate the elucidation of disease mechanisms and the identification of optimal noninvasive biomarkers. However, several challenges remain to be addressed in future research, including the generalisation of results on a global scale, the optimisation of analytical technologies and the implementation of large longitudinal studies to gain insights into the molecular mechanisms that underpin the development of advanced disease.

BACKGROUND AND AIMS:The laxative lubiprostone has been shown to decrease intestinal permeability. We aimed to assess the safety and efficacy of lubiprostone administered for 48 weeks in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). APPROACH AND RESULTS:A randomised placebo-controlled trial was conducted in a specialised MASLD outpatient clinic at the National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt. The recruited patients had radiological evidence of MASLD along with other criteria for diagnosis. Eligible patients were randomly assigned to receive either placebo or lubiprostone 24 μg orally twice daily for 48 weeks. The liver fat content was quantified by magnetic resonance imaging estimated proton density fat fraction (MRI-PDFF). Between November 2020 and February 2023, 176 patients were screened, of whom 116 were eligible. Fifty-nine patients were randomised to receive placebo, while 57 patients were randomised to receive lubiprostone. Due mostly to patient dropout (i.e., loss to follow-up), complete data were available for 40 patients in each group. Compared with placebo group, 48-week lubiprostone treatment significantly reduced fat quantity (p = 0.04). Despite a significant reduction in body weight in the control group, no significant difference was found between both groups regarding fibrosis score by transient elastography or in serum ALT levels. One patient in the lubiprostone group developed severe diarrhoea requiring treatment stoppage. No other serious adverse events occurred. CONCLUSION:Lubiprostone was well tolerated and reduced liver fat content as measured by MRI-PDFF in patients with MASLD over 48 weeks. Lubiprostone appears promising to treat MASLD and warrants more extensive studies to confirm such efficacy. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05768334.

OBJECTIVE:Primary liver cancer (PLC) is projected to be the third leading cause of cancer mortality in the United States in 2040. We examine the burden of PLC in the United States, stratified by sex, state and aetiological risk factors. METHODS:Data on PLC prevalence, incidence, death and disability-adjusted life years (DALYs) were extracted from the Global Burden of Disease Study 2021. Changes in these parameters were calculated using the Joinpoint regression model. RESULTS:There were 47,970 cases, 31,450 incident cases, 24,770 deaths and 576,920 DALYs from PLC in the United States. The highest prevalence (16,980), incidence (12,040), death (9840) and DALYs (213,410) from PLC were due to chronic hepatitis C virus infection. From 2000 to 2021, PLC incidences increased by 141%, and PLC deaths increased by 136%. Age-standardised incidence rates (ASIRs) and death rates (ASDRs) per 100,000 population for PLC increased, primarily driven by alcohol-related liver disease (ALD) (ASIR: annual percent change [APC]: +2.40%; ASDR: APC: +2.22%) and metabolic dysfunction-associated steatotic liver disease (MASLD) (ASIR: APC: +2.32%; ASDR: APC: +2.04%). CONCLUSION:The burden of PLC in the United States has risen in the past two decades, driven mainly by ALD and followed by MASLD. These findings offer policymakers an accurate assessment of the PLC burden and emphasise the need for targeted risk factor mitigation, especially regarding alcohol related policy.

BACKGROUND AND AIMS:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated long-term liver benefits in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, no direct comparison between these therapies has been conducted. This study aimed to compare major adverse liver outcomes (MALOs) between GLP-1 RAs and SGLT2is in patients with MASLD and T2D. METHODS:Using the TriNetX Research Network, a multinational and multi-institutional database, we identified adults with MASLD and T2D who received their first prescription for either a GLP-1 RA or an SGLT2i between January 2010 and June 2023. We conducted a propensity score-matched (PSM) cohort study comparing new users of GLP-1 RAs and SGLT2is. The primary outcome was the risk of MALOs, a composite endpoint consisting of decompensated cirrhosis events, hepatocellular carcinoma, and liver transplantation. Secondary outcomes included all-cause mortality and individual components of the primary outcome. RESULTS:This study included 15,176 pairs of patients treated with either a GLP-1 RA or a SGLT2i. The adjusted hazard ratio (HR) for MALO associated with GLP-1 RAs relative to SGLT2is was 0.84 (95% confidence interval [CI]: 0.73-0.97; incidence rate: 88.9 versus 105.3 events per 10,000 person-years), primarily driven by reduction in decompensated cirrhosis events (adjusted HR: 0.83, 95% CI: 0.71-0.96). GLP-1 RAs were associated with lower all-cause mortality (adjusted HR: 0.84, 95% CI: 0.75-0.94). CONCLUSION:GLP-1 RAs are associated with better long-term liver outcomes compared to SGLT2is in patients with MASLD and T2D.

Our study investigated the prevalence of lean steatotic liver disease (SLD) and its subcategories, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-related and alcohol-related SLD (MetALD), and alcohol-related liver disease (ALD) among lean adults in the US. Analysing data from 2965 lean adults (≥ 18 years) from the National Health and Nutrition Examination Survey (2017-2023), we found the age-adjusted prevalence of lean SLD to be 12.8%. Specifically, the prevalence was 9.3% for lean MASLD, 1.3% for MetALD and 1.0% for ALD. Notably, within the MASLD group, significant fibrosis, advanced fibrosis, and cirrhosis were observed in 5.6%, 2.4% and 2.0%, respectively.

BACKGROUND:The current subclassification of steatotic liver disease (SLD) relies on validated questionnaires, such as Alcohol Use Disorders Identification Test (AUDIT) and Lifetime Drinking History (LDH), which, while useful, are impractical and lack precision for their use in routine clinical practice. Phosphatidylethanol (PEth) is a quantitative, objective alcohol biomarker with high sensitivity and specificity. AIMS:To assess the diagnostic accuracy of PEth for differentiating metabolic dysfunction and alcohol-associated liver disease (MetALD) from metabolic dysfunction-associated steatotic liver disease (MASLD) in a large, population-based, prospective, multiethnic cohort of individuals with overweight or obesity. METHODS:This is a cross-sectional analysis of a prospective study including 374 adults with overweight or obesity residing in Southern California who had SLD as defined by MRI-PDFF ≥ 5%. The clinical research visit included medical history, biochemical and PEth testing, standardised validated questionnaires (including AUDIT and LDH), physical examination, and advanced imaging using MRI-PDFF and MRE. RESULTS:Among 374 adults with SLD, the prevalence of MASLD, MetALD, and ALD was 90.1%, 6.4%, and 3.5%, respectively. PEth had a robust diagnostic accuracy in the detection of MetALD (AUROC 0.81, 95%CI 0.73-0.89) and the Youden cut-off was 25 ng/mL. In head-to-head comparative efficacy analysis, PEth was both statistically and clinically superior to all previously used indirect alcohol biomarkers for diagnosing MetALD, including aspartate aminotransferase/alanine aminotransferase ratio, mean corpuscular volume, gamma glutamyltransferase, and ALD/NAFLD index (p < 0.05). CONCLUSIONS:PEth outperforms previously used non-invasive tests in differentiating MetALD from MASLD and has the potential to change clinical practice by enhancing the subclassification of SLD.

BACKGROUND:Adherence to post-polypectomy surveillance is poor despite evidence that it is associated with lower risk of future colorectal cancer. METHODS:We evaluated 6,210 bowel screening participants between 2009-2016 in NHS Greater Glasgow and Clyde to assess potential barriers to post-polypectomy surveillance. RESULTS:Increasing deprivation (Scottish Index of Multiple Deprivation quintile 1 vs 5; OR 1.68; p < 0.001), and increasing comorbidity (Charlson Comorbidity Index 1-2 vs 3-4; OR 1.80; p < 0.001, vs ≥ 5; OR 3.31; p < 0.001), were associated with non-surveillance in British Society of Gastroenterology 2002 intermediate/high-risk patients, while ACE-Inhibitor (OR 0.78; p < 0.001) and aspirin use (OR 0.34; p < 0.001) were associated with undergoing surveillance. The most deprived patients receiving surveillance had more metachronous polyps (54.0% vs 49.3%) and cancer (1.1% vs 0.4%) (p = 0.044). DISCUSSION:Patients from more socioeconomically deprived areas are less likely to have appropriate post-polypectomy surveillance, and are more likely to have metachronous polyps and colorectal cancer even when they do. CONCLUSION:Surveillance strategies must take into account factors including socioeconomic deprivation and comorbidity exist to improve surveillance uptake in this group through the design of targeted interventions which move away from the current "one size fits all" approach.