Search

Abstract Background The collagen-rich tumor stroma plays a crucial role in biliary tract cancer (BTC). Collagen biomarkers of type I collagen (reC1M), type III collagen (PRO-C3), type IV collagen (C4G), type VIII collagen (PRO-C8), type XI collagen (PRO-C11), type XVII collagen (PRO-C17) and type VIII collagen (TUM) may be used as potential non-invasive biomarkers. Methods We measured the seven biomarkers of collagen turnover in sera of 72 patients with BTC at baseline and after first and second chemotherapy cycle (CTX). Markers were also assessed in sera of 50 healthy controls and compared to levels of patients at baseline. The diagnostic and prognostic value of the markers was evaluated for overall survival (OS) and progression-free survival (PFS). Results Patients had a median age of 65 years (IQR 57–70), while healthy controls were younger, with a median age of 46 years (IQR 38–54). The majority of patients (62%) were diagnosed with intrahepatic bile duct adenocarcinoma. Except C4G, all collagen turnover markers were significantly (p

Abstract A major histologic feature of cirrhosis is the loss of liver architecture with collapse of tissue and vascular changes per unit. We developed qVessel to quantify the arterial density (AD) in liver biopsies with chronic disease of varied etiology and stage. 46 needle liver biopsy samples with chronic hepatitis B (CHB), 48 with primary biliary cholangitis (PBC) and 43 with metabolic dysfunction-associated steatotic liver disease (MASLD) were collected at the Shuguang Hospital. The METAVIR system was used to assess stage. The second harmonic generation (SHG)/two-photon images were generated from unstained slides. Collagen proportionate area (CPA) using SHG. AD was counted using qVessel (previously trained on manually labeled vessels by stained slides (CD34/a-SMA/CK19) and developed by a decision tree algorithm). As liver fibrosis progressed from F1 to F4, we observed that both AD and CPA gradually increases among the three etiologies (P 0.05). AD and CPA performed similar diagnostic efficacy in liver cirrhosis (P > 0.05). Using the qVessel algorithm, we discovered a significant correlation between AD, CPA and METAVIR stages in all three etiologies. This suggests that AD could underpin a novel staging system.

Achim Fieß,1,* Sandra Gißler,1,* Stephanie Grabitz,1 Philipp S Wild,2– 5 Karl J Lackner,6 Manfred E Beutel,7 Michael S Urschitz,8 Oliver Tüscher,5,9,10 Thomas Münzel,11 Jörn M Schattenberg,12,13 Stavros V Konstantinides,2,14 Norbert Pfeiffer,1 Alexander K Schuster1 1Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 2Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; 3German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany; 4Preventive Cardiology and Preventive Medicine-Department of Cardiology, University Medical Center Mainz, Mainz, Germany; 5Institute of Molecular Biology (IMB), Mainz, Germany; 6Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; 7Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 8Division of Pediatric Epidemiology, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 9Clinic for Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; 10Leibniz Institute for Resilience Research, Mainz, Germany; 11Center for Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; 12Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany; 13Department of Internal Medicine I, University Medical Center, Mainz, Germany; 14Department of Cardiology, Democritus University of Thrace, Alexandroupolis, 68100, Greece*These authors contributed equally to this workCorrespondence: Achim Fieß, Department of Ophthalmology, Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr 1, Mainz, 55131, Germany, Tel +49-(0)6131-17-5150, Fax +49-(0)6131-17-8495, Email achim.fiess@gmail.comAbstract: This study investigates the association between self-reported birth weight (BW) and the frequency of cataract and pseudophakia in a large population-based cohort in Germany, as part of the Gutenberg Health Study (GHS). Slit lamp examination and Scheimpflug imaging of 8205 participants, aged 35 to 74, were assessed and signs of cataract or pseudophakia analyzed. The research aimed to explore the correlation between fetal growth restriction and/or prematurity indicated by BW and the frequency of cataract and pseudophakia. In the univariable analysis, cataract was initially associated with low and high BW, but this association disappeared after adjusting for age, sex, examiner and cardiovascular risk factors. No association was found between low BW and pseudophakia or the frequency of cataract surgery within 5 years. The study reveals novel insights from a large population-based study specifically exploring this association.Keywords: Cataract, pseudophakia, birth weight, epidemiology, population-based study

BackgroundNon-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver-targeted thyroid hormone receptor-β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo.AimsTo present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO-NAFLD-1 [NCT04197479], MAESTRO-NAFLD-OLE [NCT04951219], MAESTRO-NASH [NCT03900429], MAESTRO-NASH-OUTCOMES [NCT05500222]).MethodsMAESTRO-NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy-confirmed at-risk NASH. Patients are randomised to a once-daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO-NAFLD-1 is a 52-week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non-invasive testing); ~700 patients from MAESTRO-NAFLD-1 are enrolled in MAESTRO-NAFLD-OLE, a 52-week active treatment extension to further evaluate safety. MAESTRO-NASH-OUTCOMES is enrolling 700 adults with well-compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non-invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient-reported outcomes.ConclusionThe MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long-term clinical liver-related outcomes in MAESTRO-NASH (month 54) and MAESTRO-NASH-OUTCOMES (time to event).

Background & aimsPatients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers.MethodsMembers of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey.ResultsSurveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%).ConclusionsThe perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties.Impact and implicationsOver the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR 140 ), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR 140 + CVC), or TXR 90 μg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Background & Aims: This study used the Global Burden of Disease data (2010–2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries. Methods: Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI). Results: Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5–16,361.4), annual incidence rates were 608.5 cases (598.8–617.7), and YLDs were 0.5 (0.3–0.8) years. MASLD point prevalence was higher in men than women (15,731.4 vs. 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45–49 for men and 50–54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1–34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5–34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5–33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%–18.9%), Sudan (13.3%, 95% UI 9.8%–16.7%) and India (13.2%, 95% UI 12.0%–14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels. Conclusions: MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing. Impact and implications: This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study’s reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.

Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1–6 HCC cells, with a subgroup pre-treated with CCl4 to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1–6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model’s suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing.

Introduction and Objectives: Patients increasingly use social media to share and access health-related information and experiences. This study employed social media listening to gain patient-centric insights into metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). Materials and Method: Publicly available social media data was collected between November 4th, 2020, and November 4th, 2022, about MASLD from eight countries: Brazil, China, France, Germany, Japan, South Korea, Spain, and the United Kingdom. The analysis involved capturing patient conversations on their journey stages (causes-risk factors, symptoms, diagnosis, and treatment), unmet needs, and impact on patient's quality of life (QoL) from various social media platforms to gain insights associated with MASLD. Results: A total of 1600 patient-centric posts were analyzed. The patient journey was the most prevalent topic (92 %) mentioned, followed by comorbidities (38 %) and interactions with HCPs (26 %, health care professionals). Key causes discussed included unhealthy diet (39 %) and overweight/obese (32 %), while the most mentioned symptoms were fatigue (20 %) and pain or abdominal discomfort (20 %). Ultrasound (n=170/553, 31 %) was the most used diagnosis, followed by blood tests (n=130/553, 24 %) and liver function tests (n=91/553, 16 %). Lifestyle management techniques were mainly the standard of care, followed by treatment (n=270/1061, 25 %) and follow-ups with HCPs (n=133/1061, 13 %). Over half (54 %) of the QoL discussion (n=104/192) focused on patients’ comorbidities, and 27 % on disease severity, indicating that having MASLD in moderate to severe form with comorbidities significantly affects patients’ quality of life. An emotional analysis revealed that patients were worried and frustrated about their condition but were also hopeful and determined to improve their health. Nearly 38 % of the posts mentioned that patients were emotionally affected by negative feelings, especially those with multiple comorbidities. Lack of access to knowledgeable HCPs and treatment options were the most frequently discussed unmet needs. Conclusions: This analysis of NAFLD patient experiences introduces a unique approach for deriving insights into patients' experiences and their impact on QoL. These insights have the potential to complement conventional methods and foster patient-centric research.

Summary: Background: The liver–heart axis potentially influences the risk of mortality in patients with heart failure. We aimed to identify the clinical utility of the fibrosis-4 (FIB-4) index in patients with heart failure for predicting mortality in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Patients with heart failure and a subsample of healthy participants were enrolled in the MyoVasc study (NCT04064450) and followed for nine years. Participants with excessive alcohol consumption were excluded. The Fatty Liver Index (FLI) and FIB-4 index were used to classify MASLD and hepatic fibrosis, respectively. Data were adjusted for potential confounders. The primary endpoint was all-cause mortality. Findings: 2726 participants, including 172 healthy individuals, were included in the study. The participants had a mean age of 64.4 ± 11.2 years and a median FIB-4 index of 1.59 (interquartile range [1.17; 2.17]). There were 532 deaths. The FIB-4 index was predictive for all-cause mortality (hazard ratio (HR) 1.341, 95% confidence interval (CI) [1.273; 1.412], p

BackgroundPatients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. We investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis.MethodsThis double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centres in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2·4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is closed and completed, and registered with ClinicalTrials.gov, number NCT03987451.Findings71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 (69%) patients were female and 22 (31%) were male. Patients had a mean age of 59·5 years (SD 8·0) and mean BMI of 34·9 kg/m2 (SD 5·9); 53 (75%) patients had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p=0·29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (six [13%] vs two [8%]). The most common adverse events were nausea (21 [45%] vs four [17%]), diarrhoea (nine [19%] vs two [8%]), and vomiting (eight [17%] vs none). Hepatic and renal function remained stable. There were no decompensating events or deaths.InterpretationIn patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised.FundingNovo Nordisk A/S.

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear. Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics. Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p

Background & aimsNon-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings.MethodsA survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas.ResultsThere were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of 7.5 to >20 kPa, respectively).ConclusionsThe cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management.Lay summaryOwing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Non-invasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

Background and Aims: There is a high unmet need to develop noninvasive tools to identify nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients at risk of fast progression to end-stage liver disease (ESLD). This study describes the development of a machine learning (ML) model using data around the first clinical evidence of NAFLD/NASH to identify patients at risk of future fast progression. Methods: Adult patients with ESLD (cirrhosis or hepatocellular carcinoma) due to NAFLD/NASH were identified in Optum electronic health records (2007–2018 period). Patients were stratified into fast (0.5 and 3 years) and standard progressor (6–10 years) cohorts based on retrospectively established progression time between ESLD and the earliest observable disease, and characteristics were reported using descriptive statistics. Two ML models predicting fast progression were created, performance was compared, and top predictive features from the final model were compared between cohorts. Results: Among a total of 4013 NAFLD patients with cirrhosis or hepatocellular carcinoma (mean age 58.6 ± 12.5; 65% female), 24% were fast (n = 951) and 25% standard (n = 992) progressors that were used for modeling. The cohorts were comparable for gender, body mass index, type 2 diabetes, and arterial hypertension, but differed significantly for obesity, hyperlipidemia, and age at index. The final model (NASH FASTmap) is a 44 feature light gradient boosting model which performed better (area under the curve [0.77], F1-score [0.74], accuracy [0.71], and precision [0.71]) than eXtreme gradient boosting model to predict fast progression. Conclusion: Future fast progression to ESLD in NAFLD/NASH patients can be predicted from clinical data using ML. Electronic health record implementation of NASH FASTmap could support clinical assessment for risk stratification and potentially improve disease management.

Abstract Background Spleen stiffness measurement (SSM) performed by transient elastography at 100 Hz is a novel technology for the evaluation of portal hypertension in advanced chronic liver disease, but technical aspects are lacking. We aimed to evaluate the intraexamination variability of SSM and to determine the best transient elastography protocol for obtaining robust measurements to be used in clinical practice. Methods We analyzed 253 SSM exams with up to 20 scans for each examination, performed between April 2021 and June 2022. All SSM results were evaluated according to different protocols by dividing data into groups of n measurements (from 2 to 19). Considering as reference the median SSM values across all the 20 measurements, we calculated the distribution of the absolute deviations of each protocol from the reference median. This analysis was repeated 1,000 times by resampling the data. Distributions were also stratified by etiology (chronic liver disease versus clinically significant portal hypertension) and different SSM ranges: 75 kPa. Results Overall, we observed that the spleen stiffness exam had less variability if it exceeded 12 measurements, i.e., absolute deviations ≤ 5 kPa at 95% confidence. For exams with higher SSM values (> 75 kPa), as seen in clinically significant portal hypertension, at least 15 measurements are highly recommendable. Conclusions Fifteen scans per examination should be considered for each SSM exam performed at 100 Hz to achieve a low intraexamination variability within a reasonable time in clinical practice. Relevance statement Performing at least 15 scans per examination is recommended for 100 Hz SSM in order to achieve a low intraexamination variability, in particular for values > 75 kPa compatible with clinically significant portal hypertension. Key points • Spleen stiffness measurement by transient elastography is used for stratification in patients with portal hypertension. • At 100 Hz, this method may have intraexamination variability. • A minimum of 15 scans per examination achieves a low intraexamination variability. Graphical Abstract

Abstract Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg (n = 16), 3 mg (n = 16), 6 mg (n = 17), 10 mg (n = 32) or placebo (n = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks’ treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo; n = 32), 26.5% (1 mg; n = 16), 10.4% (3 mg; n = 16), 5.0% (6 mg; n = 16), 3.3% (10 mg; n = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition (

Background and aimsElectronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.Approach and resultsResearchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.ConclusionsThis expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.