Loomba, Rohit

Background: Accurate identification of patients with metabolic dysfunction–associated steatohepatitis (MASH) at risk of disease progression (at-risk MASH) is critical for guiding resmetirom and semaglutide therapy. Inconsistent definitions of at-risk MASH complicate clinical risk classification and comparisons across studies. This study aimed to standardize the definition of at-risk MASH and propose optimized MRE-based liver stiffness (LS-MRE) cutoffs to improve noninvasive risk stratification and better guide pharmacotherapy. Methods: In this prospective study, 413 patients with suspected or diagnosed MASLD from two medical centers underwent liver biopsy and MRE. Results: A simplified definition of at-risk MASH (MASH with fibrosis stage≥2) identified a broader group of patients requiring clinical attention than a stricter definition requiring NAFLD Activity Score≥4 with ≥1 point in steatosis, inflammation, and ballooning (n=122 vs. 77). LS-MRE alone showed the highest diagnostic accuracy for identifying at-risk MASH using the simplified definition (AUC 0.91 [0.87, 0.95]) and cirrhosis (AUC 0.93 [0.88, 0.99]), compared with FIB-4 and individual laboratory parameters (AST, ALT, and platelet count) ( p <0.01 for all, paired DeLong tests). Optimized LS-MRE cutoffs (2.8–6.4 kPa) captured 25 additional biopsy-proven pharmacotherapy candidates (28% of all eligible patients) compared to AASLD guidelines–recommended cutoffs (3.1–4.4 kPa), improving sensitivity (80% vs. 50%) with acceptable specificity (73% vs. 88%). Conclusions: A simplified definition of at-risk MASH enables broader identification of treatment candidates. LS-MRE demonstrates excellent diagnostic performance and improves noninvasive risk stratification when paired with optimized cutoffs. These findings support the use of MRE to guide resmetirom and semaglutide eligibility and improve access to emerging therapies.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Background and Aims: Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive liver disease that poses significant public health challenges. Although liver biopsy remains the gold standard for diagnostic and prognostic use in patients with MASH, its invasiveness limits its practical application in routine care and large-scale trials. This narrative review explores the growing role of noninvasive tests in the assessment of disease progression and treatment efficacy in MASH. Approach and Results: This review represents expert opinion synthesizing current literature on the most widely used noninvasive tests being assessed as frontline biomarkers for identification of patients with metabolic dysfunction–associated steatotic liver disease at risk of outcomes and/or in need of pharmacological intervention, and that are being used to assess treatment response in the context of clinical trials, and how they may be translated into clinical practice. Among these, elastography and the enhanced liver fibrosis test are highlighted for their potential to replace liver biopsy in clinical settings and trials. These methods are analyzed for their accuracy and ability to monitor therapeutic response, emphasizing their growing importance in providing reliable measures of clinical improvement as drug development efforts for MASH intensify. Conclusions: This synthetic review aims to provide a roadmap for federal regulators updating and potentially revising the requirements for demonstrating histologic improvement in MASH clinical trials, and for practitioners to translate this information into clinical practice. The ultimate goal is to reduce the reliance on liver biopsy while maintaining the rigor necessary to evaluate therapeutic efficacy, thus accelerating the path to approval for new MASH treatments.

Background and Aims: Clinical hepatology research often faces limited data availability, underrepresentation of minority groups, and complex data-sharing regulations. Synthetic data—artificially generated patient records designed to mirror real-world distributions—offers a potential solution. We hypothesized that diffusion models, a state-of-the-art generative technique, could produce synthetic liver transplant waitlist data from the United Network for Organ Sharing database that maintains statistical fidelity, replicates clinical correlations and survival patterns, and ensures robust privacy protection. Approach and Results: Diffusion models were used to generate synthetic patient cohorts mirroring the United Network for Organ Sharing liver transplant waitlist database between the years 2019 and 2023. Statistical fidelity was assessed using maximum mean discrepancy (MMD) and Wasserstein distance, correlation analysis, and variable-level metrics. Clinical utility was evaluated by comparing transplant-free survival via Kaplan–Meier curves and the MELD score performance. Privacy was quantified using the Distance to Closest Record (DCR) and attribute disclosure risk assessments. The synthetic dataset was nearly indistinguishable from the original dataset (MMD=0.002, standardized Wasserstein distance <1.0), preserving clinically relevant correlations and survival patterns as evidenced by similar median survival times (110 vs. 101 days) and 5-year survival rates (22.2% vs. 22.8%). MELD-based 90-day mortality prediction was maintained (original AUC=0.839 vs. synthetic AUC=0.844). Privacy metrics indicated no identifiable patient matches, and mean DCR values ensured that synthetic individuals were not direct replicas of real patients. Conclusion: Artificial intelligence–generated synthetic data derived from diffusion models can faithfully replicate complex hepatology datasets, maintain key clinical signals, and ensure strong privacy safeguards. This approach can help address data scarcity, enhance model generalizability, foster multi-institutional collaboration, and accelerate progress in hepatology research.

ABSTRACT Background The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity‐linked insulin resistance, glucose homeostasis, lipid metabolism and pro‐inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well‐being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non‐invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD‐related problem. Aim The aim of this article was to summarise the global burden of MASLD from the payer's perspective. Methods We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient‐reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively. Conclusion The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs. Trial Registration: NCT06309992

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

SummaryBackground & AimsThe natural progression of hepatic decompensation in metabolic dysfunction‐associated steatotic liver disease (MASLD) is not well‐characterised. We aimed to describe it by conducting a retrospective analysis.MethodsThis longitudinal, retrospective analysis of well‐characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver‐related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured.ResultsOf the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow‐up of 3.2 years. Ascites was the most common first liver‐related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver‐related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy‐three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years.ConclusionThe most common first liver‐related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years.

SummaryBackgroundProgression to cirrhosis in non‐alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH‐related significant fibrosis and cirrhosis is unclear.AimTo investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH‐related significant fibrosis and cirrhosis.MethodsIn this meta‐analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI‐derived protein density fat fraction (MRI‐PDFF) were enrolled, and 296 patients with longitudinal follow‐up were analysed. MRE combined with fibrosis‐4 (MEFIB‐index), and MRI‐PDFF were used to measure liver fibrosis and fat, respectively. MEFIB‐negative, MEFIB‐positive+ MRI‐PDFF ≥5% and MEFIB‐positive+ MRI‐PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death.ResultsThe rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB‐negative) group (0%, 1% and 2% respectively). In multivariable‐adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5–235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings.ConclusionsLow liver fat content in patients with burnt‐out NASH‐related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality.

Summary Background There are limited data regarding the longitudinal association between MEFIB‐Index (MRE combined with FIB‐4) versus MAST‐Score (MRI‐aspartate aminotransferase) and hepatic decompensation. Aim To examine the longitudinal association between MEFIB‐Index versus MAST‐Score in predicting hepatic decompensation in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI‐PDFF and were followed for hepatic decompensation. Cox‐proportional hazard analyses were used to assess the association between MEFIB‐Index versus MAST‐Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment. Results This meta‐analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB‐Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST‐Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow‐up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB‐Index [HR = 49.22 (95% CI: 6.23–388.64, p < 0.001)] and a positive MAST‐Score [HR = 3.86 (95% CI: 1.46–10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB‐Index ( c ‐statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST‐Score ( c ‐statistic: 0.81, SE = 0.03) ( p < 0.0001) in predicting hepatic decompensation. Conclusion A combination of MRI‐based biomarker and blood tests, MEFIB‐Index and MAST‐Score can predict the risk of hepatic decompensation in patients with MASLD.