Background: The rs738409 C>G polymorphism in the PNPLA3 gene (I148M variant) is the strongest genetic risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Previous meta-analyses have either focused on cross-sectional associations or included mixed steatotic liver disease populations. The impact of PNPLA3 polymorphisms on longitudinal clinical outcomes specifically in MASLD remains incompletely characterized.Methods: We systematically searched observational cohort studies published up to September 2025, evaluating the impact of PNPLA3 rs738409 polymorphism on clinical outcomes in individuals with MASLD. The primary outcome was liver-related events, while secondary outcomes included hepatocellular carcinoma (HCC), liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We compared outcomes between homozygous risk allele carriers (GG genotype) versus wild-type homozygous individuals (CC genotype), and heterozygous carriers (CG genotype) versus CC genotype. The study was registered on PROSPERO (CRD420251176886).Results: Twenty-one cohort studies involving 232,033 individuals with MASLD were analyzed (132,334 with CC genotype, 84,091 with CG genotype, and 15,608 with GG genotype). Over a median follow-up of 7.2 years, individuals with GG genotype had significantly higher risks of liver-related events (HR 2.87, 95% CI 1.92-4.27, p<0.01; I²=66%) and HCC (HR 2.54, 95% CI 1.86-3.47, p<0.01; I²=0%) compared to those with CC genotype. Heterozygous carriers also demonstrated elevated risk of liver-related events (HR 1.57, 95% CI 1.12-2.19, p<0.01; I²=62%) but not HCC (HR 1.15, 95% CI 0.89-1.48, p=0.53; I²=0%). Conversely, PNPLA3 polymorphisms did not influence cardiovascular events (GG vs CC: HR 0.94, 95% CI 0.74-1.19, p=0.44; CG vs CC: HR 1.02, 95% CI 0.90-1.15, p=0.99), extrahepatic cancers (GG vs CC: HR 0.96, 95% CI 0.67-1.37, p=0.95; CG vs CC: HR 0.83, 95% CI 0.64-1.09, p=0.13), or all-cause mortality (GG vs CC: HR 1.19, 95% CI 0.97-1.45, p=0.78; CG vs CC: HR 1.05, 95% CI 0.90-1.22, p=0.75).Conclusions: PNPLA3 I148M polymorphism confers a substantial, dose-dependent increase in liver-related events and HCC risk in MASLD, with homozygous carriers showing the highest risk. However, this genetic variant does not influence cardiovascular events, extrahepatic cancers, or overall mortality, indicating liver-specific pathogenic effects. These findings support incorporating PNPLA3 genotyping into risk stratification strategies for MASLD management, particularly for identifying individuals who may benefit from enhanced hepatocellular carcinoma surveillance and aggressive treatment to prevent disease progression.

BACKGROUND & AIMS:The availability of new drugs for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) underlines the need of early predictors of response to such therapies. This study evaluated the impact of 1-year changes in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), controlled attenuation parameters (CAP), and serum alanine aminotransferase (ALT) on liver outcomes in patients with MASLD. METHODS:A large multicenter cohort of MASLD patients with LSM ≥8 kPa and prospective follow-up was enrolled. Liver-related events (LREs), including hepatocellular carcinoma (HCC) and liver decompensation (LD), were evaluated during follow-up. LSM, CAP, ALT, and Fibrosis-4 Index (FIB-4) were assessed at baseline and at 1-year follow-up. Cause-specific Cox regression analyses were performed to correlate 1-year variation in LSM, CAP, ALT, and FIB-4 with the risk of developing LRE, LD, and HCC, in terms of cause-specific hazard ratios (csHRs). RESULTS:We included 1744 patients with LSM ≥8 kPa (median age, 55 years; 52.1% male; 58.3% obese; 55.8% with diabetes) and 989 with LSM ≥10 kPa (median age, 56 years; 50.2% male; 54.7% obese; 51% with diabetes), followed for a median of 28.2 and 32 months, respectively. LREs occurred in 39 patients with LSM ≥8 kPa (26 LD, 22 HCC) and in 35 with LSM ≥10 kPa (25 LD, 19 HCC). A 1-year variation in LSM, but not in CAP, ALT, or FIB-4, was independently associated with LRE in patients with MASLD and LSM ≥8 kPa (csHR, 1.007; 95% confidence interval [CI], 1.001-1.014). Likewise, 1-year LSM variation (csHR, 1.009; 95% CI, 1.000-1.018) independently predicted LD in this population, whereas no 1-year changes in CAP, ALT, or FIB-4 were associated with LD risk. No independent associations were observed between 1-year changes in LSM, CAP, ALT, or FIB-4 and the risk of HCC. All findings were confirmed in patients with LSM ≥10 kPa and in those at high risk of progression with type 2 diabetes. CONCLUSIONS:In patients with MASLD and LSM ≥8 or ≥10 kPa, the % LSM reduction at 1 year was independently associated with lower risk of LRE and LD.

Background & Aims The rs738409C>G polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3 I148M variant) contributes to the largest fraction of metabolic dysfunction-associated steatotic liver disease (MASLD) heritability. However, its prognostic impact on long-term clinical outcomes related to MASLD remains incompletely characterized. We performed a meta-analysis of observational studies to quantify the impact of PNPLA3 polymorphisms on the risk of developing hepatic and extrahepatic outcomes in MASLD. Methods We systematically searched PubMed, Scopus, and Cochrane Central for observational studies evaluating PNPLA3 polymorphisms and clinical outcomes in MASLD. The primary outcome was liver-related events (LREs); secondary outcomes included new-onset hepatocellular carcinoma (HCC), liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We compared homozygous risk-allele carriers (GG) and heterozygous carriers (CG) with wild-type homozygous (CC) individuals using random-effects genotypic models. The study was registered on PROSPERO (CRD#420251176886). Results Twenty-one observational longitudinal studies, including 232,033 adult individuals with MASLD (median follow-up: 7.2 years), were analysed. Individuals with the GG genotype had significantly higher risks of incident LREs (hazard ratio [HR] 2.87, 95% CI 1.92–4.27) and HCC (HR 2.54, 95% CI 1.86-3.47) compared with the CC genotype. CG carriers also had an increased risk of LREs (HR 1.57, 95% CI 1.12–2.19), but not of HCC. PNPLA3 genotypes were not associated with the risk of major cardiovascular events, extrahepatic cancers, or all-cause mortality. Conclusions The PNPLA3 I148M polymorphism confers dose-dependent increases in LRE and HCC risk in MASLD, with liver-specific rather than systemic effects. These findings suggest that PNPLA3 genotyping may inform risk stratification strategies in MASLD, particularly for identifying individuals at higher risk of LREs and HCC who might benefit from closer monitoring. Impact and implications International consensus has prioritised patient education and awareness as a key research domain in MASLD, yet quantitative evidence from patients with an established diagnosis remains scarce, particularly in Europe. In 460 Italian adults with physician-diagnosed MASLD we found pervasive knowledge gaps - including the failure to recognise diabetes as a risk factor and the belief that normal transaminases exclude progressive disease - a wide gap between lifestyle counselling and actual adherence, largely self-prescribed supplement use, partly guideline-discordant pharmacotherapy, and educational attainment as the principal determinant of every cognitive domain. These results are relevant to hepatologists, primary care physicians, patient associations and policymakers, because such misconceptions may delay referral, weaken adherence, and hinder equitable access to newly available therapies such as resmetirom and incretin-based agents. The validated five-domain instrument provides a reproducible tool to profile patients, tailor education to health literacy level and monitor its effect; however, since participants were recruited through a patient association and reported data themselves without fibrosis staging, these estimates probably represent a best-case scenario of awareness and require confirmation in unselected clinical cohorts.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) are two separate entities within the spectrum of steatotic liver disease. We aimed to compare the risks of hepatic and extrahepatic outcomes between individuals with MASLD and MetALD in a comprehensive meta-analysis. METHODS:In this systematic review and meta-analysis, we systematically searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials for observational cohort studies published up to March 1, 2025, and written in English. We included studies comparing clinical outcomes between adults (>18 years) with MASLD and MetALD, if the studies incorporated appropriate statistical adjustments for known risk factors and potential confounding factors. We excluded studies that did not differentiate between MASLD and MetALD, case reports, case series, commentaries, cross-sectional or case-control studies. We evaluated each study to assess its eligibility and extracted the data. The primary outcome was liver-related events; secondary outcomes included hepatocellular carcinoma, liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We used random-effect models to calculate pooled hazard ratios (HRs) with 95% CIs. The study was registered with PROSPERO (CRD420251003928). FINDINGS:Of 5579 records identified, we included 24 cohort studies involving 11 575 558 individuals in the analysis. 9 801 312 individuals had MASLD (mean age 57·0 years [SD 4·55], ~62% male, and ~38% female) and 1 774 246 had MetALD (mean age 48·6 years [SD 4·91], ~82% male, and ~18% female). Individuals with MetALD had significantly higher risks of liver-related events (HR 1·62, 95% CI 1·16-2·25; p=0·0086), hepatocellular carcinoma (1·33, 1·00-1·77; p=0·048), and extrahepatic cancers (1·03, 1·01-1·06; p<0·0001) compared with those with MASLD. The rates of cardiovascular events (HR 0·96, 95% CI 0·85-1·09; p=0·48), extrahepatic cancer-related mortality (1·44, 0·97-2·15; p=0·065), and all-cause mortality (1·08, 0·97-1·19; p=0·14) did not differ between the two liver conditions. Substantial heterogeneity was observed across most analyses (I2=76-93%), with only extrahepatic cancer incidence showing low heterogeneity (I2=0%). Egger's regression tests suggested that publication bias was unlikely for all outcomes except extrahepatic cancer-related mortality. INTERPRETATION:MetALD might be associated with a higher risk of liver-related events, hepatocellular carcinoma, and extrahepatic cancers than MASLD, whereas all-cause mortality, extrahepatic cancer-related mortality, and cardiovascular events seem similar between the two conditions. These findings emphasise the need for distinct clinical strategies for these related yet different entities within the steatotic liver disease spectrum and highlight the importance of conducting pharmacological clinical trials in this context. FUNDING:The Italian Ministry of Education, University, and Research (MIUR).

BACKGROUND & AIMS:First and further decompensation events mark key transitions in the natural history of cirrhosis and significantly influence mortality risk. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS:We conducted an international, multicenter (17 centers), retrospective study involving 6,061 consecutive patients with cACLD due to MASLD, diagnosed either clinically (liver stiffness measurement >10 kPa) or histologically (F3-F4 fibrosis). Decompensation events were defined according to the Baveno VII criteria. Cumulative incidence functions and cause-specific Cox models (with baseline and time-dependent variables) were used to analyze competing risks. A multistate model was developed to better describe the clinical trajectory of cACLD due to MASLD. RESULTS:The 5-year cumulative incidence of first decompensation was 3.5% (95% CI 3.0-4.1), which was associated with an 18.9-fold increase (95% CI 10.8-32.9) in the cause-specific hazard of LR-D. Among patients who experienced a first decompensation, the 5-year cumulative incidence of further decompensation was 43.9% (95% CI 37.2-50.2), further increasing the hazard of LR-D by 1.52-fold (95% CI 1.02-2.34). Ascites, followed by variceal bleeding, were the most common decompensation events. Hepatocellular carcinoma independently increased the cause-specific hazard of LR-D by 2.95-fold (95% CI 2.02-4.31) in the overall cohort and by 1.43-fold (95% CI 1.03-2.00) in patients who had experienced a first decompensation. CONCLUSIONS:First and subsequent decompensation events are major inflection points in the clinical progression of cACLD due to MASLD, increasing the cause-specific hazard of LR-D by 18.9- and an additional 1.52-fold, respectively. Hepatocellular carcinoma is an independent predictor of LR-D and further exacerbates mortality risk when present alongside decompensation. IMPACT AND IMPLICATIONS:In this large international multicenter cohort of 6,061 patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD), we examined the clinical impact of first and further decompensation events. At 5 years, the cumulative incidences of first and further decompensation were 3.5% and 43.9%, respectively, each significantly increasing the cause-specific hazard of liver-related death (18.9-fold and 1.52-fold). Ascites, more so than variceal bleeding, was the predominant and most impactful event. Both acute and non-acute decompensation similarly contributed to liver-related mortality. Additionally, hepatocellular carcinoma independently increased the hazard of liver-related death, even post-decompensation. Notably, extrahepatic deaths also represented a considerable burden, reflecting the high metabolic risk of MASLD. These findings highlight key prognostic inflection points in MASLD-related cACLD.

Background and AimThe MAESTRO-NASH phase 3 trial reported that a 52-week treatment of Resmetirom is effective in improving fibrosis and metabolic dysfunction-associated steatohepatitis (MASH) in patients with MASH and F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis and the effect of Resmetirom treatment on clinical outcomes.MethodsA meta-analysis of literature data formed transition matrices for fibrosis stages and complications, defined as compensated (CC) and decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and mortality-liver-related mortality (LR-M), cardiovascular mortality (CV-M) and extra-hepatic cancer mortality (EHC-M). Markov model was developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of Resmetirom treatment on the natural history of MASLD.ResultsWe estimated the 5-year probability of Resmetirom-treated and untreated MASLD patients with baseline F2 fibrosis of developing CC (5.16% vs. 6.82%, respectively), DC (0.25% vs. 0.3%, respectively), HCC (0.25% vs. 0.32%, respectively) and mortality (0.15% vs. 0.16% for LR-M; 1.02% vs. 1.1% for CV-M; 1.07% vs. 1.2% for EHC-M, respectively). Similarly, we estimated the five-year probability of Resmetirom-treated and untreated MASLD patients with baseline F3 fibrosis of developing CC (17.12% vs. 21.34%, respectively), DC(1.1% vs. 1.47%, respectively), HCC (1.21% vs. 1.73%, respectively) and mortality (0.59% vs. 0.91% for LR-M, 1.92% vs. 2.14% for CV-M and 1.04% vs. 1.14% for EHC-M, respectively). Life Years Gained (LYG) of Resmetirom-treated patients were 0.45 and 0.63 in MASLD patients with F2 and F3 fibrosis, respectively, and the model was sensitive to changes in Resmetirom efficacy and transition probabilities.ConclusionsResmetirom decreases the 5-year and lifetime Markov-model estimated risk of CC, DC, HCC and liver-related mortality in patients with MASLD and F2 or F3 fibrosis.

BACKGROUND & AIMS:The reference for risk stratification and clinical trial selection of metabolic dysfunction-associated steatotic liver disease (MASLD) patients is fibrosis degree by histology. The noninvasive ANTICIPATE-NASH models have been validated for risk prediction of clinically significant portal hypertension (CSPH) and liver-related events (LRE). We assessed whether these models provide better risk stratification of events than histology. METHODS:A multicenter cohort 1, including 699 biopsy specimen-proven F3-F4 patients with MASLD was evaluated. The end point was LRE (hepatic decompensation, hepatocellular carcinoma, transplantation, or liver-related death). We assessed (Cox regression) whether histology provided added value to ANTICIPATE-NASH and whether model predictions differed in F3/F4 patients. Results were validated in cohort 2 (1396 F3-F4 patients) from 4 clinical trials using the clinical regulatory end point. RESULTS:In cohort 1, F3 and F4 were equally distributed. There were 56 LREs (8.0%) during follow-up, concentrated in F4 (51 LREs). The ANTICIPATE-NASH model showed excellent discrimination (C statistic, 0.93) for LRE, higher than histology (C statistic, 0.67). Model calibration was excellent. Adding histology did not improve model prediction. Thresholds of ANTICIPATE-NASH above which F3 patients developed LREs and below which F4 patients did not were identified. Results were reproduced in cohort 2 with the regulatory end point, with higher model discrimination (C statistic, 0.84) compared with histology (C statistic, 0.64). CONCLUSIONS:In MASLD patients with F3/F4, the noninvasive ANTICIPATE-NASH models provide better risk stratification of clinical events than histologic classification. These models could be very useful for clinical trials by selecting patients at risk of clinical events and patients with higher chances of observed cirrhosis regression.

BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) currently stands as one of the foremost global health challenges, with a prevalence of 38% worldwide according to the most recent estimates [1] and with a concerning upward trend due to the parallel anticipated increasing of Diabetes and Obesity epidemic in the coming years [2]. There is a long-standing agreement that the first decompensation - defined as ascites, hepatic encephalopathy (HE), variceal bleeding, and jaundice- appears the pivotal event for patients’ prognosis and marks the transition from the compensated, also known as compensated advanced chronic liver disease (cACLD), to the decompensated stage of cirrhosis [3]. Although only a small fraction of patients dies following the first decompensation episode, the risk of developing further decompensation increases and the median survival dramatically decreases [4]. The occurrence of a further decompensation event - defined according to the Baveno VII Consensus [5] as either the recurrence of the initial event or the development of a second decompensation event - represents a crucial turning point in the natural history of the liver disease, markedly increasing the risk of liver-related death (LR-D) in those patients. AIM We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on LR-D in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS International multicenter retrospective study (17 centers) on 6,061 consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD. First and further decompensation were defined according to Baveno VII criteria. Competing risk analyses estimated the cumulative incidence of first and further decompensations, treating liver-related death (LR-D), extra-hepatic death (EH-D), and liver transplantation (LT) as competing events. Cumulative Incidence Functions (CIFs) were compared using Gray’s test and stratified by decompensation type and cause of death. Time-to-event analyses were anchored at cACLD diagnosis (first decompensation) and at first decompensation (subsequent events), with 5-year CIFs reported. Cause-specific Cox models with time-dependent covariates assessed the impact of decompensations and HCC on LR-D. Multivariable models included age, sex, diabetes, and liver function markers when available. A seven-state multistate model estimated transitions from cACLD to better assess the clinical course of cACLD due to MASLD. Analyses were conducted in R (v4.3.3) using cmprsk, mstate, and related packages. RESULTS The cumulative incidence of the first decompensation was 3.5% (95% C.I 3.0-4.1) at 5 years, increasing 19-fold the risk of LR-D using Cox analysis (Figure 1A); the cumulative incidence of further decompensation was 43.9% (95% C.I 37.2-50.2) at 5 years among patients with first decompensation (Figure 1A), additionally increasing 1.5-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D by 3- and 1.4-fold in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation, respectively. CONCLUSIONS The first and further decompensations represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 19-times and additionally 1.5-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation.

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising effects on liver histology in phase 2 trials enrolling patients with metabolic dysfunction-associated steatotic liver disease. However, the impact of GLP-1RAs on the long-term risk of major adverse liver-related outcomes (MALOs) remains uncertain.ObjectiveWe performed a meta-analysis of observational cohort studies to quantify the magnitude and direction of the association between GLP-1RA use and MALOs in people with type 2 diabetes (T2D).DesignWe systematically searched eligible cohort studies comparing GLP-1RA new users versus users of other glucose-lowering medications. The primary outcome was the cumulative incidence rates of MALOs. Secondary outcomes included hepatic decompensation events, hepatocellular carcinoma (HCC) and liver-related mortality. Random-effects models were used to calculate incidence rate ratios (IRRs).Results11 retrospective cohort studies with aggregate data on 1 467 220 patients with T2D (647 903 GLP-1RA new users, 819 317 non-users) were included. GLP-1RA use was significantly associated with a lower risk of MALOs (IRR 0.71, 95% CI 0.57 to 0.88) and hepatic decompensation (IRR 0.70, 95% CI 0.52 to 0.94). Association with reduced risk of HCC was also observed (IRR 0.82, 95% CI 0.61 to 1.11). Compared with other antidiabetic medications, GLP-1RAs showed superior effectiveness versus SGLT2 inhibitors in preventing MALOs (IRR 0.93, 95% CI 0.87 to 0.99), versus DPP-4 inhibitors in preventing hepatic decompensation (IRR 0.74, 95% CI 0.66 to 0.83) and versus insulin therapy in preventing HCC (IRR 0.32, 95% CI 0.13 to 0.80).ConclusionsGLP-1RA use is associated with a lower risk of liver-related complications and hepatic decompensation in people with T2D. These findings suggest a role of GLP-1RAs in preventing liver-related complications beyond their beneficial cardiometabolic effects.

Metabolic dysfunction-associated steatotic liver disease (MASLD), with its steadily increasing prevalence, represents now a major problem in public health. A proper referral could benefit from tools allowing more precise risk stratification. To this end, in recent decades, several genetic variants that may help predict and refine the risk of development and progression of MASLD have been investigated. In this review, we aim to discuss the role genetics in MASLD plays in everyday clinical practice. We performed a comprehensive literature search of PubMed for relevant publications. Available evidence highlights the emergence of genetic-based noninvasive algorithms for diagnosing fatty liver, metabolic dysfunction-associated steatohepatitis, fibrosis progression and occurrence of liver-related outcomes including hepatocellular carcinoma. Nevertheless, their accuracy is not optimal and application in everyday clinical practice remains challenging. Furthermore, susceptible genetic markers have recently become subjects of great scientific interest as therapeutic targets in precision medicine. In conclusion, decisional algorithms based on genetic testing in MASLD to facilitate the clinician decisions on management and treatment are under growing investigation and could benefit from artificial intelligence methodology. image

Background and Aims: International regulatory agencies recommend testing drug therapy for patients with noncirrhotic high-risk metabolic dysfunction-associated steatohepatitis (MASH) because they are at risk of liver-related events (LRE). We aimed to compare the risk of LRE in patients with MASLD stratified for F2-F4 fibrosis and MASH. Approach and Results: Overall, 1938 consecutive patients with biopsy-proven MASLD were enrolled. High-risk MASH was defined as MASH with F2-F4 fibrosis. LSM was measured by transient elastography. LRE were recorded during follow-up. Cox multivariate models were used to assess the association between high-risk MASH or F2-F4 fibrosis without MASH, of LSM (>= 8 or >= 10 Kpa), and of AGILE 3+ with LRE. The diagnostic performance for the prediction of LRE was assessed using the area under the receiver operating characteristic curves. The observed 5-year actuarial rate of LRE was 0.4%, 0.2%, 5.1%, and 6.6% in patients with F0-F1 fibrosis without MASH, F0-F1 fibrosis with MASH, F2-F4 fibrosis without MASH, and high-risk MASH, respectively. At multivariate Cox regression analysis using F0-F1 fibrosis without MASH as a reference, both F2-F4 fibrosis without MASH [adjusted HR (aHR) 9.96] and high-risk MASH (aHR 10.14) were associated with LRE. In the 1074 patients with available LSM, LSM >= 10 kPa (aHR 6.31) or AGILE 3+ > 0.67 (aHR 27.45) independently predicted the development of LRE and had similarly acceptable 5-year area under the receiver operating characteristic to high-risk MASH and F2-F4 fibrosis (0.772, 0.818, 0.739, and 0.780, respectively). Conclusions: The risk of LRE is similar in patients with high-risk MASH and with F2-F4 fibrosis without MASH. The use of LSM >= 10 kPa or AGILE 3+ > 0.67 could be an accurate option to identify patients with MASLD worthy to be included in clinical trials.

Background & AimThe MAESTRO Phase 3 trial reported that 52-week treatment of Resmetirom is effective in improving fibrosis and MASH in patients with metabolic-dysfunction associated steatotic liver disease (MASLD) with F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. Moreover, data about the full spectrum of the natural history of MASLD patients with F2 or F3 fibrosis are scarce and fragmentary. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis, and the effect of Resmetirom treatment on clinical outcomes.MethodsData from 40 studies and individual sources on MASLD subjects formed transition matrices for fibrosis stages and complications, defined as cirrhosis development (CD), hepatocellular carcinoma (HCC) and liver decompensation (LD). Markov models were developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of 52-week Resmetirom treatment on the natural history.ResultsWe estimated the 5-year and lifetime probability of untreated or Resmetirom-treated MASLD patients with baseline F2 fibrosis of developing cirrhosis (11% and 39.5% in untreated; 8.8% and 37.2% in treated), LD (0.9% and 11.9% in untreated; 0.7% and 11% in treated), and HCC (0.8% and 7.2% in untreated; 0.5% and 6.8% in treated). Similarly, we estimated the 5-year and lifetime probability of untreated or resmetirom-treated MASLD patients with baseline F3 fibrosis of developing cirrhosis (27.7% and 52.6% in untreated; 22.9% and 48.7% in treated), LD (2.8% and 17.3% in untreated; 2.2% and 15.6% in treated), and HCC (2.8% and 10.4% in untreated; 2.1% and 9.8% in treated). Sensitivity analyses considering changes in transition probabilities, treatment efficacy and treatment duration are ongoing.ConclusionsResmetirom decreases the 5-year and lifetime Markov-model estimated risk of cirrhosis development, LD and HCC in patients with MASLD and F2 or F3 fibrosis.

BACKGROUND & AIMS:Individual risk prediction of liver-related events (LRE) is needed for clinical assessment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) patients. We aimed to provide point-of-care validated liver stiffness measurement (LSM)-based risk prediction models for the development of LRE in patients with NAFLD, focusing on selecting patients for clinical trials at risk of clinical events. METHODS:Two large multicenter cohorts were evaluated, 2638 NAFLD patients covering all LSM values as the derivation cohort and 679 more advanced patients as the validation cohort. We used Cox regression to develop and validate risk prediction models based on LSM alone, and the ANTICIPATE and ANTICIPATE-NASH models for clinically significant portal hypertension. The main outcome of the study was the rate of LRE in the first 3 years after initial assessment. RESULTS:The 3 predictive models had similar performance in the derivation cohort with a very high discriminative value (c-statistic, 0.87-0.91). In the validation cohort, the LSM-LRE alone model had a significant inferior discrimination (c-statistic, 0.75) compared with the other 2 models, whereas the ANTICIPATE-NASH-LRE model (0.81) was significantly better than the ANTICIPATE-LRE model (0.79). In addition, the ANTICIPATE-NASH-LRE model presented very good calibration in the validation cohort (integrated calibration index, 0.016), and was better than the ANTICIPATE-LRE model. CONCLUSIONS:The ANTICIPATE-LRE models, and especially the ANTICIPATE-NASH-LRE model, could be valuable validated clinical tools to individually assess the risk of LRE at 3 years in patients with NAFLD/NASH.

BACKGROUND & AIMS: We aimed to assess the diagnostic accuracy of AGILE 3+, a recently developed score based on the combination of aspartate aminotransferase/alanine aminotransferase ratio, platelet count, diabetes status, sex, age, and liver stiffness measurement (LSM) by transient elastography, when compared with Fibrosis-4 (FIB-4) and LSM, for the diagnosis of advanced fibrosis and for the prediction of liver-related events (LREs) occurrence in patients with NAFLD.METHODS: A total of 614 consecutive patients with biopsy-proven NAFLD or clinical diagnosis of NAFLD-related compensated cirrhosis were enrolled. LREs were recorded during follow-up. FIB-4, LSM by transient elastography (FibroScan device), and AGILE 3+ were measured. The diag-nostic performance of noninvasive criteria for advanced fibrosis and for the prediction of LREs was assessed using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis.RESULTS: In patients with biopsy-proven NAFLD (n [ 520), LSM and AGILE 3+ had higher AUROC than FIB-4 (0.88 for LSM and AGILE 3+ vs 0.78 for FIB-4; P < .001) for advanced fibrosis, and AGILE 3+ exhibited a smaller indeterminate area in the test (25.2% for FIB-4 vs 13.1% for LSM vs 8.3% for AGILE 3+). Within the entire cohort of patients, AGILE 3+ had significantly higher AUROC for predicting LREs with respect to LSM (AUROC 36 months 0.95 vs 0.93; P =.008; 60 months 0.95 vs 0.92; P = .006; 96 months 0.97 vs 0.95; P = .001). Decision curve analysis showed that all scores had modest net benefit for ruling-out advanced fibrosis at the risk threshold of 5% to 10% where advanced fibrosis was absent. At the risk threshold of 5% of false negatives or false positives in LRE at 36, 60, 96, and 120 months, AGILE 3+ outperformed both FIB-4 and LSM for ruling out LRE.CONCLUSIONS: Depending on resource availability, clinical setting, and the risk scenarios, AGILE 3+ is an accurate and valid alternative to FIB-4 and LSM for the noninvasive assessment of disease severity and prognosis in patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as ‘Metabolic dysfunction-Associated Fatty Liver Disease’ (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only – as expected – liver-related events but also of extrahepatic events, mostly cardiovascular and cancers. Available evidence suggests that these associations are not only the expression of sharing the same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its progressive form – nonalcoholic/metabolic dysfunction-associated steatohepatitis – to act as an independent risk factor via promotion of atherogenic dyslipidemia and a proinflammatory, profibrogenic, and procoagulant systemic environment. The present review summarizes available epidemiological and clinical evidence supporting the concept of NAFLD/MAFLD as a multisystemic disease, and highlights potential explanatory mechanisms underlying the association between NAFLD/MAFLD and extrahepatic disorders.

Background and aims: We aimed to assess the diagnostic accuracy of AGILE 3+, a recently developed score based on the combination of AST/ALT ratio, platelet count, diabetes status, sex, age and LSM, respect to FIB-4 and LSM, for the diagnosis of advanced fibrosis and for the prediction of liver-related events (LRE) occurrence in patients with non-alcoholic fatty liver disease (NAFLD).Method: 614 consecutive patients with biopsy-proven NAFLD or clinical diagnosis of NAFLD-related compensated cirrhosis were enrolled.LRE were recorded during follow-up.FIB-4, LSM by TE and AGILE 3+ were measured.The diagnostic performance of noninvasive criteria for advanced fibrosis and for the prediction of LRE was assessed by AUROC curve and by decision curve analysis (DCA).Results: In patients with biopsy-proven NAFLD (n = 520), LSM and AGILE 3+ had higher AUROC than FIB-4 (0.88 for LSM and AGILE 3+ vs 0.78 for FIB-4; p < 0.001) for advanced fibrosis, and AGILE 3+ exhibited the lower rate of indeterminate area of the test (25.2% for FIB-4, vs 13.1% for LSM, vs 8.3% for AGILE 3+).In the entire cohort AGILE 3+ had significantly higher AUC for predicting LRE respect to LSM (36-month AUROC 0.95 vs 0.93, p = 0.008; 60-month 0.95 vs 0.92, p = 0.006; 96-month 0.97 vs 0.95, p = 0.001).DCA showed that all scores had modest net benefit for ruling-out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis.At the risk threshold of 5% of false negative or false positive LRE at 36-, 60-, 96and 120-month, AGILE 3+ outperformed both FIB-4 and LSM for ruling-out LRE.