Although liver biopsy is considered the most reliable diagnostic tool for metabolic dysfunction-associated steatohepatitis (MASH), it is invasive and can be costly. Clinicians are increasingly relying on routine biomarkers and other noninvasive tests (NITs) for diagnosis. We examined real-world diagnostic pathways for patients newly diagnosed with MASH with a primary focus on NITs.

This retrospective, observational study analyzed healthcare claims data (Merative MarketScan Commercial and Medicare Databases) from patients in the United States newly diagnosed with MASH from October 1, 2016, to March 31, 2023. Patients ≥18 years old with ≥12 months of continuous enrollment with medical and pharmacy benefits prior to diagnosis were included. Diagnostic pathways leading up to MASH diagnosis, including NITs (blood-based and imaging-based tests) and liver biopsies were assessed. Prevalence of comorbid conditions, MASH-associated medication use, and the diagnosing physician specialty were also examined.

A total of 18,396 patients were included in the analysis. Routine laboratory tests (alanine aminotransferase [ALT], albumin, aspartate aminotransferase [AST], cholesterol, complete blood count, and hemoglobin A1c) were performed among ≥70% of patients prior to MASH diagnosis, including 89% of patients with a liver enzyme test (ALT and/or AST). More than 75% of patients had necessary laboratory tests to calculate AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4) scores. The most common imaging performed was ultrasound (62%); liver biopsy was only performed in 10% of patients. There was a high prevalence of cardio metabolic risk factors such as hyperlipidemia (66%), hypertension (62%), obesity (58%), type 2 diabetes (40%), and cardiovascular disease (21%). Nearly half of the patients (49%) were diagnosed by a primary care physician.

This study highlights real-world diagnostic pathways among patients newly diagnosed with MASH, supporting previous findings that liver biopsies are infrequently used in favor of noninvasive methods.

Currently, the Fibrosis-4 (FIB-4) and nonalcoholic fatty liver disease fibrosis score (NFS) are used to predict fibrosis and steatosis in patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). More recently, the fibrotic nonalcoholic steatohepatitis (NASH) index (FNI) and steatosis-associated fibrosis estimator (SAFE) have been created. We have compared the accuracy of these noninvasive scoring systems in MASLD patients.

This is a retrospective analysis of 244 biopsy-proven MASLD patients from a tertiary health care system. Score performances were determined by calculating the area under the receiver operating characteristic (AUROC) curve with 95% confidence intervals, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).

About 25 (10.3%) patients had fibrotic metabolic dysfunction-associated steatohepatitis (MASH). The FNI score was best at predicting fibrotic MASH with an AUROC of 0.78, while NFS was the worst at predicting fibrotic NASH with an AUROC of 0.60. In the entire cohort, FNI of 0.33, FIB-4 of 2.67, SAFE >100, and NFS >0.675 had PPVs of 17%, 31%, 17%, and 16%, respectively, and NPVs of 97%, 92%, 96%, and 91%, respectively. Specificity was greatest for FIB4 at 92% and NFS at 86%, whereas the sensitivity was greatest for FNI and SAFE scores at 88% and 80%, respectively.

FNI and SAFE scores have superior diagnostic accuracy for fibrotic MASH compared to other scoring systems. While liver biopsy remains the gold standard diagnostic method, noninvasive scores like FNI, and SAFE scores can be used in everyday clinical practice to assess for fibrotic MASH.

Liver fibrosis is an important predictor of mortality. Liver disease case definitions changed in 2023. These definitions include an easily over-looked group with no traditional etiology (NTE) of liver disease and no steatosis. We analyzed heavy metals and cardiometabolic risk factors (CMRFs) as fibrosis risk factors in the NTE group and in people with another newly-defined condition, metabolic dysfunction-associated steatotic liver disease (MASLD). Two National Health and Nutrition Examination Survey (NHANES) datasets were analyzed. In NHANES III (1988-1994), fibrosis and steatosis were defined by Fibrosis-4 scores and ultrasound, respectively, in 12,208 adults. In NHANES 2017-2020, fibrosis and steatosis were defined by transient elastography and the controlled attenuation parameter (CAP) in 5525 adults. Fibrosis risk factors varied over time and by race/ethnicity. In the earlier dataset, NTE-fibrosis had a positive, non-significant, association with high blood levels of lead (Pb). MASLD-fibrosis was associated with Pb (OR = 2.5, 95 % CI, 1.4-4.4) and not with CMRFs in non-Hispanic Blacks but was associated with CMRFs in non-Hispanic Whites. Heavy metal exposures fell between the two time periods. In the later dataset, NTE-fibrosis was associated with Pb (OR = 4.2, 95 % CI, 2.6-6.8) and cadmium (OR = 1.8, 95 % CI, 1.1-3.0) in the total population, but not with most CMRFs. MASLD-fibrosis was strongly-significantly associated with CMRFs in every racial/ethnic group except non-Hispanic Blacks in whom CMRFs were only weakly associated with MASLD-fibrosis. Heavy metal pollution, which disproportionately impacts minoritized populations, decreased over time, but remained strongly associated with liver fibrosis in people lacking traditional etiological factors for liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder involving intertwined signaling pathways, posing challenges for targeted therapeutic interventions. Cornus Fructus (CF), a traditional medicinal herb, holds potential for NAFLD treatment, with cornuside (COR) identified as its primary active component.

This study employed a cross-disciplinary approach, integrating bioinformatics, computational chemistry, and machine learning to uncover COR's therapeutic mechanisms with precision and depth.

Using bioinformatics-driven analysis, 27 core targets were identified, revealing that COR modulated critical metabolic and inflammatory pathways. COR mitigated insulin resistance by regulating the AKT/GSK3β axis, enhanced cholesterol metabolism through LXR signaling, promoted fatty acid oxidation via PPARα activation, and suppressed inflammation by inhibiting NF-κB signaling. These results highlighted COR's ability to orchestrate multi-pathway regulation essential for restoring metabolic homeostasis in NAFLD. Molecular docking and molecular dynamics (MD) simulations provided atomistic insights, demonstrating COR's stable and high-affinity interactions with key targets. Additionally, machine learning algorithms enhanced target identification and pathway prediction, improving the precision and efficiency of the discovery process.

This study offered multi-scale mechanistic insights into COR's therapeutic effects on NAFLD, bridging experimental pharmacology and computational methods. The integration of bioinformatics, molecular simulation, and machine learning established a comprehensive framework for drug discovery, positioning COR as a promising candidate for NAFLD therapy and guiding future development of precision interventions.

The LiverRisk score (LRS) has recently been proposed to predict liver fibrosis and future development of liver-related outcomes in the general population. Here, we performed an external validation of this score.

We used data from National Health and Nutrition Examination Survey 2017-2020, a United States population-based cohort to assess the diagnostic accuracy of the LRS to detect a liver stiffness measurement (LSM) ≥8 and ≥12 kPa. Performance was tested among the entire general population and clinically relevant subgroups.

The cohort comprised 7,025 participants (aged 49 [33-63], 49% male), and 9.7% had an LSM ≥8 and 3.2% had an LSM ≥12 kPa. The area under the receiver characteristic operator curve (AUC) in the overall population was 0.73 (95% confidence interval [CI] :0.71-0.75) and 0.78 (95% CI: 0.74-0.81) to detect an LSM ≥8 and ≥ 12 kPa, respectively, significantly outperforming the fibrosis 4 index (FIB-4) but not the nonalcoholic fatty liver disease fibrosis score, steatosis-associated fibrosis estimator (SAFE), or metabolic dysfunction-associated fibrosis 5 (MAF-5). Performance was consistent among most subgroups, but AUC levels to detect an LSM ≥8 kPa decreased to <0.70 among participants aged 18-40 or 60-80 years, blacks, and individuals with diabetes or liver steatosis. The LRS categorized 80.5% as very low risk, 17.7% as low risk, and 1.8% as at risk, prevalence of an LSM ≥8 in these groups was 6.3%, 20.8%, and 50.5%, respectively. The sensitivity to detect an LSM ≥8 kPa was 47.3% in the overall population (but dropped to 21.3% for individuals aged 18-40 years) despite applying the lowest cut-off, which should yield the highest sensitivity.

The LRS score is a promising new tool to predict liver fibrosis; however, its diagnostic accuracy attenuates especially among patients aged 18-40 or 60-80 years. The overall sensitivity was only 47.3% at the lowest LRS cut-off. Further studies assessing cost-benefit ratios according to the LRS compared to FIB-4 and other risk scores such as MAF-5 and SAFE are required to determine its usefulness in referral strategies.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25-30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.

Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.

Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease among people living with HIV, and preliminary evidence shows that lifestyle modification can reduce liver fat in people living with HIV with MASLD. We aimed to assess a dietitian-led lifestyle modification programme in inducing resolution of MASLD in this population.

In this single-blind, randomised controlled trial at the Prince of Wales Hospital, Hong Kong, people living with HIV with fatty liver defined by intrahepatic triglyceride content ≥5% on proton magnetic resonance spectroscopy (1H-MRS) were enrolled if they were aged 18 years or older, were on antiretroviral therapy, and had HIV RNA of ≤50 copies per mL for 6 months or longer. Participants were randomly assigned (1:1) to either receive a dietitian-led lifestyle modification programme or standard care for 12 months. Randomisation was performed using computer-generated random numbers in blocks of 4 stratified by presence or absence of diabetes. The primary outcome, assessed in the intention-to-treat population, was resolution of MASLD, defined as intrahepatic triglyceride content less than 5% at month 12, measured by 1H-MRS. This trial was registered with ClinicalTrials.gov, NCT03913351, and is completed.

From May 21, 2019, to March 22, 2022, 203 people were screened for eligibility, of whom 84 were randomly assigned to either the lifestyle modification programme (n=43) or standard care (n=41). 74 (88%) participants were male and ten (12%) were female. 78 participants completed all assessments during the 12-month intervention. In the intention-to-treat analysis, 12 (28%) participants in the intervention group and four (10%) in the control group had resolution of MASLD (p=0·040 adjusted for baseline diabetes status). No deaths were reported during the follow-up period. One serious adverse event (hospitalisation due to cellulitis) was reported in the control group. The occurrence of adverse events was similar in the intervention and control groups. The majority of adverse events were of mild severity, and none were considered to be related to study intervention.

Our findings suggest that a lifestyle modification programme could be a routine behavioural strategy to improve a range of health outcomes in people living with HIV with MASLD.

Health and Medical Research Fund from the Health Bureau, Hong Kong Special Administrative Region.

For the Chinese translation of the abstract see Supplementary Materials section.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a potential independent risk factor for cardiovascular disease (CVD)-associated and all-cause mortalities as they share common risk factors. We investigated the association between cardiometabolic risk factors for MASLD and CVD-associated and all-cause mortality risks in middle-aged and older Korean adults.

We used data from the Korean Genome and Epidemiology Study, a population-based prospective cohort study. Five cardiometabolic risk factors were assessed. MASLD was defined as liver steatosis with a fatty liver index (FLI) ≥60 and at least one cardiometabolic risk factor. The non-MASLD group included individuals with a FLI <60 or FLI ≥60 without cardiometabolic risk factors. The primary outcomes were CVD-associated and all-cause mortalities. Cox proportional hazard models were used to evaluate the association between cardiometabolic risk factors for MASLD and mortalities, adjusting for covariates. Multivariable Cox regression analysis revealed that the MASLD group had increased CVD-associated and all-cause mortality risks compared to the non-MASLD group. The presence of three or more and one or more cardiometabolic risk factors significantly increased the CVD-associated and all-cause mortality rate, respectively. The combination of hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and high glucose concentrations significantly increased both CVD-associated (hazard ratio [HR] 3.64; 95 % confidence interval [CI] 1.44-9.22; p = 0.006) and all-cause (HR 4.57; 95 % CI: 1.74-12.05; p = 0.002) mortality risks.

Cardiometabolic risk factors for MASLD are strongly associated with higher CVD-associated and all-cause mortality risks, highlighting the need to manage hypertriglyceridemia, low HDL-C, and high glucose concentrations.

Attenuation Imaging (ATI) and controlled attenuation parameter (CAP) are non-invasive ultrasound-based methods for diagnosing hepatic steatosis. However, reports on the clinical usefulness of ATI are limited. We aimed to compare the ability of ATI and CAP to diagnose hepatic steatosis with magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) as the reference standard.

We performed a prospective multicenter study of 562 patients with chronic liver disease who underwent ATI, CAP, and MRI-PDFF. Patients with skin-to-liver capsule distance (SCD) ≤ 25 mm underwent CAP with an M probe; those with SCD > 25 mm underwent CAP with an XL probe. MRI-PDFF was used as the reference standard: S0 corresponds to MRI-PDFF < 5.2%, S1 to 5.2% ≤ MRI-PDFF < 11.3%, S2 to 11.3% ≤ MRI-PDFF < 17.1%, and S3 to MRI-PDFF ≥ 17.1%.

The correlation coefficients for ATI and MRI-PDFF stratified by body mass index (< 30, ≥ 30 kg/m2), SCD (< 25, ≥ 25 mm), 2-dimensional share wave elastography (< 1.8 m/s), fibrosis-4 index (≤ 2.67), albumin-bilirubin score (< - 2.60) and type IV collagen 7 s (< 5.0 ng/ml) were significantly higher than those for CAP and MRI-PDFF. Areas under the receiver operating characteristics (95% CI) for ATI and CAP were 0.895 (0.869-0.922) and 0.845 (0.809-0.881) for ≥ S1 steatosis, 0.944 (0.926-0.963) and 0.881(0.852-0.910) for ≥ S2 steatosis, and 0.928 (95% CI 0.906-0.950) and 0.860 (95% CI 0.829-0.890) for S3 steatosis. ATI had higher diagnostic performance for all hepatic steatosis grades than CAP.

ATI is a more useful non-invasive method for diagnosing hepatic steatosis than CAP.

A noteworthy proportion of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) have an indeterminate vibration-controlled transient elastography (VCTE). Among these patients, we aimed to identify candidates for MASLD treatment by diagnosing significant fibrosis.

This was a real-world prospective study including a large dataset of MASLD patients with paired VCTE and liver biopsy from 6 centers. A total of 1196 patients were recruited and divided in training (3 centers, Spain), internal validation (2 centers, Spain), and external validation (1 center, United States) cohorts. In patients with indeterminate liver stiffness measurement (LSM) (8-12 kPa), a diagnostic algorithm was developed to identify significant fibrosis, defined as histological stage ≥F2. Statistical analysis was performed using Gaussian mixture model (GMM) and k-means unsupervised clusterization.

From the eligible population, 33%, 29%, and 31% had indeterminate VCTE in the training, internal and external validation samples, respectively. The controlled attenuation parameter allowed the differentiation of GMM clusters with a cutoff of 280 dB/m (area under the curve, 0.89; 95% confidence interval, 0.86-0.97). Within patients with <280 dB/m, a LSM between 8.0-9.0 kPa showed a 93% sensitivity and a 91% negative predictive value to exclude significant fibrosis. Among patients with ≥280 dB/m, a LSM between 10.3 and 12.0 kPa diagnosed significant fibrosis with a 91% specificity. Applying this algorithm to the validation cohorts, 36% of the indeterminate VCTE were reallocated. The reallocated high-risk group showed a prevalence of 86% significant fibrosis, opening the therapeutic window for MASLD patients.

To identify candidates for MASLD treatment among indeterminate VCTE, an algorithm-based on the sequential combination of LSM and controlled attenuation parameter thresholds can optimize the diagnosis of moderate-to-advanced fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a type of fat accumulation in the liver that can lead to cirrhosis and chronic liver disease. MASLD is recognized as the most frequent of liver-associated deaths worldwide. The SERPINA1 gene encodes a serine protease protein that plays a pivotal role in the pathogenesis of liver deficiencies. In this study, we aimed to evaluate the genetic association between rs6647 (M1), rs709932 (M2), and rs1303 (M3) variants in the SERPINA1 gene and the risk of MASLD in an Iranian population.

In this case-control study, 120 patients affected by MASLD and 120 healthy subjects participated. The Nephelometry system measured serum levels of α1-antitrypsin (A1AT). Biochemical tests were conducted to assess serum levels of blood parameters using commercially available kits. DNA extraction was performed using the salting-out method, followed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method for genotyping. Statistical analysis was performed by SPSS v16.0.

The findings showed that the rs6647 G allele significantly increased the risk of MASLD. The G allele in codominant, dominant, and over-dominant models caused an increase in the risk of MASLD. Additionally, the rs709932 T allele was more frequent among patients compared to healthy subjects and significantly enhanced the risk of MASLD. The T allele in the codominant and recessive models indicated a high risk for MASLD in our population. The G allele of rs1303 caused an enhancement in the mean serum levels of A1AT in the MASLD group.

Our results show an association between SERPINA1 gene variants and the risk of MASLD. The rs6647 (M1) and rs709932 (M2) variants of the SERPINA1 gene increased the risk of disorder in our population.

Metabolic syndrome increases the risk of developing noncommunicable diseases such as metabolic dysfunction-associated steatotic liver disease. The aim was to investigate the effects of sedentary behavior (SB) reduction on liver glucose uptake (LGU), endogenous glucose production (EGP), liver fat content (LFC), and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase]. Forty-four sedentary (daily SB time ≥ 10 h), physically inactive middle-aged adults with metabolic syndrome were randomized into intervention (INT; n = 23, 21 completed) and control (CON; n = 21, 19 completed) groups. For 6 mo, INT aimed to limit SB by 1 h/day, whereas CON aimed to maintain usual habits. SB and physical activity (PA) were measured continuously with hip-worn accelerometers. Before and at the end of the intervention, LGU was measured using positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated, and LFC was measured by magnetic resonance spectroscopy. INT reduced SB by 51 [95% confidence interval (CI): 22, 78] min/day and increased moderate-to-vigorous physical activity (MVPA) by 22 (95% CI: 12, 33) min/day, with no significant change in CON. Differences in liver health markers between the groups were not significant. However, according to the exploratory analyses among participants who successfully reduced SB, ALT decreased (-1.1 [95% CI: 0.93, 1.36] U/L) compared with the continuously sedentary participants (+0.8 [95% CI: 0.65, 1.05] U/L) (group × time, P = 0.006). To enhance liver health, reducing SB for longer durations and/or increasing the intensity of PA may be necessary. However, successfully reducing SB may lead to better levels of circulating ALT liver enzymes.NEW & NOTEWORTHY Aiming to reduce sedentary behavior (SB) by 1 h/day did not significantly influence liver health markers, suggesting that more substantial reductions or a different approach might be necessary to see improvements. However, achieving the desired behavioral change could lead to improvements in ALT levels. This study is the first to analyze how reducing SB and replacing it with nonguided physical activity impacts liver health in adults with metabolic syndrome, offering insights for future intervention strategies.

There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication.

We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094).

Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409.

Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.

Screening for advanced fibrosis (AF) resulting from metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended in diabetology. This study aimed to compare the performance of noninvasive tests (NITs) with that of two-step algorithms for detecting patients at high risk of AF requiring referral to hepatologists.

We conducted a planned interim analysis of a prospective multicenter study including participants with type 2 diabetes and/or obesity and MASLD with comprehensive liver assessment comprising blood-based NITs, vibration-controlled transient elastography (VCTE), and two-dimensional shear-wave elastography (2D-SWE). AF risk stratification was determined by a composite criterion of liver biopsy, magnetic resonance elastography, or VCTE ≥12 kPa depending on availability.

Of 654 patients (87% with type 2 diabetes, 56% male, 74% with obesity), 17.6% had an intermediate/high risk of AF, and 9.3% had a high risk of AF. The area under the empirical receiver operating characteristic curves of NITs for detection of high risk of AF were as follows: fibrosis-4 index (FIB-4) score, 0.78 (95% CI 0.72-0.84); FibroMeter, 0.74 (0.66-0.83); FibroTest, 0.78 (0.72-0.85); Enhanced Liver Fibrosis (ELF) test, 0.82 (0.76-0.87); and SWE, 0.84 (0.78-0.89). Algorithms with FIB-4 score/VCTE showed good diagnostic performance for referral of patients at intermediate/high risk of AF to specialized care in hepatology. An alternative FIB-4 score/ELF test strategy showed a high negative predictive value (NPV; 88-89%) and a lower positive predictive value (PPV; 39-46%) at a threshold of 9.8. The FIB-4 score/2D-SWE strategy had an NPV of 91% and a PPV of 58-62%. The age-adapted FIB-4 score threshold resulted in lower NPVs and PPVs in all algorithms.

The FIB-4 score/VCTE algorithm showed excellent diagnostic performance, demonstrating its applicability for routine screening in diabetology. The ELF test using an adapted low threshold at 9.8 may be used as an alternative to VCTE.

The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.

Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with metabolic dysfunction-associated steatohepatitis (MASH). We tested its effect on insulin resistance (IR) at the level of different target tissues in relation to changes in intrahepatic triglyceride (IHTG) content.

In this single-center phase II study, 38 patients with type 2 diabetes and MASLD were randomized 1:1 to receive lanifibranor 800 mg or placebo for 24 weeks. The primary endpoint was the change in IHTG (1H-MRS). The main prespecified secondary endpoint was the change in hepatic, muscle and adipose tissue insulin sensitivity using the gold-standard euglycemic hyperinsulinemic clamp technique to measure glucose turnover. Other secondary endpoints included changes in cardiometabolic parameters (i.e., HbA1c, lipid profile, adiponectin).

Lanifibranor significantly lowered IHTG compared to placebo (full analysis set [FAS] -44% vs. -12%, respectively; least squares mean difference -31%, 95% CI -51 to -12%; in completers -50% vs. -16%; both p <0.01). More patients in the lanifibranor group (vs. the placebo group) achieved a ≥30% IHTG reduction (FAS 65% vs. 22%; completers 79% vs. 29%; both p <0.01) and steatosis resolution (FAS 25% vs. 0%; p <0.05). Lanifibranor significantly improved hepatic and peripheral IR (i.e. fasting endogenous [primarily hepatic] glucose production, hepatic IR, and insulin-stimulated muscle glucose disposal or Rd). Secondary metabolic endpoints also improved (fasting glucose, insulin, HOMA-IR, HbA1c, HDL-C), and adiponectin increased 2.4-fold (all p <0.001). Lanifibranor caused modest weight gain (+2.7%). Adverse events were mild (gastrointestinal side effects, hemoglobin decrease) and drug-related treatment-emergent adverse events leading to study discontinuation were balanced between groups.

Lanifibranor significantly improves hepatic, muscle and adipose tissue IR. Lanifibranor treatment was safe and effective in reducing hepatic steatosis and cardiometabolic risk factors associated with metabolic dysfunction.

No prior studies have evaluated the effect of lanifibranor on insulin sensitivity at the level of muscle, liver and adipose tissue and its relationship to changes in intrahepatic triglyceride (IHTG) content in insulin-resistant individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. We observed a significant decrease in IHTG after 24 weeks of treatment (by ∼50%, p <0.001 vs. placebo) that was associated with a major improvement in hepatic and peripheral (Rd) insulin sensitivity, restoration of adipose tissue function and improvement in cardiometabolic risk factors. This study has important clinical implications because it offers proof-of-concept that targeting the key underlying metabolic defects in MASLD (i.e. insulin resistance, lipotoxicity and hyperglycemia) can restore cardiometabolic health. It offers a compelling rationale for lanifibranor treatment in individuals with MASLD, either alone or in combination with weight loss and other treatment strategies.

NCT03459079.

Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD.

C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro.

In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export.

Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.

Metabolic dysfunction-associated steatotic liver disease is the most prevalent liver condition worldwide. Its more severe manifestation, metabolic dysfunction-associated steatohepatitis (MASH), is accompanied by distinctive hepatocellular injury and inflammation with fibrosis. The involvement of chronic inflammation and accompanying immune cell activation in the maturation phases of MASH progression, mediated through hepatic stellate cells (HSCs), plays a central role. This review highlights the detailed molecular and cellular mechanisms of MASH, with special attention to the dynamic dialogue between HSCs and hepatic macrophages. This review will help narrow the existing gaps, with a summary of key roles HSCs and hepatic macrophages play within liver immunity to inflammation, discussing critical intercellular communication pathways as well as proposing new venues for research toward a better understanding of MASH pathobiology, which could pave ways toward breakthroughs in the clinical condition.

This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression.

This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA.

The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children.

Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.

An association between Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and the development of extrahepatic malignancies has been demonstrated. However, the association of fibrosis with extrahepatic cancer is unclear. Our study aimed to test the long-term association between liver fibrosis marker and the incidence of hepatic and extrahepatic malignancies.

A retrospective cohort study of a nationally representative sample, following 763 752 adult Clalit health services members without pre-existing liver-related diagnoses or malignancies for 14.67 years. The adjusted association between baseline liver Fibrosis-4 score (FIB-4; FIB-4 ≥ 2.67 indicated presumed advanced fibrosis), assessed from routine laboratory measurements, and incident cancer was assessed through multivariable Cox regression models.

The study included 763 752 people (mean age 54.3 ± 8.2 years, 43.9% males). Presumed advanced fibrosis was associated with a 16% greater risk for malignancy compared to the risk of those with no fibrosis (hazard ratio (HR) = 1.16; 95% CI, 1.10-1.22), adjusting for age, sex, ethnicity, socioeconomic status, peripherality index, baseline smoking, and obesity. The association of advanced fibrosis with malignancy was stronger when the age-specific FIB-4 cutoff was applied (HR = 1.40; 1.34-1.46) and in a subsample of subjects with MASLD diagnosis at baseline (HR = 1.43; 1.12-1.83). The association remained robust across sex, age, and ethnic groups. Both inconclusive fibrosis and fibrosis were strongly associated with malignancy of the liver or bile ducts [(HR = 1.41; 1.21-1.66) and (HR = 5.66; 4.19-7.64), respectively].

Liver fibrosis score is independently associated with malignancy occurrence and certain types of malignancies, and may serve as an indicator of high-risk cancer in the general population.

Metabolic dysfunction and alcohol-associated liver disease (MetALD) may increase liver fibrosis progression, but data on screening are scarce. We aimed to assess the performance of noninvasive tests (NITs) for detecting significant fibrosis in individuals with suspected MetALD.

This is a cross-sectional study of prospectively enrolled adults identified as overweight or obese. We included adults with suspected MetALD defined by ≥1 of 5 cardiometabolic criteria and self-reported alcohol use within MetALD ranges or lower self-reported alcohol use but with phosphatidylethanol (PEth) levels ≥25 ng/mL. Clinical assessment included contemporaneous magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE). Significant fibrosis was defined as MRE ≥3.14 kPa (or VCTE ≥7.6 kPa if MRE was missing). Analyses included AUROCs.

Among 617 individuals screened, we identified 97 (15.7%) with suspected MetALD. The mean age was 50.6±12.8 years, 67% were men, the mean body mass index was 31.4±6.5 kg/m2, 12.4% had diabetes, and 8% had significant fibrosis. Fibrosis-4 ≥1.3 demonstrated good performance for significant fibrosis (AUROC: 0.78, 95% CI: 0.58-0.98, sensitivity 80%, specificity 76%, positive predictive value 17%, and negative predictive value 98%). VCTE ≥8 kPa also had good performance (AUROC: 0.85, 95% CI: 0.66-1.00, sensitivity 80%, specificity 91%, positive predictive value 36%, and negative predictive value 99%). A stepwise approach using fibrosis-4 followed by VCTE yielded a low false negative rate (2% misclassified as low risk).

A clinical care algorithm utilizing a stepwise approach with fibrosis-4 and VCTE shows adequate performance in detecting significant fibrosis in individuals with suspected MetALD.

Non-alcoholic fatty liver disease (NAFLD) has become an increasing public health concern. We examined the association between serum high-sensitivity C-reactive protein(hs-CRP)to high-density lipoprotein cholesterol (HDL-C) ratio (HCHR) and the prevalence of NAFLD, extent of hepatic steatosis and fibrosis in the general US population. This cross-sectional analysis included 4039 adult participants from the 2017 to 2018 National Health and Nutrition Examination Survey. Multivariable logistic regression and multivariable linear regression analyses were used to assess the association between HCHR levels and NAFLD, fatty liver degree, and liver fibrosis. Generalized additive models examined the nonlinear relationship between the HCHR and NAFLD. In the three models, HCHR was positively associated with NAFLD, model 1 (OR  1.315, 95% CI 1.273, 1.359), model 2 (OR 1.364, 95% CI 1.317, 1.412) and model 3 (OR  1.120, 95% CI 1.074, 1.168). Stratified analyses showed that the association was more prominent in women, those younger than 40 years, Mexican-Americans, and those with a 25-30 kg/m2 BMI. Nonlinear association analysis revealed a threshold effect between HCHR and NAFLD, with a threshold inflection point of 2.598. We also found a significant link between HCHR and liver steatosis and the risk of liver fibrosis. In the US adult population, the increased risk of NAFLD, liver fibrosis, and severity of hepatic steatosis are independently associated with increased HCHR, and the HCHR may serve as a potential marker for NAFLD and liver fibrosis.

To assess the diagnostic performance of standardized qualitative assessment of hepatic steatosis on grayscale ultrasound.

This retrospective, single-center, multi-case, multi-reader study included 200 patients with ultrasound examinations of the liver. Three readers assessed hepatic steatosis based on a standardized system of 3 ultrasound features: presence of increased fine echoes, visualization of right hemidiaphragm, and visualization of portal triads, assigning a four-grade category (normal, mild, moderate, or severe). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was used as reference standard. Binary discrimination (normal vs. steatosis) was summarized with binary area under the curve (AUC), sensitivity, and specificity. Discrimination across four categories was performed with pairwise comparisons. Reader differences were tested with the Obuchowski-Rockette-Hillis model. Inter-reader agreement was calculated with Gwet's agreement coefficient (AC).

Of the 200 patients, 27% (54/200) had normal liver (MRI-PDFF < 5%), 35% (70/200) had mild steatosis (MRI-PDFF ≥ 5-17.4%), 15% (29/200) had moderate steatosis (MRI-PDFF > 17.4-22.1%), and 24% (47/200) had severe steatosis (MRI-PDFF > 22.1%). Median time interval between ultrasound and MRI exams was 4 days (IQR 1-28). Sensitivity, specific, and binary AUC for readers 1/2/3 were 90%/82%/94%, 65%/82%/54%, and 0.87/0.85/0.88 with no statistically significant difference between readers (p = 0.46). Four-class category analysis showed excellent performance of ultrasound to distinguish extreme categories (AUC > 0.95 for normal vs. severe). Inter-reader agreement was substantial (Gwet's AC 0.63) for steatosis category assignment and moderate to substantial (Gwet's AC 0.55-0.71) for ultrasound features.

Contrary to popular belief, qualitative ultrasound assessment of hepatic steatosis is accurate in detecting and grading steatosis when evaluation criteria are standardized.

Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.

The liver and heart are closely interconnected organs, and their bidirectional interaction plays a central role in cardiometabolic disease. In this review, we summarize current evidence linking liver dysfunction-particularly metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and cirrhosis-with an increased risk of heart failure and other cardiovascular diseases. We discuss how these liver conditions contribute to cardiac remodeling, systemic inflammation, and hemodynamic stress and how cardiac dysfunction in turn impairs liver perfusion and promotes hepatic injury. Particular attention is given to the molecular mediators of liver-heart communication, including hepatokines and cardiokines, as well as the emerging role of advanced research methodologies, including omics integration, proximity labeling, and organ-on-chip platforms, that are redefining our understanding of interorgan cross talk. By integrating mechanistic insights with translational tools, this review aims to support the development of multiorgan therapeutic strategies for cardiometabolic disease.

In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM).

SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (>36 vs.<30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD plus 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates versus reference (no SLD/MetS traits).

Median follow-up was 148 to 149 months. Comparing MASLD with one versus five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03-5.00) and 9.19 (4.98-16.95); for MetALD, aHRs were 1.65 (0.53-5.11) and 8.54 (3.65-19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19-1.92) and 4.81 (4.06-5.69) respectively; with MetALD, aHRs were 1.46 (1.00-2.13) and 4.64 (3.51-6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87-1.23) and 1.46 (1.29-1.66) respectively; with MetALD, aHRs were 1.01 (0.79-1.29) and 1.51 (1.24-1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72-42.61); 43.36, 20.53-91.58 respectively).

In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.

The prognostic value of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to evaluate the associations between the NHHR and all-cause and cause-specific mortality in patients with MASLD.

Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES III and the National Death Index (NDI). The NHHR was calculated according to the formula. The results of mortality associated with the NDI were recorded as of December 31, 2019. We used a multivariate Cox proportional hazard model and restricted cubic spline (RCS) regression to assess the associations between the NHHR and all-cause and cause-specific mortality. In addition, subgroup analyses were performed to explore the relationships between the NHHR and all-cause and cause-specific mortality.

This study included 3155 patients with a definite diagnosis of MASLD. A total of 1,381 (43.8%) patients with MASLD died, and 1,774 (56.2%) survived. Multivariate Cox proportional hazards model analysis showed that NHHR was not significantly associated with all-cause mortality in MASLD patients. The RCS curve showed a significant nonlinear trend between the NHHR and all-cause mortality in patients with MASLD. Subgroup analysis revealed that the NHHR was better suited to predict cardiovascular mortality in patients without advanced fibrosis.

Our study revealed the clinical value of the NHHR in the prediction of mortality in the MASLD population. The NHHR can be used as a biomarker for follow-up in people without advanced fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV.

MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV.

MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.

Lipoprotein lipase regulates triglyceride hydrolysis and contributes to cellular uptake of triglyceride-rich lipoprotein remnants. Multiple pathways modulate lipoprotein lipase activity, which has prompted interest in the development of drugs that increase lipoprotein lipase activity as means to reduce risk for acute pancreatitis, atherosclerotic cardiovascular disease, and metabolic dysfunction-associated steatohepatitis through reduction of circulating triglycerides and remnant cholesterol. The authors provide an overview of the target populations for agents that lower triglycerides and remnant cholesterol through increased lipoprotein lipase activity, the drugs being developed for these indications, including apolipoprotein C-III and angiopoietin-like protein 3, 3/8, and 4 inhibitors, and the epidemiologic and genetic evidence supporting the use of these drugs for the prevention of atherosclerotic cardiovascular disease and acute pancreatitis. In addition, the authors provide a corresponding overview of fibroblast growth factor-21 analogues that share many characteristics with these novel triglyceride-lowering drugs. Apolipoprotein C-III inhibitors, angiopoietin-like protein 3, 3/8, and 4 inhibitors, and fibroblast growth factor-21 analogues have pronounced triglyceride-lowering and remnant cholesterol-lowering effects. In clinical trials, apolipoprotein C-III inhibitors have been shown to lower risk for acute pancreatitis in patients with severe hypertriglyceridemia and are approved for this indication, while fibroblast growth factor-21 analogues reduce hepatic steatosis and fibrosis in patients with metabolic dysfunction-associated steatohepatitis. It remains to be seen whether these novel drugs may lower risk for atherosclerotic cardiovascular disease as well.

The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis.

The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome.

We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis.

Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission.

We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD.

We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007-2013) until death or 5 January 2023. Clinical and echocardiographic data were abstracted via manual chart review. Incident HF was defined as one of the following: (1) hospitalization for HF, (2) medical record diagnosis of HF, (3) ≥1 sign/symptom of HF and elevated natriuretic peptide, or (4) diastolic dysfunction on transthoracic echocardiography with ≥1 sign/symptom of HF. Univariable and multivariable logistic regression models were evaluated. Overall, 570 patients with biopsy-proven MASLD were included. The mean age was 49.5 years, 42.5% were male and 87.0% were non-Hispanic White. Ten patients (1.8%) had baseline HF, leaving 560 patients to assess for incident HF. Over a median follow up of 4009 days (11.0 years) (interquartile range 2270-4672 days), 100 (17.9%) patients developed incident HF while 268 (47.9%) met criteria for HF suspicion. In a multivariable model, increasing age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08, p < 0.001) and female sex (OR 1.85, 95% CI 1.12-3.04, p = 0.02) were associated with incident HF.

We found a high incidence of HF in patients with biopsy-proven MASLD. Despite nearly half of patients having suspected HF, very few carried a chart diagnosis. Screening for HF in high-risk patients and establishment of formal care pathways to address early HF may reduce morbidity and mortality.

This study investigates the knowledge, attitudes, and practices (KAP) of elderly patients with metabolic associated fatty liver disease (MAFLD). A cross-sectional study was conducted from August to October 2024, involving 404 patients in the Geriatrics Department of Shanghai Sixth People's Hospital. Participants provided demographic information and completed a structured questionnaire to assess KAP scores. A score of ≥ 70% was considered good for knowledge, attitudes, and practices. Structural equation modeling (SEM) was employed to analyze direct and indirect relationships among the KAP dimensions and identify the pathways through which knowledge and attitudes influence practices. The average age of participants was 72.43 ± 7.88 years. Knowledge, attitude, and practice scores were 13.47 ± 5.40, 28.68 ± 5.04, and 28.01 ± 4.61, respectively. SEM findings indicated that knowledge significantly influenced practice (β = 0.39, P < 0.001), and attitudes also notably impacted practice (β = 0.34, P < 0.001), though knowledge's indirect influence through attitudes was not significant (β = 0.03, P = 0.363). Overall, these findings highlight inadequate KAP among elderly patients with MAFLD, exemplified by 75.2% being unfamiliar of MAFLD's progression to cirrhosis or cancer, underscoring the need for targeted educational initiatives to improve self-management and health outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.