The prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease has increased in parallel with a rise in consumption of ultra-processed foods (UPF), but little is known about their association.

We cross-sectionally examined associations of UPF with hepatic steatosis and fibrosis in 2458 (mean age 54 years; 55.9 % women) community-dwelling adults who completed vibration-controlled transient elastography and a food frequency questionnaire. Dietary intake was categorized into levels of food processing via the NOVA system. We used multivariable-adjusted logistic regression models to evaluate the association of energy-adjusted UPF intake (per 1-SD unit and by quintile) with clinical hepatic steatosis (Controlled Attenuation Parameter [CAP]≥ 290 dB/m) and fibrosis (Liver Stiffness Measurement [LSM] ≥ 8.2 kPa) and tested for linear trends of UPF intake with CAP and LSM. We adjusted for age, sex, smoking, alcohol intake, physical activity, and intake of minimally processed foods. Additional models adjusted for diet quality index or body mass index (BMI).

Higher intake of UPF was directly associated with higher odds of hepatic steatosis (Odds Ratio 1.33 [95 % Confidence Interval 1.21, 1.46] per standard deviation increase). UPF intake and CAP had a dose-response relation (Ptrend <0.001). There were 2.50 times higher odds of hepatic steatosis (Confidence Interval 1.81, 3.45) with a 19.49 (standard error: 3.73) unit increase in CAP (P < 0.001) when comparing quintile 5 to quintile 1 of UPF consumption. Higher UPF was not significantly associated with hepatic fibrosis. Adjustment for BMI attenuated the strength of all UPF-hepatic associations.

UPF consumption was positively associated with hepatic steatosis. Longitudinal studies are needed to assess whether lowering consumption of UPF can decrease odds of hepatic fibrosis.

To comprehensively evaluate the therapeutic efficacy of pioglitazone and SGLT2 inhibitors (SGLT2i) in patients with MASLD and Type 2 Diabetes(T2DM).

Electronic databases, including Web of Science, PubMed, the Cochrane Library, China National Knowledge Internet (CNKI), Wan-Fang Digital Database, and China Science and Technology Journal Database (VIP) were searched from inception to December 2024. Two reviewers independently assessed study eligibility, performed continuous data extraction， and independently evaluated bias risks. Liver ultrasonography, computed tomography (CT), and biochemical indices were utilized to determine the impact of treatment in both groups. Improvement in liver biomarkers and fibrosis as primary outcome indicators; Improvement in body composition, metabolic parameters, glucose parameters, and incidence of adverse effects as a secondary outcome indicator. For continuous variables, mean and standard deviation (SD) were extracted. RevMan 5.4 software was used to systematically analyze the literature, including heterogeneity testing, odds ratios (OR) calculation, and 95 % confidence intervals (CI) for each influencing factor.

Nine randomly controlled trials with 755 Asian participants were included. Our research showed that SGLT2i was more effective than pioglitazone in improving fibrosis-4 score (SMD 0.41 [95%CI 0.18,0.64] p = 0.005), visceral fat area (SMD 0.34 [95%CI 0.14,0.54] p = 0.0007), BMI (SMD 0.29 [95%CI 0.03,0.56] p = 0.03), and low-density lipoprotein levels (SMD 0.21 [95%CI 0.04,0.38] p = 0.01). In contrast, no statistically significant differences were observed in other outcomes.

Our study demonstrated that in patients with MASLD and T2DM, SGLT2i was more effective overall in improving liver fibrosis, blood lipids, liver fat, and body composition in the short term. These findings establish a theoretical basis for safe and rational drug use in clinical practice. Additionally, they may contribute to new insights into the pathogenesis of MASLD and type 2 diabetes and drug discovery and development efforts.

The 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.

A 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.

We 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.

Resmetirom 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.

The prognostic importance of changes in vibration-controlled transient elastography (VCTE) parameters, liver stiffness measurement (LSM), and controlled attenuation parameter (CAP), in individuals with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown.

A prospective cohort of 288 patients underwent 2 VCTE exams at least 2 years apart, and the relative percentage changes in LSM and CAP were calculated. Outcomes were the occurrence of any liver-related events (LREs), cardiovascular events (CVEs), and all-cause mortality. Multivariable Cox analyses, adjusted for liver and cardiometabolic factors, assessed associations between VCTE parameters changes, both as continuous and dichotomical variables (LSM increase >15% and CAP reduction >10%), and outcomes.

During a median follow-up of 6 years, there were 22 LREs, 28 CVEs, and 37 all-cause deaths. For LREs, baseline LSM was the strongest predictor, but LSM increases added further prognostic value (hazard ratio [HR]: 1.5 [1.0-2.1], 1-SD increment). For CVEs, both LSM increase (HR: 1.7 [1.3-2.3]) and CAP reduction (HR: 1.5 [1.0-2.3], 1-SD decrease) were significant predictors. For all-cause mortality, baseline CAP was a protective predictor. When classified into subgroups based on LSM and CAP changes, the subgroup with both increased LSM and reduced CAP had the highest risks for CVEs (HR:5.3 [1.4-19.6]) and all-cause mortality (HR: 3.4 [1.2-9.6]). The highest risk for LREs was observed in the subgroup with increased LSM without CAP reduction (HR: 3.5 [0.9-12.9]).

VCTE parameters changes, LSM increase and CAP reduction, provide prognostic information for adverse liver, cardiovascular, and mortality outcomes in individuals with T2D and MASLD.

Magnetic resonance elastography (MRE) can quantify tissue biomechanics noninvasively, including pathological hepatic states like metabolic dysfunction-associated steatohepatitis.

To compare the performance of 2D/3D-MRE using the gravitational (GT) transducer concept with the current commercial acoustic (AC) solution utilizing a 2D-MRE approach. Additionally, quality index markers (QIs) were proposed to identify image pixels with sufficient quality for reliably estimating tissue biomechanics.

Prospective.

One hundred seventy participants with suspected or confirmed liver disease (median age, 57 years [interquartile range (IQR), 46-65]; 66 females), and 11 healthy volunteers (median age, 31 years [IQR, 27-34]; 5 females).

Participants were scanned twice at 1.5 T and 60 Hz vibration frequency: first, using AC-MRE (2D-MRE, spin-echo EPI sequence, 11 seconds breath-hold), and second, using GT-MRE (2D- and 3D-MRE, gradient-echo sequence, 14 seconds breath-hold).

Image analysis was performed by four independent radiologists and one biomedical engineer. Additionally, superimposed analytic plane shear waves of known wavelength and attenuation at fixed shear modulus were used to propose pertinent QIs.

Spearman's correlation coefficient (r) was applied to assess the correlation between modalities. Interreader reproducibility was evaluated using Bland-Altman bias and reproducibility coefficients. P-values <0.05 were considered statistically significant.

Liver stiffness quantified via GT-2D/3D correlated well with AC-2D (r ≥ 0.89 [95% CI: 0.85-0.92]) and histopathological grading (r ≥ 0.84 [95% CI: 0.72-0.91]), demonstrating excellent agreement in Bland-Altman plots and between readers (κ ≥ 0.86 [95% CI: 0.81-0.91]). However, GT-2D showed a bias in overestimating stiffness compared to GT-3D. Proposed QIs enabled the identification of pixels deviating beyond 10% from true stiffness based on a combination of total wave amplitude, temporal sinusoidal nonlinearity, and wave signal-to-noise ratio for GT-3D.

GT-MRE represents an alternative to AC-MRE for noninvasive liver tissue characterization. Both GT-2D and 3D approaches correlated strongly with the established commercial approach, offering advanced capabilities in abdominal imaging compared to AC-MRE.

1 TECHNICAL EFFICACY: Stage 2.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease that is heterogenous in nature with various drivers and modifiers such as metabolic dysfunction and genetic factors. MASLD and the progressive subtype, metabolic dysfunction-associated steatohepatitis (MASH) represent the most rapidly increasing cause of liver-related mortality. There are limited treatment options for patients living with MASLD and MASH, various treatments with an array of different targets are under investigation and one therapeutic has been approved since the initiation of this study. Clinical trials investigating treatments for MASLD and MASH are associated with a high screen failure rate, driven largely by the regulatory required histological inclusion criteria for clinical trial eligibility. Other available clinically utilized biomarkers, typically referred to as non-invasive tests (NITs), can assess both the presence of steatosis and the severity of liver fibrosis in patients with MASLD and MASH in the clinic but are not yet approved over histological changes as endpoints for pivotal trials. However, the use of NITs have been demonstrated to increase the likelihood of meeting clinical trial entry criteria. All-Liver Interventional Global Network (ALIGN) is the first described multi-centre global observational screening study aimed at identifying individuals with a high likelihood of MASLD/MASH interested in participating in therapeutic clinical trials using non-invasive methodologies and genetic testing. This study represents a valuable prototype for industry and academic groups looking to evaluate large populations for MASH eligibility and interest in clinical trial participation.

Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in male mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.

The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).

Based on liver stiffness measurement by vibration controlled transient elastography (LSM by VCTE), the Agile 3+ and 4 are novel noninvasive scores that accurately identify advanced fibrosis (≥ F3) and cirrhosis (F4), respectively. We investigated and compared the Agile 3+ and 4 scores' performances in predicting adverse events to LSM alone, FIB-4 and Fibroscan-AST (FAST) score.

This retrospective analysis included NAFLD patients with LSM by VCTE and laboratory testing from a tertiary care center from 2013 to 2022. Adverse events were defined as major adverse liver outcomes (MALO), hepatocellular carcinoma, liver transplant, and death. MALO was defined as ascites, hepatic encephalopathy, or esophageal variceal bleeding. We used the Cox proportional hazard rate model and the Harrell's concordance (C) statistic to compare predictive performances.

733 total subjects with median follow-up of 27.0 months were included. Average age was 58.1 years and 32.8% had type 2 diabetes. Average alanine aminotransferase was 46.6 IU/L, aspartate aminotransferase: 34.5 IU/L, albumin: 4.4 g/dL, and platelets: 241.1 × 109/L. Fourteen subjects had 21 adverse outcomes, including 10 MALO, 5 HCC, 4 liver transplants, 3 progression of MELD score, and 6 deaths. Agile 3+ and 4 respectively had the highest C stats of 0.911 (C stat SE 0.028) and 0.909 (C stat SE 0.029) compared to LSM (C stat 0.857, C stat SE 0.045), FIB-4 (C stat 0.843, C stat SE 0.037) or FAST (C stat 0.703, C stat SE 0.085).

The Agile 3+ and 4 scores had the highest likelihood of accurately predicting adverse outcomes including MALO and death compared to LSM alone, FIB-4 or FAST score.

The prevalence of obesity and metabolic syndrome (MetS) is rising among liver transplant (LT) candidates, many of whom have Metabolic-Associated Steatotic Liver Disease (MASLD). Following LT, untreated obesity often causes recurrent MASLD. We treated patients with obesity with LT and concurrent sleeve gastrectomy (LTSG), aiming to determine long-term impact on obesity, MetS and recurrent MASLD after transplantation.

A multicenter retrospective cohort study analyzed patients undergoing LTSG using a single clinical protocol (n=72), and patients with BMI >30 who underwent LT alone for MASLD (n=185). Follow-up duration was 4-153 (median 41) months for LTSG and 12-161 (median 75) months for LT. Outcomes included mortality, graft loss, BMI, MetS components, allograft steatosis and fibrosis.

Mortality and graft loss were not significantly different between LT and LTSG patients. Post-LTSG patients had significantly lower prevalence of diabetes for >8 years (p<0.05); hypertension decreased from 61.1% to 35.8% (p<0.01). LTSG patients, with average starting BMI of 45.5, had significant weight loss compared to baseline for >9 years (p<0.001). LT-alone patients, average starting BMI 34.0, experienced no significant change in BMI or diabetes. Development of allograft steatosis was significantly lower in LTSG vs LT patients (p=0.004). Fibrosis prevalence was reduced in LTSG vs LT patients 3-10 years postoperatively; although not statically significant, relative risk ratio was 0.46 (p=0.09). One LTSG patient had a gastric sleeve leak; one required hiatal hernia repair. Severe GERD occurred in 11.1% of LTSG patients; risk factors included pre-existing diabetes and GERD.

LTSG results in sustained weight loss, resolution of diabetes and hypertension, and reduced recurrence of steatosis and possibly fibrosis compared to LT alone. It confers no increase in mortality or graft loss.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease globally. Based on the 2023 definition, MASLD is characterized by the presence of metabolic dysfunction and limited alcohol consumption (<140 grams/week for women, <210 grams/week for men). Given the significant burden of MASLD in Latin America, this guidance was developed by the Latin American Association for the Study of the Liver (ALEH) Working Group to address key aspects of its clinical assessment and therapeutic strategies. In Latin America, ultrasonography is recommended as the initial screening tool for hepatic steatosis due to its accessibility, while Fibrosis-4 (FIB-4) is preferred for fibrosis risk stratification, with further evaluation using more specific techniques (i.e., vibration-controlled transient elastography or Enhanced Liver Fibrosis [ELF] test). A Mediterranean diet is advised for all MASLD patients, with a target of 7-10% weight loss for those with excess weight. Complete alcohol abstinence is recommended for patients with significant fibrosis, and smoking cessation is encouraged regardless of fibrosis stage. Pharmacological options should be tailored based on the presence of steatohepatitis, liver fibrosis, excess weight, and diabetes, including resmetirom, incretin-based therapies, pioglitazone, and sodium-glucose cotransporter-2 inhibitors. Bariatric surgery may be considered for MASLD patients with obesity unresponsive to lifestyle and medical interventions. Hepatocellular carcinoma screening is advised for all cirrhotic patients, with consideration given to those with advanced fibrosis based on individual risk. Finally, routine cardiovascular risk assessment and proper diabetes prevention and management remain crucial for all patients with MASLD.

Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1-5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of Rspo3 phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease. RSPO3 expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.

The severe alpha-1 antitrypsin deficiency (AATD) genotype Pi*ZZ increases the risk of liver disease (AATD-LD) and lung disease. While non-invasive tests (NITs) are widely used for fibrosis stage and monitoring of all liver diseases, the consensus for use in AATD-LD is limited. A Delphi panel study was conducted to address this need.

Healthcare providers who managed at least two patients with AATD-LD in the past two years participated. Two iterative surveys were developed and administered. The second survey clarified the results from the first and provided deeper feedback. As follow-up, a real-time consensus-building exercise focused on survey topics without consensus. Controlled feedback was anonymous.

A total of 20 AATD experts (hepatology [n = 9], pulmonology [n = 6], transplant hepatology [n = 3], gastroenterology [n = 1], and hepatology and transplant hepatology [n = 1]) completed the study. A strong consensus was achieved around the use and evaluation of NITs for risk stratification and monitoring. All panelists agreed that vibration-controlled transient elastography (VCTE) is the preferred NIT for the initial assessment of AATD-LD owing to its accessibility and reliability. Magnetic resonance elastography and enhanced liver fibrosis tests were also considered valuable. Most (85%) agreed that VCTE < 8 kPa could indicate no or mild fibrosis and VCTE ≥ 8 kPa could indicate clinically significant fibrosis, which may correspond to fibrosis stage ≥ F2 on the METAVIR scale. Most (85%) agreed that VCTE ≥ 13 kPa may indicate cirrhosis.

Utilizing the Delphi technique, this study identified a clinically applicable framework for the diagnosis and monitoring of AATD-LD. A high level of agreement emerged regarding preferred NITs and their usage, risk stratification and monitoring in the context of AATD-LD management. The results provide a foundation for future efforts into NIT validation and the development of clinical guidelines for AATD-LD.

Data on cause-specific mortality in metabolic dysfunction-associated steatotic liver disease (MASLD) are limited. We aimed to determine the rate and risk of death from different causes in patients with MASLD compared to the general population in Sweden.

In this population-based cohort study, we identified individuals with an ICD-10 code for MASLD in inpatient or specialized outpatient care using Swedish healthcare registers 2002-2020 (n=13,099) and matched them with up to 10 controls (median 9) from the general population for age, sex, municipality, and calendar year (n=118,884). We used Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for eleven different primary causes of death. 15-year cumulative incidences of death were calculated while accounting for competing risks.

In total, 1,628 (12.4%) deaths occurred in patients with MASLD and 9,119 (7.7%) in controls during a median follow-up of 4.7 (interquartile range [IQR] 2.0-9.2) and 5.8 years (IQR 2.7-10.5), respectively. MASLD was associated with higher all-cause mortality (HR=1.85, 95%CI=1.74-1.96) and higher rates of all specific causes of death except mental health disorder. The strongest associations were observed for non-hepatocellular carcinoma (HCC) liver-related (HR=26.9, 95%CI=19.4-37.3) and HCC-related mortality (HR=35.0, 95%CI=17.0-72.1). However, the highest estimated 15-year cumulative incidence of death in patients with MASLD was for non-HCC cancer (7.3%) and cardiovascular disease (7.2%).

MASLD was strongly associated with liver- and HCC-related mortality, but the absolute risks of death were highest for non-HCC cancer and cardiovascular disease. Mortality was increased for nearly all causes in patients with MASLD, suggesting that earlier multidisciplinary care is needed to reduce excess mortality.

Previous studies on mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were either small, restricted to liver-related mortality, relying on liver biopsy to identify patients and thus inducing selection bias, or mainly using data from old cohorts. In a nationwide cohort study of all patients diagnosed with MASLD in inpatient or specialized outpatient care in Sweden between 2002 and 2020, we found a nearly doubled all-cause mortality rate and higher mortality than the general population from a wide range of causes, indicating that earlier multidisciplinary care may be needed to reduce premature mortality in patients with MASLD. The absolute risk estimates of death in our study may be useful for clinicians and policymakers to inform patients about their prognosis and potentially implement clinical or public health strategies to reduce premature mortality.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

The biological process of aging plays an important role in the progress of liver fibrosis. However, epidemiological evidence about the associations between advanced fibrosis and epigenetic age acceleration (EAA) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is limited.

We utilized publicly available DNA methylation data (GSE180474) for our analysis. Five EAA measures were calculated in this study, including IEAA, PhenoAA, GrimAA, DunedinPACE, and DNAmTLAA. Separate linear regression models were conducted to explore the associations between different fibrosis grades and each measure of EAA.

A total of 325 participants were included in this study, with a mean (± SD) age of 48.56 ± 11.50 years. Of these participants, 64.6% with no fibrosis, 16.9% with bridging fibrosis, 11.1% with incomplete cirrhosis, and 7.4% with cirrhosis. After adjusting for demographics and medication status, MASLD individuals with advanced fibrosis were associated with a 5% increase in the pace of aging (DunedinPACE, β = 0.05, 95% CI: 0.03-0.07) and a 10% decrease in DNAmTLAA (β = -0.10, 95% CI: -0.13 to -0.07) compared those without fibrosis. Similarly, higher stages of fibrosis were associated with an increased pace of aging (DunedinPACE, β = 0.02, 95% CI: 0.01-0.03, Ptrend < 0.001) and decreased DNAmTLAA (β = -0.05, 95% CI: -0.07 to -0.04, Ptrend < 0.001). However, no significant association was found between advanced fibrosis and IEAA, PhenoAA, and GrimAA.

Our findings suggest that advanced fibrosis was associated with an accelerated pace of aging, as measured by the third-generation EA measure DunedinPACE, and shorter telomere length, captured by DNAmTLAA, among individuals with MASLD. This finding has potential prognostic implications and suggests EAA may serve as a surrogate marker of therapeutic efficacy in MASLD.

No therapy has been shown to reduce the risk of major adverse liver outcomes (MALO) in patients with cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH). The Surgical Procedures Eliminate Compensated Cirrhosis In Advancing Long-term (SPECCIAL) observational study compared the effects of metabolic surgery and nonsurgical treatment in patients with obesity and compensated histologically proven MASH-related cirrhosis. Using a doubly robust estimation methodology to balance key baseline characteristics between groups, the time-to-incident MALO was compared between 62 patients (68% female) who underwent metabolic surgery and 106 nonsurgical controls (71% female), with a mean follow-up of 10.0 ± 4.5 years. The 15 year cumulative incidence of MALO was 20.9% (95% confidence interval (CI), 2.5-35.9%) in the surgical group compared with 46.4% (95% CI, 25.6-61.3%) in the nonsurgical group, with an adjusted hazard ratio of 0.28 (95% CI, 0.12-0.64), P = 0.003. The 15 year cumulative incidence of decompensated cirrhosis was 15.6% (95% CI, 0-31.3%) in the surgical group compared with 30.7% (95% CI, 12.9-44.8%) in the nonsurgical group, with an adjusted hazard ratio of 0.20 (95% CI, 0.06-0.68), P = 0.01. Among patients with compensated MASH-related cirrhosis and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MALO. In the absence of approved medical therapies for compensated MASH-related cirrhosis, metabolic surgery may represent a safe and effective therapeutic option to influence the trajectory of cirrhosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co-factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co-factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long-term clinical events regardless of, or worsened by, other metabolic risk factors.

In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub-phenotyping (e.g., 'lean MASLD'), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non-invasive tools into polygenic risk scores.

Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies.

We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs.

TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.

One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis.

The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee.

The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified.

The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion.

NCT05740358.

Liver fibrosis progression is influenced by older age and cardiometabolic risk factors such as obesity and is associated with an increased risk of cardiovascular events. While statins may protect against cardiovascular complications, their effects in elderly individuals with obesity and liver fibrosis are unclear.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) database was used to evaluate the effect of pravastatin on major adverse cardiovascular events in an elderly population (>70 years). Subjects were categorized by BMI: lean (<25 kg/m2), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). Liver fibrosis was assessed using the FIB-4 index: low risk (<2.0), intermediate risk (2.0-2.66) and high risk (≥2.67). Time-to-event data were analysed using the Cox proportional hazards model, adjusted for confounders and compared the placebo and pravastatin groups.

A total of 5.804 subjects were included. In the placebo group, the highest risk group (high FIB-4 and obesity) had a significantly higher hazard ratio for (non-)fatal stroke (HR 2.74; 95% CI 1.19-6.29) compared to the low FIB-4, lean BMI group. This risk disappeared in the same pravastatin group. Pravastatin did not affect other cardiovascular endpoints. All-cause mortality was significantly higher in subjects with lean weight and high FIB-4 on placebo (HR 1.88; 95% CI 1.14-3.11), but not on pravastatin (HR .58; 95% CI .28-1.20).

Elderly individuals with obesity and liver fibrosis are at higher risk for (non-)fatal stroke, which is reduced with pravastatin. Pravastatin also potentially lowers all-cause mortality in subjects with lean weight and liver fibrosis.

A novel noninvasive score, Agile-4 score, combining liver stiffness measurements, aspartate aminotransferase/alanine aminotransferase, platelet count, diabetes status and sex has been developed for the identification of cirrhosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed the performance of Agile-4 for ruling-in/out liver cirrhosis in MASLD patients.

We searched Medline, Cochrane library, Web of science, Scopus and Echosens website up to May 2024. Eligible studies assessed the accuracy of Agile-4 for ruling-in (≥0.565) and ruling-out (<0.251) liver cirrhosis, using biopsy as the reference standard, at predefined thresholds. We calculated pooled sensitivity and specificity estimates for both Agile-4 thresholds alongside 95% confidence intervals following bivariate random-effect models. We assessed the risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2 tool.

We included seven studies with 6037 participants. An Agile-4 score ≥0.565 yielded a pooled specificity of 0.93 (95% CI, 0.86-0.97). Similarly, an Agile-4 score <0.251 excluded cirrhosis with a summary sensitivity of 0.90 (0.80-0.95). Assuming a cirrhosis prevalence of 30%, the positive predictive value (PPV) for ruling-in cirrhosis was 80%, while the negative predictive value for ruling-out cirrhosis was 95%. Most studies were at high or unclear risk for bias due to concerns regarding patient selection and the blinding status of Agile-4 score interpretation in relation to biopsy results.

Agile-4 score performs well for ruling-in/out liver cirrhosis in MASLD patients. Owing to the relatively low PPV, sequential application of the Agile-4 after fibrosis-4 index (FIB-4) testing might further enhance its performance.

Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs' wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management.

Antifibrotic trials rely on conventional pathology despite recognized limitations. We compared single-fiber digital image analysis with conventional pathology to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic dysfunction-associated steatohepatitis.

Fifty-one patients with metabolic dysfunction-associated steatohepatitis enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among 3 hepatopathologists, and separately assessed by a digital image analysis platform (PharmaNest) that generates a continuous phenotypic Fibrosis Composite Severity (Ph-FCS) score. Fibrosis improvement was defined as: ≥1 NASH Clinical Research Network (NASH-CRN) stage reduction; "improved" by ranked pair assessment; reduction in Ph-FCS ("any" for ≥0.3 absolute reduction and "substantial" for ≥25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (ranked pair assessment), 74.5% (any Ph-FCS reduction), and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or ranked pair assessment had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for <48 weeks versus 39% for ≥48 weeks by NASH-CRN; 43% versus 61% by ranked pair assessment, mean Ph-FCS reduction -0.54 (SD: 1.22) versus -1.72 (SD: 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3, and enhanced liver fibrosis. Changes in Ph-FCS were positively correlated with changes in liver stiffness.

Continuous fibrosis scores generated in antifibrotic trials by digital image analysis quantify antifibrotic effects with greater sensitivity and a larger dynamic range than conventional pathology.

With a steadily rising prevalence, nonalcoholic fatty liver disease (NAFLD) was a leading global cause of liver-related health problems. In the clinical management of NAFLD, various western pharmaceuticals were widely utilized. This network meta-analysis aimed to evaluate the effectiveness of common western medications for NAFLD patients.

We systematically reviewed and screened articles based on predesigned criterion about western medications for NAFLD, which were from Embase, Cochrane Library, PubMed, CNKI, WanFang, and China Science and Technology Journal Database until August 1, 2024. Eligible studies included randomized controlled trials of patients aged 18 or older with NAFLD, comparing Western medicines to placebos or other Western medicine treatments. The risk of bias assessment tool 2.0 from the Cochrane system was used to assess the quality of the included articles. A Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 with a random-effects model and Markov Chain Monte Carlo methods. Treatment rankings were based on Surface Under the Cumulative Ranking Curve (SUCRA) values, and heterogeneity was assessed with I2 and Q statistics. The outcomes were analyzed in WinBUGS and visualized using Stata 14.0, generating network plots and cumulative probability rankings to compare treatment effects. The systematic review was registered in PROSPERO (CRD42024509176).

Based on 37 included articles involving 7673 patients, pioglitazone demonstrated the most significant effects in resolving nonalcoholic steatohepatitis without worsening fibrosis, increasing high-density lipoprotein cholesterol levels, and achieving a ≥ 2-point reduction in NAFLD activity scores (odds ratio [OR] = 0.09, 95% confidence interval [CI]: 0.01 to 0.81), with a SUCRA probability of 91.4%. Aldafermin showed remarkable effects in improving liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase, with cumulative probabilities of 90% for ALT and 69.8% for AST. Cluster analysis revealed that Resmetirom and Aldafermin were superior options for enhancing liver function, while pioglitazone emerged as the best treatment for the comprehensive improvement of NAFLD.

Pioglitazone outperformed other western medicines in terms of overall efficacy when treating NAFLD, but Aldafermin and Resmetirom showed superior improvement in liver function. This study provided a certain level of support for the use of specific clinical medications.

Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.

This study investigated the prevalence and causal relationships of chronic metabolic diseases (diabetes, hypertension, and dyslipidemia) with steatotic liver disease (SLD), specifically metabolically associated alcoholic liver disease (MetALD).

We conducted a comprehensive analysis using cross-sectional data from the KNHANES from 2011 to 2021 and the NHANES from 1999 to 2020. Longitudinal data from 2001 to 2014 from the KoGES were used. Participants were categorized into the metabolic dysfunction-associated SLD(MASLD), MetALD, and ALD groups based on their hepatic steatosis index (HSI), including liver profiles, body composition, and diabetes, and alcohol consumption. Multivariable, including age and smoking status, logistic and Cox regression analyses were performed to assess the prevalence and incidence of chronic diseases.

In both the KNHANES and NHANES cohorts, an increased HSI was significantly associated with a higher prevalence of chronic metabolic diseases. Longitudinal data from the KoGES cohort showed that MASLD and MetALD were significant predictors of chronic metabolic disease in both men and women. MetALD showed a higher hazard ratio for the development of chronic metabolic diseases than MASLD in Cox regression analysis.

This study highlighted the intertwined nature of SLD and metabolic health, with an emphasis on the role of MetALD. The significant association between MetALD and chronic metabolic diseases underscores the need for integrated management strategies that address both liver health and metabolic risk factors.

The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.

The aim of this study is to analyze association between liver fibrosis with CVE, incident diabetes, and cirrhosis complications.

Historic cohort of biopsy-proven MASLD patients, divided into two groups: F0-F2 vs F3-F4 fibrosis. Baseline data included metabolic traits and liver function tests. Patients were contacted and scheduled for laboratory analysis and elastography. Endpoints were (a) CVE, defined as any of acute myocardial infarction, coronary stenting, ischemic cardiopathy, and stroke; (b) incident diabetes; (c) cirrhosis complications. Baseline data were collected at the time of liver biopsy, while follow-up data were recovered through personal interview or medical records. A stepwise logistic regression determined predictive variables for each endpoint.

Study population included 220 patients with median age 53 years, and 145 were women; baseline fibrosis was F0-F2 in 165 patients and F3-F4 in 55 patients; median follow-up was 9.9 years. A higher percentage of F3-F4 patients had CVE (29.4%) than F0-F2 ones (13.1%) (hazard ratio 2.42; 95% CI: 1.26-4.6; P = 0.008). Incident diabetes occurred in 53.3% of F3-F4 and 20.2% of F0-F2 cohort (hazard ratio 3.04; 95% CI: 1.99-4.86; P < 0.001); cirrhosis complications occurred in 9/55 F3-F4 patients and in 1/165 F0-F2 ones (hazard ratio 26.3; 95% CI: 3.3-208.3; P = 0.002). Multivariate analysis confirmed liver fibrosis as an independent predictor of incident diabetes and cirrhosis complications. CVE were associated with baseline diabetes and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio.

In a cohort of 220 MASLD patients followed for 9.9 years, baseline F3-F4 was associated with incident diabetes and cirrhosis complications. AST/ALT ratio and diabetes were associated with CVE.

Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.