Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among patients with cardiovascular disease but remains underrecognized in routine cardiology practice. To address the limited prospective evidence on its progression and clinical impact, we established the CHAIN cohort, a prospective multicenter study enrolling approximately 15 000 adults undergoing coronary evaluation across 40 tertiary hospitals in China. Baseline assessment includes comprehensive cardiometabolic profiling and vibration-controlled transient elastography for evaluation of liver fibrosis and steatosis. Participants will undergo long-term follow-up with repeated liver assessments every 6-12 months. Primary outcomes include liver-related events and major adverse cardiovascular events, while secondary outcomes include longitudinal changes in liver fibrosis and steatosis and their associations with cardiometabolic risk factors and clinical outcomes. This cohort will provide longitudinal evidence to support risk stratification and integrated heart-liver management in cardiovascular care.
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in patients with primary biliary cholangitis (PBC). While metabolic comorbidities are expected to worsen outcomes, the clinical impact of MASLD in PBC remains uncertain. We investigated whether concomitant MASLD modifies hepatic and cardiovascular outcomes in patients with PBC.Methods We conducted a retrospective international cohort study using de-identified electronic health records from the TriNetX global research network, including 172 healthcare organizations between 2010 and 2025. Adult patients with PBC with and without MASLD were matched using propensity score matching (1:1) to balance baseline characteristics. The primary outcomes were all-cause mortality. Major adverse cardiovascular events (MACE) and hepatic decompensation were evaluated as secondary outcomes. Additional outcomes included hepatocellular carcinoma, liver transplantation, and one-year biochemical response (ALP normalization).Results Among 30 934 patients with PBC (78.9% female; mean age 68 years), 5955 (19.2%) had concomitant MASLD. After matching, 10 856 patients (5428 per group) were included. Over a mean follow-up of 4 years, patients with PBC-MASLD had a lower risk of all-cause mortality (HR 0.60; 95% CI 0.54-0.67) and hepatic decompensation (HR 0.82; 95% CI 0.71-0.93), but higher risk of MACE (hazard ratio [HR] 1.30; 95% CI 1.14-1.48). One-year biochemical response rates were comparable between groups. Findings remained consistent across multiple sensitivity analyses.Conclusion MASLD identifies a distinct metabolic phenotype of PBC characterized by increased cardiovascular risk but paradoxically lower mortality and hepatic decompensation. These findings highlight the need to integrate cardiovascular risk assessment into the management of patients with PBC.
BACKGROUND &AIMS:Growth differentiation factor-15 (GDF-15), a cell stress-induced cytokine, is implicated in liver disease pathophysiology. We investigated GDF-15 in cirrhosis, focusing on its association with disease-driving pathomechanisms, platelet function, hepatic decompensation, and mortality. METHODS:We included patients with cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital. Platelet surface P-selectin and glycoprotein IIb/IIIa (GPIIb/IIIa) expression after agonist stimulation were assessed by flow cytometry as platelet activation markers. GDF-15 serum levels were quantified by electrochemiluminescence immunoassay. RESULTS:Among 106 patients (median age 55.1 years; 70.8% male), median GDF-15 was 2880 (1850-4770) pg/mL. GDF-15 correlated with hepatic dysfunction (MELD Spearman's ρ: 0.50; albumin ρ: -0.57), HVPG (ρ: 0.47), systemic inflammation (C-reactive protein ρ: 0.45; interleukin 6 [IL-6] ρ: 0.55; procalcitonin ρ: 0.58), liver stiffness (ρ: 0.67) and enhanced liver fibrosis test (ρ: 0.64) (all p < 0.001). GDF-15 was higher in patients with detectable bacterial DNA in blood (3520 vs. 2250 pg/mL; p < 0.001) and correlated with lipopolysaccharide (ρ: 0.34; p = 0.010) and lipoteichoic acid (ρ: 0.37; p = 0.004). Platelet activation was not linked to GDF-15 after adjusting for liver disease severity, yet patients with undetectable GPIIb/IIIa activation after stimulation showed significantly higher GDF-15. Over a median follow-up of 51.5 (26.0-58.2) months, 38 patients decompensated and 21 died (61.9% liver-related). GDF-15 (aHR per 100 pg/mL: 1.015; 95% CI: 1.004-1.026; p = 0.007) predicted decompensation risk independently of HVPG, MELD, albumin and IL-6. Similarly, GDF-15 was associated with higher risk of all-cause (HR: 1.019; 95% CI: 1.009-1.029; p < 0.001) and liver-related mortality (HR: 1.019; 95% CI: 1.007-1.032; p = 0.002). CONCLUSIONS:GDF-15 is a promising biomarker in cirrhosis that reflects disease-driving pathomechanisms and independently predicts decompensation and mortality.
BACKGROUND & AIMS:Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated. METHODS:Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages. RESULTS:APOB carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (Padj = 3.6 × 10-7), particularly among those with obesity (p ≤ 0.003). The prevalence and incidence of CLD were consistently higher in carriers across all risk factor categories (p ≤ 0.01), with the strongest association in those with diabetes and obesity over 15 years of follow-up (Padj = 0.03). In contrast, APOB carriers as a whole had a 57% lower ASCVD risk (Padj = 0.009), with a similar atheroprotective trend across all risk factor categories. This corresponded to an absolute risk reduction of 2.30 ASCVD events/1000 person-years (p = 0.002) and an absolute increase of 3.48 CLD events/1000 person-years (p = 0.003). CONCLUSIONS:Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies.
BACKGROUND:There is limited evidence on the prevalence of, and factors contributing to, metabolic dysfunction-associated steatotic liver disease (MASLD) among individuals with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. METHODS:We consecutively enrolled 1304 adult individuals with T1DM (n = 237) or T2DM (n = 1067) who underwent vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) assessment. MASLD was defined as a CAP ≥ 248 dB/m in the presence of diabetes. Significant and advanced liver fibrosis were defined as LSM ≥ 8 kPa and ≥ 10 kPa, respectively. RESULTS:Compared to adult patients with T1DM, those with T2DM had higher prevalence rates of MASLD (65.7% vs. 38.4%, p < 0.001), significant liver fibrosis (18.6% vs. 5.1%, p < 0.001) and advanced fibrosis (9.8% vs. 3.8%, p = 0.003). Adiposity measures (higher BMI and larger waist circumference) and increased plasma triglyceride levels were the strongest predictors of MASLD in both patient groups. After a propensity score matching analysis for age, sex and BMI, patients with T2DM maintained a higher prevalence of MASLD (65.7% vs. 52.6%, p = 0.033) than those with T1DM, but they had similar rates of significant and advanced liver fibrosis. CONCLUSIONS:Patients with T2DM have higher prevalence rates of MASLD, significant and advanced hepatic fibrosis, as detected by VCTE, compared to adult patients with T1DM. Biomarkers of insulin resistance (such as higher BMI, larger waist circumference and higher plasma triglycerides) are equally important in explaining the presence of MASLD in patients with T1DM and T2DM.
Background & Aims Metabolic associated steatotic liver disease (MASLD) is increasing in prevalence worldwide. Clinical practice is focused on identifying those with cirrhosis and monitoring for complications such as varices and hepatocellular carcinoma (HCC). Non-invasive tests of fibrosis differentiate between F3 and F4 fibrosis poorly. People with F3 fibrosis may progress and develop decompensated liver disease. The aim of this review is to examine the progression to decompensated liver disease in patients with F3 fibrosis compared to those with F4 fibrosis.Methods Searches were carried out in four databases; articles were screened by two independent reviewers against pre-specified inclusion and exclusion criteria.Results Twenty-nine studies were included in the review: 12 with paired liver biopsies, 2 progression to cirrhosis, 13 progression to decompensation, 2 portal hypertension in F3 fibrosis and 13 on HCC in F3 fibrosis. Rates of progression on paired biopsies were 16%-30% over varied follow-up. Varices were found in 16% of patients with F3 fibrosis and rates of non-cirrhotic HCC varied from 37%-75%. Pooled univariate HR for F3 progression and F4 progression to major adverse liver outcomes (MALO) were 8.15 (95% CI 3.42-19.43) and 38.16 (95% CI 11.58-125.76), respectively.Conclusions Progression to cirrhosis and decompensation events occurs in a significant proportion of patients with F3 fibrosis in MASLD. There is evidence of portal hypertension and HCC developing in F3 MASLD. Further work to identify risk groups, including those at risk of rapid progression to guide future clinical management is urgently required given the prognostic inflection of decompensated disease.
Background & Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment.Methods To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism.Results Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion.Conclusions These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.
BACKGROUND AND AIMS:Early detection of individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is important as interventions to reduce steatosis can prevent progression to advanced liver disease. Identification of individuals with hepatic steatosis relies on imaging techniques, which are costly and often unavailable in large populations. Identifying hepatic steatosis through blood tests and demographics may serve as a cost-effective alternative to identifying hepatic steatosis. Here, we aim to identify demographic, serum and genetic variables that can help predict hepatic steatosis in two large population-based cohorts. METHODS:We analysed data from 32 008 participants in the UK Biobank (UKBB) with liver fat quantified using magnetic resonance proton density fat fraction (MRI-PDFF). We created non-invasive models to predict steatosis, the Enhanced Steatosis Indexes (ESIs), using logistic regression. Candidate predictors included variables from the literature and genetic markers. ESI-1 variables included demographic and serum values. ESI-2 included the ESI-1 variables plus the genetic markers. We trained and tested these models in UKBB and validated them in the Framingham Heart Study (FHS). RESULTS:In UKBB, ESI-1 and ESI-2 predicted ≥ 5% PDFF with AUC 0.844 and 0.858, respectively, outperforming DSI, HSI, FSI and FLI (AUC 0.818-0.834 vs. ESI-1 and AUC 0.830-0.844 vs. ESI-2). In FHS, ESI-1 and ESI-2 predicted CT-measured liver steatosis with AUC 0.803 and 0.808, respectively. CONCLUSIONS:We developed a non-invasive model to diagnose steatosis that outperforms existing steatosis models. Including genetic information improved the performance of ESI-2. Deployment of our models can facilitate non-invasive screening of steatosis so that, with early intervention, disease progression can be prevented. IMPACT AND IMPLICATIONS:We developed a non-invasive model based on demographic, serum laboratory and genetic predictors that outperforms existing steatosis indices in identifying individuals with hepatic steatosis. This Enhanced Steatosis Index (ESI) enables more accurate and personalised early detection of hepatic steatosis, a highly prevalent yet underdiagnosed condition. By leveraging readily available clinical measures and genetic data, both ESI-1 and ESI-2 improve risk stratification and support large-scale screening and early intervention efforts. These advances have the potential to provide more affordable, accurate and targeted screening, facilitating earlier treatment, reducing the burden of metabolic liver disease and helping to address disparities in the diagnosis and management of hepatic steatosis.
BACKGROUND AND AIMS:Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well-characterised MASLD. APPROACH:We identified clinically relevant variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as 'pathogenic' or 'likely pathogenic' (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. RESULTS:Twenty-two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB, 10 LDLR, 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p-value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p-value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p-value 0.75) and ALT (87.4 vs. 58.1 U/L, p-value 0.06). Their LDL-c (51 vs. 147.8 mg/dL, p-value 6.1E-09) and triglycerides (91.5 vs. 160.6 mg/dL, p-value 2.8E-03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL-c levels, but these were not statistically different. CONCLUSIONS:Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case-by-case basis.
This retrospective observational cohort study was conducted using 100% Medicare fee-for-service claims data (10/01/2015-12/31/2021) to characterise risk of incident extrahepatic cancer in patients with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and for patients with MASH who progressed to more advanced liver disease (compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplant). For patients with non-cirrhotic MASH, 5-year cumulative incidence was 3.1% for breast cancer, 2.8% for lymphoma/leukaemia, 2.6% for prostate cancer and 1.4% for lung cancer. The greatest hazard of cancer incidence was observed for bladder (hazard ratio [HR] = 2.36), kidney (HR = 2.15), liver (HR = 2.48) and stomach cancers (HR = 3.38; all p < 0.05), each relative to control individuals without MASH/metabolic dysfunction-associated steatotic liver disease. Additionally, patients who progressed to advanced liver disease experienced a significantly increased hazard of several extrahepatic cancers. This study provides some of the first evidence on the incidence and risk of extrahepatic cancer among patients with MASH in the United States.
The liver is central to sex hormone metabolism, and sex hormones in turn modulate hepatic physiology and disease processes. Oestrogens are often protective, while androgens tend to worsen disease progression. The clinical implications of hormonal therapies in patients with liver disease remain an area of active investigation. To review current evidence on the interplay between sex hormones and liver disease, with a focus on the safety and impact of hormonal therapies, including contraception, hormone replacement therapy, assisted reproductive technology and gender-affirming treatments. Prolonged or high-dose oestrogen exposure, particularly via oral contraceptives, has been associated with intrahepatic cholestasis and hepatocellular adenoma (HCA), especially in predisposed individuals. In contrast, hormone replacement therapy in postmenopausal women is generally safe and may confer metabolic and hepatic benefits. Oestrogens appear to slow fibrosis progression and reduce hepatocellular carcinoma risk, whereas androgens can promote steatosis and HBV-related oncogenesis. Hormonal therapies are safe in most patients with compensated chronic liver disease but require caution in settings such as in polycystic liver disease, where oestrogens can accelerate cyst growth. Emerging data also indicate a role of sex hormones in autoimmune and cholestatic diseases, as well as in outcomes of assisted reproduction and gender-affirming therapy. Hormonal therapies are feasible in most liver disease contexts, but individualised assessment, awareness of genetic predisposition, and disease-specific risks are essential to optimise safety and therapeutic benefit.
BACKGROUND:Alcohol-related liver disease (ArLD) is a public health concern that requires multidisciplinary interventions. Digital health tools may improve retention in alcohol use disorder (AUD) treatment and enhance health outcomes. This study explores a blended intervention (brief intervention plus a serious game (SG) based on motivational interviewing and cognitive-behavioural therapy) on AUD in patients with ArLD. METHODS:Randomised, single-blinded controlled trial on patients with recent-onset ArLD and AUD. Brief intervention plus the SG was compared to standard addiction therapy. Primary outcomes were AUD treatment retention and adherence at 6 months. Secondary outcomes included liver disease progression, alcohol use patterns, quality of life, functionality, motivational changes and usability. RESULTS:Seventy-nine patients (mean age 56, MELD-Na 14) were included. Participants in the intervention arm were three times more likely to remain in treatment at month six than those in the control arm (adjusted odds ratio (aOR) 3.24; 82.9% vs. 47.4% of engagement respectively) and attended 50% more appointments. Effect sizes (Cohen's D) were moderate for adherence at months three and six (0.51-0.64). At 6 months, Model for End-Stage Liver Disease Sodium (MELD-Na) scores were lower in the experimental group (12 vs. 16, p < 0.001). Among baseline drinkers, alcohol consumption decreased more in the intervention group at month one (11 vs. 6 Standard Drink Units (SDU)/day, p = 0.031). CONCLUSION:The blended intervention increases engagement with AUD treatment, reduces the amount of consumed alcohol and improves MELD-Na scores. These results support the use of digital tailored interventions for AUD in these patients.
