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.
