GDF ‐15 Levels in Cirrhosis Are Linked to Hepatic Fibrogenesis, Bacterial Translocation, and Worse Clinical Outcomes

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.