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.