Inflammation promotes liver fibrogenesis in humans with advanced chronic liver disease

Background and Aims The enhanced liver fibrosis(ELF) score is composed by serum markers of extracellular matrix remodeling that might represent the current state of liver fibrogenesis. Experimental evidence suggests that liver disease is considerably influenced by inflammation induced by bacterial translocation, however, studies in humans are limited. Accordingly, we investigated the association between markers of systemic inflammation and liver fibrogenesis in patients with advanced chronic liver disease (ACLD)/portal hypertension.

Methods ELF score, C-reactive protein(CRP), procalcitonin(PCT), and interleukin-6(IL-6) and were assessed in 177 prospectively recruited patients with a hepatic venous pressure gradient (HVPG) ≥ 6mmHg. Patients with clinically stable ACLD, and absence of pre-/posthepatic portal hypertension, evidence of bacterial infection, hepatocellular carcinoma beyond Milan criteria, and history of liver transplantation were included.

Results Serum levels of IL-6 (Spearman’s ρ = 0.358; P < 0.001), PCT (ρ = 0.486; P < 0.001), and CRP (ρ = 0.331; P < 0.001) showed significant correlations with ELF score and continuously increased across ELF tertiles (Figure; ** P < 0.01 and *** P < 0.001).Moreover, levels of IL-6 (6-9mmHg:5.45[3.50-9.65] vs.10-15mmHg:6.65[3.44-12.48] vs.≥ 16mmHg:7.75[5.34-13.76];P = 0.015), PCT (6-9mmHg:0.06[0.03-0.10] vs.10-15mmHg:0.07[0.04-0.16] vs.≥ 16mmHg:0.09[0.05-0.14];P = 0.009), and CRP (6-9mmHg:0.19[0.06-0.28] vs.10-15mmHg:0.20 [0.08-0.41] vs.≥ 16mmHg:0.29[0.14-0.59];P = 0.009) increased with portal hypertension severity. To investigate the association between systemic inflammation and the dynamic process of liver fibrogenesis markers, we subsequently stratified/adjusted our analysis by HVPG.In patients with subclinical portal hypertension(HVPG 6-9mmHg), only PCT showed a significant correlation with ELF. Importantly, in patients with HVPG 10-15mmHg/≥ 16mmHg, IL-6 (ρ = 0.304;P = 0.026/ρ = 0.353;P < 0.001), PCT (ρ = 0.488;P < 0.001/ρ = 0.406;P < 0.001), and CRP (ρ = 0.456;P = 0.001/ρ = 0.232;P = 0.020) were directly correlated with ELF. Moreover, IL-6 (B = 0.022;P = 0.006) and PCT (B = 7.841;P < 0.001) were linked to ELF, even after adjusting for HVPG. IL-6, PCT, and HVPG were independently associated with ELF in multiple linear regression analysis.

Conclusion We observed a link between markers of systemic inflammation and ELF that is independent from portal hypertension severity, providing evidence for the role inflammation induced by bacterial translocation as an important driver of the dynamic process of liver fibrogenesis in humans.

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Publication History

Article published online:
26 May 2020