Plasma sgp130 is an independent predictor of non-alcoholic fatty liver disease severity

Background: Nonalcoholic steatohepatitis (NASH) is a metabolic disease associated with liver failure and cancer. Accurate monitoring of advancing NASH is challenging. There are few reliable, non-invasive biomarkers of early NASH. Since liver inflammation is a main driver of fibrosis, we investigated relationships between circulating components of the interleukin-6 signaling pathway (IL-6, sIL-6R and sgp130) and liver pathology in subjects with NAFLD and NASH. Methods: Predictive performance of plasma IL-6, sIL-6R and sgp130 were investigated in two independent cohorts: 1) patients with biopsy-confirmed NASH (n=49), where magnetic resonance spectroscopy (MRS), imaging (MRI) and elastography (MRE) assessed liver fat, volume and stiffness; and 2) patients with morbid obesity (n=245) undergoing bariatric surgery where Bedossa algorithm and steatosis, activity, and fibrosis scores assessed NASH severity. Correlations were evaluated between circulating IL-6, sIL-6R and sgp130 and anthropomorphic characteristics, plasma markers of metabolic disease or liver pathology, adjusting for covariates of liver disease such as age, sex, BMI and diabetes. Results: In patients with NASH, plasma IL-6 and sgp130 strongly correlated with liver stiffness, which for sgp130, was independent of age, sex, BMI, and chronic disease (diabetes, hyperlipidemia, hypertension or history of HCC). Plasma sgp130 was the strongest predictor of liver stiffness compared to commonly used biomarkers and predictive algorithms. Plasma sIL-6R correlated with liver volume independent of age, sex, and BMI. In stepwise forward regression analysis, plasma sgp130 followed by NAFLD fibrosis score and plasma globulin, predicted up to 74% of liver stiffness with/without adjustment for sex. In morbidly obese subjects, circulating IL-6 correlated with hepatocellular ballooning and sgp130 correlated with advanced liver fibrosis. Conclusions: Circulating sgp130 could represent a robust biomarker of active NASH and may be used alone or in combination with other biomarkers as a non-invasive measure of liver disease severity.