Serum endostatin is selectively reduced in non-steatotic chronic hepatitis C and normalizes after direct-acting antiviral therapy: a prospective cohort study

Background Endostatin is an endogenous inhibitor of angiogenesis that has been linked to chronic liver disease and proposed as a circulating marker of fibrosis in hepatitis C virus (HCV) infection. Although direct-acting antivirals (DAAs) reliably achieve viral eradication and improve liver-related outcomes, their effects on circulating endostatin have remained unknown. Materials and methods Serum endostatin levels were measured in 92 patients with chronic HCV infection and compared with those in 30 healthy controls. In a longitudinal subgroup of 58 patients, samples were available before treatment, at weeks 4 and 12 of therapy, and at sustained virological response 12 (SVR12). Serum from 85 patients was analyzed at SVR12. Results Patients with chronic HCV had significantly lower serum endostatin levels than healthy controls before therapy. This decrease was confined to patients without hepatic steatosis, whereas patients with steatotic liver disease exhibited endostatin levels comparable to those of healthy controls. Endostatin levels were not associated with advanced fibrosis or cirrhosis, as assessed by noninvasive fibrosis scores and ultrasound. In cirrhosis, serum endostatin levels were reduced after excluding patients with a glomerular filtration rate < 90 mL/min who had higher serum endostatin levels. During DAA therapy, serum endostatin increased in patients without steatosis and, by SVR12, reached levels similar to those in patients with steatotic liver disease and healthy controls. Endostatin was positively associated with age. After age adjustment, endostatin positively correlated with albumin, leukocyte and platelet counts, and negatively correlated with the model for end-stage liver disease score, bilirubin, international normalized ratio, glomerular filtration rate, and high-density lipoprotein. Because these variables did not differ between patients with and without steatotic liver disease, the differential regulation of endostatin in chronic HCV is likely driven by additional disease-specific mechanisms. Conclusions This study showed that chronic HCV is associated with reduced serum endostatin levels in patients without steatosis, which normalize after successful DAA therapy. Serum endostatin is not a marker of fibrosis severity in chronic HCV, either before or after viral clearance. Serum endostatin levels are increased in patients with impaired renal function, which is a confounding factor in patients with liver disease. Together, these findings provide preliminary evidence for a previously unrecognized pattern of endostatin dysregulation in chronic HCV that is almost reversed after antiviral cure.