Abstract
Background & aimsSerum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.MethodsIn serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.ResultsIn 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.ConclusionsA strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
Highlights
Cholestasis is characterized by elevated hepatic and serum bile acids (BA) and may lead to changes in liver tissue such as acute hepatocellular toxicity, bile duct proliferation and fibrosis progression up to biliary cirrhosis [1]
In cholestatic hepatitis C virus (HCV) patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed
We recently described an association between genetic predisposition for cholestasis with a polymorphism in the gene coding for the bile salt export pump (BSEP; ABCB 11 1331C allele) and non-sustained virological response (SVR) in a HCV patient cohort [6]
Summary
Cholestasis is characterized by elevated hepatic and serum bile acids (BA) and may lead to changes in liver tissue such as acute hepatocellular toxicity, bile duct proliferation and fibrosis progression up to biliary cirrhosis [1]. In HCV patients, increased BA serum levels have been previously associated with a non-response to former antiviral treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV) and were proposed as predictors for the severity of liver fibrosis [3,4,5]. Increased BA levels are associated to direct acting antiviral treatment with ombitasvir/paritaprevir/ritonavir ± dasabuvir in a recent preliminary study of 20 HCV patients probably due to alterations of bile acid transport [7]
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