Plasma myeloperoxidase levels correlate with hepatocellular carcinoma in chronic hepatitis C

Abstract

Myeloperoxidase (MPO) is an enzyme responsible for generating hypochlorous acid and reactive oxidants that may lead to liver injury and cancer in hepatitis C (HCV) infection. MPO expression level is regulated by a polymorphism in the promoter region −463 of MPO gene. In the current study, MPO plasma levels and the G-463A MPO polymorphism were determined in 158 chronically HCV infected patients with and without hepatocellular carcinoma (HCC). MPO plasma levels were determined using a commercially ELISA kit. The G-463A MPO polymorphism was accessed by real time PCR using TaqMan probes. The MPO plasma levels of patients with HCV-HCC were higher in comparison to patients with chronic hepatitis or with those patients with severe fibrosis (p = 0.01 and p = 0.04, respectively). The MPO G-463A polymorphism was not associated with HCV outcome. These findings suggest MPO levels monitoring may be a potential biological marker to HCC screening in patients with HCV.

Introduction

Chronic hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). It is the fifth most common malignancy and the third leading cause of cancer death worldwide [1]. The estimated risk of hepatocellular carcinoma is 15–20 times higher in persons infected with HCV comparing to those who are not infected, with most of the excess risk limited to those with advanced hepatic fibrosis or cirrhosis [2].

HCC early detection is important, since effective treatments are now available for the management of non-advanced neoplasms [3]. Currently, HCV high-risk patients have been screened with the use of alpha-fetoprotein (AFP) serum levels and serial abdominal ultrasonography. Studies have demonstrated controversial usefulness of AFP level determination for HCC diagnosis [3], [4], [5]. Thus, development of novel biomarkers for the early detection of HCC remains an important target for the HCC surveillance and early intervention in HCV infected patients.

The mechanisms by which HCV infected individuals with severe stage of fibrosis develop HCC are still unknown. Studies have demonstrated that oxidative stress, which results from the generation of reactive oxygen species (ROS), has been implicated with HCC development [6].

Neutrophils and macrophages (Kupffer cells) contain myeloperoxidase (MPO), an enzyme stored in large amounts in azurophilic granules of these cells and which catalyzes the reaction between chloride (Cl⁻) and hydrogen peroxide (H₂O₂) to generate hypochlorous acid (HOCl) and other reactive oxygen species (ROS) [7].

Cellular levels of MPO are influenced by a promoter polymorphism at position G-463A preceding the MPO gene. The G/A base exchange creates an SP1 transcription factor binding site in the G allele, and an estrogen receptor binding site in the A allele. The GG genotype is associated with higher expression of MPO than the GA and AA genotypes [8], [9].

Therefore, in the current study, MPO plasma levels were measured in chronically HCV infected patients with and without HCC. We also analyzed the frequency of the G-463A MPO polymorphism and its influence in the MPO plasma levels.