Ebtsam Zaher - Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
Abeer Ghazal - Microbiology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
Wael Ellabban - Queen’s Medical Center, Durham, UK
Mona El-Deeb - Clinical Pathology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
Lamyaa Al-Ghaleed - Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria, Egypt

Background: Egypt has the highest prevalence of hepatitis C virus worldwide. Monitoring hepatitis C-infected patients for hepatocellular carcinoma development is an important clinical issue to diagnose these patients during the potentially curable early-stage of disease. This study aims to evaluate the role of N-terminal procollagen III, matrix metalloproteinase- ۲, tissue inhibitor of matrix metalloproteinase-۱, alpha-fetoprotein, and conventional liver function tests as predictors of hepatocellular carcinoma development upon long-term followup of non-responding hepatitis C virus patients.Methods: The study included ۸۵۰ treatment-naïve hepatitis C virus genotype ۴a adult patients; after treatment, ۳۶۰ achieved sustained viral response while ۴۹۰ did not. Nonresponding patients had a ۵-year rate for hepatocarcinogenesis of ۸.۴% and a ۱۰-year rate of ۲۷.۵%. N-terminal procollagen III, matrix metalloproteinase-۲, tissue inhibitor of matrix metalloproteinase-۱, alpha-fetoprotein, and conventional liver function tests were evaluated in all patients before and after treatment, and after hepatocellular carcinoma development. The study also included a group of ۵۰ hepatocellular carcinoma patients who were negative for hepatitis C and hepatitis B viruses, and a group of ۵۰ healthy subjects as controls.Results: The non-responders had significantly higher age, stage, grade, viral load, alanine aminotransferase, and aspartate aminotransferase than responders. Also N-terminal procollagen III, matrix metalloproteinase-۲, tissue inhibitor of matrix metalloproteinase-۱, and alphafetoprotein were significantly higher in non-responders; after treatment they decreased in responders. In non-responders they remained higher than the control. The most significant risk factors for hepatocellular carcinoma development in non-responding hepatitis C virus patients were male gender and increased age, stage, grade, aspartate aminotransferase, Nterminal procollagen III, and tissue inhibitor of matrix metalloproteinase-۱. Patients with viral-hepatocellular carcinoma were of significantly lower age, higher grade, stage, γ-glutamyltransferase, N-terminal procollagen III, and matrix metalloproteinase-۲ than non-viral hepatocellular carcinoma patients. Percent positive N-terminal procollagen III, tissue inhibitor of matrix metalloproteinase-۱, and alpha-fetoprotein were significantly higher in viral hepatocellular carcinoma patients.Conclusion: Data suggest that high N-terminal procollagen III and tissue inhibitor of matrix metalloproteinase-۱levels after treatment might be particularly important as markers of hepatitis C virus-non-responding patients who are at higher risk of developing hepatocellular carcinoma, especially in older males with high stage and grade liver disease. However, studies of larger scale are needed to verify this suggestion.