Impact of insulin resistance and hyperferritenemia on Serum interferon gamma and early virological response to interferon therapy among Egyptian HCV patients

Introduction: Resistance to interferon therapy in HCV patients represents a major health problem. The aim of the study was to assess the effect of insulin resistance (IR) and hyperferritenemia on the antiviral and immunomodulatory activities of interferon alpha (IFNα) therapy in Egyptian patients with hepatitis C virus (HCV) Design and Methods: The current study is a prospective, observational casecontrol study, a total of 165 patients with HCV recruited from Internal Medicine and Tropical DepartementsMansoura University Hospital, Egypt were enrolled in the study. According to their response to IFN α therapy were classified into responders and non responders. Serum HCV m RNA, glucose, insulin, ferritin and interferon gamma (IFNγ) were measured. (IR) was estimated by the homeostasis model of assessment for insulin resistance (HOMA-IR). Results: Non responder patients revealed elevated levels of serum ferritin and HOMA index accompanied by elevated HCV m RNA and IFN γ levels as compared to responders patients (p<0.0001). Conclusions: The findings of the present study showed that IR and hyperferritenemia interfere with the antiviral and immnomodulatory effects of IFN α therapy as assessed by serum HCV m RNA and IFN γ levels respectively. [Maha E. Houssen, Abeer mesbah, Mona Arafa, Dina shahin. Impact of insulin resistance and hyperferritenemia on Serum interferon gamma and early virological response to interferon therapy among Egyptian HCV patients. Life Sci J 2014;11(1s):297-306] (ISSN:1097-8135). http://www.lifesciencesite. com. 55 key words: HCV, Insulin resistance, ferritin, IFN γ, IFNα Introduction: Hepatitis C virus (HCV) represents a major health problem worldwide. HCV patients are at risk of progressive liver disease which favors the generation of long term complications such as cirrhosis, end stage liver disease and hepatocellular carcinoma (Spengler and nattermann,2007) Interferons (IFNS) are key players in the innate immune response to virus infections (shoder et al., 2004). Type I interferons (IFN α, IFN β) are secreted by almost all virus infected cells and in much higher amounts by specialized T cells (Trincheri,2010). The type II IFN subtype is presented by a single gene product, interferon gamma (IFNγ), an inflammatory cytokine secreted primarily by activated T cells and (NK) cells and recognized for its antiviral and immunomodulatory effects (Horras et al.,2010) Treatment of HCV using combination of pegylated interferon (PEG-IFNα) plus ribavirin fails in about 50% of patients and is physically and economically demanding (Asselh et al., 2010). Thus, it is highly important to understand the mechanisms of non response and to identify factors that can help to predict the chance of each patient to respond to treatment (Lecube et al. 2006). Different factors are associated with non response to IFN α therapy including viral factors and host factors such as insulin resistance (Alberti et al., 2005) and iron overload (Shan et al.,2005; Fargion et al., 2002). On this basis the aim of the present study was to verify the impact insulin resistance and hyperferritenemia on modulation the antiviral and immunomodulatory effects of IFN α therapy assessed by serum HCV m RNA and IFNγ levels respectively. Subjects and methods: I. Study design The current study is a prospective, observational casecontrol study, conducted between January 2011 and January 2013 at Internal Medicine and Tropical DepartementsMansoura University Hospital, Egypt.Selected patients were assigned to pegylated interferon alpha-2a in a fixed dose of 180μg weekly by subcutaneous injections. All patients received ribavirin daily in an adjusted dose according to Life Science Journal 2014;11(1s) http://www.lifesciencesite. com 298 body weight; patients < 75 Kg were given 1000 mg and those> 75 Kg were given 1200 mg. the safety was assessed by clinical by clinical evaluation and laboratory tests at week 1, 2, 4 and monthly thereafter during treatment. Viral load, HOMA-IR, serum INF-γ, ferritin, fasting and postprandial glucose levels were assed by liver enzyme activities,, and fasting serum insulin levels were also measured at base line and 12 weeks after study entry. Patients were considered as having early virologic response (EVR) if they had HCV m RNA below the limit of detection or at least more than 2 log reduction after 12 weeks of the combination therapy. Subjects who failed to attain a decline in their HCV m RNA levels of >2log, as compared with baseline, at week 12 of combination therapy were considered non responders. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated with the formula defined by Matthews (Matthews et al., 1985) as follows: HOMA-IR= [fasting serum insulin (μIU/mL)×fasting serum glucose (mg/dL)×0.055∕22.5]. Insulin resistance was defined as HOMA-IR index>2.114. II. Inclusion criteria: Eligible patients were ≥ 18 years of age who had chronic hepatitis C (CHC), genotype 4, based on the presence of anti HCV and detectable serum HCV m RNA for 6 months or more in combination with a liver biopsy findings compatible with chronic viral hepatitis (Bedossa and poynard, 1996) In the preceding 12 months. All patients were treatment naïve. III. Exclusion criteria: Patients were excluded if they suffered from diabetes mellitus diagnosed according to the American diabetic association (ADA) classification criteria (American diabetes association, 2010). decompensated cirrhosis, other causes of liver disease, concomitant HBV, HIV, and schistosoma mansoni co-infection, autoimmune diseases. Patients with a history of alcohol intake, a serious concomitant medical conditions, and those with evidence of malignant neoplastic disease before the start of antiviral therapy were also excluded from the study. Pregnant females, females unwilling to practice contraception, non genotype 4 and age < 18 years were not eligible for the current study. The study was approved by the ethical committee of Mansoura School of Medicine, and informed consent was obtained from every study