الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Background: chronic hepatitis C infection (CHC) is a systemic disease affecting nearly 300 million people worldwide, is one of the main causes of chronic liver disease, is the commonest indication for liver transplantation and approximately 399 000 people died from hepatitis C. (WHO, 2019).CHC has been associated with several extra hepatic complications, such as essential mixed Cryoglobulinaemia, Porphyria cutanea tarda, Glomerulonephritis, Autoimmune thyroiditis, Sialadenitis, and Cardiomyopathy (Agnello et al., 1992; Johnson et al., 1993; Boadas et al., 1995; Gumber, 1995; Pawlotsky, 1995; Vanni et al., 2016).The available data suggest that patients with CHC might be characterized by a high prevalence of metabolic derangements (Mostafa et al., 2010; Adinolfi et al., 2011; Lonardo, 2014) some of which appear to be profoundly modified following viral eradication. Growing evidence shows that HCV increases the risk of incident type 2 diabetes mellitus (T2DM) in predisposed individuals (Carithers et al., 2000; Mehta, 2000; Mehta, 2003; White et al., 2008; Eslam et al., 2011; Vanni et al., 2016). The mechanism whereby HCV induces T2DM is insulin resistance (IR). HCV was shown to impair the hepatocyte insulin signalling pathway by several mechanisms, ( Kaddai and Negro, 2011) including the stimulus to the production of tumour necrosis factor-α (TNF-α), the serine phosphorylation of the insulin receptors (IRS), the over expression of the suppressor of cytokines (SOC-3) and the induction of SOC-7 (Pazienza et al., 2010).However, although HCV infects mainly the liver, whole body insulin sensitivity is also impaired in CHC patients without metabolic syndrome, as shown by recent studies (Vanni et al., 2009; Milner et al., 2010). This suggests that the infected hepatocytes might produce mediators that induce endocrine effects at extra hepatic sites, such as the skeletal muscle. The virus-induced metabolic derangements may interact with host-related genetic and environmental factors, aggravating insulin resistance and possibly leading to the development of T2DM (Vanni et al., 2016). An imbalance in the adipocytokine profile and the presence of liver steatosis /steatohepatitis could contribute to this scenario (Bernsmeier et al., 2013; Wójcik, 2014; Lemoine et al., 2015; Peta, 2015) Once it has occurred, T2DM contributes to the acceleration of the progression of liver damage, to an increase in the risk of hepatocellular carcinoma (HCC) development and to impairment of the response to antiviral therapy. Finally, a possible direct viral effect, together with a systemic chronic inflammatory state and the interaction with metabolic derangements, could play a role in the development of cardiovascular disease (Vanni et al., 2016).Diabetes mellitus is observed in more than 10% of patients with CHC. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis (Papatheodoridis et al., 2006).These observations raise the question as to whether HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus (Vanni et al., 2016).Little is known about the effect of direct acting antiviral agents (DAAS) on glycemic control. The aim of the work: The aim of our study is to assess the effect of treatment with DAAS on the glycemic state among HCV diabetic patients. Type of study: This study is case control study. Materials and Methods: Technical design: The study included 50 consecutive patients with T2DM before starting DAAs for treatment of chronic HCV. Diagnosis of HCV infection was confirmed by positive HCV antibody test by ELISA and positive PCR test for HCV RNA for more than 6months. All patients were treated by Sofosbuvir 400 mg &Daclatasvir 60 mg ± Ribavirin 800 mg for 3 months. The Study was performed at the Virology Clinic, Mansoura Specialized Medical Hospital, Mansoura University during the period from 2017 to 2018. Exclusion criteria: Type 1 diabetes mellitus. Hepatitis B. Cancer patients including hepatocellular carcinoma (HCC). Severe comorbid diseases (e.g. severe renal disease and severe heart diseases). Comorbid obesity. Methods: All cases were assessed before treatment with DAAS then reassessment after treatment was recorded. The patients were subjected to: A. Careful history: With special emphasis on history of hypertension, smoking, diabetic mellitus regarding duration of disease, and type of antidiabetic treatment; family history of diabetic mellitus; history of any endocrinal disease and other comorbid condition; and previous treatment with anti-HCV medicines (e.g. peg interferon plus ribavirin, sofosbuvir plus ribavirin, or other combination regimens), alcohol drinking and drug intake. B. Full clinical examination: Including general and abdominal examination with stress on anthropometric measurements including height (cm) and body weight (kg) to exclude comorbid obesity. C. Laboratory investigations: Complete Blood Count (CBC) (every 2 weeks). Homeostasis Model Assessment (HOMA) index (before and after treatment) [HOMA index = Fasting Insulin (micro U/L)× Fasting glucose (nmol/L) / 22.5]. Fasting Blood Glucose (FBG) and HBAIC level (%) (before and at the end of treatment and 12 weeks after the end of treatment). Alanine aminotransferase (ALT) (every 2 weeks). Aspartate aminotransferase (AST) (every 2 weeks). Serum bilirubin (every 2 weeks) (total and direct). International Normalized Ratio (INR). D. Radiological investigation: 1-Abdominal ultrasonographic (US) examination: All patients underwent US of the abdomen and pelvis. 2-Abdominal CT: To evaluate any focal lesion in the liver in suspected cases. Assessment of glycemic control: All patients were advised to maintain their usual diet regimen and physical activity, and for better evaluation of the improvement in IR and glycemic control, we used a composite end-point given by the reduction of FBG (of a minimum of 20 mg/dl) or HOMA-IR (of a minimum of 0.5) or HBA1c (of a minimum of 0.5%). Results: The mean age of the cases was 59.1 ± 8.83 years (Range 39-75 y). Regarding the gender distribution, 30 cases were males (60%) and 20 cases were females (40%).Performing US of the cases before treatment revealed that fibrosis or cirhosis were present in 29 cases (58%), normal liver found in 7 cases (14%) and fatty liver was found in 14 cases (28%). FBS, serum bilirubin, ALT, AST, HOMA index and INR revealed a statistically significant reduction after treatment with DAAs. In our study, only 32 patients (64%) showed glycemic improvement, 18 patients (36%) not achieved the end point of glycemic control. In our study, before treatment, there was a significant positive correlation between the HOMA index and HBA1c and fasting insulin. Also, there was a significant positive correlation between HBA1c and fasting insulin. After treatment, there was a significant positive correlation between the HOMA index and fasting insulin level only. Also the median values of HOMA index has no correlation with the US echo pattern of the liver before and after treatment with DAAs. Conclusion: HCV cases treated with DAAs medications have better glycemic control as regard fasting blood sugar, HbA1c and HOMA index. Diabetic patients receiving DAAs should be closely monitored during treatment for possible reduction of antidiabetic drugs, especially those treated with insulin and sulfonylurea, to avoid hypoglycemic events. Recommendations: Prospective studies should be conducted to define better the effect of DAAs on HCV suppression, to evaluate the long-term effects of DAAs on diabetes control, and to determine the sustained effects. Studies are needed to detect the effect of improvement of liver condition after DAA therapy on the complications of T2DM.