الفهرس 
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Abstract
Chronic hepatitis C (CHC) represents a leading cause of liverrelated mortality worldwide. CHC encompasses a wide spectrum of diseases, ranging from minimal disease to active hepatitis, which frequently progresses to cirrhosis and hepatocellular carcinoma (HCC). Due to the global epidemic of obesity, with parallel increase in nonalcoholic fatty liver disease (NAFLD), and to the direct effect of CHC on liver fat metabolism, liver steatosis has gained increasing attention as a modifier of CHC progression. Indeed, steatosis occurs in more than half of hepatitis C virus (HCV)-infected patients. Steatosis has been associated with more aggressive histological features, faster progression of fibrosis, and poorer response to therapy. Both viral and host factors are believed to contribute to CHC-related steatosis. A direct cytopathic effect of HCV has been proposed based on the higher prevalence of steatosis in CHC than in other liver diseases, a specific association with genotype 3 infection, and the induction of steatosis by viral proteins. Most lines of evidence support a strong association between steatosis and fibrosis severity in CHC. However, doubts have been cast as to whether steatosis is the causative factor driving accelerated hepatic fibrogenesis, or rather is a simple marker associated with increased fat stores and insulin resistance (IR), which would represent the culprits underlying disease progression. Genetic host factors have been hypothesized to influence steatosis development and insulin resistance in CHC. Lately, the adiponutrin/patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C>G single nucleotide polymorphism (SNP), encoding for the I148M protein variant, has been recognized as a genetic determinant of liver fat content, and to influence fibrosis severity in patients with NAFLD. In patients with HCV infection, homozygotes for the PNPLA3 I148M similarly have been reported to be associated with more steatosis, fibrosis, cirrhosis and HCC predominantly in Mediterranean populations. The mechanism whereby rs738409 influences liver fat is independent of body composition and IR, but likely involves a decreased ability of the PNPLA3 I148M variant to regulate hepatic lipid metabolism. Previous diverging reports have suggested that homozygosity for the PNPLA3 I148M variant, aside from being associated with more pronounced steatosis, also either negatively affects therapeutic outcome, or is not independently associated with treatment failure. Host genetics, for example, IL28B and PNPLA3, affect therapeutic outcome and liver disease severity in HCV-infected patients, especially in the setting of interferon-based therapy. Their impact on direct acting antiviral (DAA)- based treatment for HCV has diminished, but in the setting of shorter duration they appear to influence outcome following otherwise highly effective interferon-sparing regimens. Host genetic factors likely will remain significant for prediction of the natural course of HCV-related liver disease and may continue to be of importance for tailoring therapy, especially with regards to duration and possible benefit of the addition of ribavirin. Therefore, further investigations of their relevance for HCV infections may be warranted. Liver biopsy has been regarded as the gold standard for the assessment of steatosis and fibrosis. However, it has several limitations and complications. Owing to the limitations of the liver biopsy and the importance of screening and follow up of patients with chronic viral hepatitis and NAFLD patients for hepatic steatosis, fibrosis, and cirrhosis; the non-invasive diagnostic methods are obviously needed to detect early stages of hepatitis and start treatment or to monitor the changes of steatosis and fibrosis in trials of new drugs. Regarding the non-invasive assessment and quantification of liver steatosis, several large-scaled studies have used abdominal ultrasonography to assess fatty liver change. However, abdominal ultrasonography has a limitation to assess the degree of fatty liver because of the subjective interpretation by sonographers. Recently, transient elastography (FibroScan) has been emerged as a relevant tool for assessing the full spectrum of hepatic fibrosis, steatosis, cirrhosis, and its severity in liver diseases. Transient elastography has several advantages; it is quick, inexpensive, reproducible, and noninvasive and it can sample about 100 times larger portion of liver tissue than liver biopsy. In transient elastography, liver fibrosis is indicated by liver stiffness measurement (LSM), and steatosis, by controlled attenuation parameter (CAP) score. Several meta-analyses have demonstrated the usefulness of transient elastography for detection and semi-quantification of liver fibrosis and steatosis. In addition, CAP scores in transient elastography have been shown to be significantly correlated with the grades of steatosis in several studies. Evaluation of possible association of PNPLA3-I148M gene variant with liver fat content and the severity of liver fibrosis in patients with NAFLD and in those with CHC may provide predictive information regarding the risk of developing hepatic steatosis and liver injury in response to environmental stresses such as caloric excess, infections, or drugs. Furthermore, recent studies have reported that genetic polymorphisms of IL28B and PNPLA3 are predictive for HCV related rapid fibrosis progression and identify patients who require urgent antiviral treatment with new regimens. Although several previous studies have confirmed the important role of PNPLA3 I148M polymorphism in adults either with NAFLD or with CHC and in children with NAFLD among different ethnic groups in many countries, data on the relationship between this genetic polymorphism and CHC in children are lacking. Therefore, in this prospective study, we evaluated the possible association of the PNPLA3 I148M SNP with the severity of hepatic steatosis and fibrosis as assessed histologically and by FibroScan enriched with CAP in a group of normal weight Egyptian children and adolescents with CHC. The aim our study was: 1) to evaluate the possible association of PNPLA3-I148M gene variant with the severity of liver fat content and liver fibrosis and to explore the possible clinical relevance of these findings in normal weight children and adolescents with CHC. 2) to assess the relationship of liver stiffness and controlled attenuation parameter measured by FibroScan with the clinco-laboratory, and histopathological variables as well as the ultrasound grading of hepatic steatosis in children and adolescents with CHC. Patients and Methods This study was carried out upon fifty normal weight children and adolescents with chronic hepatitis C (CHC) as diagnosed by positive HCV antibodies and confirmed by positive PCR for HCV-RNA. These children were selected from those admitted to the Hepatology Unit of Pediatric Department, Tanta University Hospitals and Pediatric Department of National Liver Institute, Menoufia University, during a period from October 2016 to October 2018. Their ages ranged from 3 to 18 years.