الفهرس 
INTRODUCTION
Chronic Viral Hepatitis COnly 14 pages are availabe for public view
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Abstract
Chronic liver disease caused by infection with HCV is an important global health problem. Globally, there are almost 300 million people currently infected with HCV. The WHO estimated a worldwide prevalence of about 3%.
In Egypt viral hepatitis is hyperendemic as reported by many population-based serosurveys, especially hepatitis C, which is highly prevalent representing the most important viral threat to the Egyptian liver. Egypt has been documented as a country having relatively high prevalence rates reaching 20%. The prevalence in those under age 20 is still approximately 5-8%, demonstrating the continued presence of significant HCV transmission in Egypt.
The peak in HCV prevalence in the 40-54 year age group corresponds to the aging of the cohort of children infected through schistosomiasis intravenous treatments in the 1960s-70s. Following this initial founding event, the HCV epidemic has spread in the community through iatrogenic factors, and particularly injections. Approximately 90% of Egyptian HCV isolates belong to a single subtype, 4a, which responds less successfully to IFN therapy.
Treatment for HCV has gone through several milestones with the introduction of IFN in the early 1990s and the addition of RBV in the late 1990s. In today’s therapy mostly Peg-IFN is used showing significantly improved pharmacokinetics compared to the unmodified IFN. The primary goal of antiviral therapy is to prevent complications of HCV infection; this is principally achieved by eradication of HCV infection. Infection is considered eradicated when there is an SVR which is defined as the absence of HCV-RNA in serum 24 weeks after the end of treatment. Improvement in liver histology, including improvement in fibrosis, has been observed in patients receiving IFN-based therapy, particularly in those with an SVR.
Hepatic fibrosis is the most important factor for estimating clinical outcome and determining therapeutic strategy, especially IFN therapy, in patients with HCV-associated liver diseases. Liver biopsy has been for long regarded as the gold standard for staging of liver fibrosis in chronic liver disease. Liver biopsy has the advantage of obtaining direct information not only about fibrosis, but also about many useful parameters. However, biopsy is associated with potential morbidity and mortality and has several limitations.
In recent years, there has been increasing interest in the possibility of using non-invasive, surrogate markers measurable in the peripheral blood to assess the inflammatory activity and fibrosis in patients with chronic viral hepatitis, urging a deem need to probe in this field. YKL-40 a member of the 18 glycosyl hydrolase family is proposed to be one of these surrogate markers.
YKL-40 was shown to be strongly expressed in human liver tissue. In particular, HSCs contain YKL-40 mRNA. Several studies have found elevated YKL-40 concentrations in the sera of patients with liver diseases. It has been reported that YKL-40 serum level was elevated even in those with mild fibrosis, and correlated with histological fibrosis scores. Therefore, it has been demonstrated that serum YKL-40 measurement may be a serological marker of liver fibrosis and may be used as a noninvasive marker for evaluating the efficacy of IFN treatment in these patients.
from the aforementioned, it could be suggested that determination of serum YKL-40 level might open new avenues in the investigation, diagnosis and therapeutic monitoring of viral hepatitis, in an attempt to be considered as an additional useful marker of fibrosis in chronic viral hepatitis with the possibility of replacing follow-up biopsies. Its role in predicting outcome of IFN treatment has also been tackled.
The aim of the present study was to determine the level of YKL-40 in patients with HCV infection before and after receiving IFN treatment and to correlate it with the severity of liver damage as biochemically and histologically assessed. Levels of YKL-40 were also correlated with the results of the patients’ quantitative PCR for detection of HCV RNA before and after IFN treatment.
Five ml of blood was collected aseptically from each patient. Each blood sample was centrifuged and serum was separated and stored in 2 aliquots for each sample. Serum samples were collected from the 45 patients before receiving IFN treatment and after 6 months from start of treatment. Sera stored at -20 o C were used for assessment of YKL-40 level by means of EIA method. The second aliquot stored at -700C was subjected to the quantitative determination of HCV RNA by real time PCR, before and after 6 months from the start of treatment.
YKL-40 levels decreased significantly after treatment. The geometric mean before treatment was 102.68ng/ml while the geometric mean after treatment was 39.12ng/ml. In the 34 patients who gave response to treatment, the geometric mean of YKL-40 showed a statistically significant decrease more than that detected in the 11 patients who gave no response.
The levels of YKL-40 before treatment were higher in patients who gave NVR, with a geometric mean of 214.22ng/ml in comparison with those who gave a virological response, in whom the geometric mean of YKL-40 before treatment was 80.94ng/ml. This was statistically significant.
A needle biopsy was taken by the internist for histopathologic examination in all cases and specification of its outcome either steatosis, necroinflammation (grading), fibrosis (staging). More than half of the patients (55.56%) belonged to absent or minimal fibrosis stage (F0-F1). Patients belonging to activity grade 2 represented 48.9%, while those belonging to activity grades 1 and 3 represented 46.7% and 4.4% respectively.
The fibrosis scale was from 0-3, staging was according to METAVIR staging of fibrosis. The stages were subclassified into absent or minimal portal fibrosis (F0-F1) and significant fibrosis presented by stages (F2-F3) representing portal fibrosis with few septa (F2) and septal fibrosis without cirrhosis (F3). The level of YKL-40 increased as the stage of fibrosis increased. The geometric mean of YKL-40 level before treatment among the different stages in their ascending order was 54.37ng/ml and 227.29ng/ml. Levels of YKL-40 after treatment decreased significantly. In patients with mild stages of fibrosis (0, 1) geometric means of YKL-40 before and after treatment were 54.37ng/ml and 22.67ng/ml respectively. On the other hand the geometric means of YKL-40 before and after treatment in patients with significant fibrosis were 227.29ng/ml and 77.39ng/ml respectively. This improvement in levels of YKL-40 that was associated with staging was statistically significant.
The geometric means of YKL-40 before treatment were higher in activity grade 2 in comparison to activity grade 1. Levels of YKL-40 among patients of activity grade 1 decreased significantly after treatment as the geometric means of YKL-40 were 93.09ng/ml before treatment and 36.12ng/ml after treatment. Levels of YKL-40 among patients belonging to activity grade 2 showed a significant decrease after treatment with geometric mean 45.09ng/ml after intervention phase. The decrease in geometric mean of YKL-40 after treatment in the two patients belonging to activity grade 3 was not statistically significant.
Records of the patients have been reviewed and their routine laboratory investigations were utilized in the current study. Recorded data comprised: AST, ALT, alkaline phosphatase, albumin, platelets, GGT, prothrombin activity and total bilirubin. Levels of YKL-40 before treatment had direct correlations with AST, ALT, alkaline phosphatase, GGT, bilirubin and quantitative PCR for HCV RNA detection (before treatment). Its correlation with alkaline phosphatase, GGT and PCR was an interemediate direct statistically significant one. Levels of YKL-40 before treatment showed indirect inverse correlation with platelets, albumin and prothrombin activity. Its correlation with platelets and albumin reached a statistically significant level.
Levels of YKL-40 after treatment showed direct correlations with AST, ALT, alkaline phosphatase, GGT, bilirubin and PCR (after treatment). Its correlation with AST, alkaline phosphatase and PCR reached a statistically significant level. YKL-40 levels after treatment showed indirect correlations with platelets, albumin and prothrombin activity. These correlations were statistically significant.
ROC analysis was used to determine the diagnostic efficacy of YKL-40 in differentiating significant fibrosis stages (F2-F3) from absent and mild fibrosis stages (F0-F1). ROC analysis was also used to test its ability in predicting response to treatment. YKL-40 showed good diagnostic ability to discriminate stages (F2-F3) from stages (F0-F1) with AUC= 0.885. However YKL-40 showed a less efficient discriminating power in predicting response to treatment, AUC was 0.751.
from the aforementioned, the following could be concluded:
1- The majority of patients 63.6% who gave unfavorable response after treatment belonged to age group 40-<60 years, indicating tendency for absence of response to treatment with older age.
2- The values of YKL-40 after IFN treatment might promptly reflect the improvement of fibrogenesis and tissue remodeling, even if the virological response is not yet present.
3- YKL-40 levels might estimate the outcome of IFN treatment, since YKL-40 values before treatment were relatively lower in those who gave virological response than in the NVR group.
4- YKL-40 is associated with liver transaminases, alkaline phosphatase and quantitative PCR of the patients for HCV RNA detection. These observations suggest that measurement of YKL-40 serum levels in HCV associated liver diseases may be useful for monitoring liver fibrosis as well as fibrogenesis,
5- Levels of YKL-40 were more closely related to stages of fibrosis. Its level increased as the stage of fibrosis increased, indicating that YKL-40 can be considered in subjects with CHC, a useful marker to assess stage of fibrosis rather than reflecting the degree of activity.
6- YKL-40 proved to be more efficient in monitoring fibrosis in CHC patients than predicting response to treatment.