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Azimova Sevara Bakhodirovna, Junior Researcher, Scientific Research Institute of Hematology and Blood Transfusion, Republic of Uzbekistan Karimov Hamid Yakubovich, Head of laboratory, Scientific Research Institute of Hematology and Blood Transfusion, Republic of Uzbekistan Zakirkhodzhaev Sherzod Yahyaevich, Professor of the Tashkent Medical Academy E-mail: evovision@bk.ru
MODERN ASPECTS IN PREDICTING THE CLINICAL COURSE OF CHRONIC HEPATITIS C
Abstract: the aim of the study was to evaluate the diagnostic significance of markers of inflammatory activity and fibrosis in the clinical course of chronic HCV infection. The subject of the study were 107 patients with chronic hepatitis C and liver cirrhosis, as well as 80 healthy donors. The revealed changes in the clinical characteristics, biochemical parameters, genotypes of the virus C, polymorphism of inflammatory regulators and isoenzymes of cytochrome P450 and their interrelation should be taken into account in predictive diagnosis of the disease and in the development of further tactics of therapeutic measures. The obtained data can serve as an additional factor in assessing the risk of progression of the disease course and liver damage and be taken into account when discussing indications for therapy.
Keywords: Chronic hepatitis C, genetic profile.
Relevance. Due to the wide prevalence and high in- the widespread, increasing incidence, peculiarities of cidence of viral hepatitis C present an urgent medical the clinical course and the formation of complications and social problem for world medicine. Infection with leading to disability, an intensive study of the problem hepatitis C virus on average 85% of cases leads to chron- of chronic hepatitis C is underway. ic infection, prolonged viral replication, progressive dam- This problem is being actively studied by domestic
age to liver tissue, development of fibrosis and cirrho- and foreign researchers.
sis. According to various estimates, 20-30% of patients Important issues of medical practice are the develop-
with chronic viral hepatitis C (CVHC) develop cirrhosis ment of methods for predicting the course of H-infection within 20 years, the character of fibrosis progression be- and the improvement of therapy, based on an under-ing nonlinear [1]. The problem of chronic hepatitis and standing of the pathogenesis of the progression of HCV. cirrhosis of the liver, in addition to widespread use, is In recent years, there have been significant successes in due to the development of complications and unfavor- the study of some mechanisms of the progress of CHC. able prognostic effects in persons of working age [2; 3]. It is established that such factors as gender, age at the
It should be noted that the lack ofpronounced symp- time of infection, obesity, drug use, alcohol abuse are tomatology and delayed adverse outcomes often make it of great importance. However, the importance of other difficult to diagnose the disease in a timely manner. prognostic factors, such as regulators of inflammation of Despite the advances in the study of the pathogenesis cytokines and cytochrome P450 isoenzymes that affect ofviral liver damage, up to the present time questions of the clinical course of the disease, is not fully understood assessing the prognosis of the course and outcomes of to date, and the results of previous studies are contradic-chronic viral hepatitis remain open. In connection with tory [4; 5].
The aim of the study was to evaluate the diagnostic significance of markers of inflammatory activity and fibrosis in the clinical course of chronic HCV infection.
Material and methods. The subject of the study were patients with CVHC and cirrhosis of the liver, as well as healthy donors, in which DNA samples were obtained. According to the results of clinical and laboratory studies, 107 patients aged 22 to 81 years were included in the main group. All patients were persons of Uzbek nationality living on the territory of Uzbekistan.
To assess the association of polymorphic markers of the genes TNF-a, CTLA-4 and cytochrome P450 isoenzymes by polymerase chain reaction, the representatives of the main group were divided into three subgroups. The first subgroup included patients with HCVC with a moderate degree of activity (n = 33). The second group consisted of patients with HCVC with a high degree of activity (n = 37). The third group included patients with cirrhosis of the liver (n = 37). Diagnosis of chronic viral hepatitis C and liver cirrhosis was established on the basis of a set of clinical and laboratory and instrumental examination data, generally accepted in clinical hepatology.
Research results and discussion. In the course of the study, HCVC patients were divided into subgroups depending on the activity of alanine aminotransferase. In assessing the clinical manifestations of liver damage, the following syndromes have been identified in patients enrolled in the study: asthenic, manifested by fatigue, irritability, rapid fatigue, painful (heaviness and/or pain in the right upper quadrant), dyspepsia (abdominal discomfort, lack of appetite, belching, heaviness in the epigastric region). It should be noted that only in 86.9% of patients clinical manifestations of asthenic nature were found. These data demonstrate the importance of targeted clinical examination in patients with CHC and indicate the need for "alertness" to liver disease in patients with asthenic, dyspeptic and pain syndromes. A significant role in assessing the activity of the hepatic process in viral hepatitis is given to the study of the level of activity of serum aminotransferases, bilirubin, gamma-glutamyltransferase, alkaline phosphatase. Biochemical blood indices revealed cytolysis syndrome in patients, which was characterized by an increase in the activity of alanine aminotransferase (ALAT) and aspartate aminotransferase (ACAT) in the blood serum, and cholestasis syndrome, which was manifested by hyperbilirubinemia, increased activity of
alkaline phosphatase and gamma-glutamyltransferase. Patients also had mesenchymal inflammatory syndrome (an increase in thymol test) and hepatic-cell insufficiency syndrome (change in albumin content).
During the research it was revealed that in the subgroup of patients with moderately active HCVF, the ALT level exceeded the norm values by an average of 6.6 times. The activity of ALT in a subgroup of patients with highly active HCVC was 2.5 times higher than in the first subgroup. In a subgroup of patients with cirrhosis of the liver, the ALT level in our study was the lowest (3.3 times), but still significantly exceeded the control parameters. It should be noted that among all persons of the main group the most significant increase in ALT was observed in carriers of polymorphic variants of A/A TNF-a in the 1 and 2 subgroups (199.1 ± 25.37 U/L and 454.1 ± 31.0 U/l, respectively). In the third subgroup, the genotype G/G of the CYP2E1 gene (91.4 ± 0.0E/l) had the highest level of ALT.
In the study of AST in a subgroup of patients with moderately active HCVF, the level of this indicator exceeded the average values by 4.4 times, and in the subgroup of patients with a highly active HCVF it was 9.8 times higher. In a subgroup of patients with cirrhosis of the liver, the AST level exceeded the control indicators by 5.5 times. Evaluation of the effect of genotypic variants of the studied polymorphisms on the AST level showed that the highest values of this index in the first and second subgroups of patients were associated with the polymorphic version of TNF-a (A/A). At the same time, in the subgroup of patients with moderately active HCVC, this indicator was 114.2 ± 11.41 U/L, in the subgroup of patients with a highly active HCVC, 285.2 ± ± 10.60 U/L. In the subgroup ofpatients with cirrhosis of the liver, the most significant increase in the AST concentration was observed in carriers G/G CYP2E1 (147.3 ± ± 4.60 U/L). In the subgroup of patients with moderately active CVH, the bilirubin level exceeded the norm by an average of 3.1 times, and in the subgroup of patients with high active CVHC and with cirrhosis - 3.9 and 3.5 times, respectively. Evaluation of the influence of genotypic variants of studied polymorphisms on the level of bilirubin showed that the highest values of this index in the second and third subgroups of patients were associated with polymorphic variant CYP2E1 (G/G). And in the first subgroup the highest concentration of
bilirubin was observed in carriers of TNF-a (A/A). At the same time, in the subgroup of patients with moderately active HCVC, this indicator was 54.6 ± 3.19 ^mol/l, in the subgroup of patients with highly active HCVC, 64.1 ± 0.0 ^mol/l, in the subgroup of patients with cirrhosis of the liver - 73,1 ± 0,0 ^mol/l. In our study in a subgroup of patients with moderately active HCVF, the level of alkaline phosphatase (AFP), which is an indicator of cholestasis syndrome, was 3.7 times higher than the normals, and 6.4 times in the subgroup of patients with highly active HCVF. In a subgroup of patients with cirrhosis, the level ofAFP decreased in comparison with the second group, but exceeded the control indicators by 4.4 times, and remained above the parameters of the first subgroup. Evaluation of the effect of genotypic variants of the studied polymorphisms on the level of alkaline phosphatase showed that the highest values of this index in the first subgroup ofpatients were associated with polymorphic variants of TNF-a (A/A) and was 317.2 ± ± 65.98 U/l. And also high indexes ofAP in the first subgroup were observed in carriers CYP2E1 (S/C) - 290.2 ± ± 17.36 U/l. In the second group of patients - with polymorphisms CYP2E1 (G/G) - 592.7 ± 0.0 Ud/l and CTLA4 (G/G) - 569.1 ± 41.10 U/l. In the third group of patients, the highest values of AF were observed in patients with polymorphism CYP1A2 (A/C) - 376.6 ± ± 13.10 U/l. In our study it was shown that the level of GGT in patients with moderately active HCVC exceeds the norm by an average of 6.5 times. In patients with highly active HCVC, higher GGT values were observed and exceeded the norm by 7.5 times. When the disease progressed to the stage of liver cirrhosis, the GGT value in all cases was significantly decreased in comparison with both the second (P < 0.05) and the first group (p < 0.05), although it exceeded the control parameters by 3.3 times. Evaluation of the influence of genotypic variants of studied polymorphisms on the level of gamma-glutamyltransferase showed that the highest GGT indices in a subgroup of patients with moderately active HCV were associated with polymorphic variants of TNF-a (A/A) - 182,7 ± 12,15 U/l. The highest GGT indices in the subgroup of patients with highly active HCVF were associated with polymorphic variants of TNF-a (A/A) - 198,3 ± 13,05 U/l, and CYP2E1 (G/G) - 221,3 ± 0,0 U/l. The highest GGT indices in a subgroup of patients with liver cirrhosis were associated
with polymorphic variants of CYP2E1 (G/G) - 88,1 ± ± 0,0 Ud/l, CTLA4 (G/G) - 83.8 ± 4.20 U/L and CY-P1A2 (C/C) - 91,1 ± 0,70 U/l.
In addition, in all the study groups, a close correlation was found between the activity of cytolysis and cholestasis with polymorphic variants of the studied regulators of inflammation and isoenzymes of cytochrome P450 (p < 0.05).
The analysis of the obtained data showed that, regardless of the genotypic variant of polymorphism, the level of all the studied biochemical parameters was significantly deviated from the normal values (control). Shifts of the biochemical parameters studied by us changed in one direction or another as the inflammatory process progressed in CVHC and during the transition of the disease to the stage of cirrhosis. However, the genotypic variants to some extent determined the severity of the abnormality. The results indicate that polymorphic variants associated with a high level of cytolysis and cholestasis may be markers of unfavorable CVHC.
Among the patients examined, genotypes of HCV were determined. The prevalence analysis showed that the genotype dominated and amounted to 72.9%. Our studies showed that genotype 3a was 23.4% of patients. Genotype 2a was less common than other identified genotypes (3.7%).
The relationship between the studied biochemical parameters and the genotypes of the virus C in patients with existing subgroups was analyzed. Thus, in the first subgroup, the most pronounced changes in biochemical parameters, in particular AST, ALT, bilirubin, were noted in carriers of the genotype of the hepatitis C virus. In the group of patients with transition to cirrhosis, carriers with a 3a genotype were distinguished by the severity of clinical and biochemical indices. In patients with cirrhosis of the liver, biochemical parameters were higher in those who had a genotype of 2a.
Conclusion. Summarizing the above data, it can be concluded that among the patients with chronic liver pathology the genotype 1c of the virus C prevailed. In addition, the features of the clinical course and association of the genotype of virus C with biochemical indices were determined at different severity of the course of CVHC. The main clinical manifestations were accompanied by pronounced cholestatic, cytolytic characteristic syndromes. Also, the determination of the genetic
profile in patients with CHC may serve as an additional factor in assessing the risk of progression of the disease course and liver damage and be taken into account when discussing indications for therapy.
Risk alleles were identified that characterize the progressive type of HCV flow, which can influence the production ofpathogenetically significant factors, which leads to the activation ofpathological mechanisms (genotype G/G of the CYP2E1 gene and genotype C/C of
the CYP1A2 gene) and characterizing the "favorable" type of disease progression - (genotype of the A/A gene of TNF-a).
The revealed changes in the clinical characteristics, biochemical indices, genotypes of virus C, polymorphism of inflammatory regulators and isoenzymes of cytochrome P450 and their interrelation should be taken into account in predictive diagnosis of the disease and in the development of further tactics of therapeutic measures.
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