Impact of Polymorphisms in the Endobiotic and Xenobiotic Metabolism Involved Enzymes Coding Genes on Chronic Hepatitis C and Acute Toxic Hepatitis. Summary of the Doctoral Thesis

Abstract

Endo– and xenobiotic metabolism pathways are not separated in the human body. Proteins involved in these pathways are including many proteins starting with the enzymes, which direct substrate are endo– or xenobiotic, followed by proteins, that regulates enzyme and their coding gene activity and proteins involved in the transport of these substances in the cell and the body (transport proteins receptors). The main detoxification processes in the human body are ongoing in the liver, and if they are changed, it can cause liver and other organ damage. The thesis are discussed two most common causes of liver injury and its consequences – alcohol induced liver toxicity and hepatitis C virus–induced chronic liver damage. Study subjects comprised 60 patients with acute alcohol induced hepatitis. Eight genetic markers of the genes UGT1A1, GSTA1, GSTP1, NAT2, GSTT1 and GSTM1 were genotyped. There were analysed biochemical markers and their association with clinical outcome of toxic hepatitis as well as with analysed genetic markers. In our study was proved that female gender is risk factor for alcohol toxic hepatitis. Prothrombin and alkaline phosphatise could be used as markers for severity of hepatitis. GSTT1 null genotype was identified as a risk allele for alcohol toxic hepatitis progression. GSTT1 null genotype was found to correlate negatively with the level of prothrombin and positively with hyaluronic acid. For patients who died of toxic liver damage more frequent slow acetylation encoding alleles (NAT2 gene) were found, that were associated also with higher levels of GGT and alkaline phosphatase. There were 233 patients included in the study with chronic viral hepatitis C, 162 of them received antiviral therapy. In the case group morphological, biochemical and genetic factors (polymorphisms in genes GSTT1, GSTM1, UGT1A1, CCR5, SERPINA1, ATP7B, HFE) were analysed. There was discovered that higher levels of hyaluronic acid and GGT, leukocyte count and more progressed fibrosis are associated with lower possibility to reach sustained viral response. Hyaluronic acid and cytokeratine–18 should be included in non–invasive tests in order to predict sustained viral response. From analysed genetic markers clinical outcome of chronic viral hepatitis C were influenced by GSTM1 null genotype and polymorphisms in the CCR5 and SERPINA1 genes.