ABSTRACT
Paraoxonase [PON] is an ester hydrolase that catalyzes the hydrolysis of organophosphorus compounds, unsaturated aliphatic esters and carbamates. PON gene family contains three members: PON1, PON2 and PON3. PON I is tightly bound to HDL in serum to confer protection for LDL against oxidation. The liver plays a key role in PON1 synthesis as PON1 gene expression was only observed in the liver. The aim of this work was to investigate the relationship between serum PON1 level and the degree of liver damage in patients with chronic hepatitis, to study the genetic variability of serum PON1 and to evaluate the efficiency of serum PON1 assay in comparison with standard liver function tests in the assessment of liver damage. Thirty seven chronic hepatitis patients were included in this study. They were classified into; Group I: chronic hepatitis patients without cirrhosis [n = 21] and Group II: chronic hepatitis patients with cirrhosis [n = 16] and their results were compared to those of 15 healthy controls. Serum PON1 assay and PON1 genotyping for transitions at 192 and 54 positions were done for all subjects in addition to standard liver function tests including : total protein [TP], serum albumin [sAlb.], aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin [T bil.] and direct bilirubin [D bil.]. PON1 serum levels were significantly decreased in Group I compared to controls [p < 0.01, 52.5% decrease] and such decrease was even exaggerated in Group II when compared to controls [p < 0.01, 67% decrease]. Moreover, serum PON1 had significant positive correlations with TP and sAlb. and significant negative correlations with AST, ALT, ALP, T bil. and D bil. in patients' group [Group I and II together]. Regarding genotypes and allele frequencies for PONl enzyme at two polymorphic positions PONl[192] and PONl[54] in patients' and control groups, there were no significant differences in genotype or allele frequencies between patients and controls for either polymorphic site. Moreover the mean percent change of PONl level in different genotypes compared to controls in liver disease patients when reclassified according to genotypes was similar to percent decrease of PONl level independent of genotypes compared to controls [-52% in PONl in relation to 192 transition and -55% in PONl level in relation to 54 transition]. Moreover, different PONl genotypes [QQ, QR and RR for PONl[192] and LL, LM and MM for PON[154]] had significant positive correlations with TP and sAlb. and significant negative correlations with AST, ALT, ALP, T bil. and D bil. in patients' group. Stepwise multiregression analysis was performed in this study which revealed that serum PONl, AST and serum albumin constitute the best panel which can predict the presence of liver disease [F = 42.6, p < 0.01]. Moreover, diagnostic reliability for serum PONl and standard liver function tests were done at various cut off levels, Receiver Operator Characteristic Curve [ROC] was illustrated and area under the curve [AUC] was calculated for each parameter. In Group I, serum PONl had the best performance at 208 micro g/ml [80% sensitivity, 95% specificity and AUC = 0.89] followed by AST at 48 IU/L [72% sensitivity, 90% specificity and AUC - 0.85] and AUC for both parameters were significantly higher than AUC for the remaining parameters [p < 0.05]. In Group II, serum PONl performance was even better at cut off 139 micro g/ml [85% sensitivity, 95% specificity and AUC = 0.96] and its AUC was significantly higher than other parameters [p < 0.05]. There was a significant decrease of serum PONl level in chronic hepatitis patients [Group I and Group II] related to the degree of hepatic dysfunction irrespective of allele or genotype differences at positions 192 and 54 amino acids. Moreover, serum PONl, AST and sAlb. were found to be the best panel to predict the presence of chronic liver disease. Supporting this issue, the diagnostic performance of serum PONl followed closely by AST was the best in Group I, while the performance of serum PONl was far superior to that of other tests in Group II indicating a better over all performance for PONl for diagnosis of chronic liver disease specially severe forms [liver cirrhosis]. Hence, the addition of serum PONl assay to the current battery of liver function tests may improve the evaluation of chronic hepatitis patients