Urinary coproporhyrin isomers during therapy with IFn-RIBA in patients with chronic hepatitis due to HCV infection

Background : MRP2 transporter has a proven role in biliary export of many different products of hepatocytic metabolism. Particularly, human and animal models have demonstrated MRP2 role in biliary excretion of coproporhyrins: its preference for isomer I (CPI) export with respect to isomer III (CPIII) is responsable for the biliary CPI/CPIII ratio about 2-3:1 and the plasma and urinary CPI/CPIII ratio about 1:2-3. A significant reduction of MRP2 expression has been described in many different acquired cholestatic liver diseases and in patients with chronic hepatitis (CH) due to HCV infection. Aim of our study was to evaluate quantitative and qualitative (CPI/CPIII ratio) urinary CP excretion in patients with CH due to HCV before (T0), at 3 months (T3) and at the end of antiviral therapy (ET) (peg-IFN + Ribavirin)Materials and Methods: 60 patients (18 females, aged 46±11 years, genotype: 1 (31); 2(10); 3(15); 4(4); 51 naive) with istologically proven HCV-inducted CH were consecutively enrolled; 5 (8.4%) did not conclude the study. 10 healthy subjects sex- and age-matched were also considered for comparing the basal values. None of considered subjects had overt laboratory [i.e. serum alkaline phosphatase (AP) over the normal range] or clinical signs of cholestasis. All patients underwent a urinary evaluation (HPLC) of CPI excretion at T0, T3 and ET. SVR (n=34) was defined as serum HCV-RNA undetectable after 6 months of follow-up. Results: Basal serum FA levels resulted significantly related both to basal urinary total CPI (r=.405, p=.001), and basal CPI/CPIII ratio (r=.692, p=.000). Table I show Total urinary CPI e urinary CPI/CPIII ratio in controls and in HCV patients with respect to serum PA percentile.Table IPA ≥ 75°percentile(≥ 232 u/L) (n=16)(group A)PA < 75° percentile (<232 U/L) (n=44)(group B)Controls(n=10)Urinary CPI (g/g urinary creatinine)66.6 ± 29.4142.4±21.2232.6±12.3CPI/CPIII ratio1.71±0.610.75±0.510.38±0.121p<.012p<.05 with respect to controlsDuring IFN therapy, patients in group A significantly reduce both urinary CPI excretion (45±21 at T3 and 38±18 g/g urinary creatinine at ET, p<.05 and <.01 vs. T0, respectively) and CPI/CPIII ratio (1.1±0.4 at T3 and 0.55±0.32 at ET p<.05 and <.01 vs. T0, respectively) in case of SVR (n=10), whereas no significant effect was observed in subjects non responders to antiviral therapy (NR, n=6) . Patients of group B show a similar trend for normalization of CPI/CPII ratio and CPI/CPIII ratio (0.60 ±0.3 at T3 and 0.41±0.22 at ET, p<.05 and <.05 vs. T0, respectively) and reduction of CPI (39±12 at T3 and 36±11 g/g cretinine at ET, p<.07 and <.06 vs. T0, respectively) in case of SVR (n=24). Also in group B no significant modification of total CPI urinary excretion nor of CPI/CPIII ratio was observed in NR. Overall, a reduction of CPI/CPIII ratio >60% at T3 showed a 88% PPV for SVR, reaching 95% if considering only patients in group A.Our data indirectly confirm the effect of liver chronic infection due to HCV on MRP2 expression, whose alteration may be considered as the main responsible for the observed urinary CPI modifications (greater excretion with CPI/CPIII ratio inversion). Even if more confirmative data are needed, monitoring of urinary CPI excretion (especially CPI/CPIII ratio) may be a useful, cheap and simple tool in early prediction of the response to antiviral therapy in subjects affected by HCV CH, especially in the presence of mild laboratory signs of cholestasis.