Serum pro-collagen III peptide levels are related to lobular necrosis in untreated patients with chronic hepatitis C.

OBJECTIVE: Liver biopsy is mandatory for correctly grading and staging chronic hepatitis activity. Nevertheless, serum markers of fibrogenesis may be useful to help us understand the mechanisms of the fibrogenic process, to follow-up patients, and to establish the efficacy of therapy. In this study, our aim was to identify the relationships between pro-collagen III peptide (PIIIP) serum levels and detailed liver histology in a group of untreated patients with chronic hepatitis C (CHC). METHODS: We studied 147 CHC patients. Correlation analysis of PIIIP serum levels was performed in 109 patients, after having excluded those with alcohol abuse or concomitant hepatitis B virus infection. PIIIP serum levels were assessed using an assay that measures both Col 1-3 peptide (reflecting collagen synthesis) and Col 1 peptide (reflecting collagen degradation). Relationships of serum PIIIP with histology was carried out by evaluating grading and staging separately. Moreover, each component of the necro-inflammatory score was also taken into consideration. RESULTS: PIIIP levels were abnormal in 101 patients (93%). Moreover, PIIIP levels were no different between patients with (12.1 +/- 6.3 ng/ml) or without (13 +/- 5.8 ng/ml) fibrosis. In univariate analysis, no relationship was observed with fibrosis (rs = 0.033, not significant), while PIIIP levels were significantly correlated with lobular necrosis only (rs = 0.295, P = 0.0020). Multivariate analysis confirmed this latter finding (P = 0.0150). Among biochemical parameters, PIIIP showed relationships with aminotransferase (AST, rS = 0.294, P = 0.0022; ALT, rs = 0.236, P = 0.0142) and alkaline phosphatase (rs = 0.146, P = 0.0223). CONCLUSIONS: In patients with CHC, serum PIIIP levels reflect histological parameters strictly related to fibrogenesis. Therefore, PIIIP is a useful tool to evaluate ongoing fibrogenic activity of CHC. A complete histological score is needed in order to understand the relationships between biochemical markers of fibrogenesis and histology.

Tauroursodeoxycholic acid administration as adjuvant therapy in cirrhotic patients on transplantation waiting lists.

BACKGROUND/AIMS: The lack of organ availability and an increased number of end-stage cirrhotic patients has led to the lengthening of liver transplantation waiting lists. The progressive worsening of clinical and functional performance in patients awaiting the graft is one of the factors implicated in the increased mortality during the wait and in poor transplantation outcome. In this work our aim was to evaluate the effects of tauroursodeoxycholic acid administration on biochemical, clinical and functional parameters in a group of cirrhotic patients consecutively placed onto our liver transplantation waiting list. METHODOLOGY: Ten cirrhotic patients underwent biochemical, clinical and functional evaluation at the time of entering on our liver transplantation waiting list, then tauroursodeoxycholic acid was administered until liver transplantation. Complete evaluation was repeated every 2 months. The results were compared to those of a comparable historical control group that had undergone liver transplantation the year before the study. RESULTS: All patients were transplanted within 6 months from insertion on the waiting list. Longitudinal analysis of the treated group showed that cholestasis and cytolisis parameters constantly decreased and that gamma-glutamyl transpeptidase was significantly lower compared to baseline values at the 4th month of therapy. Clinical and functional parameters remained stable during follow-up. Comparison with the control group showed that gamma-glutamyl transpeptidase, alkaline phosphatase and both aminotransferases were reduced at the 4th month of therapy. Fewer days of hospital stay and less intensive care were required in the treated group. CONCLUSIONS: Treatment of end-stage cirrhotic patients awaiting liver transplantation with tauroursodeoxycholic acid improves biochemical parameters of cytolisis and cholestasis, and furthermore helps to maintain clinical and functional stability during the wait. Improved biochemical conditions and steady clinical-functional performance may promote better short-term transplant outcome.

Probability of non-response during interferon therapy in patients with chronic hepatitis C.

BACKGROUND/AIMS: About 50% of patients with chronic hepatitis C do not respond to interferon therapy and this failure is expensive. The aim of this study was to identify possible predictive factors of biochemical non-response during interferon therapy among biochemical, virological (HCV genotype), histological (Knodell's score) and pharmacokinetic (monoethylglycinexylidide formation test) pre-treatment parameters. METHODOLOGY: Our study included 60 patients with chronic hepatitis C undergoing a course of Interferon therapy. Patients whose serum ALT levels were normal at the 3rd month of therapy and remained so until the end of treatment were regarded as responders. RESULTS: In univariate analysis, only the gamma-glutamyltransferase (gamma-GT) and the gamma-GT/alanine aminotranferase ratio were significantly higher in non-responder patients. Multivariate logistic analysis showed that high gamma-GT levels, high histological activity index, low monoethylglycinexylidide formation rate and viral genotype 1 were the best combination for the identification of non-responder patients (16.7% error rate). By adding alanine aminotranferase modification at the 1st month of therapy the probability error was reduced to 5%. CONCLUSIONS: These results show that the combination of biochemical, histological, virological and pharmacokinetic pre-treatment variables, associated with alanine aminotranferase modification at the 1st month of therapy, can predict non-response to interferon and allow therapeutic modifications.

Can the MEGX test and serum bile acids improve the prognostic ability of Child-Pugh's score in liver cirrhosis?

BACKGROUND: Liver transplantation is nowadays the therapeutic option for end-stage liver disease. Correct disease staging is the main step towards improving the timing of listing for liver transplantation so as to avoid premature or late entry. The need for correct prognostic evaluation is due to the limited number of donors and to the increasing number of patients awaiting transplantation. Our aim was to verify whether Child-Pugh's score might be improved by adding the monoethylglycinexylidide (MEGX) formation test and/or serum bile acid determination. METHODS: We evaluated 182 cirrhotic patients (44 Child-Pugh class A, 97 class B, and 41 class C) of mixed aetiology referring to a tertiary care centre for functional staging of liver disease. These patients were prospectively followed-up for 12-72 months. During this period, 45 patients died, 46 received a transplant, and 91 survived without transplantation. The end-point of analysis was either survival or liver disease-related death at the 6th, 12th, 18th and 24th months of follow-up. The 46 transplanted patients were excluded from the study upon transplantation. RESULTS: In our study, a cut-off for Child-Pugh's score < 8 confirmed its usefulness, especially in short-term prognostic prediction, while mid- and long-term prediction improved by almost 10% by using the combination of a Child- Pugh's score > 8 and an MEGX value < 15 mg/l. Cox's multi-variate regression analysis indicated that MEGX values either with Child-Pugh's score or with prothrombin activity and ascites were independent prognostic variables. CONCLUSIONS: Besides confirming that Child-Pugh's score as the basis of prognostic evaluation of cirrhotic patients, these results suggest that the MEGX test might be a complement to the original score when a patient is being evaluated for a liver transplantation programme.

Chronic liver disease related to hepatitis C virus: age of patients seems to be a determinant of severity independently of viral genotype.

BACKGROUND: Hepatitis C virus infection accounts for varying severity of chronic liver disease. Clinical manifestations of infection have been related to different virus genotypes, with conflicting results. DESIGN: We performed a cross-sectional study on a Northern-Italian group of patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma related to hepatitis C virus infection in order to verify the association of different viral strains and the outcomes of viral disease. METHODS: Two hundred and seventy-one patients referred to our unit for liver disease were studied and clinical, biochemical, histological, and functional parameters were investigated. RESULTS: Different viral genotypes were not associated with peculiar findings in any of the degrees of liver disease. However, a progressive age increase was associated with disease severity, although clinical and functional staging of cirrhotic patients with hepatocellular carcinoma was better compared to tumour-free cirrhotic patients. There was an increased prevalence of genotype 1b related to the age of the patients. In multivariate regression analysis the patients' age and apparent duration of infection were independently associated with the presence of cirrhosis and only the age of patients was associated to hepatocellular carcinoma. CONCLUSIONS: In the population we studied age of the patients seemed to be a determinant conditioning disease severity, likely reflecting older infections and long-standing liver disease. The prevalence of certain genotypes in varying degrees of liver disease could be an epiphenomenon which might also be explained by the changing prevalence of infecting strains over the past decades.

Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats.

The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (i.p.) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected i.p. with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno-assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 +/- 18 to 164 +/- 13 ng/mL) and a parallel increase in lidocaine levels (from 73 +/- 22 to 172 +/- 47 ng/mL), consistent with cytochrome P-450 3A inhibition. Both GSH and NAC produce a significant decrease in MEGX levels (151 +/- 16 and 139 +/- 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre-treatment using either GSH or NAC with cimetidine produced a marked decrease in lidocaine levels (37 +/- 27 and 63 +/- 28 ng/mL, respectively) and no modification of MEGX levels (155 +/- 12 and 165 +/- 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of cimetidine.

Lidocaine elimination and monoethylglycinexylidide formation in patients with chronic hepatitis or cirrhosis.

BACKGROUND/AIMS: The aim of this study was to evaluate the relationship between plasma elimination of lidocaine and monoethylglycinexylidide (MEGX) formation, which is considered to be a quantitative liver function test. METHODOLOGY: The study included ten healthy subjects and 54 patients: 27 with chronic hepatitis and 27 with cirrhosis. Lidocaine and MEGX were measured at 0, 2, 5, 10, 15, 30 min and then every 30 min for 180 min using the TDX system. RESULTS: In cirrhotic patients, the lidocaine half-life of the slow decline phase of the plasma disappearance curve (beta-HL) and the lidocaine half-life of hepatic elimination from the second compartment (K20-HL) proved to be significantly abnormal, as did all parameters of MEGX formation. In chronic hepatitis, both the lidocaine kinetics and the MEGX formation parameters were within the normal range. In chronic hepatitis patients, MEGX formation (AUC 0-180) was significantly correlated to K20-HL (rs = -0.633, p < 0.001) and to the rapid decline phase of the plasma disappearance curve (alpha-HL, rs = -0.483, p < 0.05). In cirrhotic patients, MEGX was significantly correlated to K20-HL (rs = -0.423, p < 0.05) and to beta-HL (rs = -0.500, p < 0.01). CONCLUSIONS: These results show that in chronic active hepatitis, MEGX formation from lidocaine is maintained as a metabolic process, whereas it is altered in cirrhotic patients. The interrelationship between lidocaine elimination and MEGX formation were somewhat different in the two liver diseases.

Monoethylglycinexylidide formation measurement as a hepatic function test to assess severity of chronic liver disease.

OBJECTIVES: Monoethylglycinexylidide (MEGX) is the main lidocaine metabolite and its formation depends on liver microsomal activity. MEGX formation was studied in comparison with the histological score of chronic hepatitis and with the clinical score (Child-Pugh) of cirrhosis. Furthermore, we evaluated its ability to distinguish between the two liver diseases. METHODS: We studied 284 patients: 130 with chronic hepatitis (on the basis of the histological activity index, 45 had mild chronic hepatitis, 54 had moderate chronic hepatitis, and 31 had chronic hepatitis with cirrhosis) and 154 with cirrhosis (49 Child-Pugh's class A, 78 class B, and 27 class C). MEGX formation was evaluated 15, 30, and 60 min after lidocaine administration. RESULTS: MEGX formation showed a stepwise decline corresponding to worsened liver disease. MEGX values were related both to the histological score in chronic hepatitis and to the clinical score in cirrhosis. Significantly lower values were found in females < 50 yr of age than in males of the same age. The MEGX test showed great efficacy in discriminating between chronic hepatitis and cirrhosis compared with standard liver tests. CONCLUSIONS: Measurement of MEGX formation proved to be a safe test, allowing us to show that functional subgroups can be identified both in chronic hepatitis and in cirrhosis. Thus, this test could integrate both the histological grading of chronic hepatitis and the clinical staging of cirrhosis.

Caffeine clearance in subjects with constitutional unconjugated hyperbilirubinemia.

To investigate the behaviour of caffeine (CAF) in patients with Gilbert's Syndrome (GS), a combined oral loading test of caffeine and chenodeoxycholic acid was performed in 14 healthy subjects and 71 patients with GS. Indocyanine green (ICG) kinetics was tested in 50 subjects with GS and in all control subjects. Fasting serum bile acids (SBA) and clearance after CDCA loading were within normal range in normal and GS subjects. No significant difference in levels either of bilirubin or of SBA was observed in GS cases with normal (52 cases, 488 +/- 63 ml/min) or impaired (19 cases, 338 +/- 30 ml/min) caffeine clearance. Eleven GS cases showed altered ICG clearance. No correlation was found between bilirubin and bile acids, CAF or ICG. Fasting SBA were normal even in cases of CAF or ICG altered kinetics, thus excluding structural damage in unconjugated hyperbilirubinemia. CAF altered kinetics in 27% of GS cases may suggest multiple deficits in the hepatocellular metabolism, thus confirming the heterogeneity of this syndrome.

Biochemical scores could reflect histological activity in chronic hepatitis C.

Eighty-one patients with HCV positive chronic active hepatitis (CAH) were studied to correlate, in multivariate regression analysis, liver tests with the histological activity index (HAI). The median HAI value (9.4) divided the patients into two groups; 44 under the 9.4 value (moderate CAH) and 37 above (severe CAH). Multiple regression improved the significance of nine biochemical parameters related to HAI in univariate analysis, and backward stepwise analysis identified the combination of alanine-aminotransferase (ALT), gammaglobulins (gamma GL), gammaglutamyl transpeptidase (gamma GT) and prolyl-hydroxylase (PH) as the best relationship with HAI (R = 0.520, p < 0.0001). A biochemical activity index (BAI) calculated as: 2.304 + ALT x 0.013 + gamma GL x 1.76 + gamma GT x 0.008 + PH x 0.012 showed the higher significant difference between moderate (7.7 +/- 1.3) and severe (12.2 +/- 2) CAH (p < 0.0001). These results suggest that this BAI could be a pointer for checking activity of chronic liver diseases.