Transient Elastography in Patients With Chronic HBV and HCV
This cross-sectional study included treatment-naïve patients with chronic hepatitis B or chronic hepatitis C who were consecutively admitted in the Service d'Hepatologie de l'Hôpital Beaujon between 2006 and 2008 for a liver biopsy (LB) and transient elastography (TE) measurement, after giving their written informed consent. Chronic hepatitis B was defined by the presence of hepatitis B surface antigen (HBsAg) and detectable serum hepatitis B virus DNA (HBV-DNA) for at least 6 months. Chronic hepatitis C was defined by the presence of anti-HCV antibodies and detectable serum HCV-RNA by PCR (>50 IU/ml). Subjects with one or more of the following conditions were excluded: excessive alcohol consumption (>30 g/day for men, >20 g/day for women); co-infection with human immunodeficiency virus and/or hepatitis delta virus; other causes of liver disease; decompensated liver disease or hepatocellular carcinoma; and previous liver surgery or liver transplantation.
This study protocol was conformed to the ethical guidelines of the Helsinki Declaration and was approved by our institutional review board.
Percutaneous liver biopsies were performed under ultrasound guidance using the Menghini technique with disposable 16-gauge diameter needles. A single, experienced pathologist, who was unaware of the clinical data, evaluated all slides. Histological features were analysed using the METAVIR group scoring system. Significant fibrosis was defined by the presence of F2, F3, or F4 METAVIR stage and the presence of F3 or F4 stages characterized advanced fibrosis. Steatosis was categorized as absent (<5% of hepatocytes affected); mild (5–10%); moderate (11–30%); severe (>30%). The length of each liver fragment and the number of portal tracts were recorded and only patients with LB length ≥15 mm and/or at least six portal tracts were included.
Transient elastography examinations were performed prior to LB, on the same day of the procedure, and by a single experienced operator (AC). Measurements were performed by using the standard technique, as previously described. Only patients with at least 10 valid measurements, with an interquartile range of less than 30% of the median stiffness, and with at least 60% success rate were included in the final analysis. According to previous studies, the following cut-off values were used [10, 11]: (a) HCV infection: 7.1 kPa for significant fibrosis (F ≥ 2), 9.5 kPa for advanced fibrosis (F ≥ 3) and 12.5 kPa for cirrhosis (F4); (b) HBV infection: 7.2 kPa for F ≥ 2, 8.1 kPa for F ≥ 3 and 11 kPa for F4. A secondary analysis was performed to assess whether alternative cut-offs, adjusted according to ALT levels, would improve the accuracy of TE measurement for the estimation of fibrosis staging in HBV carriers [12]: (a) normal ALT level: 6.0 kPa for F ≥ 2, 9.0 kPa for F ≥ 3 and 12.0 kPa for F4; (b) ALT level between 1 and 5 times the upper limit of normal (ULN): 7.5 kPa for F ≥ 2, 12.0 kPa for F ≥ 3 and 13.4 kPa for F4.
Complete physical examination and laboratory tests (complete blood count, biochemical tests, alpha-fetoprotein and virological markers) were assessed on the same day that LB and TE were performed. Serum HCV-RNA was measured with the VERSANT HCV 3.0 Assay (bDNA; Siemens Medical Solutions, Puteaux, France) with a quantification range of 615–7 690 000 IU/ml. HCV genotype was assessed by the Line Probe Assay (InnoLiPA HCV; Innogenetics, Ghent, Belgium). HBsAg, hepatitis B e antigen (HBeAg) and antibodies were measured using standard enzyme-linked immuno-sorbent assays (Abbott Diagnostics, Abbott Park, IL, USA). HBV DNA levels were measured using COBAS Ampliprep/COBAS TaqMan HBV (CAP/CPM, Roche Molecular System Inc., Branchburg, NJ, USA).
Continuous variables were compared using the Student's t-test, the Mann–Whitney test, or the Kruskal–Wallis test when appropriate. Categorical variables were compared using the chi-square test or Fisher's exact test. Test results with P values of less than 0.05 were considered statistically significant. Statistical analysis was performed by spss software version 17.0 (SPSS Inc., Chicago, IL, USA). The diagnostic performance of TE in HCV and HBV subjects was assessed by comparison with liver histology and by measuring the area under the receiver-operating characteristics (AUROC). ROC curve comparisons were performed using the medcalc software package version 9.3 (MedCalc Software, Mariakerke, Belgium), which employs calculation of the AUROC and 95% confidence intervals by the technique described by DeLong et al.. Diagnostic accuracy was also evaluated by comparing the sensitivity, specificity, positive and negative predictive values (PPV and NPV respectively), and likelihood ratios of TE measurement to predict the absence or presence of significant fibrosis, advanced fibrosis and cirrhosis in each group (HCV and HBV), by using the appropriate set of cut-offs points, as described above.
Materials and Methods
Study Population
This cross-sectional study included treatment-naïve patients with chronic hepatitis B or chronic hepatitis C who were consecutively admitted in the Service d'Hepatologie de l'Hôpital Beaujon between 2006 and 2008 for a liver biopsy (LB) and transient elastography (TE) measurement, after giving their written informed consent. Chronic hepatitis B was defined by the presence of hepatitis B surface antigen (HBsAg) and detectable serum hepatitis B virus DNA (HBV-DNA) for at least 6 months. Chronic hepatitis C was defined by the presence of anti-HCV antibodies and detectable serum HCV-RNA by PCR (>50 IU/ml). Subjects with one or more of the following conditions were excluded: excessive alcohol consumption (>30 g/day for men, >20 g/day for women); co-infection with human immunodeficiency virus and/or hepatitis delta virus; other causes of liver disease; decompensated liver disease or hepatocellular carcinoma; and previous liver surgery or liver transplantation.
This study protocol was conformed to the ethical guidelines of the Helsinki Declaration and was approved by our institutional review board.
Liver Biopsy
Percutaneous liver biopsies were performed under ultrasound guidance using the Menghini technique with disposable 16-gauge diameter needles. A single, experienced pathologist, who was unaware of the clinical data, evaluated all slides. Histological features were analysed using the METAVIR group scoring system. Significant fibrosis was defined by the presence of F2, F3, or F4 METAVIR stage and the presence of F3 or F4 stages characterized advanced fibrosis. Steatosis was categorized as absent (<5% of hepatocytes affected); mild (5–10%); moderate (11–30%); severe (>30%). The length of each liver fragment and the number of portal tracts were recorded and only patients with LB length ≥15 mm and/or at least six portal tracts were included.
Transient Elastography
Transient elastography examinations were performed prior to LB, on the same day of the procedure, and by a single experienced operator (AC). Measurements were performed by using the standard technique, as previously described. Only patients with at least 10 valid measurements, with an interquartile range of less than 30% of the median stiffness, and with at least 60% success rate were included in the final analysis. According to previous studies, the following cut-off values were used [10, 11]: (a) HCV infection: 7.1 kPa for significant fibrosis (F ≥ 2), 9.5 kPa for advanced fibrosis (F ≥ 3) and 12.5 kPa for cirrhosis (F4); (b) HBV infection: 7.2 kPa for F ≥ 2, 8.1 kPa for F ≥ 3 and 11 kPa for F4. A secondary analysis was performed to assess whether alternative cut-offs, adjusted according to ALT levels, would improve the accuracy of TE measurement for the estimation of fibrosis staging in HBV carriers [12]: (a) normal ALT level: 6.0 kPa for F ≥ 2, 9.0 kPa for F ≥ 3 and 12.0 kPa for F4; (b) ALT level between 1 and 5 times the upper limit of normal (ULN): 7.5 kPa for F ≥ 2, 12.0 kPa for F ≥ 3 and 13.4 kPa for F4.
Laboratory Tests
Complete physical examination and laboratory tests (complete blood count, biochemical tests, alpha-fetoprotein and virological markers) were assessed on the same day that LB and TE were performed. Serum HCV-RNA was measured with the VERSANT HCV 3.0 Assay (bDNA; Siemens Medical Solutions, Puteaux, France) with a quantification range of 615–7 690 000 IU/ml. HCV genotype was assessed by the Line Probe Assay (InnoLiPA HCV; Innogenetics, Ghent, Belgium). HBsAg, hepatitis B e antigen (HBeAg) and antibodies were measured using standard enzyme-linked immuno-sorbent assays (Abbott Diagnostics, Abbott Park, IL, USA). HBV DNA levels were measured using COBAS Ampliprep/COBAS TaqMan HBV (CAP/CPM, Roche Molecular System Inc., Branchburg, NJ, USA).
Statistical Analysis
Continuous variables were compared using the Student's t-test, the Mann–Whitney test, or the Kruskal–Wallis test when appropriate. Categorical variables were compared using the chi-square test or Fisher's exact test. Test results with P values of less than 0.05 were considered statistically significant. Statistical analysis was performed by spss software version 17.0 (SPSS Inc., Chicago, IL, USA). The diagnostic performance of TE in HCV and HBV subjects was assessed by comparison with liver histology and by measuring the area under the receiver-operating characteristics (AUROC). ROC curve comparisons were performed using the medcalc software package version 9.3 (MedCalc Software, Mariakerke, Belgium), which employs calculation of the AUROC and 95% confidence intervals by the technique described by DeLong et al.. Diagnostic accuracy was also evaluated by comparing the sensitivity, specificity, positive and negative predictive values (PPV and NPV respectively), and likelihood ratios of TE measurement to predict the absence or presence of significant fibrosis, advanced fibrosis and cirrhosis in each group (HCV and HBV), by using the appropriate set of cut-offs points, as described above.
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