EVALUATION OF LIVER FIBROSIS BY FIBROSCAN

EVALUATION OF LIVER FIBROSIS BY FIBROSCAN M. Beaugrand Service d Hépatologied Hopital J. Verdier BONDY 93143 et Université Paris XIII DRESDEN 13.10.2007

ASSESSMENT OF FIBROSIS : WHY? Management of individual patients Significant fibrosis Cirrhosis Treatment Screening for varices and HCC Screening for cirrhosis or extensive fibrosis In high risk patients Evaluation of treatments Antiviral and antifibrotic drugs

ELASTOMETRY (FIBROSCAN) LB x 100 Probe 2.5 cm Volume 1 cm 4 cm Sandrin et al. Ultrasound Med Biol 2003;29:1-8

HOW TO MEASURE ELASTICITY? Generate an elastic Shear vawe Measure its spead Vs Elasticity E V S 2

Volume of exploration > 3 cm 3 Probe position Probe 2.5 cm Volume of exploration 1 cm 4 cm

PATIENTS WITH HCV CHRONIC HEPATITIS 327 HCV + patients with no ascites 23 patients excluded: unreliable stiffness measurement: success rate less than 60% upon 10 measurements 53 patients excluded biopsy not suitable for fibrosis stage assessment: less than 10 portal tracts in the absence of cirrhosis 251 patients included Small biopsy 126 patients Large biopsy 125 patients

BOX PLOTS. N=251 100 10 2 Legend Stiffness (kpa) (logarithmic scale) Elasticity (kpa) 10 10 1 maximum median minimum IQR 10 0 1 F01 F2 F3 F4 Fibrosis stage 0-1 2 3 4 Fibrosis stage (METAVIR)

ROC CURVES Sensibilité 1.0 0.8 0.6 0.4 0.2 F01 / F234 F 2 F 3 F=4 F012 / F34 F0123 / F4 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificité AUROC ( CONFIDENCE INTERVALS 95%) - F 2 2 : 0.79 (0.73-0.84) 0.84) - F 3 3 : 0.91 (0.87-0.96) 0.96) - F=4 : 0.97 (0.93-1.00)

UNI AND MULTIVARIATE ANALYSIS Univariate analysis (Kendall s s coefficient) Fibrosis Activity Stiffness r 0.55 0.21 p <0.0001 0.0003 Steatosis 0.19 0.0008 0.21 0.19 0.0003 0.0008 Fibrosis r - 0.36 0.17 p - <0.0001 0.008 Multivariate analysis (multiple regression) Only fibrosis was significantly correlated to liver stiffness measurement.

VALIDATION OF DIAGNOSIS ACCURACY IN AN INDEPENDENT HCV POPULATION Total number of included patients: 639 Number of unreliable liver samples: 86 (13%) Number of unreliable LSM: 59 (9%) Patients kept for statistical analysis : 494 METAVIR Steatosis F % A % S % 0 6 0 6 0 4 7 1 39 1 56 1-10 27 2 31 3 3 31-100 2 35 11-30 15 3 10 10 4 1 4 Sensitivity 1 0.8 0.6 0.4 Area under ROC curves (95% confidence interval) F01 versus F234 = 0.84 (0.80-0.87) F012 versus F34 = 0.93 (0.90-0.95) F0123 versus F4 = 0.96 (0.94-0.98) F01 versus F234 F012 versus F34 Univariate Spearman correlation METAVIR F: 0.70 (p << 0.001) METAVIR A: 0.45 (p << 0.001) Steatosis: 0.35 (p << 0.001) 0.2 0 F0123 versus F4 0 0.2 0.4 0.6 0.8 1 1 - Specificity

LIVER BIOPSIES > 30 mm - 103 Patients Causes : - Results 71 VHC 14 VHB 15 VHC+HIV 2 VHB+HIV 1 VHC+VHB Fibrosis Score : F0 F1 F2 F3 F4 N 9 58 14 7 15 F2 F3 = F4 AUROC 0.94 0.95 0.93

CUT-OFF VALUES * The optimum thresholds were chosen to maximize the sum of sensitivity and specificity. Threshold (kpa) F 2 8.7 Sensitivity Specificity LR 8.7 0.55 0.84 3.5 F 3 9.6 0.84 0.85 5.7 F = 4 14.5 0.84 0.94 13.0 * Obtained by the jack-knife knife method.

FIBROSIS AREA (morphometry) - Patients 69 patients with chronic hepatitis C without ascites, and previous anti-viral treatment - Results METAVIR F1 F2 F3 F4 20 21 5 23 70 25 Elasticité (kpa) 60 50 40 30 20 10 0 Elasticité Aire de fibrose F1 F2 F3 F4 Fibrosis Stage 20 15 10 5 0 Aire de fibrose (%) Spearman correlation test p < 0.001 Parameters r Fibrosis area METAVIR score 0.66 Elasticity METAVIR score 0.65 Elasticity fibrosis area 0.74 Liver elasticity is closely correlated to fibrosis area.

FIBROSCAN VERSUS BLOOD TESTS FibroScan FibroTest APRI 100 1.0 6.0 Elasticité (kpa) 10 0.7 4.0 0.3 2.0 1 F1 F2 F3 F4 Fibrosis stage 0.0 F1 F2 F3 F4 Fibrosis stage 0.0 F1 F2 F3 F4 Fibrosis stage Score METAVIR de fibrose Score METAVIR de fibrose Score METAVIR de fibrose Castera Al. Gastroenterology 2005

CONCORDANCE WITH LIVER BIOPSY AUROC F01/F234 F012/F34 F0123/F4 APRI 0.78 0.84 0.83 FibroTest 0.85 0.90 0.87 FibroScan 0.83 0.90 0.95 Combinaison 0.88 0.95 0.95 FibroTest+FibroScan Percentage of concording results F01/F234 F0123/F4 FibroTest 80 81 FibroScan 73 83 Combinaison 84 95 FibroTest+FibroScan

FIBROSCAN IN HBV PATIENTS 202 patients - 15 non interpretable biopsies - 14 LSM considered as non reliable Statistical analysis on 173 patients 1 0.9 0.8 AUROC F01 versus F234: 0.81 (0.73-0.86) F012 versus F34: 0.93 (0.88-0.96) F0.123 versus F4: 0.93 (0.82-0.98) Sensitivity 0.7 0.6 0.5 0.4 0.3 0.2 0.1 F01 versus F234 F0123 versus F34 F0123 versus F4 0 0 0.2 0.4 0.6 0.8 1 1 - Specificity

FIBROSCAN PROS AND CONS PROS CONS - easy, quick, not too costy - very specific for extensive fibrosis or cirrhosis - Allows to split patients between 3 groups. Without significant fibrosis. With extensive fibrosis or cirrhosis. Intermediate - closely related to the area of fibrosis in patients with chronic hepatitis - high rate of failure in obese patients

SCREENING IN HIGH RISK PATIENTS LSM 227 patients in alcoholic abstinence program LSM>13 kpa yes Suspected cirrhosis 41 Blood tests no LB 34 Absence of cirrhosis Confirmation of cirrhosis 33

FOLLOW-UP OF LSM IN TREATED PATIENTS WITH CHRONIC HEPATITIS C BEFORE TREATMENT END OF TREATMENT 6 MONTHS AFTER All (n=85) 14.1 ± 7.2 10.9 ± 6.5 11.2 ± 8.6 SVR 12.0 ± 6.7 9.1 ± 3.7 7.5 ± 2.4 RR 14.6 ± 5.6 11.5 ± 5.0 12.8 ± 7.2 NR 16.9 ± 8.1 13.3 ± 9.1 16.1 ± 12.2

CONCLUSION 1) In patients with chronic liver diseases LSM by fibroscan reflects fibrosis stage 2) Fibroscan is a reliable screening tool for extensive fibrosis or cirrhosis in high risk groups 3) Fibroscan might allow to assess the influence of treatments on liver fibrosis