Transient elastography in chronic viral liver diseases

4 th AISF POST-MEETING COURSE Roma, 26 Febbraio 2011 Transient elastography in chronic viral liver diseases CRISTINA RIGAMONTI, M.D., Ph.D.

Transient elastography (TE): a rapid, non-invasive technique conceived to evaluate hepatic fibrosis by measuring liver stiffness.

TE in HCV EASL Clinical Practice Guidelines Both transient elastography and biomarkers have been shown to accurately identify patients with mild fibrosis or cirrhosis. They are less discriminant for moderate to severe fibrosis. The combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of liver biopsy to resolve uncertainty. However, they increase the cost. EASL, J Hepatol 2011, in press

TE in HBV EASL Clinical Practice Guidelines A liver biopsy is recommended for determining the degree of necroinflammation and fibrosis in patients with either increased ALT or HBV DNA levels >2000 IU/ml (or both) since hepatic morphology can assist the decision to start treatment (A1). Biopsy is also useful for evaluating other possible causes of liver disease such as steatosis or steatohepatitis. A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis (A1). There is growing interest in the use of noninvasive methods, including serum markers and transient elastography, to assess hepatic fibrosis to complement or avoid a liver biopsy. EASL, J Hepatol 2009; 50: 227-42

Transient elastography Topics FibroScan : physical principles and functioning Applicability Reproducibility Performance in assessing liver fibrosis in HCV and HBV patients Histological features influencing liver stiffness Assessment of treatment efficacy Monitoring fibrosis and disease progression

FibroScan Physical principles and functioning US transducer: 3.5 MHz Vibrator: mild amplitude and low frequency (50 Hz) elastic waves Propagation speed of elastic waves: directly related to tissue stiffness

FibroScan Examination Patient: lying down in supine position with the right arm in the maximum abduction, fasting Time of examination: less than 5 minutes Examination: painless

FibroScan Examination Explored volume TE: 1/500 of the liver total mass Probe Liver biopsy: 1/50000 of the liver total mass Probe

FibroScan Quality criteria for reliable results Median liver stiffness Interquartile range Number of valid measuements Success rate <30% OF MEDIAN VALUE AT LEAST 60% AT LEAST 10

Transient elastography Unreliable results 13369 EXAMINATIONS 923 BLOOD DONORS SR <60% 8.1% 15.8% SR <60% 3.2% 18.3% IQR/LSM >30% 9.2% IQR/LSM >30% 12.8% Castera et al, Hepatology 2010; 51: 828-35 Colombo et al, Dig Liver Dis 2011; in press

Transient elastography Applicability Contraindications Pregnant women Patients with implantable devices (pacemaker or defibrillator) Failure of examination Ascites Narrow intercostal spaces Overweight / obesity 2,4-8%

Transient elastography Applicability Contraindications Pregnant women Patients with implantable devices (pacemaker or defibrillator) Failure of examination Ascites Narrow intercostal spaces Overweight / obesity / Independent factor for failure: BMI >28 kg/m 2 in 2114 patients BMI >30 kg/m 2 in 13369 examinations * Foucher et al, Eur J Gastroenterol Hepatol 2006; 18: 411-12 * Castera et al, Hepatology 2010; 51: 828-35

Transient elastography Reproducibility 200 consecutive patients with chronic liver disease of various etiologies were concurrently assessed by TE and liver biopsy TE was found to be highly reproducible, in terms of both inter- and intraobserver agreement 80 Rater 1 Rater 2 70 60 80 70 80 70 Rater 2 50 40 30 20 10 Determination 2 60 50 40 30 20 10 Determination 2 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 0 0 10 20 30 40 50 60 70 80 0 0 10 20 30 40 50 60 70 80 Rater 1 Determination 1 Determination 1 Inter-observer agreement: 0.98 (95% CI: 0.977 0.987) Intra-observer agreement: 0.98 Intra-observer agreement: 0.98 Fraquelli et al, Gut 2007; 56: 968-73

TE Factors impacting reproducibility Interobserver agreement analysis Fraquelli et al, Gut 2007; 56: 968-73

Transient elastography Normal values Corpechot et al, 2006 Roulot et al, 2008 Colombo et al, 2011 Population Healthy subjects (volunteers) Subjects without CLD (medical check-up) Blood donors without steatosis at US Blood donors with steatosis at US Number 71 429 602 144 TE, kpa * median range 95 th centile 4.8 2.5-6.9 5.5 1.5-12.7 8.6 4.4 2.1-17.5 6.7 5.3 2.7-14.1 8.4 Age No effect No effect No effect Gender M>F M>F M>F High BMI No effect Increased TE No effect Metabolic syndrome Increased TE

TE Correlation with liver fibrosis TE results significantly correlate with liver fibrosis stage: correlation coefficients ranging from 0.55 to 0.84. However, there is a substantial overlap of TE results between adjacent stages of liver fibrosis. Ziol et al, Hepatology 2005; 41: 48-54 Castera et al, Gastroenterology 2005; 128: 343-50

Chronic viral hepatitis Which end-points? F0 F1 F2 F3 F4 Indication Screening for OV for antiviral Screening for treatment HCC Assessment of treatment efficacy Monitoring fibrosis progression

TE performance in diagnosing F 2 Author, yr Etiology Patient # Cut-off kpa Sensitivity % Specificity % -LR +LR AUROC Ziol, 2005 HCV 251 8.8 56 91 0.48 6.6 0.79 Castera, 2005 HCV 183 7.1 83 82 0.37 6.0 0.83 Arena, 2008 HCV 150 7.8 83 82 0.20 4.6 0.91 Lupşor, 2008 HCV 324 7.4 76 84 0.30 4.6 0.86 Olivieri, 2008 HBV 188 7.5 93 88 0.07 8.2 0.96 Marcellin, 2009 HBV 173 7.2 70 83 0.36 4.0 0.81 Coco, 2007 HCV-HBV 159 8.3 85 91 0.16 9.4 0.93 Tsochatzis, 2011 * * meta-analysis HCV HBV 78 84 80 78 0.27 0.25 3.9 3.8

TE performance in diagnosing cirrhosis (F=4) Author, yr Etiology Patient # Cut-off, kpa Sensitivity, % Specificity % -LR +LR AUROC Ziol, 2005 HCV 251 14.6 86 96 0.14 23.0 0.97 Castera, 2005 HCV 183 12.5 87 91 0.14 9.7 0.95 Arena, 2008 HCV 150 14.8 94 92 0.07 11.3 0.98 Lupşor, 2008 HCV 324 11.8 87 91 0.14 9.4 0.94 Olivieri, 2008 HBV 188 11.8 86 96 0.14 23.2 0.97 Marcellin, 2009 HBV 173 11.0 93 87 0.08 7.0 0.93 Chan, 2009 HBV 161 12.0 79 92 0.23 9.8 0.93 Coco, 2007 HCV-HBV 159 14.0 78 98 0.22 39 0.96 Tsochatzis, 2011 * * meta-analysis HCV HBV 83 80 90 89 0.18 0.22 8.3 7.3

TE Multilevel likelihood ratios (LRs) for excluding fibrosis in HCV patients Significant fibrosis Cirrhosis Arena et al, Gut 2008; 57: 1288-93

TE Multilevel likelihood ratios (LRs) for confirming fibrosis in HCV patients Significant fibrosis Cirrhosis Arena et al, Gut 2008; 57: 1288-93

TE Dual cut-off for diagnosing fibrosis in treatment-naïve HBV patients FOR EXCLUDING FOR CONFIRMING Significant fibrosis Cut-off kpa Sensitivity % Specificity % -LR +LR Cut-off kpa Sensitivity % Specificity % -LR +LR 6.2 94 93 0.10 1.7 >9.4 55 95 0.5 11 Cirrhosis Cut-off kpa Sensitivity % Specificity % -LR +LR Cut-off kpa Sensitivity % Specificity % -LR +LR 9.4 100 82 0 5.5 >13.1 75 93 0.3 11.2 Viganò et al, submitted

TE A dual cut-off algorithm for diagnosing fibrosis in treatment-naïve HBV patients Significant fibrosis Cirrhosis 128 patients 128 patients 3 (2%) patients unreliable TE results 3 (2%) patients unreliable TE results 125 patients reliable TE results 125 patients reliable TE results TE 6.2 kpa N=31 TE >6.2 and 9.4 kpa N= 55 TE >9.4 kpa N=39 TE 9.4 kpa N=86 TE >9.4 and 13.1 kpa N=17 TE >13.1 kpa N=22 F 2 N=4 F 2 N=26 F 2 N=36 F4 N=0 F4 N=5 F4 N=15 90% correctly classified 93% correctly classified Viganò et al, submitted

Assessment of fibrosis by TE in HCV and HBV patients HCV and HBV patients Transient elastography No significant fibrosis Grey area Significant fibrosis Follow-up Liver biopsy No cirrhosis Grey area Cirrhosis Treatment Treatment, liver biopsy Treatment, GI endoscopy, US every 6 months

TE Diagnostic performance is influenced by disease activity in HBV patients Significant fibrosis Cirrhosis Cut-off 7.5 kpa Cut-off 11.8 kpa Olivieri et al, World J Gastroenterol 2008; 14: 6154-62

Features influencing TE Acute inflammation Coco et al, J Viral Hepat 2007 Arena et al, Hepatology 2008 Sagir et al, Hepatology 2008

Features influencing TE Liver congestion Millonig et al, J Hepatol 2010 Colli et al, Radiology 2010 Inflammation Coco et al, J Viral Hepat 2007 Arena et al, Hepatology 2008 Sagir et al, Hepatology 2008 Rigamonti et al, Gut 2008 Arena et al, Gut 2008 Lupşor et al, J Gastrointestin Liver Dis 2008 Fraquelli et al, J Hepatol 2011 Steatosis Lupşor et al, J Gastrointestin Liver Dis 2008 Fraquelli et al, J Hepatol 2011 Extra-hepatic cholestasis Millonig et al, Hepatology 2008

Discordant results between TE and liver biopsy in HCV and HBV patients Fibrosis stage TE cut-off TE HCV (N=453) HBV (N=104) F 2 7.9 kpa underestimation 11% 11% overestimation 10% 10% F4 12.0 kpa underestimation 0% 0% overestimation 11% 13% Fraquelli et al, J Hepatol 2011, in press

Determinants of TE in HCV patients Diagnosis of F 2 Perisinusoidal fibrosis involving most/all lobules increased the risk of overestimation of significant fibrosis by TE Fraquelli et al, J Hepatol 2011, in press

Determinants of TE in HCV patients Overestimation of F4 Moderate to severe necroinflammation and steatosis and increased γ-gt levels were independently associated with the risk of overestimation of cirrhosis by TE Fraquelli et al, J Hepatol 2011, in press

Determinants of TE in HBV patients Overestimation of F4 Moderate to severe necroinflammation increased the risk of overestimation of cirrhosis by TE Fraquelli et al, J Hepatol 2011, in press

Dynamics of TE after treatment in HCV patients 145 treated HCV patients: 93 SVR, 28 RR, 24 NR Before treatment 2 yrs after EOT 2 yrs after EOT more than half of SVR and RR patients had a significative reduction of TE results with respect to baseline 143 treated HCV patients (97 HIV coinfected): 80 SVR, 6 RR, 57 NR Arima et al, Hepatology Research 2010; 40: 383 392 6 months after EOT Macias et al, J Antimicrob Chemother 2010: 65: 2204-11

Dynamics of TE after treatment in HBV patients 20 treatment-naïve HBV patients who started entecavir 12 months after start of entecavir half of the patients had a significative decrease of TE results with respect to baseline Enomoto et al, Hepatology Research 2010; 40: 853 861

Dynamics of TE after treatment in HBV patients At baseline: 28.4 kpa A2 F4 At month 12 ETV therapy: 7.8 kpa A1 F3 At baseline: 6.0 kpa At month 12 ETV therapy: 14.5 kpa Steatosis <5% Steatosis 20% Enomoto et al, Hepatology Research 2010; 40: 853 861

Monitoring liver fibrosis progression by TE 40 consecutive liver transplanted patients with recurrent hepatitis C were prospectively evaluated by sequential paired liver biopsy and TE examinations during a 6 to 21 month follow-up An increase of TE values predicted progression of liver fibrosis at liver biopsy, while decreased or stable TE results predicted unchanged fibrosis compared to baseline STAGING CUT-OFF SENS SPEC -LR +LR 1 point Ishak score increase 30% of TE baseline value increase 86% 92% 0.15 11.1 Rigamonti et al, Gut 2008; 57: 821-7

Disease progression 14 kpa 75 kpa Garcia-Tsao et al, Hepatology 2010; 51: 1445-49

Disease progression: transition from compensated to decompensated cirrhosis Garcia-Tsao et al, Hepatology 2010; 51: 1445-49

Monitoring disease progression by TE: prediction of portal hypertension Positive significant correlation between TE results and HVPG r=0.84 p<0.001 Carrión et al, Liver Transpl 2006; 12: 1791-98 Vizzuti et al, Hepatology 2007; 45: 1290-97

Monitoring disease progression by TE: prediction of portal hypertension Weak correlation between TE results and HVPG 10-12 mmhg Vizzuti et al, Hepatology 2007; 45: 1290-97

Can portal hypertension be predicted by a TE cut-off? +LR -LR 2.7 4.7 0.07 0.12 Carrión et al, Liver Transpl 2006; 12: 1791-98 Vizzuti et al, Hepatology 2007; 45: 1290-97

Does TE have a prognostic value in the context of cirrhosis? Incidence of HCC in 866 HCV patients Masuzaki et al, Hepatology 2009; 49: 1954-61

Does TE have a prognostic value in the context of cirrhosis? Masuzaki et al, Hepatology 2009; 49: 1954-61

TE Conclusions TE is a complementary tool which adds to our diagnostic armamentarium in the assessment of chronic viral liver disease severity and progression during follow-up. TE and liver biopsy should be employed as an integrated system to maximize their potential, since integration of the information derived from liver biopsy with TE allows a more efficient and convenient management of the patient with chronic liver disease.