Transient elastography the state of the art

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1 Transient elastography the state of the art Laurent CASTERA, MD PhD Department of Hepatology, Hôpital Beaujon, Clichy Université Paris-7, France White Nights of Hepatology, St Petersburg, Russia, june

2 Available non-invasive methods 2 different but complementary approaches «Biological» approach «Physical» approach Serum Biomarkers Liver stiffness Castera & Pinzani. Lancet 2010; 375:

3 Liver stiffness Transient elastography (FibroScan ) Sandrin et al. UMB 2003; 29: Castera, Forns & Alberti. J Hepatol 2008; 48:

4 I What are the principle & limitations of transient elastography?

5 Transient elastography (FibroScan) principle 2.5 cm Explored volume 1 cm = 100 x liver biopsy 4 cm

6 Transient elastography (FibroScan) principle «The stiffer the liver, the faster the shear wave propagates» 10 5 Depth (mm) Time (ms) V S = m/s -5 % E = kpa F4 F0 Sandrin et al. UMB 2003; 12:

7 How to interpret FibroScan results manufacturer s recommendations 10 validated measures IQR < 30% median Success rate > 60% Castera, Forns & Alberti. J Hepatol 2008; 48:

8 Applicability of transient elastography Obesity Failure 3.1% Unreliable 15.8% SR < 60% 8.1% FibroScan Valid shot = 0 not applicable VS < % in 20% Operator experience of cases IQR/LSM > 30% 9.2% N=13669 examinations Castéra et al. Hepatology 2010; 51:

9 XL Probe: Does it really overcome the limitations of M probe? Failure Unreliable XL vs. M probe: Valid shot = 0 1% vs. 16% SR < 60% XL vs. M probe: 27% vs. 50% VS < 10 IQR/LSM > 30% N= 276 patients with BMI > 28 kg/m 2 Myers et al. Hepatology 2012; 55:

10 XL Probe: the cut-off issue M vs. XL 7.8 vs. 6.4 kpa N= 65 NAFLD patients Myers et al. Hepatology 2012; 55:

11 Confounding Glisson s factors capsula: for liver a distensible but non elastic envelope stiffness Others? Acute Inflammation Coco et al. J Viral Hepat 2007 Arena et al. Hepatology 2008 Sagir et al. Hepatology 2008 Liver congestion Millonig et al. J Hepatol 2010 Extra-hepatic cholestasis Millonig et al. Hepatology 2008

12 Influence of food intake TE should be performed in fasting patients N= 125 HCVpatients Mederacke et al. Liver Int 2009; 29: Arena et al. Hepatology 2013; in press.

13 II What is the performance of transient elastography?

14 Diagnostic performance Viral hepatitis summary. Castera L. Gastroenterology 2012; 142:

15 Diagnostic performance NAFLD N= 246 patients, F2F4 52%; F4 9% Wong et al. Hepatology 2010; 51:

16 Meta-analysis Significant fibrosis Cirrhosis AUROC: 0.84 ( ) AUROC: 0.94 ( ) Friedrich-Rust et al. Gastroenterology 2008; 134:

17 Transient elastography for cirrhosis (n=1007 patients with various CLD, 165 with cirrhosis) saved liver biopsy 92 % 83% 17% F < 4 96% F = 4 74% 3.5 % misclassified 4.5% misclassified Ganne-Carrié et al. Hepatology 2006; 44:

18 III How does transient elastography compare with biomarkers?

19 Diagnosing significant fibrosis TE vs. biomarkers P=NS P=NS Castera et al. Gastroenterology 2005; 128: Degos et al. J Hepatol 2010; 53:

20 Diagnosing cirrhosis TE vs. biomarkers 1,0 0,8 Sensitivity 0,6 0,4 P< FS FT APRI Lok P< ,2 Platelet PI ,0 AAR ,0 0,2 0,4 0,6 0,8 1,0 1 - Specificity Castera et al. J Hepatol 2009; 50: Degos et al. J Hepatol 2010; 53:

21 Summary: significant fibrosis = Serum markers Transient elastography

22 Summary: cirrhosis < Serum markers Transient elastography

23 IV What about combining both methods?

24 Combining methods increases diagnostic accuracy Avoided liver + biopsies for F 2: 75% Biomarkers Liver stiffness Castera et al. Gastroenterology 2005; 128:

25 Combining methods increases diagnostic accuracy N= 729 patients with CHC Boursier et al. Am J Gastroenterol 2011

26 Comparison between algorithms significant fibrosis APRI + FT FS + FT Correctly classified: 48% P<0.001? < Correctly classified: 72% N=302 HCV patients Castéra et al. J Hepatol 2010; 52:

27 Comparison between algorithms cirrhosis APRI + FT FS + FT Correctly classified: 75%? = Correctly classified: 79% N=302 HCV patients Castéra et al. J Hepatol 2010; 52:

28 Biomarkers vs. FibroScan summary Advantages Biomarkers Good reproducibility High applicability (95%) Low cost & wide availability (non patented) Disadvantages Non specific of the liver Performance for cirrhosis Cost & availability (patented) Advantages FibroScan Genuine property of the liver High performance for cirrhosis User-friendly Disadvantages Low applicability (80%) False positive (inflammation) Requires a dedicated device- Castera L. Gastroenterology 2012; 142:

29 V How to use non invasive methods in clinical practice?

30 Hepatitis C: Decision to treat HCV genotype IL28B Antiviral treatment Foie

31 Naive patients without comorbidities Use as first line assessment +or Serum markers Transient elastography Haute Autorite de Santé, 2008 EASL HCV Clinical Practice Guidelines J Hepatol 2011

32 Algorithm for clinical practice Castera L. Gastroenterology 2012; 142:

33 In the remaining patients Castera L & Bedossa P. Liver Int 2011; 31: 13-7

34 Hepatitis B: Decision to treat HBV DNA ALT/AST Antiviral treatment Foie

35 Indication of antiviral treatment Discriminate F1-F2 Foie Inflammation +++

36 Hepatitis B cirrhosis? <+ Serum markers Transient elastography

37 NAFLD? Serum markers Transient elastography

38 Is diagnosing significant fibrosis still important in the era of DAAs?? F0 F1 F2 F3 F4 Indication for antiviral treatment Boceprevir Telaprevir

39 Is diagnosing significant fibrosis still important in the era of DAAs?? F0 F1 F2 F3 F4 Indication for antiviral treatment Clinical complications Boceprevir HVPG>10 Telaprevir Significant risk of OV bleeding HVPG>12

40 Liver stiffness: a wide range of value in cirrhosis Normal 5.5 Cirrhosis kpa

41 Prognostic value of liver stiffness in cirrhosis? kpa OV grade II / III Ascites HCC N=711 patients with CLD F3F4 144 Bleeding Foucher et al. Gut 2006; 55:

42 Correlation of liver stiffness with HVPG HVPG (mm Hg) Pearson s coefficient = p < Liver stiffness (kpa) Cut-off AUROC HVPG 6 mm Hg 8.7 kpa % 81% 81% 90% N= 124 patients with post LT HCV recurrence Carrion et al. Liver Transpl 2006; 12: Vizzuti et al. Hepatology 2007; 45: Bureau et al. APT 2008; 27: Lemoine et al. APT 2008 ; 28: Se Sp PPV NPV

43 Correlation with oesophageal varices Correlation with variceal size not found in all studies P< P< LSM (kpa) None n=91 grade I n=27 grade II n=41 grade III n=6 0 None (n=45) Grade 1 (n=12) Grade 2 (n=8) Grade 3 (n=5) 165 cirrhotic; OV grade II: 28 % Vizzutti et al. Hepatology 2007; 45: Pineda et al. J AIDS 2009; 51: HCV cirrhotics; OV grade II: 19 % Kazemi et al. J Hepatol 2006; 45: Castera et al. J Hepatol 2009; 50: 59-68

44 Performance for predicting OV FibroScan Authors, [Ref.] Patients (n) Etiologies Study design End point Prevalence OV (%) Cut-offs (kpa) AUC Se (%) Sp (%) PPV (%) NPV (%) Saved endoscopy (%) Kazemi et al., [45] 165 CLD Retro. mono. OV LOV Vizzutti et al., [36] 47 HCV Pro. mono. OV Pritchett et al., [48] 211 CLD Retro. mono. OV LOV n.a n.a. 69 Bureau et al., [37] 89 CLD Pro. mono. OV LOV Castera et al., [46] 70 HCV Retro. mono. OV LOV Pineda, et al., [47] 102 HIV-HCV Pro. multi. CROV* Nguyen et al. [49] CLD HCV/HBV Alcohol Retro. mono. LOV Malik et al., [50] 124 CLD Retro. mono. OV n.a. n.a n.a. Castera, Pinzani & Bosch. J Hepatol 2012; 56:

45 Summary u Liver stiffness is strongly correlated with HVPG and with the presence (size?) of eosophageal varices. u However, the performances of TE are not sufficient thus far to confidently replace endoscopy for eosophageal varices screening.

46 Spleen stiffness: better than liver stiffness for PTH? 3.18 NPV 98% NPV 99% N= 340 patients Takuma et al. Gastroenterology 2013; 144:

47 Liver stiffness & HCC Liaisons dangereuses? p<0.001 N= 866 HCV patients N= 1130 HBV patients Masuzaki et al. Hepatology 2009; 49: 1954 Jung et al. Hepatology 2011; 53:

48 Perspectives

49 Challengers for measuring liver stiffness ARFI (VirtualTouch )) Nightingale et al. UMB 2002 ; 28: Friedrich-Rust et al. Radiology 2009 ; 252:

50 Challenger for measuring liver stiffness Supersonic shear Imaging (Aixplorer ) Muller et al. UMB 2009; 35: Bavu et al. UMB 2011;37:

51 Supersonic shear Imaging (Aixplorer ) Comparison with TE in Hepatitis C Significant fibrosis Cirrhosis P=0.002 P=NS N= 121 HCV patients Ferrraioli et al. Hepatology 2012; 56:

52 Challengers for measuring liver stiffness Advantages & disavantages ARFI Advantages Can be implemented on a regular US machine High applicability Performance close to TE Disadvantages Further validation needed Narrow range of values Quality criteria not defined SWE Advantages Can be implemented on a regular US machine High range of value (2-150 kpa) Performance higher than TE? Disadvantages Further validation needed Quality criteria? Limited data on reproducibility Berzigotti & Castera. J Hepatol 2013; in press

53 Take Home messages TE is well validated in chronic viral hepatitis and can be used as first line fibrosis evaluation. Combining two unrelated methods (TE + serum markers) increases diagnostic accuracy. TE is currently the most accurate method for detecting cirrhosis and may be of prognostic value in this setting. Although it has limitations, TE is a promising technique for the monitoring of disease progression but needs to be further evaluated in longitudinal studies.