Liver stiffness measurement ( Fibroscan ® ) Principles - indications - results - limitations

1. Liver stiffness measurement (Fibroscan®)Principles - indications - results - limitations • SamirHaffar M.D. • Assistant Professor of Gastroenterology

2. Clinical Examination Blood markers Biological work-up Fibrose FibroScan® Hepatic biopsy Imaging(US, MRI, endoscopy)

3. Ideal non-invasive test for diagnosis of liver fibrosis • Simple • Reproducible • Readily available • Less expensive than biopsy • Predicts full spectrum of fibrosis • Reflects changes occurring with therapy

4. Evaluation of chronic liver injury according to health care level Primary health care Secondary health care Tertiary health care Liver biopsy Physical examination Liver function tests Serum Hyaluronate APRI or other simple tests Fibroscan® ARFI* MR elastography* Ultrasound Fibroscan® Serum markers & algorithms HVPG * Promising but currently under investigation ARFI: Acoustic Radiation Force Impulse Imaging HVPG: Hepatic Venous Pressure Gradient Castéra L et al. Gut 2010 ; 59 : 861 – 866.

5. Liver stiffness • Assessed by US (FibroScan®) & more recently by MRI • Evaluates velocity of propagation of a shock wave within liver tissue (examines a physical parameter of liver tissue which is related to its elasticity) • Rationale Normal liver is viscous Not favorable to wave propagation Fibrosis increases hardness of tissue Favors more rapid propagation Bedossa P. Liver Int 2009 ; 29 (s1): 19 – 22.

6. Fibroscan® device • Electronic platform • Ultrasonic signals acquisition • Numerical signal processing • Integrated computer • Stiffness measurement • Examinations database • Dedicated probes with unique technology Vibrator (50 Hz) US Transducer (3,5 MHz) Fibroscan® (Echosens, Paris, France)

7. Position of probe & explored volume Cylinder of 1 cm wide & 4 cm long From 25 mm to 65 mm below skin surface This volume is at least 100 times bigger than a biopsy sample

8. Results IQR * (kPa) Intervalaroundmedian Contains50% of validshots ≤ 25% of median value Stiffness(kPa) Medianvalue of 10 shots 3.9 Kilo Pascals  At least 10 shots  Success Rate: ≥ 60%

9. Manufacturer’s criteria for LSM interpretation • First stepNumber of shots ≥ 10 • Second stepSuccess rate ≥ 60 % • Third stepInterquantile range (IQR) ≤ 25% Failure Unreliable results Zero valid shot < 10 valid shots Success rate ≤ 60% IQR ≥ 25%

10. Liver stiffness values in healthy subjects429 subjects 5.2 ± 1.5 kPa 5.8 ± 1.5 kPa p = 0.0002 Roulot D et al. J Hepatol 2008 ; 48 : 606 – 613.

11. Liver stiffness values in healthy subjectswith & without metabolic syndrome 5.3 ± 1.5 kPa 6.5 ± 1.6 kPa p < 0.0001 Roulot D et al. J Hepatol 2008; 48 : 606 – 613.

12. Liver stiffness cut-offs in chronic liver diseases F3 Matavir F0-F1 F2 F4 Severe Fibrosis Mild Sign Cirrhosis LSM 2.5 – 7 kPa→ Mild or absent fibrosis is likely LSM > 12.5 kPa→ Cirrhosis is likely Castéra L et al. J Hepatol 2008 ; 48 : 835 – 847.

13. Progression of fibrosis in viral hepatitis Photomicrographs (magnification ×40; trichrome stains) F 0 F 2 F 1 F 3 F 4 Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.

14. Perform LSM ≤6 kPa Intermediate values ≥ 12 kPa No significant fibrosis Grey area Advanced fibrosis F0 F1 F F2 F3 F4 No biopsy Biopsy if results influence management No biopsy Implementation of other NI tests Treatment or Follow-up Vizzutti et al.Gut 2009;58:156-60.

15. Shear wave propagation velocity according to severity of hepatic fibrosis (Metavir score) E = 3.0 kPa F 0 E = 7.7 kPa F 2 E = 27 kPa F 4 SandrinL. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.

16. Liver stiffness for each Metavir stage in CHCBox-and-whiskers plot Hepatology 2005;41:48 – 54. Gastroenterology 2005; 28:343 – 350. Vertical axis is in logarithmic scale (wide range of F4 values)

17. Correlation between LSM & fibrosis stage * GastroentérolClinBiol 2008;32,58-67. ** J Hepatol 2009;49:1062-68, Aliment PharmacolTher 2008;28:1188-98. *** Hepatology 2010;51:454-62. GastroentérolClinBiol 2008;32:58-67.

18. Accuracy of a diagnostic test • Dichotomous test (only 2 results) Sensibility (Sn) Specificity (Sp) Positive Predictive Value (PPV) Negative Predictive Value (NPV) Likelihood Ratios + & – (LRs) Diagnostic Odds Ratio (OR) • Multilevel test (> 2 results) Receiver Operating Characteristic (ROC) CIs Newman TB & Kohn MA. Evidence-based diagnosis. Cambridge University Press, Cambridge, UK, 1st edition, 2009.

19. Hypothetical ROC curve Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical decision rules. Blackwell’s publishing, West Sussex, UK, 2008.

20. Accuracy of diagnostic test using AUC of ROC AUROC of a ‘‘good” test should be ≥ 0.80 Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical decision rules. Blackwell’s publishing – West Sussex – UK – 2008.

21. Meta-analysis of TE for staging liver fibrosis 50 studies – random effect – all type of CLD Cirrhosis (F4): 0.94 (95% CI: 0.93 – 0.95) Cut-off value: 13.0kPa Severe fibrosis (F3): 0.89 (95% CI: 0.88 – 0.91) Significant fibrosis (F2): 0.84 (95% CI: 0.82 – 0.86) Cut-off value: 7.7kPa Friedrich R et al. Gastroenterology 2008 ; 134 : 960 – 974.

22. Significance of wide range of LSM in cirrhosis13 - 75 kPa 2.5 13 26 36 53 49 62 75 EV stage 2 or 3 Child-Pugh B or C Ascites HCC ? Variceal bleeding Foucher J et al. Gut 2006 ; 55 : 403 – 408.

23. Cumulative incidence of HCC based on LSM866 CHC – Mean follow-up 3 years LSM > 25 kPa HR 45.5 (p< 0.001) 20 < LSM ≤ 25 HR 25.6 (p< 0.001) 15 < LSM ≤ 20 kPa HR 20.9 (p< 0.001) 10 < LSM ≤ 15 kPa HR 16.7 (p< 0.001) LSM ≤ 10 kPa HR 0 LSM: Liver Stiffness Measurement – HR: Hazard Ratio Masuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961.

24. Reproducibility of TE in assessing hepatic fibrosis. Bland Altman Plot Upper limit 95% limit of agreement Mean Lower limit 200 patients with chronic liver disease 2 different operators within 3 days (800 exams) 8 patients scored outside limits of agreement Fraquelli M et al. Gut 2007 ; 56 : 968 – 973.

25. Cost of FibroScan® versus liver biopsy • Liver biopsy* Cost of liver biopsy 703 – 1 566 € in a French hospital with a one day observation period • Fibroscan® ** FibroScan equipment 70 000 € Low running cost except probe calibration twice/year Cost per FibroScan exam 100 € with 150 exams annually * Blanc J et al. Hepatol Res 2005 ; 32 : 1 – 8. ** Canadian Agency for Drugs and Technologies in Health (CADTH). Transient Elastography (FibroScan) for Non-invasive Assessment of Liver Fibrosis; 2006.

26. Liver biopsy size • Because grading, & staging of nonneoplastic diffuse parenchymal liver disease is dependent on adequate sized biopsy, a biopsy of at least 2-3 cm in length & 16-gaugein caliber is recommended • Presence of fewer than 11 complete portal tracts in pathology report may be incorrect in recognition of grading, & staging due to insufficient sample size AASLD guidelines. Hepatology, 2009 ; 49 : 1017 – 1044.

27. Limitations of liver biopsy • Sampling errors Extremely small portion of liver (1/50 000) • Intraobserver & interobserver variation Even when widely validated systems used for score • Invasive procedure Morbidity: pain in 20% of patients Major complications: bleeding or hemobilia in 0.5% Mortality:

28. Grading & staging systems for chronic hepatitis 1 Desmet VJ et all. Hepatology 1994;19:1513-1520. 2 Batts KP et all. Am J SurgPathol 1995;19:1409-1417. 3 Bedossa P et all. Hepatology 1996;24:289-293. (kappa 0.2 – 0.6) (kappa 0.5 – 0.9)

29. Interpretation of different values of kappaKappa from Greek letter κ kappa score ≥ 0.6 indicates good agreement Perera R, Heneghan C & Badenoch D. Statistics toolkit. Blackwell Publishing & BMJ Books, Oxford, 1st edition, 2008.

30. Liver biopsy is not the “gold standard” but is the “best available gold standard”

31. Contraindications of liver biopsy • Uncooperated patients • Disorders in coagulation profile • Severe ascites • Cystic lesions • Vascular tumors (hemangiomas) • Amiloidosis • Congestive liver disease

32. R0C curves for FibroScan, FibroTest, & APRI for cirrhosis (F0 – F3 vs F4) Castera L et al. Gastroenterology 2005 ;128 : 343 – 50. Castera L et al. Lancet 2010 ; 375 : 1419 – 20.

33. Pitfalls of liver stiffness measurement Obesity  Operator experience  Acute liver injury  Extrahepaticcholestasis  Increased CVP  Ascites  Narrow intercostal spaces

34. Obesity & operator experience

35. Limitations of liver stiffness measurement13 369 examinations – 5 year prospective study – 5 operators Unreliable results (16%) Failure (3%) BMI > 30 kg/m2 (OR 3.3) Operator experience (OR 3.1) Age > 52 years (OR 1.8) Female sex (OR 1.4) Hypertension (OR 1.3) Type 2 diabetes (OR 1.1) BMI > 30 kg/m2 (OR 7.5) Operator experience (OR 2.5) Age > 52 years (OR 2.3) Type 2 diabetes (OR 1.6) LSM uninterpretable in one of five cases Main raisons: obesity ( WC) – operator experience Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

36. Failure rates according to BMI7261 patients at the time of first examination Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

37. Unreliable results according to BMI 6968 patients at the time of first examination Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

38. Feasibility of LSM with FibroScan® using XL probeNew probe for obese patients 60% not measured by M probe successfully measured by XL probe de Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.

39.  Acute liver injury

40. Acute viral hepatitis increases liver stiffness18 patients with acute viral hepatitis I Peak increase in aminotransferase II Aminotransferase ≤ 50% of the peak III aminotransferase levels ≤ 2 ULN Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

41. Acute viral hepatitis increases liver stiffness18 patients with acute viral hepatitis I Peak increase in aminotransferase II Aminotransferase ≤ 50% of the peak III aminotransferase levels ≤ 2 ULN Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

42.  Extrahepaticcholestasis

43. Obstructive jaundice due to GIST occluding CBD Bilirubin 3.5 mg/dL Stiffness 5.7 kPa Stent placement Stent occlusion Bilirubin 8 mg/dL Stiffness 10 kPa Bilirubin 2 mg/dL Stiffness 5 kPa Millonig G et al. Hepatology 2008 ; 48 : 1718 – 1723.

44. Liver stiffness as a function of bile duct ligation10 German landrace pigs: 5 controls – 5 BD ligation 8.8 kPa 6.1 kPa 4.6 kPa 30 min after decompression 120 min after Bile duct ligation Control Millonig G et al. Hepatology 2008 ;48 : 1718 – 1723.

45.  Increased CVP

46. Representation of clamping site of the IVC5 German landrace pigs Experiment approved by local committee for Animal Welfare University of Heidelberg – Germany Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

47. LSM after clamping & reopening of IVC5 anesthesized landrace pigs P < 0.001 P < 0.001 27.8 kPa 5.1 kPa 3.1 kPa Before clamping 5 min after clamping 5 min after reopening Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

48. Liver stiffness directly influenced by CVP10 patients with CHF before & after recompensation Median 40.7 Median 17.8 p = 0.004 Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

49.  Ascites

50. Ascites in liver cirrhosis Diagnosis of cirrhosis is obvious Ascites grade 1: detectable only by ultrasound