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Liver stiffness measurement (Fibroscan ® ) Principles - indications - results - limitations Samir Haffar M.D. Assistant Professor of Gastroenterology.

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Presentation on theme: "Liver stiffness measurement (Fibroscan ® ) Principles - indications - results - limitations Samir Haffar M.D. Assistant Professor of Gastroenterology."— Presentation transcript:

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

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

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 Physical examination Liver function tests Serum Hyaluronate APRI or other simple tests Primary health care Ultrasound Fibroscan® Serum markers & algorithms Secondary health care Fibroscan® ARFI* MR elastography* Tertiary health care Liver biopsy 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 Stiffness (kPa) Median value of 10 shots 3.9 Kilo Pascals  At least 10 shots  Success Rate: ≥ 60%  IQR * (kPa) Interval around median Contains 50% of valid shots ≤ 25% of median value

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

10 Liver stiffness values in healthy subjects 429 subjects Roulot D et al. J Hepatol 2008 ; 48 : 606 – 613. 5.2 ± 1.5 kPa5.8 ± 1.5 kPa p = 0.0002

11 Liver stiffness values in healthy subjects with & without metabolic syndrome Roulot D et al. J Hepatol 2008; 48 : 606 – 613. 5.3 ± 1.5 kPa6.5 ± 1.6 kPa p < 0.0001

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

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

14 Perform LSM ≤ 6 kPa No significant fibrosis No biopsy F0F1 F Intermediate values Grey area Biopsy if results influence management F2 Implementation of other NI tests ≥ 12 kPa Advanced fibrosis No biopsy F4 Treatment or Follow-up F3 Vizzutti et al. Gut 2009;58:156-60.

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

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

17 Correlation between LSM & fibrosis stage * Gastroentérol Clin Biol 2008;32,58-67. ** J Hepatol 2009;49:1062-68, Aliment Pharmacol Ther 2008;28:1188-98. *** Hepatology 2010;51:454-62. Gastroentérol Clin Biol 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) Newman TB & Kohn MA. Evidence-based diagnosis. Cambridge University Press, Cambridge, UK, 1 st edition, 2009. CIs

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 ValueAccuracy 0.90 - 1.00Excellent Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical decision rules. Blackwell’s publishing – West Sussex – UK – 2008. AUROC of a ‘‘good” test should be ≥ 0.80 0.80 - 0.90Good 0.70 - 0.80Fair 0.60 - 0.70Poor

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

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

23 Cumulative incidence of HCC based on LSM 866 CHC – Mean follow-up 3 years LSM: Liver Stiffness Measurement – HR: Hazard Ratio Masuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961. LSM > 25 kPaHR 45.5 (p< 0.001) LSM ≤ 10 kPaHR 0 10 < LSM ≤ 15 kPaHR 16.7 (p< 0.001) 15 < LSM ≤ 20 kPaHR 20.9 (p< 0.001) 20 < LSM ≤ 25 HR 25.6 (p< 0.001)

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

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-gauge in 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 IASL 1 Batts–Ludwig 2 Metavir 3 1 Desmet VJ et all. Hepatology 1994;19:1513-1520. 2 Batts KP et all. Am J Surg Pathol 1995;19:1409-1417. 3 Bedossa P et all. Hepatology 1996;24:289-293. Grading system Minimal activity Mild activity Moderate activity Marked activity Marked activity & bridging Grade 1 Grade 2 Grade 3 Grade 4 A1 A2 A3 Staging system No fibrosis Fibrous portal expansion Few bridges or septa Numerous bridges Cirrhosis Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 F0 F1 F2 F3 F4 (kappa 0.2 – 0.6) (kappa 0.5 – 0.9)

29 kappa score ≥ 0.6 indicates good agreement Interpretation of different values of kappa Kappa from Greek letter κ Value of kappaStrength of agreement 0 – 0.20Poor 0.21– 0.40Fair 0.41– 0.60Moderate 0.61– 0.80Good 0.81–1.00Very good Perera R, Heneghan C & Badenoch D. Statistics toolkit. Blackwell Publishing & BMJ Books, Oxford, 1 st 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  Extrahepatic cholestasis  Increased CVP  Ascites  Narrow intercostal spaces

34 Obesity & operator experience

35 Limitations of liver stiffness measurement 13 369 examinations – 5 year prospective study – 5 operators BMI > 30 kg/m 2 (OR 7.5) Operator experience (OR 2.5) Age > 52 years (OR 2.3) Type 2 diabetes (OR 1.6) Failure (3%) BMI > 30 kg/m 2 (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) Unreliable results (16%) Castéra L et al. Hepatology 2010 ; 51 : 828 – 835. LSM uninterpretable in one of five cases Main raisons: obesity (  WC) – operator experience

36 Failure rates according to BMI 7261 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 probe New probe for obese patients de Lédinghen V et al. Liver International 2010 ; : 1043 – 1048. 60% not measured by M probe successfully measured by XL probe

39  Acute liver injury

40 Acute viral hepatitis increases liver stiffness 18 patients with acute viral hepatitis I Peak increase in aminotransferase II Aminotransferase ≤ 50% of the peak IIIaminotransferase levels ≤ 2 ULN Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

41 Acute viral hepatitis increases liver stiffness 18 patients with acute viral hepatitis I Peak increase in aminotransferase II Aminotransferase ≤ 50% of the peak IIIaminotransferase levels ≤ 2 ULN Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

42  Extrahepatic cholestasis

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

44 Liver stiffness as a function of bile duct ligation 10 German landrace pigs: 5 controls – 5 BD ligation Millonig G et al. Hepatology 2008 ;48 : 1718 – 1723. Control 4.6 kPa 120 min after Bile duct ligation 8.8 kPa 30 min after decompression 6.1 kPa

45  Increased CVP

46 Representation of clamping site of the IVC 5 German landrace pigs Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210. Experiment approved by local committee for Animal Welfare University of Heidelberg – Germany

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

48 Liver stiffness directly influenced by CVP 10 patients with CHF before & after recompensation Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210. Median 40.7Median 17.8 p = 0.004

49  Ascites

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

51  Narrow intercostal spaces

52 Position of FibreScan® probe Dorsal decubitus position Right arm in maximal abduction

53 Interpretation of the results of LSM should always be done by expert clinicians according to clinical context

54 Transient elastography in clinical practice Examination quality 10 shots at least Success rate ≥ 60% IQR ≤ 25% of median value Liver disease Not used in acute hepatitis Not used in acute exacerbation Not used in ascites & EH cholestasis Choice of cutoff point Cutoffs different for each CLD Range of value rather than cutoff De Lédinghen V et al. Gastroentérol Clin Biol 2008 ; 32 : 58 – 67.

55 Questions

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