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Imaging modalities for diagnosis& staging of hepatic fibrosisSamir Haffar M.D.Assistant Professor of Gastroenterology
Imaging modalities in hepatic fibrosisTechniques ModalitiesUltrasonography Black & white USDoppler USContrast-enhanced USE...
Structure for a study of diagnostic testSuspected targetconditionGuyatt G et all. Users’ guides to medical literature: man...
Validity of study design of diagnostic study Blind comparison with the gold standard test Gold standard test performed i...
Limitations of liver biopsy• Sampling errorMajor limitationSmall portion of liver (1/50 000)• Intra & inter-observer varia...
Liver biopsy sizeAASLD guidelines1• Biopsy of at least 2 – 3 cm in length is recommendedNeedle of 16-gauge in caliber is r...
METAVIR scoring systemMagnification 40; trichrome stainsFaria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.F 0 F 1 F 2F...
Interpretation of different values of kappaKappa from Greek letter κValue of kappa Strength of agreement0 – 0.20 Poor0.21–...
Influence of expertise degree in liver pathology254 liver specimens – 15 pathologists – Metavir score1 2 academic seniors ...
US guided biopsyAASLD guidelinesUltrasound guidance with marking of optimal biopsysite performed immediately preceding bio...
Contraindications of liver biopsy• Uncooperated patients• Disorders in coagulation profile• Severe ascites• Cystic lesion•...
For liver biopsyThe term ‘‘best standard”more appropriate than ‘‘gold standard”1 Bedossa P & Carrat F. J Hepatology 2009 ;...
Accuracy of test & number of results• Dichotomous test (only 2 results)Sensibility (Sn) & Specificity (Sp)PPV & NPVLikelih...
ROC curve & cut-off pointPeat JK. Health science research: a handbook of quantitative methods.Allen & Unwin, Australia, 1s...
Accuracy of diagnostic test using AUROC*Value of AUROC* Accuracy0.90 – 1.00 Excellent* AUROC: Area Under Receiver Operatin...
Imaging modalities for hepatic fibrosis Acoustic Radiation Force Impulse imaging (ARFI) MR elastography Transient elast...
Acoustic Radiation Force Impulse ImagingARFIRegion of interest (ROI) chosen by US guidanceResults expressed in m/sec (rang...
Meta-analysis of ARFI8 studies (518 pts) – All CLD – Metavir – Random effectFriedrich-Rust M et al. J Viral Hepat 2012 ; 1...
Elastography• Assessed by US (FibroScan®) & more recently by MRI• Evaluates velocity of propagation of a shock wavewithin ...
MR elastographyMariappan YK. Clinical Anatomy 2010 ; 23 : 497 – 511.Conventional MR Wave images at 60 HzShorter wavelength...
MR Elastography for staging of liver fibrosisProspective & blind study – 96 patients with CLDMR elastography, TE, & APRI v...
Fibroscan® (Echosens, Paris, France)
Transient elastographyPosition of probe & explored volumeCylinder of 1 cm wide & 4 cm longFrom 25 mm to 65 mm below skin s...
Results of FibroScan®Stiffness (kPa)Median value of 10 shots At least 10 shots Success Rate: ≥ 60% IQR * (kPa)Interval ...
Manufacturer’s criteria for LSM interpretation• First step Number of shots ≥ 10• Second step Success rate ≥ 60 %• Third st...
LS values in apparently healthy subjectsProspective study of 429 subjectsRoulot D et al. J Hepatol 2008 ; 48 : 606 – 613.5...
Liver stiffness cut-offs in chronic liver diseasesF2SignF3SevereF4CirrhosisMatavir F0-F1MildFibrosisCastéra L et al. J Hep...
Shear wave propagation velocity according toseverity of hepatic fibrosis (METAVIR score)Sandrin L et al. Ultrasound Med Bi...
Reproducibility of TE in assessing hepatic fibrosis.Bland Altman plotFraquelli M et al. Gut 2007 ; 56 : 968 – 973.200 pati...
Meta-analysis of TE for staging liver fibrosisSevere fibrosis (≥ F3): 0.89(95% CI: 0.88 – 0.91)Friedrich-Rust M et al. Gas...
Improving diagnostic statistical methods• When there is no perfect gold standardAUROC >0.90 could not be achieved even for...
Perform LSM≤ 6 kPaNo significant fibrosisNo biopsyF0 F1FIntermediate valuesGrey areaBiopsy if resultsinfluence managementF...
LSM according to different etiologies of CLD* Gastroentérol Clin Biol 2008 ; 32 :58 – 67.** J Hepatol 2009 ; 49 : 1062 – 6...
Place of FibroScan in chronic viral hepatitis• Two critical end points Significant fibrosis (≥ F2)Presence of cirrhosis (F...
• Liver biopsy still regarded as reference method to assessgrade of inflammation & stage of fibrosis (A2)• TE can be used ...
MA of AUROCt for advanced fibrosis in CHBMetavir – Random effect – stAUROC – ObuchowskiPoynard T et al. Curr Hepatitis Rep...
Place of transient elastography in NAFLDSecond most relevant clinical entity in hepatology• Significant fibrosis does not ...
Significance of wide range of LSM in cirrhosis13 – 75 kPaAscitesHCC ?Variceal bleedingFoucher J et al. Gut 2006 ; 55 : 403...
Cumulative incidence of HCC based on LSMProspective – 866 CHC – Mean follow-up 3 yearsLSM: Liver Stiffness Measurement – H...
Cost of FibroScan versus liver biopsy• Liver biopsy*Cost of liver biopsy 703 – 1 566 € in a French hospitalwith a one day ...
LSM in the general populationSocial Medical CenterFree medical checkup1358 healthy subjects over 45 yearsFailure, missing ...
Limitations of US transient elastography Uninterpretable results Acute liver injury Extrahepatic cholestasis Increased...
Uninterpretable results of LSM5 year prospective study – 13 369 examinations – 5 operatorsBMI > 30 kg/m2 (OR 7.5)Operator ...
Feasibility of LSM with FibroScan® using XL probeNew probe for obese patientsde Lédinghen V et al. Liver International 201...
Ascites in liver cirrhosisAscites grade 1 according to International Ascites ClubDetectable only by ultrasound
Non-invasive diagnosis of liver fibrosisOpinions of leaders“Biopsist”Biopsy as first-line estimate of liver injuryBiopsy n...
Transient elastography in clinical practiceExamination quality 10 shots at leastSuccess rate ≥ 60%IQR ≤ 25% of median valu...
Interpretation of results of LSM shouldalways be done by expert clinicians accordingto clinical contextLSM is the only est...
Does it take two to tango?Castera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.Liver biopsy & non-invasive tools especially TE...
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Imaging modalities & liver fibrosis (elastography)

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Description of all available modalities for non-invasive diagnosis of liver fibrosis with comparaison to liver biopsy.

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Imaging modalities & liver fibrosis (elastography)

  1. 1. Imaging modalities for diagnosis& staging of hepatic fibrosisSamir Haffar M.D.Assistant Professor of Gastroenterology
  2. 2. Imaging modalities in hepatic fibrosisTechniques ModalitiesUltrasonography Black & white USDoppler USContrast-enhanced USElasticity measurementsTissue strain imagingLeft lobe liver surface (LLS)Real-time elastographyTransient elastographyAcoustic Radiation Force Imaging (ARFI)Computed Tomography (CT)Positron Emission Tomography (PET)Single Photon Emission CT (SPECT)Magnetic Resonance Imaging Conventional MRIDouble contrast-enhanced MRMR elastographyDiffusion-weighted MRIMR perfusion imagingMR spectroscopyBonekamp S et al. J Hepatol 2009 ; 50 : 17 – 35.
  3. 3. Structure for a study of diagnostic testSuspected targetconditionGuyatt G et all. Users’ guides to medical literature: manual for EBP.McGraw-Hill, New York, USA, 2nd edition, 2008.Gold standard testPositiveNegativeDiagnostic testPositiveNegative
  4. 4. Validity of study design of diagnostic study Blind comparison with the gold standard test Gold standard test performed in all patients Diagnostic test evaluated in appropriate spectrum of ptsIf no → Stop here
  5. 5. Limitations of liver biopsy• Sampling errorMajor limitationSmall portion of liver (1/50 000)• Intra & inter-observer variationG (κ: 0.2 – 0.6) – S (κ: 0.5 – 0.9)• Invasive procedurePain 20%Major complications 0.5%Mortality 0.03 %Sufficient length biopsyScoring systemExperienced pathologistUS guided biopsy“preferred”AASLD position paper. Hepatology 2009 ; 49 : 107 – 1044.
  6. 6. Liver biopsy sizeAASLD guidelines1• Biopsy of at least 2 – 3 cm in length is recommendedNeedle of 16-gauge in caliber is recommendedAASLD guidelines. Hepatology 2009 ; 49 : 1017 – 1044.2 Bedossa P et al. Hepatology 2003 ; 38 : 1449 – 57.• Presence of fewer than 11 complete portal tractsmay be incorrect in recognition of grading & stagingEven a 25mm long liver biopsyhas 25% rate of discordance for fibrosis staging2
  7. 7. METAVIR scoring systemMagnification 40; trichrome stainsFaria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.F 0 F 1 F 2F 3F 4
  8. 8. Interpretation of different values of kappaKappa from Greek letter κValue of kappa Strength of agreement0 – 0.20 Poor0.21– 0.40 Fair0.41– 0.60 Moderate0.61– 0.80 Good0.81–1.00 Very goodPerera R, Heneghan C & Badenoch D. Statistics toolkit.Blackwell Publishing & BMJ Books, Oxford, 1st edition, 2008.kappa score of 0.6 indicates good agreement
  9. 9. Influence of expertise degree in liver pathology254 liver specimens – 15 pathologists – Metavir score1 2 academic seniors (1 expert – 1 non-expert)2 2 academic juniors3 2 academic experts (1 junior – 1 senior)4 Consensus reading by experts (1 junior – 1 senior)5 1 academic expert & 3 academic non-experts6 1 academic expert & 10 non-academic non-expertsRousselet MC et al. Hepatology 2005 ; 41 : 257 – 264.
  10. 10. US guided biopsyAASLD guidelinesUltrasound guidance with marking of optimal biopsysite performed immediately preceding biopsy, by theindividual performing the biopsy, is preferred, thoughnot mandatory, because it likely reduces the risk ofcomplications from liver biopsy (Class I, Level B)AASLD guidelines. Hepatology 2009 ; 49 : 1017 – 1044.
  11. 11. Contraindications of liver biopsy• Uncooperated patients• Disorders in coagulation profile• Severe ascites• Cystic lesion• Vascular tumor (hemangioma)• Amiloidosis• Congestive liver disease
  12. 12. For liver biopsyThe term ‘‘best standard”more appropriate than ‘‘gold standard”1 Bedossa P & Carrat F. J Hepatology 2009 ; 50 : 1 – 3.
  13. 13. Accuracy of test & number of results• Dichotomous test (only 2 results)Sensibility (Sn) & Specificity (Sp)PPV & NPVLikelihood Ratios (LRs)Diagnostic Odds Ratio (OR)• Multilevel test (> 2 results)Receiver Operating Characteristic (ROC)CIs
  14. 14. ROC curve & cut-off pointPeat JK. Health science research: a handbook of quantitative methods.Allen & Unwin, Australia, 1st edition, 2001.Cut-off point: Point of curve far away from chance diagonal
  15. 15. Accuracy of diagnostic test using AUROC*Value of AUROC* Accuracy0.90 – 1.00 Excellent* AUROC: Area Under Receiver Operating CharacteristicsPines JM & al. Evidence-Based emergency care: diagnostic testing & clinical decision rules.Blackwell’s publishing – West Sussex – UK – 2008.AUROC of a „„good test” should be ≥ 0.800.80 – 0.90 Good0.70 – 0.80 Fair0.60 – 0.70 Poor
  16. 16. Imaging modalities for hepatic fibrosis Acoustic Radiation Force Impulse imaging (ARFI) MR elastography Transient elastography (TE) or FibroScan®EstablishedPromising but currently under investigationCastera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.
  17. 17. Acoustic Radiation Force Impulse ImagingARFIRegion of interest (ROI) chosen by US guidanceResults expressed in m/sec (range: 0.5 – 4.4)Friedrich-Rust et al. Radiology 2009 ; 252 : 595 – 604.ROI
  18. 18. Meta-analysis of ARFI8 studies (518 pts) – All CLD – Metavir – Random effectFriedrich-Rust M et al. J Viral Hepat 2012 ; 19 : e212 – e219.ARFI can be performed with good diagnostic accuracyfor noninvasive staging of liver fibrosisFibrosis Areas under ROC curvesSignificant fibrosis (F ≥ 2) 0.87Severe fibrosis (F ≥ 3) 0.91Cirrhosis 0.93
  19. 19. Elastography• Assessed by US (FibroScan®) & more recently by MRI• Evaluates velocity of propagation of a shock wavewithin liver tissue (examines a physical parameter ofliver tissue which is related to its elasticity)• Rationale Normal liver is viscousNot favorable to wave propagationFibrosis increases hardness of tissueFavors more rapid propagationBedossa P. Liver Int 2009 ; 29 (s1): 19 – 22.
  20. 20. MR elastographyMariappan YK. Clinical Anatomy 2010 ; 23 : 497 – 511.Conventional MR Wave images at 60 HzShorter wavelengthLonger wavelengthMR elastographyNormal: 1.7 kPaCirrhosis: 18.83 kPa
  21. 21. MR Elastography for staging of liver fibrosisProspective & blind study – 96 patients with CLDMR elastography, TE, & APRI versus liver biopsyHuwart L et al. Gastroenterology 2008 ; 135 : 32 – 40.Encouraging resultsEfforts to standardize equipment & techniquesToo expensive & time-consuming for clinical practice
  22. 22. Fibroscan® (Echosens, Paris, France)
  23. 23. Transient elastographyPosition of probe & explored volumeCylinder of 1 cm wide & 4 cm longFrom 25 mm to 65 mm below skin surfaceThis volume is at least 100 times bigger than a biopsy sampleJaffer OS et al.Ultrasound 2012 ; 20 : 24 – 32.
  24. 24. Results of FibroScan®Stiffness (kPa)Median value of 10 shots At least 10 shots Success Rate: ≥ 60% IQR * (kPa)Interval around medianContains 50% of valid shots≤ 30% of median value* IQR: Inter Quantile range
  25. 25. Manufacturer’s criteria for LSM interpretation• First step Number of shots ≥ 10• Second step Success rate ≥ 60 %• Third step Interquantile range(IQR) ≤ 25%FailureZero valid shotUnreliable results< 10 valid shotsor Success rate ≤ 60%or IQR ≥ 30%
  26. 26. LS values in apparently healthy subjectsProspective study of 429 subjectsRoulot D et al. J Hepatol 2008 ; 48 : 606 – 613.5.2 1.5 kPa 5.8 1.5 kPap = 0.0002Normal liver stiffness measurement: 5.49 1.59 kPa
  27. 27. Liver stiffness cut-offs in chronic liver diseasesF2SignF3SevereF4CirrhosisMatavir F0-F1MildFibrosisCastéra L et al. J Hepatol 2008 ; 48 : 835 – 847.
  28. 28. Shear wave propagation velocity according toseverity of hepatic fibrosis (METAVIR score)Sandrin L et al. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.E = 3.0 kPaF 0E = 7.7 kPaF 2E = 27 kPaF 4
  29. 29. Reproducibility of TE in assessing hepatic fibrosis.Bland Altman plotFraquelli M et al. Gut 2007 ; 56 : 968 – 973.200 patients with chronic liver disease2 different operators within 3 days (800 exams)8 patients scored outside limits of agreementUpper limitLower limitMean95% limit ofagreement
  30. 30. Meta-analysis of TE for staging liver fibrosisSevere fibrosis (≥ F3): 0.89(95% CI: 0.88 – 0.91)Friedrich-Rust M et al. Gastroenterology 2008 ; 134 : 960 – 974.Cirrhosis (F4): 0.94(95% CI: 0.93 – 0.95)Cut-off value: 13.0 kPa50 studies – All type of CLD – Random effectSignificant fibrosis (≥ F2): 0.84(95% CI: 0.82 – 0.86)Cut-off value: 7.7 kPaFor significant fibrosis, a high variation of AUROC was found
  31. 31. Improving diagnostic statistical methods• When there is no perfect gold standardAUROC >0.90 could not be achieved even for perfect marker1Prognostic analysis (morbidity/mortality endpoints) used• Methods for spectrum effect & ordinal scaleStandardization of AUROC 2: distribution of fibrosis stagesObuchowski measure3: spectrum effect & ordinal scale1 Mehta SH et al. J Hepatol 2009 ; 50 : 36 – 41.2 Poynard T et al. Curr Hepatitis Rep 2011 ; 10 : 87 – 97.3 Lambert C et al. Clinical Chemistry 2008 ; 54 : 8 : 1372 – 1378.
  32. 32. Perform LSM≤ 6 kPaNo significant fibrosisNo biopsyF0 F1FIntermediate valuesGrey areaBiopsy if resultsinfluence managementF2Implementation ofother NI tests≥ 12.5 kPaAdvanced fibrosisNo biopsyF4Treatment orFollow-upF3Vizzutti et al. Gut 2009;58:156-60.
  33. 33. LSM according to different etiologies of CLD* 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.
  34. 34. Place of FibroScan in chronic viral hepatitis• Two critical end points Significant fibrosis (≥ F2)Presence of cirrhosis (F4)• Chronic hepatitis C ≥ F2: TE + serum markersF4: TE• Chronic hepatitis B Immunotolerant phase: TE≥ F2: more studies neededF4: TECastera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.
  35. 35. • Liver biopsy still regarded as reference method to assessgrade of inflammation & stage of fibrosis (A2)• TE can be used to assess liver fibrosis in CHC (A2)• Non-invasive serum makers can be recommended fordetection of significant fibrosis (METAVIR F2 – F4) (A2)• Combination of blood tests or TE & blood testImprove accuracy & reduce necessity of liver biopsy (C2)EASL Clinical Practice Guidelines: Management of hepatitis C virus infection.J Hepatol 2011 ; 55 : 245 – 264.Chronic hepatitis CEASL Clinical Practice Guidelines
  36. 36. MA of AUROCt for advanced fibrosis in CHBMetavir – Random effect – stAUROC – ObuchowskiPoynard T et al. Curr Hepatitis Rep 2011 ; 10 : 87 – 97.All significantly higher than random 0.50 valueNo significant heterogeneity (Cochran’s Q = 6.3)AUROC: 0.89 (0.83 – 0.96)AUROC: 0.84 (0.79 – 0.86)
  37. 37. Place of transient elastography in NAFLDSecond most relevant clinical entity in hepatology• Significant fibrosis does not represent critical end pointin absence of standardized treatment regimens• TE could be useful to select those requiring liver biopsy formore accurate staging of disease (cut-off value 7.9 kPa)Castera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.Wong VW et al. Hepatology 2010 ; 51 : 454 – 462.
  38. 38. Significance of wide range of LSM in cirrhosis13 – 75 kPaAscitesHCC ?Variceal bleedingFoucher J et al. Gut 2006 ; 55 : 403 – 408.EV stage 2 or 327Child-Pugh B or C37 49 53 622.5 7513
  39. 39. Cumulative incidence of HCC based on LSMProspective – 866 CHC – Mean follow-up 3 yearsLSM: Liver Stiffness Measurement – HR: Hazard RatioMasuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961.LSM > 25 kPa HR 45.5 (p< 0.001)LSM ≤ 10 kPa HR 010 < LSM ≤ 15 kPa HR 16.7 (p< 0.001)15 < LSM ≤ 20 kPa HR 20.9 (p< 0.001)20 < LSM ≤ 25 kPa HR 25.6 (p< 0.001)
  40. 40. Cost of FibroScan versus liver biopsy• Liver biopsy*Cost of liver biopsy 703 – 1 566 € in a French hospitalwith a one day observation period* 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.• Fibroscan® **FibroScan equipment 70 000 €Low running cost except probe calibration twice/yearCost per FibroScan® exam 100 € with 150 exams annually
  41. 41. LSM in the general populationSocial Medical CenterFree medical checkup1358 healthy subjects over 45 yearsFailure, missing dataN = 23828 subjects underwentliver biopsyRoulot et al. 2009 EASL meeting Copenhagen.D. Roulot et al. J Hepatol 2009 ; 50 : S 89.LS < 8 kPaN = 10408 kPa ≤ LS < 14.6 kPaN = 72LS ≥ 14.6 kPaN = 8Prevalence of cirrhosis was at least 0.7%
  42. 42. Limitations of US transient elastography Uninterpretable results Acute liver injury Extrahepatic cholestasis Increased CVP Ascites Narrow intercostal spaces
  43. 43. Uninterpretable results of LSM5 year prospective study – 13 369 examinations – 5 operatorsBMI > 30 kg/m2 (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/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)Unreliable results (16%)Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.LSM uninterpretable in one of five casesMain raisons: Obesity ( WC) – Operator experience
  44. 44. Feasibility of LSM with FibroScan® using XL probeNew probe for obese patientsde Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.60% not measured by M probe successfully measured by XL probe
  45. 45. Ascites in liver cirrhosisAscites grade 1 according to International Ascites ClubDetectable only by ultrasound
  46. 46. Non-invasive diagnosis of liver fibrosisOpinions of leaders“Biopsist”Biopsy as first-line estimate of liver injuryBiopsy not perfect gold standard but best estimateRarely admits biopsy as false-positive/false negativeTypically head of pathology unit“Biomarkerist’’Biomarker as first-line estimate of liver injuryBiomarker not perfect test but as accurate as biopsyDiscordance with biopsy: failure due to either (50%)In case of non-interpretability: another biomarkerIf still not interpretable: biopsy as 3rd line assessment“BioCocktailist”Biomarker first then biopsy if result not convincingColleague of Biopsist & close friend of BiomarkeristUsually also has a statistician friendPoynard T. J Hepatol 2011 ; 54 ; 586 – 587.
  47. 47. Transient elastography in clinical practiceExamination quality 10 shots at leastSuccess rate ≥ 60%IQR ≤ 25% of median valueLiver disease Not used in acute hepatitisNot used in acute exacerbationNot used in ascites & EH cholestasisChoice of cutoff point Cutoffs different for each CLDRange of value rather than cutoffDe Lédinghen V et al. Gastroentérol Clin Biol 2008 ; 32 : 58 – 67.
  48. 48. Interpretation of results of LSM shouldalways be done by expert clinicians accordingto clinical contextLSM is the only established imaging modalityfor non-invasive diagnosis of liver fibrosisat the present time
  49. 49. Does it take two to tango?Castera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.Liver biopsy & non-invasive tools especially TE should beemployed as integrated system to maximize their potentialActing like two tango dancers
  50. 50. Thank You

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