3 Ideal non-invasive test for diagnosis of liver fibrosis SimpleReproducibleReadily availableLess expensive than biopsyPredicts full spectrum of fibrosisReflects changes occurring with therapy
4 Evaluation of chronic liver injury according to health care level Physical examinationLiver function testsSerum HyaluronateAPRI or other simple testsPrimary health careUltrasoundFibroscan®Serum markers & algorithmsSecondary health careFibroscan®ARFI*MR elastography*Tertiary health careLiver biopsyHVPG* Promising but currently under investigationARFI: Acoustic Radiation Force Impulse ImagingHVPG: Hepatic Venous Pressure GradientCastéra L et al. Gut 2010 ; 59 : 861 – 866.
5 Bedossa P. Liver Int 2009 ; 29 (s1): 19 – 22. Liver stiffnessAssessed by US (FibroScan®) & more recently by MRIEvaluates 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.
7 Position of probe & explored volume Cylinder 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 sample
8 Interval around median Contains 50% of valid shots ResultsStiffness (kPa)Median value of 10 shots3.9 Kilo Pascals IQR * (kPa)Interval around medianContains 50% of valid shots≤ 25% of median value At least 10 shots Success Rate: ≥ 60%
9 Manufacturer’s criteria for LSM interpretation First step Number of shots ≥ 10Second step Success rate ≥ 60 %Third step Interquantile range (IQR) ≤ 25%FailureZero valid shotUnreliable results< 10 valid shots Success rate ≤ 60%IQR ≥ 25%
10 Liver stiffness values in healthy subjects 429 subjects 5.2 ± 1.5 kPa5.8 ± 1.5 kPap =Roulot D et al. J Hepatol ; 48 : 606 – 613.
11 Roulot D et al. J Hepatol 2008; 48 : 606 – 613. Liver stiffness values in healthy subjects with & without metabolic syndrome5.3 ± 1.5 kPa6.5 ± 1.6 kPap <Roulot D et al. J Hepatol 2008; 48 : 606 – 613.
12 Liver stiffness cut-offs in chronic liver diseases MatavirF0-F1MildFibrosisF2SignF3SevereF4CirrhosisLiver stiffness values are expressed in kilopascalsRange from 2.5 – 75 kPaValues around 5.5 kPa were recently shown to reflect normalityLSM 2.5 – 7 kPa → Mild or absent fibrosis is likelyLSM > 12.5 kPa → Cirrhosis is likelyCastéra L et al. J Hepatol 2008 ; 48 : 835 – 847.
13 Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635. Progression of fibrosis in viral hepatitis Photomicrographs (magnification ×40; trichrome stains)F 0F 1F 2F 3F 4Normal portal triads with no signs of fibrosis (stage F0)Portal fibrous expansion (stage F1)Thin fibrous septa emanating from portal triads (stage F2)Fibrous septa bridging portal triads and central veins (stage F3)Cirrhosis (stage F4), which appears as nodules of liver parenchyma separated by thick fibrous bands.Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.
14 No significant fibrosis Perform LSM≤ 6 kPaNo significant fibrosisNo biopsyF0F1FIntermediate valuesGrey areaBiopsy if resultsinfluence managementF2Implementation of other NI tests≥ 12 kPaAdvanced fibrosisNo biopsyF4Treatment orFollow-upF3The experience accumulated so far suggests that the performance of LSM is optimal for advanced stages of fibrosis (ie, >F3 according to the METAVIR scoring system).This is likely due to the proportionally reduced presence of necrosis and inflammation, which are known to affect LSM.On the contrary, within intermediate stages of fibrosis the occurrence of inflammation, steatosis, cholestasis and passive/active congestion of the liver, may affect LSM.Therefore, patients with advanced fibrosis or compensated cirrhosis represent an optimal setting for the use of LSM.The ideal candidate for TE is a lean patient with severe fibrosis.Vizzutti et al. Gut 2009;58:
15 Sandrin L. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713. Shear wave propagation velocity according to severity of hepatic fibrosis (Metavir score)E = 3.0 kPaF 0E = 7.7 kPaF 2E = 27 kPaF 4Sandrin L. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.
16 Liver stiffness for each Metavir stage in CHC Box-and-whiskers plot Gastroenterology 2005; 28:343 – 350.Hepatology 2005;41:48 – 54.Vertical axis is in logarithmic scale (wide range of F4 values)
20 Accuracy of diagnostic test using AUC of ROC ValueAccuracyExcellentGoodFairPoorAUROC of a ‘‘good” test should be ≥ 0.80Pines 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 CLDCirrhosis (F4): 0.94(95% CI: 0.93 – 0.95)Cut-off value: 13.0 kPaSevere fibrosis (F3): 0.89(95% CI: 0.88 – 0.91)Significant fibrosis (F2): 0.84(95% CI: 0.82 – 0.86)Cut-off value: 7.7 kPaFriedrich R et al. Gastroenterology 2008 ; 134 : 960 – 974.
22 Significance of wide range of LSM in cirrhosis 13 - 75 kPa 2.513263649536275EV stage 2 or 3Child-Pugh B or CAdditional advantage of Fibroscan is that it provides a wide range of stiffness values within the group of cirrhotic livers that would overcome one major limitation of the biopsy (i.e. one histological stage for all types of cirrhosis), and could thus provide an additional prognostic value within this group (i.e. one histological stage for all types of cirrhosis), and could thus provide an additional prognosticvalue within this group.Background: Transient elastography (FibroScan) is a new, non-invasive, rapid, and reproducible method allowing evaluation of liver fibrosis by measurement of liver stiffness. In cirrhotic patients, liver stiffness measurements range from 12.5 to 75.5 kPa. However, the clinical relevance of these values is unknown. The aim of this prospective study was to evaluate the accuracy of liver stiffness measurement for the detection of cirrhosis in patients with chronic liver disease.Methods: A total of 711 patients with chronic liver disease were studied. Aetiologies of chronic liver diseases were hepatitis C virus or hepatitis B virus infection, alcohol, non-alcoholic steatohepatitis, other, or a combination of the above aetiologies. Liver fibrosis was evaluated according to the METAVIR score.Results: Stiffness was significantly correlated with fibrosis stage (r = 0.73, p,0.0001). Areas under the receiver operating characteristic curve (95% confidence interval) were 0.80 (0.75–0.84) for patients with significant fibrosis (F.2), 0.90 (0.86–0.93) for patients with severe fibrosis (F3), and 0.96 (0.94–0.98) for patients with cirrhosis. Using a cut off value of 17.6 kPa, patients with cirrhosis were detected with a positive predictive value and a negative predictive value (NPV) of 90%. Liver stiffness was significantly correlated with clinical, biological, and morphological parameters of liver disease. With an NPV > 90%, the cut off values for the presence of oesophageal varices stage 2/3, cirrhosis Child-Pugh B or C, past history of ascites, hepatocellular carcinoma, and oesophageal bleeding were 27.5, 37.5, 49.1, 53.7, and62.7 kPa, respectively.Conclusion: Transient elastography is a promising non-invasive method for detection of cirrhosis in patients with chronic liver disease. Its use for the follow up and management of these patients could be of great interest and should be evaluated further.Retrospective study of 711 patients with chronic liver diseases (95 with histologically proven cirrhosis).These preliminary findings need to be confirmed in long-term prospective follow-up studies to see whether liver stiffness values can predict the occurrence of clinical events in patients with compensated cirrhosis.AscitesHCC ?Variceal bleedingFoucher J et al. Gut 2006 ; 55 : 403 – 408.
23 Cumulative incidence of HCC based on LSM 866 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 0Hazard ratio as compared to LSM<10 kPa ≤LSM kPa 16.7 (95% CI, ; P<0.001LSM kPa 20.9 (95% CI, ; P<0.001LSM kPa 25.6 (95%CI, ; P < 0.001LSM >25 kPa 45.5 (95% CI, ; P < 0.001Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV-RNApositive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent.During the follow-up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person-year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM<10 kPa, of 16.7 (95% confidence interval [CI], ; P<0.001) when LSM kPa, 20.9 (95% CI, ; P<0.001) when LSM kPa, 25.6 (95%CI, ; P < 0.001) when LSM kPa, and 45.5 (95% CI, ; P < 0.001) when LSM >25 kPa.Conclusions: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development.LSM: Liver Stiffness Measurement – HR: Hazard RatioMasuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961.
24 Reproducibility of TE in assessing hepatic fibrosis. Bland Altman Plot Upper limitLower limitMean95% limit of agreement200 patients with chronic liver disease2 different operators within 3 days (800 exams)8 patients scored outside limits of agreementFraquelli M et al. Gut 2007 ; 56 : 968 – 973.
25 Cost of FibroScan® versus liver biopsy Cost of liver biopsy 703 – € in a French hospitalwith a one day observation periodFibroscan® **FibroScan equipment €Low running cost except probe calibration twice/yearCost 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 AASLD guidelines. Hepatology, 2009 ; 49 : 1017 – 1044. Liver biopsy sizeBecause grading, & staging of nonneoplastic diffuseparenchymal liver disease is dependent on adequatesized biopsy, a biopsy of at least 2-3 cm in length& 16-gauge in caliber is recommendedPresence of fewer than 11 complete portal tracts inpathology report may be incorrect in recognition ofgrading, & staging due to insufficient sample sizeIn a study of liver biopsies, Bedossa demonstrated that the stage of fibrosis was correctly diagnosed in65% of biopsies with length of 15 mm75% of biopsies with length of 25 mmBedossa P et al. Hepatol 2003 ; 38 : 1449 – 57.AASLD guidelines. Hepatology, 2009 ; 49 : 1017 – 1044.
27 Limitations of liver biopsy Sampling errorsExtremely small portion of liver (1/50 000)Intraobserver & interobserver variationEven when widely validated systems used for scoreInvasive procedureMorbidity: pain in 20% of patientsMajor complications: bleeding or hemobilia in 0.5%Mortality:
28 Grading & staging systems for chronic hepatitis IASL1Batts–Ludwig2Metavir3Grading systemMinimal activityMild activityModerate activityMarked activityMarked activity & bridgingGrade 1Grade 2Grade 3Grade 4A1A2A3(kappa 0.2 – 0.6)Staging systemNo fibrosisFibrous portal expansionFew bridges or septaNumerous bridgesCirrhosisStage 0Stage 1Stage 2Stage 3Stage 4F0F1F2F3F4(kappa 0.5 – 0.9)1 Desmet VJ et all. Hepatology 1994;19:2 Batts KP et all. Am J Surg Pathol 1995;19:3 Bedossa P et all. Hepatology 1996;24:
29 Interpretation of different values of kappa Kappa from Greek letter κ Value of kappaStrength of agreement0 – 0.20Poor0.21– 0.40Fair0.41– 0.60Moderate0.61– 0.80Good0.81–1.00Very goodkappa score ≥ 0.6 indicates good agreementPerera 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 patientsDisorders in coagulation profileSevere ascitesCystic lesionsVascular tumors (hemangiomas)AmiloidosisCongestive 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.
35 Unreliable results (16%) Limitations of liver stiffness measurement examinations – 5 year prospective study – 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%)Waist circumference 80 cm in women or 94 cm in men.Specific probe is developed for obese patients.LSM uninterpretable in one of five casesMain raisons: obesity ( WC) – operator experienceCastéra L et al. Hepatology 2010 ; 51 : 828 – 835.
36 Castéra L et al. Hepatology 2010 ; 51 : 828 – 835. Failure rates according to BMI patients at the time of first examinationCastéra L et al. Hepatology 2010 ; 51 : 828 – 835.
37 Castéra L et al. Hepatology 2010 ; 51 : 828 – 835. Unreliable results according to BMI patients at the time of first examinationCastéra L et al. Hepatology 2010 ; 51 : 828 – 835.
38 Feasibility of LSM with FibroScan® using XL probe New probe for obese patients Feasibility of liver transient elastography with FibroScans using a new probe for obese patientsde Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.Background & Aims: Liver stiffness measurement (LSM) failure when using transient elastography occurs in 2–10% of patients, and is generally related to obesity. The aim of this prospective study was to assess the feasibility of LSM when using a new XL probe on patients with a body mass index(BMI)Z30 kg/m2.Methods: For each patient, LSM was performed using both M probe (currently available and dedicated to patients with standardmorphology) and XL probe (dedicated to overweighed patients). A blood sample was taken to assess usual biological variables and simple readily available fibrosis blood tests.Results: Ninety-nine patients were included (27 men, mean age 52 years, mean BMI 40.5 kg/m2). LSM was successful (10 valid measurements) in 45% of the cases with the M probe, vs 76% of the cases with the XL probe (P<0.001). Fifty-nine percent of those who could not be measured (< 10 valid measurements) using the M probe could successfully be measured using the XL probe. In the 44 patients successfully measured with both probes, LSM was correlated with the platelet count, prothrombin time, g-glutamyltransferase, aspartate aminotransferase, fasting glucose, AST platelet ratio index, Forns score and FIB-4.Conclusion: The new XL probe allows providing a higher rate of LSM than the M probe in patients with an increased BMI and shows promising results for the evaluation of liver fibrosis.60% not measured by M probe successfully measured by XL probede Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.
40 Arena U et al. Hepatology 2008 ; 47 : 380 – 384. Acute viral hepatitis increases liver stiffness 18 patients with acute viral hepatitisWhen interpreting LSMs, the clinical question should be defined and LSM should be interpreted in the context of a defined diagnosis, biochemical data and appropriate cutoff points.Conclusion:LSM does not represent a reliable instrument to detect the presence of advanced fibrosis and cirrhosis in patients presenting with a clinical picture of acute hepatitis.I Peak increase in aminotransferaseII Aminotransferase ≤ 50% of the peakIII aminotransferase levels ≤ 2 ULNArena U et al. Hepatology 2008 ; 47 : 380 – 384.
41 Arena U et al. Hepatology 2008 ; 47 : 380 – 384. Acute viral hepatitis increases liver stiffness 18 patients with acute viral hepatitisWhen interpreting LSMs, the clinical question should be defined and LSM should be interpreted in the context of a defined diagnosis, biochemical data and appropriate cutoff points.Conclusion:LSM does not represent a reliable instrument to detect the presence of advanced fibrosis and cirrhosis in patients presenting with a clinical picture of acute hepatitis.I Peak increase in aminotransferaseII Aminotransferase ≤ 50% of the peakIII aminotransferase levels ≤ 2 ULNArena U et al. Hepatology 2008 ; 47 : 380 – 384.
43 Obstructive jaundice due to GIST occluding CBD Bilirubin 3.5 mg/dLStiffness 5.7 kPaStent placementStent occlusionBilirubin 8 mg/dLStiffness 10 kPaBilirubin 2 mg/dLStiffness 5 kPaTransient elastography (FibroScan [FS]) is a novel non-invasive tool to assess liver fibrosis/ cirrhosis. However, it remains to be determined if other liver diseases such as extrahepatic cholestasis interfere with fibrosis assessment because liver stiffness is indirectly measured by the propagation velocity of an ultrasound wave within the liver. In this study, we measured liver stiffness immediately before endoscopic retrograde cholangiopancreatography and 3 to 12 days after successful biliary drainage in patients with extrahepatic cholestasis mostly due to neoplastic invasion of the biliary tree. Initially elevated liver stiffness decreased in 13 of 15 patients after intervention, in 10 of them markedly. In three patients, liver stiffness was elevated to a degree that suggested advanced liver cirrhosis (mean, 15.2 kPa). Successfuldrainage led to a drop of bilirubin by 2.8 to 9.8 mg/dL whereas liver stiffness almost normalized (mean, 7.1 kPa). In all patients with successful biliary drainage, the decrease of liver stiffness highly correlated with decreasing bilirubin (Spearman’s , P < 0.05) with a mean decrease of liver stiffness of 1.2± 0.56 kPa per 1 g/dL bilirubin. Two patients,in whom liver stiffness did not decrease despite successful biliary drainage, had advanced liver cirrhosis and multiple liver metastases, respectively. The relationship between extrahepatic cholestasis and liver stiffness was reproduced in an animal model of bile duct ligation in landrace pigs where liver stiffness increased from 4.6 kPa to 8.8 kPa during 120 minutes of bile duct ligation and decreased to 6.1 kPa within 30 minutes after decompression.Conclusion: Extrahepatic cholestasis increases liver stiffness irrespective of fibrosis. Once extrahepatic cholestasis is excluded (e.g., by liver imaging and laboratory parameters) transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.Millonig G et al. Hepatology 2008 ; 48 : 1718 – 1723.
44 Millonig G et al. Hepatology 2008 ;48 : 1718 – 1723. Liver stiffness as a function of bile duct ligation 10 German landrace pigs: 5 controls – 5 BD ligation120 min afterBile duct ligation8.8 kPa30 min afterdecompression6.1 kPaControl4.6 kPaConclusion:Extrahepatic cholestasis increases liver stiffness irrespective of fibrosis. Once extrahepatic cholestasis is excluded (e.g., by liver imaging and laboratory parameters) transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.Millonig G et al. Hepatology ;48 : 1718 – 1723.
46 Representation of clamping site of the IVC 5 German landrace pigs Experiment approved by local committee for Animal WelfareUniversity of Heidelberg – GermanyMillonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
47 LSM after clamping & reopening of IVC 5 anesthesized landrace pigs 27.8 kPa5 min after clamping5 min after reopening5.1 kPaBefore clamping3.1 kPaMillonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
48 Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210. Liver stiffness directly influenced by CVP 10 patients with CHF before & after recompensationMedian 40.7Median 17.8p = 0.004Median weight loss of 3.0 kgLS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis.The presence of enlarged liver and/or hepato-jugular reflux on physical examination together with dilated hepatic veins and inferior vena cava, suggestive of chronic heart failure, would have helped to anticipate the findings of liverbiopsy.Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
52 Position of FibreScan® probe Dorsal decubitus positionRight arm in maximal abduction
53 Interpretation of the results of LSM should always be done by expert clinicians accordingto 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 cutoffDe Lédinghen V et al. Gastroentérol Clin Biol 2008 ; 32 : 58 – 67.