The birth of Hepatology as a defined clinical discipline coincides with the introduction of Menghini’s needle in the late 1950s.The liver biopsy was the only available diagnostic means, and truly represented a gold standard.The introduction of scoring systems represented a step forward in the use of liver biopsy. The value of liver biopsy as gold standard started to become questionable for clinicians.
Even a 25mm long liver biopsy has a 25% rate of discordance for fibrosis staging.The level of experience (specialisation, duration and location of practice) of the pathologist may even be more important.Liver biopsy is used to stage most cases of liver disease, it is well known that this procedure has several limitations:First, liver biopsies only sample an extremely small portion of the liver (1/50,000) and therefore, sampling errors can occur, especially when smaller sized biopsies are analyzed (under-diagnosis of cirrhosis in 10 – 20%). Even a 25mm long liver biopsy has a 25% rate of discordance for fibrosis staging.In addition, histological examination is prone to intraobserver and interobserver variation, which may occur even when widely validated systems are used to score liver damage.Finally, liver biopsy is an invasive procedure with associated morbidity: pain occurs in 20% of patients and major complications (such as bleeding or hemobilia) in 0.5%.
In a study of 10 000 liver biopsies, Bedossa demonstrated that the stage of fibrosis was correctly diagnosed in 65% of biopsies with length of 15 mm 75% of biopsies with length of 25 mmBedossa P et al. Hepatol 2003 ; 38 : 1449 – 57.
F0: No fibrosisF1: Portal fibrosis without septaF2: Portal fibrosis with few septaF3: Numerous septa without cirrhosisF4: cirrhosis.Major limitation of the biopsy: one histological stage for all type of cirrhosis.Normal 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.
level of experience (specialization, duration, and location of practice) has more influence on agreement than the characteristics of the specimen (length, fibrosis class number, miscellaneous factors). Agreement can be improved by experienced pathologist or consensus reading.
Cut-off value: distinguish between patients with disease & patients without diseasePoint of the curve which is far away from thechance diagonal.Because liver biopsy is an imperfect gold standard, a perfect surrogate will never reach the maximal value (1.0). Taking into accounta range of accuracies of the biopsy and a range of prevalence of significant disease (that influence the AUROC), Mehta et al have shown that in the most favorable scenario, an AUROC >0.90 cannot be achieved even for a perfect marker.An alternative gold standard is needed to assess the accuracy of tests used to stage HCV-related liver diseaseIn particular, long-term prospective studies of markers against clinical gold standards, such as development of end-stage liver disease are needed to assess the best measures of intermediate disease stages.
Promising:Studies with higher numbers of patients under different settings are needed in order to successfully incorporate this promising new tool into clinical practice.
ARFI (Acuson S2000 Virtual Touch Tissue Quantification, Siemens, Erlangen, Germany).The shear velocity is estimated in a central window of 5 mm axial by 4 mm width within a region of interest graphically displayed at a size of 1 cm axial by 6 mm width. The shear-wave propagation velocity is proportional to the square root of tissue elasticity. Results are expressed in meters per second (range, 0.5– 4.4 m/sec; ± 20% accuracy over the range).A measurement depth of 2 cm below the liver capsule was chosen to standardize the examination.Consistent with the TE protocol, 10 successful acquisitions were performed in each patient.
Both, ARFI and transient elastography median values were available for 312 patients from four studies.The diagnostic accuracy of ARFI was inferior to transient elastography for the diagnosis of significant fibrosis [mean difference of AUROC 0.05, P = 0.037 ] and for the diagnosis of liver cirrhosis (mean difference of AUROC 0.04, P = 0.048). No significant difference but a significant heterogeneity was found for the diagnosis of severe fibrosis (mean difference of AUROC 0.04, P = 0.092).
Left:Conventional abdominal MR magnitude images of the two patients, showing no significant difference between the two livers.Boundaries of the livers marked with dotted lines.Middle:Wave images from the MRE acquisition at 60 Hz showing shear waves with a shorter wavelength in the first patient, and a substantially longer wavelength in the second patient.Shear waves in the cirrhotic liver are longer than the shear waves in the normal liver.Right:The corresponding elastograms indicating that the two livers were normal (1.7 kPa) and cirrhotic (18.83 kPa), respectively.Increased stiffness of the cirrhotic liver is evident.Areas toward red end of spectrum are stiffer & contain more fibrosis than areas toward violet end of spectrum.
Magnetic Resonance Elastography for the Noninvasive Staging of Liver FibrosisHuwart L et al. Gastroenterology 2008 ; : 32 – 40. Belgium & France Background & Aims: The purpose of our study was to prospectively compare the success rate and diagnostic accuracy of magnetic resonance elastography, ultrasound elastography, and aspartateaminotransferase to platelets ratio index (APRI) measurementsfor the noninvasive staging of fibrosis in patients with chronic liver disease. Methods: We performed a prospective blind comparison of magnetic resonance elastography, ultrasound elastography, and APRI in a consecutive series of patients who underwent liver biopsy for chronic liver disease in a university-based hospital. Histopathologicstaging of liver fibrosis according to the METAVIR scoring system served as the reference.Results: A total of 141 patients were assessed. The technical success rate of magnetic resonance elastography was higher than that of ultrasound elastography(133/141 [94%] vs 118/141 [84%]; P= .016). Magnetic and ultrasound elastography, APRI measurements, and histopathologic analysis of liver biopsy specimens were technically successful in 96 patients. The areas under the receiver operatingcharacteristic curves of magnetic resonance elasticity (0.994 for F ≥ 2; 0.985 for F ≥ 3; 0.998 for F = 4) were larger (P < .05) than those of ultrasound elasticity, APRI, and the combination of ultrasound elasticity and APRI (0.837, 0.709, and 0.849 for F ≥ 2; 0.906, 0.816, and 0.936 for F ≥ 3; 0.930, 0.820, and 0.944 for F = 4, respectively).Conclusions: Magnetic resonance elastography has a higher technical success rate than ultrasound elastography and a better diagnostic accuracy than ultrasound elastography and APRI for staging liver fibrosis.
Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndromeJournal of Hepatology 48 (2008) 606–613.Background/Aims: Liver stiffness measurement by transient elastography is a very promising non-invasive method for the diagnosis of fibrosis in chronic liver diseases. However, studies on normal values of liver stiffness in healthy subjects are still lacking. The aim of the present study was to prospectively assess liver stiffness values in the general population and to determine potential factors, which may influence these values.Methods: Liver stiffness measurements were performed in 429 consecutive apparently healthy subjects, without overt cause of liver disease and normal liver enzymes, undergoing a free medical check-up. Results: Mean liver stiffness value was 5.49 ± 1.59 kPa. Transient elastography failure was observed in 4.6% of the cases. The failure rate increased with BMI, reaching 88% for values above 40 kg /m2. Liver stiffness values were higher in men than in women (5.81 ± 1.54 vs 5.23 ± 1.59 kPa, p = 0.0002) and in subjects with BMI > 30 kg/m2 (6.26 ± 1.89 vs 5.37 ± 1.51 kPa, p = 0.0003). Metabolic syndrome was diagnosed in 59 (13.7%) subjects. After adjustment for gender and BMI, liver stiffness values were higher in subjects with metabolic syndrome than in those without (6.51 ± 1.64 vs 5.33 ± 1.51 kPa, p < 0.0001).Conclusions: Liver stiffness values in the general population are influenced independently by gender, BMI and metabolic syndrome.
Liver stiffness values are expressed in kilopascalsRange from 2.5 – 75 kPaValues around 5.5kPa were recently shown to reflect normality
To assess the reproducibilityof LSM, Fraquelli performed interobserver and intraobserver agreement.TE reproducibility was proven excellent for both inter-observer & intra-observer agreement, with intraclass correlation coefficients (ICC) of 0.98.
Performance of Transient Elastography for the Staging of Liver Fibrosis: a Meta-analysisGastroenterology 2008;134:960–974.Background & Aims: Transient elastography has been studied in a multitude of liver diseases for the staging of liver fibrosis with variable results. A meta-analysis was performed to assess the overall performance of transient elastography for the diagnosis of liver fibrosis and to analyze factors influencing the diagnostic accuracy. Methods: Literature databases and international conference abstracts were searched. Inclusion criteria were as follows: evaluation of transient elastography, liver biopsy as reference, and assessment of the area under the receiver operating characteristic curve (AUROC). The meta-analysis was performed using the random-effects model for the AUROC, summary receiver operating curve techniques, as well as meta-regression approaches. Results: Fifty studies were included in the analysis. The mean AUROC for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.84 (95% confidence interval [CI], 0.82– 0.86), 0.89 (95% CI, 0.88 – 0.91), and 0.94 (95% CI, 0.93– 0.95), respectively. For the diagnosis of significant fibrosis a significant reduction of heterogeneity of the AUROC was found when differentiating between the underlying liver diseases (P < .001). Other factors influencing the AUROC were the scoring system used and the country in which the study was performed. Age, body mass index, and biopsy quality did not have a significant effect on the AUROC. Conclusions: Transient elastography can be performed with excellent diagnostic accuracy and independent of the underlying liver disease for the diagnosis of cirrhosis. However, for the diagnosis of significant fibrosis, a high variation of the AUROC was found that is dependent on the underlying liver disease.
proposal of a clinical reference (liver-related death, end-stage liver complications) for comparing the performances of Fibroscan and biopsy for diagnosis of cirrhosis.
LSM can clearly separate 3 groups of patients with (1) absent or low-grade fibrosis; (2) Advanced fibrosis/cirrhosis; (3) intermediate stages of fibrosis (so-called ‘‘grey area’’).The ideal candidate for TE is a lean patient with severe fibrosis.A liver biopsy of 25-mm length has also a lower accuracy (“gray zone”) between two adjacent stages.
Place of TE in the 2 most frequent cause of CLD: chronic viral hepatitis & NASH. Two critical end pointsPresence of significant fibrosis which is an indication for antiviral treatment in chronic hepatitis B and CPresence of cirrhosis which is an indication for specific monitoring of complications related to PHT & to increased risk of developing hepatocellular carcinoma.
Advanced fibrosis: F0-F1 versus F2-F4the penalty function was 0.25 when the difference between stages was 1; 0.50 when the difference between stages was 2; 0.75 when the difference was 3; and 1 when the difference was 4.ALT flares occur frequently in HBV-infected patients and may lead to overestimation of liver stiffness values by TE.Sensitivity analysis assessed the impact of several factors, including authors’ independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanineaminotransferase value.
Diagnosis of fibrosis & cirrhosis using LSM in nonalcoholic fatty liver diseaseNonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Accurate noninvasive tests for liver injury are urgently needed. The aim of this study was to evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. 246 consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver-operating characteristics curve (AUROC) of transient elastography for F3 or higher andF4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartateaminotransferase–to–alanineaminotransferase ratio, aspartateaminotransferase–to–platelet ratio index, FIB-4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P<0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negativepredictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0-2 disease were associated withdiscordance. Conclusion: Transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered inNAFLD patients with liver stiffness of at least 7.9 kPa. (HEPATOLOGY 2010;51:454-462.)
Additional 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 prognostic value 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 oesophagealvarices 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.Although retrospective and conducted in a single centre, the study by Foucher et al has provided the first ‘proof of concept’ that liver stiffness values may have prognostic value in the context of cirrhosis.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.there is a pressing need for a new classification of cirrhosis integrating clinical, biological, histological, & haemodynamic features of this stage of chronic liver disease.
Although these findings need to be confirmed in other settings (Caucasian patients or HBV infected patients) and with longer follow-up. Hazard ratio as compared to LSMLSM <10 kPa 0LSM 10.1-15 kPa 16.7 (95% CI, 3.71-75.2; P<0.001 LSM 15.1-20 kPa 20.9 (95% CI, 4.43-98.8; P<0.001LSM 20.1-25 kPa 25.6 (95%CI, 5.21-126.1; P < 0.001LSM >25 kPa 45.5 (95% CI, 9.75-212.3; 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-RNA positive 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], 3.71-75.2; P<0.001) when LSM 10.1-15 kPa, 20.9 (95% CI, 4.43-98.8; P<0.001) when LSM 15.1-20 kPa, 25.6 (95%CI, 5.21-126.1; P < 0.001) when LSM 20.1-25 kPa, and 45.5 (95% CI, 9.75-212.3; 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.
What about the cost of FibroScan comparing to the cost of liver biopsy.Acoording to blanc, the cost of liver biopsy
LSM may be confounded by a variety of factors expected to alter liver stiffness, including hepatic inflammation, steatosis, hepatic vascular congestion, cholestasis, and portal hypertension.
Concerning the operator experience, the learning curve of LSM is short & the operator could be performant after 50 exams. Conerning obesity, a special probe for obese patients is developped.
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 successfullymeasured with both probes, LSM was correlated with the platelet count, prothrombin time, g-glutamyltransferase, aspartateaminotransferase, 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.
The aim of this article is to provide for the first time a critical analysis of the current situation based on clinical needs and realistic end points.
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 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.
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
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
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.
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
METAVIR scoring systemMagnification 40; trichrome stainsFaria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.F 0 F 1 F 2F 3F 4
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
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.
Contraindications of liver biopsy• Uncooperated patients• Disorders in coagulation profile• Severe ascites• Cystic lesion• Vascular tumor (hemangioma)• Amiloidosis• Congestive liver disease
For liver biopsyThe term ‘‘best standard”more appropriate than ‘‘gold standard”1 Bedossa P & Carrat F. J Hepatology 2009 ; 50 : 1 – 3.
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
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
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
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.
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
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
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.
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
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.
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
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%
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
Liver stiffness cut-offs in chronic liver diseasesF2SignF3SevereF4CirrhosisMatavir F0-F1MildFibrosisCastéra L et al. J Hepatol 2008 ; 48 : 835 – 847.
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
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
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
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.
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.
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.
• 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
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)
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.
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
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
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%
Limitations of US transient elastography Uninterpretable results Acute liver injury Extrahepatic cholestasis Increased CVP Ascites Narrow intercostal spaces
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
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
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 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.
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.
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
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