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 fibrosis
Samir Haffar M.D.
Assistant Professor of Gastroenterology
Imaging modalities in hepatic fibrosis
Ultrasonography Black & white US
Tissue strain imaging
Left lobe liver surface (LLS)
Acoustic Radiation Force Imaging (ARFI)
Computed Tomography (CT)
Positron Emission Tomography (PET)
Single Photon Emission CT (SPECT)
Magnetic Resonance Imaging Conventional MRI
Double contrast-enhanced MR
MR perfusion imaging
Bonekamp S et al. J Hepatol 2009 ; 50 : 17 – 35.
Structure for a study of diagnostic test
Guyatt G et all. Users’ guides to medical literature: manual for EBP.
McGraw-Hill, New York, USA, 2nd edition, 2008.
Gold standard test
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 pts
If no → Stop here
Limitations of liver biopsy
• Sampling error
Small portion of liver (1/50 000)
• Intra & inter-observer variation
G (κ: 0.2 – 0.6) – S (κ: 0.5 – 0.9)
• Invasive procedure
Major complications 0.5%
Mortality 0.03 %
Sufficient length biopsy
US guided biopsy
AASLD position paper. Hepatology 2009 ; 49 : 107 – 1044.
Liver biopsy size
• Biopsy of at least 2 – 3 cm in length is recommended
Needle of 16-gauge in caliber is recommended
AASLD guidelines. Hepatology 2009 ; 49 : 1017 – 1044.
2 Bedossa P et al. Hepatology 2003 ; 38 : 1449 – 57.
• Presence of fewer than 11 complete portal tracts
may be incorrect in recognition of grading & staging
Even a 25mm long liver biopsy
has 25% rate of discordance for fibrosis staging2
METAVIR scoring system
Magnification 40; trichrome stains
Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.
F 0 F 1 F 2
Interpretation of different values of kappa
Kappa from Greek letter κ
Value of kappa Strength of agreement
0 – 0.20 Poor
0.21– 0.40 Fair
0.41– 0.60 Moderate
0.61– 0.80 Good
0.81–1.00 Very good
Perera 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 biopsy
Ultrasound guidance with marking of optimal biopsy
site performed immediately preceding biopsy, by the
individual performing the biopsy, is preferred, though
not mandatory, because it likely reduces the risk of
complications 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)
• Congestive liver disease
For liver biopsy
The 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 & NPV
Likelihood Ratios (LRs)
Diagnostic Odds Ratio (OR)
• Multilevel test (> 2 results)
Receiver Operating Characteristic (ROC)
ROC curve & cut-off point
Peat 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* Accuracy
0.90 – 1.00 Excellent
* AUROC: Area Under Receiver Operating Characteristics
Pines 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 ≥ 0.80
0.80 – 0.90 Good
0.70 – 0.80 Fair
0.60 – 0.70 Poor
Imaging modalities for hepatic fibrosis
Acoustic Radiation Force Impulse imaging (ARFI)
Transient elastography (TE) or FibroScan®
Promising but currently under investigation
Castera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.
Acoustic Radiation Force Impulse Imaging
Region of interest (ROI) chosen by US guidance
Results expressed in m/sec (range: 0.5 – 4.4)
Friedrich-Rust et al. Radiology 2009 ; 252 : 595 – 604.
Meta-analysis of ARFI
8 studies (518 pts) – All CLD – Metavir – Random effect
Friedrich-Rust M et al. J Viral Hepat 2012 ; 19 : e212 – e219.
ARFI can be performed with good diagnostic accuracy
for noninvasive staging of liver fibrosis
Fibrosis Areas under ROC curves
Significant fibrosis (F ≥ 2) 0.87
Severe fibrosis (F ≥ 3) 0.91
• 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.
MR Elastography for staging of liver fibrosis
Prospective & blind study – 96 patients with CLD
MR elastography, TE, & APRI versus liver biopsy
Huwart L et al. Gastroenterology 2008 ; 135 : 32 – 40.
Efforts to standardize equipment & techniques
Too expensive & time-consuming for clinical practice
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
Jaffer OS et al.Ultrasound 2012 ; 20 : 24 – 32.
Results of FibroScan®
Median value of 10 shots
At least 10 shots
Success Rate: ≥ 60%
IQR * (kPa)
Interval around median
Contains 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%
Zero valid shot
< 10 valid shots
or Success rate ≤ 60%
or IQR ≥ 30%
LS values in apparently healthy subjects
Prospective study of 429 subjects
Roulot D et al. J Hepatol 2008 ; 48 : 606 – 613.
5.2 1.5 kPa 5.8 1.5 kPa
p = 0.0002
Normal liver stiffness measurement: 5.49 1.59 kPa
Liver stiffness cut-offs in chronic liver diseases
Castéra L et al. J Hepatol 2008 ; 48 : 835 – 847.
Shear wave propagation velocity according to
severity of hepatic fibrosis (METAVIR score)
Sandrin L et al. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.
E = 3.0 kPa
E = 7.7 kPa
E = 27 kPa
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
95% limit of
Meta-analysis of TE for staging liver fibrosis
Severe 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 kPa
50 studies – All type of CLD – Random effect
Significant fibrosis (≥ F2): 0.84
(95% CI: 0.82 – 0.86)
Cut-off value: 7.7 kPa
For significant fibrosis, a high variation of AUROC was found
Improving diagnostic statistical methods
• When there is no perfect gold standard
AUROC >0.90 could not be achieved even for perfect marker1
Prognostic analysis (morbidity/mortality endpoints) used
• Methods for spectrum effect & ordinal scale
Standardization of AUROC 2: distribution of fibrosis stages
Obuchowski measure3: spectrum effect & ordinal scale
1 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.
≤ 6 kPa
No significant fibrosis
Biopsy if results
other NI tests
≥ 12.5 kPa
Vizzutti 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 markers
• Chronic hepatitis B Immunotolerant phase: TE
≥ F2: more studies needed
Castera L & Pinzani M. Gut 2010 ; 59 : 861 – 866.
• Liver biopsy still regarded as reference method to assess
grade of inflammation & stage of fibrosis (A2)
• TE can be used to assess liver fibrosis in CHC (A2)
• Non-invasive serum makers can be recommended for
detection of significant fibrosis (METAVIR F2 – F4) (A2)
• Combination of blood tests or TE & blood test
Improve 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 C
EASL Clinical Practice Guidelines
MA of AUROCt for advanced fibrosis in CHB
Metavir – Random effect – stAUROC – Obuchowski
Poynard T et al. Curr Hepatitis Rep 2011 ; 10 : 87 – 97.
All significantly higher than random 0.50 value
No 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 NAFLD
Second most relevant clinical entity in hepatology
• Significant fibrosis does not represent critical end point
in absence of standardized treatment regimens
• TE could be useful to select those requiring liver biopsy for
more 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 cirrhosis
13 – 75 kPa
Foucher J et al. Gut 2006 ; 55 : 403 – 408.
EV stage 2 or 3
Child-Pugh B or C
37 49 53 622.5 7513
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
* 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/year
Cost per FibroScan® exam 100 € with 150 exams annually
LSM in the general population
Social Medical Center
Free medical checkup
1358 healthy subjects over 45 years
Failure, missing data
N = 238
28 subjects underwent
Roulot et al. 2009 EASL meeting Copenhagen.
D. Roulot et al. J Hepatol 2009 ; 50 : S 89.
LS < 8 kPa
N = 1040
8 kPa ≤ LS < 14.6 kPa
N = 72
LS ≥ 14.6 kPa
N = 8
Prevalence of cirrhosis was at least 0.7%
Uninterpretable results of LSM
5 year prospective study – 13 369 examinations – 5 operators
BMI > 30 kg/m2 (OR 7.5)
Operator experience (OR 2.5)
Age > 52 years (OR 2.3)
Type 2 diabetes (OR 1.6)
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 cases
Main raisons: Obesity ( WC) – Operator experience
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
Ascites in liver cirrhosis
Ascites grade 1 according to International Ascites Club
Detectable only by ultrasound
Non-invasive diagnosis of liver fibrosis
Opinions of leaders
Biopsy as first-line estimate of liver injury
Biopsy not perfect gold standard but best estimate
Rarely admits biopsy as false-positive/false negative
Typically head of pathology unit
Biomarker as first-line estimate of liver injury
Biomarker not perfect test but as accurate as biopsy
Discordance with biopsy: failure due to either (50%)
In case of non-interpretability: another biomarker
If still not interpretable: biopsy as 3rd line assessment
Biomarker first then biopsy if result not convincing
Colleague of Biopsist & close friend of Biomarkerist
Usually also has a statistician friend
Poynard T. J Hepatol 2011 ; 54 ; 586 – 587.
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.
Interpretation of results of LSM should
always be done by expert clinicians according
to clinical context
LSM is the only established imaging modality
for non-invasive diagnosis of liver fibrosis
at 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 be
employed as integrated system to maximize their potential
Acting like two tango dancers