3. Ideal non-invasive test for diagnosis
of liver fibrosis
• Simple
• Reproducible
• Readily available
• Less expensive than biopsy
• Predicts full spectrum of fibrosis
• Reflects changes occurring with therapy
4. Evaluation of chronic liver injury according
to health care level
Physical examination
Liver function tests
Serum Hyaluronate
APRI or other simple tests
Primary health care
Ultrasound
Fibroscan®
Serum markers &
algorithms
Secondary health care
Fibroscan®
ARFI*
MR elastography*
Tertiary health care
Liver biopsy
HVPG
* Promising but currently under investigation
ARFI: Acoustic Radiation Force Impulse Imaging
HVPG: Hepatic Venous Pressure Gradient
Castéra L et al. Gut 2010 ; 59 : 861 – 866.
5. Liver stiffness
• Assessed by US (FibroScan®) & more recently by MRI
• Evaluates velocity of propagation of a shock wave
within liver tissue (examines a physical parameter of
liver tissue which is related to its elasticity)
• Rationale Normal liver is viscous
Not favorable to wave propagation
Fibrosis increases hardness of tissue
Favors more rapid propagation
Bedossa P. Liver Int 2009 ; 29 (s1): 19 – 22.
7. Position of probe & explored volume
Cylinder of 1 cm wide & 4 cm long
From 25 mm to 65 mm below skin surface
This volume is at least 100 times bigger than a biopsy sample
8. Results
Stiffness (kPa)
Median value of 10 shots
3.9 Kilo Pascals
At least 10 shots
Success Rate: ≥ 60%
IQR * (kPa)
Interval around median
Contains 50% of valid shots
≤ 25% of median value
9. Manufacturer’s criteria for LSM interpretation
• First step Number of shots ≥ 10
• Second step Success rate ≥ 60 %
• Third step Interquantile range(IQR) ≤ 25%
Failure
Zero valid shot
Unreliable results
< 10 valid shots
Success rate ≤ 60%
IQR ≥ 25%
10. Liver stiffness values in healthy subjects
429 subjects
Roulot D et al. J Hepatol 2008 ; 48 : 606 – 613.
5.2 1.5 kPa 5.8 1.5 kPa
p = 0.0002
11. Liver stiffness values in healthy subjects
with & without metabolic syndrome
Roulot D et al. J Hepatol 2008; 48 : 606 – 613.
5.3 1.5 kPa 6.5 1.6 kPa
p < 0.0001
12. Liver stiffness cut-offs in chronic liver diseases
F2
Sign
F3
Severe
F4
Cirrhosis
Matavir F0-F1
MildFibrosis
Castéra L et al. J Hepatol 2008 ; 48 : 835 – 847.
LSM 2.5 – 7 kPa → Mild or absent fibrosis is likely
LSM > 12.5 kPa → Cirrhosis is likely
13. Progression of fibrosis in viral hepatitis
Photomicrographs (magnification 40; trichrome stains)
Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.
F 0 F 1 F 2
F 3
F 4
14. Perform LSM
≤ 6 kPa
No significant fibrosis
No biopsy
F0 F1F
Intermediate values
Grey area
Biopsy if results
influence management
F2
Implementation of
other NI tests
≥ 12 kPa
Advanced fibrosis
No biopsy
F4
Treatment or
Follow-up
F3
Vizzutti et al. Gut 2009;58:156-60.
15. Shear wave propagation velocity according to
severity of hepatic fibrosis (Metavir score)
Sandrin L. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.
E = 3.0 kPa
F 0
E = 7.7 kPa
F 2
E = 27 kPa
F 4
16. Liver stiffness for each Metavir stage in CHC
Box-and-whiskers plot
Vertical axis is in logarithmic scale (wide range of F4 values)
Gastroenterology 2005; 28:343 – 350.Hepatology 2005;41:48 – 54.
20. Accuracy of diagnostic test using AUC of ROC
Value Accuracy
0.90 - 1.00 Excellent
Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical
decision rules. Blackwell’s publishing – West Sussex – UK – 2008.
AUROC of a ‘‘good” test should be ≥ 0.80
0.80 - 0.90 Good
0.70 - 0.80 Fair
0.60 - 0.70 Poor
21. Meta-analysis of TE for staging liver fibrosis
Severe fibrosis (F3): 0.89
(95% CI: 0.88 – 0.91)
Friedrich R et al. Gastroenterology 2008 ; 134 : 960 – 974.
Cirrhosis (F4): 0.94
(95% CI: 0.93 – 0.95)
Cut-off value: 13.0 kPa
Significant fibrosis (F2): 0.84
(95% CI: 0.82 – 0.86)
Cut-off value: 7.7 kPa
50 studies – random effect – all type of CLD
22. Significance of wide range of LSM in cirrhosis
13 - 75 kPa
Ascites
HCC ?
Variceal bleeding
Foucher J et al. Gut 2006 ; 55 : 403 – 408.
EV stage 2 or 3
26
Child-Pugh B or C
36 49 53 622.5 7513
23. Cumulative incidence of HCC based on LSM
866 CHC – Mean follow-up 3 years
LSM: Liver Stiffness Measurement – HR: Hazard Ratio
Masuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961.
LSM > 25 kPa HR 45.5 (p< 0.001)
LSM ≤ 10 kPa HR 0
10 < LSM ≤ 15 kPa HR 16.7 (p< 0.001)
15 < LSM ≤ 20 kPa HR 20.9 (p< 0.001)
20 < LSM ≤ 25 HR 25.6 (p< 0.001)
24. Reproducibility of TE in assessing hepatic fibrosis.
Bland Altman Plot
Fraquelli M et al. Gut 2007 ; 56 : 968 – 973.
200 patients with chronic liver disease
2 different operators within 3 days (800 exams)
8 patients scored outside limits of agreement
Upper limit
Lower limit
Mean
95% limit of
agreement
25. Cost of FibroScan® versus liver biopsy
• Liver biopsy*
Cost of liver biopsy 703 – 1 566 € in a French hospital
with a one day observation period
• Fibroscan® **
FibroScan equipment 70 000 €
Low running cost except probe calibration twice/year
Cost per FibroScan exam 100 € with 150 exams annually
* Blanc J et al. Hepatol Res 2005 ; 32 : 1 – 8.
** Canadian Agency for Drugs and Technologies in Health (CADTH).
Transient Elastography (FibroScan) for Non-invasive Assessment of Liver Fibrosis; 2006.
26. Liver biopsy size
• Because grading, & staging of nonneoplastic diffuse
parenchymal liver disease is dependent on adequate
sized biopsy, a biopsy of at least 2-3 cm in length
& 16-gauge in caliber is recommended
• Presence of fewer than 11 complete portal tracts in
pathology report may be incorrect in recognition of
grading, & staging due to insufficient sample size
AASLD guidelines. Hepatology, 2009 ; 49 : 1017 – 1044.
27. Limitations of liver biopsy
• Sampling errors
Extremely small portion of liver (1/50 000)
• Intraobserver & interobserver variation
Even when widely validated systems used for score
• Invasive procedure
Morbidity: pain in 20% of patients
Major complications: bleeding or hemobilia in 0.5%
Mortality:
28. Grading & staging systems for chronic hepatitis
IASL1 Batts–Ludwig2 Metavir3
1 Desmet VJ et all. Hepatology 1994;19:1513-1520.
2 Batts KP et all. Am J Surg Pathol 1995;19:1409-1417.
3 Bedossa P et all. Hepatology 1996;24:289-293.
Grading system
Minimal activity
Mild activity
Moderate activity
Marked activity
Marked activity & bridging
Grade 1
Grade 2
Grade 3
Grade 4
Grade 4
A1
A2
A3
A3
A3
Staging system
No fibrosis
Fibrous portal expansion
Few bridges or septa
Numerous bridges
Cirrhosis
Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
F0
F1
F2
F3
F4
(kappa 0.2 – 0.6)
(kappa 0.5 – 0.9)
29. kappa score ≥ 0.6 indicates good agreement
Interpretation of different values of kappa
Kappa from Greek letter κ
Value of 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.
30. Liver biopsy is not the “gold standard”
but is the “best available gold standard”
31. Contraindications of liver biopsy
• Uncooperated patients
• Disorders in coagulation profile
• Severe ascites
• Cystic lesions
• Vascular tumors (hemangiomas)
• Amiloidosis
• Congestive liver disease
32. R0C curves for FibroScan, FibroTest, & APRI
for cirrhosis (F0 – F3 vs F4)
Castera L et al. Gastroenterology 2005 ;128 : 343 – 50.
Castera L et al. Lancet 2010 ; 375 : 1419 – 20.
35. Limitations of liver stiffness measurement
13 369 examinations – 5 year prospective study – 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)
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 cases
Main raisons: obesity ( WC) – operator experience
36. Failure rates according to BMI
7261 patients at the time of first examination
Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.
37. Unreliable results according to BMI
6968 patients at the time of first examination
Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.
38. Feasibility of LSM with FibroScan® using XL probe
New probe for obese patients
de Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.
60% not measured by M probe successfully measured by XL probe
40. Acute viral hepatitis increases liver stiffness
18 patients with acute viral hepatitis
I Peak increase in aminotransferase
II Aminotransferase ≤ 50% of the peak
III aminotransferase levels ≤ 2 ULN
Arena U et al. Hepatology 2008 ; 47 : 380 – 384.
41. Acute viral hepatitis increases liver stiffness
18 patients with acute viral hepatitis
I Peak increase in aminotransferase
II Aminotransferase ≤ 50% of the peak
III aminotransferase levels ≤ 2 ULN
Arena U et al. Hepatology 2008 ; 47 : 380 – 384.
44. Liver stiffness as a function of bile duct ligation
10 German landrace pigs: 5 controls – 5 BD ligation
Millonig G et al. Hepatology 2008 ;48 : 1718 – 1723.
4.6 kPa
8.8 kPa
6.1 kPa
46. Representation of clamping site of the IVC
5 German landrace pigs
Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
Experiment approved by local committee for Animal Welfare
University of Heidelberg – Germany
47. LSM after clamping & reopening of IVC
5 anesthesized landrace pigs
Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
P < 0.001 P < 0.001
Before
clamping
3.1 kPa
5 min after
reopening
5.1 kPa
27.8 kPa
5 min after
clamping
48. Liver stiffness directly influenced by CVP
10 patients with CHF before & after recompensation
Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.
Median 40.7 Median 17.8
p = 0.004
53. Interpretation of the results of LSM should
always be done by expert clinicians according
to clinical context
54. Transient elastography in clinical practice
Examination quality 10 shots at least
Success rate ≥ 60%
IQR ≤ 25% of median value
Liver disease Not used in acute hepatitis
Not used in acute exacerbation
Not used in ascites & EH cholestasis
Choice of cutoff point Cutoffs different for each CLD
Range of value rather than cutoff
De Lédinghen V et al. Gastroentérol Clin Biol 2008 ; 32 : 58 – 67.
Liver stiffness values are expressed in kilopascalsRange from 2.5 – 75 kPaValues around 5.5kPa were recently shown to reflect normality
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.
The 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.
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 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 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.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.
Hazard ratio as compared to LSM<10 kPa≤LSM 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-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], 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.
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.
Waist circumference 80 cm in women or 94 cm in men. Specific probe is developed 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 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.
When 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.
When 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.
Transient 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 extrahepaticcholestasis 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 extrahepaticcholestasis 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 0.67, P < 0.05) with a mean decrease of liver stiffness of 1.2± 0.56 kPa per 1 g/dLbilirubin. 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 extrahepaticcholestasis 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:Extrahepaticcholestasis increases liver stiffness irrespective of fibrosis. Once extrahepaticcholestasis is excluded (e.g., by liver imaging and laboratory parameters) transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.
Conclusion:Extrahepaticcholestasis increases liver stiffness irrespective of fibrosis. Once extrahepaticcholestasis is excluded (e.g., by liver imaging and laboratory parameters) transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.
Median 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.