Jean Michel Correas, place and role of shear wave elastography for liver fibrosis assessment by US jfim-ifupi milan 2018

1. Place and role of Shear-Wave Elastography for liver
fibrosis assessment
Pr JM Correas MD PhD
Paris-Descartes University & Department of Adult Radiology, Necker University Hospital
Ecole Supérieure de Physique et Chimie Industrielles, Paris Tech,
Institut Langevin (CNRS UMR 7587) & INSERM ERL 979 Paris France
1st Italian-French Update Imaging – IFUPI
Advanced Multiparametric Imaging - How to use in daily practice
MILAN March 23-24 2018
www.jfim.org

2. Conflict of Interest:
- Toshiba MS: expert and lecturer
- Philips US: expert and lecturer
- SuperSonic Imagine: expert and lecturer
- Hitachi MS: expert and lecturer
- Bracco SA: expert and lecturer, principal investigator of
BR1-127 and SonoCap protocol
- Guerbet SA: expert and lecturer, principal investigator of
NsSafe and Secure protocol, lecturer
jean-michel.correas@aphp.fr

3. Shiina T et al. WFUMB guidelines and
recommendations for clinical use of
ultrasound elastography: Part 1: basic
principles and terminology.
Ultrasound Med Biol. 2015 May;41(5):
1126-47.
Barr RG et al. WFUMB guidelines and
recommendations for clinical use of
ultrasound elastography: Part 2: breast.
Ultrasound Med Biol. 2015 May;41(5):
1148-60
Ferraioli et al. WFUMB guidelines and
recommendations for clinical use of
ultrasound elastography: Part 3: liver.
Ultrasound Med Biol. 2015 May;41(5):
1161-79.

4. EFSUMB guidelines and recommendations on the
clinical use of ultrasound elastography.
Part 1: Basic principles and technology.
Ultraschall Med. 2013 Apr;34(2):169-84.
EFSUMB guidelines and recommendations on the clinical use of
ultrasound elastography. Part 2: Clinical applications.
Ultraschall Med. 2013 Jun;34(3):238-53.
EFSUMB Guidelines and
Recommendations on the Clinical
Use of Liver Ultrasound
Elastography,
Update 2017 (Short/Long Version)
Ultraschall Med. 2017
DOI
http://dx.doi.org/10.1055/
s-0043-103952
Published online: 2017

5. The Natural History of Chronic Liver Disease
Time
OVB
Death
HCC
3%/yr
3%/yr
Liver function failure
Infections
Survival rate: 50% at 5 Yr after diagnosis

6. The Diagnosis of Liver Fibrosis
Clinical Impact
• Evaluation of fibrosis (presence & severity)
=> change in disease management: follow-up
- Screening for eosophageal varices
- Screening for hepatocellular carcinoma
• Monitoring fibrosis progression
- Natural history of liver fibrosis
- Treatment decision
- Monitoring treatment efficacy

7. The Liver Biopsy
• Reference test (« gold standard »)
• Advantage
- Information about etiology and cofactors
- Additional information with immuno-histochemical
biochemical and biohumoral studies
- Iron content assessment
- Grading (activity) and staging (fibrosis)

8. • Due to the procedure: • Due to pathology:
- Invasive procedure - Sampling error
- Poor patient compliance - Intra/interobserver variability in
- Complications fibrosis stage assessment
morbidity: 1/1000 mortality: 1/10000 - Non dynamic evaluation of fibrosis
- Disease progression beyond F4
=> Not ideal procedure for disease progression evaluation
=> Not useful in the evaluation of antifibrotic agents in
patients with advanced disease
The Limitations of Liver Biopsy
Regev et al. Am J Gastroenterol 2002; Bedossa et al. Hepatology 2003; Rousselet et al. Hepatology 2005

9. The Limitations of Liver Biopsy
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
%Concordant/Discordant
F0 F1 F2 F3 F4
Score Metavir
Discordant
Concordant
Discordance between
3 pathologists (n=234)
Rousselet et al. Hepatology 2005
The level of experience
of the pathologist is
the most important factor

10. Non invasive assessment of Liver Fibrosis
• Biochemical tests
• Conventional imaging test (US)
• Liver stiffness evaluation
- 1D-stiffness evaluation (FibroScan™)
- 2D-stiffness evaluation
- Real time acquisition (SWE –AixPlorer™
SuperSonic Imagine)

11. Non invasive assessment of Liver Fibrosis
Diagnostic performance: misclassification rate
Cales et al. Liver int 2009N= 1056 HCV patients

12. US Elastography
What is it?
• A method to evaluate soft tissue elasticity in a
qualitative, semi-quantitative or quantitative ways
K
µ
e
s • Elasticity modulus= Young modulus
E = S/e (Pa)
• 2 coefficients to characterize the
mechanical properties of a solid:
- Compression modulus K: deformation with
volume change; K almost constant and very high
in soft tissues (109 Pa)
- Shear modulus: deformation at constant
volume (102 - 107 Pa)
K>> µ => E ≈ 3 µ

13. US elastography
Two different approaches
• Strain imaging: Strain E (All?) / ARFI Imaging (Siemens)
• Shear Wave Elastography: quantitative
- Shear Wave speed MEASUREMENTS
- Transient Elastography FibroScan® (Echosens); NO image (1D)
- ARFI Quantification: point shear wave elastography (B-mode, 1D)
(Siemens, Philips, Hitachi-Aloka)
- Shear Wave speed IMAGING (2D/3D-SWE)
- US induced ARFI focused at various depths: B-mode ref., E. 2D map,
SINGLE (Siemens) / REFRESHED (Toshiba, Philips, Mindray-Zonare)
- US induced ARFI with multiple simultaneous lines in a « comb push »
combined with directional filtering B-mode ref., E. 2D map (GE)
- US induced radiation force swept over depth faster than shear wave
speed to create a Mach cone (Supersonic Imagine) RT - E. 2D map
Dietrich C. et al. Ultraschall Med. 2017

14. • Quantitative stiffness measurement
– shear-wave generation using a low
frequency vibration (50 Hz)
– US transducer to measure the shear-wave speed
- elastogram allowing stiffness calculation
t
z
VS
Δ
Δ
=Speed calculation
2
3 SVE ρ=Elasticity calculation
%
-5
0
5
Profondeursouslasurface(mm)
Temps (ms)
0 20 40 60
10
20
30
40
50
60
Δz
Δt
The stiffer the faster
Transient Elastography
(FibroScan®, Echosens)

15. Transient Elastography
(FibroScan®, Echosens)
Success rate > 60%
10 validated measures
IQR < 30% median
Castera, Forns & Alberti. J Hepatol 2008;
Reliability criteria

16. Transient Elastography
Diagnostic performance for F≥2
Friedrich-Rust et al. Gastroenterology 2008; Talwalkar et al. Clin
Gastroenterol Hepatol 2007;
Optimal cut-off: 7.6 kPa
AUROC:
0.84 (0.82-0.86)
Se: 70% (67-73) Spe: 84% (80-88)

17. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of
liver disease severity and prognosis European Association for the Study of the
Liver, Asociación Latinoamericana para el Estudio del Hígado

18. Transient Elastography
Limitations (n=13369)
Castéra et al. EASL 2009;
Cournane Phys Med Biol 2012
Failure rate: 3.1 %
- Operator experience
- BMI > 30, ascitis
no overlaying fat layer 45 mm thick overlaying
fat layer
SW velocity from a linear fit (white line)=>
clearly problematic in the case fat layer

19. Algorithm in clinical practice
FibroScan
+ FibroTest
Liver
Biopsy
Treatment
or
Follow-up
Follow-up Treatment
Mild
fibrosis
(FS < 7.1 + FT <
F2)
Severe
fibrosis
(FS ≥ 9.5 + FT ≥
F3)
Moderate
fibrosis
(FS ≥ 7.1 + FT ≥
F2)
Treatment
monitoring
Castera et al. Gastroenterology 2005;
Do not agree Agree
Liver
Biopsy
Treatment
or
Follow-up
Agree
Mild
fibrosis
(FS < 7.1 + FT <
F2)
Follow-up
Moderate
fibrosis
(FS ≥ 7.1 + FT ≥
F2)
Treatment
Severe
fibrosis
(FS ≥ 9.5 + FT ≥
F3)
Treatment
monitoring

20. Algorithm in clinical practice
FibroScan
+ FibroTest
Liver
Biopsy
Treatment
or
Follow-up
Follow-up Treatment
Mild
fibrosis
(FS < 7.1 + FT <
F2)
Severe
fibrosis
(FS ≥ 9.5 + FT ≥
F3)
Moderate
fibrosis
(FS ≥ 7.1 + FT ≥
F2)
Treatment
monitoring
Castera et al. Gastroenterology 2005;
Do not agree Agree
Liver
Biopsy
Treatment
or
Follow-up
Agree
Mild
fibrosis
(FS < 7.1 + FT <
F2)
Follow-up
Moderate
fibrosis
(FS ≥ 7.1 + FT ≥
F2)
Treatment
Severe
fibrosis
(FS ≥ 9.5 + FT ≥
F3)
Treatment
monitoring
75% of saved liver biopsies

21. Roulot et al. Gut 2011;
Transient Elastography
Screening for cirrhosis
• Screening subjects with significant fibrosis
• 1190 subjects > 45 Yr
• 89 subjects (7.5%) had LS measurements >8 kPa
• Though liver biochemistry was normal, a cause of
chronic liver disease was found in 43% !!!!!!

22. Shear Wave Elastography
Principles
STEP 1
Radiation Force:
Shear wave generation by
inducing local excitation
STEP 2
UltraFast Imaging:
Shear wave propagation is
captured with planes waves
22
STEP 3
Quantification
processing:
From velocity movie to
elasticity
Total time: 20 ms
Acquisition speeds of up to 20 000 Hz
MultiWave™ Interaction
Courtesy SuperSonic Imaging

23. SWE liver elastography
Liver examination protocol
• Patient preparation:
– Fasting >2h (as for liver US) + resting for 10min
- Patient position: supine slight left oblique
decubitus with right arm up
- Preset: liver, SWE penetration,
scale: 30-50 kPa
- Optimize intercostal windows on right liver +++
=> homogeneous pattern + no shadowing
- Using significant pressure on transducer to:
open space and reduce attenuation (gel)
- During breath hold (avoid deep inspiration)

24. Non invasive assessment of Liver Fibrosis
Shear-Wave Elastography
• Advantage
- easy acquisition coupled to US examination
- double screen window: simultaneous display of B-mode for
(guidance) and SWE frame (elasticity measurement)
- “quasi” real time acquisition allowing identification of
artifacts (movement artifact, capsule, vessels…)
- Large ROI that can be fitted to anatomical structure
- 2D-map evaluation of liver stiffness
- Local true quantitative measurement in kPa

25. SWE liver elastography
Stiffness measurement
• Quantification using the Q-Box™:
- position: over a homogeneous area of the ROI
excluding acoustic shadows
- size: large (10-20 mm in diameter) fitting an homogeneous area
=> allows evaluation of heterogeneity (SD) and highest stiffness values
- elasticity information in Q-Box™:
- Mean: average of elasticity values: most relevant information
- Min: minimal elasticity value
- Max: maximal elasticity value
- SD: standard deviation of the mean
- Average 3-5 acquisitions of mean elasticity

26. Criteria for reliable SWE measurements
• Stability Index > 90%
• Minimum elasticity value ≥ 0.2 kPa
• Depth of measurement < 5.6 cm
• SD < 1.75 kPa and Qbox > 18 mm
• SD/median < 10%
• IQR/median ≤ 30%
• SD/mean < 30%
Poynard T. et al. Real-Time Shear Wave versus Transient Elastography for Predicting Fibrosis:
Applicability, and Impact of Inflammation and Steatosis. A Non-Invasive Comparison. PLoS One. 2016
Oct 5;11(10)
Thiele M. et al. Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment
of Alcoholic Liver Fibrosis and Cirrhosis. Gastroenterology. 2016 Jan;150(1):123-33.

27. F0-F1
F4
F2
F3

28. SWE liver elastography
Stiffness measurement interpretation
• Normal liver stiffness (transducer) SC6-1: 2.6 – 6.2 kPa
4.5 – 5.5 kPa (95th percentile 6.2 kPa)
Healthy men> women, no influence of BMI and age
- Qbox position: 1-2 cm below the liver capsule
• Analysis of 9 studies with healthy volunteers: 5.0 ± 1.4 kPa
vs F0-F1 with chronic liver disease (8 studies):
mean SWE 6.7 ± 2.0 kPa
Suh CH et al. Determination of normal hepatic elasticity by using real-time
shear-wave elastography. Radiology. 2014;271:895-900
Huang Z. et al. Normal liver stiffness in healthy adults assessed by real-time
shear wave elastography and factors that influence this method. UMB 2014
Arda K. et al. Indian J Med Res 2013; Ferraioli G. et al. Eur J Radiol 2012;
Franchi-Abella S. et al. Radiology 2016; Hudson JM. et al. UMB 2013; Leung
VY. et al. Radiology 2013; Suh CH. et al. Radiology 2014; Wang CZ. et al.
UMB 2014; Yoon JH. et al. KJR 2013; Yoon JH. et al. JUM 2014

29. Shear-Wave Elastography
Intra-observer agreement
0.95 (95% CI, 0.93-0.98)
Expert Novice
0.93 (95% CI, 0.90-0.96)
45678
4 5 6 7 8
45678
4 5 6 7 8
Mean of ratings in kiloPascal Mean of ratings in kiloPascal
DifferencesbetweenratingsinkiloPascal
DifferencesbetweenratingsinkiloPascal
Ferraioli et al. European J of Radiology 2012

30. 345678
DifferencesbetweenratingsinkiloPascal
4 5 6 7 8
Mean of ratings in kiloPascal
Shear-Wave Elastography
Inter-observer agreement
Ferraioli et al. European J of Radiology 2012

31. On the same day:
§ Transient Elastography (FibroScan™)
§ Shear Wave Elastography (AixPlorer™)
§ ARFI (S2000)
§ Liver Biopsy
Consecutive 349 patients with chronic viral
hepatitis scheduled for liver biopsy
Shear-Wave Elastography
Comparison with FibroScan, ARFI, and liver biopsy
Cassinotto et al. Journal of Hepatology 2014

32. Shear-Wave Elastography
Comparison with FibroScan™, ARFI,
and liver biopsy
Fibrosis score (Metavir) n = 121
F0-F1 134 (38%)
F2 70 (20%)
F3 51 (15%)
F4 93 (27%)
Steatosis
S0 (<5%) 101 (29%)
S1 (5-33%) 128 (37%)
S2 (33-66%) 64 (18%)
S3 (>66%) 56 (16%)
Activity Grade
A0/A1 112 (61%)
A2 105 (30%)
A3 31 (9%)
CLD patients:
n = 349
Males: n= 188
Females: n= 141
Age: 54.8 y [15-85]
BMI: 27.4 [15-52]
Cassinotto et al. Journal of Hepatology 2014

33. Shear-Wave Elastography
Comparison with FibroScan, ARFI, and liver biopsy
Cassinotto et al. Journal of Hepatology 2014
FibroScan ARFISWE

34. F0-F2 versus F3-F4
Cut-off index
F0-F3 versus F4
Cut-off index
SWE CO
8.0kPa
Se 83%
Spe 82%
AUROC 0.89
TE CO
8.5kPa
Se 76%
Spe 81%
AUROC 0.83
Cassinotto et al. Journal of Hepatology 2014
ARFI CO
1.4m/s
Se 72%
Spe 81%
AUROC 0.81
SWE CO
10.7kPa
Se 85%
Spe 83%
AUROC 0.89
TE CO
14.6kPa
Se 77%
Spe 91%
AUROC 0.83
ARFI CO
1.6m/s
Se 81%
Spe 77%
AUROC 0.81

35. 13 studies (QUADAS), 2303 patients
Shear-Wave Elastography
Meta-analysis
Jiang et al. PlosOne 2016
S-ROC for ≥ F3 0.93 (0.91-0.95) and for ≥ F4 0.94 (0.92-0.96)
S-ROC for ≥ F1 0.85 (0.81-0.88) and for ≥ F2 0.87 (0.84-0.90)

36. - 1134 patients included from 13 sites (BE, CN, DE1, DE2,
DK, FR1, FR2, FR3, FR4, GR, HK, IT, RO)
- SWE (n = 1134), TE (n = 665)
- Chronic hepatitis C (HCV, n = 379), hepatitis B (HBV, n =
400) or non-alcoholic fatty liver disease (NAFLD, n = 156)
Assessment of biopsy-proven liver fibrosis by 2D-shear
wave elastography: an individual patient data based
meta-analysis
E. Herrmann, V. de Ledinghen, C. Cassinotto, W.C.-W. Chu,
V.Y.-F. Leung, G. Ferraioli, C. Filice, L. Castera, V. Vilgrain, M. Ronot,
J. Dumortier, A. Guibal, S. Pol, J. Trebicka, C. Jansen, C. Strassburg, R.
Zheng, J. Zheng, S. Francque, T. Vanwolleghem, L. Vonghia, E.K. Manesis,
P. Zoumpoulis, I. Sporea, M. Thiele, A. Krag, C. Cohen-Bacrie, A. Criton,
J. Gay, M. Friedrich-Rust
Herrmann E. et al. Hepatology 2017

37. Assessment of biopsy-proven liver fibrosis by 2D-shear
wave elastography: an individual patient data based
meta-analysis
Herrmann E. et al. Hepatology 2017
AUROC for ≤ F1 vs ≥ F2: SWE = 0.86 / TE = 0.81 (+5.3%, p<0.01)
AUROC for ≤ F3 vs F4: SWE = 0.93 / TE = 0.91 (+1.8%, p=0.02)

38. Diagnostic Performance
Fibrosis
Stage
Other HCV HBV NAFLD
≤1 vs. ≥2 7.1 7.1 7.1 7.1
Sensitivity (CI) 99.3% (93%-100%) 92.5% (82%-99%) 87% (80%-93%) 91.3% (81%-98%)
Specificity (CI) 36.0% (12%-63%) 50.3% (27%-74%) 74.3% (64%-84%) 52.0% (23%-80%)
≤2 vs. ≥3 9.2 9.2 8.1 9.2
Sensitivity (CI) 98.7% (93%-100%) 93.6% (83%-100%) 93.1% (86%-98%) 88.6% (77%-97%)
Specificity (CI) 79.6% (64%-93%) 76.5% (59%-91%) 74.5% (64%-84%) 80.4% (71%-89%)
≤3 vs. 4 13.5 13.5 11.5 13.5
Sensitivity (CI) 87.6% (68%-100%) 90.7% (82%-97%) 84.8% (57%-100%) 79.2% (77%-96%)
Specificity (CI) 90.7% (78%-100%) 91.3% (80%-99%) 94.6% (90%-98%) 88.1% (76%-97%)
Assessment of biopsy-proven liver fibrosis by 2D-shear
wave elastography: an individual patient data based
meta-analysis
Herrmann E. et al. Hepatology 2017

39. - 291 NAFLD patients with liver biopsy correlation
- liver stiffness measurement (LSM) evaluated by SWE (SSI),
FibroScan, and Acoustic Radiation Force Impulse (ARFI)
Shear-Wave Elastography
NAFLD
Cassinotto et al.
Hepatology 2016

40. ≥ F2 ≥ F3
SWE CO 6.3 kPa
Se 90%
Spe 50%
Best Acc 80%
AUROC 0.86
TE CO 6.2 kPa
Se 90%
Spe 45%
Best Acc 77%
AUROC 0.82
ARFI CO 0.95m/s
Se 90%
Spe 36%
Best Acc 74%
AUROC 0.77
F4
SWE CO 8.3 kPa
Se 91%
Spe 71%
Best Acc 85%
AUROC 0.89
TE CO 8.2 kPa
Se 90%
Spe 61%
Best Acc 79%
AUROC 0.86
ARFI CO 1.15m/s
Se 90%
Spe 63%
Best Acc 79%
AUROC 0.84
SWE CO 10.5 kPa
Se 90%
Spe 72%
Best Acc 87%
AUROC 0.88
TE CO 9.5 kPa
Se 92%
Spe 62%
Best Acc 89%
AUROC 0.87
ARFI CO 1.3m/s
Se 90%
Spe 67%
Best Acc 84%
AUROC 0.84
Cassinotto et al.
Hepatology 2016

41. Modified from Dr M Munteanu, Centre de Bilan Anti-Fibrose, GH Pitié Salpétrière, Paris
Poynard T. et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and
transient elastography (FibroScan®). J Hepatol. 2014 Apr;60(4):706-14.
Procopet B. et al. Real-time shear-wave elastography: applicability, reliability and accuracy for clinically
significant portal hypertension. J Hepatol. 2015 May;62(5):1068-75.
Elkrief L. et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient
elastography for detection of portal hypertension in cirrhosis. Radiology. 2015 May;275(2):589-98.
Jansen C. et al. Shear-wave elastography of the liver and spleen identifies clinically significant portal
hypertension: A prospective multicentre study. Liver Int. 2017 Mar;37(3):396-405.
Liver-SWE
(kPa)
Spleen-SWE
(kPa)
7.1
9.2/8.1
13.5/11.5

42. Liver elastography
SWE Main issues
• Reproducibility & thresholds
• Mechanics and fundamental physical properties of solids
Elastic
Isotropic
Linearity
Passive
The ideal solid material
Anisotropy
i,j =
x,y,z x
y
zA complex solid
{µij}
Viscoelasticity
η
Voigt
µ
µ, η
Non Linearity t
v
µ, A
Active movementµ(t)

43. Liver elastography
New tools
• Visco-elasticity => inflammation
• Combination of Strain Elastography (RTE) and Shear
Wave Measurement => inflammation and attenuation
Fibrosis
F value
inflammation
A value
Attenuation
ATT
Quantitative index
Items Unit Contents
Vs m/s Propagation velocity of shear
wave (median of Vs group)
E kPa Vs value converted to kPa
ATT dB/cm/MHz Attenuation
F Fibrosis related index
A Inflammation related index
LFI LF Index
IQR/M ％ ±25% range median/Median
Courtesy Hitachi MS

44. • SWE high diagnostic performance
• Spleen SWE: feasible, correlated to CSPH
• SWE advantages:
=> Easy to perform => quick learning curve
=> Diagnosis of early fibrosis (F1F2) and cirrhosis
=> Good reproducibility and limited intra/inter observer variability
=> No limitation due to ascites (at the contrary of TE)
=> Part of routine liver US: fibrosis screening, nodule characterization
• New tools (WiP): visco-elasticity, attenuation, inflammation
Conclusion