Overview of ultrasound elastography in hepatology

1. WFUMB
Slide Series
World Federation for Ultrasound
in Medicine & Biology
Overview of ultrasound elastography in
hepatology
December 2019
1
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2. 2
Overview of ultrasound elastography in
hepatology
Prof. Ioan Sporea, MD, PhD
Department of Gastroenterology and Hepatology
University of Medicine and Pharmacy
WFUMB Center of Education
EFSUMB Ultrasound Learning Center
Timişoara, Romania

3. •Chronic liver diseases are frequent in daily hepatological
practice (HCV, HBV, NAFLD/NASH, ASH, autoimmune,
cholestatic, others), maybe in a different order (in
different regions).
•Assessment of chronic liver diseases severity can be
performed invasively (by liver biopsy) or non- invasively
(biological tests and elastography methods).

4. Liver Elastography
Liver Elastography can be performed with:
1. Ultrasound (Ultrasound based Liver Elastography),
developed a lot in Europe and Asia;
2. MRI ( using MRI machine-MRE), developed specially in
USA.
Ultrasound based Elastography is easy to be performed (by clinicians or radiologists),
is not expensive and can be performed in less than 5 minutes, with high tech US
machines!

5. Ultrasound based Liver Elastography can be divided:
1. Shear Waves Elastography:
a) Transient Elastography-TE (FibroScan)
b) Point Shear wave- pSWE [using Acoustic Radiation Force Impulse
Quantification (ARFI): VTQ (Siemens), Elast PQ (Phillips), Hitachi]
c) Real Time Shear Wave Elastography- 2D SWE [SuperSonic Imaging
Elastography (SSI) (Aixplorer) GE, Toshiba, Philips]
2. Strain Elastography (RTE)
1.Dietrich CF, Bamber J, Berzigotti A et al: EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, update 2017. Ultraschall Med. 2017 Aug;
38(4):e16-e47 doi: 10.1055/s-0043-103952

6. Ultrasound based Elastography
B. SWE: Shear Wave Elastography
Acoustic radiation force
impulse
(ARFI technology)
Transient
Elastography
(TE)
A. Strain Elastography
2D-SWEPoint SWE

7. Shear Waves Elastography
• The probe produces the shear waves (without any manual pressure).
• A button is pressed and the result is immediately displayed, expressed
in kPa (FibroScan) or in meters/second (VTQ) or both (all others
ultrasound machines).
• Learning curve is not very long (>50 examination)
• For 2D SWE (SSI) some ultrasound examination experience is
necessary (1).
1.Gradinaru-Tascau O, Sporea I, Bota S et al. Does experience play a role in the ability to perform liver stiffness measurements by means of supersonic shear imaging (SSI)?
Med Ultrason 2013 Sep;15(3):180-3.

8. Essential points in liver elastography
• Good feasibility of the elastography methods!
• Shear wave elastography (SWE) is used now in daily practice (1)!
• Evidence based medicine (published papers)!
• Important cut-off values: especially for advanced liver fibrosis, to start
screening for HCC!
• The importance of liver stiffness evaluation to start the antiviral
treatment (HCV, HBV) is now decreasing (treating all cases!).
1. Dietrich CF, Bamber J, Berzigotti A et al: EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, update 2017. Ultraschall Med. 2017
Apr 13. doi: 10.1055/s-0043-103952

9. When to use elastography in hepatology?
• Rule in and rule out significant fibrosis in different liver diseases (and
different cut-off values can be used).
• To follow the regression/progression of liver fibrosis (stiffness) post
treatment.
• To establish the moment of starting ultrasound screening for HCC
(cirrhosis/severe fibrosis).
• Non-invasive assessment of portal hypertension.

10. 1. Rule in and rule out significant fibrosis in
different liver diseases
• All elastography methods had good feasibility and good accuracy,
increasing with the severity of fibrosis (being between around 0.80-0.85
for significant fibrosis and reaching 0.90-0.95 for liver cirrhosis).
• Cut-offs differ for different etiologies and for different systems (but
seem to be the same for the same company).

11. FibroScan
(Echosens,
Paris) with M
and XL probes

12. TE: Meta-analysis HCV patients
•For significant fibrosis (F≥2 Metavir):
• In the Friedrich-Rust meta-analysis, based on 50 studies [1], the mean
AUROC was 0.84, with a suggested optimal cut-off of 7.6 kPa.
• In the Tsochatzis meta-analysis, the pooled cut-off for F≥2 Metavir was
also 7.6 kPa, with 0.78 pooled sensitivity and 0.89 pooled specificity [2].
1.Friedrich-Rust M et al: Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134(4): 960-74
2. Tsochatzis EA et al. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol. 2011;54(4):650-6

13. Liver stiffness for the diagnosis of cirrhosis
• LS measurement by means of FibroScan is a reliable method for the
diagnosis of cirrhosis, with 87% sensitivity (95%CI: 84-90%), 91%
specificity (95%CI: 89-92 as shown in a meta-analysis(1).
• Meta-analysis: for F 4 optimal cut-off: 13 kPa with AUROC : 0.94 (0.93-
0.95) (2).
• In the Tsochatzis meta-analysis, for HCV patients, proposed cut-off: 12
kPa (3).
1.Talwalkar JA. et al: Clin Gastroenterol Hepatol. 2007; 5: 1214-20.
2. Friedrich-Rust et al : Gastroenterology 2008;134:960-974
3. Tsochatzis EA et al.. J Hepatol. 2011;54(4):650-6

14. Diagnostic performance for F≥2 in others
hepatopathies
• HBV: Cut off 7 kPa AUROC 0.81
• NAFLD: Cut off 6.6/7.4 kPa AUROC 0.86
• PBC: Cut off 7,3 kPa AUROC 0.92
Marcelin et al: Liver Int 2008
Yoneda et al: Gut 2007
Nahon et al: J Hepatol 2009

15. Acoustic Radiation Force Impulse
(ARFI) techniques
•These techniques are based on the generation of shear
waves by the push-pulse of the ultrasound beam.
•Implemented in ultrasound machines!
•This techniques are divided in :
•a) Point SWE (very simple)
• b) 2D-SWE (seem to be more precise!)

16. Point SWE (VTQ) – very simple

17. Meta-analysis: 13 studies, 1163 patients
Predicting significant fibrosis (F≥2)
• For ARFI (VTQ) elastography the summary Se was 0.74 (95% CI: 0.66-
0.80), the summary Sp was 0.83 (95%CI: 0.75-0.89).
• For TE, the summary Se was 0.78 (95%CI: 0.72-0.83), the summary Sp
was 0.84 (95%CI:0.75-0.90).
•The diagnostic odds ratio of ARFI (VTQ) and TE did not
differ significantly [mean difference in rDOR =0.27 (95%CI -0.69 to 0.14)].
1. Bota S, Herkner H, Sporea I, et al. Liver Int. 2013; 33: 1138-1147

18. Meta-analysis - Predicting Liver cirrhosis (F=4)
• For ARFI (VTQ) elastography, the summary Se was 0.87 (95%CI: 0.79-0.92),
the summary Sp was 0.87 (0.81-0.91).
• For TE, the summary Se was 0.89 (95%CI: 0.80-0.94), the summary Sp was
0.87 (95%CI: 0.82-0.91).
•The diagnostic odds ratio of ARFI (VTQ) and TE did not
differ significantly [mean difference in rDOR =0.12 (95%CI -0.29 to
0.52)].
1. Bota S, Herkner H, Sporea I, et al. Liver Int. 2013; 33: 1138-1147

19. VTQ- Meta-analysis
• 36 studies with 3951 patients (1):
• The mean diagnostic accuracy of ARFI (VTQ) expressed as the AUROC
were:
a) 0.84 for the diagnosis of significant fibrosis (F ≥ 2),
b) 0.89 for the diagnosis of severe fibrosis (F ≥ 3) and
c) 0.91 for the diagnosis of liver cirrhosis (F = 4).
1. Nierhoff et al. Eur Radiol. 2013 ; 23(11):3040-53.

20. 2D-SWE (color coded and numeric values)
SuperSonic Imagine (SSI)
(Aixplorer): kPa or m/s
2D SWE.GE: kPa or m/s

21. Results of 2D-SWE (SSI)
• Meta-analysis : Data on both 2D-SWE and liver biopsy in 1134 patients from
13 sites (1).
Main aetiologies: Most patients had chronic hepatitis C (HCV, n = 379),
hepatitis B (HBV, n = 400) or non-alcoholic fatty liver disease (NAFLD, n =
156).
Histology: 40.8% of the patients had minimal or no fibrosis, 19.3% had
significant fibrosis, 14.0% had severe fibrosis and 26.0% had cirrhosis.
1.Herrmann E, de Lédinghen V, Cassinotto C al : Assessment of biopsy-proven liver fibrosis by 2D-shear wave elastography: an individual patient data based meta-analysis. Hepatology
2018; 67(1):260-272

22. Results of the study
• AUROCs of 2D-SWE (SSI) in patients with HCV, HBV and NAFLD
were:
• 86.3%, 90.6% and 85.5% for diagnosing significant fibrosis
(F≥2),
• 92.9%, 95.5% and 91.7% for diagnosing cirrhosis, respectively.
1.Herrmann E, de Lédinghen V, Cassinotto C al : Assessment of biopsy-proven liver fibrosis by 2D-shear wave elastography: an individual patient data based meta-analysis. Hepatology
2018; 67(1):260-272 DOI: 10.1002/hep.29179

23. 2. To follow the regression/progression of
liver fibrosis(stiffness) post treatment.
• “Dynamics of Liver Stiffness Values by means of Transient Elastography in
Patients with HCV Liver Cirrhosis undergoing Interferon Free Treatment”
Ioan Sporea, Raluca Lupușoru, Ruxandra Mare, Alina Popescu, Liana Gheorghe, Speranța
Iacob, Roxana Șirli
J Gastrointestin Liver Dis, June 2017 Vol. 26 No 2: 145-150

24. • In our cohort that included 256 HCV patients, treated successfully with
DAA(130 women and 126 men, mean age of 628.1, BMI 28.23.3), we
obtained the follow results EOT:
• 152/256 (59.7%) presented a decrease of the liver stiffness with more
than 10%,
• 59/256 (23%) had stationary liver stiffness,
• 42/256 (17.3%) presented an increase of the liver stiffness.
Results

25. • The mean LS values before the treatment and after the treatment
(EOT) were 25.811.7 and 22.512, and there was a significant
difference between them, p=0.009.
• In the subgroup (180 patients ) followed for more 12 weeks, the
mean LS values were significantly lower 12 weeks after EOT (SVR 12)
as compared to baseline 20.3 10.8 kPa vs 25.5 11.4 (p<0.001) and
also compared to EOT 20.3 10.8 vs 22.8 12.2 (p=0.04).
Results

26. Post DAA follow up in HCV patients

28. From Systematic Review and Meta-analysis
• This was a systematic review of 24 studies, with 2934 patients with HCV
chronic infection, from which 2214 achieved SVR.
• Liver stiffness decreases significantly with 3.1 kPa, at 6-12 months post
SVR.
• In patients that obtained SVR, the decline of LS is increasing during the time
(from - 2.4 kPa at EOT to - 4.1 kPa at 12 months).
• Approx. half of patients with LS >9,5 kPa (advanced fibrosis) before
treatment, have posttreatment LS below 9.5 kPa!
1. Singh S et al. Magnitude and Kinetics of Decrease in Liver Stiffness After Anti-viral Therapy in Patients with Chronic Hepatitis C: A Systematic Review and
Meta-analysis. Clin Gastroenterol Hepatol 2017

30. 3.To establish the moment of starting ultrasound
screening for HCC (cirrhosis/severe fibrosis)
• Meta-analysis for TE: for F 4 optimal cut-off: 13 kPa with AUROC : 0.94
(0.93-0.95)(1).
• Meta-analysis for VTQ (ARFI technology): AUROC 0.91 for the diagnosis
of liver cirrhosis (2).
• AUROCs of 2D-SWE (SSI) for HCV, HBV and NAFLD cirrhosis were: 92.9%,
95.5% and 91.7%.
1. Friedrich-Rust et al : Gastroenterology 2008;134:960-974
2. Nierhoff et al. Eur Radiol. 2013 ; 23(11):3040-53.
3. Herrmann E et al. Hepatology 2018; 67(1):260-272

31. 4. Non-invasive assessment of portal hypertension.
• Liver stiffness evaluation was used for more than 10 years to assess
portal hypertension.
• First Transient Elastography was used for this purpose, later point SWE
(VTQ) and 2D-SWE (SSI) with quite good results.
• In the last years, spleen stiffness evaluation, or combination
liver+spleen stiffness seem to increase the accuracy of the evaluation.

32. • 18 studies with >3,500 patients (1)
• Conclusion - due to the low specificity of this method, TE cannot replace
endoscopy for EV screening
Transient Elastography for portal hypertension: meta-analysis
1.Shi KQ, et al.Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in
chronic liver disease.Liver Int. 2013;33(1):62-71
Summary Se Summary Sp AUROC
CSPH (HVPG≥10 mmHg) 0.90 0.79 0.93
Any EV 0.87 0.53 0.84
At least grade 2 EV 0.86 0.59 0.78

33. • Patients with a liver stiffness < 20 kPa and with a platelet count >
150,000 have a very low risk of having varices requiring treatment, and
can avoid screening endoscopy (1b;A)
• These patients can be followed up by yearly repetition of TE and platelet
count (5;D)
• If liver stiffness increases or platelet count declines, these patients
should undergo screening Upper Endoscopy (5;D)
Baveno VI Consensus: TE
de Franchis R. J. Hepatol 2015 Sep;63(3):743-52

34. • Multicentre prospective study (1)
• 310 patients with cACLD included, all with LS by TE > 10 kPa and with
recent Upper Endoscopy.
• 33% of them met the Baveno VI criteria (LS<20 kPa, platelet count >
150.000/mm3)
• The Baveno VI criteria (gave a sensitivity of 0.87, and negative predictive
value 0.98) performed well, correctly identifying 98% of patients, who
could safely avoid endoscopy.
Baveno VI Consensus - confirmation
1.Maurice JB et al: Validation of the BavenoVI criteria to identify low risk cirrhotic patients not
requiring endoscopic surveillance for varices. J Hepatol. 2016;65:899-905

35. Liver 2D-SWE as predictor of portal
hypertension
• Liver Stiffness by 2D-SWE to predict portal hypertension assessed by
HVPG measurement:
• For a cut-off value of 15.2 kPa, 2D-SWE accurately predicted CSPH
(HVPG > 10 mmHg), AUROC 0.819, with 85.7% sensitivity and 80%
specificity [1].
• LS by 2D-SWE: the best cut-off for predicting CSPH was 15.4 kPa
(AUROC 0.94, with sensitivity and specificity higher than 90%) [2].
1.Kim TY et al.. Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients. Liver Int. 2015
2. Procopet B et al. Real-time shear wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol 2015

36. • Study on 200 cirrhotics (1):
• SS > 40.8 kPa had 94% Se, 76% Sp, 91% PPV and 84% NPV for any EV.
• SS by TE - significantly correlated with HVPG (r=0.433, P=0.001).
• Modified software for SS (mSS – up to 150kPa):
• Grade 3 EV: cut-off 75 kPa, with 100% Se, 69% Sp, 100% NPV and
29% PPV, AUROC 0.903 (2)
• Grade 2-3 EV: cut-off 54 kPa, with 80% Se, 70% Sp, AUROC 0.82 (3)
Spleen stiffness (SS) by TE
1. Sharma P, et al. Am J Gastroenterol. 2013;108(7):1101-7.
2. Stefanescu H, et al J Hepatol 2011; 54 (Suppl 1): S545.
3. Calvaruso V, et al J Viral Hepat 2013; 20: 867-874.

37. FS new version: with
ultrasound probe and
spleen software

38. Baveno VI criteria and spleen stiffness
• 498 patients with cACLD were evaluated retrospectively, in which
LSM/SSM by TE, platelet count and upper endoscopy where performed
(1).
• SSM, LSM and Child-Pugh were independent predictors for high risk
varices.
• They identify a new cut-off of SSM of < 46 kPa, that in combination of
Baveno VI criteria (LSM <20 kPa and platelets>150.00) have 0% high risk
varices missed.
1. Colecchia A et al. A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic
liver disease. J Hepatol. 2018;69:308-317

39. Have in mind in liver Elasto!
• Different elastography systems give different values for the same
degree of liver fibrosis! Than the cut-off values must be known for
the system with which we work!
• There are some confounding factors in liver elastography: fasting or
not (liver elastography must be performed in fasting conditions),
increases aminotranpherasis (confident values < 100 iu/ml),
obstructive jaundice, right hearth failure (all increasing elastography
values), others.

40. One or more elastography methods for liver fibrosis assessment? (1)
• Transient Elastography is a validated method for liver stiffness
assessment [being proposed too by EASL Guidelines (2,3)].
• But, in this moment, the body of evidence for other methods (like
pointSWE or 2D-SWE) is enough strong (meta-analyses or large
multicenter studies) for the use (reimbursement) of this techniques in
clinical practice in hepatology!
1.Sporea I. One or more elastographic methods for liver fibrosis assessment? Med Ultrason. 2015 Jun;17(2):137-138
2. EASL Recommendations on Treatment of Hepatitis C 2015
3. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis

42. CONCLUSIONS
• Body of evidence regarding the value of ultrasound based elastographic
methods for significant liver fibrosis evaluation is large enough to
enable their use in daily hepatological activity.
• The new EFSUMB Guideline on Liver Elastography 2017 and WFUMB
Guideline 2018, support this reality.
• The accuracy of elastography for diagnosis of cirrhosis is very high!
• US Elastography can be used for dynamic assessment of fibrosis
(including post treatment) and for portal hypertension evaluation.

43. Center of Elastography Timișoara:
a team working together

44. E-book on Liver Elastography, revised Edition
(free download):
http://ebooks.benthamscience.com/book/97
81681084015

45. Last Slide
45
WFUMB
Slide Series
Overview of ultrasound elastography in hepatology
Prepared by Prof. Ioan Sporea, MD, PhD