Stéphanie FRANCHI-ABELLA, MD

Service de Radiopédiatrie

Hôpital Bicêtre

Liver Elastography

Conflict of Interest

• PhD at the Institut Langevin that developsultrafast ultrasound imaging

A work in progress….

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Plan

• Liver stiffness and pathology

• Technical principal of elastography

• Main validated results

• Practical examples in pediatric clinical pratice

Liver stiffness and pathology

Liver tumorDiffuse liver disease

Diffuse or focal modification of liver stiffness due to fibrosis,Liver mass, vascular congestion, inflammation, cholestasis...

Evaluation of Liver fibrosis

Agression

= Fibrose

Palpation Liver biopsy

Imaging:- Liver Architecture - Hemodynamics

portal Hypertension GI bleeding

Hepatic failure

Hepatocellular carcinoma

Liver Biopsy

• Gold standard (best standard)

• Limitations :

– Invasive, general anesthesia

– Sampling error, inter et intra observateur variability

– Cost

– No dynamic evaluation

• Complications

– Minor : 7,4 %

– Major : 1 %

Lee, Gastroenterol Hepatol, 2005

Non invasive evaluation of liver fibrosis

Serum markers:In adults diagnostic of exclusion og cirrhosisNo validation in children

Elastometry= US ou IRM

Non invasive evaluation of liver stiffness

• To improve characterization

• To avoid liver biopsy

• To indicate liver biopsy

• To monitorate treatment

ElastographyTwo approaches

• Strain imaging • Shear Wave imaging

Strain elastography

• Only qualitative or semi-quantitative technic

• Mainly detection and caracterisation of focal lesion

• Not adapted for liver stiffnessassessment

No quantification

Or internal stress (heart or vascular beats)

Shear Wave Elastography

• Camera : 50 fps

• BHW (Belly Half Width) : 20 cm

• Shear Wave speed : c = BHW/0.2 s = 1 m/s

• c = 1 m/s gives E = 3 kPa = Fat stiffness!

Quantitative methods

M Tanter, Institut Langevin, ESPCI

Shear Wave Elastography

• Transient Elastography (TE)

• ARFI

• Supersonic Shear Wave Elastography (s SWE)

Transient Elastometry Fibroscan®

Frulio J Radiol 2013

• Results in kPa• 3 probes: S+, L+, XL+

Transient Elastography

In vivo human liver elastograms

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VS = 1.1 m/s

E ~ 3 kPaVS = 1.6 m/s

E ~ 8 kPaVS = 3.6 m/s

E ~ 40 kPa

F0 F2 F4F1 F3

Courtesy of JM Corréas

Fibroscan®

Haffar

Transient ElastographyLimitations (n=13369)

Castéra et al. EASL 2009;Cournane Phys Med Biol 2012Goldschmidt JPGN 2013

Failure rate: 3.1 %

- Operator experience

- BMI > 30, ascitis

- Not possible in the left lobe- Limited in children < 2 or 6 yo

No anatomic information

ARFIAcoustic Radiation Force Impulse

Gennisson et Frulio, J Radiol 2013

• Results in m/s• Linear and curvilinear probes • Conventionnal US platform for dg

• Localisation of LSM• Possible if ascites

SuperSonic Shear Wave Elastography(sSWE)

Aixplorer®

• Conventionnal US platform for dg• Localisation of LSM• Possible if ascites

~ 100 µs

Step 1

Creation of a shear wave

By US

fps= 3000 Hz

Texp=20 ms~ 0.3 ms

Step 2

UltraFast Imaging

SuperSonic Shear Wave Elastography (sSWE)

J. Bercoff, M. Tanter, M. Fink.IEEE Transactions on Ultrasonics, Ferroelectrics And Frequency Control., 2004. slide M Tanter

Ultrafast imaging of shear wave propagation

10000 frames/second

Frame to frame correlation

M. Fink, M. Tanter, “Multiwave Imaging and Superresolution”

Physics Today, 63(2), 28-33, Feb. 2010

Elastogramm

• Freehand / does not change anything to the echographic exam

• Quantitative

• Operator independent = reproducible

• Ultrafast / less sensitive to motion artefacts and boundary conditions.M. Fink, M. Tanter, “Multiwave Imaging and Superresolution”

Physics Today, 63(2), 28-33, Feb. 2010

• Aucun échec de mesure

7,01 kPa, F0 8,5 kPa, F1

21 kPa, F3 87 kPa, F4

15,7 kPa, F2

ElastoMR

ElastoMR

Comparison of Elastography methods

Fibroscan ARFI sSWE Elasto-MR

Morphologicalstudy

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Failure Adults: 3,1 %Children : 10 %<2 yo: 17 %

children

Limitation ObesityAscites< 2 or 6 yo.

Obesity Obesity No

Results Unity kPa m/s kPa and m/s kPa

Elasticity map 0 0 Few cm2 Whole liver

sedation 0 0 0 < 6 y

Interpretation of the results

• Technical conditions:

– Technique

– Frequency of the transducer

• Clinics:

–Causative disease

–Confounding factors

Interpretation of the results

• Normal liver stiffness values vary with

– the technique

– the frequency of the transducer

TE(*) ARFi (**) SWE (***)

Liver Stiffness 5,96 – 6,82 kPa 3,89-4 kPa (converted)1,11-1,16 m/s

SC6-1: 7,41 ± 4,2 kPa

SC6-1: 6,94 ± 1,42 kPaL15-4: 5,96 ± 1,31 kPa

*: Engelmann Eur J Pediatr 2011, **: Hanquinet, Ped Radiol 2012; Eiler Ultraschall 2012; Noruegas Ped radiol 2012***: Tutar JPGN 2014; Franchi-Abella, Radiology (accepted for publication)

Influence of age, sex not clearly demonstrated

• Interpretation of the LSM according to the technique• Do not compare LSM obtained for one patient with different techniques • Follow-up with the same technique

Interpretation of the results

• Technical conditions:– Technic

– Frequency of the transducer

• Objectives of the test : Cut-off values for pathology vary with:

– Either you select sensitivity or specificity

• Clinics:

– Causative disease

– Confounding factors

Influence of the causative diseaseon cut-off values for pathology

From Haffar S: http://fr.slideshare.net/shaffar75/imaging-modalities-liver-fibrosis-21148654

Interpretation of LSM values according to the underlying disorder

Confounding factors

• Will have to take into account confoundingfactors:

– Cardiac failure

– Hepatic vein obstruction

– Inflammation

– Biliary obstruction

– Steatosis?

Liver stiffness ≠ fibrosis

Applications and results

• Diffuse liver disorders

• Focal liver lesions

ElastographyDiffuse Liver disorder

• Is there fibrosis?

• Is there portal hypertension ?

Diagnostic performance of a test

• Evaluated with liver biopsy as the best Standard

• Expressed with Area Under Receiver OperativeCurve AUROC

Perfect exam:AUROC = 1

From Samir Haffar

Diagnostic performanceof LSM for fibrosis

Fibroscan TE * ARFI** sSWE***

Significant ≥ F2 0,84 0,87 0,88-0,92

Severe ≥ F3 0,89 0,91 0,93-0,98

Cirrhosis F4 0,94 0,93 0,98

* Metanalysis 50 studies** Friedrich-Rust, J Viral Hepatol 2012 (518 pts)*** Ferraioli, Hepatology 2012, Leung Radiology 2013

(1) EASL clinical practice guidelines; managements hepatite C virus infection, J Hepatol 2011

• Good diagnostic performance for significant and severe liver fibrosis, and cirrhosis• Very few reports on low stages of fibrosis: F1 and F2 /vs F0

Adults

• TE can be used to assess liver fibrosis in chronic viral C hepatitis in adults (1)• No validation for other techniques

Diffuse liver disorders

– Work in progress:• Serum biomarkers + Elastometry to improve diagnostic accuracy

– Need for algorithmes with multiple methods:

• Fibrotest + Fibroscan

• Fibrometre + Fibroscan

• Fibroscan + ARFI

Castera , J Hepatol 2010, Boursier, liver int 2009, Sporea, World J Gastroenterl 2011

Algorithm in HCV chronic

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

Diffuse liver disorders

• No validation in children

• Only few series

Hanquinet, Ped Radiol 2013; Iacobelli,WJG 2006; Noruegas, Ped Radiol 2012; De Ledinghen, JPGN 2007; Fitzpatrick , JPGN 2013; Tutar, JPGN 2014

Fibroscan TE * ARFI**

≥ F1 0,81 0,83

Significant ≥ F2 0,78 0,82

Severe ≥ F3 0,79 Non available

Cirrhosis F4 0,88-0,96 0,98

Diagnostic accuracy of sSWEfor liver fibrosis assessment

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0.00 0.25 0.50 0.75 1.001 - Specificity

Area under ROC curve = 0.9357

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Area under ROC curve = 0.9307

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Area under ROC curve = 0.9582

METAVIRthreshold

F0 vs F1-F2Seuil = 7,23 kPa

> Ou = F2Seuil =12,1 kPa

> Ou = F3Seuil = 17,6 kPa

= F4Seuil = 23,5 kPa

AUROC [IC] 0,95 [0,89-1] 0.94 [0.87-1] 0.93 [0.85-1] 0.9582 [0.9-1]

Se 90% 87% 78.6 % 85.7 %

Spe 95,70% 92% 97.1 % 95.1 %

Accuracy 92,30% 89.6 % 91.7 % 93.8 %

Franchi-Abella and al, accepeted for publication, Radiology

45 pts

What about liver stiffnessfor the assessement of portal hypertension?

• Foucher Gut 2006; Colecchia Gastroenterology 2012; Berzigotti Ultraschall in med 2011; Leung Radiology 2013; Chongsriwat BMC Gastrenterol 2011;

• Spleen stiffness• Variable results

What about liver stiffnessand prognosis?

• 1457 patient with chronic hepatitis C

TE > 9.5 kPa = reduced 5 year-survival

Vergniol, Gastroenterology 2011

What about liver stiffnessfor the assessement of prognosis?

LSM < 20 kPa =Negative PredictiveValue for complications = 97 %

Pang, PlosOne 2014

Focal liver disorder

• Can we improve characterisation of livernodules?

Focal liver disease

• Stiffness: – FNH > Hepatocellular Adenoma

– Cholangiocarcinoma > hepatocellular carcinoma

• Overlap, No cut-off

• Evaluation of « non tumoral parenchyma » searching for underlying liver disorder

• Monitoring of percutaneous treatment?

Practical clinicalpediatric cases

1 mo, Cholestasis

High quality B mode = diagnostic:Micro cyst and tringular cord sign= biliary atresia

SWE = prognosis= liver fibrosis= early evolution to portal hypertension

21 to 25 kPa

Biliary atresia, successful surgeryFollow-up

1 mo35 kPaF4

Liver transpl.At 2 yo

Well at 3 yo

2 yo50 kPa

3 yo6,5 kPa

11 mo4,5 kPa

SWE prognostic factor for portal hypertension ?

1 mo Down syndromeCholestasis

Patent Ductus Venosus at 1 month : 1. Malformation2. Arterio-portal fistula3. Neonatal « cirrhosis »

1mo Down syndromecholestasis

Patent Ductus Venosus at 1 month : 1. Malformation2. Arterio-portal fistula3. Neonatal « cirrhosis »

1mo Down syndromecholestasis

Patent Ductus Venosus at 1 month : 1. Malformation2. Arterio-portal fistula3. Neonatal « cirrhosis»

Favorable outcomeSpontaneous closure of Ductus Venosus

5 to 6 kPa

Liver Transplantation, systematic follow-up

Chronic rejectionOn liver biopsy

4 yo girl.Liver transplantation 2 weeks ago. Ascites.

Very slow flow in the portal vein.

Liver Biopsy = Severe acute rejection

Normal in hepatic vein

High SWE in favor of an intrahepaticdisorder

20 to 25 kPa

Portal anastomotic obstacle ?

2 yo boy,Ascites 1 month after liver transplantation

No venous obstacle

SWE near normal values = probably no rejection

8 to 9 kPa

Progressive resolution

Liver Transplantation (left lobe)Ascites +++hepatic vein anastomosis stenosis

Hepatic vein obstruction↗ SWE

1 year after stent placement

Liver Transplantation 7 years beforeincreasing splenomegaly with thrombopenia

high suspicion of portal stenosis

Liver = 10 kPa Spleen= 43 kPa

2 yo boyFever, liver mass at palpation

Focal Nodular Hyperplasia?

29 to 45 kPa

Contrast enhanced US

Focal Nodular Hyperplasia

11 yo boy, Acute hepatitis with hepatic failure revealing Wilson disease

March 2014 March 2015

8 yo girl,Biliary atresia succesfully treated by surgery, cirrhosisLiver nodule, α-FP normal

Mass stiffness < liver stiffness

Hepatocellular adenoma confirmed on biopsy

SWE liver: 35 – 40 kPaSWE mass: 15-16 kPa

Conclusion

• US-based elastography is safe, easy to use

• Evaluation of diffuse liver disease and liver mass

• Only compare LSM obtained with the same technique and the same transducer

• Integration to the diagnostic workshop for liver diseases in children:– At diagnosis– For follow-up