Assessment of liver fibrosis by us elastography

Samir Haffar MD
World hepatitis day – July 28, 2019
Dama Rose Hotel – Damascus – Syrian Arab Republic
Liver fibrosis assessment by US elastography

Staging of liver fibrosis in Metavir score
magnification ×40 – trichrome stains
Faria SC et al. RadioGraphics 2009;29:1615–1635.
F0: no fibrosis F1: portal fibrosis F2: portal fibrosis, few septa
F3: septa without cirrhosis F4: cirrhosis

Limitations of liver biopsy
• Sampling error
Major limitation
Small portion of liver (1/50 000)
• Intra/inter-observer variation
G (κ: 0.2 – 0.6) – S (κ: 0.5 – 0.9)
G: grading – κ : kappa – S: staging
AASLD position paper. Hepatology 2009;49:107–1044.
2-3 cm – 10 portal tracts
scoring system
experienced pathologist
• Invasive procedure
Pain 20%
Major complications 0.5%
Mortality 0.03 %
US guided biopsy

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

Contraindications of liver biopsy
• Uncooperated patients
• Disorders in coagulation profile
• Severe ascites
• Cystic lesion
• Vascular tumor (hemangioma)
• Amyloidosis
• Congestive liver disease

for liver biopsy
The term ‘‘best standard” is
more appropriate than ‘‘gold standard”
Bedossa P & Carrat F. J Hepatology 2009;50:1–3.

ARFI – point SWE Acuson/S2000 & S3000
Esaote/My lab 9
Hitachi/Hi-Vision
Medison/HS70 A, RS80 A
Philips/Epiq series
VTQ®
QElaXto®
Shear wave measurement
S-shearwave®
ElastPQ®
Transient elastography Echosens/FibroScan® 430 mini, 502 touch,
530 compact, 630 expert
Techniques of US-based elastography
Technique Manufacturer/Model Version or Software
ARFI: acoustic radiation force impulse imaging – SWE: shear wave elastography
Ferraioli G et al. Ultrasound Med Biol 2018;44(12):2419–2440.
ARFI – 2D SWE Acuson/S3000
GE/Logic E9
Mindray/Resona series
Philips/Epiq series
Explorer/SuperSonic Imagine
Toshiba/Aplio 500, i-series
VTIQ®
–
STE®, STQ®
ElastQ®
SSI®
–
Strain elastography Hitachi/EUB-8500, EUB-900 Hi-RTE®

Interpretation of liver US based elastography
Guidelines of EFSUMB 2017*
• Past medical history
• Current complaints
• Physical examination: signs of chronic liver disease
• Liver biochemical & function tests
• Ultrasound of upper abdomen (B-mode & Doppler)
* EFSUMB: European Federation of Societies for Ultrasound in Medicine and Biology
Dietrich CF et al. Ultraschall Med 2017;38:e16–e47.

Confounders of US-based elastography
Guidelines of EFSUMB 2017*
• Acute hepatitis
• Transaminases flares (ALT &/or AST > 5 ULN)
• Extra-hepatic cholestasis
• Congestive heart failure
• Infiltrative liver diseases: amyloidosis, lymphoma
ULN: upper limit of normal
* EFSUMB: European Federation of Societies for Ultrasound in Medicine and Biology
Dietrich CF et al. Ultraschall Med 2017;38:e16–e47.
Should be excluded before SWE to avoid overestimation
and/or should be considered when interpreting the results

Confounders of liver stiffness measurements
Pathologic and normal physiologic processes
Sigrist RMS et al. Theranostics 2017;7(5):1303–1329.

Probes of transient elastography
Fibroscan®
Probe Application Frequency Depth from skin
S probe Children:
thoracic Ø < 75 cm
5 MHz 1 – 5 cm
M probe Non-obese adult:
SCD < 2.5 cm
3.5 MHz 2.5 – 6.5 cm
XL probe Obese adult:
SCD > 2.5 cm
2.5 MHz 3.5 – 7.5 cm
SCD: skin to capsule distance
Ferraioli G et al. Ultrasound Med Biol 2018:44(12):2419-2440.

Explored liver volume by transient elastography
FibroScan®
Cylinder of 4 cm long & 1 cm wide
From 2.5 to 6.5 cm from skin surface
This volume is at least 100 times larger than a liver biopsy
Ferraioli G et al. Ultrasound in Med & Biol 2015;41(5):1161–1179.
M probe

Reliable results of transient elastography
according to manufacturer’s instructions
• Number of valid shots ≥ 10
• Valid shots/total number of shots ≥ 60%
• Inter-quantile range/median ≤ 30% reliable*
“most important” ≤ 10% very reliable**
* Castera L et al. J Hepatol 2008;48:835–847.
** Boursier J et al. Hepatology 2013;57:1182–1191.
Unreliable results
Zero valid shots
Failure

Symetric data distribution
classic ‘bell’ shape
Harris M Taylor G. Medical statistics made easy. Martin Dunitz, 1st edition, London, 2003.
Peak in middle – Symmetrical tails
Mean = median = mode
Mean: Sum of values/number of observations
Median: Number of observations above = number below
Mode: Most frequently occurring value
Mean ≠ median ≠ mode
Skewed data distribution
Mean overestimates median value

Box and whisker plot
Interquartile range
IQR: Q3 – Q1
reflects variability
of measurements
75%
25%

©Echosens2011.Tousdroitsréservés.Toutereproductiontotaleoupartiellesurquelquesupportquecesoitouutilisationducontenudece
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CONFIDENTIAL
Statistical reminder
17
•Presentation of the Device
Ten valid
measurements
Sorted in
ascending order
(S1 to S10)
S1 S2 S3 S4 S5 S6 S7 S8 S9 S10
Q0
minimum
Q2
median
Q4
maximum
Q1 Q3
IQR (interquartile range) = Q3 – Q1

Transient elastography (Fibroscan®)
10 successful measurements: success rate 100%
Interquartile ratio (IQR): 0.3
IQR/median: 0.3/5.2 = 6%
Median value: 5.2 kPa (very reliable result)
Controlled attenuation parameter (CAP): 198 dB/m

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

Normal value of transient elastography (Fibroscan®)
Individual participant data meta-analysis
• 3 882 healthy individuals examined by M probe
• Non-obese (BMI < 30 kg/m2)
• No diabetes and no liver steatosis on ultrasound
• No excessive alcohol intake*
• Normal ALT and AST
• HBsAg and anti-HCV negative
* 21 units/week for men and 14 units/week for women
Bazerbachi F et al. Clin Gastroenterol Hepatol 2019;17:54–64.
Mean: 4.68 kPa (95% CI: 4.64 – 4.73)

Transient elastography & liver fibrosis stages
Sandrin L et al. Ultrasound Med Biol 2003;29:1705–1713.
E = 3.0 kPa
F 0
E = 7.7 kPa
F 2
E = 27 kPa
F 4

Quantifying fibrosis with FibroScan®
www.fibroscan.com/en/expertise

Rule of 5 in transient elastography
<5 kPa Normal result
<10 kPa Rule-out cACLD
10-15 kPa cACLD (need further confirmation)
15-20 kPa Rule-in cACLD
> 20 kPa Rule-in clinically significant PHT
cACLD: compensated advanced chronic liver disease – kPa: kilopascal
VNT: varices needing treatment
de Franchis R, Baveno VIF. J Hepatol 2015;63:743–752.

Baveno VI consensus workshop on PHT
kPa: kilopascal – HVPG: hepatic vein pressure gradient – PHT: portal hypertension
de Franchis R, Baveno VIF. J Hepatol 2015;63:743–752.
Transient elastograpgy ≤ 20 kPa
Platelets ≥ 150.000 106/mL
+
Rule out clinically significant PHT
(HVPG ≥ 10 mmHg)

Steatosis quantification by CAP (FibroScan®)
Fatty deposit in ≥ 5% of hepatocytes
Steatosis Hepatocytes
with fat
Cutt-off
dB/m*
Sensibility Specificity AUROC
S1 5 – 33% 248 0.688 0.822 0.823
S2 34 – 66% 268 0.773 0.812 0.865
S3 > 66% 280 0.882 0.776 0.882
*CAP range: 100 – 400 dB/m
AUROC: area under receiver operating characteristic curve
CAP: controlled attenuation parameter – CLD: chronic liver diseases
Karlas T et al. J Hepatol 2017;66(5):1022–1030.
Individual participant data meta-analysis of 2.735 patients
Various etiologies of CLD compared to liver biopsy
Overlap between adjacent grades

Failure and unreliable results of FibroScan®
13 369 exams – 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%)
OR: odds ratio – WC: waist circumference
Castéra L et al. Hepatology 2010;51:828–835.
FibroScan® uninterpretable in one of five cases
Main raisons: obesity (increased WC) – operator experience

Advantages & limitations of Fibroscan®
Advantages Limitations
Probe calibration every 12 m
Acute liver injury (>5 x ULN)
Extra-hepatic cholestasis
Increased central venous pressure
Narrow inter-costal spaces
Obesity (need for XL probe)
Ascites
CIs: pregnancy & pacemakers
More published materials
Prognostic values
Steatosis quantification
CIs: contraindications – ULN: upper limit of normal

Principle of ARFI (pSWE and 2D SWE)
operator-independent, quantitative, reproducible
ARFI: acoustic radiation force impulse imaging
Zhao CK et al. Ultrasonography 2019;38(2):106–124.
2D SWE
2 dimensions shear wave elastography
pSWE
point shear wave elastography
Mechanical excitation of target
tissue in single location
creating lateral shear wave
Generation of shear waves in
full field of view

ARFI – point shear wave elastography (pSWE)
range: 0.5 – 4.4 m/sec
59-year-old woman with chronic hepatitis C
Region of interest (green box) with 10 measurement in same location
Median value 2.38 m/sec (consistent with cirrhosis)
Metavir F4 confirmed at liver biopsy
ARFI: acoustic radiation force impulse imaging – SWE: shear wave elastography
Barr RG et al. Ultrasound Quarterly 2016;32:94–107.
ROI
ROI
10 x 5 mm

Positioning of region of interest for pSWE
Avoid imaging <1.5 cm deep to liver capsuleAvoid imaging at depth
Avoid imaging at vesselsAvoid imaging at angles
pSWE: point shear wave elastography
Elastography: A practical approach. Editor: RG Barr. Thieme – New York – 2017.

Reliable results of point SWE
• Number of valid shots ≥ 10
• Valid shots/total number of shots ≥ 60%
• Inter-quantile range/median ≤ 15 – 30%
SWE: shear wave elastography
Ferraioli G et al. Ultrasound Med Biol 2018:44(12):2419-2440.

Fibrosis staging in pSWE (Acuson S2000 – S3000)
normal value: 1.07 – 1.19 m/s
F≥2
significant fibrosis
F≥3
severe fibrosis
F=4
cirrhosis
HCV1 1.21 – 1.34 1.54 – 1.70 1.75 – 2
HBV1 ≥ 1.35 ≥ 1.55 ≥ 1.87
NAFLD1-2 – ≥ 1.77 ≥ 1.90
ALD3 1.63 1.84 1.94
AIH – – –
PBC – – –
WFUMB: World Federation of Ultrasound in Medicine & Biology
1 Sporea I et al. Point SWE. In: EFSUMB course book 2nd ed – Ed: Dietrich CF – 2018.
2 Cut-off value of > 1.10 m/s can discriminate between simple steatosis & NASH
3 Kiani A er al. World J Gastroenterol 2016;22(20):4926-35.
Cut-off values related to etiology of chronic liver disease

ARFI – 2D shear wave elastography (2D SWE)
Normal values (GE: 6 ± 1.4 kPa – Explorer: 5.1 ± 1.3 kPa)
Field of view (FOV) where elastography will be obtained
Regions of interest (ROI) within FOV to obtain 3 – 5 measurements
ROI
FOV

Advantages & limitations of ARFI
pSWE & 2D SWE
Integrated in ultrasound systems
More cost-effectiveness
No need for probe calibration
Not limited by obesity
Not limited by ascites
Safe in pregnant women
Advantages
Less published materials
No cutoff values for prognosis
Acute liver injury (> 5 x ULN)
Extra-hepatic cholestasis
Increased central venous pressure
Narrow inter-costal spaces
Limitations
2D SWE: two dimensions shear wave elastography – pSWE: point shear wave elastography

Comparison of elastography methods
• 21 chronic hepatitis C and 5 healthy individuals
Transient elastography (Fibroscan®) as reference standard
pSWE: Acuson S2000, Philips EPIQ7, Hitachi Hi-Vision, MyLab
2D SWE: SuperSonic Imagine, Toshiba
• Agreement of measurements w different systems good to excellent
Values follow same direction but absolute values not the same
Cutoff values not used interchangeably across different US systems
• Cutoffs are system specific & related to etiology of liver disease
pSWE: point shear wave elastography – 2D SWE: two dimensions shear wave elastography
Ferraioli G et al. Ultraschall Med 2019;40(1):64–75.

Principle of strain elastography
electronic palpation
Zhao CK et al. Ultrasonography 2019;38(2):106–124.
Elastographic image acquired through tissue displacement
caused by free-hand compression with a transducer

Strain elastography
mainly in Japan – long learning curve
Dietrich CF et al. EFSUMB Guidelines. Ultraschall in Med 2017;38:e16–e47.
Scores: LF index, German elasticity score, Japanese elasticity score
Only LF Index recommended by the manufacturer
Positive results in Japanese series not confirmed in other series
Not recommended for clinical use in Europe

Recommendations to perform liver elastography
adherence to a strict protocol
• Fasting for 4 hours and rest for 10 min before examination
• Supine/slight left lateral position & arm raised above head
• Choice of FibroScan® transducer based on SCD
• Transducer perpendicular to liver capsule
• Measurement 1.5 – 2.0 cm below liver capsule in ARFI
• Region of interest avoids large vessels, bile duct & masses
• 10 measurements for TE & pSWE & 3 – 5 for 2D SWE
• IQR/median: < 30% for kPa – < 15% for m/s
kPa: kilopascal – SCD: skin to capsule distance – SWE: shear wave elastography
TE: transient elastography – WFUMB: World Federation of Ultrasound in Medicine & Biology
Ferraioli G et al. Ultraschall Med 2018;44(12):2419-2440.

Future of US-based elastography

12 centers - 132 CHB patients - SuperSonic Imagine vs liver biopsy
Deep learning radiomics of 2D SWE (DLRE)
2D SWE: 2 dimensions shear wave elastography
CHB: chronic hepatitis B – ROC: receiver operating characteristic
Wang K et al. Gut 2019;68(4):72–741.
Area under ROC curve
0.97 (95% CI: 0.94-0.99)
Cirrhosis F=4Significant fibrosis ≥F2
0.85 (95% CI 0.81-0.89)
Advanced fibrosis ≥F3
0.98 (95% CI: 0.96-1.00)

Accuracy of diagnostic test by area under ROC curve
Value Accuracy
0.60 – 0.70 poor
0.70 – 0.80 fair
0.80 – 0.90 good
0.90 – 1.00 excellent
UAC: area under the curve – ROC: receiver operating characteristic
Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical
decision rules. Blackwell’s publishing – West Sussex – UK – 2008.
The higher AUC the better the overall performance of the test

Conclusion
• Strict protocol necessary to obtain accurate measurements
• Elastography techniques used to distinguish 2 cutoff values:
- No or minimal fibrosis (Metavir F0 & F1): no liver biopsy
- Severe fibrosis or cirrhosis (Metavir F3 & F4): no liver biopsy
- Middle group between these cutoff values requires more clinical
evaluation/additional tests (blood tests, liver biopsy)
• Cutoffs are system specific & related to etiology of liver disease
Ferraioli G. J Ultrasound Med 2019;38:9–14.

Assessment of liver fibrosis by us elastography

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