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Assessment of liver fibrosis by us elastography
- 1. Samir Haffar MD World hepatitis day – July 28, 2019 Dama Rose Hotel – Damascus – Syrian Arab Republic Liver fibrosis assessment by US elastography
- 2. 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
- 3. 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
- 4. 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
- 5. Contraindications of liver biopsy • Uncooperated patients • Disorders in coagulation profile • Severe ascites • Cystic lesion • Vascular tumor (hemangioma) • Amyloidosis • Congestive liver disease
- 6. for liver biopsy The term ‘‘best standard” is more appropriate than ‘‘gold standard” Bedossa P & Carrat F. J Hepatology 2009;50:1–3.
- 7. 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®
- 8. 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.
- 9. 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
- 10. Confounders of liver stiffness measurements Pathologic and normal physiologic processes Sigrist RMS et al. Theranostics 2017;7(5):1303–1329.
- 11. 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®
- 12. 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.
- 13. 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
- 14. 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
- 15. 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
- 16. Box and whisker plot Interquartile range IQR: Q3 – Q1 reflects variability of measurements 75% 25%
- 17. ©Echosens2011.Tousdroitsréservés.Toutereproductiontotaleoupartiellesurquelquesupportquecesoitouutilisationducontenudece documentestinterditesansl’autorisationécritepréalabled’Echosens 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
- 18. 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
- 19. 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
- 20. 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)
- 21. 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
- 22. Quantifying fibrosis with FibroScan® www.fibroscan.com/en/expertise
- 23. 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.
- 24. 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)
- 25. 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
- 26. 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
- 27. 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
- 28. 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®
- 29. 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
- 30. 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
- 31. 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.
- 32. 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.
- 33. 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
- 34. ARFI – 2D shear wave elastography (2D SWE) Normal values (GE: 6 ± 1.4 kPa – Explorer: 5.1 ± 1.3 kPa) ARFI: acoustic radiation force impulse imaging Barr RG et al. Ultrasound Quarterly 2016;32:94–107. Field of view (FOV) where elastography will be obtained Regions of interest (ROI) within FOV to obtain 3 – 5 measurements ROI FOV
- 35. 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 ARFI: acoustic radiation force impulse imaging 2D SWE: two dimensions shear wave elastography – pSWE: point shear wave elastography
- 36. 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.
- 37. 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®
- 38. 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
- 39. 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
- 40. 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.
- 41. Future of US-based elastography
- 42. 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 Area under ROC curve 0.85 (95% CI 0.81-0.89) Advanced fibrosis ≥F3 Area under ROC curve 0.98 (95% CI: 0.96-1.00)
- 43. 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
- 44. 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 Barr RG et al. Ultrasound Quarterly 2016;32:94–107. Ferraioli G. J Ultrasound Med 2019;38:9–14.
- 45. Thank You
- 46. Questions?
Editor's Notes
- F0: No fibrosis F1: Portal fibrosis without septa F2: Portal fibrosis with few septa F3: Numerous septa without cirrhosis F4: cirrhosis. Major limitation of the biopsy: one histological stage for all type of cirrhosis. 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.
- Even a 25mm long liver biopsy has a 25% rate of discordance for fibrosis staging. The level of experience (specialisation, duration and location of practice) of the pathologist may even be more important. Liver biopsy is used to stage most cases of liver disease, it is well known that this procedure has several limitations: First, liver biopsies only sample an extremely small portion of the liver (1/50,000) and therefore, sampling errors can occur, especially when smaller sized biopsies are analyzed (under-diagnosis of cirrhosis in 10 – 20%). Even a 25mm long liver biopsy has a 25% rate of discordance for fibrosis staging. In addition, histological examination is prone to intraobserver and interobserver variation, which may occur even when widely validated systems are used to score liver damage. Finally, liver biopsy is an invasive procedure with associated morbidity: pain occurs in 20% of patients and major complications (such as bleeding or hemobilia) in 0.5%.
- Abdominal US: - features of established cirrhosis - biliary dilation (extrahepatic cholestasis) - signs of cardiac failure or hepatic vein disease - focal liver lesions - splenic size - venous collaterals - ascites - other signs of portal hypertension
- Median mean
- Bell: جرس
- Liver stiffness values are expressed in kilopascals Range from 2.5 – 75 kPa Values around 5.5 kPa were recently shown to reflect normality
- Waist circumference 80 cm in women or 94 cm in men. Specific probe is developed for obese patients.
- LSM may be confounded by a variety of factors expected to alter liver stiffness, including hepatic inflammation, steatosis, hepatic vascular congestion, cholestasis, and portal hypertension.
- Median mean
- 398 patients: training cohort patients 266 patients– validation cohort 132 patients