transient elastography and other...
TRANSCRIPT
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TRANSIENT ELASTOGRAPHY AND OTHER TECHNIQUES
Raj Vuppalanchi, MDAssociate Professor of Medicine
Division of Gastroenterology and HepatologyMay 5, 2017
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Financial Disclosure
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• None
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Overview
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• Liver Stiffness and Liver Elastography
• Vibration-Controlled Transient Elastography
– Liver Stiffness Measurement (LSM) and
– Optimal Cut-offs
– Controlled Attenuation Parameter (CAP)
• Role of combined LSM and CAP in NAFLD/NASH
• Other techniques of Elastography
• Optimal Strategies for use of Elastography
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Liver Stiffness
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Fibrosis
Sinusoidal pressure Heart failure
Portal blood flow Post prandial
Biliary pressure PSC
Inflammation Acute hepatitis
Glisson’s capsule
NAFLD? ALT<80 U/L
? ALT<100 U/L
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Liver Elastography
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Liver Elastography- Current Approaches
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Techniques that image the tissue response to a mechanical stimulus
Excitation Source
Mechanical (surface of the body)
Acoustic Radiation Force (inside liver)
Physiological Motion
Imaging Modality
Ultrasound
Magnetic Resonance
Property Displayed
Strain Elastography
Transient Elastography
Harmonic Elastography
Point Shear Wave Elastography
2D Shear Wave Elastography
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Liver Elastography- Current Approaches
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Ultrasound based Shear Wave Imaging
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SWI
VCTE
(A mode imaging)
pSWE
(B mode imaging)
2D-SWE
(B mode imaging)
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Probe Size
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Probe size Depth (mm) US Freq (MHz)M+ 25-65 3.5XL+ 35-75 2.5
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LSM (VCTE) and Fibrosis in NAFLD
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Pathik et al. Ann Gastroenterol. 2015 Apr-Jun; 28(2): 281–286
N=110
kP
a
Park et al. Gastroenterology 2017; 152:598-607
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Optimal VCTE- LSM Cut-Off for ≥F2
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Study Probes No. of Pts % with ≥ F2 LSM Cut-off AUROC Sensitivity (%) Specificity (%)
Yoneda (2008) M+ 97 52 6.6 0.86 88 74
Nobili (2008) M+ 50 48 7.4 0.99 100 92
Wong (2010) M+ 246 17 7.0 0.84 79 76
Petta (2011) M+ 169 30 7.3 0.79 69 70
Lupsor (2010) M+ 69 26 6.8 0.79 67 84
Gaia (2011) M+ 72 64 7.0 0.80 76 80
Myers (2012) M+ 75 7.8 0.86 79 64
Wong (2012) M+ 193 23 7.0 0.83 79 64
Cassinotto (2015) M+ 291 71 6.20.82
90 45
9.8 60 90
Imajo (2016) M+ 142 54 11.0 0.82 65 89
Naveau (2014) M+ and XL+ 100 22 7.6 0.81 73 78
Park (2017) M+ and XL+ 94 30 6.9 0.86 79 85
Chen (2017) M+ and XL+ 111 36 7.8 0.83 82 78
NAFLD with F0/F1 vs. F2 to F4 (Clinically Significant Fibrosis )
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Optimal VCTE-LSM Cut-off for Cirrhosis
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Study Probe No. of Pts % with F4 LSM Cut-off AUROC Sensitivity (%) Specificity (%)Yoneda (2008) M+ 97 9 17 0.99 100 97Wong (2010) M+ 246 10 10.3 0.95 92 88Gaia (2011) M+ 72 12.5 10.5 0.94 78 96Myers (2012) M+ 75 22.3 0.88 80 91Wong (2012) M+ 193 13 10.3 0.89 81 83Cassinotto (2015) M+ 291 16.8 9.5
0.8792 62
16.1 65 90Imajo (2016) M+ 140 8 14 0.92 100 76Park (2017) M+ and XL+ 94 9 6.9 0.69 63 66Chen (2017) M+ and XL+ 111 10 14.6 0.90 82 92
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Current Dilemma
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• What are the cut-offs for ≥ F2 or F4?– Optimal
– 90% sensitivity
– 90% specificity
• Do the cut-offs vary depending on the distribution of NAFLD phenotype
• Are the cut-offs study cohort specific?
• How do we address the spectrum bias?
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Controlled Attenuation Parameter
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Ultrasound Attenuation Rate : dB/M (decibels per meter)
Range: 100 to 400 dB/M
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CAP and Hepatic Steatosis
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Normal liver
Fatty liver
de Lédinghen et al. J Gastroenterol Hepatol. 2015 Oct 29.
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CAP and 1H-MRS
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• 1H-MR Spectroscopy and CAP in 50patients with biopsy proven NAFLDand healthy volunteers
• Steatosis defined by % hepatocytesaffected by steatosis
• S1 – 5 to 33%
• S2 – 34 to 66%
• S3 – ≥ 67%
• CAP cut-off of 300 dB/m fordetection of S3 steatosis
• CAP cut-off of 215 dB/m for healthy
Karlas et al. PLoS One. 2014 Mar 17;9(3):e91987
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CAP and MRI-PDFF
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MRI-based protondensity fat fraction(PDFF) and TE-basedCAP for assessment ofsteatosis in 142 liverbiopsy proven NAFLD
Imajo et al. Gastroenterology. 2016 Mar;150(3):626-637
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CAP and Hepatic Fat Fraction
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M probe XL probe P-Value
S ≥ 2% AUROC = 0.83 (0.71-0.95)Cut-off 251 dB/mSe= 0.78 Sp= 0.78Acc = 0.80
AUROC = 0.84 (0.73-0.95)Cut-off 254 dB/mSe= 0.83 Sp= 0.78Acc = 0.83
0.76
S ≥ 8% AUROC = 0.87 (0.78-0.97)Cut-off 267 dB/mSe= 0.80 Sp= 0.79Acc = 0.81
AUROC = 0.90 (0.82-0.99)Cut-off 270 dB/mSe= 0.88 Sp= 0.79Acc = 0.85
0.50
S ≥ 16% AUROC = 0.92 (0.85-0.99)Cut-off 299 dB/mSe= 0.92 Sp= 0.88Acc = 0.90
AUROC = 0.91 (0.83-0.99)Cut-off 301 dB/mSe= 0.92 Sp= 0.81Acc = 0.85
0.78
S = steatosis; AUROC = area under the receiver operating characteristic curve; Se = sensitivity; Sp = specificity; Acc = accuracy
Sasso et al. Ultrasound Med Biol. 2016 Jan;42(1):92-103
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MRE vs. TE and PDFF vs. CAP
19Park et al. Gastroenterology. 2017 Feb;152(3):598-607
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ARFI-based Shear Wave Elastography
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• B mode imaging requires expertise and prone to operator bias
• Simultaneous steatosis quantification is currently lacking
• Encouraging data using SSI in NAFLD
Excitation method Modalities Technique Options
ARFI (acoustic radiation force impulse)
Point SWE Point shear wave speed measurement
Virtual Touch Quantification (Siemens Healthcare)ElastPQ (Philips)Smart-Shearwave elastography (Samsung Medison)
2D-SWE Shear wave speed imaging
SWE (Aixplorer SuperSonic Imagine -SSI)Virtual Touch Image Quant, (Siemens Healthcare) Shear Wave Elastography (GE Healthcare)Shear Wave Elastography (Toshiba Medical Systems)
Manual compression or ARFI
Strain or displacement
Real-time tissue elastography (Hitachi)Virtual Touch Imaging (Siemens Healthcare)
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Feasibility in Multi-Center Study –NASH CRN Experience
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➢A total of 1706 exams were performed in992 NAFLD patients across eight clinicalcenters
➢Cohort—➢65% women➢BMI 33.6 (± 6.8) kg/m2➢Waist circumference 107 (± 14) cm
➢XL+ probe – 60%➢Failure rate – 3.2%➢Proportion of Unreliable scans – 2.4%
Vuppalanchi et al. AASLD 2015 (Manuscript under review)
N=55Skin to capsule distance > 3.5 cm 19 35%All readings were invalid 6 11%No liver detected 1 2%Machine/technician error 13 24%Patient in too much pain 4 7%Patient refusal 11 20%Unknown reason 1 2%
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Performance Characteristics
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BMI categoryNormal /
Overweight*<30 kg/m2 (n=311)
Obese30-34.9 kg/m2
(n=311)
Extreme Obese≥35 kg/m2
(n=358)
Total†(n=992)
P-value
Probe type - % XL probe 26.7% 60.8% 87.4% 59.7% <0.001
Liver Stiffness Measurement (LSM)Average 1st and 2nd reading
Mean (SD) - kPa 9.0 (9.6) 11.0 (11.8) 13.8 (12.8) 11.4 (11.7) <0.001Median [IQR] - kPa 6.0 [4.4, 9.3] 7.1 [5.2, 11.8] 9.3 [6.6, 15.0] 7.5 [5.3, 12.2]
Difference 1st and 2nd readingMean (SD) - kPa -0.2 (4.8) 0.3 (6.3) 0.0 (5.2) 0.0 (5.5) 0.96Median [IQR] – kPa 0.0 [-0.7, 0.7] 0.0 [-0.7, 1.1] 0.1 [-1.3, 1.4] 0.0 [-0.9, 1.1]95% limits of agreement† - kPa ±2.0 ±2.6 ±3.9 ±2.9
Controlled Attenuation Parameter (CAP)
Average 1st and 2nd readingMean (SD) – dB/m 284 (56) 303 (47) 336 (42) 307 (53) <0.001Median [IQR] – dB/m 284 [254, 321] 306 [270, 337] 340 [311, 366] 312 [272, 347]
Difference 1st and 2nd readingMean (SD) – dB/m 3 (32) -2 (38) 5 (36) 2 (36) 0.07Median [IQR] – dB/m 3 [-14, 18] -3 [-21, 16] 0 [-16, 24] 0 [-16, 19]95% limits of agreement† - dB/m ±46 ±54 ±58 ±51
Vuppalanchi et al. AASLD 2015 (Manuscript under review)
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Covariates of Unreliable LSM
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Unreliable examsQuartile No. prior exams Total exams No. %
1 1 to 11 244 11 4.92 12 to 27 250 10 4.13 28 to 58 245 14 5.04 59 to 180 253 4 1.6
Proportion of operator’s experience as quartiles and Unreliable VCTE scans
Odds of unreliable liver stiffness measurementCovariate Odds Ratio 95% CI P valueBody Mass Index (per category†) 2.7 1.5, 4.8 0.001International normalized ratio (%) 0.94 0.89, 0.99 0.01Ethnicity (Hispanic vs non-Hispanic) 3.2 1.1, 9.3 0.03Age (per yr) 1.03 1.00, 1.07 0.08Prior operator-specific readings (per quartile) 0.75 0.52, 1.08 0.12ALT (per 10 U/L) 0.91 0.78, 1.05 0.19
Variables associates with Unreliable VCTE scans
Vuppalanchi et al. AASLD 2015 (Manuscript under review)
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Relationship between Probe and LSM / CAP
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XL+ probe M+ probe BMI-AdjustedDifference (XL – M)
N BMI-Adjusted
Mean
N BMI-Adjusted
Mean
Mean 95% CI P-value
LSM (kPa)Fibrosis stage0 132 5.4 112 6.5 -1.0 -1.6, -0.5 <0.0011 136 6.4 106 7.2 -0.9 -1.7, -0.1 0.032 90 7.2 57 7.8 -0.5 -1.7, 0.6 0.353 137 11.3 70 13.7 -2.4 -4.6, -0.2 0.044 57 21.3 30 26.2 -4.8 -12.6, 2.9 0.22Total 552 8.0 375 8.8 -0.8 -1.4, -0.3 0.003
CAP (dB/m)Steatosis score0 20 268 41 289 -21 -50, 9 0.171 160 313 155 300 13 0, 25 0.052 117 321 106 306 15 1, 29 0.043 80 342 73 310 32 18, 46 <0.001Total 377 319 375 303 16 8, 24 <0.001
Vuppalanchi et al. AASLD 2015 (Manuscript under review)
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Accuracy of VCTE to Detect Cirrhosis
25
0.0
00.2
50.5
00.7
51.0
0
Sensitiv
ity
0.00 0.25 0.50 0.75 1.001 - Specificity
Area under ROC curve = 0.8517
Optimal LSM: 15.5 kPa• Specificity fixed at 90%: AUROC
0.93 (95% CI: 0.86-0.99) for
differentiating cirrhosis from lesser
fibrosis stage
• Sensitivity: 0.76
• Positive Predictive Value: 0.37
• Negative Predictive Value: 0.98
M. Shadab Siddiqui et al. EASL 2017
N=62
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High Success Rate in Multi-Center
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• A failure rate of 3% when FibroScan is used forestimation of LSM and CAP in patients withNAFLD
• Excellent inter- and intra-operator agreement forLSM and CAP
• Use of the XL+ was associated with• lower LSM values• higher CAP values
Vuppalanchi et al. AASLD 2015
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Longitudinal Assessment
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Change in LSM (VCTE) over time (ΔLSM/Δt )
• Understand the natural history (placebo arm)
• Assess therapeutic response to treatmentintervention
• ΔLSM/Δt : Change in fibrosis + (inflammation)
• ΔCAP/Δt : Change in hepatic fat
• ΔLSM/Δt• ΔCAP/Δt
Hard outcomes• Death or transplant
Composite endpoints• Improvement in NAS• Improvement in Fibrosis• Resolution of NASH
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Elastography in Drug Development
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VCTE with LSM and CAP
MRE with PDFF
Histology – L. Bx
Hard Outcomes
Phase 1
• Safety
Phase 2a
• Demonstrate ability to reduce liver fat content
• Trends in improvement in ALT and other blood based markers (inflammation)
• Metabolic indices
• Continued safety profile
Phase 2b
• Confirm effect on reducing liver fat content
• Reduce inflammation
• Significant improvement in metabolic syndrome
• Confirmation of clean safety profile
Phase 3
• Resolution of NASH with no worsening in fibrosis
• Reduction in fibrosis with no worsening in NASH
Screening Enrichment
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Summary
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• Liver elastography can be obtained through US or MRIbased approaches
• Simultaneous LSM and CAP by VCTE or MRE with PDFF isvery convenient.
• One-time measurement of LSM and CAP – riskstratification and screening enrichment tool
• Change over time (ΔLSM/Δt or ΔCAP/Δt or Δ PDFF%/Δt)when linked to hard outcomes or surrogate endpointsmay be a game changer
• Strategies to minimize confounders is very critical in aclinical trial setting
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Liver Stiffness Revisited
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Liver hand palpation: “The living are soft and yielding; the dead are rigid
and stiff”, Lao Tzu, (6th century BCE).
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Thank youQ and A
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NAFLD- Evaluation
34The diagnosis and management of non-alcoholic fatty liver disease: practice guideline. HEPATOLOGY 2012;55:2005-2023.
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Reliability: Effect of Confounders
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Confounders for LSM
ObesityAlcohol
Congestion
Inflammation
Inexperience Non-fasting
Cholestasis
Fast >3 hrs
Check ALP and T.Bili
Check ALT
Operator experience >100 exams
Right heart failure
Alcohol history XL+ probe
Patel et al. Semin Liver Dis. 2015 May;35(2):166-83.
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Effect of Food Intake on LSM
36Arena et al. Hepatology. 2013 Jul;58(1):65-72.
Standardized liquid meal (400 mL, 600 Kcal, 16.7% protein, 53.8% carbohydrates, 29.5% fat) in HCV patients.
Echosens: 3 hours fastNASH CRN : Overnight fast
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Myths and Mysteries
37
Technology Technician/Technique Tissue Tablets/Tonics
Shear wave propagation Operator experience Probe to liver distance Medication usage
TM mode Variability - Ascites - Beta Blockers
A mode - Intra-operator - Adiposity Etiology specific therapy
Algorithm - Inter-operator - Altered anatomy Significant weight loss
Software Acute hepatitis - Bariatric surgery
Probe size Cholestasis Recent alcohol use
- Medium Portal flow
- Extra-large - Postprandial state
TIPSS
Tumor
Cysts
Infiltrative liver disease
Hemangioma
Congestive hepatopathy
Hepatic steatosis
Vuppalanchi and Sanyal. Clin Gastroenterol Hepatol. 2015 Apr;13(4):780-2.
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38
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39
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Fibroscan – Clinical Trial Setting
40
• Successful recruiting by enrichment• CAP>300 dB/m for MRI-PDFF>10%
• LSM >10.3kPa for ≥ F2 stage of fibrosis
• LSM ≥ 14kPa for NASH cirrhosis
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COMBINED LSM and CAP
41
CAPLSM
Probe
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NAFLD Phenotype
42
• NAFLD
• NAFL
• NASH– Without Fibrosis
– With Fibrosis
• Early (F1)
• Clinically significant (≥ F2)
• Advanced (F3-F4)
Where does my patient fall on the
spectrum?
BMS NuSirt Intercept Genfit Galectin
Phase 2 ≥10% hepatic fat ≥15% hepatic fat NASH cirrhosis with HVPG ≥ 6 mm Hg
Phase 3 NASH with F2-F3 NASH with F1-3
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43
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44
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45
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46
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47
Excitation method Modalities Technique Options
ARFI (acoustic radiation force impulse)
Point SWE Point shear wave speed measurement
Virtual Touch Quantification
2D-SWE Shear wave speed imaging SWE (Aixplorer Supersonic Imagine); Virtual Touch Image Quantification, (Siemens Healthcare); Shear Wave Elastography (GE Healthcare): Shear Wave Elastography (Toshiba Medical Systems)
Manual compression or ARFI Strain or displacement Real-time tissue elastography (Hitachi); Virtual Touch Imaging (Siemens Healthcare)
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MRE
48
Clinical Gastroenterology and Hepatology
Volume 5, Issue 10, Pages 1207-1213.e2
(October 2007)
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SWE
49