MRMR Elastography:Elastography: AssessmentAssessment ofof DiffuseDiffuse LiverLiver DiseaseDisease

SCBT·MRSCBT·MR AnnualAnnual CourseCourse OctoberOctober 26,26, 20112011

RichardRichard L.L. Ehman,Ehman, M.D.M.D.

Disclosure:Disclosure: TheThe MayoMayo ClinicClinic andand thethe presenterpresenter havehave patentpatent rightsrights andand aa relevantrelevant financialfinancial interest.interest.

Assurance:Assurance: CompliantCompliant withwith oversightoversight byby thethe MayoMayo ClinicClinic ConflictConflict ofof InterestInterest ReviewReview Board.Board. ImportanceImportance ofof ChronicChronic LiverLiver Disease,Disease, Fibrosis,Fibrosis, CirrhosisCirrhosis

• A leading cause of death world-wide • Increasing prevalence of conditions that cause hepatic fibrosis • Hepatitis C - 170 M people globally • Hepatitis B • Obesity / Fatty liver disease • Fibrosis can be reversed, if diagnosed early and treated

Progression of Liver Disease NormalNormal FibrosisFibrosis CirrhosisCirrhosis

ReversibleReversible IrreversibleIrreversible SilentSilent HighHigh mortalitymortality LiverLiver BiopsyBiopsy StandardStandard DiagnosticDiagnostic ProcedureProcedure toto rule-outrule-out FibrosisFibrosis •• RiskRisk ofof ComplicationsComplications •• PotentialPotential SamplingSampling ErrorsErrors •• SubjectiveSubjective HistologyHistology GradingGrading Noninvasive Tests

• Serum Biomarkers • Direct and Indirect • Conventional Imaging • MRI, US, CT • US Elastography • Fibroscan • ARFI • MRI Techniques • Contrast enhanced • Diffusion-weighted • MR Elastography

MR Elastography 1.1. DriverDriver 2.2. MREMRE SequenceSequence 3.3. InversionInversion (30-500(30-500 Hz)Hz)

Tissue-simulating gel phantom with stiff inclusions

2.5cm2.5cm -10 0 +10 0 40 80 ConventionalConventional DisplacementDisplacement ((m)m) ShearShear StiffnessStiffness (kPa)(kPa) MRMR ImageImage WaveWave ImagesImages ElastogramElastogram AcousticAcoustic Driver SystemSystem forfor MREMRE

MREMRE VibrationVibration SourceSource

MREMRE AbdominalAbdominal DriverDriver

ConventionalConventional MRIMRI examexam ofof Abdomen:Abdomen: ~~ 4545 minmin

MRMR Elastography:Elastography: addsadds ~~ 55 minmin (15(15 secondsecond scan)scan)

10 2.1 kPa Normal 8

6

4

2 Shear Stiffness (kPa) Shear Stiffness Shear Stiffness (kPa) Shear Stiffness Elastogram 0 LiverLiver FibrosisFibrosis Biopsy:Biopsy: Biopsy:Biopsy: Biopsy:Biopsy: Biopsy:Biopsy: StageStage F1F1 StageStage F2F2 StageStage F3F3 StageStage F4F4

Normal

2.1 kPa

3.1kPa 3.5 kPa 4.8 kPa 10.8 kPa

0102468 ShearShear StiffnessStiffness (kPa)(kPa)

MRE-Assessed Liver Stiffness 10 Normal F0 F1 438 patients with biopsy < 1 year 8 F2 F3 F4

6

082 46 Shear Stiffness (kPa) 4

Fibrosis Std No. Mean 95% CI Stage Dev 0 109 2.77 0.97 (2.59, 2.96) 2

1 76 3.01 0.87 (2.81, 3.21) Mean Liver Stiffness (kPa) 2 70 3.68 1.52 (3.32, 4.04) 3 89 4.32 1.93 (3.92, 4.73) 0 4 94 5.78 2.26 (5.31, 6.24) Normal 01234 Fibrosis Stage Sensitivity and Specificity of MRE for Hepatic Fibrosis • Rouviere O, Yin M, Dresner MA, et al. MR elastography of the liver: preliminary results. Radiology. 2006;240:440-448. • Huwart L, Peeters F, Sinkus R, et al. Liver fibrosis: non-invasive assessment with MR elastography. NMR Biomed. 2006;19:173-179. • Yin M, Woollard J, Wang X, et al. Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography. Mag Reson Med. 2007;58:346-353. • Salameh N, Peeters F, Sinkus R, et al. Hepatic viscoelastic parameters measured with MR elastography. 2007;26:956-962. • Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5:1207-1213. • Huwart L, Sempoux C, Salameh N, et al. Liver fibrosis: Noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index. Radiology. 2007;245:458-466. • Huwart L, Salameh N, ter Beek L, et al. MR elastography of liver fibrosis: preliminary results comparing spin-echo and echo-planar imaging. Eur Radiol. 2008;18:2535-2541. • Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135:32-40. • Salameh N, Larrat B, Abarca-Quinones J, et al. Early detection of steatohepatitis in fatty rat liver by using MR elastography. Radiology. 2009;253:90-97. • Asbauch P, Klatt D, Schlosser B, et al. Viscoelasticity-based staging of hepatic fibrosis with multifrequency MR elastography. Radiology. 2010;257:80-86.

Comparability to Transient Ultrasound Elastography • Oudry J, Chen J, Glaser KJ, et al. Cross-validation of magnetic resonance elastography and ultrasound-based transient elastography: a preliminary phantom study. J Magn Reson Imaging. 2009;30:1145-50.

Reproducibility • Hines CD, Bley TA, Lindstrom MJ, Reeder SB. Repeatability of magnetic resonance elastography for quantification of hepatic stiffness. J Magn Reson Imaging. 2010;31:725-731. • Motosugi U, Ichikawa T, Sano K, et al. Magnetic resonance elastography of the liver: preliminary results and estimation of inter-rater reliability. Jpn J Radiol. 2010;28:623-627. • Hines CD, Lindstrom MJ, Varma AK, Reeder SB. Effects of postprandial state and mesenteric blood flow on the repeatability of MR elastography in asymptomatic subjects. J Magn Reson Imaging. 2011;33:239-244. • Shire NJ, Yin M, Chen J, et al. Test-Retest Reproducibility of Magnetic Resonance Elastography for Non-Invasive Liver Fibrosis Assessment in Hepatitis C. Submitted. Safety • Ehman EC, Rossman PJ, Kruse SA, Sahakian AV, Glaser KJ. Vibration safety limits for magnetic resonance elastography. Phys Med Biol. 2008;53:925-935. DiagnosticDiagnostic Performance:Performance: APRI,APRI, UTE,UTE, && MREMRE HuwartHuwart LL etet al.al. GastroenteroGastroenterologylogy 235235 (2008)(2008) –– 141 141 PatientsPatients

100%100% CorrectCorrect 1.0 MREMRE 94%94% UTEUTE 0.9 84%84% APRIAPRI AreaArea underunder 0.8 ROCROC CurveCurve Technical Technical AST to 0.7 AST to SuccessSuccess plateletplatelet ratioratio indexindex 0.6 F≥1F≥2F≥3F≥4 WorthlessWorthless 0.5 FibrosisFibrosis StageStage

4141 yo Patient ––Fatty Fatty Liver DiseaseDisease

2.3

•• BiopsyBiopsy :: NoNo fibrosisfibrosis 048 Shear Stiffness (kPa) 69 yo Patient - Fatty Liver Disease

7.5

•• BiopsyBiopsy : Stg. 3 fibrosis 048 Shear Stiffness (kPa)

SteatosisSteatosisDoes Does NotNot AffectAffect LiverLiver StiffnessStiffness 14 Normal Stage 0 12 Stage 1 Stage 2 Stage 3 Liver Patient 10 Liver Patient Stage 4

8

6

0.68 4 0.68 Liver Stiffness (kPa) Liver Stiffness (kPa) Liver Stiffness (kPa)

2 0 5 10 15 20 25 FatFat // WaterWater RatioRatio HowHow EarlyEarly CanCan MREMRE DemonstrateDemonstrate NASHNASH inin PatientsPatients withwith FattyFatty LiverLiver Disease?Disease? cp685 cp910cp484 cp765 cp478 cp958

Detection of Steatohepatitis MR Elastograms before the onset of Fibrosis

Liver stiffness measurement (kPa) 2.02 2.05 4.38 3.59 10.24 7.52 Liver biopsy findings

Fibrosis Stage 00 0044 Inflamm Grade 00 1121

55 yo Patient – Chronic Hepatitis C

11.7

• Biopsy: Not performed 048 Shear Stiffness (kPa) 59 yo Patient – Alcohol

6.0

• Biopsy : Stg. 4 fibrosis 048 Shear Stiffness (kPa)

76 yo Patient - Alcohol 048 Shear Stiffness (kPa)

5.5

3.4 Abstinent 9 months later 47 yo female with Autoimmune Hepatitis

8/14/07 6/18/09 8 04 Shear Stiffness (kPa)

Mean Liver Stiffness: 4.0 kPa Mean Liver Stiffness: 2.9 kPa Liver Biopsy Score = F2 Liver Biopsy Score = F0

MRMR Elastography

• Emerging as a reliable non-invasive method for diagnosing hepatic fibrosis • Safer, less expensive, and less affected by sampling error than liver biopsy • Other potential applications (heart, lung, pancreas, breast) are being explored