MR ELASTOGRAPHY UPDATE

Jonathan R. Dillman, MD, MSc Associate Professor Associate Chair, Research Medical Director, Imaging Research Center

@CincyKidsRad facebook.com/CincyKidsRad Disclosures

• Investigator-initiated research support from: – Siemens US, Toshiba US • In-kind research support from: – Perspectum Diagnostics • Travel support from: – Philips Healthcare – GE Healthcare Learning Objectives

1. Review MR elastography (MRE) and how it works 2. Review the evidence for MRE in the pediatric population – Diagnostic performance – Failure rate – Accelerated imaging Pediatric Chronic Liver Diseases & Fibrosis • Many causes – Hepatitis (infection, autoimmune) – Biliary obstruction (BA, PSC, CF) – Iron, copper deposition – Steatosis/NASH – Metabolic/genetic defects (α-1 antitrypsin) • Chronic injury (inflammation/necrosis)  myofibroblast activation  fibrogenesis (scarring) Liver Fibrosis & Biopsy • “Gold” standard for fibrosis detection/measurement – Invasive, high cost, sampling error • Staged semi-quantitatively (e.g., Metavir, Ishak, NASH CRN) – Imperfect inter-pathologist agreement

Asselah, et al. Gut 2009; 58:846-858 Unmet Need • Noninvasive, rapid, well-tolerated method for accurately 1) detecting, 2) measuring, and 3) following liver fibrosis Elasticity Imaging

• Analogous to palpation • Unique form of image contrast at US & MRI • Indirectly detects/measures liver fibrosis Shear Wave Elastography

• Based on measurement of shear wave speed propagation through tissue • SWS is related to Young’s modulus, E (kPa) – Defines relationship between stress (force) and strain (deformation) for material • Wide dynamic range!

푬 SWS (m/s) ≅ ퟑ흆 MRE – How it Works

• Based on imaging of mechanically-generated hepatic shear waves • Provides color map (elastogram) of stiffness/ fibrosis distribution – LARGER than US SWE MRE Basics

• Driver frequency ± 60 Hz • 2D GRE vs. SE-EPI sequence – Modified phase contrast sequence – detects μm displacements • Motion encoded gradient (MEG) synchronized to driver  encodes shear wave amplitude into phase of MR image • Reported in kPa (shear modulus)

Serai, et al. Dig Dis Sci 2012; 57:2713-2719 MRE Wave Images

1.8 kPa >10 kPa! 4.1 kPa (normal) (abnormally stiff) MRE Reporting

• Mean stiffness measured on 4 slices through mid liver – Confidence maps identify “reliable data” • “Mean of means” presented, with range Diagnostic Performance in Adults

Yin, et al. Radiology 2016; 278:114-124 Diagnostic Performance in Children

• n=35 – Median age = 13 years • Histology: – F0-F1, n=27 AUC=0.92 • Cutoff: ~2.7 kPa for detecting significant fibrosis – Sens 88%, spec 85%

Xanthakos, et al. J Pediatr 2014; 164:186-188 Diagnostic Performance in Children… an Update

AUC=0.82 AUC=0.53

Cut-off value: 2.49 kPa (sensitivity=86%, specificity=71%)

Trout, et al. Radiology 2018; Epub ahead of print MRE Reproducibility

• Test-retest repeatability (“coffee break”) ICCs: 0.77-0.94

Trout, et al. Radiology 2016; 281:793-804 Variability in Shear Wave Elastography

Barr, et al. Radiology 2015; 276:845-861 MRE Failure in Children

Technical, 1 Hardware Artifact, 1 • 18 of 449 CCHMC exams

failed Large Body Breathing/ Habitus, 6 – 96% success rate Motion, 3 (2D GRE MRE sequence)

Unable to Tolerate, 3 Iron Overload, 4

Joshi, et al. Pediatr Radiol 2017; 47:838-843 Shear Wave Elastography is Confounded

Take-Away: Other Processes Can Cause Liver Stiffening

PRE-OP POST-OP

DiPaola and Dillman. Eur Radiol 2017; 27:2434-2442 Shear Wave Elastography US vs. MRI • US advantages: – Cost (infrastructure & exam) – Length of exam – No sedation/GA – Portable – Better spatial resolution • MRI advantages: – Imaging depth/more global look at tissue – Fat & iron quantification – Less variability? MRE in the Clinic Obesity, Elevated LFTs, suspect NAFLD

PDFF = 44% MRE in the Clinic Known NASH

2012 – 8Y 2016 – 12Y kPa = 2.2 kPa = 5.5 MRE in the Clinic Autoimmune Hepatitis

2014 – 8Y 2016 – 10Y kPa = 5.5 kPa = 2.1 ALT = 129 U/L ALT = 44 U/L What about Patients that Cannot Breath-Hold?

• 25 young adult volunteers – 5 with Fontan liver disease • Compared breath-hold MRE to: – Free breathing – “Hybrid” compressed sensing • CS=1.5, 2, 3 Results – Mean Stiffness (kPa)

Breath-Held Free-Breathing Conventional MRE CS=1.5 MRE CS=2 MRE CS=3 P-valuep=NS MRE 2D GRE

2.47 ± 1.08 2.59 ± 1.09 2.45 ± 1.06 2.27 ± 0.88 2.26 ± 0.69 Reader 1 0.09 (1.54-5.22) (1.69-5.17) (1.54-5.25) (1.54-4.60) (1.51-4.01) 2.56 ± 1.07 2.38 ± 0.96 2.36 ± 0.92 2.32 ± 0.94 2.36 ± 0.76 Reader 2 (1.67-4.96) 0.02 (1.57-4.66) (1.55-4.62) (1.44-4.40) (1.40-3.86) [23] 2.28 ± 0.89 2.36 ± 0.97 2.24 ± 0.85 2.20 ± 0.78 2.27 ± 0.68 Reader 3 0.06 (1.46-4.27) (1.35-4.71) (1.49-4.21) (1.42-3.98) (1.44-3.69)

*No significant difference for 2 of 3 Readers Results – Mean ROI Size (mm2)

Breath-Held Free-Breathing Conventional MRE CS=1.5 MRE CS=2 MRE CS=3 P-value MRE 2D GRE

2618 ± 766 2156 ± 757 2096 ± 782 1719 ± 594 1170 ±389 Reader 1 <0.0001 (1060-4086) (470-3281) (453-3542) (535-2667) (359-1644)

2123 ± 581 1795 ±474 1737 ± 485 1422 ±399 1102 ± 387 Reader 2 <0.0001 (1000-3086) (698-2490) (629-2960) (562-2213) (492-1805)

3941 ± 1099 2465 ± 1040 2705 ± 863 2064 ± 861 1253 ± 500 Reader 3 <0.0001 (1610-6205) (413-5007) (653-4404) (507-4830) (286-2476)

*Significant difference for all 3 Readers Results – Scatter/Bland-Altman Plots

FB CS=1.5 CS=2 CS=3 Example – Fontan Volunteer

BH (13.3 sec) FB (13.3 sec) CS=1.5 (8.9 sec)

CS=2 (6.9 sec) CS=3 (4.9 sec) Conclusions • MRE can be readily performed in most children – Low failure rate • Diagnostic performance may be disease specific – More research needed • Ultimately, stiffness is confounded biomarker – Inflammation, congestion, fat • Need more research showing how stiffness/change over time correlate with important clinical outcomes