MRI OF LIVER FIBROSIS

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1 MRI OF LIVER FIBROSIS Jonathan R. Dillman, MD, MSc Associate Professor Co-Director, Thoracoabdominal Imaging Medical Director, Imaging Research facebook.com/cincykidsrad

2 Disclosures Investigator-initiated research support from: Siemens US, Toshiba US Guerbet, Bracco In-kind research support Perspectum Diagnostics Travel support Philips Healthcare, GE Healthcare

3 Learning Objectives 1. Review current and emerging MRI techniques for detecting & measuring liver fibrosis 2. Present illustrative cases

4 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)

5 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:

6 Past Imaging of Liver Fibrosis Morphology US, CT, and MRI Detects moderate/ severe fibrosis Difficult to quantify Findings include: Surface nodularity Segmental atrophy/ hypertrophy

7 Past Imaging of Liver Fibrosis Portal Hypertension US, CT, and MRI Detects late fibrosis Findings include: Splenomegaly Varices Ascites

8 Past Imaging of Liver Fibrosis Altered MRI Signal/Enhancement Detects moderate/severe fibrosis Difficult to quantify T2W signal Often peripheral, reticular Delayed postcontrast hyperenhancement vs. hypoenhancement (Eovist)

9 Critical Unmet Need Noninvasive, rapid, well-tolerated method for 1) detecting, 2) measuring, and 3) following liver fibrosis

10 Present Imaging of Liver Fibrosis Elasticity Imaging Analogous to palpation Unique form of image contrast at US & MRI Indirectly detects/measures liver fibrosis

11 Present Imaging of Liver Fibrosis Shear Wave Elastography (SWE) Based on measurement of shear wave speed (SWS) 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! SWS (m/s) E 3ρ

12 Present Imaging of Liver Fibrosis MR Elastography (MREL) Based on imaging of mechanically-generated hepatic shear waves Provides color map (elastogram) of stiffness/fibrosis distribution LARGER than US SWE

13 Present Imaging of Liver Fibrosis MREL Basics Driver frequency ± 60 Hz Usually 2D GRE 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:

14 Present Imaging of Liver Fibrosis MREL Wave Images 1.8 kpa (normal) >10 kpa! 4.1 kpa (abnormally stiff)

15 Present Imaging of Liver Fibrosis MREL Reporting Mean stiffness measured on 4 slices through mid liver Confidence maps identify reliable data Mean of means presented, with range

16 Present Imaging of Liver Fibrosis MREL in Adults Yin, et al. Radiology 2016; 278:

17 Present Imaging of Liver Fibrosis MREL in Children n=35 Median age = 13 years Histology: F0-F1: n=27 Cutoff: ~2.7 kpa for detecting significant fibrosis Sens 88%, spec 85% Xanthakos, et al. J Pediatr 2014; 164:

18 Present Imaging of Liver Fibrosis MREL Reproducibility 4 scanners (Philips, GE, 1.5T, 3T) Overall ICC (n=10): 0.68 ICC at 1.5T: 0.78 ICC at 3T: 0.64 ICC Philips: 0.83 ICC GE: 0.65 Trout, et al. Radiology 2016; 281:

19 Present Imaging of Liver Fibrosis MREL Repeatability Test-retest repeatability ( coffee break ) ICCs: Trout, et al. Radiology 2016; 281:

20 Present Imaging of Liver Fibrosis How Often Does it Fail? Hardware Artifact, 1 Technical, 1 18 of 449 CCHMC exams failed 96% success rate (2D GRE pulse sequence) Breathing/ Motion, 3 Large Body Habitus, 6 Unable to Tolerate, 3 Iron Overload, 4 Joshi, et al. Pediatr Radiol 2017; 47:

21 Present Imaging of Liver Fibrosis US SWE Before/After Fontan Take-Away: Other Processes Can Cause Liver Stiffening PRE-OP POST-OP DiPaola and Dillman. Eur Radiol 2017

22 Present Imaging of Liver Fibrosis MREL & Fontan Operation 15 MREL exams in Fontan patients All abnormally stiff ( kpa) Negative correlation between stiffness and measures of cardiac function Positive correlation between stiffness and time Congestion, fibrosis, both? Wallihan DB, et al. J Magn Reson Imaging 2014; 40:

23 Present Imaging of Liver Fibrosis SWE Variability in Humans Barr, et al. Radiology 2015; 276:

24 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 quantification Reliability?

25 MREL in the Clinic 12Y Obese Boy, Elevated ALT/AST

26 MREL in the Clinic 12Y Obese Boy, Elevated ALT/AST Diagnosis: Diffuse Steatosis, Normal Stiffness (no biopsy, no vitamin E per CCHMC protocol)

27 MREL in the Clinic Obesity, Elevated LFTs, suspect NAFLD PDFF = 44%

28 MREL in the Clinic Known NASH Y kpa = Y kpa = 5.5

29 MREL in the Clinic Autoimmune Hepatitis Y kpa = 5.5 ALT = 129 U/L Y kpa = 2.1 ALT = 44 U/L

30 Future Imaging of Liver Fibrosis T1 Mapping Quantitative images based on T1 (longitudinal or spin-lattice) relaxation Exponential recovery ( msec) M z M z M 0 M xy x 63% magnetization recovery t

31 Future Imaging of Liver Fibrosis T1 Mapping T1 = how quick nuclei recover 63% of longitudinal magnetization Impacted by extracellular water, collagen Commonly use modified Look-Locker inversion recovery approach (MOLLI) May be corrected for iron = corrected T1 (ct1) ct1 = T X T2* Commercialized by Perspectum Diagnostics (Oxford, UK) Kim, et al. Korean J Radiol 2017; 18:

32 Future Imaging of Liver Fibrosis ct1 79 unselected patients, both MRI & biopsy NL = msec Banerjee, et al. J Hepatol 2014; 60:69-77

33 Future Imaging of Liver Fibrosis ct1 ct1 = msec

34 Future Imaging of Liver Fibrosis ct1 >10 kpa ct1 = 1040 msec

35 Future Imaging of Liver Fibrosis ct kpa ct1 = 879 msec 3.96 kpa ct1 = 1048 msec

36 Future Imaging of Liver Fibrosis T2 Mapping Quantitative images based on T2 (transverse) relaxation Exponential (1 st -order) decay (~ msec) z M xy M z M 0 x transverse magnetization vector at 37% of original magnitude M xy t

37 Future Imaging of Liver Fibrosis T2 Mapping T2 prolonged in regions of water content Measuring fibrosis/edema, inflammation, both? Can be fit with mono- or bi-exponential curve Bi-exponential relaxometry commercialized by Magnepath (Perth, Australia) Multi-echo SE (10 equally spaced TEs) Extra-cellular water fraction (ECWF) = proxy for fibrosis Ratio of intra-/extra-cellular water fractions = proxy for inflammation Kim, et al. Korean J Radiol 2017; 18:

38 Future Imaging of Liver Fibrosis T2 Mapping 53 NASH patients (MRI & biopsy), 9 volunteers, 3T Mean ECWF: NASH: 25.7 ± 4.1% Volunteers: 17.6 ± 2.7% AuROC: 0.99 (healthy vs. F1) Could differentiate all grades but F3/F4 Intra-/extra-cellular transverse relaxation ratio: NASH: 3.4 ± 0.08 Volunteers: 2.4 ± 0.1 AuROC: 0.96 (healthy vs. mild lobular inflammation) Filho, et al. J Hepatol 2017; 66:S

39 Future Imaging of Liver Fibrosis T2 Mapping 7.4 kpa ct1 = msec T2 = 71.5 msec

40 Future Imaging of Liver Fibrosis T2 Mapping 2.42 kpa T2 = 58.0 msec 4.91 kpa T2 = 77.2 msec

41 Future Imaging of Liver Fibrosis T1rho Mapping = spin-lattice relaxation time in the rotating frame Equilibrium magnetization (M 0 ) flipped into transverse plane Transverse magnetization relaxes in presence of on-resonant continuous wave RF pulse = spin-lock radiofrequency pulse, which locks magnetization in transverse plane T1rho = decay of locked magnetization Martino and Damadian. Phys Chem Phys Med NMR 1984; 16:49-55

42 Future Imaging of Liver Fibrosis T1rho Mapping Related to magnetization transfer imaging Depicts interactions between water & local macromolecular environment Think of as macromolecule sat pulse Sensitive to slow precessing protons (e.g., collagen, proteoglycans) Increasing fibrosis Increasing T1rho

43 Future Imaging of Liver Fibrosis T1rho Mapping Healthy controls (n=7) vs. liver fibrosis (n=7), 1.5T Singh A, et al. J Transl Med 2015; 13:292

44 Future Imaging of Liver Fibrosis T1rho Mapping kpa = 1.89 T1rho = 52.6 msec kpa = 1.93 T1rho = 62.5 msec

45 Conclusions No single imaging test is perfect Inflammation & fibrosis commonly confound each other MRI of future increasingly multi-parametric, quantitative Fibrosis, fat, inflammation, iron, etc. Multiple emerging quantitative measures of liver fibrosis is something to be excited about!

46 Acknowledgments Suraj Serai, PhD CCHMC Andrew Trout, MD CCHMC Others: Stavra Xanthakos, MD, MSc (CCHMC Peds GI; Director, Steatohepatitis Center) Alexander Miethke, MD (CCHMC Peds GI; Director, Autoimmune Liver Disease Center; Director, Liver Transplant Program) Diana Lindquist, PhD (CCHMC Imaging Research Center)