MRI: What Can It Deliver - Virology Educationregist2.virology-education.com/2017/NASHbiomarkers/11_Sirlin.pdf · MRI: What Can It Deliver Claude B. Sirlin, MD ... GE, Guerbet, Bayer,

MRI: What Can It Deliver

Claude B. Sirlin, MD

Liver Imaging Group, Dept. of Radiology

University of California, San Diego

[email protected]

2nd International

NASH Biomarkers WorkshopWashington, DC May 5, 2017

Email me for PPT:[email protected]

Industry grant support

Siemens, GE, Guerbet, Bayer, Philips

Consulting and service agreements

Alexion, AstraZeneca, Bioclinica, BMS, Bracco, Fibrogen,

Galmed, Genentech, Genzyme, Gilead, Icon, Intercept, Isis,

Janssen, NuSirt, Perspectum, Pfizer, Profil, Sanofi, Shire,

Synageva, Tobira, Takeda, Virtual Scopics

Federal grant support

U01 DK061734, R01 DK106419, R01 DK088925, T32

EB005970, R01 DK088831

Disclosures

Today• Body composition

• Proton density fat fraction (PDFF)

• Corrected T1

• “Stiffness”

Tomorrow• Beyond “stiffness”

The future• Pie in the sky

• Intrinsic meaning

What Can MRI Deliver

< 30 min


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Body Composition

Magnus BorgaOlof Leinhard

MRI-based whole body composition profiling

Advanced MR Analytics (AMRA)

Feasible and Precise

Exam = 5-10 minutes

Exam = 5-10 minutes

Exam = 5-10 minutes

Manual analysis = 15 hours



Exam 1 Exam 2 Exam 3

Semi-automated analysis = minutes; coefficient of variation 1.5-3.6%

Body Composition

Weight loss BMI 41 kg/m2 BMI 33 kg/m2 BMI 30 kg/m2

VAT 5.7 L VAT 4.1 L VAT 3.1 L

SCAT 18.3 L SCAT 12.0 L SCAT 9.7 L

Longitudinal monitoring

Body Composition

Today•


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PDFF

Proton Density Fat Fraction (PDFF)

S(TE) = [W + F rpei 2p DfpTE

p=1

P

å ]ei 2p yTEe-TE T2*

Hero HussainW Tom Dixon Takeshi YokooMark Bydder Michael Middleton Gavin HamiltonScott Reeder Huanzhou Yu Jean Brittain An Shimakawa

PDFF = proportion of all MRI visible protons from fat

Water Fat

PDFF

PDFF = proportion of all MRI visible protons from fat (triglyceride)

Steatosis Triglyceride

PDFF

≈wikipedia/Trimyristin-3D-vdW

Proton density fat fraction50%: ~ maximum PDFF in human liver

3%: metabolic syndrome

5.5%: 95th percentile in normals

6.5%: hepatic steatosis

0% 100%

Lidia Szczepaniak, PhD

Jennifer Rehm, MD

An Tang, PhD

PDFF

Two Basic Approaches

Magnitude data-based MRI Complex data-based MRI

40 40

373640 41

38 3938 39 4039

3637

3638

928

100% 100%

0% 0%

PDFF

Magnitude data-based MRI Complex data-based MRI

40 40

373640 41

38 3938 39 4039

3637

3638

100%

0%

Two Basic Approaches100%

0%

PDFF

1.5TSiemens

3TGE

Geri Kang et al. JMRI 2011 Children & Adults with NAFLD

Liver proton density fat fraction is “portable”PDFF

Baseline T = 2 weeks T = 1.5 months T = 3.5 months T = 6.5 months

20.5% 17.2% 8.1% 6.5% 6.3%

Liver proton density fat fraction can monitor change longitudinally

100%

0%

50%

PDFF

Liver proton density fat fraction can be used as an endpoint in phase 2 clinical trials

RohitLoomba

PDFF

Today•

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• Corrected T1

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cT1

Corrected T1

Rajarshi Banerjee Stefan Neubauer Matthew Robson

cT1 1055 ms

cT1 906 ms

cT1 869 ms

cT1 733 ms

cT1

Corrected T1

cT1 1055 ms

cT1 906 ms

cT1 869 ms

cT1 733 ms

Ishak6

Ishak3

Ishak2

Ishak0

600 ms 1200 ms≥ 800 ms

cT1

Corrected T1

Mixed population (viral hepatitis n=31, FLD n=31, other n=17)

Detection of any diseaseCutoff cT1 ≥ 800 msAUROC 0·94sensitivity 86% specificity 93%

Journal Hepatology Volume 60(1): 69-77 (2014)

cT1

T1corrections

cT1

cT1

1200 ms

600 ms

Free Water

Edema

Watery fibrosis

Bound Water

Collagen

Glycogen

cT1

Theory

Question: can cT1 separate the opposing effects of free and bound water?

Today•

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• “Stiffness”

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Stiffness

“Stiffness”

Phil RossmanDick Ehman Raja Muthupillai

29 September 1995

Stiffness Ability to resist deformation from external pressure

Slide concept adapted from www.physicstutorials.org

Pressure Pressure

Stiff

Pressure Pressure

Not Stiff

Stiffness

http://www.physicstutorials.org/

How do you measure stiffness without palpation?

Sound (waves) travels faster through solid ground (hard) than through air (soft)

http://www.corbisimages.com/stock-photo/rights-managed/DEC452-14/indian-scout-putting-his-ear-to-ground

Stiffness

Shear Wave Propagation in Liver

Stiffness

MR Elastography Diagnoses Advanced Fibrosis

“Stiffness” cutoff: 3.63 kPaSensitivity 0.86Specificity 0.91

Loomba et al 2014

Dick EhmanRohit Loomba David Brenner

Anthony Gamst Jonathan HookerAUC for diagnosis of advanced fibrosis

0.924

Stiffness

Singh et al 2015

MR Elastography Not Sensitive to Early Fibrosis

Meta-Analysis

• 12 Studies• 697 patients

Stiffness

Stiffness

NASH: Advanced Fibrosis

Collagen Stiffness

NASH: Early Fibrosis

Conventional MRE (“stiffness”) cannot differentiate mild fibrosis from inflammation

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Beyond Stiffness

Beyond Stiffness

Beyond Stiffness

Beyond Stiffness Stiffness has elastic and viscous components

Slide concept adapted from www.physicstutorials.org

Pressure Pressure

Elastic

Returns to original size and shape

Pressure Pressure

Viscous

Does not return to original size and shape

Pressure released Pressure released

http://www.physicstutorials.org

Beyond Stiffness

Elastic Viscous

bouncy ball silly putty


Beyond Stiffness

Elastic Viscous

Fibrosis Inflammation


Beyond Stiffness 3D MR elastography analyzes wave motion in all 3 planes

Beyond Stiffness

Shea

r St

iffn

ess

(kP

a)

0

5

2

3

4

1

X Y Z |G*|

Slide courtesy of Meng Yin, PhD

Beyond Stiffness 3D MR elastography analyzes wave motion in all 3 planes

Beyond Stiffness

Dick Ehman Meng Yin

stiffness. As shown in

Figures 5 and 6, G’ typically dominates G”, and

the normal damping ratio is

small. 3D-MRE also can be

processed to filter out the shear waves, leaving only

the longitudinal data.

Inversion of this data can generate maps of the bulk

modulus or “volumetric

strain” (ev), a marker of compressive deformation.

ev has been shown to correlate with portal pressure78, and so may

provide insights into

NAFLD pathophysiology,

which this application will explore. In summary, 3D-MRE can generate

multiparametric maps of mechanical properties (|G*|, G’, G”, ζ, ev), as shown in two examples of obese patients with NAFLD (Figure 6). The relevant

technology is operational at UW and UCSD.

Multiparametric 3D-MRE Detects NASH in Animal Models. In mouse

models of NASH79, one of our co-investigators, Dr. Yin, showed that hepatic

inflammation correlates with the loss modulus G”, while fibrosis correlates with the storage modulus G’25. Similarly, she observed that G” and the damping

ratio are elevated in early NASH. This permitted detection of NASH prior to

fibrosis development (Figure 7). Since the storage modulus, G’, is the dominant component of G*, the shear stiffness |G*| is relatively insensitive to

inflammation, which may explain the limited efficacy of 2D-MRE for detecting

early NASH. By comparison, multiparametric 3D-MRE quantifies inflammation-

sensitive parameters (G”, damping ratio), potentially permitting early NASH detection. This will be examined in our proposed study.

Complex Modulus Depends on Frequency: Optimization & Opportunity.

i) Optimization of single best frequency to quantify complex modulus: Mechanical frequency is a key determinant of the quality and analyzability of

the wave field. Maximizing wave quality is particularly important in obesity,

because large body habitus may hinder wave propagation. Previous work by our group has shown that frequencies below 30Hz generate shear waves prone to interference effects and are

unreliable (unpublished), while frequencies above 75 Hz result in rapid80,81. Thus, the optimal frequency for

MRE is thought to be in the 30-75 Hz range but the single optimal frequency is unknown, a knowledge gap that

Phase 1 will address.

ii) Opportunity to examine the dispersion of viscoelastic parameters of liver: Frequency also affects the

magnitude of MRE mechanical parameters, a phenomenon known as “dispersion”. For most tissues, |G*|, G’,

and G” increase as the shear wave frequency increases. Importantly, different tissues and pathologic conditions (normal liver, inflammation, fibrosis) have different dispersion characteristics. Multifrequency MRE

enables dispersion characterization, potentially assisting in the discrimination between inflammation, fibrosis,

and other processes. Numerous physical models have been proposed to model dispersion based on underlying assumptions of viscoelastic properties of tissue. An incomplete list includes Voigt, Maxwell, Zener,

Jeffreys, fractional Zener, springpot-1, springpot-2, springpot-3, and fractional derivative models82-84. These

models quantify numerous viscoelastic parameters some of which correlate with the fibrosis, primarily in viral

hepatitis11

. To date, there are no published data using multifrequency dispersion to evaluate obesity-associated NAFLD in humans.

A problem with measuring viscoelastic dispersion is that they typically require MRE acquisition at three or

more frequencies, limiting clinical practicality. Dr. Yin recently showed, however, that multifrequency dispersion

Figure 6: 3D-MRE can quantify multiparametric mechanical properties of liver in obesity.

Magnitude images and maps of complex shear modulus (G*=G’+iG”), damping ratio (ζ

=G”/(2G’)), and volumetric strain (ev), acquired at 60Hz are shown. Patient 1 (top row,

23yo F, BMI=44kg/m2) has NASH but no fibrosis at biopsy. Liver “stiffness” (|G*|) is

normal. Damping ratio (ζ) is elevated (based on preliminary data, normal ζ≈0.05-0.08).

Patient 2 (bottom row, 28yo F, BMI=43 kg/m2) has NASH with stage 4 fibrosis. Liver

“stiffness” (|G*|) and damping ratio are both elevated. As illustrated in Patient 1, damping

ratio shows promise for detecting NASH even if overall stiffness is normal.

Figure 7: Mouse model of NASH. Damping ratio detects NASH prior to fibrosis development. Liver stiffness (|G*|) detects fibrosis.

Data obtained in mice fed fast

food diet for 1, 24, and 48 weeks

NASH Fibrosis No liver injury

Da

mp

ing

R

ati

o

1

2

3

Sti

ffn

es

s

(kP

a)

1

2

2.5

1.5

Inflammation?Fibrosis

Beyond Stiffness 3D MR elastography measures multiple tissue parameters

Beyond Stiffness

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Future

https://media.licdn.com

Pie in the sky• Automation

• Blood flow

• Liver function

• Fat composition

• Glycogen content

• Fibrogenesis

• Fibrolysis

• Portal pressure

• Pancreatic beta cell function

• Metabolic pathways

• Stellate cell activation

• Mitochondrial function

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The future•



Future

Intrinsic meaning50

0

%

PDFF 25.0%

Chemical Shift MRI

8

0

kPa

Shear stiffness 3.23 kPa

MRE

LIF

Liver Inflammation and Fibrosis Score 2.7

Liver MultiScan

Steatosis Fibrosis

https://upload.wikimedia.org/wikipedia/commons/8/8a/Steatohepatitis_high_mag.jpg

Inflammation and Fibrosis

PDFF Shear stiffness Corrected T1

•MRI measurements no intrinsic meaning

•Must be translated into a histology score

Current Paradigm

Future

Intrinsic meaning50

0

%

PDFF 25.0%

Chemical Shift MRI

8

0

kPa

Shear stiffness 3.23 kPa

MRE

LIF

Liver Inflammation and Fibrosis Score 2.7

Liver MultiScan

PDFF Shear stiffness Corrected T1

•MRI measurements acquire intrinsic meaning

•Do not have to be translated into a histology score

FutureParadigm

[Triglyceride] within

MRI visible protons

Elastic and viscous components of shear stiffness

Water content within

MRI visible protons

Outcomes

Future

Intrinsic meaning

StiffnessElasticity

PDFFcT1

Beyond stiffness

Tetri Grid

Future

Intrinsic meaning

StiffnessElasticity

PDFFcT1

Beyond stiffness



• Corrected T1

• “Stiffness”





Documents

MRI: What Can It Deliver - Virology Educationregist2.virology-education.com/2017/NASHbiomarkers/11_Sirlin.pdf · MRI: What Can It Deliver Claude B. Sirlin, MD ... GE, Guerbet, Bayer,