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Quantitative MRI Biomarkers of Fibrosis
Hans Popper Hepatopathology Society Baltimore, MD
March 3rd, 2013 Scott B. Reeder, MD, PhD
Department of Radiology University of Wisconsin
Madison, WI
Outline • Quantitative Imaging Biomarkers (QIB) • Fatty liver disease • MR Elastrography and Liver Fibrosis
Quantitative Imaging Biomarkers
• Biomarker = Biological marker – Objective indicator of a biological,
pathological or pathogenic process • Imaging biomarker
– Imaging-based objective indicator of a biological, pathological or pathogenic process
4.5 mm2/s 0 mm2/s
ADC Map 300s-‐1
0s-‐1
195s-‐1
R2* Map
100% 0%
Fat-Fraction Map
How do Imaging Biomarkers Differ from Conventional Biomarkers?
Parametric Maps Quantity and distribution of biomarker
What Makes a QIB Valid? • Accurate
– Good correlation with an accepted reference standard • Precise (repeatability)
– Repeatability within subjects (low variability)
• Reproducible – Low variability across sites and platforms
• Robust – Insensitive to platform and scan parameters
• Clinical Utility – Must have an important clinical application
Quantitative Imaging Biomarkers: Translating Invention to Reality
Idea Quantitative Biomarker
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Quantitative Imaging Biomarkers: An Incomplete List
Physiological Parameter
Imaging Method Biomarker
Hemodynamics Phase Velocity MRI v, Q, ΔP, wall shear stress, etc
Tissue Cellularity DWI ADC
Triglyceride Concentration
Chemical Shift Based Water-Fat Imaging Fat-Fraction
Iron Concentration R2/R2* relaxometry R2, R2* Fibrosis MR Elastography Shear stiffness
Tissue Perfusion DCE, DSC ktrans, fa, Vd
Fascicular tissue structure Diffusion Tensor Imaging Fractional anisotropy,
Axial/Radial diffusivity
Macromolecule Content
Quantitative Magnetization Transfer
bound pool fraction, exchange rate, T2 bound pool
Case: 61yo obese female
• Obese, type II diabetes • No known liver disease, No EtOH • Presents with cryptogenic cirrhosis • Develops HCC 1 year after presentation • Necessitated liver transplant Presumed Etiology: Non-Alcoholic Fatty Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD) • First described by Ludwig et al (Mayo Clin Proc 1980) • Most common cause of chronic liver disease
– 30% of people in the USA (100 million) have fatty liver disease (Harrison et al, ClinLivDis 2004)
– 10% of all children have fatty liver disease (Schwimmer et al, Semin Liver Dis 2007)
• Fatty liver can progress to injury and scarring, leading to – Cirrhosis – Liver failure – Hepatocellular carcinoma (HCC)
• Fatty Liver Disease: a feature of the “Metabolic Syndrome” – Obesity, Diabetes (type II) – Increasing cause of cancer, cardiovascular disease, ? Diabetes type II – Underlying etiology: Insulin Resistance
Non-Alcoholic Fatty Liver Disease
Prevalence of Childhood Obesity in the USA, 1971-2006
At the University of Wisconsin, fatty liver disease is … - 2nd leading cause of liver failure - 3rd leading indication for liver transplantation - Expected to be the leading cause of liver failure in a decade
Fatty Liver Disease: Terminology
NAFLD
NASH - Steatosis - Ballooning degeneration - Inflammation - Fibrosis
- Isolated Steatosis
NASH has worse prognosis, but isolated steatosis is not “benign” or “simple”
NASH is aggressive subset of NAFLD
Key Clinical Issues: • Identification of NASH • Risk factors for progression to NASH
Necrosis, Inflammation
Cirrhosis
Cx
Fibrosis
Initial Abnormality (Fat, Iron, Infection, etc.)
5-40
yea
rs
Portal HTN Liver failure
HCC Death
Slide courtesy Claude Sirlin, MD
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• Biopsy – Expensive – Risky (death 1:10000, hospitalization 1:1000) – Sampling errors
• Liver disease is patchy • Sampling 1/50,000th of the organ inherently flawed • Agreement between two adjacent biopsies = 62% (Ratziu et al 2005)
– Utility of biopsy very limited in children • Missed or delayed diagnosis
Current Diagnosis of Fatty Liver
Biopsy 1 Biopsy 2
Same Patient
Histology images courtesy Claude Sirlin, MD
MRI Biomarkers of Fibrosis
• Diffusion weighted imaging (DWI) – Measures apparent diffusion coefficient (ADC) – Utility undetermined – Animal models suggest measurable effect is from differences
in perfusion with cirrhosis, not fibrosis – Koinuma et al, JMRI 2005
• Double contrast (SPIO and Gd) excellent method for advanced fibrosis – Aguirre et al Radiology 2006
• MR Elastography …
MR Elastography Driver MRE sequence Inversion
Wave Images Elastogram Conventional
MR Image Courtesy Richard Ehman, MD Mayo Clinic
MR Elastography: Overview
• Concept: image mechanical waves in tissue by phase-locking microscopic motion with gradients to amplify motion in phase images
• Use a mechanical driver to create shear waves in tissue at same frequency as an oscillating gradient – Phase lock the gradients with the motion
• Phase images will reveal underlying wavelength which is directly related to tissue stiffness
• First described by Muthupillai, Ehman et al (Mayo Clinic, Rochester, MN) in Science 1995
Acoustic Driver
Shear waves propagate through
the tissue
Displacement is very small (microns)
x (cm)
MRE: Phase Locking Motion and Gradients
Microscopic Motion (µm)
Phase of Spin
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MRE: Phase Locking Motion and Gradients
Motion
Motion Encoding Gradient
Slice Selection
Readout
Trigger Delay
MRE: Phase Locking Motion and Gradients
Motion
Motion Encoding Gradient
Slice Selection
Trigger Delay
Flip Motion Encoding Gradient
Readout
MRE: Phase Locking Motion and Gradients MRE: Phase Locking Motion and Gradients
Motion
Motion Encoding Gradient
Slice Selection
Readout
Trigger Delay Delay
MRE: Phase Locking Motion and Gradients
Wavelength
MRE: Wavelength
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MRE: Wavelength and Stiffness
Measurement of wavelength is required to measure tissue stiffness
( ) ρλµ 2f=
Shear stiffness (kPA)
Mechanical Frequency
Wavelength
Tissue Density Velocity
-90 0 +90 Displacement (µm)
Vibrations Applied (90 Hz) Shear Waves Imaged
Total Acquisition Time: 20 - 40 sec
Courtesy Richard Ehman Mayo Clinic
0 5 10 Shear Stiffness (kPa)
MR Elastogram – Normal Liver
ROI mean: 1.8 kPa (Normal: <2.9 kPa)
Courtesy Richard Ehman Mayo Clinic
-90 0 +90 Displacement (µm)
Chronic Liver Disease - ? Fibrosis Shear Waves Imaged
Courtesy Richard Ehman Mayo Clinic
0 5 10 Shear Stiffness (kPa)
MR Elastogram Shows Liver Fibrosis
ROI mean: 5.6 kPa (Normal: < 2.9 kPa)
+ Heterogeneity
Courtesy Richard Ehman Mayo Clinic
Study of 35 Normal Volunteers and 48 Patients with Chronic Liver Disease
0
2
4
6
8
10
Shea
r Stif
fnes
s (kP
a)
Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
Normal Chronic Liver Disease
9
7
5
3
1
20 kPa
0
10
(35) (14) (6) (5) (5) (18)
Yin et al 2007 Clin Gastroenterol & Hepatol
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Performance of MRE: Accuracy for Detection of Fibrosis
Comparison Cutoff (kPa) Specificity Sensitivity
Normal vs All Patients (F0-4) 2.93 98% 99%
F0,1 vs F2,3,4 4.89 86% 85%
F0,1,2 vs F3,4 6.47 78% 96%
F0,1,2,3 vs F2 6.47 89% 90%
Yin et al 2007 Clin Gastroenterol & Hepatol
Fibrosis & Inflammation: Increased Stiffness
• Relationship between fibrosis and stiffness established • Other factors also impact stiffness - Steatosis? Probably no (Yin et al 2007 Clin Gastro & Hepatol) - Inflammation, edema - Portal venous pressure, blood flow
o No impact in normals o Increased flow accentuates stiffness in cirrhosis (Yin)
Stiff Liver = Abnormal Liver
Fibrosis & Inflammation: Increased Stiffness
How to differentiate isolated steatosis from NASH? Does a fatty liver with increased stiffness = NASH? Does a fatty liver with normal stiffness = isolated steatosis?
Hypothesis: can MRE differentiate isolated steatosis from NASH?
Case: 27 yo male with increased AST/ALT, BMI = 27kg/m2
ALT = 241, AST = 79 : grade 3 steatosis (95%), no evidence of steatohepatitis
28% fat
T2*=27ms
Stiffness 1.9kPa
MRE Wave Images Elastogram
Fat-fraction image R2* Map
100%
0%
200 s-1
0 s-1
Case: 46yo M elevated AST/ALT, 36 lbs weight gain (4 years), presumed NAFLD Clinical Question - NASH vs Steatosis?
Opposed-Phase In-Phase
Case: 46yo M elevated AST/ALT, 36 lbs weight gain (4 years), presumed NAFLD Clinical Question - NASH vs Steatosis?
43% Fat
Stiffness 3.5kPa
Biopsy: Grade 3 steatosis, stage 1 fibrosis
10kPa
0 kPa
MRE Wave Images
Elastogram
Fat-fraction image
100%
0%
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Case: 51yo F Acute Alcoholic Steatohepatitis
CT
T2W SSFSE
In-phase Opposed Phase
Hepatomegaly
Steatosis
HU = 16 (non-con)
Case: 51yo F Acute Alcoholic Steatohepatitis
Biopsy: Grade II-III steatohepatitis, Stage III fibrosis, Grade III steatosis (80% of cells)
31% Fat
Stiffness 12kPa
MRE Wave Images
Elastogram
Fat-fraction image
100%
0%
Out of Phase In Phase
T2 with Fat-Sat Coronal T2 SSFSE
Case: 10 yo boy with abdominal pain
100%
0%
200 s-1
0 s-1
Case: 10 yo boy with abdominal pain
10kPa
22% 40ms
Biopsy: severe steatohepatitis with severe fibrosis, just short of cirrhosis
Grade 2 steatosis, Grade 3 steatohepatitis, stage 3-4 fibrosis Findings and clinical history consistent with NASH
Case: 10 yo male with abdominal pain
100%
0%
200s-1
0s-1
31%
3.6kPa
20ms
Case: 16 yo girl with PCOS
Biopsy: severe steatohepatitis with mild fibrosis
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Outline • Quantitative Imaging Biomarkers (QIB) • Fatty liver disease • MR Elastrography and Liver Fibrosis
Thank you! • Rashmi Agni, MD • Jean Brittain, PhD • Chris Francois, MD • Alex Frydrychowicz, MD • Diego Hernando, PhD • Jen Kuhn, MD • Ben Landgraf • Alejandro Roldan, PhD • Oliver Wieben, MD • Emily Winslow, MD • Huanzhou Yu, PhD
Grant Support • WARF Accelerator • NIH: R01 DK083380
R01 DK088925 R01 DK096169 RC1 EB010384