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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