Magnetic resonance imaging of hepatic fibrosis - Wiley Online Library

Magnetic Resonance Imaging of Hepatic Fibrosis: Emerging Clinical Applications Jayant A. Talwalkar,1 Meng Yin,3 Jeff L. Fidler,1,3 Schuyler O. Sanderson,2 Patrick S. Kamath,1 and Richard L. Ehman3 Chronic liver disease and cirrhosis remains a major public health problem worldwide. While the majority of complications from chronic liver disease result from progressive hepatic fibrosis, the available diagnostic tests used in clinical practice are not sensitive or specific enough to detect occult liver injury at early or intermediate stages. While liver biopsy can stage the extent of fibrosis at diagnosis, its utility as a tool for longitudinal monitoring will be limited at the population level. To date, a number of methods including serum marker panels and ultrasound-based transient elastrography have been proposed for the non-invasive identification of hepatic fibrosis. Novel techniques including magnetic resonance (MR) spectroscopy, diffusion weighted MR, and MR elastography have also emerged for detecting fibrosis. In contrast to other non-invasive methods, MR imaging holds the promise of providing functional and biological information about hepatic pathophysiology as it relates to the natural history and future treatment of hepatic fibrosis. (HEPATOLOGY 2008;47:332-342.)

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hronic liver disease and cirrhosis remains a major public health problem worldwide. In the United States during 2004, disease-related complications were associated with nearly 40,000 deaths1 and greater than 1.4 billion dollars being spent on medical services.2 Furthermore, these trends are expected to increase based on an aging population, the growing epidemic of obesity, and the continued emergence of clinical manifestations among individuals with longstanding chronic hepatitis C infection.3,4 In terms of patients as well as populations, there remains a great need to develop and identify methods of risk stratification and prognosis for individuals with chronic liver disease. To date, the noninvasive diagnostic tests available from clinical practice are not sensitive or specific enough to function as screening tests for detecting occult yet significant liver Abbreviations: ADC, apparent diffusion coefficient; ATP, adenosine triphosphate; HVPG, hepatic venous pressure gradient; MR, magnetic resonance; MRI, magnetic resonance imaging; PDE, phosphodiesters; PME, phosphomonoesters; RF, radio frequency; SPIO, superparamagnetic iron oxide; T, tesla. From the 1Advanced Liver Diseases Study Group, Miles and Shirley Fitterman Center for Digestive Diseases, the 2Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, and the 3Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN. Received January 22, 2007; accepted August 8, 2007. Supported by grant number RR024151 (to J.A.T.) and grant number EB01981 (to R.L.E) .from the National Institutes of Health (NIH) Address reprint requests to: Jayant A. Talwalkar, MD, MPH, Associate Professor of Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]; fax: 507-284-0538. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21972 Potential conflict of interest: Nothing to report. 332

injury. In turn, this often results in the application of invasive procedures such as liver biopsy and hepatic venous pressure gradient (HVPG) measurement as diagnostic tests. Given the inability to target the appropriate use of these procedures for asymptomatic patients at high risk for progressive disease, their widespread application and clinical usefulness will remain hampered by issues related to procedure-related complications, patient acceptance, and cost. Nevertheless, there remains an opportunity to improve the detection rate of individuals with progressive fibrosis who might benefit from early intervention. In this regard, the development of several noninvasive methods to detect the major consequences of chronic hepatic injury has been ongoing. Although most recent investigations have focused on serum indices (indirect and direct) for detecting hepatic fibrosis, the common thread underlying these studies is that assessments are done in isolation of other manifestations related to chronic liver injury such as inflammation and portal blood flow.5,6

Current Methods for Detecting Hepatic Fibrosis Liver Biopsy. To date, liver biopsy has been the gold standard for detecting hepatic fibrosis. However, the focus in clinical practice today has shifted from diagnosis to risk stratification and monitoring. For many situations, the application of conventional and disease-specific laboratory and imaging tests allow for the recognition of entities such as chronic viral hepatitis and nonalcoholic fatty liver disease. Distinguishing nonalcoholic steatohepatitis from nonalcoholic fatty liver disease or determining ex-

HEPATOLOGY, Vol. 47, No. 1, 2008

tent of fibrosis in hepatitis C for consideration of treatment are more common indications for liver biopsy. Most classification systems recognize 5 stages of fibrosis, graded as F0 (no fibrosis), F1 (portal fibrosis), F2 (periportal fibrosis), F3 (bridging fibrosis), and F4 (cirrhosis). Clinically significant fibrosis is generally defined by F2 involvement or greater. However, a number of studies have demonstrated excessive rates of sampling error (25%-40%) resulting in poor reproducibility regardless of underlying liver disease origin.7 In addition, the extent of variation from observer interpretation by expert histopathologists may be as high as 20%.8 However, there is mounting evidence that liver biopsy has a number of limitations for its use in these roles as well. These include (1) the effect of reduced biopsy size (⬍25 mm) and complete portal tract number (⬍11) on understaging fibrosis: (2) interobserver variation in histological interpretation; and (3) the qualitative nature of assessing fibrosis in 2 dimensions with descriptive staining techniques. Existing histological scoring systems such as the Ishak9 and Metavir 10 classifications provide a semiquantitative assessment of fibrosis extent, which, in theory, has the potential to allow for serial assessments to document progression. However, there has been little documentation of strong reproducibility for existing methods despite their widespread use in clinical practice and controlled trials. Finally, these limitations make reliable and valid serial assessments to document progressive fibrosis nearly impossible to perform.11 Although computerized image analysis protocols may offer the potential for quantitative analysis of liver fibrosis,12 this method requires further study to provide standardized approaches to ensure reliability.13 Ultimately, the method of percutaneous liver biopsy is an invasive procedure with poor acceptance by patients. The associated morbidity from this technique is estimated at 3% with a mortality rate of 0.03%.14 In turn, the strict requirement for using liver biopsy will not allow for the ability to assess populations at risk. Despite these concerns, the assessment of prognostic histological features including degree of steatosis and inflammation can only be provided by histology from liver biopsy.11,12 Most current imaging strategies looking at fibrosis, however, have been unable to decipher these histological correlates separately.15 Serum Markers. A number of serum markers representing the process of hepatic fibrosis have been studied. However, most of these studies are limited by retrospective study designs, low rates of liver biopsy reproducibility, and the inclusion of patients with a narrow spectrum of disease severity. In turn, a number of indices contain parameters that only correspond to an indirect assessment rather than to direct quantification of hepatic fibrosis.15,16

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Nevertheless, the detection of advanced fibrosis with more recent serum marker panels has been considered good to excellent among individual studies. Combined indirect and direct serum marker panels can avoid the need for liver biopsy in up to 50% of cases.5,15 The detection of intermediate fibrosis has been most difficult for most assays.15 Pooling estimates from selected studies, however, is noted for between-study heterogeneity and only modest diagnostic power in providing a diagnosis.16 Based on its potential for widespread clinical availability and economic cost, there would be incentive to enhance the diagnostic performance of serum marker tests. Emerging data have shown that a sequential algorithmtype approach to improve the posttest likelihood of detecting advanced fibrosis may be more effective than application of a single test alone.17 Conventional Imaging Techniques. Advances in cross-sectional imaging that focus on detecting hepatic morphologic alterations and features of portal hypertension can be used to identify cases of established cirrhosis. However, the ability to detect early and intermediate stages of fibrosis with these techniques remains limited.18 Conventional ultrasound with standard Doppler assessment of the hepatic vasculature is insufficient for detecting early and intermediate stages of fibrosis.19,20 Emerging data on hepatic vein blood flow pattern assessment by Doppler21 or contrast-enhanced22 methods suggest that notable improvements in detecting advanced fibrosis or cirrhosis are possible. Helical and multidetector row computed tomography provide improved resolution of early morphological changes with cirrhosis (in the absence of portal hypertension) but remain unhelpful with respect to fibrosis detection.23 Specific features on magnetic resonance imaging (MRI) including hepatic vein narrowing,24 caudate to right lobe ratio,25 and expanded gallbladder fossa,26 reliably identify cirrhosis but remain absent in earlier stages of fibrosis.

Novel MR Applications for In Vivo Detection of Hepatic Fibrosis Over the past decade, a number of technological advances have been made in developing clinical applications for MRI of the liver. Recent improvements have focused on exploiting the physiological and biomechanical properties of human liver tissue to improve the detection of focal and diffuse pathological conditions. Contrast-Enhanced Magnetic Resonance Imaging. The introduction of breath-hold sequences with gadolinium chelates have facilitated the development of dynamic contrast-enhanced imaging of the liver in clinical practice.27,28 In turn, a number of studies have described changes in hepatic parenchyma texture after contrast-enhanced imaging by

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Table 1. Summary of Contrast-Based MRI Investigations for Detecting Hepatic Fibrosis in Human Subjects Author

Year

Method

MR Hardware

Elizondo et al.

1990

SPIO

0.3 T Body coil

Yamashita et al.

1996

SPIO

1.5 T Body coil

Hundt et al.

2000

SPIO

Semelka et al.

2001

Gd

1.5 T Circular polarized body coil 1.5T Body coil

Tanimoto et al.

2002

SPIO

1.5 T Torsoarray coil

Lucidarme et al.

2003

SPIO

1.5 T Body or torso coil

Aguirre et al.

2006

Gd ⫹ SPIO

1.5 T Anterior, posterior phase array coils

Major Etiologies

MR Technique

N

Spin echo ROI 250 pixels 60 min post infusion Spin echo

7 patients 8 normal

N/A

Biopsy

Ref Std

Cirrhosis

Outcome

Reduced SNR in normal versus compensated cirrhosis versus decompensated cirrhosis

Results

11 patients 2 normal

n/a

Clinical and Biopsy

GRE, FSE ROI 0.6 cm2 15 min SGE, HASTE 45s, 90s, and 10 min GRE, FSE ROI 0.6 cm2 40,109 min FSE, GRE 60 min ROI 256 or 512 pixels Spin echo, SGE 30 min after SPIO 180 s after Gd


Alcohol Viral

Biopsy

Serum tests, fibrosis stage Cirrhosis

29 patients

Various

Biopsy

Fibrosis stage

No significant correlations between SNR and fibrosis stage / serum tests Reduced SNR in normal versus cirrhosis Reduced SNR across CTP class Gd enhancement patterns correlated with inflammation and fibrosis


Viral

Clinical and Biopsy

Cirrhosis

Reduced SNR in normal vs. cirrhosis


Viral Alcohol

Biopsy

Fibrosis stage

Moderate correlation (kappa ⫽ 0.51) between reticular pattern and fibrosis

101 patients

Viral Alcohol

Clinical and Biopsy

Fibrosis stage

Double-enhanced image scores best to detect advanced versus mild fibrosis

Abbreviations: MR, magnetic resonance; Ref Std, reference standard; Gd, gadolinium; SPIO, superparamagnetic iron oxide; T, Tesla; SSEP, single-shot echo planar; N/A, not available; GRE, gradient echo; FSE, fast spin echo, SNR, signal to noise ratio; SGE, spoiled gradient echo; HASTE, half-Fourier acquisition single-shot turbo spin echo; ROI, region of interest; CTP, Child-Turcotte-Pugh

MRI (Table 1).27-35 Early patchy enhancement may correlate with increased numbers of macrophages and necroinflammation on liver histology. In contrast, a delayed, heterogeneous enhancement pattern is associated with bright-appearing reticulations suggestive of hepatic fibrosis.28,29 Reduced distribution of gadolinium in hepatic extracellular spaces may explain this observed finding.28 In contrast, the administration of superparamagnetic iron oxide (SPIO) contrast agents creates hypointensity within liver parenchyma based on its accumulation in reticuloendothelial cells.30-32,34,35 Recently, the sequential administration of gadolinium followed by SPIO contrast media was done to determine whether improved detection of liver fibrosis architecture could be observed (Fig. 1). Although SPIO-based images were highly accurate (85%) for detecting fibrosis compared with histopathological features, the combination of gadolinium-based and SPIO contrast agents yielded even greater accuracy (93%) overall.32 Further refinements in image acquisition, additional validation of semiquantitative fibrosis criteria including nodularity and reticulation stage, and prospective application to verify the diagnostic performance of this technique is anticipated.33 Diffusion-Weighted Magnetic Resonance Imaging. Diffusion-weighted magnetic resonance imaging (DWI) is a technique that assesses the freedom of diffusion of water protons in tissues and has been extensively applied for the early detection of cerebral ischemia. Recent advances have made it feasible to apply diffusion MRI techniques for abdominal imaging.36 In hepatic fibrosis, it is

thought that collagen is not rich in free unbound water. Thus, the accumulation of fibrosis causes a reduction in the amount of water proton diffusion in affected liver tissue.36,37 Recent advances in MRI technology have facilitated the performance of diffusion-weighted MRI of the liver.

Fig. 1. Transverse MR images of liver in 39-year-old woman with METAVIR score of F4 on liver biopsy. Double-enhanced spoiled gradientecho image shows hyperintense reticulations (arrows) in addition to hypointense nodules. Findings are thought to represent regenerating nodules surrounded by fibrotic septal tissue. (Adapted from Aguirre DA, Behling CA, Alpert E, Hassanein TI, Sirlin CB. Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging. Radiology 2006;239:425-437.)


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Table 2. Summary of Diffusion-Weighted MRI Investigations for Detecting Hepatic Fibrosis in Human Subjects Major Causes

Author

Year

Method

MRI Hardware

MRI Technique

n

Girometti et al.

2007

DWI

1.5 T Phased array surface coil and spine array coil

28 cirrhosis 29 normal

Viral Alcohol

Biopsy

Cirrhosis

Koinuma et al.

2005

DWI


Viral

Biopsy or clinical

Fibrosis stage

Aube et al.

2004

DWI

1.5 T Circular polarization body array coil 1.5 T Body coil


Alcohol

Biopsy

Cirrhosis

Boulanger et al.

2003

DWI

1.5 T Body coil

Spoiled GRE SSEP b values: 0, 150, 250, 400 s/mm2 SSEP MPG pulses b values:.01, 128 s/mm2 Spin echoplanar b values: 200, 400, 600, 800 s/mm2 Spin echoplanar b values: 50, 100, 150, 200, 250 s/mm2

Ref Std

Outcome


Hepatitis C

Biopsy

Fibrosis stage

Results Mean ADC lower in cirrhosis (1.11 ⫻ 10⫺3 versus 1.54 ⫻ 10⫺3) Sens 93% / Spec 100% ADC decreased with increasing fibrosis Mean ADC lower in cirrhosis (2.05 ⫻ 10⫺3 versus 2.9 ⫻ 10⫺3) ADC correlated with CTP score, serum HA Mean ADC lower in cirrhosis (2.3 ⫻ 10-3 versus 1.8 ⫻ 10⫺3) No correlation between ADC, inflammation, or fibrosis

Abbreviations: MRI, magnetic resonance imaging; Ref Std, reference standard; Sens, sensitivity; Spec, specificity; DWI, diffusion-weighted imaging; MRE, magnetic resonance elastography; T, Tesla; GRE, gradient echo; SSEP, single-shot echo planar; MPG, motion probing gradient; ADC, apparent diffusion coefficient; n/a, not available; CTP, Child-Turcotte-Pugh; HA, hyaluronic acid.

Previous experience with physiological motion artifacts and poor image resolution have been addressed by the use of faster pulse sequences, cardiac and respiratory triggering, and modifying the acquisition to allow data collection during suspended respiration.38,39 Reported times for breath-holding are usually between 10 and 20 seconds per measurement. Typical examination time for both standard and diffusion-weighted MRI is approximately 45 to 60 minutes. In “diffusion-weighted imaging” the observed signal intensity of tissue varies inversely with the freedom of water proton diffusion. Tissues with reduced water proton diffusion will be brighter than those with normal water proton diffusion, all other factors being equal. The strength of the diffusion weighting is determined by the so-called “b” value of the sequence, which increases with the duration and amplitude of the diffusion sensitizing gradients. If two or more diffusion-weighted images are obtained, then it is possible to calculate the apparent diffusion coefficient (ADC) of water protons in tissues, which is determined by the slope of the log intensity versus b value.39,40 The calculated ADC values can be displayed as an image and quantitative analysis can be performed by placing measuring the mean value within a region of interest, which is typically positioned in the right hepatic parenchyma to avoid major vascular structures. Several reports have described lower ADC value in patients with varying degrees of cirrhosis as compared with healthy individuals undergoing diffusion-weighted MRI (Table 2). Recent studies among patients with varying degrees of chronic liver disease from hepatitis C, however, are mixed with respect to demonstrating a specific relationship between ADC values and fibrosis stage.40,41 Sampling error from liver biopsy may be responsible, in part, for this result.41 Using a single-shot spin-echo planar se-

quence to improve reproducibility of measurement, the mean ADC in patients with cirrhosis was lower compared with healthy individuals. In this experience, a 93% sensitivity and 100% specificity for detecting cirrhosis was associated with a cutoff ADC value of 1.31 ⫻ 10-3 mm2/s.39 Notably, the change in ADC with greater degrees of fibrosis may not be related to reductions in water diffusion. Recent data suggest that decreased ADC values in rodents with hepatic fibrosis were observed in vivo but not when DWI was performed in euthanized rats or fixated livers. This suggests that reduced hepatic perfusion may explain the decrease seen for in vivo ADC values with increasing degrees of fibrosis, which has been theorized when using lower b values.38 Several aspects of diffusion-weighted MRI liver imaging require attention before extending its application in human subjects. Studies have used small numbers of patients and various hardware and sequencing profiles, rendering comparisons between experiences difficult. Significant hepatic iron accumulation may reduce signal intensity so much that diffusion imaging may not be possible in patients with genetic or secondary hemochromatosis.37 Hepatic steatosis may also affect diffusion imaging and impact ADC values unless fat suppression techniques are employed to minimize this phenomenon.39 Reproducibility has not been widely established given the limited experience thus far. Technical factors such as accounting for cardiac motion despite breath-holding as well as employing surface rather than body coils to reduce signal-to-noise ratio are being addressed to allow further study.37,40,41 High-field (3T) imaging also may enhance signal-to-noise ratio, reduce image misregistration, and subsequently improve hepatic ADC detection.42 Magnetic Resonance Spectroscopy. The technique of in vivo magnetic resonance (MR) spectroscopy has been available for over 2 decades to investigate the metabolic

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Table 3. Summary of MRI Spectroscopy Investigations for Detecting Hepatic Fibrosis in Human Subjects MRI Hardware

MRI Technique

N

Outcome

Results

Schlemmer et al.

Author

2005

Year

31P

Method MRS

1.5 T 14 cm 1H/31P surface coil


Alcohol

Biopsy

Fibrosis stage

Lim et al.

2003

31P

MRS



HepatitisC

Biopsy

Fibrosis stage

Cho et al.

2001

31P

MRS

1.5 T No data on body coil


Viral

Biopsy

Fibrosis stage

GPE/GPC, PE/PC, and PME/PDE ratios increase from normal to cirrhosis PME/PDE ratio increased with fibrosis stage Sens 80%, Spec 80% Glx, PME, Glu spectral ratios increased with fibrosis stage

Taylor-Robinson et al.

1997

31P

MRS


31 cirrhosis

Various

Clinical and Biopsy

CTP score

Increased PME and reduced PDE with worsening cirrhosis

Menon et al.

1995

31P

MRS


ISIS TR 1100 ms 500 slice width Voxel 45 ml ISIS TR 800, 10,000 ms Voxel 7 cm3 CSI TR 3000 ms NA 128 Voxel 8 cm3 CSI TR 500 ms NA 80 30 mm slice width CSI TR 500 ms NA 80 30 mm slice width

Major Causes

Ref Std


Various

Biopsy

Cirrhosis

Van-Wassenar et al.

1995

31P

MRS



Various

Clinical and Biopsy

Jalan et al.

1995

31P

MRS



PBC

Clinical

Serum enzymes, histology CTP Score

Munakata et al.

1993

31P

MRS


ISIS TR 1500 ms NA 256 Voxel 200-500 ml CSI TR 500 ms NA 80 30 mm slice width CSI TR 500 ms


Various

Clinical

Cirrhosis

Increased PME/PDE, PME/ATP and lower PDE/ATP in cirrhosis Higher Pi/ATP in viral disease PME/P correlation with AST, and inflammation No relationship with fibrosis. Spectral ratios higher in cirrhosis PME/Pi correlates with CTP score Increased PME with worsening cirrhosis

Abbreviations; MRI, magnetic resonance imaging; Ref Std, reference standard; Sens, sensitivity; Spec, specificity; 1H, labeled hydrogen; 31P, labeled phosphorus; ISIS, image selected in vivo spectroscopy; TR, repetition time; NA, number of acquisitions; PBC, primary biliary cirrhosis; CSI, chemical shift imaging; PME, phosphomonoester; Pi, inorganic phosphate; Glx, glutamate; Glu, glucose; GPE, glycerophosphorylethanolamine; GPC, glycerylphosphorylcholine; PE, phosphoethanolamine; PC, phosphocholine; PDE, phosphodiester; ATP, adenosine triphosphate; P, inorganic phosphorus; n/a, not available; CTP, Child-Turcotte-Pugh; HA, hyaluronic acid; MRE, magnetic resonance elastography.

processes of organ tissue.43 Based on its anatomical location and increased metabolic demands, the liver is considered an ideal organ for MR spectroscopy investigation.44,45 In vivo MR spectroscopy is most commonly used to assess signals from hydrogen (1H) and phosphorus (31P). Although 1H-based MR spectroscopy allows for quantification of certain metabolites and lipids, 31P-based MR spectroscopy provides insights on processes including cell turnover and energy state based on substantial concentrations within hepatocytes.43-45 Within the spectrum of 31P compounds, 6 discrete signals have frequently been analyzed by MR spectroscopy in human subjects, including (1) phosphomonoesters (PME), (2) inorganic phosphate, (3) phosphodiesters (PDE), (4) adenosine triphosphate (ATP), alpha-ATP, and beta-ATP. The chemical precursors phosphocholine, phosphoethanolamnine, adenosine monophosphate, and glycolytic intermediates such as glucose-6-phosphate contribute to the PME peak. Glycerophosphorylcholine, glycerophosphorylethanolamine, and mobile phospholipids from the endoplasmic reticulum are the main components of the PDE peak. Both PME and PDE appear to provide information on cellular degradation.46,47 The methodology used for performing MR spectroscopy has varied over time and between studies. MR spectroscopy of the liver is performed using a whole body MRI system at field strengths of 1.5 Tesla (T) or higher. Once typical contraindications for MRI are excluded, the patient lies supine on the MRI table with RF coils posi-

tioned appropriately. After a standard MR imaging for localization, special MR pulse sequences are applied to generate spectroscopic data within the appropriate anatomical location and volume (defined by voxels) of interest. As with diffusion-weighted imaging, a typical examination will take 45 to 60 minutes.43-45 The spectral analysis of data requires processing to reduce noise and perform analysis. Metabolite concentrations can be expressed in absolute or relative terms. In general, the peak area of a metabolite signal is directly related to its concentration. Because the absolute quantitation of metabolites is difficult to achieve in vivo, many studies have used metabolite ratios for assessing spectral profiles.43,46 Peak areas in a spectrum are referenced to standards for correlation with MR signal intensities. An internal standard such as adenosine triphosphate (ATP) can be used, given its natural occurrence in tissue.43 Whereas a number of in vivo studies have explored the diagnostic performance of MR spectroscopy for characterizing hepatic lesions,44 there has been some interest in the role of MR spectroscopy for detecting hepatic fibrosis (Table 3). Among patients with established cirrhosis, an increased hepatic PME signal measured by MR spectroscopy has been reported.48-51 The relationship between PDE and cirrhosis, however, is not well understood.45 For patients with varying degrees of involvement with chronic hepatitis, an increasing PME/PDE ratio was found to correlate with necroinflammatory and fibrosis scores on liver histology compared with healthy volunteers.52-55 Although differences between means for each group were


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Fig. 2. Setup for applying shear waves to the abdomen for MR elastography of the liver. Acoustic pressure waves (at 60 Hz) are generated by an active audio driver, located away from the magnetic field of the MRI unit, and transmitted via a flexible tube to a passive pneumatic driver placed over the anterior body wall. The left diagram is a coronal illustration of the location of the passive pneumatic driver (circle) with respect to the liver. (Adapted from Yin M, Talwalkar JA, Glaser KJ, Manduca A, Grimm RC, Rossman PJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastro Hep 2007;5:1207-1213.e2.)

statistically significant, there was some overlap between the patient groups.45 Reconciling the biologic plausibility of MR spectroscopy results with histological manifestations of chronic liver disease has been attempted. Changes in phospholipid metabolites seen in liver disease are believed to represent regenerative activity.50 An increased PME signal may represent extensive membrane remodeling that occurs in liver disease.44 Reduced PDE may be because of a decrease in the rate of cell membrane breakdown. Reduced ATP levels have also been discovered in association with cirrhosis. However, the presence of ATP and other phosphorus-based compounds have yet to be clearly associated with clinically relevant outcomes.45 Several limitations with current MR spectroscopy approaches, however, are observed when comparisons between existing studies are made. Most studies contain small numbers of patients from heterogeneous populations assessed by varying MR spectroscopy methods.43 Scan time and volume of liver examined in terms of voxel number are also different between studies. In addition, the variation in reproducibility of data acquisition from healthy volunteers can range between 4% and 20% for both subject and examination. The appearance of individual signals can be affected by variations in data acquisition and subsequent analysis.45 The overall specificity of calculated signals may also be reduced based on contributions from nonhepatocyte cells (macrophages, endothelial cells) and overlap between certain spectral profiles.44,45,47 Ultimately, the role of in vivo MR spectoscopy for detecting hepatic fibrosis requires assessment in larger diagnostic accuracy studies among patients with various hepatobiliary disorders. Magnetic Resonance Elastography. Disease processes such as malignancy create increased tissue stiffness, which may be identified by manual palpation of selected organs on physical examination. Based on ex vivo and intraoperative studies, the elasticity (or stiffness) of hepatic parenchymal

tissue is well known to be influenced by the presence of fibrosis.56 Normal liver tissue is similar to adipose tissue in stiffness at palpation, while cirrhotic liver is hard. Recent research has suggested that the stiffness of hepatic matrix may be stimulatory for continued hepatic stellate cell transdifferentiation and fibrosis production.57 With recent advances in biomedical imaging, the ability to quantify in vivo stiffness by detecting shear wave propagation velocity through specific human tissue has now become possible.56,58 For example, the measurement of in vivo liver stiffness by ultrasoundbased transient elastography appears feasible and valid to predict the severity of hepatic fibrosis for selected patients with advanced histological disease.59-62 Recently, the technique of MR elastography has also been described for assessing shear stiffness in various tissue types.58,63,64 MR elastography uses a modified phasecontrast technique to sensitively image the propagation characteristics of acoustic shear waves that are generated with the organ of interest.64 The technique can be implemented on a conventional MRI system with modest additional hardware and software. The technique is typically added to a conventional MR examination of the upper abdomen. A pneumatic or electromechanical driver is placed in contact with abdominal wall in the supine patient and used to generate propagating mechanical waves in the liver at frequencies between 40 and 120 Hz.65-68 In our experience, the pneumatic driver can be implemented as a simple passive drumlike device that is placed over the anterior abdominal wall and activated using air pressure waves from a remotely located speakerlike device.66,68 (Fig. 2). A single breath-hold of 10 to 15 seconds is required to allow imaging of wave propagation in a crosssection of the abdomen.68 A specialized phase-contrast MRI sequence is then used to image the propagating waves in the liver. This sequence uses motion-encoding gradients that are oscillated synchronously with the applied vibrations, allowing waves with amplitudes

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Fig. 3. (A) MR elastography of the liver in a healthy volunteer and a patient with cirrhosis. The middle column of images shows wave image data in the liver and spleen, superimposed on the corresponding anatomical images. The resulting elastograms are shown in the far right column. Elastograms show a higher mean stiffness of the fibrotic liver compared with the normal liver (12.1 ⫾ 1.2 kPa versus 1.8 ⫾ 0.3 kPa, respectively). (Adapted from Yin M, Talwalkar JA, Glaser KJ, Manduca A, Grimm RC, Rossman PJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastro Hepatol 2007;5: 1207–1213.e2. (B) MR elastography of the liver in patients with obesity and ascites. The top row demonstrates a patient with obesity (BMI ⫽ 36) and stage 2 fibrosis on liver biopsy with a mean liver stiffness of 3.2 ⫾ 0.8 kPa. The bottom row illustrates a patient with ascites. Excellent shear wave illumination of the liver was obtained, and the mean liver stiffness was 11.3 ⫾ 2.8 kPa. (Adapted from Yin M, Talwalkar JA, Glaser KJ, Manduca A, Grimm RC, Rossman PJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastro Hepatol 2007; 5:1207-1213.e2.)

in the micron range to be readily imaged. Each MR elastographic acquisition provides an image that represents the displacement caused by shear wave propagation in the medium.63,64 The wave images are then processed using a specially developed inversion algorithm to generate quantitative images that depict tissue stiffness called elastograms (Fig. 3A,B).58 Mean elasticity values measured in regions of interest within the liver are obtained. The unit of measurement for elasticity is kilopascals, as it is with ultrasound-based transient elastography. Preliminary studies have established the feasibility of MR elastography of the liver in humans (Table 4).65-67 Shear waves can be readily generated in the liver, even though ribs are present in the path between the acoustic driver and the

liver.66 Reliability assessed by coefficients of variation within subjects is reported at 7% to 9%.65 In initial publications,65,66 the mean liver shear stiffness in patients with chronic liver disease was found to be significantly higher (P ⬍ 0.001) compared with the mean value for healthy volunteers. The results suggested a quadratic relationship between histological fibrosis stage versus elasticity measurements as observed in studies with ultrasoundbased transient elastography.59-61 Issues with biopsy quality, sampling error, and observer variation may, in part, explain this relationship. Moreover, it was observed that elastogram values in the liver demonstrated heterogeneous patterns, further suggesting the validity of its relationship with fibrosis.66,68 Recently, the reproduction and


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Table 4. Summary of MR Elastography Investigations for Detecting Hepatic Fibrosis in Human Subjects Author Huwart et al.

Year 2006

Method

MRI Hardware

MRI Technique

MRE

1.5 T Body coil

MEG Spin echo TE 61 ms TR 431 ms Wave frequency ⫽ 65 Hz MEG SSFP TR 980 ms Wave frequency ⫽ 51 Hz MEG GRE TE 18 ms TR 33 ms Wave frequency ⫽90 Hz

Klatt et al.

2006

MRE

1.5 T Body coil

Rouviere et al.

2006

MRE

1.5 T Body coil

Major Etiologies

Ref Std

Outcome

Results


Viral Alcohol

Biopsy

Fibrosis stage

2 patients 12 normal 12 patients 12 normal

n/a

Biopsy

Fibrosis

Hepatitis C

Biopsy

Fibrosis stage

Mean liver elasticity increased with fibrosis; mean liver viscosity higher in cirrhosis Mean elastic moduli was higher in patients Mean liver stiffness greater in patients

N

Abbreviations: MRI, magnetic resonance imaging; Ref Std, reference standard; MRE, magnetic resonance elastography; T, Tesla; GRE, gradient echo; MPG, motion probing gradient; N/A, not available; CTP, MRE, magnetic resonance elastography; MEG, motion encoding gradient; SSFP, steady-state free precision; GRE, gradient echo.

validation of MR elastography was performed in an independent population of 35 healthy individuals and 48 patients with varying degrees of chronic liver disease. In this experience, a sensitivity of 86% and specificity of 85% were noted for the detection of stages 2 to 4 fibrosis compared with liver histology from biopsy. No relationship between liver stiffness and degree of hepatic steatosis was observed. High negative predictive value (97%) for excluding the presence of fibrosis was also noted, suggesting that MR elastography could have a role for improving the ability to risk-stratify patients for liver biopsy to exclude occult advanced fibrosis.68 Several unique qualities are observed with MR elastography with respect to its potential broad application in heterogeneous populations. These include (1) a freely oriented field of view, (2) no acoustical window requirement, (3) operator independence, (4) insensitivity to body habitus, (5) potential assessment of the entire hepatic parenchyma as the region of interest, and (6) the ability to obtain a conventional MR examination at the same time.6,65,66 As with the other techniques, efforts to standardize the equipment and techniques used for MR elastography should be pursued to maximize diagnostic accuracy and facilitate comparison of results in different settings. Reproducibility appears good from initial studies (coefficient of variation ⬍10%) but requires additional study for verification. Further prospective evaluation is required for characterizing the diagnostic performance characteristics of MR elastography, including its longitudinal reproducibility among patients with stable and progressive liver disease.

Conduct of Prospective MR Studies in Human Subjects Issues in Study Design. The design and conduct of high-quality diagnostic accuracy studies is essential for ongoing validation of emerging noninvasive techniques for hepatic fibrosis. Specific recommendations have been published to improve the reporting of study results while minimizing the effects of bias as much as possible.69 Particular features of note include (1) the use of consecutive pa-

tients, (2) the study of a wide spectrum of disease severity, (3) the application of test and reference standards in all patients, (4) interpreter blinding of results for all tests, and (5) the appropriate measurement and reporting of diagnostic test parameters including measurements declared to be indeterminate or incomplete. The majority of published studies in hepatology to date have not explicitly described the use of formal methods to prevent observer error.70 As with other investigations of noninvasive methods to detect hepatic fibrosis, the inclusion of small patient numbers and lack of independent assessment for test results is also observed with MRI techniques. In addition to considering the criteria listed above when designing future diagnostic accuracy studies, there should also be an emphasis placed on rationale and justification for power and sample size calculations. The decision to employ a continuous or dichotomous outcome variable will require an explicit description of the goal to be sought. A binary primary endpoint (such as the detection of advanced versus early fibrosis) will be useful when this knowledge can facilitate a change in clinical management strategy (in other words, institution of surveillance procedures associated with cirrhosis). Greater statistical complexity arises, however, when designing clinical trials to examine multiple categorical stages of fibrosis, which is needed to assess treatment candidacy. In this instance, there will be greater demands for larger samples sizes to preserve study power. It is generally recognized that measurement of a continuous outcome would be an ideal situation to provide a means for assessing prognosis and treatment response as antifibrotic therapies emerge in the future. Substantial work will be required, however, to verify the surrogate or biological properties of such an endpoint with conduct of validation studies of sufficient length given the slowly progressive nature of diseases such as chronic hepatitis C and nonalcoholic steatohepatitis. Issues with Reference Standard. Regardless of acquisition method and specimen length, the persistence of sampling variability associated with liver biopsy remains a significant obstacle in considering this as a true reference

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standard. However, the use of liver biopsy will still be required unless alternate methods are recognized as reliable and valid. Recent interest has focused the role of portal venous pressure as a potential reference standard representing the pathophysiological effects of hepatic fibrosis. A recent analysis verified the strong correlations between septal fibrosis thickness and regenerative nodule size with portal venous hypertension.71 In turn, the use of HVPG measurement could also serve as a reliable and valid reference standard for diagnostic accuracy studies given its ability to assess prognosis.72 This has already been demonstrated in the setting of recurrent hepatitis C after liver transplantation as liver stiffness by transient elastography was more strongly correlated with HVPG measurement as compared with histology from transjugular biopsy methods.73 However, further clarification of potential limitations with HVPG will likely be required. For example, hemodynamic alterations within the intrahepatic vasculature may occur independently of architectural changes related to fibrosis. Therefore, additional evidence is still required to demonstrate the sensitivity of HVPG to mild changes in fibrosis. Using multiple or objective end points such as death and clinical hepatic decompensation may address these issues. Finally, the use of HVPG as a corroborative reference standard will most likely be successful within the context of clinical trials because physician and patient acceptance of this technique remains questionable in practice. Further assessments incorporating physiological endpoints such as HVPG appear inevitable as interest in developing noninvasive detection techniques continues to grow.74

Defining the Role of MR Imaging for Hepatic Fibrosis in Clinical Practice Even with further advances in MRI, a number of issues remain unsettled before these methods can be effectively translated into clinical practice. The ability to perform multiple examinations without concern over the cumulative risk of ionizing radiation is advantageous for MRI.75 In turn, patient acceptance rates of image-based assessments for hepatic fibrosis should be higher when compared with liver biopsy, especially if these methods can provide serial assessments in detecting fibrosis progression. The clinical applicability of any MRI-based technology, however, will require endorsement by practitioners for use in the examination of their patients. As with any emerging technology, cost and available expertise will play important roles in determining the utility of MRIbased technologies for detecting hepatic fibrosis. Moreover, the pragmatic advantages of less expensive and,


perhaps, more readily available methods (for example, serum markers) needs to be balanced against any incremental benefit in diagnostic accuracy that imaging would produce. While new MRI techniques are typically only available initially at tertiary medical centers, experience has shown that sophisticated MRI technologies that prove to be useful in clinical practice have rapidly diffused to community-based medical imaging facilities. Finally, there will need to be alternative strategies for patients who are unable or unwilling to undergo MRI examination (for example, those with claustrophobia requiring conscious sedation). Establishing the cost-effectiveness of MRIbased techniques would assist greatly in facilitating the rate of translation of these techniques into clinical practice. Although the number of patients screened for hepatic fibrosis could increase using MRI, proof will be required that early detection and intervention can reduce morbidity and resource utilization associated with the clinical sequelae of advanced disease. This is particularly important in patients with advanced fibrosis, where surveillance for hepatocellular carcinoma could also be performed assuming its value is established in clinical trial settings.76

Conclusions The development of a reliable and valid noninvasive method to assess hepatic fibrosis could result in comparable or, perhaps, improved accuracy in terms of staging. Several MR techniques (or combination of approaches) are being refined to meet these requirements and demonstrate early promise. As described previously,77 the absence of robust noninvasive markers now provides the most significant barrier to clinical trial development for novel pharmacological strategies to combat hepatic fibrosis. Should quantitative assessment by novel MRI techniques be predictive of clinical outcomes of hepatic fibrosis, then perhaps additional study to demonstrate reliable longitudinal assessment in the setting of therapy may be possible. Nevertheless, the emergence of MRI techniques (singly or in combination with other methods) could result in the performance of true functional hepatic imaging.76

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