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DOI: 10.1148/radiol.2452061673
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(Radiology 2007;245:458-466.)
© RSNA, 2007

Gastrointestinal Imaging

Liver Fibrosis: Noninvasive Assessment with MR Elastography versus Aspartate Aminotransferase–to-Platelet Ratio Index1

Laurent Huwart, MD, Christine Sempoux, MD, PhD, Najat Salameh, MSc, Jacques Jamart, MD, Laurence Annet, MD, PhD, Ralph Sinkus, PhD, Frank Peeters, PhD, Leon C. ter Beek, PhD, Yves Horsmans, MD, PhD, and Bernard E. Van Beers, MD, PhD

1 From the Diagnostic Radiology Unit (L.H., N.S., L.A., F.P., B.E.V.B.), Department of Pathology (C.S.), and Laboratory of Gastroenterology (Y.H.), Université Catholique de Louvain, St-Luc University Hospital, Avenue Hippocrate 10, B-1200 Brussels, Belgium; Center of Biostatistics and Medical Documentation, Université Catholique de Louvain, Mont-Godinne University Hospital, Yvoir, Belgium (J.J.); Laboratoire Ondes et Acoustique, Université Paris 7, Paris, France (R.S.); and Philips Medical Systems, Best, the Netherlands (L.C.t.B.). Received September 9, 2006; revision requested December 5; revision received January 10, 2007; accepted January 29; final version accepted April 3. Supported by grants FRSM 3.4578.00 and 3.4580.06 from the Fonds National de la Recherche Scientifique, Belgium. Address correspondence to L.H. (e-mail: laurent.huwart{at}clin.ucl.ac.be).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Purpose: To prospectively compare the sensitivity and specificity of magnetic resonance (MR) elastography with those of the routinely available aspartate aminotransferase–to-platelet ratio index (APRI) test for staging hepatic fibrosis in patients who have undergone liver biopsy for suspicion of chronic liver disease, with histopathologic examination as the reference standard.

Materials and Methods: The study was approved by the ethics committee. All patients gave written informed consent. Eighty-eight patients (37 men, 51 women; mean age, 54.0 years ± 13.1 [standard deviation]) who underwent liver biopsy for suspicion of chronic liver disease underwent MR elastography and APRI testing within 2 days after liver biopsy. At histopathologic examination, the fibrosis stage was assessed according to METAVIR scores (fibrosis scores F0 [no fibrosis] to F4 [cirrhosis]). MR elastography was performed by transmitting mechanical waves within the liver and measuring the small cyclic displacement of the liver spins with a phase-contrast spin-echo sequence. The performances of MR elastography and APRI testing were assessed, and the optimal cutoff values for fibrosis stage were determined with receiver operating characteristic (ROC) curve analysis.

Results: At MR elastography, areas under the ROC curves (Az) for elasticity and viscosity, respectively, were 0.999 and 0.863 at fibrosis scores greater than or equal to F2, 0.997 and 0.962 at scores greater than or equal to F3, and 1.000 and 0.986 at score F4. Az values for elasticity at MR were significantly larger than those for the APRI (0.854 at scores ≥ F2, P < .001; 0.886 at scores ≥ F3, P = .003; and 0.851 at score F4, P = .004). Optimal cutoff values of elasticity were 2.5 kPa for fibrosis scores greater than or equal to F2, 3.1 kPa for scores greater than or equal to F3, and 4.3 kPa for score F4.

Conclusion: Large Az values for elasticity (>0.990 for scores ≥ F2, ≥ F3, and F4) show that MR elastography was accurate in liver fibrosis staging and superior to biochemical testing with APRIs.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
All chronic liver diseases may lead to liver fibrosis. An abundance of data now emphasize that fibrosis is evolving and, with effective intervention, reversible (1–4). The stage of liver fibrosis is used to determine the prognosis and the treatment options. Although liver biopsy is the current reference standard for determining fibrosis stage, it is invasive and is not well accepted by patients, especially when repeated examinations are needed. In addition, the accuracy of liver biopsy in the assessment of fibrosis may be questioned because of sampling variability and interobserver variation in the interpretation of semiquantitative fibrosis scores (5–8).

Thus, there is a clear need for noninvasive alternatives to liver biopsy. Ideally, these noninvasive tests would enable one to reliably distinguish, at minimum, three stages of fibrosis: no or early fibrosis, intermediate fibrosis, and advanced fibrosis or cirrhosis (2). Many hepatologists believe that among patients with hepatitis B and C, as among patients with nonalcoholic liver disease, those with at least intermediate fibrosis should be treated (2,4). With early disease, the toxicity and costs of treatment may outweigh the benefits. In addition, patients with advanced fibrosis or cirrhosis need follow-up for detection of esophageal varices and hepatocellular carcinomas (9–11). Several noninvasive methods for staging liver fibrosis have been proposed. These methods include the use of biochemical scores, such as the aspartate aminotransferase–to-platelet ratio index (APRI), and liver imaging techniques (12–16). However, the value of these diagnostic methods, especially for the diagnosis of intermediate fibrosis, remains debatable (2).

Magnetic resonance (MR) elastography is a noninvasive method of measuring the viscoelastic properties of the liver. Preliminary reports suggest that MR elastography is a feasible method for staging liver fibrosis (17,18). Thus, the purpose of our study was to prospectively compare the sensitivity and specificity of MR elastography with those of the routinely available APRI test for staging hepatic fibrosis in patients who have undergone liver biopsy for suspicion of chronic liver disease, with histopathologic analysis as the reference standard.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Experimental Setup
The authors from the Université Catholique de Louvain had sole control of the data generated in this study. The elastographic method used in this study has been described in detail previously (18–20): Briefly, the transducer contains a piston with a diameter of 6.5 cm and a coil driven by the pulse generator, which is triggered by the MR spectrometer. The time-dependent magnetic moment of the coil couples to the static magnetic field, and the resulting torque leads to the longitudinal oscillations of the piston. Low-frequency (65-Hz) longitudinal mechanical waves are transmitted into the right liver lobe by the piston, which is placed against the last ribs in the back of the patient in the supine position.

Patients
Ninety-six consecutive patients who had undergone liver biopsy in the gastroenterology department of St-Luc University Hospital between September 2004 and April 2006 because they were suspected of having chronic liver disease were prospectively included in the study. The study protocol was approved by the ethics committee of this institution. Patients were enrolled after giving written informed consent. MR elastography and APRI measurement were performed within 2 days after liver biopsy. After study inclusion, three patients were removed from the investigation because of claustrophobia during MR elastography and five were removed because their liver biopsy findings were unsuitable for fibrosis staging. Thus, the final study group comprised 88 patients (37 men, 51 women; mean age, 54.0 years ± 13.1 [standard deviation]; mean body mass index, 25.9 kg/m2 ± 4.0). Ascites was diagnosed at imaging in 13 patients. The cause of chronic liver disease was viral in 69 patients (chronic hepatitis C in 66, chronic hepatitis B in three), alcohol abuse in 10, autoimmune disease in two (autoimmune hepatitis in one, primary biliary cirrhosis in one), {alpha}1-antitrypsin deficiency in one, and unclassified in six.

MR Elastography
Images were obtained with a 1.5-T whole-body MR unit (Gyroscan Intera; Philips Medical Systems, Best, the Netherlands) by using a four-element torso coil. The MR elastography sequence was a motion-sensitized spin-echo sequence with sinusoidal displacement-encoding gradients that were synchronized to the mechanical excitation by using a trigger on the MR spectrometer. Five sagittal sections through the right liver were acquired with 431/61 (repetition time msec/echo time msec), a 4-mm section thickness, a 250-mm field of view, a 64 x 64 matrix (2), two acquired signals, and respiratory gating with a navigator in the right hemidiaphragm. The sections were placed distant from the hepatic hilum to avoid inclusion of large hepatic vessels in the field of view. Four time points were obtained by changing the phase offset between the mechanical excitation and the MR sequence to assess the amplitude and phase of the displacement in one direction. The motion-encoding gradients were applied successively in three orthogonal directions to capture all components of the three-dimensional displacement vector. The total acquisition time was about 20 minutes, depending on the efficiency of the respiratory-gating navigator.

Longitudinal mechanical waves were used for excitation because they are less attenuated than shear waves and therefore have good penetration throughout the liver (17,18). The shear waves were generated by means of mode conversion at interfaces and were separated from the longitudinal contribution by applying the curl operator on the total displacement vector field. The phase images were then analyzed by using the Voigt model to obtain shear elasticity and viscosity maps. The described MR elastographic method has been validated previously, and the reproducibility of this technique has been assessed in healthy volunteers (18–20).

For each patient, a junior radiologist (L.H.) with 3 years experience in MR imaging placed the largest rectangular region of interest (ROI) that fit in the liver on the central section. This observer was blinded to the patients' clinical and biochemical data and histopathologic results. The shear elasticity (in kilopascals) and viscosity (in pascals times seconds) of the liver were measured as the mean values within the large ROI on the elasticity and viscosity maps. For each patient, the intrasubject heterogeneities of the liver elasticity and viscosity were measured as the standard deviations of the mean measurements within the large ROI on the elasticity and viscosity maps. The intersubject heterogeneities of the liver elasticity and viscosity were measured as the standard deviations of the mean elasticity and viscosity measurements at each fibrosis stage. It should be noted that the shear elasticity modulus measured with this three-dimensional MR elastographic method differs from the Young modulus reported in studies of one-dimensional transient ultrasonographic (US) elastography (Fibroscan; EchoSens, Paris, France) by a scaling factor of three: The Young modulus equals three times the shear elasticity modulus in soft tissues (21).

APRI Measurement
Aspartate aminotransferase level (AST, in international units per liter, divided by upper limit of normal) (22) and platelet count (PLC, in 109 cells per liter) were measured, respectively, with Synchron Clinical System LX20 (Beckman-Coulter, Fullerton, Calif) and Advia 120 Hematology System (Bayer, Leverkusen, Germany) autoanalyzers. The APRI was calculated as follows: (AST·100)/PLC (23).

Histopathologic Analysis
In 73 patients, percutaneous liver biopsy was performed by two senior hepatologists (including Y.H., 20 years experience) by using the Menghini technique with a 1.4-mm diameter needle (Hepafix; Braun, Melsungen, Germany). In 15 patients with ascites and/or blood coagulation difficulty, liver biopsy was performed with a transjugular approach by using a catheter needle (Cook, Bjaeverskov, Denmark).

After biopsy, the liver samples were fixed in formalin for 24 hours, embedded in paraffin, and stained with hematoxylin-eosin and Masson trichrome. All biopsy specimens were analyzed by a senior hepatopathologist (C.S., 15 years experience) who was blinded to the MR elastography results and the biologic and clinical data. The fibrosis stage was evaluated semiquantitatively according to the METAVIR scoring system (24,25). The METAVIR scoring system was originally used to stage fibrosis in patients with chronic hepatitis C, but it has also been applied in patients with other chronic liver diseases (26,27). METAVIR scores range from F0 to F4: F0 means no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis and a few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis. The liver biopsy specimens had to contain at least 10 portal tracts or obvious regenerating nodules to be included in the analysis. The length of each liver biopsy specimen was measured in millimeters.

Statistical Analyses
Pearson coefficients were used to assess the correlations between viscoelastic parameter and METAVIR score (expressed as the nontransformed METAVIR score and the exponential function of the METAVIR score) and between APRI and METAVIR score. These coefficients were then compared by using the Hotelling test for correlated correlations (28). The performances of the various parameters in discriminating the fibrosis stages were studied by using nonparametric receiver operating characteristic (ROC) curves. Cutoff values of elasticity were chosen by maximizing the Youden index on the estimated curves. Sensitivity, specificity, and positive and negative predictive values were computed with exact 95% confidence intervals based on F distribution (29). All tests were two tailed. Because 10 comparisons were performed, a Bonferroni adjusted {alpha} value of .005 (.05/10) was used to preserve the overall .05 error rate. The analyses were performed by using SC (Lambda-Plus, Gembloux, Belgium) and SPSS (SPSS, Chicago, Ill) statistical software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
Fibrosis Staging
Performing MR elastography and liver biopsy led to no objective adverse events in the examined population. The mean length of the liver biopsy specimens was 34.5 mm ± 10.5 (standard deviation). Twenty-two (25%) of the 88 patients had a METAVIR score of F0; 13 (15%), a score of F1; 15 (17%), a score of F2; 14 (16%), a score of F3; and 24 (27%), a score of F4 (Fig 1). Elasticity, viscosity, intrasubject heterogeneity, and APRI increased with increasing liver fibrosis stage (Figs 2, 3). Elasticity (r = 0.86, P < .001), viscosity (r = 0.75, P < .001), intrasubject heterogeneity of elasticity (r = 0.70, P < .001), and intrasubject heterogeneity of viscosity (r = 0.68, P < .001) measurements correlated with fibrosis stage. Higher correlations were observed between the viscoelastic parameters and the exponential function of the METAVIR score: r = 0.94 and P < .001 for elasticity, r = 0.85 and P < .001 for viscosity, r = 0.79 and P < .001 for intrasubject heterogeneity of elasticity, and r = 0.77 and P < .001 for intrasubject heterogeneity of viscosity. All correlation coefficients computed with the exponential function of the METAVIR score, except that for the heterogeneity of viscosity (P = .006, greater than Bonferroni {alpha} of .005), were significantly greater than those computed with the nontransformed METAVIR score (P ≤ .002).


Figure 1
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  		Figure 1: Flow diagram of patients suspected of having chronic liver disease and who underwent liver biopsy during the 20-month study period.

 

Figure 2A
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  		Figure 2a: Box plots of (a) elasticity, (b) intrasubject heterogeneity of elasticity, (c) viscosity, (d) intrasubject heterogeneity of viscosity, and (e) APRI for each METAVIR fibrosis stage. Boundary of boxes closest to zero indicates 25th percentile, line within boxes indicates median, and boundary of boxes farthest from zero indicates 75th percentile. Error bars indicate smallest and largest values within 1.5 box lengths of 25th and 75th percentiles. Outliers are represented as individual points. In e, one outlier is not represented in the F4 group to maintain the clarity of the graph.

 

Figure 2B
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  		Figure 2b: Box plots of (a) elasticity, (b) intrasubject heterogeneity of elasticity, (c) viscosity, (d) intrasubject heterogeneity of viscosity, and (e) APRI for each METAVIR fibrosis stage. Boundary of boxes closest to zero indicates 25th percentile, line within boxes indicates median, and boundary of boxes farthest from zero indicates 75th percentile. Error bars indicate smallest and largest values within 1.5 box lengths of 25th and 75th percentiles. Outliers are represented as individual points. In e, one outlier is not represented in the F4 group to maintain the clarity of the graph.

 

Figure 2C
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  		Figure 2c: Box plots of (a) elasticity, (b) intrasubject heterogeneity of elasticity, (c) viscosity, (d) intrasubject heterogeneity of viscosity, and (e) APRI for each METAVIR fibrosis stage. Boundary of boxes closest to zero indicates 25th percentile, line within boxes indicates median, and boundary of boxes farthest from zero indicates 75th percentile. Error bars indicate smallest and largest values within 1.5 box lengths of 25th and 75th percentiles. Outliers are represented as individual points. In e, one outlier is not represented in the F4 group to maintain the clarity of the graph.

 

Figure 2D
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  		Figure 2d: Box plots of (a) elasticity, (b) intrasubject heterogeneity of elasticity, (c) viscosity, (d) intrasubject heterogeneity of viscosity, and (e) APRI for each METAVIR fibrosis stage. Boundary of boxes closest to zero indicates 25th percentile, line within boxes indicates median, and boundary of boxes farthest from zero indicates 75th percentile. Error bars indicate smallest and largest values within 1.5 box lengths of 25th and 75th percentiles. Outliers are represented as individual points. In e, one outlier is not represented in the F4 group to maintain the clarity of the graph.

 

Figure 2E
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  		Figure 2e: Box plots of (a) elasticity, (b) intrasubject heterogeneity of elasticity, (c) viscosity, (d) intrasubject heterogeneity of viscosity, and (e) APRI for each METAVIR fibrosis stage. Boundary of boxes closest to zero indicates 25th percentile, line within boxes indicates median, and boundary of boxes farthest from zero indicates 75th percentile. Error bars indicate smallest and largest values within 1.5 box lengths of 25th and 75th percentiles. Outliers are represented as individual points. In e, one outlier is not represented in the F4 group to maintain the clarity of the graph.

 

Figure 3A
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  		Figure 3a: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3B
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  		Figure 3b: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3C
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  		Figure 3c: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3D
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  		Figure 3d: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3E
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  		Figure 3e: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3F
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  		Figure 3f: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3G
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  		Figure 3g: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 

Figure 3H
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  		Figure 3h: MR elastography images and reconstructed MR images (431/61) in (a–d) 36-year-old man with F2 disease and (e–h) 59-year-old woman with F4 disease. (a, e) Magnitude MR elastography images show the largest rectangular ROI within the liver. (b, f) Corresponding reconstructed (postprocessed) phase images (after application of the curl operator) show good penetration of the shear waves. Reconstructed (c) elasticity and (d) viscosity maps in patient with stage F2 fibrosis are relatively homogeneous: The mean elasticity and viscosity measured within the ROI on these sections are 2.9 kPa ± 0.7 and 2.3 Pa·sec ± 1.5, respectively. Reconstructed (g) elasticity and (h) viscosity maps in patient with stage F4 disease are heterogeneous: Mean elasticity and viscosity measurements are 6.8 kPa ± 2.4 and 7.0 Pa·sec ± 4.1, respectively.

 
APRI Measurement
APRI measurement was only weakly correlated to METAVIR score (r = 0.42 and P < .001 for linear correlation between APRI and nontransformed METAVIR score, r = 0.48 and P < .001 for correlation between APRI and exponential function of METAVIR score). The coefficient for the correlation between APRI and exponential function of the METAVIR score was not significantly greater than that for the correlation between APRI and nontransformed METAVIR score (P > .05).

ROC Analysis
For each METAVIR fibrosis score threshold, the area under the ROC curve (Az) for elasticity was larger than that for the other measurements (Fig 4, Table 1). Az values for elasticity were significantly larger than those for the APRI at all fibrosis score thresholds (P = .003 for ≥F1, P < .001 for ≥F2, P = .003 for ≥F3, P = .004 for F4) and than those for intrasubject heterogeneity of elasticity, viscosity, and intrasubject heterogeneity of viscosity at fibrosis scores greater than or equal to F1 (P = .001, P = .004, and P = .001, respectively) and greater than or equal to F2 (P ≤ .001).


Figure 4A
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  		Figure 4a: ROC curves for elasticity (green), intrasubject heterogeneity of elasticity (blue), viscosity (pink), intrasubject heterogeneity of viscosity (turquoise), and APRI (red) at METAVIR fibrosis score thresholds of (a) ≥F1, (b) ≥F2, (c) ≥F3, and (d) F4.

 

Figure 4B
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  		Figure 4b: ROC curves for elasticity (green), intrasubject heterogeneity of elasticity (blue), viscosity (pink), intrasubject heterogeneity of viscosity (turquoise), and APRI (red) at METAVIR fibrosis score thresholds of (a) ≥F1, (b) ≥F2, (c) ≥F3, and (d) F4.

 

Figure 4C
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  		Figure 4c: ROC curves for elasticity (green), intrasubject heterogeneity of elasticity (blue), viscosity (pink), intrasubject heterogeneity of viscosity (turquoise), and APRI (red) at METAVIR fibrosis score thresholds of (a) ≥F1, (b) ≥F2, (c) ≥F3, and (d) F4.

 

Figure 4D
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  		Figure 4d: ROC curves for elasticity (green), intrasubject heterogeneity of elasticity (blue), viscosity (pink), intrasubject heterogeneity of viscosity (turquoise), and APRI (red) at METAVIR fibrosis score thresholds of (a) ≥F1, (b) ≥F2, (c) ≥F3, and (d) F4.

 

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  		Table 1. Az Values for Elasticity, Viscosity, Intrasubject Heterogeneity of Elasticity and Viscosity, and APRI according to METAVIR Score

 
The most discriminating cutoff values of elasticity were 2.4 kPa for METAVIR fibrosis scores greater than or equal to F1, 2.5 kPa for scores greater than or equal to F2, 3.1 kPa for scores greater than or equal to F3, and 4.3 kPa for score F4. Corresponding sensitivities, specificities, and positive and negative predictive values are given in Table 2.


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  		Table 2. Most Discriminant Elasticity Cutoff Values at Different METAVIR Scores, with Corresponding Sensitivities, Specificities, and Positive and Negative Predictive Values

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 
The results of our study show that MR elastography is an accurate noninvasive method of staging liver fibrosis and is superior to biochemical testing with APRI values. The current reference standard for the diagnosis and staging of liver fibrosis is histopathologic analysis of biopsy samples (5). Although histopathologic analysis is limited because it is invasive and owing to a potential lack of reproducibility due to the heterogeneity of liver fibrosis, the small size of hepatic samples (30–32), and the inter- and intraobserver variability in histopathologic examinations (33–35), it remains the only validated and universally accepted clinical method that enables differentiation of early or no fibrosis (F0–F1), intermediate fibrosis (F2), and advanced fibrosis or cirrhosis (F3–F4), which is essential to the decision to treat (2,36).

In our study, the elasticity measurements enabled us to clearly separate the intermediate fibrosis stages and to more precisely differentiate between stage F2 and stages F0–F1. With an optimized cutoff value of 2.5 kPa for stages greater than or equal to F2, the sensitivity of elasticity was 98% at a specificity of 100%. This high accuracy is clinically important, because according to the American Association for the Study of Liver Diseases, patients with hepatitis C genotype 1 infection should be treated only when substantial fibrosis (≥F2) is observed (4,37).

In our study, advanced fibrosis and cirrhosis were also diagnosed accurately. The cutoff value of 3.1 kPa for fibrosis stages greater than or equal to F3 had a sensitivity of 95% and a specificity of 100%. This high accuracy in the diagnosis of advanced fibrosis is also important because patients with advanced fibrosis should be screened for portal hypertension and hepatocellular carcinoma (9–11). Correlation coefficients for the relationship between viscoelastic parameter and exponential function of the METAVIR score were significantly better than those for the correlation between viscoelastic parameter and nontransformed METAVIR score (P ≤ .002). This observation reflected the exponential accumulation of fibrous tissue within the liver, as seen by Bedossa et al (31).

The intersubject heterogeneity of elasticity for cirrhosis (stage F4) was large. This may be explained by the variable macroscopic patterns of cirrhosis, which may appear as micronodular, macronodular, or incomplete septal cirrhosis (38). Moreover, the intersubject heterogeneity of elasticity in cirrhosis may be related to the severity of the disease, as shown in studies involving US elastography (26,39).

In our study, the viscosity measurements were less accurate compared with the elasticity measurements in the staging of liver fibrosis, as shown by the correlation coefficients, box plots, and Az values—particularly for stages greater than or equal to F1 and stages greater than or equal to F2. Even if living tissues have both elastic and viscous properties—and, thus, a viscoelastic model seems more appropriate than a single elastic model—further studies are needed to determine if an improved model would yield more accurate results for viscosity than the Voigt model used in our study (18).

We also observed that measurements of the intrasubject heterogeneities of elasticity and viscosity increased with increasing fibrosis stage. This finding is consistent with the known variability in the distribution of fibrosis within the liver (31). In particular, it should be noted that the intrasubject heterogeneity was much higher with cirrhosis than with the other fibrosis stages (38). However, the clinical relevance of the intrasubject heterogeneities of elasticity and viscosity appeared to be limited because the mean elasticity measurements alone had high accuracy.

Several other noninvasive alternatives to biopsy have been proposed for staging liver fibrosis. Serum tests include measurement of the doses of specific markers of fibrosis, such as hyaluronic acid and N-terminal collagen III propeptide, which are products of the degradation or synthesis of the extracellular matrix (40,41). The usefulness of these markers is limited because fibrosis is not specific to the liver. The use of more comprehensive biomarkers based on proteome or glycome fingerprints has been proposed (42,43). However, these methods are costly and are not readily available.

Scoring systems such as the FibroTest (Biopredictive, Paris, France) and APRI methods have also been developed. These serum tests involve the use of biochemical markers that have no direct relationship with fibrosis and a purely statistical approach to predicting the fibrosis stage (23,44). The APRI was measured in our study because of its simplicity and because it is fairly effective (14,23). However, APRI measurements were less reliable than elasticity measurements in the staging of liver fibrosis. These results are in agreement with previous study findings (2,3), which showed that serum scoring systems enable accurate differentiation of only two stages of the fibrosis spectrum—namely, minimal and advanced fibrosis. These scoring systems are less effective for differentiating intermediate fibrosis stages. Moreover, the main drawback of these tests is that some parameters can be influenced by extrahepatic diseases.

Several liver imaging methods have also been used to diagnose and stage liver fibrosis. Most of these methods, including double contrast material–enhanced MR imaging, perfusion MR imaging, and diffusion MR imaging, are limited to the detection of advanced fibrosis (12,13,45). The effectiveness of these methods in the detection of substantial fibrosis (≥F2) remains unproved.

Transient US elastography has been proposed as a more direct method of assessing liver fibrosis (14–16,26,46,47). In patients with chronic hepatitis C, reported Az values for transient US elastography are 0.79–0.83 for substantial fibrosis (≥F2) and 0.95–0.97 for cirrhosis (F4). These results appear to be somewhat lower than those that we obtained with MR elastography for several reasons: First, the volumes assessed with MR elastography were much larger than those evaluated with US elastography. Second, MR elastography enables assessment of the entire three-dimensional displacement vector induced by the mechanical waves. Third, the use of compressional waves at MR elastography permits good penetration throughout the liver. However, the advantages of MR elastography are balanced by higher cost and increased examination time compared with those of US elastography. The clinical effectiveness and cost-effectiveness of MR elastography and US elastography need to be compared in the same patients in future studies.

Our study was limited by the lack of precise correlation between the hepatic sample analyzed by the pathologist and the viscoelastic maps constructed at MR elastography. Because of the heterogeneity of liver fibrosis, the length of the biopsy sample is known to influence the accuracy of METAVIR score–based categorization. Bedossa et al found that correct categorization of liver fibrosis increased when the length of the biopsy sample was increased to 25 mm, without any substantial benefit from longer specimens (31). In our study, the mean length of the biopsy specimens was 34.5 mm ± 10.5 and thus adequate for correct categorization.

Like previous study investigators, we used a transcostal approach for liver MR elastography (17,18). It has been shown that a transcostal approach yields better shear waves in the liver than does the subcostal approach and that both approaches yield similar elasticity results (17).

In our study, some hepatic vessels that were included in the field of view might have influenced results. However, we think that this influence was minimal because the ROIs were placed on a sagittal section away from the large vessels of the hepatic hilum. Therefore, the hepatic vessels represented only a small area on the viscoelastic maps. Although we were able to use only rectangular ROIs, we are currently working to develop a software that permits the placement of arbitrary ROIs.

We did not study the influence of steatosis, edema, or iron overload on elasticity and viscosity measurements. In a study of US elastography, Ziol et al (16) reported that at multivariate analysis of fibrosis, necroticoinflammatory activity, and steatosis, fibrosis was the only parameter significantly correlated to liver elasticity. The influences of steatosis, edema, and iron overload on hepatic viscoelastic parameters should be further studied in larger series and experimental models.

In conclusion, the results of our study show that MR elastography is a reliable imaging method and is superior to APRI measurement for staging liver fibrosis. These findings suggest that noninvasive MR elastography potentially has a role in determining the treatment and the prognosis of patients with chronic liver disease because it enables substantial and advanced fibrosis to be readily diagnosed.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
References
 


   ACKNOWLEDGMENTS
 
Philips Medical Systems provided the experimental setup—including the pulse generator, transducer, and software for data acquisition and image analysis—used in this study.


   FOOTNOTES
 

Abbreviations: APRI = aspartate aminotransferase–to-platelet ratio index • Az = area under the ROC curve • ROC = receiver operating characteristic • ROI = region of interest

Author contributions: Guarantors of integrity of entire study, L.H., C.S., B.E.V.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, L.H., F.P., L.C.t.B., B.E.V.B.; clinical studies, L.H., C.S., N.S., L.A., Y.H., B.E.V.B.; experimental studies, R.S., F.P., L.C.t.B.; statistical analysis, J.J., R.S., F.P.; and manuscript editing, L.H., R.S., F.P., L.C.t.B., B.E.V.B.

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE...
 References
 

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J. A. Carrion, M. Navasa, X. Forns, B. E. Van Beers, L. Huwart, and Y. Horsmans
MR Elastography to Assess Liver Fibrosis
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