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Original Research |
1 Department of Diagnostic Radiology, The University of Texas M. D. Anderson
Cancer Center, 1515 Holcombe Blvd., Box 368, Houston TX 77030.
2 Department of Pathology, The University of Texas M. D. Anderson Cancer Center,
Houston TX.
3 Department of Biostatistics and Applied Mathematics, University of Texas M. D.
Anderson Cancer Center, Houston TX.
4 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer
Center, Houston TX.
Received July 28, 2006;
accepted after revision October 31, 2006.
Address correspondence to C. S. Ng
(cng{at}di.mdacc.tmc.edu).
Abstract
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MATERIALS AND METHODS. This retrospective study was approved by our institutional review board. Consecutively registered patients who underwent liver resection for metastatic disease formed the study group. Attenuation measurements were obtained from 12 regions of interest in the liver and three in the spleen on both unenhanced and portal phase contrast-enhanced preoperative hepatic CT images. Hepatic attenuation measurements were analyzed both with and without normalization with the spleen. Normalization included both differences and ratios between hepatic and splenic attenuation values. Pathologic fat content was graded semiquantitatively as a percentage of the nonneoplastic liver parenchyma of the resected specimen. Average attenuation values of the liver were compared with pathologic fat content, as were the differences and ratios between hepatic and splenic attenuation values. Linear regression analysis was conducted on a log-log scale.
RESULTS. Data on 88 patients were analyzed. On unenhanced and contrast-enhanced CT images, all associations between pathologic fat content and attenuation measurements were significant (p < 0.0001). All series of R2 values for unenhanced CT scans were much higher than those for contrast-enhanced CT scans. The R2 values of liver-only measurement were higher than those of hepatic values normalized with splenic values on both unenhanced (0.646-0.649 > 0.523, 0.565) and contrast-enhanced (0.516 > 0.242, 0.344) CT.
CONCLUSION. Measurement of attenuation of liver only on unenhanced CT scans is best for prediction of pathologic fat content.
Keywords: CT fat measurement liver disease
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Histologic examination is accurate in detection of hepatic fat content, but it is invasive and time consuming, and sampling errors can occur. Noninvasive methods for diagnosing fatty liver include sonography, MRI, and CT. Among these methods, sonography is the easiest, but it is only a qualitative assessment of the fatty liver. MRI is probably the best method for detecting a small amount of fatty infiltration, but it is relatively expensive [16]. CT is the most widely accepted first imaging technique for staging liver metastasis [17].
CT depicts fatty infiltration of the liver as a decrease in attenuation [14, 18-30]. The degree of decrease in CT attenuation has been shown to be related to the degree of fatty infiltration of the liver [18, 22-24]. One issue is that there are several methods for determining the appropriate CT values. These methods include measurement of hepatic attenuation only [18] and normalization of hepatic attenuation with splenic attenuation, such as measurement of the difference in attenuation between liver and spleen [19-21] and calculation of the ratio of these values [22]. To our knowledge, the methods have not been compared. The purpose of this retrospective analysis was to assess which method of measuring attenuation on CT scans is best for prediction of hepatic fat content.
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Multiphasic (triphasic or biphasic) contrast-enhanced and unenhanced CT scans of the liver were evaluated for all patients included in the study. Triphasic studies consisted of the early hepatic arterial, late hepatic arterial, and portal venous phases of contrast enhancement 20, 40, and 60 seconds after administration of contrast medium. An IV injection of 150 mL of nonionic iodinated contrast material (Optiray, Mallinckrodt) was administered at a concentration of 320 mg I/mL and a rate of 5 mL/s. CT was performed at 120 kVp, 240-340 mAs, 5-mm collimation, pitch of 1.5, and 5-mm reconstruction interval. Biphasic studies consisted of late hepatic arterial and portal venous phase images obtained approximately 40 and 60 seconds after IV injection of 150 mL of nonionic iodinated contrast material at a concentration of 320 mg I/mL and a rate of 3 mL/s. CT was performed at 120 kVp, 240-340 mAs, 7.5-mm collimation, pitch of 0.75, and 7.5-mm reconstruction interval. Biphasic studies were generated in cases in which patients had undergone combined chest and abdominal CT. The images from the portal venous phase (i.e., 60 seconds after contrast injection) were used as contrast-enhanced images in the analyses. All scans were obtained with 4-MDCT scanners (Light-Speed, GE Healthcare).
Attenuation Measurements
We delineated 12 regions of interest (ROIs) within the liver on the CT
scans of each patient and obtained the attenuation measurements for each ROI.
One radiologist with 11 years of experience used both unenhanced and
contrast-enhanced CT images to delineate the ROIs by selecting three
representative levels. The levels contained the confluence of the right
hepatic vein (Figs. 1A and
2A), the umbilical portion of
the left portal vein (Figs. 1B
and 2B), and the posterior
branch of the right portal vein (Figs.
1C and
2C). At each representative
level, the liver was apportioned into four sectors (right posterior, right
anterior, left medial, and left lateral). These sectors were defined with a
modification of the Couinaud
[31] segmentation system. The
right posterior sector included segments VI and VII, the right anterior sector
included segments V and VIII, the left medial sector included segment IV, and
the left lateral sector included segments II and III. One ROI randomly drawn
inside each sector, avoiding the large vessels and any focal lesions, was
considered representative of the sector. Each ROI measured 1.0 ± 0.1
cm2. We also drew one ROI inside the spleen in each representative
slice (Fig. 2A,
2B,
2C).
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Statistical Analysis
For each patient, average attenuation in the ROIs in whole sectors of the
liver and that in the resected sectors of the liver was calculated on both
unenhanced and contrast-enhanced CT scans. A sector was considered resected
only if it actually contained a resected segment. For example, in the case of
a patient who had undergone right extended hepatectomy, the right posterior,
right anterior, and left medial sectors were defined as resected sectors. The
average attenuation of the ROIs in the spleen also was calculated.
We first transformed the value for pathologic fat content to -log[-log (pathologic fat content)]. This is a common transformation for proportions to meet the normality assumptions of the least-squares linear regression model. Because pathologic fat content values less than 1 were undefined in this transformation, such values were imputed with Markov chain Monte Carlo methods (20,000 replicates). Linear regression equations for prediction of the transformed pathologic fat content were estimated from whole-liver attenuation, attenuation of whole liver minus spleen, ratio of whole-liver attenuation to splenic attenuation, attenuation of the resected portion of the liver, attenuation of the resected portion of the liver minus the spleen, and ratio of resected liver attenuation to splenic attenuation. Coefficient of determination (R2), mean square error of the regression line (S2), and p values were calculated. In comparisons of regression models, larger R2 values and smaller S2 values imply superior predictive ability.
Back-transformed estimates of the predicted pathologic fat content with 90% CIs have a sensible lower bound of zero. Regressions incorporating Markov chain Monte Carlo methods were conducted with R Project software (R Foundation for Statistical Computing) (free software available at: www.r-project.org). Graphs of observed and predicted models with 90% CIs were constructed with S-Plus software (Insightful).
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Table 1 shows the data (mean ± SD) for all attenuation calculations for both unenhanced and contrast-enhanced CT scans. Table 2 shows the mean (± SD) data for attenuation calculations for unenhanced CT scans categorized by pathologic fat content. Overall, the mean pathologic fat content was 12.9% ± 16.9% (range, 0-70%). This value includes data on the 19 (22%) of the patients in whom no fat was detected in the liver. All regression estimates of the slopes predicting pathologic fat content from attenuation calculations for both unenhanced and contrast-enhanced CT scans were statistically significant at p < 0.0001 (Table 3). All series of R2 values for the unenhanced CT scans were much higher than those for the contrast-enhanced images (Table 3). The difference in R2 values between whole-liver attenuation and resected-liver attenuation was very small for both unenhanced (0.649 and 0.646) and contrast-enhanced CT images (0.516 and 0.516). The R2 values for whole-liver attenuation and resected-liver attenuation without comparison with splenic attenuation were higher than the values in which splenic measurements were considered (i.e., whole liver minus spleen, resected liver minus spleen, ratio of whole-liver to splenic attenuation, and ratio of resected-liver to splenic attenuation) on both unenhanced (0.646-0.649 > 0.523-0.565) and contrast-enhanced (0.516 > 0.242-0.344) images (Table 3).
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The regression line of pathologic fat content versus unenhanced resected-liver attenuation was pathologic fat content = exp[-exp(-1.915 + 0.051 x resected-liver attenuation)] and is plotted in Figure 3A along with observed pathologic fat content values. On the basis of this regression equation, if the liver attenuation on unenhanced CT scans is 40 H, the predicted hepatic fat content is approximately 30%. Similarly, if the unenhanced CT attenuation is 30 H, the predicted hepatic fat content is approximately 50%. The regression line of pathologic fat content versus contrast-enhanced resected-liver attenuation was pathologic fat content = exp[-exp(-1.781 + 0.024 x resected-liver attenuation)] and is plotted in Figure 3B along with the observed pathologic fat content values.
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In our study, all series of R2 values for the unenhanced CT images were much higher than those for the contrast-enhanced images, indicating that contrast-enhanced CT was not the most suitable method for prediction of hepatic fat content. This finding was similar to those previously reported [20, 21]. On contrast-enhanced CT, attenuation is greatly affected by the concentration of the contrast medium, which is greatly affected by volume, rate of administration, and circulation of contrast material and the timing of measurements [20]. We used two different injection rate protocols, which likely contributed to the variability. The SD of attenuation in contrast-enhanced series was larger than in unenhanced series. Thus any difference in attenuation due to fat content was masked by the effect of the contrast medium, which resulted in a decrease in prediction power.
The spleen provides a suitable organ to which the liver might potentially be normalized. Overall splenic attenuation is not affected by most diffuse pathologic processes, and the spleen is usually located on the same axial CT slice as the liver, making it easy to measure the attenuation [20]. In our study, we measured attenuation not only of the liver but also of the spleen and analyzed both the differences and the ratios between the hepatic and splenic attenuation values.
In comparisons of attenuation measurements of liver only and of liver normalized with spleen, the R2 values of liver only were higher than those of liver normalized with spleen. The difference was not small, indicating that attenuation measurement in the spleen did not contribute to the prediction of hepatic fat content. We were somewhat surprised by this result because we were anticipating a normalizing effect with the inclusion of splenic measurement.
The R2 value of resected-liver attenuation was a bit smaller than that of whole-liver attenuation, although this difference was inconsequential. We expected that the attenuation of the resected portions of the liver would be more useful than that of whole liver for prediction of fat content, which was obtained from the resected portions of liver. The difference was very small, however, leading us to conclude that there is no difference in predictive capacity between the attenuation of whole liver and that of resected liver segments.
We recognize that this study had limitations. First, the exact sites from which the pathologic sections were obtained for evaluation of pathologic fat content were not precisely defined. Thus we did not undertake location-to-location correlation between the pathologic specimens and the attenuation measurements. Second, liver attenuation is affected not only by fat infiltration but also by other metabolic conditions, such as iron deposition [32] and hepatic edema, as in hepatitis. When fatty infiltration and iron deposition coexist, a change in attenuation of the liver can be masked [15]. Third, focal fatty infiltration sometimes occurs, and in those cases, attenuation of the liver is heterogeneous rather than homogeneous [25, 26]. Because it is difficult to define the degree of heterogenicity, we included all cases, even those with heterogenicity. We measured a large number of ROIs and used the average value for analysis. We believe that this method minimizes the effect of heterogenicity.
Comparison of hepatic attenuation with splenic attenuation is a more complex method than measuring liver attenuation alone. The liver-spleen method requires more time and effort. Because our results showed that splenic measurements did not contribute to accurate prediction of fat content, we consider comparison methods unnecessary. Simple liver attenuation measurement not only saves time and effort but also gives an intelligible and useful result.
It has been suggested [1, 10, 11] that a hepatic fat content greater than 30% increases the risk of morbidity after hepatic resection. For this reason, it also has been suggested [15] that persons with a hepatic fat content greater than 30% should not be liver donors. Results with our regression model indicate that a practical cutoff value for predicting 30% liver fat content may be an attenuation of 40 H on unenhanced CT scans. We conclude that radiologists and clinicians can use liver only attenuation to easily define the degree of fatty infiltration of the liver.
Acknowledgments
We thank Valen E. Johnson for statistical consultation, Delise H. Herron
and Ella F. Anderson for technical assistance, and Karen Phillips and Kathryn
Hale for invaluable assistance in preparing the manuscript.
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