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Gastrointestinal Imaging |
1 From the Departments of Radiology (A.C.A.W., A.Q., J.A.L., B.M.Y., Y.L., F.V.C.), Pathology (A.L.), and Medicine (R.B.M.), University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0628. Received December 12, 2005; revision requested February 7, 2006; revision received March 30; final version accepted June 1. Address correspondence to A.Q. (e-mail: Aliya.Qayyum{at}radiology.ucsf.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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Materials and Methods: Committee on Human Research approval was obtained, and compliance with HIPAA regulations was observed. Patient consent was waived by the committee. Thirty-eight patients with cirrhosis (30 men, eight women; mean age, 58 years; range, 34–76 years) who underwent abdominal MR imaging and had contemporaneous liver biopsy were retrospectively identified. Two radiologists independently quantified liver fat according to the relative loss of signal intensity and compared this loss on opposed-phase and in-phase T1-weighted gradient-echo images. Liver fat percentage and presence of iron deposition were independently recorded by a pathologist. Generalized linear models, which included a mixed–random effects model, were used to determine the effect of iron deposition on the Spearman correlation coefficient for relative signal intensity loss versus histopathologically determined fat percentage.
Results: Liver iron deposition was found in 25 of 38 patients. Liver fat percentage (mean, 3%; range, 0%–25%) was identified histopathologically in 14 of 38 patients and in nine of 25 patients with iron deposition. For both readers, relative signal intensity loss at opposed-phase imaging was closely and significantly correlated (P < .05) with histopathologically determined liver fat percentage in patients without iron deposition (r = 0.7 for reader 1, r = 0.6 for reader 2), but no such correlation was found in patients with iron deposition (r = 0.1 for reader 1, r = –0.31 for reader 2; P > .05).
Conclusion: Signal intensity loss on in-phase images caused by the presence of liver iron is a potential pitfall in the determination of liver fat percentage at opposed-phase MR imaging in chronic liver disease.
© RSNA, 2007
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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Identification and quantification of liver fat by using noninvasive imaging has been extensively studied, and signal intensity loss on opposed-phase gradient-echo T1-weighted magnetic resonance (MR) images frequently is regarded as an accurate method of detection and quantification of liver fat (7–10). Increased secondary iron deposition, however, occurs in many chronic liver diseases, such as hepatitis C, nonalcoholic fatty liver disease, and cirrhosis (11,12). The presence of liver iron is reported to cause signal intensity loss on in-phase gradient-echo MR images in patients with hereditary hemochromatosis who have massive iron deposition (13,14).
Recognition of a possible confounding factor, such as iron deposition, is essential to the understanding of the limitations and development of imaging protocols for the evaluation of diffuse liver disease. To our knowledge, there are no prior studies in which the effect of more subtle secondary iron deposition on liver fat quantification was determined by using opposed-phase imaging in nonhemochromatosis chronic liver disease. We hypothesized that liver iron deposition influences fat detection by using T1-weighted opposed-phase gradient-echo MR imaging in chronic liver disease. Thus, the purpose of our study was to retrospectively determine the effect of liver iron deposition on the evaluation of liver fat by using opposed-phase MR imaging.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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We searched our radiology and pathology information systems to identify patients who met the following inclusion criteria: (a) The patient underwent abdominal MR imaging between 1999 and 2004, and imaging included T1-weighted in-phase and opposed-phase gradient-echo sequences (these sequences were part of our standard abdominal MR imaging protocol during this period). (b) The patient received a histopathologic diagnosis of cirrhosis that was based on findings at liver biopsy, either percutaneous biopsy or biopsy at surgical resection, performed within 30 days before or after MR imaging. Forty-eight patients fulfilled these criteria.
Patients were excluded on the basis of the following criteria: (a) Available imaging data did not correspond to available histopathologic data because of interval surgery (n = 6), (b) histopathologic slides or paraffin blocks were not available (n = 2), (c) an artifact was observed on MR images and precluded accurate measurement of signal intensity (n = 1), and (d) MR studies were incomplete (n = 1).
Thirty-eight patients formed the final study group (30 men and eight women; mean age, 58 years; range, 34–76 years). Histopathologic sampling of all patients included in the study was performed after MR imaging (mean, 14 days; range, 1–30 days). The clinical indication for MR imaging in these patients was evaluation of cirrhosis and/or screening for hepatocellular carcinoma. The cause of cirrhosis in the study group was hepatitis C (n = 22), hepatitis B (n = 6), cryptogenic cirrhosis (n = 5), primary sclerosing cholangitis (n = 2), alcoholic liver disease (n = 1), nonalcoholic steatohepatitis (n = 1), and autoimmune hepatitis (n = 1). A review of medical charts was performed by an individual (R.B.M.), and all reported diagnoses were based on clinical, biochemical, cytologic, and histopathologic information obtained. None of the patients had a clinical diagnosis of hemochromatosis that was based on review of medical records.
MR Imaging Technique
MR imaging was performed with a 1.5-T superconducting magnet (Signa; GE Medical Systems, Milwaukee, Wis) and a four-element torso phased-array coil (GE Medical Systems). Nonenhanced transverse T1-weighted in-phase and opposed-phase breath-hold spoiled gradient-echo MR imaging sequences were performed with repetition time msec/echo time msec of 90–200/1.8–2.3 (opposed-phase imaging) and 4.2–4.6 (in-phase imaging), flip angle of 70°–90°, section thickness of 8 mm, intersection gap of 1 mm, matrix of 256 x 128–192, field of view of 32–40 cm, and one signal acquired. A dual-echo acquisition was used in 30 of 38 patients. In eight patients, the dual-echo technique was not used; however, these patients were included in the study because an internal standard of reference (the spleen) was used.
Histopathologic Analysis
To our knowledge, none of the patients were receiving dietary modification therapy or lipid-lowering drug treatment. Tissue was obtained with needle biopsy (n = 2), hepatic segmentectomy (n = 7), or hepatectomy (n = 29). Indications for total hepatectomy, partial hepatic resection, and needle biopsy were hepatic transplantation (n = 29), resection of hepatocellular carcinoma (n = 7), and staging of chronic hepatitis (n = 2), respectively. One pathologist (A.L.), with 6 years of experience that included subspecialty training in hepatic pathology, independently reviewed the histopathologic slides in all patients. The pathologist did not have knowledge of imaging data and was unaware of clinical data obtained from chart review during histopathologic analysis.
In each patient, one representative histopathologic slide was reviewed for fat and iron quantification. For the purpose of this study, hepatic steatosis was defined as any presence of macrovesicular fat deposits, not necessarily a percentage greater than 5%; a percentage greater than 5% is considered indicative of clinical disease (15,16). Hepatic steatosis was characterized by the presence of large fat droplets that enlarged the hepatocytes and eccentrically displaced the nucleus to the periphery. Liver fat quantification was retrospectively determined as the overall impression of the percentage of fat-containing hepatocytes on hematoxylin-eosin–stained specimens (15,16).
Hepatic iron deposition was identified with Perls Prussian blue stain of biopsy specimens. The severity of iron deposition was assigned a grade on the basis of the ease of observation of iron deposits and the magnification required to do so. The scale was as follows: grade 0, granules were absent or barely discernible at x400 magnification; grade 1, granules were barely discernible at x250 magnification or were easily confirmed at x400 magnification; grade 2, discrete granules were visible at x100 magnification; grade 3, discrete granules were visible at x25 magnification; and grade 4, masses were visible at x10 magnification or with visual observation (17).
Data Collection and Image Analysis
Two radiologists (A.C.A.W, J.A.L., with 7 and 5 years of experience that included subspecialty training in abdominal imaging, respectively) who were unaware of histopathologic results independently reviewed the MR images on a picture archiving and communication system workstation (Impax; Agfa, Mortsel, Belgium). The radiologists were unaware of clinical data obtained from chart review during image analysis. The signal intensity from regions of interest in the liver and spleen was recorded for T1-weighted in-phase gradient-echo and opposed-phase gradient-echo sequences. These regions of interest were drawn so as to be between 1.5 and 2.0 cm2, to include representative areas of parenchyma that did not contain blood vessels or an artifact, and to be at a similar location and depth from the surface coil at paired sequences.
Liver signal intensity was recorded as the mean of multiple readings from regions of interest placed in the anterior and posterior segments of the right lobe and those placed in the medial and lateral segments of the left lobe. The signal intensity was acquired for areas above, at the level of, and below the porta hepatis whenever possible (12 regions of interest). The minimum number of readings acceptable for the case to be included in the study was three for the right lobe and one for the left lobe. The mean number of regions of interest obtained was 9.7 (range, 5–12). Relative liver signal intensity loss was quantified on in-phase and opposed-phase T1-weighted gradient-echo images as the percentage relative signal intensity change in the liver by using the following formula (18): (SIin – SIopp)/SIin · 100, where SI is average liver signal intensity divided by the average spleen signal intensity, SIin is signal intensity on in-phase images, and SIopp is signal intensity on opposed-phase images. The signal intensity of the spleen was used as a denominator in the formula to adjust for the lack of an objective signal intensity scale on MR images (18,19). The signal intensity of the spleen was obtained at levels that corresponded to the three levels at which the signal intensity of the liver was obtained; however, in some patients the size of the spleen was too small for placement of regions of interest at three levels. The regions of interest were placed on the spleen to include representative areas of parenchyma that did not contain blood vessels or an artifact, and we avoided any regions of obvious visual inhomogeneity in signal intensity, such as siderotic nodules. The regions of interest were between 1.5 and 2.0 cm2. The mean number of regions of interest that were placed on the spleen in each patient was 2.8 (range, 2–3). The average of these readings was used as the denominator in the previously described formula to adjust for the lack of an absolute signal intensity scale on MR images.
Statistical Analysis
A statistician (Y.L.) with 16 years of experience in biomedical research performed the data analysis by using a statistical software package (SAS, version 8.2; SAS Institute, Cary, NC). A 
of 5% was used for statistical significance. The intraclass correlation coefficient for reader agreement and the corresponding 95% confidence interval were calculated by using the Fleiss and Shrout method (20). Generalized linear models, which included a mixed–random effects model, were used, and the Spearman correlation coefficient was used to assess the association between relative signal intensity loss and percentage fat measured by using histopathologic analysis for each reader.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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For both readers, relative signal intensity loss on opposed-phase images was significantly correlated (P < .05) with histopathologically determined liver fat percentage in patients without iron deposition (reader 1, r = 0.6; reader 2, r = 0.7), but no such correlation was found in patients with iron deposition (reader 1, r = 0.1; reader 2, r = –0.31; P > .05) (Figs 1 and 2). For reader 1, only three of nine patients with liver fat and liver iron deposition demonstrated the expected signal intensity loss on opposed-phase images seen in association with liver fat, whereas signal intensity loss was not observed by reader 2 (reader 1, mean signal intensity change of 21.7% to –50.8%; reader 2, 0% to –64.4%) (Fig 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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Even though in-phase gradient-echo images are T1 weighted, they are frequently obtained with an echo time of approximately 4.2 msec, which is long enough to allow T2*-shortening effects. Opposed-phase images are then acquired by using a shorter echo time, approximately 2.1 msec, that does not permit as much signal intensity loss (7,23). In other words, iron deposition causes an accelerated decay of signal as echo time increases from opposed-phase to in-phase sequences, and this phenomenon is perceived as a signal intensity loss on the in-phase images. Although the technique settings can be modified for use of a longer echo time for in-phase and opposed-phase images, the recognition of liver iron as a potential pitfall to the determination of liver fat by using opposed-phase MR imaging suggests that other MR techniques such as spectroscopy may be preferable in patients with more advanced liver disease or increased likelihood of liver iron deposition.
Hepatic steatosis is a common feature of the two most prevalent chronic liver diseases, hepatitis C and nonalcoholic fatty liver disease, and a common feature of potential donors in living donor liver transplantation. The presence and severity of liver fat has diagnostic, prognostic, and therapeutic implications (5,24). Liver iron deposition is a common secondary feature of many chronic liver diseases. Though the clinical significance of such secondary iron loading is controversial and appears minimal at most (11), recognition of the effect of iron accumulation on the determination of liver fat with MR imaging is crucial. This is especially true in nonalcoholic fatty liver disease because MR imaging is being increasingly explored as an alternative to invasive liver sampling (25).
In the patients with cirrhosis in our study, we found that only 37% (14 of 38) had liver fat seen at histopathologic analysis, and the mean fat percentage (3%) was small. This is not an unexpected observation because the development of cirrhosis may be associated with a diminution in the severity of steatosis (26).
Several limitations of our study should be noted. First, this was a retrospective study with a patient population that consisted of a small number of individuals with proved cirrhosis. To increase the likelihood of liver iron deposition, we purposely selected this population and introduced a selection bias, which may explain the lower prevalence of fat in these subjects. Further studies in larger groups of patients are needed to confirm our results in patients with higher grades of liver fat and to evaluate the differences in the effect of specific degrees of steatosis. Nevertheless, in spite of modest grades of steatosis, we were able to demonstrate a difference in the correlation of liver fat percentage and MR signal intensity changes when we compared in-phase with opposed-phase images in the absence or presence of iron deposits. Although we recognize the importance of evaluating whether signal intensity loss correlates with the severity of iron deposition among patients with or without liver fat, we were unable to determine this correlation because of the small number of patients classified in each iron grade category and, thus, the consequent lack of statistical power.
Second, because of the retrospective nature of this study, dual gradient-echo acquisition was not used in eight patients. The spleen, however, was used as an internal standard of reference for all sequences to account for differences in acquisition.
Third, we used the spleen as an internal standard of reference that may itself be a site of iron deposition (27). In patients with cirrhosis, however, splenic iron is generally seen in the form of Gamna-Gandy bodies, or siderotic nodules, which are identified in approximately 10% of patients with portal hypertension and are recognized on MR images as foci of low signal intensity or as signal void on T1- and T2-weighted images (28,29). In our study, regions of interest were placed on the spleen, and any regions of obvious inhomogeneous signal intensity, such as siderotic nodules, were avoided.
It is becoming increasingly important to detect and precisely quantify liver fat in patients with common liver diseases, including cirrhosis, of all stages, and opposed-phase MR imaging is a popular method for this purpose. Our study findings indicate that the recognition of a confounding factor, such as iron deposition, is essential to the understanding of the limitations of this technique for the evaluation of common chronic liver diseases.
In conclusion, signal intensity loss on in-phase images caused by the presence of liver iron is a potential pitfall in the determination of mild degrees of liver fat by using opposed-phase MR imaging in common chronic liver diseases.
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ADVANCE IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCE IN KNOWLEDGEReferences |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, A.C.A.W., A.Q.; 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, A.C.A.W., A.Q., B.M.Y.; clinical studies, A.C.A.W., J.A.L., A.L.; statistical analysis, Y.L.; and manuscript editing, all authors
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