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Quantification of Skeletal Involvement in Adults with Type I Gaucher's Disease: Fat Fraction Measured by Dixon Quantitative Chemical Shift Imaging as a Valid Parameter

¹ Department of Radiology, Academic Medical Center, Meibergdreef 9, G1-231, 1105 AZ Amsterdam, The Netherlands.
² Department of Hematology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
³ Department of Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.

Received August 10, 2001; accepted after revision March 22, 2002.

 
Address correspondence to M. Maas.

Abstract

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OBJECTIVE. The objective of our study was to determine the merit of the fat fraction of axial bone marrow measured by Dixon quantitative chemical shift imaging (Dixon QCSI) as a clinical parameter to quantitatively assess the extent of skeletal involvement in type 1 Gaucher's disease.

MATERIALS AND METHODS. Dixon QCSI was performed in 30 adult patients (age range, 18-69 years; mean, 39 years) with type 1 Gaucher's disease who were untreated. The relationship between the mean value of the fat fraction in vertebrae L3, L4, and L5 and the presence, absence, and severity of clinical bone complications (chronic bone pain, bone crisis, fracture, avascular necrosis, and joint replacement) as well as the conventional MR imaging of bone marrow involvement were studied. Also the relationship of fat fraction to sex, age, and other disease parameters (history of splenectomy, liver and spleen volume, plasma chitotriosidase, hemoglobin level, and platelet count) was evaluated. Our results were compared with the fat fraction of healthy volunteers.

RESULTS. The fat fraction measured in patients with Gaucher's disease ranged from 0.08 to 0.40 (mean, 0.20). Bone complications occurred primarily in patients with a fat fraction of less than 0.23. Univariate logistic regression analysis indicated that for every decrease of 0.1 of the fat fraction, the risk of bone complications increased 85% (p < 0.05). The fat fraction was correlated with liver size, but no correlation with other disease parameters was found. In the patient population, the fat fraction was significantly lower than in the healthy population (range, 0.27-0.55; mean, 0.37; p < 0.001).

CONCLUSION. The fat fraction of the lumbar spine when measured with Dixon QCSI is associated with the occurrence of bone complications. It may, therefore, be a clinically useful parameter.

Introduction

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Gaucher's disease is the most prevalent lysosomal storage disorder, first described in 1882 by the French pathologist Phillippe C. E. Gaucher [1]. The nonneuronopathic type 1 variant of the disease is the most common phenotype. The decreased activity of the lysosomal hydrolase, glucocerebrosidase, results in the accumulation of macrophages laden with glucosylceramide (glucocerebroside) (Gaucher's cells) in the liver, spleen, and in bone marrow. Bone disease is the most debilitating feature of type 1 Gaucher's disease: in almost all patients, skeletal involvement ranges from mild osteopenia with minimal symptoms to major bone disease such as bone infarcts, osteonecrosis, or fractures [2,3,4,5,6,7].

MR imaging is the modality of choice for the evaluation of the extent of bone marrow disease due to its excellent soft-tissue contrast and its sensitivity for the detection of both focal and diffuse disease [8,9,10,11,12,13]. The striking feature of Gaucher's disease infiltration on MR imaging is the focal or diffuse low signal intensity both on T1- and T2-weighted sequences in the bone marrow of the axial and peripheral skeleton [9,10,11]. The epiphyses of the long bones are relatively spared in mild disease, and their infiltration is thought to represent severe Gaucher's disease [9,10,11]. Areas in the bone marrow with high signal intensity on T2-weighed images are considered to represent acute disease [10].

Quantification of bone marrow involvement has become increasingly important in clinical management, both for determining eligibility for therapy and for monitoring of therapy because the currently used enzyme supplementation therapy is costly. For these reasons, Dixon quantitative chemical shift imaging (Dixon QCSI) of the lumbar spine has been investigated [4, 10,11,12, 14]. This noninvasive technique is based on the phasecontrast technique described by Dixon [15], in which the MR imaging signal is separated into the individual contributions of fat signal and water signal [12]. In this way, the amount of fat can be quantified and is represented as a fat fraction [4, 10,11,12, 14]. Evidence has been presented that infiltration of bone marrow in Gaucher's disease causes a decrease of fat fraction because the total mass of lipids is less than normal due to displacement of triglyceride-rich adipocytes by Gaucher's cells [3, 4, 13, 14]. These data support a model of a dynamic process of bone marrow alterations in which the fat fraction is inversely correlated with the amount of Gaucher's cells in the bone marrow, thus reflecting the severity of bone marrow involvement [4, 11, 12, 14].

The use of fat fraction as a parameter for invasion by Gaucher's disease is recognized among researchers and clinicians. Also the excellent reproducibility of this technique has recently been addressed [16]. Because the fat fraction is a bone marrow parameter, it may be useful as a parameter of bone disease. This would be convenient because a validated dynamic bone disease parameter is currently not available in the management of Gaucher's disease.

The goal of our study was to validate lumbar fat fraction as a quantitative overall bone disease parameter. Therefore, we analyzed the relationship of lumbar fat fraction to the presence and the clinical extent of skeletal disease, and we also studied the value of fat fraction as a prognostic parameter for bone disease, by calculating the relative risk. Furthermore, fat fraction in healthy volunteers is compared with data from the population of patients with Gaucher's disease. In addition, we studied the correlation of fat fraction with the degree of organomegaly and cytopenia, as measures of visceral and hematologic involvement of Gaucher's disease.

Materials and Methods

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Patients and Volunteers
Our study was performed in a university hospital setting, a national referral center for Gaucher's disease [17], between July 1993 and June 1998. We consecutively included adult patients with type 1 Gaucher's disease who were untreated and referred for evaluation of eligibility for treatment. All patients underwent Dixon QCSI analysis as part of the diagnostic workup that also included MR imaging of the lumbar spine and the femur [18]. The measurement of glucocerebrosidase activity in leukocytes and genotyping was used to confirm the diagnosis of Gaucher's disease in all patients [19,20,21]. The data from healthy volunteers were reported in a previous study in which the reproducibility of Dixon QCSI as a technique of measuring the fat fraction of bone marrow was evaluated [16].

Dixon QCSI Fat Fraction of the Axial Skeleton
In-phase and opposed-phase proton density—weighted spin-echo sequences were performed on a 1.5-T magnet (Magnetom SP4000 and Vision; Siemens, Erlangen, Germany) with the following parameters: TR/TE, 2500/22.3; slice thickness, 4 mm; matrix, 256x256; number of excitations, 1; field of view, 350x350 mm². The coronal measurement acquisition slices were positioned on a midsagittal localizer image, passing through the middle of the posterior parts of L3, L4, and L5, as illustrated in Figure 1A,1B,1C,1D [16]. The direction of the measurement slice was selected with care to avoid motion artifacts. Postprocessing and data analysis were performed on a Sun Sparc 20-51 workstation (Sun Microsystems, Mountain View, CA), using a previously described algorithm [22, 23]. To obtain one fat fraction value for each vertebra, we averaged the pixel values over a user-defined region of interest. This region of interest covered all except the peripheral edges of the vertebral bodies, thus avoiding inclusion of reactive changes due to degenerative disk disease and avoiding partial-volume averaging (Fig. 1A,1B,1C,1D). The mean fat fraction of the vertebrae L3, L4, and L5 was used as the overall fat fraction.

View larger version (62K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —35-year-old healthy male volunteer in whom placement of measurement slice and determination of region of interest is illustrated. Measurement slice is indicated on midsagittal localizer image. It is perpendicular to localizer image and passes through junction of anterior three quarters and posterior quarter of vertebral body L4. Slight angulation from true coronal plane is applied to make slice pass optimally through posterior parts of L3 and L5.

View larger version (87K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —35-year-old healthy male volunteer in whom placement of measurement slice and determination of region of interest is illustrated. In coronal in-phase magnitude image, vertebrae are clearly distinguishable from their surroundings.

View larger version (78K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —35-year-old healthy male volunteer in whom placement of measurement slice and determination of region of interest is illustrated. Interactively, with help of mouse, contours of vertebrae L3, L4, and L5 are drawn.

View larger version (82K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1D. —35-year-old healthy male volunteer in whom placement of measurement slice and determination of region of interest is illustrated. By applying four erosion operations to interior region of contours, we obtained regions of interest in coronal plane.

Clinical Assessment of Bone Disease
The clinical signs related to severity of skeletal disease in patients with Gaucher's disease were assessed as follows: the presence of a history of bone complications was recorded for each patient. To analyze the relationship between the severity of skeletal disease and the fat fraction, we clinically subdivided bone complications according to the presence or absence of either of the following: chronic bone pain, bone crisis, fracture, avascular necrosis, and joint replacement. If a fracture, avascular necrosis, or a joint replacement was present, the complications were considered to be severe. If only bone pain or a history of a bone crisis was present, then the complications were considered to be mild. The sex of the patients was analyzed because being male is a risk factor for osteonecrosis [7].

Radiologic Assessment of Bone Disease by Conventional MR Imaging
The radiologic involvement of bone marrow was assessed using conventional MR imaging of the peripheral skeleton as described previously [5, 11]. The scoring system was based on the fact that Gaucher's disease spreads centrifugally starting from the diaphysis. The infiltration of the femoral diaphysis was scored as 1 point, the infiltration of the proximal epiphysis—apophysis was scored as 2 points, and the infiltration of the distal epiphysis of the femurs was scored as 3 points.

Other Clinical and Laboratory Parameters
The history of splenectomy was recorded. The exact volumes of liver and spleen were measured with CT using a method described previously [17]. Plasma chitotriosidase levels served as a marker for total visceral Gaucher's cell burden [24]. The hemoglobin levels and platelet counts were determined as hematologic parameters.

Data Analysis and Statistics
Data were analyzed using SPSS 10.0 software (Statistical Package for the Social Sciences, Chicago, IL). Differences between groups were tested using the nonparametric Mann-Whitney test. A p value of less than 0.05 was considered significant. Correlation was calculated using the two-tailed non-parametric Spearman's rank correlation coefficient. Furthermore an univariate logistic regression analysis was performed to analyze the fat fraction as a bone disease parameter for the prediction of relative risk. For this purpose, the fat fraction was subdivided in categories of 10% fat fraction.

Results

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Patients and Volunteers
Thirty consecutive adult patients with type 1 Gaucher's disease were included. One patient was diagnosed with an additional bone marrow disorder, and multiple myeloma and was excluded from our study. Twenty-nine patients remained for further analysis, including 16 men, and 13 women (age range, 18-69 years; mean, 40 years). Nine patients had a clinical history of bone disease, of which six had severe bone disease (Table 1). Of these nine patients, seven underwent splenectomy. The total number of patients having a splenectomy was nine. The healthy volunteers group consisted of eight men and eight women (age range, 24-60 years; mean, 39 years).

Fat Fraction
The fat fractions measured in the vertebral marrow of patients with Gaucher's disease ranged from 0.08 to 0.40 (mean, 0.20). The value of the fat fractions in the healthy population ranged from 0.27 to 0.55 (mean, 0.37). The difference between the groups was statistically significant (p < 0.001) (Fig. 2). In Figure 3, the distribution of the fat fraction among the various subgroups is shown. No significant relationship between the fat fraction and age (p = 0.12) and no statistically significant difference between men and women (p = 0.88) were found.

View larger version (8K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —Plot of fat fraction for healthy volunteers and patients with Gaucher's disease. Dixon QCSI = Dixon quantitative chemical shift imaging, dark gray = women, light gray = men.

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —Plot of distribution of fat fraction in relation to clinical bone complications. A = healthy, B = Gaucher's disease without complications, C = Gaucher's disease with mild complications, D = Gaucher's disease with severe complications.

Skeletal Disease and Fat Fraction
When analyzing the relationship between clinical bone complications and the fat fraction, eight of nine patients with bone complications had a fat fraction of less than 0.23. To determine the relationship between the fat fraction and bone complications, we performed a univariate analysis. (The outlier was excluded in this analysis.) This univariate logistic regression analysis showed that an increase of 10% of the fat fraction meant a decrease in the relative risk for developing bone complications by 85% (p < 0.05). The radiologic skeletal involvement measured by conventional MR imaging (in the healthy volunteers scored as zero) showed a significant inverse correlation with the fat fraction (r = -0.78, p < 0.001). Also a relationship was established between the MR imaging score and the occurrence of bone complications (r = 0.58, p < 0.001).

Fat Fraction in Relation to Other Disease Parameters
In general, a lower fat fraction was found in patients having undergone splenectomy; this finding was nearly significant compared with the group who had not undergone splenectomy (p = 0.06). The inverse relationship between the fat fraction and the volume of the liver is significant (r = -0.77, p < 0.0001) but did not reach significance for the volume of the spleen (r = -0.52, p = 0.79). In a univariate analysis, the occurrence of bone complications was significantly associated with the presence or absence of the spleen (p = 0.002) and with platelet count (p = 0.01) (a higher risk for bone complications in patients without a spleen and with a high platelet count). These two parameters are obviously related. Pancytopenia in patients having undergone splenectomy may reflect bone marrow infiltration and is possibly related to fat fraction. However, only four of nine patients having undergone splenectomy showed slightly decreased hemoglobin levels or platelet counts. In these patients, no relationship was established between the fat fraction and these parameters. The relationship between chitotriosidase levels and the fat fraction did not reach significance.

Discussion

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Ours is the first report that describes, in an adult population of patients with Gaucher's disease who were untreated, a close relationship between the extent of skeletal disease and a quantitative secondary parameter—that is, lumbar bone marrow fat fraction. The detailed comparison of the lumbar fat fraction and both clinical and radiologic (MR imaging) skeletal disease suggests that the lumbar fat fraction may be a sensitive predictor of ongoing skeletal disease in patients with Gaucher's disease. The fact that the fat fraction correlates well with the peripheral MR imaging score, a parameter that is known to detect response to therapy [14], suggests that the fat fraction is a potentially sensitive quantitative parameter for the evaluation of skeletal response to enzyme supplementation therapy.

Our study revealed that Dixon QCSI as assessed with MR imaging in patients with Gaucher's disease significantly relates the extent of mainly peripheral bone disease to the axial lumbar bone marrow fat fraction. Bone complications preferentially occurred in patients with a fat fraction of less than 0.23. In a univariate logistic regression analysis, we established a further relationship between the fat fraction and the risk of the occurrence of bone complications: when the fat fraction decreases 10%, the relative risk of developing bone complications increases 85% (p < 0.05).

This analysis is limited by the small sample size and the lack of longitudinal data. Nevertheless, we believe that on the basis of these data, the group of patients with Gaucher's disease and a low fat fraction without bone complications are at risk. This result is in concordance with an earlier observation made by Rosenthal et al. [11], who reported that marrow infiltration and replacement by Gaucher's cells can remain silent for a long period before the appearance of clinically significant bone disease. This relationship between a low fat fraction and a relative risk of bone complications is further supported by the observation made during follow-up. The two patients who had bone complications during enzyme therapy had a low fat fraction at baseline and showed no or minor improvement in the fat fraction during therapy [25]. The correlation that was suggested between low fat fraction and the development of bone complications but could not be proven earlier is supported in our study. Furthermore, a significant difference was found in the mean fat fraction between patients with Gaucher's disease and that in healthy volunteers.

In our data, one patient was an outlier in fat fraction as well as liver volume, but not in genotype (N370S/L444P). It is difficult to find an explanation for this finding. The fact that he is the only patient who had a bone crisis several weeks before the Dixon QCSI measurements may influence the local bone marrow composition and, therefore, the fat fraction. However, to our knowledge, no literature data supports this assumption.

Two other studies have reported on the lumbar fat fraction in untreated patients with type 1 Gaucher's disease. Johnson et al. [4] performed Dixon QCSI measurements in 24 patients. Their fat fraction ranged from 0.006 to 0.32, with a mean of 0.10. Rosenthal et al. [14] studied 12 patients with type 1 Gaucher's disease using Dixon QCSI; their fat fraction ranged from 0.006 to 0.26 with a mean of 0.073. Compared with these data, our fat fractions are higher and suggest that our patient population was less severely affected. An additional explanation for the difference may be the age difference. In the two studies mentioned, a considerable number of children and adolescents were included. The younger, healthy age groups will intrinsically show a lower fat fraction because of the predominant presence of red cellular marrow in their axial skeleton [26]. During adolescence, a marked conversion of red to fatty marrow occurs, resulting in a dynamic increase in fat fraction values [8, 25,26,27,28]. Thus, in a young person, a measured low fat fraction may be the sum of Gaucher's disease infiltration and the presence of more red marrow. Our study is the first that compared the distribution of the lumbar fat fraction of patients with adult type 1 Gaucher's disease with the distribution of the lumbar fat fraction in adult controls with a comparable age distribution. The lumbar fat fraction of patients with adult type 1 Gaucher's disease is significantly reduced.

In two other reports of Dixon QCSI data, MR imaging scores and skeletal disease manifestations are compared [7, 13]. Rodrique et al. [7] did not find the fat fraction to be a significant determinant for the occurrence for osteonecrosis. However, correlation of lumbar fat fraction with less severe manifestations of skeletal disease was not evaluated in that particular study. In the study by Rosenthal et al. [14], the MR imaging score of the peripheral skeleton and the fat fraction measured by Dixon QCSI were analyzed as a response parameter to therapy. The relationship between fat fraction and the conventional MR imaging score, however, was not analyzed.

Our study has a few limitations. First, Dixon QCSI is not a standard sequence on MR imaging and, therefore, is not widely available. Thus the fat fraction as such is not a parameter that is used worldwide. The statistical evaluation is hampered because our study, like that in almost every article concerning Gaucher's disease, is limited by the small number of patients.

In Gaucher's disease, the various parameters that monitor the possible sites of involvement such as organ volume, platelet count, and history of skeletal disease show a poor correlation [4, 7, 14]. Although a significant correlation between fat fraction and liver volume was found in our study, this correlation was not found with spleen volume. The burden of Gaucher's disease in the liver and spleen does not necessarily predict the burden of Gaucher's disease in bone marrow; a considerable individual variation may exist in the extent of involvement of visceral and bone marrow compartments. This variation could imply that nonskeletal parameters will not adequately reflect skeletal or bone marrow involvement and emphasizes the need for adequate separate quantitative assessment of bone marrow to allow overall interpretation of disease severity.

In summary, to answer the goals of our study, we conclude that fat fraction measurements obtained through the use of Dixon QCSI showed a close correlation with the clinical occurrence of skeletal involvement. A significant difference was found between the fat fraction in patients with untreated Gaucher's disease compared with that of healthy volunteers. Finally, the fat fraction may serve as a prognostic marker because univariate regression analysis showed that a decrease in the fat fraction of 10% is associated with an increased risk for occurrence of bone complications of 85%. Only a longitudinal study in patients undergoing treatment can prove the value of the fat fraction in clinical decision-making and outcome. For optimal patient care, the skeletal involvement must be monitored on a regular basis, and Dixon QCSI seems to be a valuable tool.

Acknowledgments
 
We thank C. van Kuijk and G. Hassan Bouber for their support in the preparation of this manuscript.

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