Journal of X-Ray Science and Technology 22 (2014) 541–549 DOI 10.3233/XST-140444 IOS Press
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Detection of uric acid depositing in tophaceous gout using a new dual energy spectral CT technology Xiaohu Lia,1 , Xu Wangb,1 , Yonqqiang Yua,∗ , Bin Liua,∗ , Jing Caic , Li Xiad , Li Luod , Wanqin Wanga , Qianyun Dinga , Chao Zhanga and Jie Wanga a Department
of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China of Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China c Department of Rheumatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China d Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China b Department
Received 23 February 2014 Revised 24 April 2014 Accepted 27 April 2014 Abstract. OBJECTIVE: To assess the feasibility and diagnostic value of detecting uric acid depositing among patients with tophaceous gout using a dual energy CT based Gemstone spectral imaging (GSI) technology for qualitative analysis of uric acid. METHODS: Thirty one patients with clinically detectable tophaceous gout and 10 healthy volunteers underwent Discovery CT 750 HD scan with GSI mode. We selected four case groups of tophi, muscles, cortical bone, and cancellous bone. Each has a region of interest (ROI) of 10 mm diameter. We then analyzed and compared the difference of CT imaging spectroscopy quantitative parameters including concentration of uric acid, calcium, and water levels. The univariate analysis of variance and independent samples t-test were applied in data analyses. RESULTS: In case group of tophi base substance, the concentration levels were 1268.8 ± 32.2 mg/cm3 for uric acid (Ca), 19.4 ± 9.5 mg/cm3 for calcium (uric acid), 10.8 ± 9.5 mg/cm3 for calcium (water), and 1171.0 ± 26.8 mg/cm3 for water (calcium), respectively. In cortical bone case group, the four base substance concentration levels changed to 1333.6 ± 83.8 mg/cm3 , 271.1 ± 85.0 mg/cm3 , 262.6 ± 85.4 mg/cm3 , and 1230.8 ± 77.0 mg/cm3 . In muscles case group, the four base substance concentration levels were 1143.5 ± 15.7 mg/cm3 , 12.3 ± 5.0 mg/cm3 , 4.4 ± 1.9 mg/cm3 , and 1054.1 ± 14.6 mg/cm3 . Finally, in cancellous bone case group, the corresponding base substance concentration became 1070.9 ± 26.4 mg/cm3 , 85.1 ± 46.9 mg/cm3 , 77.4 ± 46.7 mg/cm3 , and 988.0 ± 23.4 mg/cm3 . Except tophi and muscle differences between Calcium (uric acid) concentration and differences in Calcium (water) concentration, which were not significantly different (p > 0.29), the remaining group pairwise comparisons of the parameters were significantly different (p < 0.05).
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Li Xiaohu and Wang Xu are the first authors who contributed equally to the article. This paper was also published in Chinese in the Chinese Journal of Radiology 2014; 48: 303∼307. The authors have received permission from the Chinese Journal of Radiology to publish it in English in the Journal of X-ray Science and Technology. ∗ Corresponding authors: Bin Liu, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Er Rd, Hefei 230022, Anhui, China. Tel.: +86 0551 62922368; Fax: +86 0551 62922368; E-mail: [email protected]. Yongqiang Yu, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Er Rd, Hefei 230022, Anhui, China. Tel.: +86 0551 62923223; Fax: +86 0551 62923223; E-mail: [email protected]. c 2014 – IOS Press and the authors. All rights reserved 0895-3996/14/$27.50
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CONCLUSION: Dual-energy spectral CT can detect gout tophi within the peripheral joints of the patients. The quantitative measurement of the tophi concentration provides a new imaging method for quantitatively monitoring clinical outcomes of tophi. Keywords: Hyperuricemia, tomography, X-ray computed, comparative study
1. Introduction Gout is caused by excessive uric acid in the body with the form of monosodium urate (MSU) crystals deposition in the joint and surrounding tissue. The gout accumulation and repeated attacks can eventually cause joint deformities and thus seriously affect the quality of life in patients with gout [1]. At present, the conventional imaging diagnosis modalities of gouty arthritis include X-ray, CT and MRI. However, all these imaging examination methods lack the clinically required specificity and sensitivity, especially for early diagnosis of gouty arthritis [2]. Recently, using dual-source CT (DSCT) has shown the promising results of not only detecting uric acid crystallization of peripheral joint, and also quantifying the tophi number and total gout volume of patients, which assist to estimate tophi deposition [3, 4]. The dual energy spectral CT using instantaneous switching between high and low energy can realize the simultaneous acquisition of two sets of 40 ∼ 140 keV monochromatic CT image data. Then, using the dual-energy projection data space analysis, the researchers are able to compute and generate the spectrum curves of different substances, and thus to some extent to achieve a qualitative and quantitative measurements of substance separation [5]. The purpose of the present study was to assess the utility of dual energy spectral CT in detecting uric acid depositing in tophaceous gout with base material mapping. With the improvement of people’s living standard, the high purine dietary intake results in the changes of their diet structure. Recently, the incidence of gout also presents an increasingly rising momentum [6]. Hyperuricemia is one of the risk factors of gout. With the increase in blood uric acid level, the prevalence rate of gout also increases. However, the gout is not always accompanied by hyperuricemia. In fact, the blood uric acid level of approximate 40% of patients does not exceed the normal reference value range in the process of acute gout attacks. Currently, the gold standard in diagnosis of gout is to find distinctive needle uric acid sodium crystal through the joint puncture. The joint puncture is not only an invasive procedure, the detection sensitivity also varies widely depending on the extracted quantity of uric acid sodium crystallization as well as the deep puncture site and/or insufficient technical level of operating personnel. As a result, this procedure may actually miss acquiring samples from some atypical sites and make the diagnosis difficulty for the cases containing the regions with normal serum uric acid level [2, 7]. Therefore, the non-invasive detection of early joint MSU deposition by imaging methods has been attracting increasingly interest in the clinical practice. Preliminary studies indicated that dual-energy CT can detect early and much smaller tophi than using the traditional CT technology [7,8]. The imaging theory of dual-energy CT was first proposed and tested in 1970s [9], some researches related to the dual energy subtraction technology were unable to be routinely applied in clinical practice due to the limitation of imaging equipment and technology in the 1980s [10]. After 2009, instantaneous dual voltage technology as the core technology of dual-energy spectrum CT was emerged. It acquires two sets of absorption projection data with good consistency through the low and high voltage transient. It can translate the absorption projection data to material density projection data and achieve the qualitative classification and quantitative measurement [5]. The Material decomposition does not identify materials, but rather, given two selected basis materials, material decomposition determines how much of each material would be needed to produce the observed low and high voltage measurements (such as iodine/water pairing, calcium/water pairing, uric acid/calcium pairing, etc.) then quantitative analysis pairing base material content of this tissue. In the clinical practice, when paired two base materials have
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similar constituent with the tissue’s actual composition, base material concentration imaging can more accurately reflect the corresponding component content of this organization, for instance, we can use the iodine-based map to measure the thyroid iodine concentration and evaluate thyroid function [11]. Wu et al. [12] apply the quantitative analysis of the iodine-based map which can effectively reflect the hemodynamic changes of the lung parenchyma, also provide more objective and scientific reasons in detecting small embolisms or pulmonary embolisms of occult sites, as well as their extent, which can better assist for disease evaluation and treatment. 2. Materials and methods 2.1. Subjects of the study The study dataset includes two groups. The first patient group involves 31 gout patients who were diagnosed by the clinical and laboratory findings in the First Affiliated Hospital of AnHui Medical University from May 2011 to September 2012. All patients had the history of acute gout attacks in this patient group. The group includes 30 male and one female patients with the age ranging from 22 to 65 years old. The mean age is 42 years old with a standard deviation of 13 years old. The diagnostic criteria promulgated by the American College of Rheumatology (ACR) in 1977 were used in our study [13]. In our laboratory tests, the uric acid of acute exacerbations varied from 381 to 777 µmol/L (the normal reference value ranged from 208 to 428 µmol/L). Five patients also underwent foot radiography. Four patients underwent resection of lesions and confirmed as gout nodules by the pathological exams. The second case group includes 10 healthy young doctors of Radiology Department, the First Affiliated Hospital of Anhui Medical University, as volunteers. The CT data of these volunteer cases were acquired during April 2012 to September 2012, which were collected as control cases in this study. Those volunteers include 8 men and 2 women with the age ranging from 21 to 35 years and mean (26 ± 7) years old. There were no positive findings in both blood uric acid test and physical examination among all of those volunteers who also had no history of arthritis, joint trauma, joint pain or peripheral joint disease. An informed consent form was signed before the examination. 2.2. Techniques of computed tomography All CT examinations involved in our dataset were performed using a single source dual-energy CT system (Discovery CT750 HD, GE Healthcare, Milwaukee, WI, USA), equipped with 64 detectors and a 50-cm field of view. This system is capable of rapidly switching tube voltage between 80 and 140 kVp in less than 0.5 ms. Suspected tophi deposition in ankle joint was scanned in the patient group, while both sides of the ankle joint were scanned in the healthy control group. The detail CT scanning protocol includes following parameters of scan layers of 10 layers, slice thickness of 5.00 mm, interlayer spacing of 5.00 mm, the tube voltage of 80 to 140 kVp, instantaneous switch time of 0.5 ms, the tube current of 600 mA, pitch of 1.375, detector collimation of 64 × 0.625 mm, X-ray tube speed of 0.8 s/cycle, field of view (FOV) of 14.8 cm × 14.8 cm. The final CT images were reconstructed with slice thickness of 1.25 mm. 2.3. Image analysis and data measurement Both the image analysis and data measurement were performed in the GE Healthcare AW 4.4 workstation, using an imaging spectral browser of GSI Viewer. Using the system interface, an observer manu-
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Fig. 1. A foot X-ray plain film of a patient without high density shadow around the joints and obvious signs of damage.
Fig. 2. An uric acid (ca) base image of the same patient shown in Fig. 1. The image shows the visible class round tophus sedimentation between the medial tarsal joints of foot and spread to the adjacent bone erosion.
ally defined the physical separation (region segmentation) for feature data analysis. Uric acid-calcium, water-calcium were selected as basics to access four separate mappings which were uric acid based (calcium) mapping, calcium based (uric acid) mapping, water based (calcium) mapping and calcium based (water) mapping, respectively. The size of tophi was measured in the largest cross-sectional distance (diameter). All sections or slices depicting tophi with estimated diameter greater than 10 mm were selected. For each case, a Region of interest (ROI) with the greatest cross-sectional diameter was selected. The area of ROI was about 1/4 to 1/3 of that section determined by the greatest cross-sectional diameter in order to avoid the calcifications as much as possible. ROIs of the same size were placed in the muscle, compact bone and spongy bone regions in the same CT slice plane [14]. In the control case group, we chose roughly the same ankle joint sections as those selected in the patient group and redid the same mapping procedures. Two radiologists with more than 10-year CT radiological image diagnosis working experiences repeated those steps three times separately. We then took the average region segmentation and feature measurement as the final results. 2.4. Statistics methods A publically available statistical data analysis software package, SPSS 16.0, was used for statistical analysis in this study. One-way ANOVA test was used in comparing the tophi concentration levels of the baseline substances in each selected ROI of one CT examination. LSD (least significant difference) was used for pairwise comparison within each group when the homogeneity of variance was satisfied. Otherwise, Tamhane T2 test was chosen. In addition, the independent sample t-test was used to compare the above quantitative parameters between the patient case group and the control group. The criterion of P < 0.05 was considered to be a measurement index of statistical significance. 3. Results We detected 106 pieces of tophi with diameters greater than 10 mm in 31 ankle joints of gouty patients’ using the dual energy CT uric acid (calcium) image. In the control case group, 60 ROIs were selected.
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Table 1 The different base substance concentration between the subjects of patient group and control group among different tissues imaged with spectral CT (mg/cm3 , x ¯ ± s) Position ROI (n) Ua (ca) Ca (ua) Ca (wa) Wa (ca) Patient group Tophi 106 1268.8 ± 32.2 19.4 ± 9.5 10.8 ± 9.5 1171.0 ± 26.8 Muscle 106 1143.5 ± 15.7 12.3 ± 5.0 4.4 ± 1.9 1054.1 ± 14.6 CAB 106 1070.9 ± 26.4 85.1 ± 46.9 77.4 ± 46.7 988.0 ± 23.4 COB 106 1333.6 ± 83.8 271.1 ± 85.0 262.6 ± 85.4 1230.8 ± 77.0 F 665.04 646.13 642.10 692.41 P < 0.01 < 0.01 < 0.01 < 0.01 Control group Muscle 60 1139.8 ± 4.8 12.8 ± 1.7 4.9 ± 1.6 1050.7 ± 4.7 CAB 60 1067.5 ± 9.3 51.6 ± 16.8 44.1 ± 16.6 983.4 ± 9.0 COB 60 1320.1 ± 61.6 299.0 ± 70.2 291.4 ± 70.6 1219.9 ± 56.7 ta 2.200 0.912 1.044 2.197 Pa < 0.05 > 0.05 > 0.05 < 0.05 1.204 6.642 6.638 1.763 tb Pb > 0.05 < 0.01 < 0.01 > 0.05 tc 1.183 2.159 2.340 1.035 Pc > 0.05 < 0.05 < 0.05 > 0.05 Notes: Ua (ca): uric acid (Calcium); Ca (ua): Calcium (uric acid); Ca (wa): Calcium(water); Wa(ca): Water(Calcium). CAB: cancellous bone COB: cortical bone. a , b and c represent the statistical comparison results (t-value and p-value) between the patient group and control group for the muscles, cancellous bone and cortical bone, respectively.
All clinical palpation confirmed tophi were detected by using uric acid (calcium) mapping of CT images. Although the conventional X-ray images of the feet show negative in 5 cases (e.g., Fig. 1), the uric acid (Ca) based CT images show MSU clearly (e.g., Figs 2 and 3 of the same patient as shown in Fig. 1). For another patient (as shown in Figs 4 and 5), the calcium (uric acid)-based CT images also enabled to clearly demonstrate MSU on adjacent region with bone erosion (Fig. 4), including those with eroded bone formation with hardened edges. In addition, the uric acid (Ca) based substances images enabled to show a high concentration level of uric acid deposition tophi using a pseudo-color in uric acid (calcium) based maps because the areas of high concentration of uric acid can be more easily labeled, which help visually view the distribution of tophi (Fig. 5). Table 1 shows the summary of the different base substance concentration between the subjects of patient and control groups. The values of the patient group were computed based on the substances pairwise comparison. The results showed that except tophi and muscle differences between Calcium (uric acid) concentration and differences in Calcium (water) concentration, which were not significantly different with p = 0.342 and p = 0.291, respectively, the remaining group pairwise comparisons of the parameters were significantly different (p < 0.05). 4. Discussion 4.1. Diagnostic value of detecting uric acid depositing using Gemstone spectral imaging (GSI) with base material mapping In this study we chose uric acid and calcium as the first base material pairing because the main composing organizations of the affected joint are composed of tophus and adjacent joint bone in gouty arthritis. The results of this study showed that the calcium concentration of cortical bone was higher than tophi
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Fig. 3. A calcium (uric acid) base image of the same patient of Figs 1 and 2. It shows a clear hardening zone in bone erosion edges.
Fig. 4. This calcium (uric acid) base image shows adjacent bone erosion situation and the calcification of the tophus.
and muscle, which can well display the eroded edge of bone in calcium-based image. Meanwhile, the intra-articular tophi has erodent characteristic of bone, which is one of the most important determinants of bone destruction in gouty arthritis [15]. Thus, we can detect tophi using uric acid-based image that clearly shows the bone destruction and condition of tophi adjacent joint using calcium-based image at the same time. As a second base material pairing, we chose water and calcium because water is one of the standard substances in conventional CT imaging and calcium is not only the main component of human bones, but also the main composition of many calcified lesions. As a result, these two substances have the most content in the body [14]. In this study, we analyzed spectrum CT scan data in 31 patients with clinically diagnosed gout and also quantitatively analyzed the ankle intra-articular tophi by using base material image. The results showed that uric acid (calcium) concentration of tophus was higher than spongy bone and muscle, thus MSU in ankle joint and soft tissue can be clearly displayed on the uric acid based image. This will help us in detecting possibly MSU which deposited in the peripheral intra-uric acid in base material images. Next, we comprehensively analyzed the cortical bone and tophi in uric acid (calcium) image according to the calcium concentration distribution area in calcium based image and uric acid concentration distribution area in uric acid based image, while selecting uric acid-calcium pairing based material images. For this purpose, we used pseudo color to mark tophi with high uric acid content according to the difference in its concentration in base material image. Thus, it can better display tophi’s presence, size, position and distribution. Due to the quantitative analysis, the relative contents of uric acid in both surrounding cortical bone and tophi were > 1200 mg/cm3 . The cortical bone expresses higher concentration in both uric acid (calcium) image and calcium (uric acid) image, which are difficult to distinguish. Although cortical bone has higher relative content of calcium than the tophi, it expresses a low concentration in calcium (uric acid) image. 4.2. The value of the concentration measured using uric acid based image with dual energy spectral CT The comparison between the case group and the control group showed that uric acid (calcium) concentration of muscle around peripheral joints was statistically different in gout patients and normal cases.
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Fig. 5. Applying a pseudo color to mark high uric acid concentration based on uric acid (ca) image of Fig. 4 shows the distribution of tophus more intuitively.
Fig. 6. The X-ray plain film of a patient with clinically suspected gouty arthritis shows soft tissue swelling beside the first right metatarsophalangeal joints with patchy dense shadow inside.
Fig. 7. CT scan image of right foot of the patient shows visible patchy dense shade beside the first right metatarsophalangeal joints, consistent with X-ray plain film (Fig. 6).
Fig. 8. The calcium (uric acid) base image of the patient (Figs 6 and 7) shows patchy high calcium (uric acid) concentration area around the first right metatarsophalangeal joints.
However, there is no difference in uric acid (calcium) concentration between cortical bone and cancellous bone. These results show that uric acid may be first deposited in the muscle tissue around the joint during disease process of gouty arthritis. Thus, it can sensitively reflect the periarticular uric acid levels in gout patients by monitoring uric acid (calcium) concentration changes in juxta articular muscle tissue, which may be used as a new diagnostic tool to predict the risk of gout in patients with hyperuricaemia and assess curative effect after the treatment. The author confirmed that all the MSU deposition site in patient group without any puncture, but the results of four patients with ankle tophus were confirmed pathologically as tophus after resection of the lesion. Uric acid base material image can detect high uric acid (calcium) concentration deposition, but cannot find other types of high concentration crystal deposition. This suggests the result of spectrum CT based material image and pathology biopsy have good consistency. For example, one patient (case) was found with suspicious gouty arthritis in the clinical diagnostic practice. The foot X ray film showed soft tissue beside the first plantar toe joint at right
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Fig. 9. The uric acid (ca) base image of the patient (Figs 6 to 8) shows none obvious high uric acid concentration area in same part of the first right metatarsophalangeal joints. d
swelling foot with patchy dense shadow inside (Fig. 6). However, spectrum CT examination found multiple patchy dense shadows (Fig. 7) around some plantar toe joint of the right foot. In the uric acid (calcium) based image of the same areas, there is no observably high uric acid concentration (Fig. 8). The calcium (uric acid) based image of above areas demonstrated high calcium concentration (Fig. 9), so that the patient was considered to have pseudo-gout (articular cartilage calcification syndrome) with multiple calcifications formed around, after confirmation by clinical follow-up (Figs 8 and 9). This detailed analysis of the patient data preliminary provides the evidence that the spectrum CT based material image may have good specificity in the identification between gouty arthritis and non-gouty arthritis. 4.3. The limitations of this study 1) Due to the special heterogeneity in pathogenesis of gouty arthritis and their lower similarity to other types of arthritis, this study did not include patients without gouty arthritis in control group. 2) At the same time the study sample size is small and the age structure has certain differences between control group and case group, which make the results need to be further confirmed through the expansion of the sample quantity and perfect age structure in the future. 3) Because of the peripheral joints with thin bone cortex, part of the ROI in this study cannot be completely placed within it, causing some data differences in bone cortex and this may cause a certain deviation from the real value. 4) MSU deposition was sometimes fractured and scattered to several pieces with different sizes and unclear boundaries which made it harder to select the location and size for ROI. 5) Scanning area of most patients just include ankle joint with clinical suspicious tophus. It failed to include all peripheral joints of scanning, which may miss some tophus whose clinical manifestations are not obvious. Therefore, the result of the research needs to be further improved by optimizing the selection of the ROI and validated using large and more balanced image database in the future. 5. Conclusions In summary, we enabled to detect uric acid depositing with tophaceous gout and quantitatively measure base material concentration of tophus using base material images generated by a dual energy spec-
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tral CT. The quantified detection index can provide a valuable reference for the early clinical diagnosis and monitoring gouty curative effect in gouty patients. Acknowledgments This study was supported by the grant from National Natural Science Foundation of China (81301224) and Anhui Provincial Education Department (KJ2013A144), The First Affiliated Hospital of Anhui Medical University (2012KJ02). The authors thank Jian-Ying Li, CT Advanced Application and Research, GE Healthcare, 100176 China, for their editorial assistance. The authors also thank the effort of the following people for their contribution to CT imaging in this study: Jian Song, and Shi-Yu Wang of the Department of Radiology, The First Affiliated Hospital of AnHui Medical University. References [1]
C.Q. Li, J.B. Fu, Q.J. Sun et al., Imaging diagnosis of gouty arthritis, Journal of Taishan Medical College 27 (2006), 384–386. [2] X. Wang and B. Liu, Imaging diagnosis and progress of gouty arthritis, International Journal of Medical Radiology 35 (2012), 251–254. [3] H.K. Choi, A.M. Al-Arfaj, A. Eftekhari et al., Dual energy computed tomography in tophaceous gout, Ann Rheum Dis 68 (2009), 1609–1612. [4] A.K. Bacani, C.H. McCollough, K.N. Grazebrook et al., Dual energy computed tomography for quantification of tissue urate deposits in tophaceous gout: help from modern physics in the management of an ancient disease, Rheumatol Int 32 (2012), 235–239. [5] X.H. Li, B. Liu, Y.Q. Yu et al., The principle and clinical value of spectral CT, China Medical Device Information 10 (2011), 1–5. [6] K.G. Sang and H. Choi, Epidemiology, risk factors, and lifestyle modifications for gout, Arthritis Res Ther 8(Suppl I: S2) (2006). [7] W. Liu, H.D. Xue, X.J. Zeng et al., Application of dual-energy computed tomography for detecting uric acid deposition in patients with gout, ACTA Academiae Medicinae Sinicae 32 (2010), 645–648. [8] L. Zheng, C.S. Zhou, L.Q. Zhang et al., Preliminary experience of dual source, dual energy CT in detection of gout, Journal of China Clinic Medical Imaging 22 (2011), 105–107. [9] G.D. Chiro, R.A. Brooks, R.M. Kessler et al., Tissue signatures with dual-energy computed tomography, Radiology 131 (1979), 521–523. [10] W.A. Kalender, E. Klotz and C. Suess, Vertebral bone mineral analysis: An integrated approach with CT, Radiology 164 (1987), 419–423. [11] X.P. Zhang, The spirit and pleasure of scientific exploration: Many thoughts in spectral CT imaging clinical application, Chinese Journal of Radiology 45 (2011), 709–712. [12] H.W. Wu, J.J. Cheng, J.Y. Li et al., Spectral CT imaging in the diagnosis of pulmonary embolism using quantitative iodine-based material decomposition images, Chinese Journal of Radiology 45 (2011), 727–730. [13] S.L. Wallace, H. Robinson, A.T. Masi et al., Preliminary criteria for the classification of the acute arthritis of primary gout, Arthritis Rheum 20 (1977), 895–900. [14] X.H. Li, Y.Q. Yu, W.Q. Wang et al., Spectral CT imaging in the evaluation of composition of kidney stones, Chinese Journal of Radiology 45 (2011), 1216–1219. [15] N. Dalbeth, B. Clark, K. Gregory et al., Mechanisms of bone erosions in gout: a quantitative analysis using plain radiography and computed tomography, Ann Rheum Dis 68 (2009), 1290–1295.
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Detection of uric acid depositing in tophaceous gout using a new dual energy spectral CT technology Xiaohu Lia,1 , Xu Wangb,1 , Yonqqiang Yua,∗ , Bin Liua,∗ , Jing Caic , Li Xiad , Li Luod , Wanqin Wanga , Qianyun Dinga , Chao Zhanga and Jie Wanga a Department
of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China of Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China c Department of Rheumatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China d Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China b Department
Received 23 February 2014 Revised 24 April 2014 Accepted 27 April 2014 Abstract. OBJECTIVE: To assess the feasibility and diagnostic value of detecting uric acid depositing among patients with tophaceous gout using a dual energy CT based Gemstone spectral imaging (GSI) technology for qualitative analysis of uric acid. METHODS: Thirty one patients with clinically detectable tophaceous gout and 10 healthy volunteers underwent Discovery CT 750 HD scan with GSI mode. We selected four case groups of tophi, muscles, cortical bone, and cancellous bone. Each has a region of interest (ROI) of 10 mm diameter. We then analyzed and compared the difference of CT imaging spectroscopy quantitative parameters including concentration of uric acid, calcium, and water levels. The univariate analysis of variance and independent samples t-test were applied in data analyses. RESULTS: In case group of tophi base substance, the concentration levels were 1268.8 ± 32.2 mg/cm3 for uric acid (Ca), 19.4 ± 9.5 mg/cm3 for calcium (uric acid), 10.8 ± 9.5 mg/cm3 for calcium (water), and 1171.0 ± 26.8 mg/cm3 for water (calcium), respectively. In cortical bone case group, the four base substance concentration levels changed to 1333.6 ± 83.8 mg/cm3 , 271.1 ± 85.0 mg/cm3 , 262.6 ± 85.4 mg/cm3 , and 1230.8 ± 77.0 mg/cm3 . In muscles case group, the four base substance concentration levels were 1143.5 ± 15.7 mg/cm3 , 12.3 ± 5.0 mg/cm3 , 4.4 ± 1.9 mg/cm3 , and 1054.1 ± 14.6 mg/cm3 . Finally, in cancellous bone case group, the corresponding base substance concentration became 1070.9 ± 26.4 mg/cm3 , 85.1 ± 46.9 mg/cm3 , 77.4 ± 46.7 mg/cm3 , and 988.0 ± 23.4 mg/cm3 . Except tophi and muscle differences between Calcium (uric acid) concentration and differences in Calcium (water) concentration, which were not significantly different (p > 0.29), the remaining group pairwise comparisons of the parameters were significantly different (p < 0.05).
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Li Xiaohu and Wang Xu are the first authors who contributed equally to the article. This paper was also published in Chinese in the Chinese Journal of Radiology 2014; 48: 303∼307. The authors have received permission from the Chinese Journal of Radiology to publish it in English in the Journal of X-ray Science and Technology. ∗ Corresponding authors: Bin Liu, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Er Rd, Hefei 230022, Anhui, China. Tel.: +86 0551 62922368; Fax: +86 0551 62922368; E-mail: [email protected]. Yongqiang Yu, Department of Radiology, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Er Rd, Hefei 230022, Anhui, China. Tel.: +86 0551 62923223; Fax: +86 0551 62923223; E-mail: [email protected]. c 2014 – IOS Press and the authors. All rights reserved 0895-3996/14/$27.50
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X. Li et al. / Detection of uric acid depositing in tophaceous gout using a new dual energy spectral CT technology
CONCLUSION: Dual-energy spectral CT can detect gout tophi within the peripheral joints of the patients. The quantitative measurement of the tophi concentration provides a new imaging method for quantitatively monitoring clinical outcomes of tophi. Keywords: Hyperuricemia, tomography, X-ray computed, comparative study
1. Introduction Gout is caused by excessive uric acid in the body with the form of monosodium urate (MSU) crystals deposition in the joint and surrounding tissue. The gout accumulation and repeated attacks can eventually cause joint deformities and thus seriously affect the quality of life in patients with gout [1]. At present, the conventional imaging diagnosis modalities of gouty arthritis include X-ray, CT and MRI. However, all these imaging examination methods lack the clinically required specificity and sensitivity, especially for early diagnosis of gouty arthritis [2]. Recently, using dual-source CT (DSCT) has shown the promising results of not only detecting uric acid crystallization of peripheral joint, and also quantifying the tophi number and total gout volume of patients, which assist to estimate tophi deposition [3, 4]. The dual energy spectral CT using instantaneous switching between high and low energy can realize the simultaneous acquisition of two sets of 40 ∼ 140 keV monochromatic CT image data. Then, using the dual-energy projection data space analysis, the researchers are able to compute and generate the spectrum curves of different substances, and thus to some extent to achieve a qualitative and quantitative measurements of substance separation [5]. The purpose of the present study was to assess the utility of dual energy spectral CT in detecting uric acid depositing in tophaceous gout with base material mapping. With the improvement of people’s living standard, the high purine dietary intake results in the changes of their diet structure. Recently, the incidence of gout also presents an increasingly rising momentum [6]. Hyperuricemia is one of the risk factors of gout. With the increase in blood uric acid level, the prevalence rate of gout also increases. However, the gout is not always accompanied by hyperuricemia. In fact, the blood uric acid level of approximate 40% of patients does not exceed the normal reference value range in the process of acute gout attacks. Currently, the gold standard in diagnosis of gout is to find distinctive needle uric acid sodium crystal through the joint puncture. The joint puncture is not only an invasive procedure, the detection sensitivity also varies widely depending on the extracted quantity of uric acid sodium crystallization as well as the deep puncture site and/or insufficient technical level of operating personnel. As a result, this procedure may actually miss acquiring samples from some atypical sites and make the diagnosis difficulty for the cases containing the regions with normal serum uric acid level [2, 7]. Therefore, the non-invasive detection of early joint MSU deposition by imaging methods has been attracting increasingly interest in the clinical practice. Preliminary studies indicated that dual-energy CT can detect early and much smaller tophi than using the traditional CT technology [7,8]. The imaging theory of dual-energy CT was first proposed and tested in 1970s [9], some researches related to the dual energy subtraction technology were unable to be routinely applied in clinical practice due to the limitation of imaging equipment and technology in the 1980s [10]. After 2009, instantaneous dual voltage technology as the core technology of dual-energy spectrum CT was emerged. It acquires two sets of absorption projection data with good consistency through the low and high voltage transient. It can translate the absorption projection data to material density projection data and achieve the qualitative classification and quantitative measurement [5]. The Material decomposition does not identify materials, but rather, given two selected basis materials, material decomposition determines how much of each material would be needed to produce the observed low and high voltage measurements (such as iodine/water pairing, calcium/water pairing, uric acid/calcium pairing, etc.) then quantitative analysis pairing base material content of this tissue. In the clinical practice, when paired two base materials have
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similar constituent with the tissue’s actual composition, base material concentration imaging can more accurately reflect the corresponding component content of this organization, for instance, we can use the iodine-based map to measure the thyroid iodine concentration and evaluate thyroid function [11]. Wu et al. [12] apply the quantitative analysis of the iodine-based map which can effectively reflect the hemodynamic changes of the lung parenchyma, also provide more objective and scientific reasons in detecting small embolisms or pulmonary embolisms of occult sites, as well as their extent, which can better assist for disease evaluation and treatment. 2. Materials and methods 2.1. Subjects of the study The study dataset includes two groups. The first patient group involves 31 gout patients who were diagnosed by the clinical and laboratory findings in the First Affiliated Hospital of AnHui Medical University from May 2011 to September 2012. All patients had the history of acute gout attacks in this patient group. The group includes 30 male and one female patients with the age ranging from 22 to 65 years old. The mean age is 42 years old with a standard deviation of 13 years old. The diagnostic criteria promulgated by the American College of Rheumatology (ACR) in 1977 were used in our study [13]. In our laboratory tests, the uric acid of acute exacerbations varied from 381 to 777 µmol/L (the normal reference value ranged from 208 to 428 µmol/L). Five patients also underwent foot radiography. Four patients underwent resection of lesions and confirmed as gout nodules by the pathological exams. The second case group includes 10 healthy young doctors of Radiology Department, the First Affiliated Hospital of Anhui Medical University, as volunteers. The CT data of these volunteer cases were acquired during April 2012 to September 2012, which were collected as control cases in this study. Those volunteers include 8 men and 2 women with the age ranging from 21 to 35 years and mean (26 ± 7) years old. There were no positive findings in both blood uric acid test and physical examination among all of those volunteers who also had no history of arthritis, joint trauma, joint pain or peripheral joint disease. An informed consent form was signed before the examination. 2.2. Techniques of computed tomography All CT examinations involved in our dataset were performed using a single source dual-energy CT system (Discovery CT750 HD, GE Healthcare, Milwaukee, WI, USA), equipped with 64 detectors and a 50-cm field of view. This system is capable of rapidly switching tube voltage between 80 and 140 kVp in less than 0.5 ms. Suspected tophi deposition in ankle joint was scanned in the patient group, while both sides of the ankle joint were scanned in the healthy control group. The detail CT scanning protocol includes following parameters of scan layers of 10 layers, slice thickness of 5.00 mm, interlayer spacing of 5.00 mm, the tube voltage of 80 to 140 kVp, instantaneous switch time of 0.5 ms, the tube current of 600 mA, pitch of 1.375, detector collimation of 64 × 0.625 mm, X-ray tube speed of 0.8 s/cycle, field of view (FOV) of 14.8 cm × 14.8 cm. The final CT images were reconstructed with slice thickness of 1.25 mm. 2.3. Image analysis and data measurement Both the image analysis and data measurement were performed in the GE Healthcare AW 4.4 workstation, using an imaging spectral browser of GSI Viewer. Using the system interface, an observer manu-
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Fig. 1. A foot X-ray plain film of a patient without high density shadow around the joints and obvious signs of damage.
Fig. 2. An uric acid (ca) base image of the same patient shown in Fig. 1. The image shows the visible class round tophus sedimentation between the medial tarsal joints of foot and spread to the adjacent bone erosion.
ally defined the physical separation (region segmentation) for feature data analysis. Uric acid-calcium, water-calcium were selected as basics to access four separate mappings which were uric acid based (calcium) mapping, calcium based (uric acid) mapping, water based (calcium) mapping and calcium based (water) mapping, respectively. The size of tophi was measured in the largest cross-sectional distance (diameter). All sections or slices depicting tophi with estimated diameter greater than 10 mm were selected. For each case, a Region of interest (ROI) with the greatest cross-sectional diameter was selected. The area of ROI was about 1/4 to 1/3 of that section determined by the greatest cross-sectional diameter in order to avoid the calcifications as much as possible. ROIs of the same size were placed in the muscle, compact bone and spongy bone regions in the same CT slice plane [14]. In the control case group, we chose roughly the same ankle joint sections as those selected in the patient group and redid the same mapping procedures. Two radiologists with more than 10-year CT radiological image diagnosis working experiences repeated those steps three times separately. We then took the average region segmentation and feature measurement as the final results. 2.4. Statistics methods A publically available statistical data analysis software package, SPSS 16.0, was used for statistical analysis in this study. One-way ANOVA test was used in comparing the tophi concentration levels of the baseline substances in each selected ROI of one CT examination. LSD (least significant difference) was used for pairwise comparison within each group when the homogeneity of variance was satisfied. Otherwise, Tamhane T2 test was chosen. In addition, the independent sample t-test was used to compare the above quantitative parameters between the patient case group and the control group. The criterion of P < 0.05 was considered to be a measurement index of statistical significance. 3. Results We detected 106 pieces of tophi with diameters greater than 10 mm in 31 ankle joints of gouty patients’ using the dual energy CT uric acid (calcium) image. In the control case group, 60 ROIs were selected.
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Table 1 The different base substance concentration between the subjects of patient group and control group among different tissues imaged with spectral CT (mg/cm3 , x ¯ ± s) Position ROI (n) Ua (ca) Ca (ua) Ca (wa) Wa (ca) Patient group Tophi 106 1268.8 ± 32.2 19.4 ± 9.5 10.8 ± 9.5 1171.0 ± 26.8 Muscle 106 1143.5 ± 15.7 12.3 ± 5.0 4.4 ± 1.9 1054.1 ± 14.6 CAB 106 1070.9 ± 26.4 85.1 ± 46.9 77.4 ± 46.7 988.0 ± 23.4 COB 106 1333.6 ± 83.8 271.1 ± 85.0 262.6 ± 85.4 1230.8 ± 77.0 F 665.04 646.13 642.10 692.41 P < 0.01 < 0.01 < 0.01 < 0.01 Control group Muscle 60 1139.8 ± 4.8 12.8 ± 1.7 4.9 ± 1.6 1050.7 ± 4.7 CAB 60 1067.5 ± 9.3 51.6 ± 16.8 44.1 ± 16.6 983.4 ± 9.0 COB 60 1320.1 ± 61.6 299.0 ± 70.2 291.4 ± 70.6 1219.9 ± 56.7 ta 2.200 0.912 1.044 2.197 Pa < 0.05 > 0.05 > 0.05 < 0.05 1.204 6.642 6.638 1.763 tb Pb > 0.05 < 0.01 < 0.01 > 0.05 tc 1.183 2.159 2.340 1.035 Pc > 0.05 < 0.05 < 0.05 > 0.05 Notes: Ua (ca): uric acid (Calcium); Ca (ua): Calcium (uric acid); Ca (wa): Calcium(water); Wa(ca): Water(Calcium). CAB: cancellous bone COB: cortical bone. a , b and c represent the statistical comparison results (t-value and p-value) between the patient group and control group for the muscles, cancellous bone and cortical bone, respectively.
All clinical palpation confirmed tophi were detected by using uric acid (calcium) mapping of CT images. Although the conventional X-ray images of the feet show negative in 5 cases (e.g., Fig. 1), the uric acid (Ca) based CT images show MSU clearly (e.g., Figs 2 and 3 of the same patient as shown in Fig. 1). For another patient (as shown in Figs 4 and 5), the calcium (uric acid)-based CT images also enabled to clearly demonstrate MSU on adjacent region with bone erosion (Fig. 4), including those with eroded bone formation with hardened edges. In addition, the uric acid (Ca) based substances images enabled to show a high concentration level of uric acid deposition tophi using a pseudo-color in uric acid (calcium) based maps because the areas of high concentration of uric acid can be more easily labeled, which help visually view the distribution of tophi (Fig. 5). Table 1 shows the summary of the different base substance concentration between the subjects of patient and control groups. The values of the patient group were computed based on the substances pairwise comparison. The results showed that except tophi and muscle differences between Calcium (uric acid) concentration and differences in Calcium (water) concentration, which were not significantly different with p = 0.342 and p = 0.291, respectively, the remaining group pairwise comparisons of the parameters were significantly different (p < 0.05). 4. Discussion 4.1. Diagnostic value of detecting uric acid depositing using Gemstone spectral imaging (GSI) with base material mapping In this study we chose uric acid and calcium as the first base material pairing because the main composing organizations of the affected joint are composed of tophus and adjacent joint bone in gouty arthritis. The results of this study showed that the calcium concentration of cortical bone was higher than tophi
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Fig. 3. A calcium (uric acid) base image of the same patient of Figs 1 and 2. It shows a clear hardening zone in bone erosion edges.
Fig. 4. This calcium (uric acid) base image shows adjacent bone erosion situation and the calcification of the tophus.
and muscle, which can well display the eroded edge of bone in calcium-based image. Meanwhile, the intra-articular tophi has erodent characteristic of bone, which is one of the most important determinants of bone destruction in gouty arthritis [15]. Thus, we can detect tophi using uric acid-based image that clearly shows the bone destruction and condition of tophi adjacent joint using calcium-based image at the same time. As a second base material pairing, we chose water and calcium because water is one of the standard substances in conventional CT imaging and calcium is not only the main component of human bones, but also the main composition of many calcified lesions. As a result, these two substances have the most content in the body [14]. In this study, we analyzed spectrum CT scan data in 31 patients with clinically diagnosed gout and also quantitatively analyzed the ankle intra-articular tophi by using base material image. The results showed that uric acid (calcium) concentration of tophus was higher than spongy bone and muscle, thus MSU in ankle joint and soft tissue can be clearly displayed on the uric acid based image. This will help us in detecting possibly MSU which deposited in the peripheral intra-uric acid in base material images. Next, we comprehensively analyzed the cortical bone and tophi in uric acid (calcium) image according to the calcium concentration distribution area in calcium based image and uric acid concentration distribution area in uric acid based image, while selecting uric acid-calcium pairing based material images. For this purpose, we used pseudo color to mark tophi with high uric acid content according to the difference in its concentration in base material image. Thus, it can better display tophi’s presence, size, position and distribution. Due to the quantitative analysis, the relative contents of uric acid in both surrounding cortical bone and tophi were > 1200 mg/cm3 . The cortical bone expresses higher concentration in both uric acid (calcium) image and calcium (uric acid) image, which are difficult to distinguish. Although cortical bone has higher relative content of calcium than the tophi, it expresses a low concentration in calcium (uric acid) image. 4.2. The value of the concentration measured using uric acid based image with dual energy spectral CT The comparison between the case group and the control group showed that uric acid (calcium) concentration of muscle around peripheral joints was statistically different in gout patients and normal cases.
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Fig. 5. Applying a pseudo color to mark high uric acid concentration based on uric acid (ca) image of Fig. 4 shows the distribution of tophus more intuitively.
Fig. 6. The X-ray plain film of a patient with clinically suspected gouty arthritis shows soft tissue swelling beside the first right metatarsophalangeal joints with patchy dense shadow inside.
Fig. 7. CT scan image of right foot of the patient shows visible patchy dense shade beside the first right metatarsophalangeal joints, consistent with X-ray plain film (Fig. 6).
Fig. 8. The calcium (uric acid) base image of the patient (Figs 6 and 7) shows patchy high calcium (uric acid) concentration area around the first right metatarsophalangeal joints.
However, there is no difference in uric acid (calcium) concentration between cortical bone and cancellous bone. These results show that uric acid may be first deposited in the muscle tissue around the joint during disease process of gouty arthritis. Thus, it can sensitively reflect the periarticular uric acid levels in gout patients by monitoring uric acid (calcium) concentration changes in juxta articular muscle tissue, which may be used as a new diagnostic tool to predict the risk of gout in patients with hyperuricaemia and assess curative effect after the treatment. The author confirmed that all the MSU deposition site in patient group without any puncture, but the results of four patients with ankle tophus were confirmed pathologically as tophus after resection of the lesion. Uric acid base material image can detect high uric acid (calcium) concentration deposition, but cannot find other types of high concentration crystal deposition. This suggests the result of spectrum CT based material image and pathology biopsy have good consistency. For example, one patient (case) was found with suspicious gouty arthritis in the clinical diagnostic practice. The foot X ray film showed soft tissue beside the first plantar toe joint at right
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Fig. 9. The uric acid (ca) base image of the patient (Figs 6 to 8) shows none obvious high uric acid concentration area in same part of the first right metatarsophalangeal joints. d
swelling foot with patchy dense shadow inside (Fig. 6). However, spectrum CT examination found multiple patchy dense shadows (Fig. 7) around some plantar toe joint of the right foot. In the uric acid (calcium) based image of the same areas, there is no observably high uric acid concentration (Fig. 8). The calcium (uric acid) based image of above areas demonstrated high calcium concentration (Fig. 9), so that the patient was considered to have pseudo-gout (articular cartilage calcification syndrome) with multiple calcifications formed around, after confirmation by clinical follow-up (Figs 8 and 9). This detailed analysis of the patient data preliminary provides the evidence that the spectrum CT based material image may have good specificity in the identification between gouty arthritis and non-gouty arthritis. 4.3. The limitations of this study 1) Due to the special heterogeneity in pathogenesis of gouty arthritis and their lower similarity to other types of arthritis, this study did not include patients without gouty arthritis in control group. 2) At the same time the study sample size is small and the age structure has certain differences between control group and case group, which make the results need to be further confirmed through the expansion of the sample quantity and perfect age structure in the future. 3) Because of the peripheral joints with thin bone cortex, part of the ROI in this study cannot be completely placed within it, causing some data differences in bone cortex and this may cause a certain deviation from the real value. 4) MSU deposition was sometimes fractured and scattered to several pieces with different sizes and unclear boundaries which made it harder to select the location and size for ROI. 5) Scanning area of most patients just include ankle joint with clinical suspicious tophus. It failed to include all peripheral joints of scanning, which may miss some tophus whose clinical manifestations are not obvious. Therefore, the result of the research needs to be further improved by optimizing the selection of the ROI and validated using large and more balanced image database in the future. 5. Conclusions In summary, we enabled to detect uric acid depositing with tophaceous gout and quantitatively measure base material concentration of tophus using base material images generated by a dual energy spec-
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tral CT. The quantified detection index can provide a valuable reference for the early clinical diagnosis and monitoring gouty curative effect in gouty patients. Acknowledgments This study was supported by the grant from National Natural Science Foundation of China (81301224) and Anhui Provincial Education Department (KJ2013A144), The First Affiliated Hospital of Anhui Medical University (2012KJ02). The authors thank Jian-Ying Li, CT Advanced Application and Research, GE Healthcare, 100176 China, for their editorial assistance. The authors also thank the effort of the following people for their contribution to CT imaging in this study: Jian Song, and Shi-Yu Wang of the Department of Radiology, The First Affiliated Hospital of AnHui Medical University. References [1]
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