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(Radiology. 2001;220:381-385.)
© RSNA, 2001


Nuclear Medicine

Use of 99mTc (V) DMSA Scintigraphy in the Detection and Localization of Intestinal Inflammation: Comparison of Findings at Colonoscopy and Biopsy1

Bi-Fang Lee, MD, Nan-Tsing Chiu, MD, Deng-Chyang Wu, MD, Kun-Bow Tsai, MD, Gin-Chung Liu, MD, Hsin-Su Yu, MD and Shan-Tair Wang, PhD

1 From the Department of Nuclear Medicine (B.F.L., N.T.C.) and Institute of Public Health (S.T.W.), National Cheng Kung University Hospital, 138 Sheng-Li Rd, Tainan 704, Taiwan; and the Departments of Internal Medicine (D.C.W.), Pathology (K.B.T.), and Radiology (G.C.L.) and Institute of Medicine (H.S.Y.), Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Received July 24, 2000; revision requested September 19; final revision received February 21, 2001; accepted February 26. Supported by grant NSC 89-2314-B037-099-M08 from the Taiwan National Science Council. Address correspondence to N.T.C. (e-mail: ntchiu@mail.ncku.edu.tw).


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the potential use of technetium 99m (99mTc) (V) dimercaptosuccinic acid (DMSA) scintigraphy in the detection and localization of intestinal inflammation.

MATERIALS AND METHODS: In a prospective study, 62 patients who were suspected of having intestinal inflammation and 30 control subjects were enrolled. All patients underwent 99mTc (V) DMSA scintigraphy and colonoscopy with biopsy within 1 week. 99mTc (V) DMSA scintigrams were interpreted blindly with respect to clinical information, and radiotracer uptake in the bowel segments was graded. The findings were then compared with the results of the colonoscopy and colonoscopic biopsy.

RESULTS: In the detection of intestinal inflammation, findings at 99mTc (V) DMSA scintigraphy were as follows: true-positive in 55, false-positive in two, true-negative in 32, and false-negative in three. Overall sensitivity was 95%; overall specificity, 94%; and overall accuracy, 95%.

CONCLUSION: Our results show that 99mTc (V) DMSA scintigraphy is a useful noninvasive diagnostic test for the detection and localization of intestinal inflammation.

Index terms: Colonoscopy • Enteritis, 75.26 • Inflammation, radionuclide studies, 75.26, 75.1217 • Intestines, biopsy, 75.126 • Intestines, radionuclide studies, 75.1217


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scintigraphic techniques frequently are used for the evaluation of intestinal inflammation. Radiolabeled leukocytes are currently chosen for this purpose because of their high sensitivity and specificity (1,2). They have been validated as both specific and sensitive for use in the detection of intestinal inflammation. However, the expense, concerns about radiation microdosimetry, and the lack of ready availability of indium 111 (111In) have inhibited the wide adoption and use of radiolabeled leukocytes.

Use of technetium 99m (99mTc) hexamethylpropyleneamine oxine has many theoretical advantages compared with the use of 111In oxine in labeling leukocytes, including better image quality, shorter acquisition time, smaller radiation dose, and lower cost (2). In one study (3), a high rate of false-positive scans (5% in high-probability and 15% in low-probability cases of intestinal inflammation) occurred because of nonspecific intestinal accumulation when 99mTc was used to label autologous leukocytes. In addition, the preparation of radiolabeled autologous leukocytes has several disadvantages that limit its application. In particular, the necessity to draw and handle possibly contaminated blood constitutes an inherent risk to other patients and staff (4,5). Furthermore, isolation and labeling of leukocytes is a relatively complicated and time-consuming procedure that is not possible in every nuclear medicine facility (6). To overcome these difficulties, research has been directed toward developing agents that are equally effective but easier to produce from instant, ready-to-use radiolabeling kits.

The use of 99mTc (V) dimercaptosuccinic acid (DMSA) has been recognized as advantageous in the scintigraphic diagnosis of inflammations, such as osteomyelitis (7), psoas muscle abscess (8), and bone and joint infection (9). To our knowledge, there is no systematic study in which the effectiveness of 99mTc (V) DMSA in the detection of intestinal inflammation has been evaluated. The aim of the present study was to evaluate the potential use of this simple technique in the detection and localization of inflamed intestine.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients
From May 1996 through June 2000, 78 patients with abdominal symptoms (abdominal pain, diarrhea with and without blood or mucus, and rectal bleeding) that caused clinical suspicion of intestinal inflammation were initially entered consecutively into this prospective study. Sixteen of the 78 patients were excluded from the study because they did not complete the 99mTc (V) DMSA scintigraphy or colonoscopy with biopsy examinations. A total of 62 patients (30 men, 32 women; mean age, 33.9 years; age range, 22–87 years) were enrolled in this study. The initial clinical diagnoses in the 62 patients were ulcerative colitis in 16 and miscellaneous colitis in 46. The diagnosis of miscellaneous colitis included infective colitis in four patients, antibiotic-associated colitis in one, appendicitis in one, and colitis without standard clinical criteria of ulcerative colitis or Crohn disease in 40. They subsequently underwent examinations, including 99mTc (V) DMSA scintigraphy and colonoscopy with biopsy. None of these 62 patients received treatment before the completion of all examinations.

In addition, the control group included 30 subjects (15 men, 15 women; mean age, 54.3 years; age range, 49–62 years) who underwent 99mTc (V) DMSA scintigraphy for suspected septic loosening of a knee prosthesis. None of them were receiving nonsteroidal antiinflammatory drugs, and all were free of intestinal disease.

In addition to 99mTc (V) DMSA scintigraphy, colonoscopy with biopsy was performed in all 92 patients. The two examinations were completed within 1 week. Each examination was conducted without knowledge of the findings obtained in the other, and the results of each were reported on separate occasions in a different random order. Informed consent was obtained from all patients after a full explanation of the examination. The protocol for this study was approved by the review board of Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

99mTc (V) DMSA Scintigraphy
Two to 4 hours after intravenous injection of 20 mCi (740 mBq) 99mTc (V) DMSA (INER DMS Kit; Institute of Nuclear Energy Research, Taoyuan, Taiwan), pelvic outlet images and anterior views of the abdomen with the patient standing and supine were obtained with a gamma camera (Vertex; ADAC Labs, Milpitas, Calif) equipped with a low-energy, general-purpose collimator. In each scan, the radiotracer uptake distribution was recorded. The bowel was divided into five segments (rectosigmoid, descending colon, transverse colon, ascending colon, and small bowel).

Any uptake in the bowel was interpreted as a positive study finding and was graded relative to uptake in the iliac crest as follows: 0, no uptake; 1, uptake less than that of the iliac crest; 2, uptake equal to that of the iliac crest; and 3, uptake greater than that in the iliac crest. The scintigrams were assessed independently by two nuclear medicine physicians (B.F.L., N.T.C.) who were unaware of any patient’s clinical details. The scans of patients with suspected intestinal inflammation and those of control subjects were given to the two physicians in a randomly mixed order. Interobserver variability was recorded, and the Cohen {kappa} statistic (SPSS for Windows, version 7.0; SPSS, Chicago, Ill) was calculated. Interobserver disagreements were resolved by discussion between observers. The same two nuclear medicine physicians who assessed the scintigrams compared the colonoscopy and biopsy findings with the location and radioactivity of the lesions on the images. Adverse reactions to 99mTc (V) DMSA, if any, were documented.

Colonoscopy with Biopsy
Colonoscopy was performed by using a colonoscope (Olympus CF 100; Olympus Optical, Tokyo, Japan) with the patient receiving intravenous sedatives with meperidine hydrochloride (pethidine) (1 mg per kilogram of body weight) and either diazepam (0.3 mg/kg) or midazolam hydrochloride (0.1 mg/kg). The proportion of the colon seen at colonoscopy was recorded. The endoscopic findings of inflammatory activity were classified as absent (noninflamed mucosa), mild (granularity, edema, invisible vascular pattern), moderate (hyperemia, friability, plus all features of mild inflammatory activity), or severe (ulceration in addition to features of moderate inflammatory activity). A biopsy sample was taken at any visually abnormal area and, routinely, at each segment, even if the segment appeared normal.

Statistical Evaluation
The sensitivity, specificity, and accuracy of 99mTc (V) DMSA scintigraphy were calculated (Table).


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Results of 99mTc (V) DMSA Scintigraphy

 

    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Control Subjects
99mTc (V) DMSA scintigraphy findings were true-negative in all 30 control subjects. In none of the control subjects was there evidence of radiotracer accumulation in the bowel. Normal uptake distribution during the 4 hours was similar to that previously reported (10). Physiologic uptake was demonstrated in the kidneys, urinary bladder, liver, spleen, bone marrow, and the blood pool (Fig 1). Also, findings at colonoscopy with biopsy revealed no intestinal pathologic abnormalities. No false-positive 99mTc (V) DMSA study findings were seen among the control subjects.



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Figure 1a. 99mTc (V) DMSA scintigrams in a control subject. (a) Anterior image. (b) Caudal image of pelvic outlet. Images show physiologic uptake in the kidneys (large curved arrows), urinary bladder (long straight arrows), liver (small curved arrow), large blood vessels (short straight arrows), and bone marrow (arrowheads).

 


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Figure 1b. 99mTc (V) DMSA scintigrams in a control subject. (a) Anterior image. (b) Caudal image of pelvic outlet. Images show physiologic uptake in the kidneys (large curved arrows), urinary bladder (long straight arrows), liver (small curved arrow), large blood vessels (short straight arrows), and bone marrow (arrowheads).

 
Patients
Fifty-seven of the 62 patients had positive findings at 99mTc (V) DMSA scintigraphy (Figs 2, 3), and five had negative findings. The initial clinical diagnosis of ulcerative colitis in one patient was changed to Crohn disease because small-bowel involvement was depicted at 99mTc (V) DMSA scintigraphy (Fig 4), and the colonoscopy and biopsy results revealed inflammation in the terminal ileum, which confirmed the diagnosis. In the 62 patients, the final diagnoses were ulcerative colitis in 15 patients (including previously proved ulcerative colitis but without active inflammation during this episode in two patients; one of the two had active gastrointestinal bleeding); Crohn disease in one; and miscellaneous colitis in 46 (nonspecific acute colitis in 30, eosinophilic colitis in six, infective colitis in four, ischemic colitis in two, pseudomembranous colitis in one, appendicitis with abscess in one, adenocarcinoma in one, and previously proved eosinophilic colitis but without active inflammation during this episode in one).



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Figure 2a. 99mTc (V) DMSA scintigrams in a patient with ulcerative colitis. (a) Anterior image shows abnormal activity outlining the sigmoid and distal descending colon (arrowheads). (b) Caudal image of pelvic outlet shows accumulation of radiotracer in the rectum (arrowhead), separate from bladder activity (arrow).

 


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Figure 2b. 99mTc (V) DMSA scintigrams in a patient with ulcerative colitis. (a) Anterior image shows abnormal activity outlining the sigmoid and distal descending colon (arrowheads). (b) Caudal image of pelvic outlet shows accumulation of radiotracer in the rectum (arrowhead), separate from bladder activity (arrow).

 


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Figure 3. Anterior scintigram of the abdomen in a patient with pseudomembranous colitis. Image shows abnormal uptake of 99mTc (V) DMSA in the transverse and descending colon (arrows). The uptake is intense and bowel-shaped.

 


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Figure 4. Anterior 99mTc (V) DMSA scan in a patient with Crohn disease. The image shows inflammation in the small bowel (arrow). The results of colonoscopy and biopsy revealed inflammation in the terminal ileum.

 
The radioactivity and location of inflammation were consistent with those depicted at 99mTc (V) DMSA scintigraphy in 57 of 62 patients. Findings were false-negative in three 99mTc (V) DMSA studies; these findings occurred in two patients with miscellaneous colitis and in one patient with ulcerative colitis. These three patients had visually normal colonic mucosa during colonoscopy, but mild chronic inflammation was seen at biopsy. Findings were false-positive in two 99mTc (V) DMSA studies; these findings occurred in a patient with previously confirmed ulcerative colitis and active bleeding from the gastrointestinal tract during this episode and in another (Fig 5) patient with colonic adenocarcinoma seen at biopsy.



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Figure 5. Anterior false-positive 99mTc (V) DMSA scan shows accumulation of radiotracer in the ascending colon (arrows). The histologic specimens revealed adenocarcinoma.

 
In the small-bowel segments (1 segment x 62 patients = 62 segments), 99mTc (V) DMSA study findings were positive in 19 and negative in 43. Findings of active disease in 11 terminal ileal segments (10 in patients with miscellaneous colitis and one in a patient with Crohn disease) were confirmed with findings at colonoscopy and colonoscopic biopsy. In the remaining 51 segments, no supporting data were available to clarify the nature of the accumulation. In the large-bowel segments (4 segments x 62 patients = 248 segments), 99mTc (V) DMSA study findings were true-positive in 74, true-negative in 163, false-positive in four, and false-negative in seven. In the detection of inflammation of the large bowel, the sensitivity of 99mTc (V) DMSA scintigraphy was 91% (74 of 81); specificity, 97.6% (163 of 167); and accuracy, 95.6% (237 of 248).

Overall, on a patient-by-patient basis, the sensitivity of 99mTc (V) DMSA scintigraphy was 95% (55 of 58); specificity, 94% (32 of 34); and accuracy, 95% (87 of 92). No adverse reaction to 99mTc (V) DMSA in any patient was reported. A summary of results is given in the Table. For image evaluation, there was excellent (56 [90%] of 62 interpretations) interobserver agreement in the 62 scans in patients with suspected intestinal inflammation and excellent (28 [93%] of 30 interpretations) interobserver agreement in 30 scans in control subjects. The {kappa} value for both the control and patient groups was 0.82 (95% CI: 0.6, 1.0).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To our knowledge, this is the first study in which the use of 99mTc (V) DMSA scintigraphy in the assessment of intestinal inflammation was systematically evaluated. The results show that 99mTc (V) DMSA scintigraphy is promising because of its high accuracy. We compared the findings of 99mTc (V) DMSA scintigraphy and biopsy in two groups: patients who were suspected of having intestinal inflammation and control subjects. Diagnoses in the group of patients included a broad spectrum of intestinal inflammatory lesions, including ulcerative colitis, Crohn disease, appendicitis with abscess, pseudomembranous colitis, eosinophilic colitis, infective colitis, and ischemic colitis. Inflammatory bowel disease includes ulcerative colitis and Crohn disease. It is much more prevalent in the West than in East Asia, where incidence is characteristically low (10,11). It is not surprising, therefore, that in the 62 patients who were suspected of having intestinal inflammation in this study, only 16 (26%) actually manifested the disease. Our control subjects were suspected of having an infected knee prosthesis. None showed abnormalities in the bowel at 99mTc (V) DMSA scintigraphy. If the control subjects had not had intestinal inflammation but had symptoms or other indications of the suspected problem, the specificity most likely would have been lower.

In this study, false-negative 99mTc (V) DMSA results were seen in one patient with ulcerative colitis and two with miscellaneous colitis. All three patients had mild chronic inflammation. These findings suggest that 99mTc (V) DMSA scintigraphy may not be sensitive to minute microscopic inflammation. Findings were false-positive in two patients, one with active bleeding and another with colonic adenocarcinoma. We suspect the former false-positive finding was caused by extravasation of the radiotracer from the bleeding site and that the latter occurred because, as suggested by Ohta et al (7) and Lee et al (9), 99mTc (V) DMSA scintigraphy cannot help in the discrimination between malignant and benign lesions.

For detecting bowel inflammation, a variety of radionuclide scintigraphic techniques have been developed. Gallium 67 (67Ga) citrate (12), one of the first techniques, has several limitations. It is excreted into the gastrointestinal tract, which may obscure areas of inflammation or falsely suggest regions of involvement. Because 67Ga imaging may take several days to complete, its use in the assessment of an acutely ill patient is diminished. Use of 111In- or 99mTc-labeled leukocytes has some advantages compared with use of 67Ga, and many specialist centers have recognized leukocyte scanning as a reliable technique for the diagnosis and assessment of an inflamed bowel (2,1317); however, there are still some shortcomings, and a simpler alternative technique is clearly desirable.

Previous approaches aimed at simplifying scintigraphic techniques have included the use of labeled antigranulocyte monoclonal antibodies, chemotactic peptides, simple colloids phagocytosed by leukocytes, human immunoglobulins, and labeled anti-E-selectin monoclonal antibodies (1823). Unfortunately, none of these agents fulfilled their early promise because of problems with nonspecific binding or insufficient selective uptake into inflammatory sites.

99mTc (V) DMSA, developed by Yokoyama et al (24) in 1981, has been recognized as advantageous for the scintigraphic diagnosis of various malignant tumors and their metastases (2528). Ohta et al (7) found that accumulation of 99mTc (V) DMSA was seen not only in malignant tumors but also in benign tumors, fractures, and osteomyelitis. In some inflammatory lesions, 99mTc (V) DMSA showed behavior similar to that of 67Ga, but the superior physical properties of 99mTc (V) DMSA and its lower cost justify its use (7,9). The physical properties include a half-life of 6 hours; a 140-keV photon, which provides good tissue penetration; and a substantially larger number of detectable gamma rays for use with gamma cameras.

Turan et al (29) reported that 99mTc (V) DMSA demonstrated acute appendicitis in five of eight rabbits. The localization mechanism of 99mTc (V) DMSA in tumors and inflammation is not well known. Ohta et al (30) thought 99mTc (V) DMSA resembled the phosphate ion because they found that it accumulated in tumors in which calcification was present, as indicated by pathologic examination results. However, Clarke et al (31) showed that 99mTc (V) DMSA is taken up into more sites than are visualized with 99mTc medronate disodium, suggesting that this may not be the explanation for the uptake. Physiologic uptake has been demonstrated in breast tissues, kidneys, nasal mucosa, and the blood pool (32). Consequently, more work is needed to clarify the mechanism of uptake of 99mTc (V) DMSA.

In comparison with other modalities, 99mTc (V) DMSA scintigraphy is ideally suited to obtain a precise snapshot of the distribution and radioactivity of inflammation in the bowel, whereas radiographic modalities tend to depict more chronic changes. An additional advantage is high patient acceptability, because endoscopic and radiographic methods of disease localization are more invasive than 99mTc (V) DMSA scintigraphy, and they tend to produce more discomfort related to instrumentation and preparation for the procedure (eg, bowel cleansing). Moreover, several studies are needed to analyze the entire bowel, since colonoscopy cannot be used for this purpose. Finally, while the accuracy of colonoscopy is 89% (33), the accuracy of 99mTc (V) DMSA scintigraphy is more than 90%. 99mTc (V) DMSA scintigraphy has a number of advantages, and further work is needed to develop techniques for its general use.

In conclusion, compared with endoscopic and radiographic methods, 99mTc (V) DMSA scintigraphy requires no bowel preparation and causes no discomfort. It is noninvasive, economical compared with colonoscopy, and has excellent diagnostic sensitivity, according to our results. Moreover, 99mTc (V) DMSA has many advantages compared with other radiopharmaceuticals, such as low price, availability (suitable for daily clinical use), good physical characteristics (good counting statistics in imaging), no need for blood manipulation, and an easy preparation procedure. 99mTc (V) DMSA scintigraphy has the potential to be useful in the detection and localization of intestinal inflammation.


    ACKNOWLEDGMENTS
 
The authors thank Rei-Seng Sheu, MD, and Ying-Fong Huang, MD, for their useful comments, and Kuei-Lan Chang, MSc, Show-Lan Ju, BS, Jin-Ya Chen, BS, Fan-Ping Liu, BS, Su-Min Chang, BS, and Chuan-Hsiao Li, BS, for their technical assistance. We also thank Bill Franke, MA, for proofreading and revising the English in this manuscript.


    FOOTNOTES
 
Abbreviation: DMSA = dimercaptosuccinic acid

Author contributions: Guarantor of integrity of entire study, N.T.C.; study concepts, B.F.L., N.T.C.; study design, B.F.L., N.T.C., G.C.L., H.S.Y.; literature research, B.F.L., N.T.C.; clinical studies, B.F.L., N.T.C., D.C.W.; data acquisition, B.F.L., N.T.C.; data analysis/interpretation, S.T.W., B.F.L., N.T.C., D.C.W., K.B.T.; statistical analysis, B.F.L., N.T.C.; manuscript preparation and editing, B.F.L., N.T.C.; manuscript definition of intellectual content, B.F.L., N.T.C., D.C.W., K.B.T., G.C.L., H.S.Y.; manuscript revision/review and final version approval, all authors.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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I. E. Koutroubakis, S. I. Koukouraki, P. D. Dimoulios, A. A. Velidaki, N. S. Karkavitsas, and E. A. Kouroumalis
Active Inflammatory Bowel Disease: Evaluation with 99mTc (V) DMSA Scintigraphy
Radiology, October 1, 2003; 229(1): 70 - 74.
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