HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spalinger, J. Articles by Seidman, E. G. Search for Related Content PubMed PubMed Citation Articles by Spalinger, J. Articles by Seidman, E. G.

Doppler US in Patients with Crohn Disease: Vessel Density in the Diseased Bowel Reflects Disease Activity¹

¹ From the Division of Pediatric Gastroenterology and Nutrition, Departments of Pediatrics (J.S., G.M., D.H., M.D., E.G.S.) and Medical Imaging (H.P., M.C.M., J.D.), Hôpital Sainte-Justine, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. Received May 21, 1999; revision requested July 22; final revision received May 30, 2000; accepted June 28. Supported in part by the Crohn’s and Colitis Foundation of Canada. E.G.S. supported by a research scholarship award from the FRSQ. Address correspondence to H.P. (e-mail: hpatriquin@videotron.ca).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine if neovascularization associated with Crohn disease, as detected with Doppler ultrasonography (US), reflects clinical disease activity.

MATERIALS AND METHODS: A devised measurement, vessel density, was estimated with color Doppler US. Patients with Crohn disease underwent clinical and laboratory assessment in which the Crohn disease activity index was measured; patients underwent abdominal US the same week. Color Doppler US was performed by using a 7.5–10.0- or 8.0–12.0-MHz transducer, the lowest possible pulse repetition frequency without aliasing, a low wall filter, and high Doppler gain settings. The length and thickness of the affected loops were measured, and the number of color Doppler signals per square centimeter in the bowel loop was counted. Pulsed Doppler US was used to confirm that the signals originated from arteries or veins and not from movement artifacts.

RESULTS: Ninety-two patients (aged 7–20 years; mean, 14.85 years; 44 female, 48 male) underwent 119 examinations; 85 were performed in patients with active disease. Affected loops were thicker (10.6 vs 4.6 mm; P < .001) and had a higher vessel density with disease (69 of 119 examinations) than during remission (two of 34 examinations; P < .001).

CONCLUSION: Vessel density in affected bowel loops, as estimated with Doppler US, and bowel wall thickness (>5 mm) reflect disease activity in patients with Crohn disease.

Index terms: Abdomen, US, 74.1298, 74.12983, 74.12989 • Blood vessels, US, 95.12983 • Crohn disease, 74.262 • Intestines, abnormalities, 74.262 • Ultrasound (US), Doppler studies, 74.12983 • Ultrasound (US), pulsed, 74.12984

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Active Crohn disease is associated with intestinal neovascularization, as demonstrated at pathologic examination (1), and with elevated serum levels of the angiogenesis promoter basic fibroblast growth factor (2). Bowel loops (in small intestine or colon) affected by Crohn disease are thickened and readily visible with high-frequency ultrasonography (US) (3). The vascularization in these loops is greatly increased, and blood flow in macroscopic vessels can be depicted with Doppler US (4,5). The aim of this study was to determine if neovascularization associated with Crohn disease, as detected with Doppler US, reflects disease activity measured clinically.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pilot Study
A pilot study was conducted in 20 patients (aged 3–14 years; eight male, 12 female) with known active Crohn disease. We devised a method of estimating vessel density, or the number of vessels per square centimeter of intestinal wall. With the use of high-frequency US, we identified the intestinal loop (or loops) thickened by Crohn disease and then counted the number of color Doppler signals per square centimeter in the affected loop. Ten patients (aged 5–15 years; six male, four female) without bowel disease were similarly examined. The pilot study was performed by one author (H.P.).

Clinical Study
Prospective clinical and US studies were started. Patients (aged 7–20 years; mean, 14.5 years; 44 female, 48 male) referred to our gastroenterology clinic and inpatient service for assessment of Crohn disease were included in the study. The diagnosis of Crohn disease was established with standard clinical, radiologic, histopathologic, and endoscopic criteria. A pediatric gastroenterologist (J.S.) evaluated each patient’s disease activity (active or quiescent) on the basis of results of a complete history, a physical examination, and standard laboratory tests. The Crohn disease activity index (CDAI) was determined with the use of a validated index for children (6) modified from that of Best et al (7). The clinical and laboratory factors listed in Table 1 were recorded over 1 week. Disease was classified as active if the CDAI exceeded 150, the value previously validated (6,7).

Conventional abdominal US was performed and was followed with high-frequency (7.5–10.0- or 8.0–12.0-MHz) US and color Doppler examination of the intestine by using a ATL 5000 or ATL Ultramark 9 machine with high-definition imaging (Advanced Technology Laboratories, Seattle, Wash). A single layer of normal intestinal wall, as well as the lumen, can be identified with high-frequency US.

In most patients, bowel loops infiltrated with Crohn disease were readily visible, with a thickness at least double that of a normal wall (2.5 mm) and narrow fixed lumen (3). The diseased bowel loop was identified with gray-scale US, and its thickness (from mucosa to serosa) and length were measured. Because the thickening of the diseased loops was constant at echoscopy and because the loops were usually far from the stomach, they were measured in their natural state without the oral or rectal addition of water. Color Doppler US was then performed with the use of a low wall filter, the highest Doppler gain setting possible without flash artifacts, and the lowest possible pulse repetition frequency that would prevent aliasing. These technical factors were kept constant for all examinations.

The thickened bowel loops were scanned with color Doppler US, and the area of highest vascularity was selected for study. The area of interest at color Doppler US was restricted to 1–2 cm², and the number of color Doppler signals per square centimeter was counted. Flash or movement artifacts were excluded by means of repeated pulsed Doppler sampling of the visible color signals to ensure that these signals originated from arteries or veins (Fig 1c). This determination served as an estimate of vessel density, which was classified as low if there were no or up to two color Doppler signals per square centimeter (Fig 1a), moderate if there were three to five signals per square centimeter, and high if there were more than five signals per square centimeter (Fig 1b and 1c).

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Color Doppler US scans of a bowel loop thickened with Crohn disease obtained in two children show (a) quiescent disease, with one to two signals per square centimeter, and (b) active disease, with more than five signals per square centimeter. The rectangular box defines the area examined at pulsed Doppler US. (c) Pulsed Doppler US scan obtained in the same loop as in b shows low-resistance high-diastolic arterial flow compatible with peripheral vasodilatation, as seen with inflammation. Pulsed Doppler US is performed to verify that the detected color signals originate from vessels and not from motion artifacts.

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Color Doppler US scans of a bowel loop thickened with Crohn disease obtained in two children show (a) quiescent disease, with one to two signals per square centimeter, and (b) active disease, with more than five signals per square centimeter. The rectangular box defines the area examined at pulsed Doppler US. (c) Pulsed Doppler US scan obtained in the same loop as in b shows low-resistance high-diastolic arterial flow compatible with peripheral vasodilatation, as seen with inflammation. Pulsed Doppler US is performed to verify that the detected color signals originate from vessels and not from motion artifacts.

View larger version (163K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Color Doppler US scans of a bowel loop thickened with Crohn disease obtained in two children show (a) quiescent disease, with one to two signals per square centimeter, and (b) active disease, with more than five signals per square centimeter. The rectangular box defines the area examined at pulsed Doppler US. (c) Pulsed Doppler US scan obtained in the same loop as in b shows low-resistance high-diastolic arterial flow compatible with peripheral vasodilatation, as seen with inflammation. Pulsed Doppler US is performed to verify that the detected color signals originate from vessels and not from motion artifacts.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Pilot Study
In the 20 patients with known active Crohn disease, the thickened affected loops yielded many color Doppler signals (more than five per square centimeter). In the 10 patients without bowel disease, the intestinal wall was thin (<3 mm), and only occasional Doppler signals (fewer than one per square centimeter) were detected within it.

Clinical Study
All 92 patients (44 female, 48 male) who were referred for Doppler US were successfully examined. There were 119 clinical and US examinations in the 92 patients; 85 examinations were performed during active disease (as indicated by a CDAI > 150) and 34 during quiescent disease. Data obtained from the comparison of affected bowel length and thickness with the CDAI are summarized in Tables 2 and 3. Patients with active disease had loops of affected bowel that were thicker and longer than those of patients with quiescent disease (P < .001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Intense neovascularization, as well as multifocal infarctions, have been found in specimens resected from patients with Crohn disease (1). Pathologically, there is growth of new blood vessels into inflamed tissue (8). X-ray images obtained during angiography in patients with Crohn disease show an increase in the number and caliber of vessels that lead to diseased bowel loops (9–12).

Recently, Bousvaros et al (2) reported increased serum levels of basic fibroblast growth factor, or BFGF, a strong stimulator of angiogenesis in patients with active Crohn disease. Basic fibroblast growth factor induces the proliferation of fibroblasts, smooth muscle cells, endothelial cells, and new blood vessels both in vitro and in vivo (2). Detection of blood flow in these microscopic vessels is impossible with present-day Doppler US equipment. However, it is possible to depict blood flow in macroscopic vessels (also shown at angiography) that supply the new vessels created by angiogenesis. The number of these vessels is increased, as was previously noted at angiography (1) and at color Doppler US in the present study.

A similar increase in blood flow velocity and number of vessels depicted with modern clinical Doppler US is noted in appendicitis (13) and other inflammatory diseases. Angiogenesis is likely to be involved in these diseases as well; angiogenesis stimulators have been isolated from inflammatory tissue and wound fluid (14).

The neovascularization that occurs with active Crohn disease is also accompanied by changes in blood flow in the main intestinal arteries. Doppler flowmetry has been used to investigate splanchnic hemodynamics in inflammatory bowel disease and has demonstrated increased volume of blood flow in the superior mesenteric artery (15), as well as an increased mean velocity of flow in the portal vein in adults with active disease (16,17). Measurements of flow velocity and volume with Doppler US require exact repeated measurements during breath holding in cooperative patients and are not always possible in children. We therefore explored the affected bowel loop, which is visible with US (7).

Findings from our pilot study of 20 patients with clinically active Crohn disease showed many color Doppler signals in the thickened bowel wall. We verified with repeated pulsed Doppler examinations that the color signals originated from blood vessels and not from extraneous movement (Fig 1). Afterward, we counted the number of color Doppler flow signals per square centimeter of the thickened bowel and obtained an estimation of vessel density in the affected loop. The number of color Doppler signals is an estimate and not a direct count of vessels present in the area examined because a single tortuous vessel may result in several color Doppler signals.

We found that gray-scale and Doppler examinations of the intestine were easily performed in our patients and were successful in all patients in the pilot and clinical studies. At gray-scale US, we found that the thickness (diameter) and length of the affected loops were correlated with disease activity; the loop was thicker (>5 mm) and longer when the disease was active. At pathologic examination, a loop affected with Crohn disease is thick and hardened. At barium study, the lumen is narrowed and changes little with peristalsis or with the presence of food or fluid in the bowel lumen. For this reason, we did not attempt to fill the bowel lumen with water prior to US. We limited our study to the thickened loops. Acute disease without thickening of the bowel was not studied. We found that measurements of length in affected bowel loops were difficult to obtain when the loops were tortuous and because of the limited field of view of the US transducer.

There was a close correlation between our estimate of vessel density in the affected bowel loops and the disease activity as assessed by using the CDAI (Tables 2, 3). Fourteen patients with moderate vessel density had active disease compared with eight patients with moderate vessel density and clinically quiescent disease. The moderate vessel density seems to be related to active disease. For the purpose of statistical analysis with the use of the ² test, moderate and high vessel density estimates were combined and were considered to represent active disease.

By combining the two criteria of vessel density (more than two vessels per square centimeter) and thickness (>5 mm) (Fig 2), we observed specificities and positive predictive values that were higher than those obtained by using each criterion alone. This observation has important therapeutic implications.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Receiver operating characteristic curve obtained at analysis of diseased bowel loop thickness and CDAI suggests that children with a bowel thickness exceeding 5 mm risk having active disease (area under the curve = 85.3%; P < .001; sensitivity, 85.7%; specificity, 78.1%).

Future US machines that improve resolution and Doppler sensitivity, power Doppler, three-dimensional imaging, and US contrast agents should increase the visibility of blood flow in the neovasculature of bowel loops affected by Crohn disease. Monitoring of disease activity under such circumstances will be more sensitive, and standards for the estimation of vessel density in active versus nonactive disease will have to be reset and kept constant in each laboratory.

The effects of angiogenesis that accompany active Crohn disease are detectable with Doppler US in visible vessels that are upstream from the microscopic vascular bed directly created by the stimulation of angiogenesis. Blood flow in these macroscopic vessels that feed the angiogenic bed is increased, and more vessels are detectable when the disease is active. These findings mirror the results of a previous study, which showed that serum levels of basic fibroblast factor angiogenesis stimulator are increased in active disease. Active disease also thickens the affected loop.

What do the results of our study mean to the clinician and to the patient with Crohn disease? Careful analysis of the results of high-resolution Doppler US of the intestine yields a noninvasive test of disease activity that is faster than estimation of the CDAI. US can be used to test the affected bowel directly and is independent of secondary effects such as anemia that affect the CDAI but develop more slowly. US may therefore reflect recent changes in the disease more accurately than the CDAI, especially if serial examinations are performed when the patient’s clinical status changes. Length and thickness of the affected bowel loop reflect disease activity; when assessed with the vessel density estimate, these yield a positive predictive value of 94%. However, of the three parameters tested, vessel responsive density is probably the one most responsive to changes in disease activity both during disease activation and healing.

Doppler US of bowel wall affected by Crohn disease not only reflects disease activity but also offers the potential to assess the effects of therapy on the bowel wall. This potential may become useful as an ever increasing number of experimental treatments of the disease, including angiogenesis inhibitors, are being tested in clinical trials.

With the use of strictly controlled and constant technical factors, color Doppler US estimation of vessel density in a bowel loop affected by Crohn disease reflects disease activity. This noninvasive test may prove to be useful for monitoring the course of the disease and the response to therapy.

	ACKNOWLEDGMENTS

 
We thank Diane Lefebvre, Dec Sc, for preparation of the manuscript.

	FOOTNOTES

 
Abbreviation: CDAI = Crohn disease activity index

Author contributions: Guarantor of integrity of entire study, H.P.; study concepts, H.P.; study design, H.P., E.G.S.; definition of intellectual content, H.P., E.G.S.; literature research, H.P., E.G.S., J.S.; clinical studies, all authors; data acquisition, J.S., M.C.M., H.P., M.D.; data analysis, J.S., H.P., E.G.S., G.M.; statistical analysis, D.H., G.M.; manuscript preparation, H.P., J.S., M.C.M.; manuscript editing, E.G.S., M.C.M.; manuscript review, H.P., E.G.S.; manuscript final version approval, all authors.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Wakefield AJ, Sawyerr AM, Dhillon AP, et al. Pathogenesis of Crohn’s disease: multifocal gastrointestinal infarction. Lancet 1989; 2:1057-1062.[Medline]
2. Bousvaros A, Zurakowski D, Fishman SJ, et al. Serum basic fibroblast growth factor in pediatric Crohn’s disease: implications for wound healing. Dig Dis Sci 1997; 42:378-386.[Medline]
3. Sarrazin J, Wilson SR. Manifestations of Crohn disease at US. RadioGraphics 1996; 16:499-520.[Abstract]
4. Quillin SP, Siegel MJ. Gastrointestinal inflammation in children: color Doppler ultrasonography. J Ultrasound Med 1994; 13:751-756.[Abstract]
5. Faure C, Belarbi N, Mougenot JF, et al. Ultrasonographic assessment of inflammatory bowel disease in children: comparison with ileocolonoscopy. J Pediatr 1997; 130:147-151.[Medline]
6. Herzog D, Delvin E, Seidman E. Fecal -1 antitrypsin: a marker of intestinal versus systemic inflammation in pediatric Crohn’s disease?. Inflamm Bowel Dis 1996; 2:236-243.
7. Best WR, Becktel JM, Singleton JW. Rederived values of eight coefficients of the Crohn’s disease activity index (CDAI). Gastroenterology 1979; 77:843-846.[Medline]
8. Hurley JV. Inflammation. In: Anderson JR, eds. Muir’s textbook of pathology. 12th ed. London, England: Arnold, 1985; 4.1-4.38.
9. Brahme F, Lindstrom C. A comparative radiographic and pathological study of intestinal vaso-architecture in Crohn’s disease and in ulcerative colitis. Gut 1970; 11:928-940.[Abstract/Free Full Text]
10. Erikson U, Fagerberg S, Krause U, Olding L. Angiographic studies in Crohn’s disease and in ulcerative colitis. Am J Roentgenol Radium Ther Nucl Med 1970; 110:385-392.[Medline]
11. Hulten L, Lindhagen J, Lundgren O, Fasth S, Ahren C. Regional intestinal blood flow in ulcerative colitis and Crohn’s disease. Gastroenterology 1977; 72:388-396.[Medline]
12. Lunderquist A, Knutsson H. Angiography in Crohn’s disease of the small bowel and colon. Am J Roentgenol Radium Ther Nucl Med 1967; 101:338-344.[Medline]
13. Patriquin HB, Garcier JM, Lafortune M, et al. Appendicitis in children and young adults: Doppler sonographic-pathologic correlation. AJR Am J Roentgenol 1996; 166:629-633.[Abstract/Free Full Text]
14. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442-447.[Abstract/Free Full Text]
15. van Oostayen JA, Wasser MN, van Hogezand RA, et al. Doppler sonography evaluation of superior mesenteric artery flow to assess Crohn’s disease activity: correlation with clinical evaluation, Crohn’s disease activity index, and ₁-antitrypsin clearance in feces. AJR Am J Roentgenol 1997; 168:429-433.[Abstract/Free Full Text]
16. Silvan Delgado M, Juanco Pedregal C, Parra Blanco JA, Barreda Gonzalez M. Usefulness of Doppler ultrasound in the evaluation of patients with active Crohn’s disease. Rev Esp Enferm Dig 1997; 89:677-684.[Medline]
17. Bolondi L, Gaiani S, Brignola C, et al. Changes in splanchnic hemodynamics in inflammatory bowel disease: non-invasive assessment by Doppler ultrasound flowmetry. Scand J Gastroenterol 1992; 27:501-507.[Medline]

This article has been cited by other articles:

				J. H. Chidlow Jr., D. Shukla, M. B. Grisham, and C. G. Kevil Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G5 - G18. [Abstract] [Full Text] [PDF]

				J. H. Chidlow Jr., W. Langston, J. J.M. Greer, D. Ostanin, M. Abdelbaqi, J. Houghton, A. Senthilkumar, D. Shukla, A. P. Mazar, M. B. Grisham, et al. Differential Angiogenic Regulation of Experimental Colitis Am. J. Pathol., December 1, 2006; 169(6): 2014 - 2030. [Abstract] [Full Text] [PDF]

				J F Colombel, C A Solem, W J Sandborn, F Booya, E V Loftus Jr, W S Harmsen, A R Zinsmeister, K D Bodily, and J G Fletcher Quantitative measurement and visual assessment of ileal Crohn's disease activity by computed tomography enterography: correlation with endoscopic severity and C reactive protein Gut, November 1, 2006; 55(11): 1561 - 1567. [Abstract] [Full Text] [PDF]

				S. Goebel, M. Huang, W. C. Davis, M. Jennings, T. J. Siahaan, J. S. Alexander, and C. G. Kevil VEGF-A stimulation of leukocyte adhesion to colonic microvascular endothelium: implications for inflammatory bowel disease Am J Physiol Gastrointest Liver Physiol, April 1, 2006; 290(4): G648 - G654. [Abstract] [Full Text] [PDF]

				T. Ripolles, M. J. Martinez, V. Morote, and J. Errando Appendiceal involvement in Crohn's disease: gray-scale sonography and color Doppler flow features. Am. J. Roentgenol., April 1, 2006; 186(4): 1071 - 1078. [Abstract] [Full Text] [PDF]

				E F Stange, S P L Travis, S Vermeire, C Beglinger, L Kupcinkas, K Geboes, A Barakauskiene, V Villanacci, A Von Herbay, B F Warren, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis Gut, March 1, 2006; 55(suppl_1): i1 - i15. [Full Text] [PDF]

				A. Sitek and R. G. Sheiman Small-Bowel Perfusion Measurement: Feasibility with Single-Compartment Kinetic Model Applied to Dynamic Contrast-enhanced CT Radiology, November 1, 2005; 237(2): 670 - 674. [Abstract] [Full Text] [PDF]

				R. Faingold, A. Daneman, G. Tomlinson, P. S. Babyn, D. E. Manson, A. Mohanta, A. M. Moore, J. Hellmann, C. Smith, T. Gerstle, et al. Necrotizing Enterocolitis: Assessment of Bowel Viability with Color Doppler US Radiology, May 1, 2005; 235(2): 587 - 594. [Abstract] [Full Text] [PDF]

				E M Danse, J Jamart, P Hoang, P F Laterre, A Kartheuser, and B E Van Beers Focal bowel wall changes detected with colour Doppler ultrasound: diagnostic value in acute non-diverticular diseases of the colon Br. J. Radiol., November 1, 2004; 77(923): 917 - 921. [Abstract] [Full Text] [PDF]

				S. S. Lee, H. K. Ha, S.-K. Yang, A. Y. Kim, T. K. Kim, P. N. Kim, M.-G. Lee, S.-J. Myung, H.-Y. Jung, J. H. Kim, et al. CT of Prominent Pericolic or Perienteric Vasculature in Patients with Crohn's Disease: Correlation with Clinical Disease Activity and Findings on Barium Studies Am. J. Roentgenol., October 1, 2002; 179(4): 1029 - 1036. [Abstract] [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spalinger, J. Articles by Seidman, E. G. Search for Related Content PubMed PubMed Citation Articles by Spalinger, J. Articles by Seidman, E. G.