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Chronic nonspecific multiple ulcers of the small intestine: a proposal of the entity from Japanese gastroenterologists to Western enteroscopists
Chronic nonspecific multiple ulcers of the small intestine: a proposal of the entity from Japanese gastroenterologists to Western enteroscopists Takayuki Matsumoto, MD, Mitsuo Iida, MD, Toshiyuki Matsui, MD, Tsuneyoshi Yao, MD Fukuoka, Japan
With the widespread use of video capsule endoscopy (VCE)1 and double balloon endoscopy (DBE),2,3 it has become possible to examine an extensive area of the small intestine by endoscopy. Both VCE and DBE are valuable for patients suspected of having small intestinal pathology, especially for those with GI bleeding of obscure origin.4-11 Although vascular lesions are the most frequent source of bleeding from the small intestine, mucosal breaks are also identified in a certain proportion of patients.4-11 Although Crohn’s disease and nonsteroidal anti-inflammatory drug (NSAID) enteropathy are representative among such ulcerous diseases, there have been other rare but significant ulcerous diseases of the small intestine. During the past 40 years, there has been a distinctive small intestinal pathology in the Japanese population characterized by persistent blood and protein loss and histologically nonspecific ulcers. Although we have recently reported on its histologic and enteroscopic features and referred to the condition as chronic nonspecific multiple ulcers of the small intestine (CNSU),12,13 there have also been descriptions of a similar small intestinal pathology with different nomenclature. In this article, we review CNSU with a special reference to its clinicopathologic and enteroscopic features and to other ulcerous diseases of the small intestine. Such a review seems inevitable in an area in which DBE has become widely accepted and routinely applied.
Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.01.004
A 10-year-old Japanese girl initially visited her neighboring clinic in 1960, complaining of lower abdominal pain. She was treated by appendectomy under a diagnosis of acute appendicitis, but her abdominal pain recurred 3 weeks after the surgery. One year later she was treated by cholecystectomy under a putative diagnosis of chronic cholecystitis. During the perioperative period of the second surgery, she was diagnosed as having positive fecal occult blood and anemia and was thus referred to our institution in August 1963. At the time, she was 136 cm in height and 26.5 kg in weight. Physical examination revealed a thin, pale, and malnourished girl. She was afebrile, but her abdomen was slightly distended with an increase in bowel sound. Her feces were neither soft nor tarry, but they were positive for occult blood. Her hemoglobin value was decreased to 9.2 g/dL (normal 12-16 g/dL) and serum protein value to 5.2 g/dL (normal 6.7-8.2 g/dL). She did not have leukocytosis (white blood cell count 6600/mL). Small-bowel radiography showed eccentric deformities and multiple stenoses in the ileum (Fig. 1A). At laparotomy, the stenoses were distributed within a segment measuring 30 cm in length, the most distal site of which was 50 cm from the ileocecal valve. Macroscopically, there were 3 shallow and sharply demarcated circular or oblique ulcers in the ileum (Fig. 1B). Histologic examination of the ileum showed ulcers restricted to the submucosa accompanied by minimal submucosal edema and mild chronic inflammatory infiltrates (Fig. 1C). However, there were not any caseating or noncaseating granulomas. Although the patient recovered uneventfully, she again experienced abdominal pain 18 months after the surgery. At that time, her anemia and hypoproteinemia recurred with circular ulcers around the ileal anastomosis. She was subsequently readmitted because of small intestinal obstruction, and small-bowel radiography and surgery confirmed recurrence of the ileal ulcers. During the subsequent 40-year period, she had ileal resections 6 times for the recurrence of stenoses. When she was 54 years of age, we examined her by DBE. A severe stenosis with sharply demarcated ulcer in the ileum and a circular ulcer proximal to the stenosis was revealed (Figs. 1D and E). On the basis of the anecdotal but extremely important case series, the clinicopathologic features of CNSU have been summarized as (1) absence of causative factors related
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TYPICAL CASE OF CNSU IN JAPAN Okabe and Sakimura,14 from our department, were the first to report CNSU in the Japanese literature. During the period 1963 to 1968, the 2 gastroenterologists handled 6 cases of CNSU. The cases comprised 3 males and 3 females. The patients’ presumed ages at onset ranged from 5 to 51 years, and their ages at diagnosis of small intestinal ulcers ranged from 13 to 59 years. Following is a summary of one of the cases initially described by Okabe and Sakimura.14,15 The patient was under observation by one of the authors at the time of this writing.
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Figure 1. Small intestinal lesions in a case of CNSU (case 7 in Table 1). A, Barium follow-though examination performed when the patient was aged 13 years shows multiple eccentric deformities and strictures in the ileum. B, Macroscopic view of the resected ileum at the time of the first surgery shows sharply demarcated linear or geographical ulcers. The ulcers are arranged in circular or oblique alignment. C, Histologically there is a distinctive mucosal defect with minimal inflammatory infiltrates and fibrosis. The ulcer is restricted to the submucosal layer. D, Retrograde DBE performed when the patient was aged 54 years shows severe stenosis with a sharply demarcated ulcer in the ileum. E, Antegrade DBE shows a shallow and sharply demarcated ulcer. The ulcer aligns in a spiral configuration.
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to the onset and perpetuation of the disease, (2) persistent anemia because of continuing occult GI bleeding, and (3) small intestinal ulcers restricted to the submucosal layer, occurring predominantly in the ileum without any specific histology.
NONSPECIFIC ULCEROUS DISEASES OF THE SMALL INTESTINE As mentioned above, CNSU is a chronic and recurrent small intestinal disease initially identified in Japan in the 1960s. During the same period, the classification of chronic ulcerous diseases of the small intestine was proposed in Western countries.16,17 In the West, the etiology of nonspecific ulcers of the small intestine included congenital causes, infection, trauma, ischemia, chemicals, and neoplasia.16-18 Although regional enteritis (Crohn’s disease) was the most rigorously investigated, there have been a large number of descriptions of nonspecific ulcers of the small intestine in the West. Although the chemical compounds, especially thiazides and enteric potassium chloride tablets,19-22 drew much attention as a cause of nonspecific ulcers in the West,16,17 there were other cases of small intestinal ulcers without any provisional etiology that were restricted to the submucosal layer and recurred even after surgical resection.23-25 The nomenclatures for these conditions differed from case to case and included primary nonspecific small-bowel ulceration,23 idiopathic ulcerations of the small bowel,24 and nonspecific smallbowel ulceration.25 There have recently been case descriptions in the West that show small intestinal pathology presumed to be similar to CNSU. In 2001, Santolaria et al26 reported on a peculiar small intestinal pathology. The male patient initially manifested diarrhea, weight loss, and edema, and later complained of recurrent intestinal obstruction during a 25-year period of his life. Even though the patient was treated 3 times by surgery, the small intestinal lesion recurred with a feature compatible with diaphragm disease. What should be noted in the case is that the patient was completely free of NSAID use. There has also been a clinicopathologic entity characterized by nonspecific ulcers of the small intestine, which has been referred to as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE).27 The disease was first reported by Debray et al28 in 1964, when Okabe and Sakimura14 identified their first case of CNSU. Since then, 18 cases of CMUSE have been reported, mainly in French literature.28-39 Perlemuter et al27,38 reviewed cases of CMUSE in 1996, and subsequently attempted a multicenter retrospective analysis of 12 cases in 2001. In those articles, the clinicopathological features of CMUSE have been summarized as (1) unexplained small intestinal strictures found in adolescent and middle-aged subjects, (2) superficial ulceration of the mucosa and submucosa, (3) chronic or relapsing clinical course, even after www.giejournal.org
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\surgery, (4) no biological signs of systemic inflammatory reaction, and (5) beneficial effect of steroids. Perlemuter et al27,38 hypothesized that CMUSE is closely associated with vasculitis because stenosis and aneurysm were verified in superior mesenteric arteries and steroid is efficacious in a certain proprtion of the subjects. Although it still remains inconclusive whether CNSU and CMUSE belong to the same category, the 2 diseases share common clinicopathologic features with respect to chronic and recurrent clinical course and nonspecific stenosing small intestinal ulcers. There is another small intestinal pathology characterized by persistent nonspecific ulcers of the small intestine and associated with celiac disease.40-42 The disease has been referred to as chronic ulcerative jejunoileitis, and it predominantly involves the proximal part of the small intestine. The clinical symptoms include fever, pain, steatorrhea, and protein-losing enteropathy. The small intestinal lesions are characterized by multiple and circular ulcers occurring predominantly in the jejunum. The circular ulcer progresses to stenosis and obstruction, and furthermore, penetrating ulcers may lead to perforation in some cases. What is most characteristic of the disease is various degrees of villous atrophy in the intervening mucosa. Although an extensive review by Biagi et al43 indicated that only 38 cases of chronic ulcerative jejunoileitis have been reported during the period 1967 to 1999, the clinicopathologic features seem to be conspicuously different than those of CNSU and CMUSE.
DIAGNOSTIC CRITERIA OF CNSU Even in Japan, without taking clinical features into consideration, some gastroenterologists misinterpreted CNSU as a small intestinal pathology of nonspecific pathology. The misinterpretaion led to heterogeneity in descriptions of clinicopathologic features of CNSU. Because chronic, recurrent clinical course is a diagnostic feature of CNSU, and because the phenotype of CNSU can easily progress to the diaphragm in patients treated with total parenteral nutrition, Yao, who is a colleague of Okabe and Sakimura (and one of the authors of this review), proposed a modified diagnostic criteria of CNSU in 2004 (Table 1).44 The criteria are based on clinical course and specific morphology of ‘‘nonspecific’’ small intestinal ulcers. During the period 1964 to 2006, we encountered, at our institutions, 15 patients with small intestinal lesions that were compatible with CNSU (Table 2), while more than 500 cases of Crohn’s disease were diagnosed during the equivalent period. However, a review of the Japanese literature from 1969 to 2006 identified fewer than 20 cases of CNSU that fulfilled the above-mentioned diagnostic criteria.45-51
Clinical symptoms The symptoms of CNSU are characterized by those attributed to chronic and persistent blood loss from the intestine occurring early in life. Thus, patients manifest Volume 66, No. 3 : 2007 GASTROINTESTINAL ENDOSCOPY S101
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fatigue, edema, and growth retardation, and they usually have repeated episodes of treatment for anemia. However, the patients rarely manifest diarrhea, hematochezia, or fever. On the basis of these manifestations, patients visit gastroenterologists long after the onset of symptoms. In addition to the symptoms, the physical examination reveals anemia, but the abdomen is unremarkable.
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TABLE 1. Diagnostic criteria of CNSU 1. Persistent and occult blood loss from the GI tract except during bowel rest or postoperative period. 2. Confirmation of characteristic small intestinal lesions by macroscopy, radiography, or enteroscopy. i Circular or oblique in alignment.
Macroscopic findings The small intestinal ulcers in CNSU occur predominantly in the ileum; the terminal ileum is usually spared. The ulcers usually number more than 20, and each is characterized by a discrete margin and shallow and flat ulcer bed (Fig. 2A). Each ulcer is linear or a tall triangle in configuration, and alignment is circular or oblique in fashion. The ulcers occasionally fuse, thus showing geographic configuration. Even though the ulcers develop into luminal narrowing, the small intestinal lesions in CNSU never progress to cobblestone appearance, fissure, or fistula formation or adhesion. In more advanced cases, however, small intestinal stenoses are the major manifestation. Because of the oblique nature of the preexisting ulcers, the stenoses are not always concentric but may show spiral patterns. Such a healing process progresses, especially in circumstances treated by total parenteral nutrition (Fig. 2B).
Histologic findings The depth of the ulcers is restricted to the mucosa or the submucosa, and they never extend to the proper muscular layer. The mucosal defect is accompanied by mild infiltration of plasma cells, lymphocytes, and eosinophils. Lymph follicles may also be seen. Even in histology, the margin of the ulcer is clearly demarcated by the surrounding villous mucosa. Although submucosal fibrosis occurs in the healing stage, it is restricted to the area of mucosal defect with minimal epithelial repair and restitution. These histologic features have been referred to as an ulcerative nonproliferative process by Okabe and Sakimura.14,15
CLINICOPATHOLOGIC FEATURES OF CNSU Age, sex, and duration of symptoms As has been summarized in Table 2, our cases of CNSU comprised 11 females and 4 males. While the ages of onset ranged from 10 to 52 years, 13 of 15 patients had anemia during their second or third decade of life. Most patients had histories of long-term anemia, and 9 patients had symptoms for more than 10 years before confirmation of small intestinal lesions.
Laboratory data
ii Sharply demarcated from surrounding normal mucosa. iii Geographic or linear in shape. iv Multiplicity in number with !4-cm distance from each other. v Ulcers not reaching proper muscular layer. vi Scarred ulcers presumed to be the healing stage of those characterized by i-v* in cases treated by bowel rest. *Depicted as symmetric and eccentric rigidity under small-bowel radiography, and concentric or nonconcentric stricture under enteroscopy.
edly decreased unless the patient is treated by iron supplementation. In addition to anemia, most patients manifest hypoproteinemia and hypoalbuminemia. However, acute inflammatory reactions, such as C-reactive protein, a1- and a2-globulins, are usually within their normal ranges or slightly increased. Unlike intestinal tuberculosis, intradermal tuberculin test is negative in most cases.
Small-bowel radiography Until recently, small-bowel radiography, including smallbowel follow-through (BFT) and double-contrast barium study (DCBS), was the first-choice procedure for the diagnosis of CNSU. However, it is not easy for radiologists to recognize the small intestinal lesions as barium flecks because the ulcers are extremely shallow. The ulcers are usually shown to be asymmetric and characterized by multiple rigidity or eccentric deformities (Fig. 3A). When examined precisely by DCBS together with compression procedure, linear or tall triangle mucosa defects may be depicted as sharply demarcated barium flecks (Fig. 3B). In cases treated by total enteral or parenteral nutrition, the ulcer heals with stricture formation. Although the stenoses apparently mimic those seen in NSAID enteropathy and intestinal tuberculosis, the stenoses in CNSU may manifest in a spiral configuration with pseudodiverticular formation because of oblique alignment of the initial ulcer (Fig. 1A).
Endoscopy
There are no specific laboratory tests for the diagnosis of CNSU. The feces are continuously positive for occult blood. Peripheral blood test reveals hypochromatic and microcytic anemia. However, leukocyte and platelet counts are within normal ranges. Serum iron level is mark-
It was not easy for gastroenterologists to observe the small intestinal lesions of CNSU with enteroscopy. With the development of DBE, however, we have recently been able to confirm enteroscopic features of CNSU. Among 15 patients with CNSU diagnosed at our institution, we attempted DBE in 6 patients. On the basis of
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TABLE 2. Cases of CNSU diagnosed at our institutions from 1964 to 2006 Age (y)/sex
Case no.
Onset
Laboratory data
Diagnosis of CNSU
Presenting symptoms
Hemoglobin (g/dL)
Serum protein (g/dL)
CRP (mg/dL)
Follow-up after diagnosis (y)
Number of ileal resections
1.
20/F
27
Anemia, edema
8.2
4.9
–*
22
2
2.
15/F
24
Anemia, edema
3.5
5.0
–*
22
3
3.
10/M
26
Anemia, growth retardation
4.4
4.5
–*
24
6
4.
15/F
28
Anemia, edema
4.7
5.3
–*
43
3
5.
12/F
27
Anemia, abdominal pain
9.7
5.8
0.3
26
2
6.
17/F
34
Anemia
9.6
4.6
0.5
19
1
7.
10/F
13
Anemia, abdominal pain
7.4
5.4
0.1
42
6
8.
37/F
38
Anemia
9.5
6.7
0.5
31
2
9.
15/M
30
Anemia, edema
7.4
8.2
0.1
15
2
10.
52/M
57
Anemia
6.5
3.5
0.1
9
1
11.
14/F
36
Anemia
8.6
5.0
1.8
7
1
12.
24/M
24
Anemia
11.9
6.9
0.2
5
0
13.
13/F
29
Anemia
5.9
4.6
0.2
17
2
14.
16/F
52
Anemia
5.3
6.3
0.1
4
0
15.
13/F
40
Anemia
9.4
4.1
1.1
5
3
*CRP was determined to be negative under semiquantitative measurement.
the results, the enteroscopic features of CNSU are sharply demarcated linear and geographical ulcers arranged in circular or oblique alignment (Figs. 1C, 4A and B). The intervening mucosa is apparently normal, without any diminutive lesions. Even though the ulcers may be accompanied by fold convergency or severe stenosis, thus mimicking diaphragms seen in NSAID enteropathy, most of the ulcers have thin and faint exudates (Figs. 1D and E). The enteroscopic features again indicate the ulcers in CNSU are intractable. We have not performed VCE in our patients with CNSU because of the possibility of retention or impaction of the capsule. The VCE findings of CNSU have not been reported to date. There have been cases of duodenal and colonic involvement of CNSU.46,47 Gastroduodenal ulcers were found in 7 of our 15 cases, and colonic ulcers in 3 cases. One of the former cases had an intractable ulcer at the gastroduodenal anastomosis (Fig. 4C), and another in the latter cases had concentric ulcers with severe stenosis in the right side of the colon (Fig. 4D). These endoscopy findings suggest that CNSU is a disease that involves any site within the GI tract.
after surgery. Enteral or parenteral nutrition coupled with iron supplementation are transiently effective, but the small intestinal ulcers recur within a short period of time. Although all of our patients were treated with oral 5-aminosalicylic acid, 6 were also treated with oral prednisolone, and 1 was also treated with oral azathioprine. The medications failed to induce mucosal healing or prevent recurrence of small intestinal ulcers. As shown in Table 2, our patients have been under observation for periods ranging from 4 to 43 years, during which time 10 of 15 patients required 2 or more ileal resections. Histological examination of the resected specimens showed exactly the same findings as were found in the initial surgical specimens. It should also be noted that our patients have been free from any extraintestinal manifestations, such as oral, skin, joint, genital, or perianal lesions, as found in Crohn’s disease and Behcet’s disease.
DIFFERENTIAL DIAGNOSIS Crohn’s disease
Clinical course As has been discussed above, CNSU is characterized by recurrence of small intestinal ulcers and stenoses even www.giejournal.org
Ulcerous lesions separated by normal mucosa (which may be widely separate along the length or around the circumference) or discrete ulcers are 2 of the Volume 66, No. 3 : 2007 GASTROINTESTINAL ENDOSCOPY S103
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Figure 2. Macroscopic view of the small intestine in cases of CNSU. A, In a case without any treatment (case 9), shallow and linear ulcers are seen in the ileum. The linear ulcers align in circular fashion. B, In a case treated by total parenteral nutrition (case 6 [patient aged 52 years]), the ulcers healed with stenoses.
characteristics of Crohn’s disease.52 Thus, the stenosing lesions in CNSU may be interpreted as small intestinal Crohn’s disease of upper GI location and stricturing behavior according to Vienna53 or Montreal54 classification. Furthermore, one tenth of patients with Crohn’s disease, especially those with ileitis, manifest persistent low C-reactive protein (CRP) values.55 These observations in Western countries would suggest that the recurrent course and the gastroduodenal and colonic involvement of CNSU is compatible with Crohn’s disease. However, the intestinal lesions of CNSU are not suggestive of Crohn’s disease with respect to the lack of transmural inflammation, fissuring, fistula, and granuloma. Furthermore, macroscopic, radiographic, and endoscopic characteristics of the small intestinal ulcer are completely different from Crohn’s ileitis. Finally, unlike CMUSE, glucocorticoid has never had any therapeutic effect in patients with CNSU. These clinicopathologic findings suggest that CNSU is distinct from Crohn’s disease. S104 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 3 : 2007
Figure 3. Radiography of the small intestine in case 6 (patient aged 34 years; before total parenteral nutrition). A, A double-contrast study shows circular barium flecks and slight eccentric deformities in the small intestine. B, A compression study shows a sharply demarcated barium fleck in the ileum.
NSAIDs enteropathy It is well known that NSAIDs damage the small intestinal mucosa.56,57 Various interventional studies by means of sonde enteroscopy58 and VCE59,60 have shown that NSAIDs induce acute mucosal lesions in the small intestine in humans. Furthermore, intraoperative enteroscopy61-64 and DBE65 have revealed circular, stenosing ulcers in the small intestine of long-term NSAID users. In addition, both patients with CNSU and those with NSAID enteropathy share common clinical features characterized by anemia with fecal occult blood and hypoproteinemia. However, NSAID enteropathy responds dramatically after discontinuance of the causative drugs.11,12 Although we have not measured www.giejournal.org
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Chronic nonspecific multiple ulcers of the small intestine
Figure 4. Endoscopic findings in cases of CNSU. A, Antegrade DBE in case 6 (patient aged 51 years) shows a thin and linear ulcer in the ileum. The ulcer shows circular alignment. B, Retrograde ileoscopy in case 6 (at the same age) shows a thin, circular ulcer in the ileum. C, EGD in case 8 (patient aged 70 years) shows a clear ulcer in the duodenum. D, Colonoscopy in case 3 (patient aged 71 years) shows a concentric stenosis with a shallow ulcer in the ascending colon.
drug concentrations or prostaglandin biosynthesis in our patients, they were free from chronic NSAID use of any kind at the time of the initial diagnosis and subsequent follow-up periods.
Intestinal tuberculosis Infection of mycobacterial species in the GI tract results in chronic inflammation of the ileocecal region. However, the infection damages the small intestine multifocally with circumferential ulcers. Thus, during the healing stage of intestinal tuberculosis, the small intestinal lesions manifest findings mimicking CNSU. However, the small intestinal ulcers in tuberculosis are characterized by an irregular margin and dense mucous exudates. Unlike CNSU, the ulcers in an individual with intestinal tuberculosis manifest various stages. Finally, the ileocecal region is uniformly affected in patients with intestinal tuberculosis, and such patients will show positive results on an intradermal tuberculin test. www.giejournal.org
CONCLUSION With the development of DBE and VCE, it has become possible for gastroenterologists to diagnose small intestinal ulcers more accurately. It thus seems necessary to recognize CNSU as a distinctive entity and a candidate diagnosis in patients with occult GI bleeding of obscure origin. Such an approach would result in the accumulation of a larger number of diagnosed patients, thereby making our proposal of CNSU more accurate and practical by clarifying the pathophysiology and phenotype of the disease.
DISCLOSURE None of the authors have any disclosures to make. Volume 66, No. 3 : 2007 GASTROINTESTINAL ENDOSCOPY S105
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REFERENCES 1. Iddan G, Meron G, Glukhovsky A, et al. Wireless capsule endoscopy. Nature 2000;405:17. 2. Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53: 216-20. 3. Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases. Clin Gastroenterol Hepatol 2004;2:1010-6. 4. May A, Nachbar L, Wardak A, et al. Double-balloon enteroscopy: preliminary experience in patients with obscure gastrointestinal bleeding or chronic abdominal pain. Endoscopy 2003;35:985-91. 5. Saurin JC, Delvaux M, Gaudin JL, et al. Diagnostic value of endoscopic capsule in patients with obscure digestive bleeding: Blinded comparison with video push-enteroscopy. Endoscopy 2003;35:576-84. 6. Lewis BS, Swain P. Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: results of a pilot study. Gastrointest Endosc 2002;56:349-53. 7. Ell C, Remke S, May A, et al. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 2002;34:685-9. 8. Adler DG, Knipschield M, Gostout C. A prospective comparison of capsule endoscopy and push enteroscopy in patients with GI bleeding of obscure origin. Gastrointest Endosc 2004;59:492-8. 9. Bordas MA, Feu F, Gines A, et al. Wireless capsule endoscopy in patients with obscure gastrointestinal bleeding: a comparative study with push enteroscopy. Aliment Pharmacol Ther 2004;20:189-94. 10. Pennazio M, Santucci R, Rondonotti E, et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy: report of 100 consecutive cases. Gastroenterology 2004;126:643-53. 11. Mylonaki M, Frischer-Ravens A, Swain P. Wireless capsule endoscopy: a comparison with push enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding. Gut 2003;52:1122-6. 12. Matsumoto T, Iida M, Matsui T, et al. Nonspecific multiple ulcers of the small intestine unrelated to nonsteroidal anti-inflammatory drugs. J Clin Pathol 2004;57:1145-50. 13. Matsumoto T, Nakamura S, Esaki M, et al. Endoscopic features of chronic nonspecific multiple ulcers of the small intestine: comparison with nonsteroidal anti-inflammatory drug induced enteropathy. Dig Dis Sci 2006;51:1357-63. 14. Okabe H, Sakimura M. Nonspecific multiple ulcers of the small intestine [Japanese]. Stomach Intestine 1968;3:1539-49. 15. Sakimura M. Clinical study on ‘‘nonspecific multiple ulcers of the small intestine’’ [Japanese with English abstract]. Fukuoka Igaku Zasshi 1970;61:318-40. 16. Watson MR. Primary nonspecific ulceration of the small bowel. Arch Surg 1963;8:600-3. 17. Wayte DM, Helwig EB. Small-bowel ulcerationdiatrogenic or multifactorial origin? Am J Clin Pathol 1968;49:26-40. 18. Roberts HJ. Atypical abdominal syndromes due to systemic disease. Am J Gastroenterol 1962;37:130-67. 19. Ashby WB, Humphreys J, Smith S. Small-bowel ulceration induced by potassium chloride. Br Med J 1960;2:1400-2. 20. Baker DR, Schrader WH, Hitchcock CR. Small-bowel ulceration apparently associated with thiazide and potassium therapy. JAMA 1964;190:586-90. 21. Berg EH, Schuster F, Segal GA. Thiazides with potassium producing intestinal stenosis. Arch Surg 1965;91:998-1001. 22. Boley SJ, Allen AC, Schultz L, et al. Potassium-induced lesions of the small bowel. Clinical aspects. JAMA 1965;192:763-8. 23. Graham DY, Bynum TE. Primary nonspecific mall bowel ulceration as a source of chronic bleeding. Report of a case and review of the approach to localization of the site of small bowel hemorrhage. Am J Gastroetnerol 1974;62:350-5. 24. Glynn MJ, Pendower J, Shousha S, et al. Recurrent bleeding from idiopathic ulceration of small bowel. Br Med J 1984;288:975-6.
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Matsumoto et al 25. Thomas WE, Williamson RC. Nonspecific small bowel ulceration. Postgrad Med J 1985;61:587-91. 26. Santolaria S, Cabezali R, Ortego J, et al. Diaphragm disease of the small bowel: a case without apparent nonsteroidal anti-inflammatory drug use. J Clin Gastroenterol 2001;32:344-6. 27. Perlemuter G, Guillevin L, Legman P, et al. Cryptogenic multifocal ulcerous stenosing enteritis: an atypical type of vasculitis or a disease mimicking vasculitis. Gut 2001;48:333-8. 28. Debray C, Besanc¸on F, Hardoin JP, et al. Ente´rite ste´nosante ulce´reuse plurifocate cryptoge´ne´tique [French]. Arch Fr Mal App Dig 1964;53: 193-206. 29. Rocha A, Artigas V. La maladie ulce´reuse ste´nosante du hehuno-ile´on [French]. Arch Fr Mal App Dig 1959;10:1230-6. 30. Gauthier AP, Rampal M, Lieutaud R, et al. Ste´noses multiples ‘‘ideopathiques’’ de l’intestin gre´le. A propos de deux observations [French]. Arch Fr Mal Dig 1966;55:31-43. 31. Paille F, Champigneulle B, Brucker P, et al. L’entee´rite ste´nosante ulce´reuse plurifocale cryptoge´netique. A propos de deux observations [French]. Ann Gastroenterol Hepatol 1981;17:405-9. 32. Macinot C, Lorenzini C, Ravey M, et al. Ente´rite segmentaire ste´nosante plurifocale [French]. Semin Hop Paris 1974;50:2518-20. 33. Lescut J, Gre´goire L, Weisemburger JP. Ste´noses multiples cryptoge´ne´tiques de l’intestin gre´le. A propos d’une nouvelle observation [French]. Lille Med 1969;14:602-6. 34. Chagnon JP, Devars du Mayne JF, Marche C, et al. L’ente´rite ste´nosante ulce´reuse multifocale cryptoge´ne´tique. Une entite´autonome? [French] Gastroenterol Clin Biol 1984;8:808-13. 35. Doute LP, Paccalin J, Pe´rissat J, et al. Ente´rite ste´nosante ulce´reuse plurifocale. Une nouvelle observation [French]. Arch Fr Mal App Dig 1966;55:537-40. 36. Shoesmith JH, Tate GT, Wright CJ. Multiple strictures of the jejunum. Gut 1964;5:132-5. 37. Bokemeyer B, Schmidt FW, Galanski M. Kryptogene multifokale stenosierende enteritis [German]. Z Gastroenterol 1987;25:745-8. 38. Perlemuter G, Chaussade S, Soubrane O, et al. Multifocal stenosing ulcerations of the small intestine revealing vasculitis associated with C2 deficiency. Gastroenterology 1996;100:1628-32. 39. Spencer H, Kitsanta P, Riley S. Cryptogenic multifocal ulcerous stenosing enteritis. JR Soc Med 2004;9:538-40. 40. Bayless TM, Kapelowitz RF, Shelley WM, et al. Intestinal ulceration: a complication of celiac disease. N Engl J Med 1967;276:996-1002. 41. Baer AN, Bayless TM, Yardley JH. Intestinal ulceation and malabsorption syndromes. Gastroenterology. 1980;79;754-65. 42. Robertson DA, Dixon MF, Scott BB, et al. Small intestinal ulceration: diagnostic difficulties in relation to celiac disease. Gut 1983;24: 565-74. 43. Biagi F, Lorenzini P, Corazza GR. Literature review on the clinical relationship between ulcerative jejunoileitis, celiac disease, and enteropathy-associated T-cell lymphoma. Scand J Gastroenterol 2000;35: 785-90. 44. Yao T, Iida M, Matsumoto T. Chronic hemorrhagic ulcers of the small intestine or chronic nonspecific multiple ulcers of the small intestine. In: Yao T, Iida M, editors. Diseases of the small intestine. Tokyo: IgakuShoin; 2004. p. 176-86. 45. Koyama S, Soga J, Muto T. Primary nonspecific ulcers of the small intestine: a clinicopathological study with special reference to occurrence in the siblings of two families. Stomach Intestine 1972;7: 1643-8. 46. Mikami M, Taketomi Y, Okita H, et al. Nonspecific multiple ulcers of the small intestine occurring in two sisters. Hiroshima Igaku 1976;29: 1247-53. 47. Matsui T, Iida M, Kuwano Y, et al. Long-term follow-up study on nonspecific multiple ulcers of the small intestine. Stomach Intestine 1989;24:1157-69. 48. Hoashi T, Matsui T, Takenaka K, et al. Non-specific multiple ulcer of the small intestine accompanied by duodenal ulcer lesion: report of a case. Stomach Intestine 1991;26:1407-11.
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Matsumoto et al 49. Moriyama T, Hoshika K, Inoue S, et al. Effective nutritional therapy for nonspecific multiple ulcers of the small intestine. Kawasaki Igakkaishi 1999;25:307-12. 50. Wakabayashi K, Katsumata T, Yoshizawa S, et al. A case of nonspecific multiple ulcers of the small intestine under long-term of home enteroal nutrition. JJPEN 1999;9:651-3. 51. Matsui T, Seki T, Yao K, et al. Diagnosis of inflammatory diseases of the small intestine: comparison between double balloon enteroscopy and double contrast radiography. Stomach Intestine 2005;40: 1491-502. 52. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol 1989;24:S2-6. 53. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn’s disease: report of the working party for the world congress of gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000;6:8-15. 54. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55:749-53. 55. Florin THJ, Paterson EWJ, Fowler EV, et al. Clinically active Crohns disease in the presence of a low C-reactive protein. Scand J Gastroenterol 2006;41:306-11. 56. Bjarnason I, Zanelli G, Smith T, et al. Nonsteroidal anti-inflammatory drug-induced intestinal inflammation in humans. Gastroenterology 1987;93:480-9. 57. Lang J, Price AB, Levi AJ, et al. Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures. J Clin Pathol 1988;41:516-26. 58. Morris AJ, Madhok R, Sturrock RD, et al. Enteroscopic findings of small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs. Lancet 1991;337:520.
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Chronic nonspecific multiple ulcers of the small intestine 59. Maiden L, Thjodleifsson B, Theodors A, et al. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroetneorlogy 2005;128:1172-8. 60. Goldstein JL, Eisen GM, Lewis B, et al. Video-capsule endsocopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and plasebo. Clin Gastroenterol Hepatol 2005;3:133-41. 61. Matsushita N, Yamada A, Hiraishi M, et al. Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy. Am J Gastroetnerol 1992;87:1183-6. 62. Hershfield NB. Endoscopic demonstration of non-steroidal anti-inflammatory drug-induced small intestinal pathology. Gastrointest Endosc 1992;38:388-90. 63. Acahnta KK, Petros JG, Cave DR, et al. Use of intraoperative enteroscopy to diagnose nonsteroidal anti-inflammatory drug injury to the small intestine. Gastrointest Endosc 1999;49:544-6. 64. Shumaker DA, Bladen K, Katon RM. NSAID-induced small bowel diaphragms and strictures diagnosed with intraoperative enteroscopy. Can J Gastroetnerol 2001;15:619-23. 65. Hayashi Y, Yamamoto H, Kita H, et al. Non-steroidal anti-inflammtory drug-induced small bowel injuries identified by double-balloon endoscopy. World J Gastroenterol 2005;21:4861-4.
Current affiliations: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Reprint requests: Takayuki Matsumoto, MD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
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With the widespread use of video capsule endoscopy (VCE)1 and double balloon endoscopy (DBE),2,3 it has become possible to examine an extensive area of the small intestine by endoscopy. Both VCE and DBE are valuable for patients suspected of having small intestinal pathology, especially for those with GI bleeding of obscure origin.4-11 Although vascular lesions are the most frequent source of bleeding from the small intestine, mucosal breaks are also identified in a certain proportion of patients.4-11 Although Crohn’s disease and nonsteroidal anti-inflammatory drug (NSAID) enteropathy are representative among such ulcerous diseases, there have been other rare but significant ulcerous diseases of the small intestine. During the past 40 years, there has been a distinctive small intestinal pathology in the Japanese population characterized by persistent blood and protein loss and histologically nonspecific ulcers. Although we have recently reported on its histologic and enteroscopic features and referred to the condition as chronic nonspecific multiple ulcers of the small intestine (CNSU),12,13 there have also been descriptions of a similar small intestinal pathology with different nomenclature. In this article, we review CNSU with a special reference to its clinicopathologic and enteroscopic features and to other ulcerous diseases of the small intestine. Such a review seems inevitable in an area in which DBE has become widely accepted and routinely applied.
Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.01.004
A 10-year-old Japanese girl initially visited her neighboring clinic in 1960, complaining of lower abdominal pain. She was treated by appendectomy under a diagnosis of acute appendicitis, but her abdominal pain recurred 3 weeks after the surgery. One year later she was treated by cholecystectomy under a putative diagnosis of chronic cholecystitis. During the perioperative period of the second surgery, she was diagnosed as having positive fecal occult blood and anemia and was thus referred to our institution in August 1963. At the time, she was 136 cm in height and 26.5 kg in weight. Physical examination revealed a thin, pale, and malnourished girl. She was afebrile, but her abdomen was slightly distended with an increase in bowel sound. Her feces were neither soft nor tarry, but they were positive for occult blood. Her hemoglobin value was decreased to 9.2 g/dL (normal 12-16 g/dL) and serum protein value to 5.2 g/dL (normal 6.7-8.2 g/dL). She did not have leukocytosis (white blood cell count 6600/mL). Small-bowel radiography showed eccentric deformities and multiple stenoses in the ileum (Fig. 1A). At laparotomy, the stenoses were distributed within a segment measuring 30 cm in length, the most distal site of which was 50 cm from the ileocecal valve. Macroscopically, there were 3 shallow and sharply demarcated circular or oblique ulcers in the ileum (Fig. 1B). Histologic examination of the ileum showed ulcers restricted to the submucosa accompanied by minimal submucosal edema and mild chronic inflammatory infiltrates (Fig. 1C). However, there were not any caseating or noncaseating granulomas. Although the patient recovered uneventfully, she again experienced abdominal pain 18 months after the surgery. At that time, her anemia and hypoproteinemia recurred with circular ulcers around the ileal anastomosis. She was subsequently readmitted because of small intestinal obstruction, and small-bowel radiography and surgery confirmed recurrence of the ileal ulcers. During the subsequent 40-year period, she had ileal resections 6 times for the recurrence of stenoses. When she was 54 years of age, we examined her by DBE. A severe stenosis with sharply demarcated ulcer in the ileum and a circular ulcer proximal to the stenosis was revealed (Figs. 1D and E). On the basis of the anecdotal but extremely important case series, the clinicopathologic features of CNSU have been summarized as (1) absence of causative factors related
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TYPICAL CASE OF CNSU IN JAPAN Okabe and Sakimura,14 from our department, were the first to report CNSU in the Japanese literature. During the period 1963 to 1968, the 2 gastroenterologists handled 6 cases of CNSU. The cases comprised 3 males and 3 females. The patients’ presumed ages at onset ranged from 5 to 51 years, and their ages at diagnosis of small intestinal ulcers ranged from 13 to 59 years. Following is a summary of one of the cases initially described by Okabe and Sakimura.14,15 The patient was under observation by one of the authors at the time of this writing.
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Figure 1. Small intestinal lesions in a case of CNSU (case 7 in Table 1). A, Barium follow-though examination performed when the patient was aged 13 years shows multiple eccentric deformities and strictures in the ileum. B, Macroscopic view of the resected ileum at the time of the first surgery shows sharply demarcated linear or geographical ulcers. The ulcers are arranged in circular or oblique alignment. C, Histologically there is a distinctive mucosal defect with minimal inflammatory infiltrates and fibrosis. The ulcer is restricted to the submucosal layer. D, Retrograde DBE performed when the patient was aged 54 years shows severe stenosis with a sharply demarcated ulcer in the ileum. E, Antegrade DBE shows a shallow and sharply demarcated ulcer. The ulcer aligns in a spiral configuration.
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to the onset and perpetuation of the disease, (2) persistent anemia because of continuing occult GI bleeding, and (3) small intestinal ulcers restricted to the submucosal layer, occurring predominantly in the ileum without any specific histology.
NONSPECIFIC ULCEROUS DISEASES OF THE SMALL INTESTINE As mentioned above, CNSU is a chronic and recurrent small intestinal disease initially identified in Japan in the 1960s. During the same period, the classification of chronic ulcerous diseases of the small intestine was proposed in Western countries.16,17 In the West, the etiology of nonspecific ulcers of the small intestine included congenital causes, infection, trauma, ischemia, chemicals, and neoplasia.16-18 Although regional enteritis (Crohn’s disease) was the most rigorously investigated, there have been a large number of descriptions of nonspecific ulcers of the small intestine in the West. Although the chemical compounds, especially thiazides and enteric potassium chloride tablets,19-22 drew much attention as a cause of nonspecific ulcers in the West,16,17 there were other cases of small intestinal ulcers without any provisional etiology that were restricted to the submucosal layer and recurred even after surgical resection.23-25 The nomenclatures for these conditions differed from case to case and included primary nonspecific small-bowel ulceration,23 idiopathic ulcerations of the small bowel,24 and nonspecific smallbowel ulceration.25 There have recently been case descriptions in the West that show small intestinal pathology presumed to be similar to CNSU. In 2001, Santolaria et al26 reported on a peculiar small intestinal pathology. The male patient initially manifested diarrhea, weight loss, and edema, and later complained of recurrent intestinal obstruction during a 25-year period of his life. Even though the patient was treated 3 times by surgery, the small intestinal lesion recurred with a feature compatible with diaphragm disease. What should be noted in the case is that the patient was completely free of NSAID use. There has also been a clinicopathologic entity characterized by nonspecific ulcers of the small intestine, which has been referred to as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE).27 The disease was first reported by Debray et al28 in 1964, when Okabe and Sakimura14 identified their first case of CNSU. Since then, 18 cases of CMUSE have been reported, mainly in French literature.28-39 Perlemuter et al27,38 reviewed cases of CMUSE in 1996, and subsequently attempted a multicenter retrospective analysis of 12 cases in 2001. In those articles, the clinicopathological features of CMUSE have been summarized as (1) unexplained small intestinal strictures found in adolescent and middle-aged subjects, (2) superficial ulceration of the mucosa and submucosa, (3) chronic or relapsing clinical course, even after www.giejournal.org
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\surgery, (4) no biological signs of systemic inflammatory reaction, and (5) beneficial effect of steroids. Perlemuter et al27,38 hypothesized that CMUSE is closely associated with vasculitis because stenosis and aneurysm were verified in superior mesenteric arteries and steroid is efficacious in a certain proprtion of the subjects. Although it still remains inconclusive whether CNSU and CMUSE belong to the same category, the 2 diseases share common clinicopathologic features with respect to chronic and recurrent clinical course and nonspecific stenosing small intestinal ulcers. There is another small intestinal pathology characterized by persistent nonspecific ulcers of the small intestine and associated with celiac disease.40-42 The disease has been referred to as chronic ulcerative jejunoileitis, and it predominantly involves the proximal part of the small intestine. The clinical symptoms include fever, pain, steatorrhea, and protein-losing enteropathy. The small intestinal lesions are characterized by multiple and circular ulcers occurring predominantly in the jejunum. The circular ulcer progresses to stenosis and obstruction, and furthermore, penetrating ulcers may lead to perforation in some cases. What is most characteristic of the disease is various degrees of villous atrophy in the intervening mucosa. Although an extensive review by Biagi et al43 indicated that only 38 cases of chronic ulcerative jejunoileitis have been reported during the period 1967 to 1999, the clinicopathologic features seem to be conspicuously different than those of CNSU and CMUSE.
DIAGNOSTIC CRITERIA OF CNSU Even in Japan, without taking clinical features into consideration, some gastroenterologists misinterpreted CNSU as a small intestinal pathology of nonspecific pathology. The misinterpretaion led to heterogeneity in descriptions of clinicopathologic features of CNSU. Because chronic, recurrent clinical course is a diagnostic feature of CNSU, and because the phenotype of CNSU can easily progress to the diaphragm in patients treated with total parenteral nutrition, Yao, who is a colleague of Okabe and Sakimura (and one of the authors of this review), proposed a modified diagnostic criteria of CNSU in 2004 (Table 1).44 The criteria are based on clinical course and specific morphology of ‘‘nonspecific’’ small intestinal ulcers. During the period 1964 to 2006, we encountered, at our institutions, 15 patients with small intestinal lesions that were compatible with CNSU (Table 2), while more than 500 cases of Crohn’s disease were diagnosed during the equivalent period. However, a review of the Japanese literature from 1969 to 2006 identified fewer than 20 cases of CNSU that fulfilled the above-mentioned diagnostic criteria.45-51
Clinical symptoms The symptoms of CNSU are characterized by those attributed to chronic and persistent blood loss from the intestine occurring early in life. Thus, patients manifest Volume 66, No. 3 : 2007 GASTROINTESTINAL ENDOSCOPY S101
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fatigue, edema, and growth retardation, and they usually have repeated episodes of treatment for anemia. However, the patients rarely manifest diarrhea, hematochezia, or fever. On the basis of these manifestations, patients visit gastroenterologists long after the onset of symptoms. In addition to the symptoms, the physical examination reveals anemia, but the abdomen is unremarkable.
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TABLE 1. Diagnostic criteria of CNSU 1. Persistent and occult blood loss from the GI tract except during bowel rest or postoperative period. 2. Confirmation of characteristic small intestinal lesions by macroscopy, radiography, or enteroscopy. i Circular or oblique in alignment.
Macroscopic findings The small intestinal ulcers in CNSU occur predominantly in the ileum; the terminal ileum is usually spared. The ulcers usually number more than 20, and each is characterized by a discrete margin and shallow and flat ulcer bed (Fig. 2A). Each ulcer is linear or a tall triangle in configuration, and alignment is circular or oblique in fashion. The ulcers occasionally fuse, thus showing geographic configuration. Even though the ulcers develop into luminal narrowing, the small intestinal lesions in CNSU never progress to cobblestone appearance, fissure, or fistula formation or adhesion. In more advanced cases, however, small intestinal stenoses are the major manifestation. Because of the oblique nature of the preexisting ulcers, the stenoses are not always concentric but may show spiral patterns. Such a healing process progresses, especially in circumstances treated by total parenteral nutrition (Fig. 2B).
Histologic findings The depth of the ulcers is restricted to the mucosa or the submucosa, and they never extend to the proper muscular layer. The mucosal defect is accompanied by mild infiltration of plasma cells, lymphocytes, and eosinophils. Lymph follicles may also be seen. Even in histology, the margin of the ulcer is clearly demarcated by the surrounding villous mucosa. Although submucosal fibrosis occurs in the healing stage, it is restricted to the area of mucosal defect with minimal epithelial repair and restitution. These histologic features have been referred to as an ulcerative nonproliferative process by Okabe and Sakimura.14,15
CLINICOPATHOLOGIC FEATURES OF CNSU Age, sex, and duration of symptoms As has been summarized in Table 2, our cases of CNSU comprised 11 females and 4 males. While the ages of onset ranged from 10 to 52 years, 13 of 15 patients had anemia during their second or third decade of life. Most patients had histories of long-term anemia, and 9 patients had symptoms for more than 10 years before confirmation of small intestinal lesions.
Laboratory data
ii Sharply demarcated from surrounding normal mucosa. iii Geographic or linear in shape. iv Multiplicity in number with !4-cm distance from each other. v Ulcers not reaching proper muscular layer. vi Scarred ulcers presumed to be the healing stage of those characterized by i-v* in cases treated by bowel rest. *Depicted as symmetric and eccentric rigidity under small-bowel radiography, and concentric or nonconcentric stricture under enteroscopy.
edly decreased unless the patient is treated by iron supplementation. In addition to anemia, most patients manifest hypoproteinemia and hypoalbuminemia. However, acute inflammatory reactions, such as C-reactive protein, a1- and a2-globulins, are usually within their normal ranges or slightly increased. Unlike intestinal tuberculosis, intradermal tuberculin test is negative in most cases.
Small-bowel radiography Until recently, small-bowel radiography, including smallbowel follow-through (BFT) and double-contrast barium study (DCBS), was the first-choice procedure for the diagnosis of CNSU. However, it is not easy for radiologists to recognize the small intestinal lesions as barium flecks because the ulcers are extremely shallow. The ulcers are usually shown to be asymmetric and characterized by multiple rigidity or eccentric deformities (Fig. 3A). When examined precisely by DCBS together with compression procedure, linear or tall triangle mucosa defects may be depicted as sharply demarcated barium flecks (Fig. 3B). In cases treated by total enteral or parenteral nutrition, the ulcer heals with stricture formation. Although the stenoses apparently mimic those seen in NSAID enteropathy and intestinal tuberculosis, the stenoses in CNSU may manifest in a spiral configuration with pseudodiverticular formation because of oblique alignment of the initial ulcer (Fig. 1A).
Endoscopy
There are no specific laboratory tests for the diagnosis of CNSU. The feces are continuously positive for occult blood. Peripheral blood test reveals hypochromatic and microcytic anemia. However, leukocyte and platelet counts are within normal ranges. Serum iron level is mark-
It was not easy for gastroenterologists to observe the small intestinal lesions of CNSU with enteroscopy. With the development of DBE, however, we have recently been able to confirm enteroscopic features of CNSU. Among 15 patients with CNSU diagnosed at our institution, we attempted DBE in 6 patients. On the basis of
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TABLE 2. Cases of CNSU diagnosed at our institutions from 1964 to 2006 Age (y)/sex
Case no.
Onset
Laboratory data
Diagnosis of CNSU
Presenting symptoms
Hemoglobin (g/dL)
Serum protein (g/dL)
CRP (mg/dL)
Follow-up after diagnosis (y)
Number of ileal resections
1.
20/F
27
Anemia, edema
8.2
4.9
–*
22
2
2.
15/F
24
Anemia, edema
3.5
5.0
–*
22
3
3.
10/M
26
Anemia, growth retardation
4.4
4.5
–*
24
6
4.
15/F
28
Anemia, edema
4.7
5.3
–*
43
3
5.
12/F
27
Anemia, abdominal pain
9.7
5.8
0.3
26
2
6.
17/F
34
Anemia
9.6
4.6
0.5
19
1
7.
10/F
13
Anemia, abdominal pain
7.4
5.4
0.1
42
6
8.
37/F
38
Anemia
9.5
6.7
0.5
31
2
9.
15/M
30
Anemia, edema
7.4
8.2
0.1
15
2
10.
52/M
57
Anemia
6.5
3.5
0.1
9
1
11.
14/F
36
Anemia
8.6
5.0
1.8
7
1
12.
24/M
24
Anemia
11.9
6.9
0.2
5
0
13.
13/F
29
Anemia
5.9
4.6
0.2
17
2
14.
16/F
52
Anemia
5.3
6.3
0.1
4
0
15.
13/F
40
Anemia
9.4
4.1
1.1
5
3
*CRP was determined to be negative under semiquantitative measurement.
the results, the enteroscopic features of CNSU are sharply demarcated linear and geographical ulcers arranged in circular or oblique alignment (Figs. 1C, 4A and B). The intervening mucosa is apparently normal, without any diminutive lesions. Even though the ulcers may be accompanied by fold convergency or severe stenosis, thus mimicking diaphragms seen in NSAID enteropathy, most of the ulcers have thin and faint exudates (Figs. 1D and E). The enteroscopic features again indicate the ulcers in CNSU are intractable. We have not performed VCE in our patients with CNSU because of the possibility of retention or impaction of the capsule. The VCE findings of CNSU have not been reported to date. There have been cases of duodenal and colonic involvement of CNSU.46,47 Gastroduodenal ulcers were found in 7 of our 15 cases, and colonic ulcers in 3 cases. One of the former cases had an intractable ulcer at the gastroduodenal anastomosis (Fig. 4C), and another in the latter cases had concentric ulcers with severe stenosis in the right side of the colon (Fig. 4D). These endoscopy findings suggest that CNSU is a disease that involves any site within the GI tract.
after surgery. Enteral or parenteral nutrition coupled with iron supplementation are transiently effective, but the small intestinal ulcers recur within a short period of time. Although all of our patients were treated with oral 5-aminosalicylic acid, 6 were also treated with oral prednisolone, and 1 was also treated with oral azathioprine. The medications failed to induce mucosal healing or prevent recurrence of small intestinal ulcers. As shown in Table 2, our patients have been under observation for periods ranging from 4 to 43 years, during which time 10 of 15 patients required 2 or more ileal resections. Histological examination of the resected specimens showed exactly the same findings as were found in the initial surgical specimens. It should also be noted that our patients have been free from any extraintestinal manifestations, such as oral, skin, joint, genital, or perianal lesions, as found in Crohn’s disease and Behcet’s disease.
DIFFERENTIAL DIAGNOSIS Crohn’s disease
Clinical course As has been discussed above, CNSU is characterized by recurrence of small intestinal ulcers and stenoses even www.giejournal.org
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Figure 2. Macroscopic view of the small intestine in cases of CNSU. A, In a case without any treatment (case 9), shallow and linear ulcers are seen in the ileum. The linear ulcers align in circular fashion. B, In a case treated by total parenteral nutrition (case 6 [patient aged 52 years]), the ulcers healed with stenoses.
characteristics of Crohn’s disease.52 Thus, the stenosing lesions in CNSU may be interpreted as small intestinal Crohn’s disease of upper GI location and stricturing behavior according to Vienna53 or Montreal54 classification. Furthermore, one tenth of patients with Crohn’s disease, especially those with ileitis, manifest persistent low C-reactive protein (CRP) values.55 These observations in Western countries would suggest that the recurrent course and the gastroduodenal and colonic involvement of CNSU is compatible with Crohn’s disease. However, the intestinal lesions of CNSU are not suggestive of Crohn’s disease with respect to the lack of transmural inflammation, fissuring, fistula, and granuloma. Furthermore, macroscopic, radiographic, and endoscopic characteristics of the small intestinal ulcer are completely different from Crohn’s ileitis. Finally, unlike CMUSE, glucocorticoid has never had any therapeutic effect in patients with CNSU. These clinicopathologic findings suggest that CNSU is distinct from Crohn’s disease. S104 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 3 : 2007
Figure 3. Radiography of the small intestine in case 6 (patient aged 34 years; before total parenteral nutrition). A, A double-contrast study shows circular barium flecks and slight eccentric deformities in the small intestine. B, A compression study shows a sharply demarcated barium fleck in the ileum.
NSAIDs enteropathy It is well known that NSAIDs damage the small intestinal mucosa.56,57 Various interventional studies by means of sonde enteroscopy58 and VCE59,60 have shown that NSAIDs induce acute mucosal lesions in the small intestine in humans. Furthermore, intraoperative enteroscopy61-64 and DBE65 have revealed circular, stenosing ulcers in the small intestine of long-term NSAID users. In addition, both patients with CNSU and those with NSAID enteropathy share common clinical features characterized by anemia with fecal occult blood and hypoproteinemia. However, NSAID enteropathy responds dramatically after discontinuance of the causative drugs.11,12 Although we have not measured www.giejournal.org
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Figure 4. Endoscopic findings in cases of CNSU. A, Antegrade DBE in case 6 (patient aged 51 years) shows a thin and linear ulcer in the ileum. The ulcer shows circular alignment. B, Retrograde ileoscopy in case 6 (at the same age) shows a thin, circular ulcer in the ileum. C, EGD in case 8 (patient aged 70 years) shows a clear ulcer in the duodenum. D, Colonoscopy in case 3 (patient aged 71 years) shows a concentric stenosis with a shallow ulcer in the ascending colon.
drug concentrations or prostaglandin biosynthesis in our patients, they were free from chronic NSAID use of any kind at the time of the initial diagnosis and subsequent follow-up periods.
Intestinal tuberculosis Infection of mycobacterial species in the GI tract results in chronic inflammation of the ileocecal region. However, the infection damages the small intestine multifocally with circumferential ulcers. Thus, during the healing stage of intestinal tuberculosis, the small intestinal lesions manifest findings mimicking CNSU. However, the small intestinal ulcers in tuberculosis are characterized by an irregular margin and dense mucous exudates. Unlike CNSU, the ulcers in an individual with intestinal tuberculosis manifest various stages. Finally, the ileocecal region is uniformly affected in patients with intestinal tuberculosis, and such patients will show positive results on an intradermal tuberculin test. www.giejournal.org
CONCLUSION With the development of DBE and VCE, it has become possible for gastroenterologists to diagnose small intestinal ulcers more accurately. It thus seems necessary to recognize CNSU as a distinctive entity and a candidate diagnosis in patients with occult GI bleeding of obscure origin. Such an approach would result in the accumulation of a larger number of diagnosed patients, thereby making our proposal of CNSU more accurate and practical by clarifying the pathophysiology and phenotype of the disease.
DISCLOSURE None of the authors have any disclosures to make. Volume 66, No. 3 : 2007 GASTROINTESTINAL ENDOSCOPY S105
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Current affiliations: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Reprint requests: Takayuki Matsumoto, MD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
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