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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 159-163

Cryptogenic multifocal ulcerous stenosing enteritis


Institute of Gastroenterology, Hepatology and Transplantation, SRM Institutes for Medical Science, MGM Health Care, Chennai, Tamil Nadu, India

Date of Submission19-Dec-2020
Date of Decision10-Jul-2021
Date of Acceptance08-Aug-2021
Date of Web Publication24-Sep-2021

Correspondence Address:
Doraiswami Babu Vinish
SRM Institutes for Medical Science, No. 1 Jawaharlal Nehru Salai, Vadapalani, Chennai - 600 026, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ghep.ghep_35_20

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  Abstract 


Crytpogenic multifocal ulcerous setnosing enteritis is an unusual cause of gastrointestinal bleed. The objective of this report is to highlight small bowel ulcerations as a cause of anemia and the role of wireless capsule endoscopy in the diagnosis of CMUSE. We present here two young women who had been evaluated for anemia with normal gastroscopy, colonoscopy and contrast CT's and requiring multiple blood transfusions over the years. Both patients had wireless capsule endoscopy which showed multiple ulcerations with stenosis in the small intestine, resulting in capsule retention in the small intestine which was retrieved. Both patients improved with steroids and azathioprine. To summarize CMUSE could be cause of obscure GI bleed, when CMUSE is a consideration as the cause of GI bleed wireless capsule endoscopy should be used in caution.

Keywords: Anemia, angiodysplasia, cryptogenic multifocal ulcerous stenosing enteritis, retained capsule


How to cite this article:
Vinish DB, Balasundaram P, Ramakrishna B, Palaniappan AB, Sarangapani A, Ramakrishna BS. Cryptogenic multifocal ulcerous stenosing enteritis. Gastroenterol Hepatol Endosc Pract 2021;1:159-63

How to cite this URL:
Vinish DB, Balasundaram P, Ramakrishna B, Palaniappan AB, Sarangapani A, Ramakrishna BS. Cryptogenic multifocal ulcerous stenosing enteritis. Gastroenterol Hepatol Endosc Pract [serial online] 2021 [cited 2021 Oct 24];1:159-63. Available from: http://www.ghepjournal.com/text.asp?2021/1/4/159/326634




  Introduction Top


Nonspecific ulcerations involving only the small intestine have been described as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), chronic nonspecific ulcers (CNSU), chronic enteropathy associated with SLCO2A1 gene (CEAS), or nongranulomatous ulcerating jejunoileitis (NGUJI).[1] Japanese consider CMUSE and CNSU as different entities.[2] CMUSE is considered an exclusion diagnosis after Crohn's disease, tubercular enteritis, and NSAID-induced enteropathy are ruled out. We present here two cases of CMUSE who were diagnosed in this tertiary care institute between September 2015 and December 2017.


  Case Report Top


Case 1

This 24 year old female presented in February 2017 with anemia, exertional dyspnea and a weight loss of 10 kgs. No history of bloody or loose stools, joint pain, oral ulcers,oliguria or chest pain. She persisted to have anemia despite multiple blood transfusions and hematamics. She had been evaluated for anemia since December 2009. Upper gastrointestinal endoscopy and ileocolonoscopy showed antral and ileal erosion with ileal biopsy reported as eosinophilic enterocolitis. Antegrade endoscopy showed scalloped duodenal folds; HPE showed mild chronic inflammation. Isotope scan showed blood loss in the terminal ileum. She had left subclavian, brachiocephalic, and internal jugular vein thrombosis with high fibrinogen levels and had previously been treated with anticoagulants, mesalamine, and frequent short course of steroids.

On examination, she was anemic with anasarca and ascites. Investigations revealed hemoglobin of 5.1 g/dL with serum iron of 12 mcg/cL and total iron-binding capacity of 102 mcg/dL. Serum B12 was 359 pg/mL, total protein: 3.3 g/dl, albumin: 1.5 g/dl, and globulin: 1.8 g/dl. C-reactive protein (CRP) was 90.31 mg/L. Stool occult blood was positive. Gastroscopy showed scalloped duodenal folds, colonoscopy showed blunting of the villi of the ileal mucosa. HPE from the duodenum, ileum, cecum, and rectum revealed no specific pathology. Contrast-enhanced computerized tomography (CECT) of the abdomen showed ascites with centrally placed bowel loops with no evidence of narrowing, multiple prominent nonnecrotic mesenteric nodes [Figure 1]. Further evaluation of the gastrointestinal bleed with capsule endoscopy was advised, patient refused hence treated conservatively.
Figure 1: Coronal computed tomography images show gross ascites with centrally placed small bowel loops mild mucosal prominence and showing no significant narrowing

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In April 2017, she returned with persistent anemia and hypoalbuminemia. Video capsule endoscopy (VCE) showed multiple discrete circumferential ulcers involving the entire circumference of the jejunum causing luminal narrowing with intervening normal mucosa. The capsule was retained at one of these strictures [Figure 2]. Since the capsule did not pass out spontaneously after a period of 2 weeks, she was advised surgical resection of the strictured bowl which would also help to obtain a histological diagnosis. At laparotomy, the capsule was found in the small bowel 60 cm from the duodenojejunal flexure with multiple strictures and dilations in the entirety of the small bowel and a long stricture in the terminal ileum with ascites. The capsule was removed with resection of terminal ileal stricture.
Figure 2: The axial computed tomography section shows intraluminal foreign body (capsule) with surrounding artifacts seen within the small bowel loop

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Surgical pathology of the full thickness resected ileal segment showed foci of mucosal ulceration with moderate mixed inflammatory cell infiltrate in lamina propria composed of neutrophils, eosinophils, lymphocytes, and plasma cells, extending up to the submucosa. Transmural inflammation was not identified. The ulcerated area was covered with an acute inflammatory exudate and bacterial colonies. Focal hypertrophy and splaying of muscularis mucosa with mild submucosal fibrosis were noted. The serosal aspect revealed mild congestion. There was no evidence of crypt disarray, mucodepletion, or granulomas. Lymph nodes showed reactive follicular hyperplasia. This finding of multiple ulcers extending up to the submucosa with submucosal fibrosis, no chronicity features, and absence of transmural inflammation coupled with the imaging and operative findings confirmed a diagnosis of cryptogenic multifocal ulcerating stenosing enteritis [Figure 3] and [Figure 4].
Figure 3: Small intestinal mucosa with ulceration and dense mixed inflammatory cell infiltrate consisting of neutrophils, eosinophils, lymphocytes, and plasma cells in lamina propria

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Figure 4: Ulceration of lining epithelium with splaying of smooth muscle fibers in lamina propria (×10)

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Post surgery, the patient was started on a tapering dose of prednisolone 40 mg, azathioprine 50 mg, and mesalamine. The patient improved with no further drop in hemoglobin. She is presently on azathioprine 100 mg/day and mesalamine 1 g/day and at the last follow-up in 2021, she has remained well.

Case 2

The second patient was a 42-year-old female who presented to us in May 2017 with melena. She had been evaluated for anemia since 2013 and diagnosed to have iron deficiency anemia. She had received 10 units of blood transfusion in the last 4 years. She underwent resection anastomosis of the small bowel in September 2013 for acute abdominal distention. Neither surgical notes nor the pathology reports were available for review. In 2014, she underwent a colonoscopy which showed a rectal ulcer.

On examination, the patient had pallor, pedal edema with a midline abdominal scar, and tenderness in the right iliac fossa. Blood investigations showed a hemoglobin of 4.4 g/dL and ferritin: 4.6 ng/mL. Thyroid-stimulating hormone was 17.36 mi croIU/mL, serum albumin: 3.2 g/dL, globulin: 2.4 g/dL, and CRP: 0.67 mg/L. Gastroscopy showed small angiodysplastic lesions on the aryepiglottic folds and cuneiform cartilages along with a sliding hiatus hernia. Colonoscopy revealed a large superficial semi-circumferential ulcer 10 cm from the anal verge. Histopathological examination of the gastric body, duodenum, ileum, and cecum had no specific pathology, while antrum revealed mild chronic active gastritis. Rectal biopsy was suggestive of solitary rectal ulcer syndrome. CECT of the abdomen was normal. The patient refused further evaluation, so with a provisional diagnosis of angiodysplasia, she was started on estrogen 0.05 mg and norethisterone 2 mg daily. She presented again in June 2017 with melena. VCE showed multiple circumferential ulcers in the small intestine with normal intervening mucosa with a stricture, at which point the capsule got retained. The patient was advised surgery but refused, and the capsule was retrieved with a double-balloon enteroscope.

A diagnosis of CMUSE was made on the basis of diagnostic criteria suggested by Zhang et al.[3] [Table 1]. She had medical history (1.1, 1.2), clinical features (2.2–2.5 and a single episode of partial bowel obstruction), and capsule endoscopic and enteroscopic features (4.1, 4.2). Histological criteria could not be fulfilled in this patient. The patient was started on tapering steroids, azathioprine, and mesalamine: 1 g/day. A review in August 2017, she had no further drop in hemoglobin and was advised to remain on azathioprine and mesalamine. She reviewed through telephone call 6 months later and had continued to remain well.
Table 1: Update diagnostic criteria of cryptogenic multifocal ulcerous stenosing enteritis/chronic nonspecific ulcers

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  Discussion Top


CMUSE involves only the small bowel. It was first reported in 1964 by Debrey as cryptogenetic plurifocal ulcerative stenosing enteritis subsequently reported by Obake and Sakimura in 1968.[3] Perlemuter and Matsumoto et al. have extensively reported on CMUSE from 1965 to 2005.[4]

The exact etiopathogenesis of CMUSE is not known. The most accepted version is CMUSE which is an immunological disease as most patients improve with glucocorticoids.[5] There is fibroblast proliferation with a minor or absent inflammatory response along with a disturbance in the degradation of collagen.[1]

CMUSE could be due to vasculitis or due to genetic mutations.[1],[6] Chung classified CMUSE as idiopathic and vasculitis related with 15% of patients having extraintestinal manifestations;[7] however, Kohotova suggested that vasculitis or extraintestinal manifestations should be considered as small bowel vasculitis rather than CMUSE. Recent studies show that CMUSE is an autosomal recessive disease due to mutations of PLA2G4A gene or SLCO2A1 gene. While the former is responsible for the release of arachidonic acid from membrane phospholipids, the latter encodes for the prostaglandin transporter. These mutations result in a decrease in prostaglandins causing ulcerations of the small intestine.[8],[9] Japanese studies have shown SLCO2A1 gene mutations in CNUSE patients; hence, they have changed their terminology from CMUSE to CEAS. Only one case of CEAS has been reported outside Japan.[10] We did not do genetic studies in our patients.

CMUSE patients present in their twenties or thirties with anemia and recurrent abdominal pain due to subacute obstruction. Anemia precedes the diagnosis. Diarrhea and malabsorption are rare. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and CRP are negative. Hypoalbuminemia is not a common occurrence.[1],[6],[11] Both our patients presented with anemia and hypoalbuminemia. Case 1 had an elevated CRP. Chen and Guilherme[12],[13] have stated that inflammatory markers and hypoalbuminemia can be elevated in CMUSE patients in the presence of intestinal stenosis. Anemia had preceded the diagnosis in both the patients.

The stomach and colonic mucosa are normal. In this report, the 2nd patient had angiodysplasia in the larynx, this has been reported in CMUSE by Singh et al.[14] Computed tomography enterography might miss out on the superficial ulcerations but is useful to diagnose strictures. Small bowel visualization can be done through VCE or enteroscopy which shows multiple small shallow ulcers with luminal narrowing. In both our patients, there was capsule retention, the same has been noted by Tao et al. who stated that capsule should be either contraindicated or used with utmost caution in individuals suspected with CMUSE,[15] thus emphasizing that enteroscopy should be preferred over capsule endoscopy for a suspected case of CMUSE.

Histology shows superficial ulcers with associated strictures and stenosis with intervening normal intestine. Ulcers usually confined to the mucosa and submucosa. On microscopic examination, fibrinous exudates are observed in the mucosa with infiltrate of mixed acute and chronic inflammatory cells in the mucosa and submucosa. The margin of the ulcer is clearly demarcated with normal mucosa and the ulcer is infiltrated with plasma cells, lymphocytes, and eosinophils. Submucosal fibrosis occurs in the healing stage of the ulcer but is restricted to that region only.[1] Inflammation is limited to areas of stenosis, which shows submucosal fibrosis. The muscularis propria and subserosal layers are typically normal. Granulomas are absent. Cases with focal phlebitis and thrombosis of small venules have been described.[16],[17]

Due to the difficulty in obtaining a histopathological sample Matsumoto proposed a clinical diagnostic criteria for diagnosis of CMUSE which was latter modified by Zhang et al. Recent diagnostic criteria proposed by Singh[4] [Table 2] can also be used to diagnose CMUSE.
Table 2: Proposed diagnostic criteria of cryptogenic multifocal ulcerous stenosing enteritis/chronic nonspecific ulcers

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There is no standard therapy. Corticosteroid is the cornerstone with which 50% become corticosteroid dependent.[6] Mesalamine is not useful.[1] Azathioprine has shown to be useful in the presence of SLCO2A1 gene.[3],[18] De Schepper et al. reported remission of CMUSE with anti-TNF-alpha therapy.[19] Surgery is the option for recurrent stenosis and obstruction. Complete recovery after surgery has been reported in the range of 40%–70% of patients.[7] Diet modifications of having a low-fiber diet and medium-chain triglycerides can be used in patients with strictures to prevent recurrent subacute intestinal obstruction.


  Conclusion Top


CMUSE can be summarized as a chronic relapsing disease of young presenting as recurrent abdominal pain, anemia with unexplained small intestinal ulcers, and strictures in the absence of elevated inflammatory markers with response to corticosteroids and variable response to azathioprine. The presentation of this case is to emphasize to be cautious on CE while the provisional diagnosis is CMUSE and that extraintestinal manifestations may occur in CMUSE, as in our cases of thrombotic state and angiodysplasia.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kohoutová D, Bártová J, Tachecí I, Rejchrt S, Repák R, Kopáčová M, et al. Cryptogenic multifocal ulcerous stenosing enteritis: A review of the literature. Gastroenterol Res Pract 2013;2013:918031.  Back to cited text no. 1
    
2.
Matsumoto T, Iida M, Matsui T, Yao T. Chronic nonspecific multiple ulcers of the small intestine: A proposal of the entity from Japanese gastroenterologists to Western enteroscopists. Gastrointest Endosc 2007;66:S99-107.  Back to cited text no. 2
    
3.
Zhang Y, Huang L, Liu R, Wang M, Jiang Z, Zhou W, et al. Case report of a pair of siblings with cryptogenic multifocal ulcerating stenosing enteritis: A rare disease easily to be misdiagnosed as Crohn disease. Medicine (Baltimore) 2017;96:e7527.  Back to cited text no. 3
    
4.
Singh A. Cryptogenic Multifocal Ulcerating Stenosing Enteropathy (CMUSE) and/or chronic non-specific multiple ulcers of the small intestine (CNSU) and non-granulomatous ulcerating jejunoileitis (NGUJI). Curr Gastroenterol Rep 2019;21:53.  Back to cited text no. 4
    
5.
Kohoutová D, Bures J, Tycová V, Bártová J, Tachecí I, Rejchrt S, et al. Severe cryptogenic multifocal ulcerous stenosing enteritis. A report of three cases and review of the literature. Acta Medica (Hradec Kralove) 2010;53:25-9.  Back to cited text no. 5
    
6.
Perlemuter G, Chaussade S, Soubrane O, Degoy A, Louvel A, Barbet P, et al. Multifocal stenosing ulcerations of the small intestine revealing vasculitis associated with C2 deficiency. Gastroenterology 1996;110:1628-32.  Back to cited text no. 6
    
7.
Chung SH, Un Park S, Cheon JH, Kim ER, Byeon JS, Ye BD, et al. Clinical characteristics and treatment outcomes of cryptogenic multifocal ulcerous stenosing enteritis in Korea. Dig Dis Sci 2015;60:2740-5.  Back to cited text no. 7
    
8.
Brooke MA, Longhurst HJ, Plagnol V, Kirkby NS, Mitchell JA, Rüschendorf F, et al. Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α. Gut 2014;63:96-104.  Back to cited text no. 8
    
9.
Umeno J, Hisamatsu T, Esaki M, Hirano A, Kubokura N, Asano K, et al. A Hereditary Enteropathy caused by mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. PLoS Genet 2015;11:e1005581.  Back to cited text no. 9
    
10.
Sun X, Hosoe N, Miyanaga R, Kimura K, Mizuno S, Takabayashi K, et al. A male Korean who was diagnosed with chronic enteropathy associated with SLCO2A1 (CEAS): Case report with literature review. BMJ Open Gastroenterol 2018;5:e000223.  Back to cited text no. 10
    
11.
Chang DK, Kim JJ, Choi H, Eun CS, Han DS, Byeon JS, et al. Double balloon endoscopy in small intestinal Crohn's disease and other inflammatory diseases such as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). Gastrointest Endosc 2007;66:S96-8.  Back to cited text no. 11
    
12.
Ramos GP, Bartlett DJ. Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): A 20-year single-center clinical and radiologic e0xperience. Gastroenterology 2021;160:S12-3.  Back to cited text no. 12
    
13.
Chen D, Liu W, Zhou W, Zheng W, Wu D, Qian J. Retrospective study of the differential diagnosis between cryptogenic multifocal ulcerous stenosing enteritis and small bowel Crohn's disease. BMC Gastroenterol 2020;20:252.  Back to cited text no. 13
    
14.
Singh A, Sahu MK, Panigrahi MK, Misra D. Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): A tale of three decades. ACG Case Rep J2017;15;4:e44.  Back to cited text no. 14
    
15.
Tao EW, Zou TH, Wang YF, Tang JT, Chen YX, Gao QY. Case report of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): A rare disease may contribute to endoscopy-capsule retention in the small intestine. BMC Gastroenterol 2019;19:49.  Back to cited text no. 15
    
16.
Hwang J, Kim JS, Kim AY, Lim JS, Kim SH, Kim MJ, et al. Cryptogenic multifocal ulcerous stenosing enteritis: Radiologic features and clinical behavior. World J Gastroenterol 2017;23:4615-23.  Back to cited text no. 16
    
17.
Robert ME, Gibson JA. Inflammatory disorders of small intestione. In: Odze and Goldblum Surgical Pathology of the Gi Tract, Liver, Biliary Tract and Pancreas. Ch. 16. Philadelphia: Elseiver; 2008. p. 402-35.e9.  Back to cited text no. 17
    
18.
Eda K, Mizuochi T, Takaki Y, Ushijima K, Umeno J, Yamashita Y. Successful azathioprine treatment in an adolescent with chronic enteropathy associated with SLCO2A1 gene: A case report. Medicine (Baltimore) 2018;97:e12811.  Back to cited text no. 18
    
19.
De Schepper H, Macken E, Van Marck V, Spinhoven M, Pelckmans P, Moreels T. Infliximab induces remission in cryptogenic multifocal ulcerous stenosing enteritis: First case. World J Gastroenterol 2013;19:1661-4.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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