CMUSE, CEAS, Crohn's disease

Crohn's disease로 잘못 진단될 수 있는 질환으로 CMUSE[cryptogenic multifocal ulcerous stenosing enteritis, CEAS[chronic enteropathy associated with SLCO2A1 gene]가 있습니다. CMUSE는 남성 우세, jejunum 호발, steroid에 반응하고 CEAS는 여성 우세, ileum 호발, steroid와 면역억제제에 반응하지 않습니다. 

 

1. Introduction

Small intestinal ulcers are sometimes caused by drugs, particularly nonsteroidal anti-inflammatory drugs [NSAIDs], infectious diseases such as tuberculosis, and inflammatory bowel diseases [IBDs] such as Crohn’s disease and Behçet’s disease. Most small intestinal ulcers are difficult to diagnose, and the pathogenesis of these ulcers is still unknown. In Western countries and in Korea, a unique type of enteritis, called ‘cryptogenic multifocal ulcerous stenosing enteritis [CMUSE]’, has been reported.Additionally, a Japanese group of investigators reported another unusual type of enteritis, called chronic nonspecific multiple ulcers of the small intestine [CNSU]. CNSU is characterised by chronic blood and protein loss through persistent small intestinal ulcers. Recently, Umeno et al. identified four candidate mutations in the solute carrier organic anion transporter family, member 2A1 [SLCO2A1] gene, encoding a prostaglandin transporter by whole-exome sequencing in patients with CNSU. Furthermore, they confirmed actual loss of function in the mutated SLCO2A1 gene. Since the nomenclature ‘CNSU’ is ambiguous, researchers have suggested the more appropriate nomenclature of ‘chronic enteropathy associated with SLCO2A1 gene’ [CEAS]. To date, however, the endoscopic features of ‘CNSU’ have been reported only in a small case series. In this review article, we collected endoscopic and clinical data of genetically diagnosed CEAS by a nationwide survey, and summarised the endoscopic and clinical features of CEAS in an atlas format.

 

 

6. Discussion

In this article, we have provided an overview of CEAS and demonstrated endoscopic and clinical features of genetically confirmed CEAS in the atlas format. The objective of this article was to disseminate accurate knowledge of endoscopic and clinical features of CEAS to clinicians worldwide. Such an approach should reduce misdiagnosis of CEAS and result in the diagnosis of a larger number of patients with CEAS. CEAS is characterised by refractory small intestinal ulcers and stenoses even after surgery, because effective therapy has not been established. Enteral or parenteral nutrition coupled with iron supplementation is transiently effective; however, oral 5-aminosalicylic acid and prednisolone as immunosuppressive therapies are not effective. Umeno et al. reported that CEAS predominantly occurs in women [male:female ratio of 4:14], and the age at disease onset ranged from 1 to 53  years [average, 24.3  years]. Whereas all patients had ileal ulcers, Umeno et  al. also reported that the stomach and duodenum were affected in five [27.8%] and eight [44.4%] patients, respectively. Clinical symptoms of CEAS are explained by chronic and persistent blood loss from small intestinal ulcers, namely, anaemia, hypoproteinaemia, oedema, and abdominal pain. As shown in Table 1, profiles of enrolled patients used for the current atlas are similar to those of previously reported cases. Although mutations in the SLCO2A1 gene, encoding a prostaglandin transporter, have been reported to be pathognomonic for primary hypertrophic osteoarthropathy [PHO], a certain proportion of CEAS patients have digital clubbing, periostosis, and/ or pachydermia. Umeno et  al. also reported that the SLCO2A1 gene encodes a prostaglandin transporter which mediates the uptake and clearance of prostaglandins, and the urinary levels of prostaglandin E in CEAS patients were significantly higher than those in another disease. Furthermore, they showed that the SLCO2A1 mutations found in the patients caused functional impairment of prostaglandin E2 uptake within cells. Actually, the clinical features of PHO were thought to be caused by excessive prostaglandin E2 [PGE2]. Although elevated levels of PGE2 in gastrointestinal tissues are known to protect against mucosal inflammation via the prostaglandin receptor, multiple intestinal ulcers occur in CEAS. Thus, it has not yet been elucidated how prostaglandins are involved in the pathogenesis of CEAS. The pathological characteristics of CEAS are as follows: 1] depth of the ulcers is restricted to the mucosa or the submucosa; and 2] submucosal fibrosis is restricted to the area of the mucosal defect with minimal epithelial repair and restitution. Umeno et al. reported that a certain proportion of patients with CEAS were misdiagnosed as having other IBDs, such as Crohn’s disease, presumably due to clinical features. Since corticosteroids and immunosuppressives are not effective for CEAS, recognition and definite diagnosis of CEAS is necessary for the selection of appropriate therapies. Cases of a similar enteropathy referred to as cryptogenic multifocal ulcerous stenosing enteritis [CMUSE] have been reported in Western countries and Korea. This enteropathy has been shown to be inherited in an autosomal recessive manner owing to mutations in the PLA2G4A gene. CMUSE, which occurs predominantly in middle-aged or young patients, is characterised by intermittent bouts of intestinal obstruction, ulcerative stenoses of the small bowel, recurrence even after surgical resection, and steroid sensitivity. CEAS and CMUSE seem to share similar clinical characteristics; however, the male predominance, response to steroid therapy, and predominant involvement of the jejunum as found in CMUSE are uncommon in CEAS. As shown in the current atlas, ulcers in CEAS are characterised by multiple, circular or eccentric oblique, shallow lesions with discrete margins. The most frequently affected site in CEAS is the ileum. However, small intestinal mucosal damages in CEAS, CMUSE, and NSAID-induced enteropathy presumably share common and pathognomonic features of impaired prostaglandin metabolism in vivo. We believe that accumulation of a larger number of patients with CEAS by investigators worldwide will improve our understanding of the pathogenesis of prostaglandin-associated enteropathies, such as CEAS, CMUSE, and NSAID-induced enteropathy. Moreover, other enteropathies may also be related to prostaglandins.

 

REF

J Crohns Colitis. 2017 Oct 1;11(10):1277-1281. doi: 10.1093/ecco-jcc/jjx068.

제8회 염증성 장질환 센터 심포지엄, 서울아산병원