Endoscopic Findings and Diagnosis of Other Inflammatory Bowel Diseases of the Lower GI Tract

Etiology known

– Infection

– Small intestinal ischemia

– Ulcer in Meckel’s diverticulum

– Drug-induced enteropathy

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Anti-cancer drugs

– Radiation enteritis

– Enteritis in association with systemic diseases

– Inherited human cPLA2a deficiency

– Chronic duodenojejunoileitis associated with celiac disease

– Others

Etiology unknown

– Crohn’s disease

– Behçet’s disease/simple ulcer of the small intestine

– Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE)

– Chronic nonspecific multiple ulcers of the small intestine (CNSU)

– Others

In this chapter, the clinical features and endoscopic findings of chronic nonspecific multiple ulcers of the small intestine (CNSU) and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) will be discussed. These diseases have become the topics of this chapter because they are characterized by clinical features and endoscopic findings mimicking Crohn’s disease.

11.2 Chronic Nonspecific Multiple Ulcers of the Small Intestine (CNSU)

CNSU is a chronic and recurrent small intestinal disease initially identified in Japan in the 1960s [1–5]. The disease is characterized by chronic and occult gastrointestinal bleeding and histologically nonspecific ileal ulcers in multiplicity. However, some gastroenterologists have misinterpreted CNSU as a small intestinal pathology of nonspecific pathology without taking clinical features into consideration. The misinterpretation has led to heterogeneity in descriptions of clinicopathologic features of CNSU. Because chronic, recurrent clinical course is a diagnostic feature of CNSU, and since the phenotype of CNSU can easily progress to the diaphragm by treating patients with total parenteral nutrition, Yao proposed a modified diagnostic criteria of CNSU in 2004 [1]. The criteria have recently been revised, with an emphasis on enterosocopic findings (Table 11.2.).

Table 11.2

Diagnostic criteria of CNSU

Major criteria

A. Clinical features

(1) Positive fecal occult blood in multiple sampling

(2) Microcytic, hypochromic anemia for a prolonged period

B. Findings obtained by small-bowel radiography and/or enteroscopy

(1) Neighboring and non-concentric stenosis in multiplicity (radiography)

(2) Sharply demarcated shallow multiple ulcers in circumferential or oblique alignment (enteroscopy)

C. Macroscopic and microscopic findings of the small intestine

(1) Sharply demarcated flat ileal ulcers

(2) Circular or oblique ulcer in geographical or tape-like configuration

(3) Histologically nonspecific ulcer restricted to the submucosal layer

Diseases to be excluded

(1) Intestinal tuberculosis

(2) Crohn’s disease

(3) Intestinal Behçet’s disease/simple ulcer of the small intestine

(4) Drug-induced enteritis

Definite diagnosis of CNSU should satisfy following (1) or (2)

(1) Positive for major criteria A and B-(1) or B-(2) or any one of C

(2) Positive for all of major criteria C

Cases which satisfy major criteria A but do not satisfy B or C should be regarded as having suspected CNSU

The symptoms of CNSU are characterized by those attributed to chronic and persistent blood loss from the intestine occurring early in their life. Thus patients manifest fatigue, edema, and growth retardation, and they usually have repeated episodes of treatment for anemia. However, the patients rarely manifest diarrhea, hematochezia, or fever. Based on these manifestations, patients visit gastroenterologists long after the onset of symptoms. As well as the symptoms, the physical examination reveals anemia, but the abdomen is unremarkable.

Although the small intestinal ulcers in CNSU occur predominantly in the ileum, the terminal ileum is usually spared. The ulcers usually count more than 20 in number, each of which is characterized by discrete margin and shallow and flat ulcer bed. Each ulcer appears as a linear or tall triangle in configuration, which align in a circular or oblique 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 pre-existing ulcers, the stenoses are not always concentric, but rather they may show spiral patterns.

The depth of 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.

11.2.1 Genetic Background

We have recently reviewed family histories of 13 patients with CNSU, and found six patients who were offspring of consanguineous marriage of three or five degrees. In addition, three of 13 patients had siblings showing enteropathy, and two of them were siblings of consanguineous marriage. Based on such segregation in offspring from consanguinity, we speculated that CNSU is an autosomal recessive disorder. According to the present case series of CNSU, eight of 16 patients were offspring of consanguinity marriage. In addition, four of the other eight patients who denied consanguinity in their family pedigrees had siblings of CNSU. Such dense inheritance again reconfirms that CNSU is distinctive of hereditary disease. More recently, it has been reported that homozygous mutations or compound heterozygous mutations of SLCO2A1 gene encoding a prostaglandin transporter are closely associated with the pathogenesis of the disease [21].

11.2.2 Clinicopathologic Features of CNSU

The disease occurs predominantly in females. While the ages of onset ranged from ten to 52 years, most of the patients manifest anemia during their second or third decade of life. The patients had histories of long-term anemia, and they had usually suffered from the symptoms for more than ten years before confirmation of small intestinal lesions.

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