非特異性多発性小腸潰瘍症

Chronic enteropathies characterized by multiple superficial ulcers of the small intestine have long been under-recognized, particularly in their early stage. However, the occurrence of refractory occult bleeding and episodes of partial bowel obstruction in this disease severely impacts quality of life, while targeted therapeutic options remain limited. Although dysfunction of the prostaglandin metabolic pathway has been associated with mucosal damage, the underlying molecular mechanisms and potential therapeutic targets remain unclear. In recent years, in-depth investigations of nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy, along with the discovery of rare monogenic disorders affecting the prostaglandin metabolic pathway, have helped bridge this knowledge gap. A broader concept, termed "prostaglandin-associated enteropathy (PGAE)", has since emerged, representing a monumental breakthrough in the differential diagnosis of nonspecific small intestinal ulcers. This narrative review focuses on prostaglandin metabolism and chronic intestinal ulcers, including NSAID-induced enteropathy and chronic enteropathies associated with solute carrier organic anion transporter family member 2A1 (SLCO2A1) and phospholipase A2 group IVA (PLA2G4A). By unraveling molecular connections and highlighting innovative therapeutic avenues, we aim to advance clinical management and improve the well-being and quality of life for patients with PGAE.

BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare hereditary disorder characterized by multiple small intestinal ulcers, chronic anemia, and hypoproteinemia. Initially reported by Okabe et al. [J Jpn Soc Gastroenterol. 1968;65:1114-7] in 1968 as chronic nonspecific multiple ulcers of the small intestine, the condition was later identified as a genetic disorder caused by mutations in the SLCO2A1 gene, which encodes a prostaglandin (PG) transporter. Unlike typical autosomal recessive disorders, CEAS predominantly affects females and is frequently present with extraintestinal manifestations such as digital clubbing, pachydermia, and periostosis. SUMMARY: This review provides a comprehensive summary of the epidemiology, pathogenesis, clinical features, diagnostic criteria, and management of CEAS, with an emphasis on newly established diagnostic protocols in Japan. CEAS is characterized by multiple shallow circumferential or oblique ulcers in the small intestine, often resembling NSAID-induced enteropathy. Laboratory findings typically include iron deficiency anemia and hypoproteinemia, while urinary PG metabolite levels are significantly elevated. Genetic testing for SLCO2A1 mutations, particularly the c.940 + 1G>A splice site mutation, confirms the diagnosis. While symptomatic management with enteral nutrition, iron supplementation, blood transfusions, and albumin infusion is the mainstay of therapy, definitive treatments remain unavailable. Endoscopic balloon dilation may be useful in cases of intestinal strictures, but surgical intervention is frequently required. KEY MESSAGES: (i) CEAS should be considered in cases of chronic iron deficiency anemia and hypoproteinemia with unexplained small intestinal ulcers. (ii) Genetic testing for SLCO2A1 mutations, combined with assessment of small intestinal morphology, is essential for accurate diagnosis. (iii) Current treatment options are limited to symptomatic management and surgical intervention, highlighting the need for further research to develop effective therapies.

INTRODUCTION: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare protein-losing enteropathy primarily recognized in Asia. Its uncommon nature and limited research usually complicate diagnosis and treatment. This review examines the course of a pediatric patient with CEAS, who underwent three surgeries during medical treatment. CASE PRESENTATION: A 12-year-old girl was referred for significant anemia and hypoalbuminemia during evaluation for short stature. Initial lab results included hemoglobin of 6.1 g/dl, normal CRP, and positive stool tests, without hematochezia. Capsule endoscopy revealed chronic ulcers and strictures in small bowel, and genetic testing identified a variant in SLCO2A1 gene, finally confirming CEAS. Because the capsule kept retained for 19 days, surgical removal was performed. Alongside the incision made at ileum, extensive circular stenoses were observed. Postoperatively, the patient was started on steroid and Azathioprine. After three months, she visited the emergency room with abdominal pain and fever. CT revealed diffuse free air and abscess, but no definite perforation was identified during emergency surgery, suggesting it was sealed-off. Two weeks after discharge, infliximab treatment was initiated. But she returned with vomiting a few days after second infusion. CT showed small bowel ischemia due to closed-loop obstruction, prompting urgent surgery. Multiple fibrotic bands were twisting part of jejunum, but the strictures seemed nearly normalized compared to earlier findings. We concluded that her disease was not worsening, and the last surgery was rather due to postoperative adhesions. DISCUSSION: This case highlights the challenges in early diagnosis of CEAS, given its rarity and nonspecific symptoms. However, it should be included in differential diagnosis for atypical clinical findings, with genetic testing as a potential diagnostic tool. Also, long-term immunosuppressive therapy often leads to complications requiring multiple surgeries, so minimally invasive approaches should always be considered. Additionally, the resolution of circular stenosis seen in the final surgery during infliximab treatment indicates a reversible component. Further research for effective treatment for CEAS is essential.

Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a rare, autosomal recessive disorder characterized by multiple chronic ulcerative and structuring lesions in the small intestine, primarily affecting the ileum. It often presents with symptoms of chronic blood loss and protein loss, including iron deficiency anemia and abdominal pain, similar to other nonspecific small bowel enteropathies. This case report describes a 15-year-old boy with a 10-year history of recurrent abdominal pain, melena, anemia, and hypoalbuminemia. Initial clinical, endoscopic, and radiological findings suggested inflammatory bowel disease, which led to trials of various therapies, including corticosteroids, antivirals, and biologicals, with incomplete remission. Molecular analysis identified a homozygous SLCO2A1 gene mutation, confirming CEAS. Histopathology revealed extensive mucosal ulceration and submucosal fibrosis in the ileum, with repeat biopsies showing chronic inflammation and villous atrophy. The case underscores the need for comprehensive clinical, histopathological, and molecular evaluation in pediatric patients presenting with chronic nonspecific small bowel ulcers to ensure accurate diagnosis and management of CEAS. This report also adds to the limited global literature on CEAS, being the first documented case in India with a unique exon 11 mutation in SLCO2A1 , contributing to the understanding of disease heterogeneity in non-consanguineous populations.

Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia. PDP with these three features, along with cutis verticis gyrata (CVG), is categorized as the "complete form," whereas cases without CVG are categorized as the "incomplete form." The condition is linked to elevated levels of systemic prostaglandin E2 (PGE2). About half of PDP patients experience arthralgia. The standard treatment for PDP is selective cyclooxygenase (COX)-2 inhibitors, but long-term usage can cause gastrointestinal side effects. Additionally, mutations in the SLCO2A1 can lead to chronic enteropathy associated with the SLCO2A1 gene (CEAS), making the use of selective COX-2 inhibitors particularly risky for PDP patients with CEAS. This has prompted the search for alternative treatments. In this study, five PDP patients-three with the complete form and two with the incomplete form-were treated with acetaminophen. The PGE-major urinary metabolite (PGE-MUM) was monitored as a biomarker of disease activity, reflecting systemic PGE2 levels. Before treatment, PGE-MUM levels were significantly elevated in patients with complete form and mildly elevated in those with incomplete form. Following acetaminophen, PGE-MUM levels decreased in patients with complete form, and all patients reported improvement in arthralgia without developing gastrointestinal symptoms. In conclusion, acetaminophen shows promise as an alternative treatment for PDP, effectively reducing PGE-MUM levels in certain patients and alleviating arthralgia while avoiding the gastrointestinal side effects associated with long-term COX-2 inhibitor usage.