Obscure gastrointestinal (GI) bleeding refers to GI bleeding of unknown origin that persists after a non-diagnostic upper GI endoscopy, colonoscopy, and radiologic assessment of the small bowel. It can manifest as either overt bleeding or occult bleeding, the latter typically presenting as iron deficiency anemia. In approximately 75% of cases, the source of the bleeding is located within the small bowel. Potential causes include angioectasias, diverticula, ulcers, or neoplasms. A recently identified condition, chronic enteropathy associated with SLCO2A1 mutation (CEAS) has been associated with small bowel ulcers or strictures and commonly presents as iron deficiency anemia. This condition, which involves a mutation in a gene that codes for a prostaglandin transporter, has been rarely reported outside of Japan and Korea. We report the case of a young boy who presented with recurrent iron deficiency anemia and a positive stool occult blood test. He was found to have an SLCO2A1 mutation, marking the first reported case of its kind from India.

A 13-year-old boy, born of a consanguineous marriage, presented to our center in 2018 with a three-month history of easy fatigability. He was diagnosed with severe anemia. Upon detailed inquiry, it was revealed that he had a recurrent history of similar episodes dating back to 2009, which required blood transfusions and parenteral iron therapy. His parents and two younger siblings did not exhibit similar symptoms and had normal hemograms. The patient had no history of non-steroidal anti-inflammatory drug (NSAID) use, jaundice, abdominal distension, or bleeding from any site. He had not undergone any surgical procedures in the past. On examination, he had a low body mass index of 16.5 kg/m², pallor, and no evidence of clubbing or hepatosplenomegaly.

Over the last 8 years, the patient experienced repeated episodes of low hemoglobin. Laboratory investigations revealed hypochromic microcytic anemia with a mean corpuscular volume of 62 fL. An extensive hematological workup, including osmotic fragility, red blood cell enzyme defect studies, bone marrow examination, serum immunoglobulin A (IgA) tissue transglutaminase, and IgA deamidated gliadin peptide tests, failed to identify any significant abnormalities. The patient’s stool occult blood test was positive on each occasion.

A provisional diagnosis of iron deficiency anemia secondary to occult GI bleeding was established. The patient’s upper GI endoscopy, colonoscopy, and push enteroscopy revealed no abnormalities. Following a normal CT enterography (Fig. 1), he underwent a capsule endoscopy, which identified multiple superficial ulcers in the jejunum and proximal ileum (Fig. 2). An attempt at double-balloon enteroscopy was made but proved unsuccessful due to excessive looping. His inflammatory markers—erythrocyte sedimentation rate (5 mm/hr) and CRP (0.3 mg/dL)—were within normal ranges. Upon a presumptive diagnosis of Crohn’s disease, the patient was initiated on oral prednisolone (40 mg) and azathioprine (50 mg) daily. When there was no response to this treatment, the regimen was escalated to include adalimumab injections, of which the patient received 16 doses. However, adalimumab was discontinued due to persistent anemia. The patient then began hyperbaric oxygen therapy (HBOT)¹ at pressures ranging from 1.5 to 2 atmospheres for 1 hour per session, in conjunction with exclusive enteral nutrition² using an elemental formulation, aiming to reduce gut inflammation. After completing 10 cycles of HBOT, the therapy was stopped because the patient could not tolerate the associated headaches.

Figure 1. Normal computed tomography enterography, with no evidence of strictures or mucosal thickening.

Figure 2. Multiple semi-circumferential and circumferential superficial ulcers with overlying slough in jejunum and proximal ileum.

As the patient remained unresponsive, a diagnosis of cryptogenic multisystemic ulcerous stenosing enteritis (CMUSE) was suspected. Consequently, treatment with infliximab and methotrexate injections was initiated. Concurrently, a sample was sent for whole genome sequencing to test for the SLCO2A1 mutation. The results revealed a homozygous mutation in exon 12 of the SLCO2A1 gene. The patient continues to receive infliximab and methotrexate injections. In addition, he has been provided with supportive care, including blood transfusions and intravenous iron therapy as required. The patient continues to exhibit symptoms of anemia; however, there has been a reduction in both the severity of the anemia and the frequency at which intravenous iron therapy and transfusions are required. To date, he has remained stable and has not experienced any opportunistic infections or complications associated with immunosuppressive therapy. Since it was a retrospective analysis, we got a waiver from institutional ethical committee of Lokmanya Tilak Municipal Medical College and General Hospital (IEC-97/23). The consents were obtained from the legal guardians.

CEAS was initially described in 1968 as chronic non-specific multiple ulcers of the small intestine due to the absence of specific histological findings, such as granulomas and eosinophilic infiltration. It is a rare, intractable autosomal recessive disease characterized by a loss-of-function mutation in the SLCO2A1 gene, which encodes a prostaglandin transporter.³ The majority of cases have been reported in Japan, where a nationwide study conducted from 2012 to 2016 confirmed 46 patients with SLCO2A1 mutations.⁴ Outside of Japan, two cases have been reported: one in China in 2020,⁵ and another in Korea in 2018.⁶ Additionally, the KASID multicenter study in Korea identified 14 genetically confirmed cases of CEAS.⁷

The SLCO2A1 gene encodes a prostaglandin transporter that is responsible for the efflux of newly synthesized prostaglandins from cells, as well as for epithelial prostaglandin transport, clearance, and degradation. Mutations in the SLCO2A1 gene, whether homozygous or heterozygous, are known to cause CEAS and a subtype of primary hypertrophic osteoarthropathy (PHO).⁸ As prostaglandin E2 is known to protect the mucosa of the small intestine from inflammatory damage, its impaired function may lead to the formation of ulcers. Additionally, it may initiate fibrogenic activity that results in short-segment strictures. Conditions such as CMUSE, CEAS, and NSAID enteropathy may collectively be referred to as prostaglandin-associated enteropathies.⁹

CEAS has a female preponderance, with the average age of onset occurring in adolescence (around 16.5 years), although it can manifest at any age between 1 and 69 years. When small intestine ulcers are present, patients typically experience obscure GI bleeding or anemia. Conversely, small bowel strictures often present with abdominal pain. The condition is characterized by intermittent episodes, with periods of normal health in between.¹⁰ The endoscopic appearance of CEAS is marked by multiple small, shallow, and superficial ulcers that can be circular or oval in shape, including eccentric ulcers that are not associated with the mesenteric side. Histologically, these ulcers are non-specific and involve only the mucosa or submucosa, without the presence of granulomas.¹¹

In conclusion, there is a pressing need to raise awareness about this disease and to expand testing efforts. Doing so will aid in identifying cases and provide a larger sample size for further studies, which is essential for the development of an effective treatment modality.

None.

The data are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.