Shuji Kochi

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS).

Prediction of 6-thioguanine nucleotides levels in Japanese patients with inflammatory bowel diseases during long-term thiopurine administration

Abstract Background. The monitoring of 6-thioguanine nucleotides (6-TGN) levels is warranted during thiopurine therapy for patients with inflammatory bowel diseases. Aims. The aim of this study was to elucidate the parameters that can predict the 6-TGN levels among Japanese patients with inflammatory bowel diseases undergoing thiopurine therapy. Material and methods. The 6-TGN levels were measured in 54 patients with inflammatory bowel diseases (32 with ulcerative colitis and 22 with Crohns disease), who had been administered azathioprine or 6-mercaptopurine for more than 90 days. Possible correlations between the hematologic parameters and 6-TGN levels were investigated. The clinical and hematologic variables were evaluated to determine the 6-TGN levels of less than or over 235 pmol/8 × 108 RBCs. Results. The 6-TGN levels correlated significantly with changes in the mean corpuscular volume (R = 0.423, p = 0.001) and the lymphocyte counts (R = −0.280, p = 0.04). A multivariate analysis revealed changes in the mean corpuscular volume (OR: 1.22, 95% CI: 1.07–1.40) and hemoglobin levels (OR: 0.59, 95% CI: 0.35–0.99) to be factors predictive of the 6-TGN levels. An increase in the mean corpuscular volume of 3.5 fl was determined to be the most preferable cut-off value to distinguish patients with 6-TGN ≥ 235 pmol/8 × 108 RBCs from those with a lower concentration. Conclusions. Changes in the mean corpuscular volume are considered to be predictive of the 6-TGN levels in patients with inflammatory bowel diseases receiving thiopurine therapy.

Giant Inflammatory Polyposis of the Cecum With Repeated Intussusception in Ulcerative Colitis: Report of a Case

Giant Inflammatory Polyposis of the Cecum With Repeated Intussusception in Ulcerative Colitis: Report of a Case

Time Trends of the Impact of Helicobacter pylori Infection and Nonsteroidal Anti-Inflammatory Drugs on Peptic Ulcer Bleeding in Japanese Patients

Background/Aims:Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are the main causes of peptic ulcers. The purpose of the present study was to elucidate the time trends of the impact of H. pylori infection and use of NSAIDs and/or antithrombotic agents on peptic ulcer bleeding (PUB) in Japanese patients. Methods: We retrospectively reviewed 719 patients who had received endoscopic hemostasis for PUB between 2002 and 2013. Subjects were divided into either the first-half group (2002-2007, n = 363) or the second-half group (2008-2013, n = 356). The clinical characteristics of the patients, including the prevalence of H. pylori infection and use of NSAIDs and antithrombotic agents, were compared between the two groups. Results: Compared to the first-half group, patients in the second-half group were characterized by older age (proportion of the patients above 60 years old, 63.9 vs. 76.7%, p = 0.0002), less frequent H. pylori infection (71.6 vs. 57.9%, p < 0.001) and more frequent NSAID intake (39.9 vs. 48.6%, p = 0.02). No significant difference was observed regarding the use of antithrombotic agents between the two groups (18.6 vs. 23.3%, p = 0.13). The prevalence of H. pylori infection and proportion of patients above 60 years old were significantly different between the two groups in a multivariate analysis. Conclusion: The main cause of PUB has clearly shifted from H. pylori infection to the use of NSAIDs over the last decade.

Capsule endoscopy findings for the diagnosis of Crohn’s disease: a nationwide case–control study

BackgroundCapsule endoscopy can be used to identify the early stage of small bowel Crohn’s disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD.MethodsWe retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups.ResultsUnder SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers.ConclusionsCircumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE.

SMALL EARLY GASTRIC CANCER OCCURRING IN A YOUNG WOMAN WITH NODULAR GASTRITIS

We found a small gastric cancer in a 25‐year‐old woman with nodular gastritis. Endoscopically, the cancer was identified as a whitish area in the gastric antrum. There was also a miliary pattern in the gastric antrum and corpus. In addition, serology and histology revealed the patient to have been infected by Helicobacter pylori. Histological examination of the resected stomach showed that the cancer was poorly differentiated adenocarcinoma with signet‐ring cell restricted to the mucosal layer. In the surrounding mucosa, there were chronic inflammatory cell infiltrates and enlarged lymphoid follicles with germinal centers. Our case suggests that nodular gastritis may be at a high risk for the development of gastric cancer of poorly differentiated type.

Case of amebic colitis complicated by intestinal spirochaetosis

Dear Editor, Human intestinal spirochaetosis (HIS) is considered a zoonotic agent. In Japan, only a few cases of HIS have been previously reported, although many reports have described HIS as a common condition in the developing countries and Western countries, especially in homosexual men and HIVinfected patients. The diagnosis of HIS is established by histological demonstration of the organism in colonic biopsies. Warthin-Starry staining has been shown to be superior to hematoxylin and eosin staining. We herein report a Japanese case of amebic colitis complicated by intestinal spirochaetosis, in which diminutive endoscopic findings may have been a consequence of HIS infection. A 34-year-old Japanese man visited our institution with a complaint of hematochezia and persistent diarrhea in October, 2005. He was homosexual. His serum was positive for antibody to Entamoeba histolytica. The patient refused the assessment of antibody to HIV. Subpopulations of lymphocytes such as CD4, CD8, CD4/CD8 ratios, were within normal ranges. On colonoscopy, multiple reddish erosions with yellowish exudates were found in the cecum and rectum (Fig. 1a). In addition, multiple tiny aphthous lesions were found throughout the colon (Fig. 1b). Histological examination of the biopsy specimen from the erosion in the cecum and rectum revealed chronic mucosal inflammation with numerous trophozoites of E. histolytica (Fig. 2a). In other biopsy specimens from aphthous lesions in the colon, a basophilic, fuzzy fringe accompanied by minimal inflammatory infiltrates was found on the apical surface of the mucosal epithelium. The fringe was stained in a brownish line with Warthin-Starry staining (Fig. 2b). These findings were compatible with HIS. We treated the patient with metronidazole (500 mg twice a day) for 14 days. Follow-up colonoscopy performed 3 weeks later revealed the colorectal lesions to have healed. Although HIS has been shown to be a secondary invader in amebiasis, there have been few reports describing colonoscopic features of amebiasis complicated by HIS. In earlier reports, tiny aphthous ulcerations in the colon, referred to as ‘strawberry lesions’, were described as the characteristic endoscopic feature of HIS. However, colonoscopy-negative HIS has also been reported. In the present case, tiny aphthous lesions were found throughout the colon and large, swollen aphthous ulcers in the cecum and rectum. While the latter seems to be characteristic of amebiasis, the former lesions may rather be a consequence of HIS, because trophozoites of E. histolytica were not evident in the biopsy specimens. In prior cases of endoscopy-negative HIS, tiny aphthous ulcerations as found in the present case may have been overlooked. Shuji Kochi, Takayuki Matsumoto, Motohiro Esaki, Shotaro Nakamura, Yutaka Ohji, Takashi Yao, Shuichiro Nuki and Mitsuo Iida Department of Medicine and Clinical Science, Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, and Nuki Surgery and Gastrointestinal Clinic, Fukuoka, Japan