Arginase 2 attenuates ulcerative colitis by antioxidant effects of spermidine.

BACKGROUND: Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis. METHODS: The physiological role of ARG2 and spermidine was investigated using Arg2-deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients. RESULTS: In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2-deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2-deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2-deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients. CONCLUSIONS: ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

White Blood Cell Counts and Future Relapse in Ulcerative Colitis under Low-Dose Thiopurine Treatment in Real-World Practice: A 3-Year Japanese Multi-Center Retrospective Cohort Study.

Introduction: Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multi-center study. Methods: This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for 3 years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts <3,000/µL (N = 31), 3,000-4,000/µL (N = 167), 4,000-5,000/µL (N = 241), and ≥5,000/µL (N = 284) using a Cox regression model analysis. Moreover, exploratory analyses were conducted to identify other factors predicting relapse. Results: During a median follow-up period of 1,095 (interquartile range, 1,032-1,119) days, relapse occurred in 17.2% (125/723). In a crude analysis, WBC counts were not associated with relapse; hazard ratios (HRs) (95% confidence interval [CI]) were 1.50 (0.74-3.06), 1.02 (0.66-1.59), and 0.67 (0.43-1.05) in WBC <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively (WBC ≥5,000/µL group, as reference). Multivariable-adjusted analyses showed similar results; HRs (95% CI) were 1.21 (0.59-2.49), 1.08 (0.69-1.69), and 0.69 (0.44-1.07), in <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively. In the exploratory analyses, thiopurine use <1 year and a mean corpuscular volume <90 fL were predictors for relapse. Discussion/Conclusion: WBC counts were not predictors for future relapses in patients with UC treated with thiopurine as a maintenance therapy.

Duodenal microbiome in chronic kidney disease.

BACKGROUND: The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its importance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. METHODS: Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes. RESULTS: The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database. CONCLUSION: The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients.

Ustekinumab Decreases Circulating Th17 Cells in Ulcerative Colitis.

Objective T helper (Th) cells play a central role in the pathogenesis of ulcerative colitis (UC). The present study analyzed the changes in circulating T cells by administration of ustekinumab (UST), an interleukin-12/23p40 antibody. Methods CD4 T cells were isolated from peripheral blood at 0 and 8 weeks after UST treatment, and we analyzed the proportion of CD4 T cells by flow cytometry. Clinical information and laboratory data were obtained at 0, 8, and 16 weeks. Patients We evaluated 13 patients with UC who received UST for the induction of remission between July 2020 and August 2021. Results The median partial Mayo score improved from 4 (1-7) to 0 (0-6) (p<0.001) with UST. Among serological parameters, albumin concentrations, C-reactive protein concentrations, the sedimentation rate, and leucine-rich alpha 2 glycoprotein concentrations showed significant improvement with UST. A flow cytometric analysis of circulating CD4 T cells showed that the percentage of Th17 cells was significantly decreased by UST treatment in all patients (1.85% to 0.98%, p<0.0001). Th1 cells were significantly increased by UST treatment (9.52% to 10.4%, p<0.05), but Th2 and regulatory T cells were not significantly different. The high-Th17 subgroup had a significantly better partial Mayo score than the low-Th17 subgroup at 16 weeks after UST treatment (0 vs. 1, p=0.028). Conclusion Treatment with UST decreases circulating Th17 cells, suggesting that this change may be related to the anti-inflammatory effect of UC.

Immunomodulators after the discontinuation of anti-tumor necrosis factor-alpha antibody treatment and relapse in ulcerative colitis: A multicenter cohort study.

BACKGROUND AND AIM: Strategies to reduce relapse using immunomodulators (IMs) after discontinuing anti-tumor necrosis factor-alpha (TNF-α) antibody treatment are controversial in patients with ulcerative colitis (UC). In this study, we assessed the association between IMs after discontinuing anti-TNF-α antibody treatment and relapse in patients with UC. METHODS: This retrospective, multicenter cohort study included 257 patients with UC in clinical remission. These patients discontinued anti-TNF-α antibody treatment between June 2010 and March 2019 and were followed up until March 2020. We evaluated the differences in relapse rates between patients with IMs (IM group) and those without IMs (non-IM group) after discontinuing the treatment. Relapse was defined as further undergoing an induction treatment or colectomy. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for relapse. Exploratory analyses were performed to identify other factors that could predict relapse. RESULTS: During the median follow-up period of 22 months (interquartile range: 10-41), 114 relapses occurred: 42/100 (42.0%) in the IM group and 72/157 (45.9%) in the non-IM group. In the multivariable analysis, IMs were not associated with relapse (HR, 0.95 [95% CI, 0.64-1.41]). In the exploratory analyses, discontinuation due to side effects (HR, 1.83 [95% CI, 1.18-2.82]) and younger age (HR, 0.99 [95% CI, 0.98-1.00]) predicted relapse. CONCLUSION: Immunomodulators were not associated with relapse after discontinuing anti-TNF-α antibody treatment in patients with UC. Careful patient follow-up is needed when discontinuing due to side effects or when the patient is of a younger age at the time of discontinuation.

Disease Flares Following COVID-19 Vaccination in Patients with Inflammatory Bowel Disease.

Objective Flares of inflammatory bowel disease (IBD) can occur infrequently after vaccination for coronavirus disease 2019 (COVID-19), although the details of this phenomenon are poorly understood. To clarify the possibility of an unfavorable response in patients with IBD, we investigated IBD-related symptoms during the COVID-19 vaccination. Methods Between October 2021 and February 2022, we obtained the COVID-19 vaccination status of 411 IBD patients who were being treated at our institution. The disease course of IBD after vaccination was investigated in 188 patients with ulcerative colitis (UC) and 119 patients with Crohn's disease (CD) who had received at least one dose of the vaccine during the clinical remission phase. The baseline characteristics before vaccination were compared between the patients with UC with or without disease flares. Results During the 30-day follow-up period, eight patients with UC (4.3%) and one patient with CD (0.8%) experienced disease flares following vaccination. Disease flares occurred after the first vaccination in six patients and after the second vaccination in three patients. As for the timing of onset of disease flares, eight events (88.9%) occurred within one week of vaccination. Two patients required hospitalization, and one patient with CD required surgery for an intra-abdominal abscess. The baseline characteristics did not significantly differ between patients with UC who experienced flares and those who did not. Conclusion IBD flares following COVID-19 vaccination are rare and vaccination should therefore be recommended for patients with IBD. However, the possibility of disease flares should be considered for approximately one week after each vaccination, especially in patients with UC.

Usefulness of Serum Leucine-Rich Alpha-2 Glycoprotein as a Surrogate Marker of Small Bowel Mucosal Injury in Crohn's Disease.

Introduction: Although the importance of mucosal healing has been suggested in Crohn's disease, it is difficult to repeat endoscopy, especially for the entire small bowel. Recently, serum leucine-rich alpha-2 glycoprotein (LRG) has been used as a surrogate marker of endoscopy. However, few studies have investigated a correlation between LRG and mucosal injury of the entire small bowel. Methods: We retrospectively analyzed the clinical data of 30 patients with Crohn's disease from June 2020 to August 2022 at Yamaguchi Red Cross Hospital. All the patients were surveyed through the gastrointestinal tract by esophagogastroduodenoscopy, total colonoscopy, and capsule endoscopy (CE). Subjects with mucosal injury only in the small bowel were selected. Then, we assessed the relationship between serum biomarkers (LRG, C-reactive protein [CRP], hemoglobin, albumin) and small bowel mucosal injury scores (Lewis score [LS], Capsule Endoscopy Crohn's Disease Activity Index [CECDAI], and Crohn's Disease Activity in Capsule Endoscopy [CDACE]) calculated by CE. Results: LRG and CRP were significantly correlated with small bowel mucosal injury scores (LS, CECDAI, CDACE) (p < 0.05, Spearman's rank correlation coefficient). The degree of correlation was greater for LRG than for CRP. Conclusions: LRG is a useful surrogate marker that closely reflects small bowel mucosal injury in the entire small bowel.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

Ferroptosis in the colon epithelial cells as a therapeutic target for ulcerative colitis.

BACKGROUND: Ferroptosis, a type of programmed cell death triggered by oxidative stress, was suspected to play a role in ulcerative colitis. Indigo naturalis is highly effective against ulcerative colitis, but its mechanism is unclear. This study found that indigo naturalis treatment suppressed ferroptosis. METHODS: We analyzed 770 mRNA expressions of patients with ulcerative colitis. Suppression of ferroptosis by indigo naturalis treatment was shown using a cell death assay. Malondialdehyde levels and reactive oxygen species were analyzed in CaCo-2 cells treated with indigo naturalis. Glutathione metabolism was shown by metabolomic analysis. Extraction of the ingredients indigo naturalis from the rectal mucosa was performed using liquid chromatograph-mass spectrometry. RESULTS: Gene expression profiling showed that indigo naturalis treatment increased antioxidant genes in the mucosa of patients with ulcerative colitis. In vitro analysis showed that nuclear factor erythroid-2-related factor 2-related antioxidant gene expression was upregulated by indigo naturalis. Indigo naturalis treatment rendered cells resistant to ferroptosis. Metabolomic analysis suggested that an increase in reduced glutathione by indigo naturalis. The protein expression of CYP1A1 and GPX4 was increased in the rectum by treatment with indigo naturalis. The main ingredients of indigo naturalis, indirubin and indigo inhibited ferroptosis. Indirubin was detected in the rectal mucosa of patients with ulcerative colitis who were treated with indigo naturalis. CONCLUSIONS: Suppression of ferroptosis by indigo naturalis in the intestinal epithelium could be therapeutic target for ulcerative colitis. The main active ingredient of indigo naturalis may be indirubin.

Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries.

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.

Clinical Features of Gastroduodenal Ulcers in Kidney Transplant Patients.

Objective The risk of developing peptic ulcers and gastrointestinal bleeding is high in patients with chronic kidney disease (CKD). Whether or not kidney transplant patients, who are treated with multiple medications, including immunosuppressive drugs, are at an increased risk of developing peptic ulcers is unclear. Methods In this retrospective study, we compared the clinical and endoscopic features of gastroduodenal ulcers between kidney transplant patients and CKD patients. The subjects underwent upper gastrointestinal endoscopy between January 2015 and March 2021. Results Gastroduodenal ulcers were observed more frequently (6.5%) in kidney transplant patients than in CKD patients (2.1%) (p=0.026). Due in part to the lower median age in the kidney transplant ulcer group than in the CKD ulcer group (59 vs. 70 years old, p=0.016), the rates of atrophic gastritis and Helicobacter pylori infection were also lower in the kidney transplant ulcer group than in the CKD ulcer group. Significantly more kidney transplant patients were treated with acid secretion inhibitors than CKD ulcer patients (100% vs. 34.8%, p=0.0005). Peptic ulcers were observed frequently in kidney transplant patients, even though common risk factors for gastroduodenal ulcers other than immunosuppressive drugs were few. All kidney transplant patients were taking immunosuppressive medications, and tacrolimus, mycophenolate mofetil, and methylprednisolone were taken more frequently than others. Conclusion Kidney transplant patients have a high risk of developing gastroduodenal ulcers. All kidney transplant patients take immunosuppressive medications, so there may be an association between immunosuppressive medications and gastroduodenal ulcer development.

Clinical Guidelines for Diagnosis and Management of Juvenile Polyposis Syndrome in Children and Adults-Secondary Publication.

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood. JPS is classified into three categories according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juvenile polyposis coli, and juvenile polyposis of the stomach. Juvenile polyposis of the stomach is caused by germline pathogenic variants of SMAD4 with a high risk leading to gastric cancer. Pathogenic variants of SMAD4 are also associated with hereditary hemorrhagic telangiectasia-JPS complex, inducing regular cardiovascular survey. Despite growing concerns regarding the managing JPS in Japan, there are no practical guidelines. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labor and Welfare involving specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of JPS with three clinical questions and corresponding recommendations based on a careful review of the evidence and involve incorporating the concept of the Grading of Recommendations, Assessment, Development, and Evaluation system. Herein, we present the clinical practice guidelines of JPS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with JPS.

Clinical Guidelines for Diagnosis and Management of Juvenile Polyposis Syndrome in Children and Adults­Secondary Publication

Juvenile polyposis syndrome (JPS) is a rare disease characterized by multiple hamartomatous polyps within the gastrointestinal tract. SMAD4 or BMPR1A is known as a causative gene of JPS. Approximately 75% of newly diagnosed cases have an autosomal-dominantly inherited condition, whereas 25% are sporadic without previous history of polyposis in the family pedigree. Some patients with JPS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood. JPS is classified into three categories according to phenotypic features of polyp distributions, including generalized juvenile polyposis, juvenile polyposis coli, and juvenile polyposis of the stomach. Juvenile polyposis of the stomach is caused by germline pathogenic variants of SMAD4 with a high risk leading to gastric cancer. Pathogenic variants of SMAD4 are also associated with hereditary hemorrhagic telangiectasia-JPS complex, inducing regular cardiovascular survey. Despite growing concerns regarding the managing JPS in Japan, there are no practical guidelines. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labor and Welfare involving specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of JPS with three clinical questions and corresponding recommendations based on a careful review of the evidence and involve incorporating the concept of the Grading of Recommendations, Assessment, Development, and Evaluation system. Herein, we present the clinical practice guidelines of JPS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with JPS.

Predictive factors of the clinical efficacy of ustekinumab in patients with refractory Crohn's disease: tertiary centers experience in Japan.

PURPOSE: Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn's disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. METHODS: We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn's Disease Activity Index < 150 and CRP < 0.3 mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. RESULTS: The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2 years) and higher baseline serum albumin levels (≥ 3.1 g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19 mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. CONCLUSION: A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels.

Continuous use of antithrombotic medications during peri-endoscopic submucosal dissection period for colorectal lesions: A propensity score matched study.

BACKGROUND AND AIM: The aim of this study was to elucidate the continuous use of antithrombotic medications during the peri-colorectal endoscopic submucosal dissection (ESD) period. METHODS: This study included 468 patients with colorectal epithelial neoplasms treated by ESD, consisting of 82 under antithrombotic medications and 386 patients without the medications. Among patients taking antithrombotic medications, antithrombotic agents were continued during the peri-ESD period. Clinical characteristics and adverse events were compared after propensity score matching. RESULTS: Before and after propensity score matching, post-colorectal ESD bleeding rate was higher in patients continuing antithrombotic medications (19.5% and 21.6%, respectively) than in those not taking antithrombotic medications (2.9% and 5.4%, respectively). In the Cox regression analysis, continuation of antithrombotic medications was associated with post-ESD bleeding risk (hazard ratio, 3.73; 95% confidence interval, 1.2-11.6; P < 0.05) compared with patients without antithrombotic therapy. All patients who experienced post-ESD bleeding were successfully treated by endoscopic hemostasis procedure or conservative therapy. CONCLUSIONS: Continuation of antithrombotic medications during the peri-colorectal ESD period increases the risk of bleeding. However, the continuation may be acceptable under careful monitoring for post-ESD bleeding.

A rare case of an enterochromaffin-like neuroendocrine tumor associated with parietal cell dysfunction treated using endoscopic submucosal dissection.

Most gastric neuroendocrine tumors (NETs) develop from enterochromaffin-like (ECL) cells. ECL-cell NETs are classically categorized into three types according to their etiology. A 50-year-old woman presented with submucosal tumor-like lesions in the stomach, which were identified via esophagogastroduodenoscopy. Although esophagogastroduodenoscopy and pathological findings of biopsy specimens showed an absence of mucosal atrophy in the body of the stomach, sticky, adherent, dense mucus was observed. All lesions were diagnosed as ECL-cell NETs based on histological examination findings; however, ECL-cell NETs did not apply to any of the classic types I-III categorization based on laboratory, computed tomography, and 24-h intragastric pH monitoring test findings. Endoscopic submucosal dissection of the tumor was performed. Pathological findings of the excised specimen indicated that parietal cell hyperplasia with a protrusion, dilated fundic glands, and endocrine cell hyperplasia in the background mucosa, and parietal cells were not immunostained for the α-subunits of H+/K+-ATPase. Genetic analysis identified mutation in the ATP4A gene. The patient opted for additional gastric resection due to the risk of lymph node metastasis with deeper submucosal invasion and vascular infiltration. This report describes the first case of ECL-cell NETs caused by parietal cell dysfunction, which was treated via endoscopic submucosal dissection.

[A case of chronic enteropathy associated with SLCO2A1 gene diagnosed by capsule endoscopy and successfully treated by ferric carboxymaltose].

Chronic non-specific multiple ulcers of the small intestine is a disease condition postulated in Japan. It is an uncommon gastrointestinal disease that causes chronic anemia and hypoalbuminemia by causing numerous ulcers without any histopathologically identifiable features. In recent years, it has been revealed that the mutations of SLCO2A1, which codes the prostaglandin transporter protein, are the cause of this disease;it is called the new name "chronic enteropathy associated with SLCO2A1 gene." The ileum, except the terminal ileum, is the most common place making it difficult to identify major lesions. Other than conservative treatments, such as nutrition therapy and iron supplements, no effective treatment has been identified so far. We present a case of chronic non-specific multiple ulcers of the small intestine diagnosed by capsule endoscopy and effectively treated by ferric carboxymaltose. A 48-year-old female had chronic iron deficiency anemia since around the age of 15. Because of severe anemia, the patient had upper and lower endoscopy at the age of 47 to find the source of the bleeding, but it was not detected. Except for the terminal ileum, the capsule endoscopy revealed ring-like ulcers, tape-like ulcers, and oblique ulcer scars in the ileum. Genetic analysis showed a homozygous mutation in intron 7, c.940+1G>A, indicating a definitive diagnosis of non-specific multiple ulcers of the small intestine. Anemia and anemia-related symptoms such as general malaise persisted despite continuous oral administration of iron drugs. Three intravenous injections of ferric carboxymaltose increased hemoglobin and enhanced the symptoms.