Development and validation of machine learning model for predicting treatment responders in patients with primary biliary cholangitis.

AIMS: Ursodeoxycholic acid is the first-line treatment for primary biliary cholangitis, and treatment response is one of the factors predicting the outcome. To prescribe alternative therapies, clinicians might need additional information before deciphering the treatment response to ursodeoxycholic acid, contributing to a better patient prognosis. In this study, we developed and validated machine learning (ML) algorithms to predict treatment responses using pretreatment data. METHODS: This multicenter cohort study included collecting datasets from two data samples. Data 1 included 245 patients from 18 hospitals for ML development, and was divided into (i) training and (ii) development sets. Data 2 (iii: test set) included 51 patients from our hospital for validation. An extreme gradient boosted tree predicted the treatment response in the ML model. The area under the curve was used to evaluate the efficacy of the algorithm. RESULTS: Data 1 showed that patients complying with the Paris II treatment response had significantly lower serum alkaline phosphatase and total bilirubin levels than those who did not respond. Three factors, total bilirubin, total protein, and alanine aminotransferase levels were selected as essential variables for prediction. Data 2 showed that patients complying with the Paris II criteria had significantly high prothrombin time and low total bilirubin levels. The area under the curve of extreme gradient boosted tree was good for (ii) (0.811) and (iii) (0.856). CONCLUSIONS: We demonstrated the efficacy of ML in predicting the treatment response for patients with primary biliary cholangitis. Early identification of cases requiring additional treatment with our novel ML model may improve prognosis.

Severe steatosis and mild colitis are important for the early occurrence of hepatocellular carcinoma.

The number of patients with non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease (IBD) is increasing. This study elucidates the effect of both NASH and IBD on hepatocellular carcinoma (HCC) using a mouse model combining NASH and IBD. The melanocortin 4 receptor-deficient (Mc4r-KO) mice were divided into four groups with or without a high-fat diet (HFD) and with or without dextran sulfate sodium (DSS) to induce colitis, and the differences in liver damage and occurrence of HCC were analyzed. In the HFD + DSS group, the body weight, liver weight/body weight ratio, and serum levels of albumin and alanine aminotransferase were significantly lower than those in the HFD group. We further found that steatosis was significantly lower and lobular inflammation was significantly higher in the HFD + DSS group than those in the HFD group, and that individual steatosis and lobular inflammation state in the HFD + DSS mice varied. We detected HCC only in the HFD + DSS group, and mice with severe steatosis and mild colitis were found to be at high risk of HCC. Presently, the prediction of HCC is very difficult. In some cases, severe colitis reverses the fat accumulation due to appetite loss. Our findings clearly showed that severe steatohepatitis and mild colitis are simultaneously essential for the occurrence of HCC in patients with NASH and IBD.

Early injection of human adipose tissue-derived mesenchymal stem cell after inflammation ameliorates dextran sulfate sodium-induced colitis in mice through the induction of M2 macrophages and regulatory T cells.

Inflammatory bowel diseases (IBDs) are sometimes refractory to current therapy or associated with severe adverse events during immunosuppressive therapy; thus, new therapies are urgently needed. Recently, mesenchymal stem cells (MSCs) have attracted attention based on their multitude of functions including anti-inflammatory effects. However, proper timing of MSC therapy and the mechanisms underlying the therapeutic effects of MSCs on colitis are not fully elucidated. Human adipose tissue-derived mesenchymal stem cells (hAdMSCs; 1 × 106) were administrated via the tail vein on day 3 (early) or 11 (delayed) using a 7-day dextran sulfate sodium (DSS)-induced mouse model of colitis. The effects were evaluated based on colon length, disease activity index (DAI) and histological score. Cytokine-encoding mRNA levels T cells and macrophages were evaluated by real-time PCR and flow cytometry. Regarding the timing of administration, early (day 3) injection significantly ameliorated DSS-induced colitis in terms of both DAI and histological score, compared to those parameters with delayed (day 11) injection. With early cell injection, the tissue mRNA levels of anti-inflammatory cytokine genes (Il10, Tgfb) increased, whereas those of inflammatory cytokine genes (Il6, Tnfa and Il17a) decreased significantly. Regarding the associated mechanism, hAdMSCs suppressed T cell proliferation and activation in vitro, increased the number of regulatory T cells in vivo and changed the polarity of macrophages (into the anti-inflammatory M2 phenotype) in vitro. Timing of injection is critical for the effective therapeutic effects of hAdMSCs. Furthermore, part of the associated mechanism includes T cell activation and expansion and altered macrophage polarization.

Novel Magnified Single-Balloon Enteroscopy Enables Observation of Jejunal White Spots Associated with Lymphangiectasia.

A 59-year-old woman was diagnosed with primary intestinal lymphangiectasia (PIL), with characteristic findings on capsule enteroscopy and confirmation by histopathological examination of biopsy specimens. We viewed the abnormal jejunal mucosa using a newly developed magnifying single-balloon enteroscope (SIF-Y0007). Conventional observation showed leakage of chyle. However, using this new scope, we could see scattered white villi, representing dilated lymphatic vessels within the intestinal villi protruding from the dilated submucosal lymphoid vessels (D2-40 positive) within an edematous jejunal lesion. This report is the first to describe the white villi in a patient with PIL observed clearly using a newly developed magnifying enteroscope. Technological advancements and the accumulation of reported pathological data would further improve our understanding of the pathophysiological aspects of this disease entity, even in the jejunum.

Overlap in disease concept of functional esophageal disorders and minor esophageal motility disorders.

BACKGROUND AND AIM: Functional gastrointestinal disorders are the most common disorders in gastroenterology and are currently considered as gut-brain interaction disorders with multiple related factors including motility disturbance. However, high-resolution manometry (HRM) had revealed a new disease concept known as minor esophageal motility disorders. This study aimed to investigate the correlation between functional esophageal disorders (FEDs) and minor esophageal motility disorders. METHODS: Functional esophageal disorders were diagnosed using upper endoscopy, pH monitoring, and HRM, to exclude achalasia, esophago-gastric junction outflow obstruction, and other major esophageal motility disorders. FEDs with or without minor esophageal motility disorders were compared using the Chicago classification. RESULTS: Twelve healthy volunteers also subjected to HRM showed no minor esophageal motility disorders. Of the 40 patients with FEDs, 15 (37.5%) were diagnosed with minor esophageal motility disorders. Characteristics were not different between patients with and without minor esophageal motility disorders (sex: P = 0.609, age: P = 0.054, body mass index: P = 0.137, and presence of psychiatric disorders: P = 0.404). The type and location of symptoms were not related to the comorbidity rate of minor esophageal motility disorders (P = 0.744 and 0.094). No patients with FEDs developed major esophageal motility disorders. CONCLUSIONS: Minor esophageal motility disorders were frequently observed in FEDs, but the causal relationship between esophageal symptoms remains unclear. The disease concepts of FEDs and minor esophageal motility disorders are considered to overlap and are both independent of major esophageal motility disorders.

Immunohistochemical differentiation of eosinophilic esophageal myositis from eosinophilic esophagitis.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is a Th2-mediated allergic disease of the esophageal epithelium, associated with antigen. We previously reported a case series for eosinophilic esophageal myositis (EoEM)-a novel eosinophilic gastrointestinal disorder defined as eosinophilic infiltration localized in the esophageal muscle layer-and diagnosed it by peroral endoscopic muscle biopsy. Here, we investigated the immunopathology of EoEM to differentiate it from EoE. METHODS: Histological analysis was performed for three cases of EoEM and EoE, respectively. The results were compared with those of two control samples (non-eosinophilic gastrointestinal disorder full-layer esophagus). Using immunofluorescence, we analyzed the expression of the chemokine receptor CCR3 and its ligands eotaxin-1 and eotaxin-3 to investigate the eosinophilic reaction. Additionally, we determined the expression patterns of desmoglein-1 in the esophageal epithelium, which shows dysregulated expression in EoE. RESULTS: Eosinophil infiltration was observed in the muscle layer (maximum number, 30, 36, 73/high-power field) and the epithelium (50, 44, 40/high-power field) for EoEM and EoE, respectively. In EoE esophageal epithelium, the number of eotaxin-3-positive epithelial cells was significantly increased together with CCR3-positive infiltrating cells. However, in EoEM, a number of eotaxin-1-positive and eotaxin-3-positive myocytes and vascular endothelial cells were increased in the esophageal muscle layer. A significant loss of desmoglein-1 expression was only observed in EoE, not in EoEM. CONCLUSIONS: Eotaxin-1 and eotaxin-3 expression on the smooth muscle and vessels plays a role in the pathogenesis of EoEM, while EoE shows an epithelial eotaxin-3-dominant immunoreaction. Thus, the EoEM immunological pattern displays clear differences from that of EoE.

Urinary NGAL in gastrointestinal diseases can be used as an indicator of early infection in addition to acute kidney injury marker.

Background and Aim: Neutrophil gelatinase-associated lipocalin (NGAL) is characterized by increased expression before the rise in serum creatinine and has been used as a biomarker for the early prediction of acute kidney injury (AKI). However, there have been no comprehensive analyses of its significance in gastrointestinal diseases. This study aimed to analyze the usefulness of measuring urinary NGAL levels in patients with gastrointestinal diseases. Methods: This study included 171 patients with a wide range of gastrointestinal diseases. Urinary NGAL levels were measured in all patients within 24 h of admission and 72 h later. Results: Urinary NGAL levels were higher in patients with acute pancreatitis and acute cholangitis/cholecystitis than in those with other diseases. Although lower than in these diseases, urinary NGAL tends to be higher in inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, as well as in acute and chronic liver diseases, and is higher in liver cirrhosis as the Child-Pugh grade increases. Furthermore, we found that the group with higher urinary NGAL levels, which continued to increase over time, had worse hospital stays and prognosis. Conclusion: Urinary NGAL could be used as an indicator of infectious diseases rather than an indicator of AKI in inflammatory bowel diseases and cirrhosis, and could predict the prognosis of patients with gastrointestinal diseases.

An updated review on the treatment for diversion colitis and pouchitis, with a focus on the utility of autologous fecal microbiota transplantation and its relationship with the intestinal microbiota.

Diversion colitis (DC) is characterized by mucosal inflammation in the defunctioned segment of the colon following a colostomy or ileostomy. The major causes of DC are an increase in the number of aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon. However, its exact pathogenesis remains unknown. Various treatment strategies for DC have been explored, although none have been definitively established. Treatment approaches such as SCFAs, 5-aminosalicylic acid enemas, steroid enemas, and irrigation with fibers have been attempted, yielding various degrees of efficacies in mitigating mucosal inflammation. However, only individual case reports demonstrating the limited effect of the following therapies have been published: leukocytapheresis, dextrose (hypertonic glucose) spray, infliximab, an elemental diet, and coconut oil. The usefulness of probiotics for treating DC has recently been reported. Furthermore, fecal microbiota transplantation (FMT) has emerged as a promising treatment for DC. This review provides an update on the treatment strategies of DC, with a particular focus on FMT and its relationship with the intestinal microbiota. FMT may become the first choice of treatment for some patients in the future because of its low medical costs, ease of use, and minimal side effects. Furthermore, FMT can also be used for postoperative DC prophylaxis.

Diagnosis and resolution of olmesartan-associated sprue-like enteropathy confirmed by capsule endoscopy: a case report and literature review.

Herein, we describe a case of olmesartan-associated sprue-like enteropathy, in which improvement in villous atrophy was confirmed using small bowel capsule endoscopy. The patient was a 69-year-old woman who had persistent watery diarrhea (20 bowel movements/day) for 1 year and experienced a weight loss of 10 kg in the same period. Abdominal computed tomography revealed no abnormalities, and blood test results revealed no inflammatory reactions. Upper endoscopy and colonoscopy revealed villous atrophy in the duodenum and terminal ileum. As the patient was administered olmesartan for a long time and capsule endoscopy showed villous atrophy throughout the small bowel, she was diagnosed with olmesartan-associated sprue-like disease. Following the discontinuation of the medication, symptoms of diarrhea soon improved, and repeat capsule endoscopy indicated improvement in small intestinal villous atrophy. Olmesartan-associated sprue-like enteropathy should be considered a differential diagnosis in patients with severe chronic watery diarrhea. Our report is the first in which capsule endoscopy was performed multiple times over a long period for follow-up observation of improvements in the small intestine. In addition, our literature review regarding capsule endoscopy for olmesartan-associated enteritis might aid clinicians in the early diagnosis of the condition and the assessment of treatment efficacy.

Benign Duodenal Stenosis Caused by Huge Mesenteric Hematoma Conservatively Improved with Long-term Use of Double Elementary Diet Tube.

Mesenteric hematoma is an uncommon condition caused by focal bleeding in the mesenteric vessels. Hematomas are related to trauma, pancreatitis, arteriopathy, and the use of antithrombotic agents. Although hematomas cause intestinal stenosis by compressing the adjacent small bowel, duodenal stenosis due to hematoma is rare. Therefore, the treatment indications for cases of hematoma with stenosis have not been established. We herein report a case with a large mesenteric hematoma that caused duodenal stenosis by compressing the third portion of the duodenum. Stenosis was successfully ameliorated after long-term use of a double elementary diet tube.

Hydrogen-producing small intestinal bacterial overgrowth is associated with hepatic encephalopathy and liver function.

Overt hepatic encephalopathy (HE) is one of the complications of liver cirrhosis (LC), which negatively affects the prognosis and quality of life of patients. Small intestinal bacterial overgrowth (SIBO) is significantly associated with LC and its complications, including HE. We investigated the relationship between SIBO and LC, and the difference between hydrogen-producing and methane-producing SIBO (H-SIBO and M-SIBO, respectively). This is a prospective cohort study of 107 cases. Breath measurements of hydrogen and methane concentrations were performed for the diagnosis of SIBO. The study cohort included 81 males with a median age of 70 (40-86) years, and SIBO was detected in 31 cases (29.0%). There were no significant differences between the SIBO positive and SIBO negative groups. Reclassification into H-SIBO (16 cases) and others (91 cases) was performed, and the Child-Pugh score was only derived in the multivariate logistic analysis (P = 0.028, odds ratio 1.39, 95% confidence interval 1.04-1.85). Furthermore, H-SIBO was significantly associated with covert HE in chi-square test (50.0% vs. 24.2%, P = 0.034). In addition, we evaluated the therapeutic response on SIBO of rifaximin in eight covert HE patients. 20% patients with M-SIBO and 67% patients with H-SIBO showed an improvement of the breath test. In conclusion, H-SIBO, but not M-SIBO, is significantly associated with liver function, and rifaximin might be more effective for covert HE with H-SIBO. Therefore, the diagnosis of SIBO, including the classification as H-SIBO and M-SIBO, might help to determine the choice of treatment for HE.

Intestinal duplication diagnosed preoperatively with double-balloon enteroscopy: an extremely rare case report and literature review.

Gastrointestinal duplications are congenital malformations that are usually observed in pediatric patients. Diagnosis in adulthood is quite rare, and preoperative diagnosis of gastrointestinal duplication is difficult, particularly in the small intestine. We encountered an extremely rare adult case of duplication of the jejunum, which showed a stomach-like form diagnosed using double-balloon enteroscopy (DBE). The patient was an 18-year-old male who had been experiencing upper abdominal pain and vomiting repeatedly without any triggers for 3 years. Various examinations were performed, but no cause of symptoms was found. DBE revealed a narrow opening of the lumen at the upper jejunum, and the lumen was covered with mucosal folds similar to those of the stomach. Enteroclysis via DBE showed a tubular structure on the mesenteric side of the jejunum. We diagnosed a jejunal tubular duplication with ectopic gastric mucosa and underwent partial small bowel resection. The patient's abdominal symptoms resolved. From this, DBE can be a useful tool for diagnosing intestinal duplication in adults. We believe that this case and literature review will facilitate the accurate and prompt diagnosis of small intestinal duplication.

Utility of autologous fecal microbiota transplantation and elucidation of microbiota in diversion colitis.

Objectives: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

New cine magnetic resonance imaging parameters for the differential diagnosis of chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder whose diagnosis currently relies on subjective imaging assessments. Cine magnetic resonance imaging (MRI) may potentially improve the quantitative analysis of gastrointestinal motility; however, suitable CIPO detection parameters should be determined. Cine MRI was performed in seven patients with CIPO and 11 healthy controls. The logarithm of the Mahalanobis distance (x1) and distance variation per time (x2) were used as the original parameters to determine CIPO diagnostic thresholds. Furthermore, the correlation between cine MRI findings and CIPO severity was investigated. Threshold values of α = 1.10 and ß = 0.15 for x1 and x2, respectively, produced a CIPO diagnosis sensitivity of 1.00 (7/7) and specificity of 0.82 (9/11). The resulting error was 0.11 (2/18). The two parameters were correlated (Pearson's correlation coefficient: - 0.52). Any of the intestinal tracts of patients with severe CIPO requiring home parenteral nutrition belonged to the region defined by x1 ≥ 1.10 and x2 ≤ 0.15. Cine MRI is effective for the quantitative evaluation of small intestinal motility and CIPO diagnosis when using the abovementioned parameters and can be useful for treatment decision-making. However, these parameters have a wide distribution in healthy volunteers; this may complicate the detection of other disorders.

Long-term survival of 11 years with multidisciplinary therapy for hepatocellular carcinoma metastasis to the ovary and peritoneum: a case report.

We herein report a rare case of HCC metastases to the ovary and peritoneum in a 61-year-old female patient who has achieved 11-year survival with multidisciplinary therapy. The patient was diagnosed with HCC during balloon angioplasty performed for Budd-Chiari syndrome in 1994 and underwent partial hepatectomy twice. Five years after the second hepatectomy, allochronic recurrence of a single nodule detected in S8 was treated by radiofrequency ablation, followed by percutaneous ethanol injection therapy and stereotactic body radiotherapy. However, her α-fetoprotein level rose to 1862 ng/mL within one year and computed tomography revealed a large pelvic tumor suggesting HCC metastasis to the ovary. The subsequent laparotomy revealed one 11-cm left ovarian tumor, one small right ovarian nodule, and numerous peritoneal nodules. Bilateral salpingo-oophorectomy and peritoneal resection of as many nodules as possible were performed. Combination therapy with intravenous 5-fluorouracil plus cisplatin and ramucirumab monotherapy effectively suppressed tumor progression with maintenance of hepatic functional reserve, and she has achieved long-term survival of 11 years, illustrating that multidisciplinary therapy with favorable hepatic functional reserve maintenance can contribute to long-term survival in HCC with extrahepatic spread.

Evaluation of intestinal microbiota, short-chain fatty acids, and immunoglobulin a in diversion colitis.

It is reported that an increase in aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon are major causes of diversion colitis. However, the precise pathogenesis of this condition remains unclear. The aim of the present study was to examine the microbiota, intestinal SCFAs, and immunoglobulin A (IgA) in the diverted colon. Eight patients underwent operative procedures for colostomies. We assessed the diverted colon using endoscopy and obtained intestinal samples from the diverted colon and oral colon in these patients. We analyzed the microbiota and SCFAs of the intestinal samples. The bacterial communities were investigated using a 16S rRNA gene sequencing method. The microbiota demonstrated a change in the proportion of some species, especially Lactobacillus, which significantly decreased in the diverted colon at the genus level. We also showed that intestinal SCFA values were significantly decreased in the diverted colon. Furthermore, intestinal IgA levels were significantly increased in the diverted colon. This study was the first to show that intestinal SCFAs were significantly decreased and intestinal IgA was significantly increased in the diverted colon. Our data suggest that SCFAs affect the microbiota and may play an immunological role in diversion colitis.

Variation in small bowel transit time on capsule endoscopy.

BACKGROUND: Small bowel motility remains inadequately understood because of the complex and various functions as well as its anatomical position. The aimed of the study was to investigate the small bowel transit time (SBTT) of capsule endoscopy (CE) and to analyze the clinical factors affecting SBTT. METHODS: SBTT was analyzed in patients who underwent small bowel CE. Factors contributing to SBTT and CE retention were investigated. RESULTS: Among 397 patients enrolled in this study, 336 (84.6%) completed CE. The mean SBTT (± standard deviation) was 282.1±132.2 min. According to the univariate and multivariate analyses, aging and small bowel stenosis extended SBTT. In 38 patients who underwent multiple CE studies, considerable variation in SBTT were observed [mean of standard deviations (SDs) =97.97 min, SD of the SDs =81.99 min]. CE retention was observed in 61 patients (13.3%), and it was statistically associated to small bowel lesion. CONCLUSIONS: Aging and small bowel stenosis were associated with longer SBTT. Furthermore, SBTT analyzed by CE should be interpreted carefully considering the intra-individual differences in SBTT.

Cytapheresis for pyoderma gangrenosum associated with inflammatory bowel disease: A review of current status.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the information summarized, cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.

Rare Genotype of His/His in NUDT15 Codon 139 and Thiopurine-associated Adverse Events in a Case of Ulcerative Colitis.

Thiopurine drugs are commonly used to treat immunologic diseases. However, the narrow therapeutic safety margin demands evidence-based precision medicine approaches. NUDT15 variants are associated with thiopurine-induced adverse events, particularly in Asians. We herein report a rare genotype of His/His in NUDT15 codon 139 in a case of ulcerative colitis and review the relevant literature. The patient experienced severe thiopurine-associated adverse events, including leukopenia and alopecia. There is no literature on the His/His genotype in NUDT15 codon 139, and our case suggests cautious use or the contraindication of thiopurines for patients with this genotype.

Rare case of circumferential esophageal peeling.

This report highlights the easy peeling of the esophageal epithelium with Nikolsky phenomenon after swallowing the foreign body and the healing status of the esophagus only 3 days later in a patient of pemphigus vulgaris.