Absence of Paneth Cell Metaplasia to Predict Clinical Relapse in Ulcerative Colitis with Endoscopically Quiescent Mucosa.

BACKGROUND: Paneth cells play multiple roles in maintaining intestinal homeostasis. However, the clinical role of Paneth cell metaplasia (PCM) in ulcerative colitis (UC) remains unclear. We aimed to investigate the relationship between PCM and relapse in patients with UC and compare the usefulness of PCM with other histological indexes, including mucin depletion (MD) and basal plasmacytosis (BP). METHODS: Patients with UC in clinical remission (CR) who underwent colonoscopy to confirm a Mayo endoscopic subscore (MES) ≦1 with biopsies from the distal colon were enrolled into this retrospective cohort study. Biopsy samples were evaluated for histological findings of PCM, MD, and BP. Clinical relapse was defined as partial Mayo score ≧3 or medication escalation. Multivariate analysis was performed to determine independent predictors of relapse among the three histological findings, MES, and patient background, and relapse prediction models were generated. RESULTS: Eighty-three patients were enrolled in this study (MES 0, n = 47; MES 1, n = 36). The number of PCM cases was significantly higher in patients with prolonged CR than that in those with relapse (p = 0.01). Multivariate analysis showed that the absence of PCM and MD were related to relapse in all the patients. In patients with MES 1, the absence of PCM was the only risk factor significantly and independently associated with relapse (hazard ratio, 4.51 [1.15-17.7]; p = 0.03). CONCLUSION: The absence of PCM was a histological risk factor for relapse in patients with MES 1, implying a protective role for PCM in remission and a new index for mucosal healing.

Background factors of idiopathic peptic ulcers and optimal treatment methods: a multicenter retrospective Japanese study.

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.

Fulminant necrotizing fasciitis by Edwardsiella tarda in a patient with alcoholic liver cirrhosis: A case report.

We herein present a unique and extremely rare fulminant case of Edwardsiella tarda infection-related necrotizing fasciitis. The patient had alcoholic cirrhosis and preferred to consume raw fish. He experienced painful swelling of the right forearm one day after he got a minor injury when falling from the ladder, and visited our hospital. His accompanied symptoms were diarrhea and general fatigue. His consciousness got deteriorated after the admission. The lesion of the right forearm had spread and the color had deteriorated with epidermolysis in a few hours. Necrotizing soft-tissue infection was suspected, and emergency debridement of the swollen forearm was performed 4 hours after the admission. However, unfortunately, he died of sepsis approximately 5 hours later. Histological examination of the biopsy specimen revealed features consistent with those of necrotizing fasciitis. The bacterial cultures of blood and the wound identified E. tarda. Since this microorganism is usually isolated from aquatic environments and can cause intestinal infection, sometimes followed by bacteremia especially in immunocompromised hosts, two possible infection routes were suspected. One route was from the skin injury, leading to bacteremia. Another possible route was per oral: orally taken E. tarda invaded deeper tissues from the intestine and reach the bloodstream, leading to extraintestinal infections, although direct evidence remains elusive. Raw fish eaten 1 week prior is considered to be the most possible contaminated food. Overall mortality rate of E. tarda bacteremia is very high and the clinician should pay attention on characteristic clinical findings of E. tarda infection on cirrhotic patients.

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

Moderate Splenic Injury Caused by Colonoscopy.

Little is known about iatrogenic splenic injury (SI) as an adverse event after colonoscopy. SI is sometimes fatal because of hemorrhaging. We herein report a man who developed SI after colonoscopy. He recovered conservatively. His history of left hydronephrosis and insertion with a maximally stiffened scope were suspected as possible risk factors. Endoscopists should consider the possibility of SI when they encounter patients suffering from left-sided abdominal pain after colonoscopy. Careful interview concerning the medical history and gentle maneuvering around the splenic flexure can help avoid SI.

Initial experience of coaxial percutaneous liver biopsy with tract embolization using N-Butyl cyanoacrylate.

OBJECTIVE: Bleeding occurs after liver biopsy in up to 10.9% cases, and patients with impaired hemostasis or ascites are considered to have absolute or relative contraindications. N-butyl cyanoacrylate enables immediate hemostasis, even in lethal situations. Therefore, percutaneous liver biopsy combined with tract embolization using N-butyl cyanoacrylate is expected to enable safe biopsy, even in patients for whom conventional biopsy is contraindicated. Here we describe our initial experience with coaxial percutaneous biopsy with tract embolization using N-butyl cyanoacrylate. MATERIALS AND METHODS: Eighty-six patients who underwent tract embolization using N-butyl cyanoacrylate between October 2014 and July 2020, including 21 patients who had absolute or relative contraindications for liver biopsy, were retrospectively analyzed. Tract embolization using N-butyl cyanoacrylate comprised two steps: (1) liver biopsy with a biopsy needle inserted via a coaxial introducer needle and (2) embolization of the puncture route by injecting N-butyl cyanoacrylate via the coaxial needle. RESULTS: No complications occurred in any patient. The mean number of biopsies per patient was 3.30 (range, 1-7). Histologically adequate samples were acquired in all cases, and pathological diagnoses were obtained. The mean time required for tract embolization was 52.8 s (range, 6-132 s). The mean peak skin dose was 9.97 mGy (range, 2-68 mGy), which is far below the 3-Gy threshold dose for temporary erythema. CONCLUSIONS: This proposed technique may be a promising and straightforward alternative to improve the management of patients with severe liver disease by allowing safer biopsy, including patients for whom conventional liver biopsy is contraindicated.

Modulation by luminal factors on the functions and migration of intestinal innate immunity.

Luminal antigens, nutrients, metabolites from commensal bacteria, bile acids, or neuropeptides influence the function and trafficking of immune cells in the intestine. Among the immune cells in the gut, innate lymphoid cells, including macrophages, neutrophils, dendritic cells, mast cells, and innate lymphoid cells, play an important role for the maintenance of intestinal homeostasis through a rapid immune response to luminal pathogens. These innate cells are influenced by several luminal factors, possibly leading to dysregulated gut immunity and intestinal disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and intestinal allergy. Luminal factors are sensed by distinct neuro-immune cell units, which also have a strong impact on immunoregulation of the gut. Immune cell trafficking from the blood stream through the lymphatic organ to lymphatics, an essential function for immune responses, is also modulated by luminal factors. This mini-review examines knowledge of luminal and neural factors that regulate and modulate response and migration of leukocytes including innate immune cells, some of which are clinically associated with pathological intestinal inflammation.

New and Emerging Treatments for Inflammatory Bowel Disease.

BACKGROUND: The specific etiopathogenesis of inflammatory bowel disease (IBD) is still unknown. Although the conventional anti-inflammatory or immunomodulatory drugs relatively nonspecific to pathogenesis have been quite useful in many cases, elucidating the pathogenesis has gradually facilitated developments of disease-specific therapies for refractory cases in the last 2 decades. SUMMARY: With a greater understanding of the multiple overactive signaling pathways of the gut mucosal immune response and enhanced leukocyte trafficking, several biological agents or small molecule drugs following the first novel biologic, anti-tumor necrosis factor α (anti-TNFα), have been developed against several modes of action including adhesion molecules, sphingosine-1-phospate receptors, cytokines (IL-12/23, TL1A, and IL-36), Janus kinase (JAK), and phosphodiesterase. Although preceding biological agents have dramatically changed the IBD treatment strategy, many patients still require alternative therapies due to failure or side effects. Newer treatments are now expected to be provided for better efficacy with an improved adverse event profile. In addition, translational studies have highlighted the new therapeutic concepts' potential, including modulation of host-microbiome interactions, stem therapy for perianal fistula, regulation of fibrosis, regulation of the gut-brain axis, and control of previously less targeted immune cells (B cells and innate lymphoid cells). This paper comprehensively reviewed not only the latest already or shortly available therapies but also emerging promising treatments that will be hopefully established in the future for IBD. KEY MESSAGES: Many kinds of new treatments are available, and promising treatments with new perspectives are expected to emerge for refractory IBD in the future.

Hepatic portal venous gas and bacteremia after colonic endoscopic submucosal dissection: A case report.

Hepatic portal venous gas (HPVG) is considered to be a sign of poor prognosis in abdominal diseases and a potentially fatal condition. However, HPVG after colonic endoscopic submucosal dissection (ESD), is an even rarer complication that there is just one report of it at the moment. In this report, we present a case of HPVG and bacteremia that happened a day after colonic ESD in the descending colon. A 79-year-old female was referred to perform endoscopic treatment for a 40-mm elevated tumor in the descending colon and surgery for clinical T1b cancer in the rectosigmoid colon. With a preoperative diagnosis of intramucosal carcinoma in adenoma, we performed ESD using carbon dioxide insufflation. The tumor was resected en bloc without any adverse events including perforation. On the following day, shivering and a fever of 38°C suddenly developed with no abdominal symptoms. Computed tomography revealed the presence of HPVG and gas in the middle colic vein without pneumoperitoneum. The patient was managed conservatively with fasting and intravenous antibiotic treatment. We confirmed the disappearance of the findings with computed tomography on the next day of the first computed tomography and with a colonoscope, we observed the base of ESD ulcer 5 days post-ESD. HPVG might be treated conservatively, but it might cause more severe conditions such as air embolism, so this rare complication still needs to be thoroughly monitored.

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan.

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

Immunoglobulin G4-related disease accompanying a small intestinal ulcer: A case.

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a systemic condition associated with fibroinflammatory lesions and is characterized by elevated serum IgG4 levels and IgG4-positive cell infiltration into the affected tissues. It has been reported that IgG4-RD affects a variety of organs but uncommonly affects the gastrointestinal tract. In particular, there are few cases of lesions in the small intestine, except for sclerosing mesenteritis, which were mostly diagnosed from surgical specimens. Herein, we describe the case of a 70-year-old man who initially presented with abdominal pain, headache, later cognitive decline, and gait disturbance caused by IgG4-RD. Colonoscopy revealed irregular ulcers in the terminal ileum, and computed tomography of the head showed hypertrophic pachymeningitis. Numerous IgG4-positive cells were detected in the ileal and dural biopsies. We diagnosed the patient with IgG4-RD and started steroid pulse therapy. After initiation of treatment, the symptoms quickly improved. The patient was discharged from the hospital after starting oral prednisolone treatment (30 mg). The dosage was gradually reduced to 10 mg. A follow-up colonoscopy revealed scarring of the ileal ulcers. This case may provide valuable information regarding the endoscopic findings of small intestinal lesions in IgG4-RD.

Acute pancreatitis coincided with multiple arteriolar aneurysms in a patient with polyarteritis nodosa.

A 78-year-old man presented to our hospital with a history of 10 kg weight loss within 6 months previously and general fatigue and fever for 2 and 1 months, respectively. On hospitalisation, the patient was diagnosed with polyarteritis nodosa after multiple microaneurysms were observed in the liver, kidney, pancreas, and mesenteries. He achieved remission with the administration of 1000 mg methylprednisolone for 3 days, followed by prednisolone (55 mg/day). Steroids were successfully tapered with no re-elevation in inflammation. Two months after the administration of steroids, the patient complained of acute abdominal pain and developed severe acute pancreatitis. During treatment for pancreatitis, the patient died due to septic shock and disseminated intravascular coagulation. An autopsy revealed necrotising vasculitis in the intrapancreatic arteries and ischaemia of the downstream arterioles resulting in acute pancreatitis.

Active and passive smoking and risk of ulcerative colitis: A case-control study in Japan.

BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

Dietary intake of vegetables, fruit, and antioxidants and risk of ulcerative colitis: A case-control study in Japan.

OBJECTIVES: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk. METHODS: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively). CONCLUSIONS: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk.

Evidence-based clinical practice guidelines for irritable bowel syndrome 2020.

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.

T1ρ magnetic resonance imaging value as a potential marker to assess the severity of liver fibrosis: A pilot study.

PURPOSE: Assessment of liver fibrosis is essential for the management of liver disease. Although liver biopsy is the gold-standard modality for the diagnosis of liver fibrosis, it has some limitations. Thus, other methods are required to overcome the disadvantages of a liver biopsy. T1ρ magnetic resonance imaging (MRI) values are potential biomarkers for liver cirrhosis. This study aimed to assess the relationship between T1ρ MRI values and liver fibrosis severity by measuring the correlation between T1ρ values and shear wave elastography (SWE) values, which are routinely used for the diagnosis of liver fibrosis. METHODS: T1ρ imaging and SWE values were obtained from four healthy volunteers and 16 patients with chronic liver disease. The regions of interest on MR images were drawn and matched with those of the right liver lobe on SWE images. RESULTS: The mean T1ρ values of the right liver lobe correlated positively with the mean SWE values (Pearson's correlation coefficient: 0.783; p < 0.0001; 95 % confidence interval: 0.623-0.880). CONCLUSION: The mean T1ρ values of the right liver lobe may be correlated with the severity of liver fibrosis.

Very early-onset inflammatory bowel disease in Japan: A nationwide survey.

BACKGROUND AND AIM: Very early-onset inflammatory bowel disease is defined as inflammatory bowel disease diagnosed before 6 years of age. Very early-onset inflammatory bowel disease has various differential diagnoses, including primary immunodeficiency disorders, and is known to be resistant to conventional treatment. Therefore, global attention is required to manage this challenging condition. We conducted a retrospective epidemiological survey of the number of patients, final diagnosis, and examinations performed to diagnose very early-onset inflammatory bowel disease in Japan. METHODS: A primary questionnaire about the number of very early-onset bowel disease cases and its diagnosis was administered to 630 pediatric facilities nationwide in Japan. A secondary survey about the examinations performed to achieve diagnosis was sent to the facilities that responded to the first survey. RESULTS: The answering rate was 92.2% (581/630 facilities); 81 facilities had 225 very early-onset bowel disease patients undergoing their care during the past 68 months. Twenty-six patients (11.6%) were diagnosed with immunodeficiency-associated inflammatory bowel disease. The answering rate of the secondary survey was 70.4% (57/81 facilities). Colonoscopy, esophagogastroduodenoscopy, and small bowel imaging were performed for 99.4%, 67.5%, and 28.8% of patients, respectively. Genetic analysis was performed for 26.9% (43/160 patients) of patients, and 51.2% (22/43) of patients were diagnosed with immunodeficiency-associated inflammatory bowel disease. CONCLUSIONS: Approximately 40 patients are diagnosed yearly in Japan. Imaging studies, especially for small bowel lesions, can be challenging for this unique group of patients. However, a comprehensive approach including immunological and genetic analyses appears useful for diagnosing immunodeficiency-associated inflammatory bowel disease.

Relation of geriatric nutritional risk index with clinical risks in elderly-onset ulcerative colitis.

BACKGROUND AND AIM: Worldwide increasing aging societies have many elderlies with intractable diseases including ulcerative colitis (UC). Reportedly, each patients' frailty as well as chronological age is a clinical risk factor of elderly-onset UC (EOUC). Because malnutrition is one of the major manifestations of frailty, we aimed to investigate the effect of malnutrition on the prognosis of EOUC with geriatric nutritional risk index (GNRI), a prognostic tool for several diseases in the elderly to estimate malnutrition, and to evaluate clinical risks among EOUC patients in Japan, the world-leading aging society. METHODS: The EOUC patients (≥ 65 years at diagnosis, n = 2778) in the previous nationwide survey were classified by age and GNRI, and odds ratios (ORs) of hospitalization and UC-related surgery were determined to evaluate the effects of malnutrition on the EOUC patients as well as aging. RESULTS: The risks of hospitalization and surgery were elevated as age advanced. The value of GNRI, negatively correlated with disease activity (r = -0.53), could distinguish severe activity (cutoff ≤ 86.82, sensitivity = 0.79, and specificity = 0.77) and discriminate the EOUC patients suffering from surgery and hospitalization. In a multivariate analysis, GNRI ≤ 86.82 was a higher risk of hospitalization (OR: 4.0, 95% CI, 2.5-6.5) and surgery (OR: 2.7, 95% CI, 0.98-7.4) than cutoff age ≥ 75 years old (OR of hospitalization and surgery were 1.4 [95% CI, 0.99-2.0] and 2.3 [95% CI, 0.8-6.3], respectively). CONCLUSION: Malnutrition estimated by GNRI was significantly related with poor clinical courses of the EOUC patients, suggesting that evaluation of nutritional status at the onset might be useful for predicting risks of clinical courses.