Tomoya Iida

Role of autophagy in the pathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. Recently, some studies provided strong evidence that the process of autophagy affects several aspects of mucosal immune responses. Autophagy is a cellular stress response that plays key roles in physiological processes, such as innate and adaptive immunity, adaptation to starvation, degradation of aberrant proteins or organelles, antimicrobial defense, and protein secretion. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including IBD. Autophagy plays multiple roles in IBD pathogenesis by altering processes that include intracellular bacterial killing, antimicrobial peptide secretion by Paneth cells, goblet cell function, proinflammatory cytokine production by macrophages, antigen presentation by dendritic cells, and the endoplasmic reticulum stress response in enterocytes. Recent studies have identified susceptibility genes involved in autophagy, such as NOD2, ATG16L1, and IRGM, and active research is ongoing all over the world. The aim of this review is a systematic appraisal of the current literature to provide a better understanding of the role of autophagy in the pathogenesis of IBD. Understanding these mechanisms will bring about new strategies for the treatment and prevention of IBD.

Rare type of pancreatitis as the first presentation of anti-neutrophil cytoplasmic antibody-related vasculitis

A pancreatic tumor was suspected on the abdominal ultrasound of a 72-year-old man. Abdominal computed tomography showed pancreatic enlargement as well as a diffuse, poorly enhanced area in the pancreas; endoscopic ultrasound-guided fine needle aspiration biopsy and endoscopic retrograde cholangiopancreatography failed to provide a definitive diagnosis. Based on the trend of improvement of the pancreatic enlargement, the treatment plan involved follow-up examinations. Later, he was hospitalized with an alveolar hemorrhage and rapidly progressive glomerulonephritis; he tested positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA) and was diagnosed with ANCA-related vasculitis, specifically microscopic polyangiitis. It appears that factors such as thrombus formation caused by the vasculitis in the early stages of ANCA-related vasculitis cause abnormal distribution of the pancreatic blood flow, resulting in non-uniform pancreatitis. Pancreatic lesions in ANCA-related vasculitis are very rare. Only a few cases have been reported previously. Therefore, we report our case and a review of the literature.

Heparin bridge therapy and post-polypectomy bleeding

AIM To identify risk factors for post-polypectomy bleeding (PPB), focusing on antithrombotic agents. METHODS This was a case-control study based on medical records at a single center. PPB was defined as bleeding that occurred 6 h to 10 d after colonoscopic polypectomy and required endoscopic hemostasis. As risk factors for PPB, patient-related factors including anticoagulants, antiplatelets and heparin bridge therapy as well as polyp- and procedure-related factors were evaluated. All colonoscopic hot polypectomies, endoscopic mucosal resections and endoscopic submucosal dissections performed between January 2011 and December 2014 were reviewed. RESULTS PPB occurred in 29 (3.7%) of 788 polypectomies performed during the study period. Antiplatelet or anticoagulant agents were prescribed for 210 (26.6%) patients and were ceased before polypectomy except for aspirin and cilostazol in 19 cases. Bridging therapy using intravenous unfractionated heparin was adopted for 73 patients. The univariate analysis revealed that anticoagulants, heparin bridge, and anticoagulants plus heparin bridge were significantly associated with PPB (P < 0.0001) whereas antiplatelets and antiplatelets plus heparin were not. None of the other factors including age, gender, location, size, shape, number of resected polyps, prophylactic clipping and resection method were correlated with PPB. The multivariate analysis demonstrated that anticoagulants and anticoagulants plus heparin bridge therapy were significant risk factors for PPB (P < 0.0001). Of the 29 PPB cases, 4 required transfusions and none required surgery. A thromboembolic event occurred in a patient who took anticoagulant. CONCLUSION Patients taking anticoagulants have an increased risk of PPB, even if the anticoagulants are interrupted before polypectomy. Heparin-bridge therapy might be responsible for the increased PPB in patients taking anticoagulants.

Systemic amyloidosis with gastrointestinal involvement: Diagnosis from endoscopic and histological views: Endoscopic views of systemic amyloidosis

Amyloid tends to deposit in the gastrointestinal tract, which, being easily accessible, is often the target organ for a pathological diagnostic examination. Although a mucosal biopsy is necessary for a definitive diagnosis and several studies have reported positive results for each possible biopsy site, there remain many unclear features in various aspects. This review focuses on the current literature to determine a better understanding of the diagnosis from endoscopic and histological views in patients with systemic amyloidosis with gastrointestinal involvement. A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed. Endoscopic findings vary based on the organ and the depositing amyloids. A fine granular appearance or polypoid protrusions are likely to occur in the duodenum. AL, Aβ2M, and ATTR amyloids are likely to deposit submucosally, while AA amyloid is easily deposited in the superficial layer of the mucous membrane. Furthermore, it is necessary to consider the collection of biopsy specimens from the duodenum, which has high positive biopsy rates. However, the difference in the positive biopsy rates depends on whether endoscopic findings are available or whether the appropriate number has not been fully elucidated. A duodenal biopsy is strongly recommended to confirm the deposition of amyloid in patients with systemic amyloidosis having gastrointestinal involvement. Because amyloidosis is a disease with a poor prognosis, early diagnosis and treatment are required; gastroenterologists and endoscopists play important roles.

Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases

Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.

Clinical outcomes of sigmoid colon volvulus: identification of the factors associated with successful endoscopic detorsion

Background/Aims Although multiple treatment options exist for the management of sigmoid colon volvulus, no study has examined the factors associated with successful endoscopic detorsion. This study aimed to examine the clinical course of patients with sigmoid colon volvulus and to identify factors related to successful endoscopic detorsion. Methods This study included 30 cases (21 patients) of sigmoid volvulus from among 545 cases of intestinal obstruction at a single center. We retrospectively examined the clinical course and the factors associated with the possibility of endoscopic detorsion of sigmoid colon volvulus. Results The rate of laxative use among the study participants was 76.2%; the rate of comorbid neuropsychiatric disorders was 61.9%; and 57.1% of patients had a history of open abdominal surgery. All patients were initially treated with endoscopic detorsion, and this procedure had a 61.9% success rate. The recurrence rate after detorsion was as high as 46.2%, but detorsion during revision endoscopy was possible in all cases. Statistical analysis revealed that the absence of abdominal tenderness (P=0.027), the use of laxatives (P=0.027), and a history of open abdominal surgery (P=0.032) were factors predictive of successful endoscopic detorsion. Conclusions The results of our study are consistent with previous reports with respect to the success rate of endoscopic detorsion, the subsequent recurrence rate, and the proportion of patients requiring surgical treatment. In addition, we identified the absence of abdominal tenderness, the use of laxatives, and history of open abdominal surgery as factors predicting successful endoscopic detorsion of sigmoid colon volvulus.

The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis

Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.

Clinicopathological comparison between acute gastrointestinal-graft-versus-host disease and infectious colitis in patients after hematopoietic stem cell transplantation

The aim of this study is to elucidate the differences of the clinicopathological characteristics between acute gastrointestinal (GI)-graft-versus-host disease (GVHD) and infectious colitis (IC) after hematopoietic stem cell transplantation (HSCT). Of the 282 patients who underwent HSCT at our institution between January 1991 and December 2015, we could investigate 182 patients in detail. Of the 182 patients, we selected those who underwent colonoscopy and were diagnosed with acute GI-GVHD or IC after HSCT. Patients’ backgrounds, colonoscopic findings, and pathological findings were retrospectively analyzed. There were 30 patients who had colonoscopy performed and diagnosed with acute GI-GVHD or IC after HSCT. Of the 30 patients, 20 had acute GI-GVHD and 10 had IC. All the cases of acute GI-GVHD were diagnosed by endoscopic biopsy and 4 of the IC patients had Clostridium difficile associated colitis. In the IC group, the period from the transplantation up to diagnosis was significantly shorter than acute GI-GVHD group (10.0 days vs. 43.2 days, p = 0.03). In the acute GI-GVHD group, tortoiseshell-like mucosal patterns were significantly more common than the IC group (70% vs. 0%, p < 0.001). Furthermore, there were some cases presenting normal mucosal appearance despite the diagnosis with acute GI-GVHD by pathological findings. Clinically, we should consider IC when abdominal symptoms appeared in the early period after HSCT. Endoscopically, tortoiseshell-like mucosal pattern was a characteristic feature of acute GI-GVHD. In addition, it is essential to perform mucosal biopsy for diagnose of acute GI-GVHD even in patients showing the normal mucosal appearance.

Mucosal Healing in Ulcerative Colitis

Nowadays, the relevance of the endoscopic activity of ulcerative colitis (UC) has been translated into the new concept of “mucosal healing (MH)” as the therapeutic goal to achieve, because considerable scientific evidence indicated the favorable prognostic value of a healed mucosa in clinical outcome of UC. In this regard, MH assessed by endoscopy seems almost like the “gold standard” for evaluating UC activity. On the other hand, we should recognize that there were no prospectively validated endoscopic scoring systems of UC activity in previous clinical trials. In the future, development of new endoscopic scoring systems, which are prospectively validated, will standardize the definition of MH. In addition, recent interest on mucosal healing skews toward not only endoscopic remission but also histological improvement (so-called histological MH). To be precise, histological MH can be an ideal goal for treatment of UC. However, it seems to be more difficult to decide the exact definition of histological MH than that of endoscopic MH. New endoscopic techniques, “confocal endomicroscopy in vivo”, might be promising modalities in the assessment of MH. We should await data concerning the real-time evaluation of MH in UC patients by confocal endomicroscopy. There are many issues to be addressed with regard to standardization of MH, therefore, “The road to justification of MH in the treatment of UC has just started ”.

Apoptotic Cell Clearance in Gut Tissue: Role of Intestinal Regeneration

Intestinal epithelial cells play a critical role in nutrient absorption as well as in protection against infection by pathogenic microorganisms. The cells drop out in a few days, and regeneration occurs subsequently; cells are eliminated by apoptosis. Clearance of dead cells frequently occurs in the intestinal tract, and apoptotic cells and phagocytes cooperate to facilitate cell clearance quickly and efficiently. The complex signaling network for cell clearance is well-understood. In recent years, the mechanism of programmed cell death accompanied by autophagy has been elucidated, and it has become clear that autophagy is involved in inflammation and intestinal tract diseases. In this review, we discuss intestinal regeneration and intestinal diseases through phagocytic clearance and autophagy of apoptotic cells.