Clinical and pharmacogenetic features of patients with upper gastrointestinal lesions at a multidisciplinary hospital: the role of nonsteroidal anti-inflammatory drugs.

OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. METHODS: The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients' intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985, CYP2C9*3 rs1057910, CYP2C8*3 rs11572080, CYP2C8*3 rs10509681, PTGS-1 rs10306135, PTGS-1 rs12353214, and PTGS-2 rs20417 using real-time PCR. RESULTS: In NSAIDs+ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30-22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15-8.46), and alcohol intake (OR=4.09, 95 % CI=1.05-15.87) increased odds of gastrointestinal damage. In NSAIDs+ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04-0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02-0.75) reduced the chance of upper gastrointestinal lesions. CONCLUSIONS: Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.

Molecular mechanism of portal hypertensive gastropathy: An update.

Portal hypertensive gastropathy (PHG) is a serious complication and the most common gastric mucosal injury amongst patients afflicted with cirrhotic or non-cirrhotic portal hypertension (PHT). The pathogenesis of PHG is not completely understood and is likely to be complex. The roles of portal hypertension pressure, parenchymal liver disease, Child-Pugh classification, variceal pressure and Helicobacter pylori infection in the development of PHG are controversial. Splanchnic blood flow, the distribution of mucosal blood, vascular ectasia, local disturbances, inflammatory cell infiltration and increased cytokine production have also been examined to elucidate the underlying mechanisms of PHG. Moreover, various other elements, including prostaglandin E2 (PGE2), endothelin-1 (ET-1), tumour necrosis factor-α (TNF-α), Fas ligand (FasL)/Fas, nitric oxide (NO), oxygen free radicals and vascular endothelial growth factor (VEGF), have also been revealed to participate in the pathogenesis of PHG. This review provides an overview of the risk factors, classification and potential molecular processes involved in PHG, followed by a concise summary of our and other studies. This review aims to integrate information to deepen our understanding of the interplay between different signalling pathways involved the pathogenesis of PHG and provides insights into how these signalling pathways are regulated to control the development of PHG.

Mitochondrial Dysfunction by FADDosome Promotes Gastric Mucosal Injury in Portal Hypertensive Gastropathy.

Mucosal epithelial death is an essential pathological characteristic of portal hypertensive gastropathy (PHG). FADDosome can regulate mucosal homeostasis by controlling mitochondrial status and cell death. However, it remains ill-defined whether and how the FADDosome is involved in the epithelial death of PHG. The FADDosome formation, mitochondrial dysfunction, glycolysis process and NLRP3 inflammasome activation in PHG from both human sections and mouse models were investigated. NLRP3 wild-type (NLRP3-WT) and NLRP3 knockout (NLRP3-KO) littermate models, critical element inhibitors and cell experiments were utilized. The mechanism underlying FADDosome-regulated mitochondrial dysfunction and epithelial death in PHG was explored. Here, we found that FADD recruited caspase-8 and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to form the FADDosome to promote Drp1-dependent mitochondrial fission and dysfunction in PHG. Also, FADDosome modulated NOX2 signaling to strengthen Drp1-dependent mitochondrial fission and alter glycolysis as well as enhance mitochondrial reactive oxygen species (mtROS) production. Moreover, due to the dysfunction of electron transport chain (ETC) and alteration of antioxidant enzymes activity, this altered glycolysis also contributed to mtROS production. Subsequently, the enhanced mtROS production induced NLRP3 inflammasome activation to result in the epithelial pyroptosis and mucosal injury in PHG. Thus, the FADDosome-regulated pathways may provide a potential therapeutic target for PHG.

Bioactive arabinogalactan from Ferulopsis hystrix roots: characterization of gastroprotective and antioxidant potentials against drug-induced gastropathy.

Bristled ferula (Ferulopsis hystrix (Bunge) Pimenov) is a perennial plant belonging to the Apiaceae family, and its aqueous extract is utilised in Eastern medicine to treat digestive system diseases. In this study, water-soluble polysaccharides from F. hystrix were isolated for the first time, and the basic polymer FH-3 was separated and characterised. FH-3 was found to contain arabinose and galactose in a 1:5 ratio, with a molecular weight of 52.3 kDa. Methylation analysis confirmed the structure of FH-3 to be arabino-3,6-galactan. Administration of FH-3 at 10 and 30 mg/kg doses in rats with drug-induced gastropathy effectively limited the development of large and strip-like erosions in the gastric mucosa. FH-3 prevented the development of oxidative stress, normalising malondialdehyde (MDA) and catalase (CAT) and reducing glutathione (GSH) serum levels. Arabinogalactan FH-3 is a new gastroprotective and antioxidant plant component in F. hystrix roots, offering promising prospects for treating stomach diseases.

Induction of mitochondrial toxicity by non-steroidal anti-inflammatory drugs (NSAIDs): The ultimate trade-off governing the therapeutic merits and demerits of these wonder drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are most extensively used over-the-counter FDA-approved analgesic medicines for treating inflammation, musculoskeletal pain, arthritis, pyrexia and menstrual cramps. Moreover, aspirin is widely used against cardiovascular complications. Owing to their non-addictive nature, NSAIDs are also commissioned as safer opioid-sparing alternatives in acute trauma and post-surgical treatments. In fact, therapeutic spectrum of NSAIDs is expanding. These "wonder-drugs" are now repurposed against lung diseases, diabetes, neurodegenerative disorders, fungal infections and most notably cancer, due to their efficacy against chemoresistance, radio-resistance and cancer stem cells. However, prolonged NSAID treatment accompany several adverse effects. Mechanistically, apart from cyclooxygenase inhibition, NSAIDs directly target mitochondria to induce cell death. Interestingly, there are also incidences of dose-dependent effects where NSAIDs are found to improve mitochondrial health thereby suggesting plausible mitohormesis. While mitochondria-targeted effects of NSAIDs are discretely studied, a comprehensive account emphasizing the multiple dimensions in which NSAIDs affect mitochondrial structure-function integrity, leading to cell death, is lacking. This review discusses the current understanding of NSAID-mitochondria interactions in the pathophysiological background. This is essential for assessing the risk-benefit trade-offs of NSAIDs for judiciously strategizing NSAID-based approaches to manage pain and inflammation as well as formulating effective anti-cancer strategies. We also discuss recent developments constituting selective mitochondria-targeted NSAIDs including theranostics, mitocans, chimeric small molecules, prodrugs and nanomedicines that rationally optimize safer application of NSAIDs. Thus, we present a comprehensive understanding of therapeutic merits and demerits of NSAIDs with mitochondria at its cross roads. This would help in NSAID-based disease management research and drug development.

Ischaemic Gastropathy: An Under-Recognised cause of Abdominal Pain.

Ischaemic gastropathy is an under-recognised phenomenon with a particularly poor prognosis, where early diagnosis is crucial for successful medical intervention and the prevention of life-threatening complications. We present a case involving a 42-year-old female with no history of vascular insufficiency who developed ischaemic gastropathy following a prolonged stay in the intensive care unit, from septic shock secondary to Escherichia coli bacteraemia due to complicated acute appendicitis. This case underscores the importance of the physician's awareness regarding this rare entity and the necessity to consider it in the differential diagnosis of abdominal pain and haematemesis. Prompt diagnosis and treatment may significantly improve survival outcomes in this less-documented pathology, especially in the younger adult population. LEARNING POINTS: Awareness needs to be increased regarding the consideration of ischaemic gastropathy as a differential diagnosis.A patient without a history of vascular compromise could have a diagnosis of ischaemic gastropathy.This is possibly the first noted case of ischaemic gastropathy occurring after an appendectomy, which is complicated by gram-negative bacteraemia and haemodynamic instability.

The Great Mimicker of Gastric Cancer: A Case Report of Ménétrier's Disease.

This is the case of a 52-year-old Indian lady who presented with hematemesis, severe anemia, and an abdominal lump in cardiac failure. On radiographic evaluation, the lesion appeared to be gross circumferential asymmetric proximal gastric wall thickening, with suspicion of gastric lymphoma or tubercular hypertrophic gastritis. After stabilization with multiple transfusions, she underwent proximal D2 gastrectomy with esophago-gastric anastomosis and a total splenectomy. Grossly, the gastric rugae appeared to be hypertrophied and firm. No growth was identified grossly; however, necrotic areas were identified at the distal end. Microscopic examination of multiple sections studied showed significant foveolar hyperplasia, tortuous glands, and a few cystically dilated foveolar glands, which were limited up to the muscle layer. Mild serosal congestion was seen. No atypia or invasion was seen. An impression to consider is the possibility of Ménétrier's disease (MD). MD is an acquired protein-losing enteropathy with giant gastric rugal folds, decreased acid secretion, and increased gastric mucous production. Radiographically, endoscopically, and grossly, the condition can be confused with malignant lymphoma or carcinoma. It is difficult to diagnose, and histopathological confirmation of the resected specimen is needed for a definitive diagnosis. Our intention in presenting this case is to emphasize that MD can present as massive hematemesis and should be considered in a differential diagnosis. Surgical treatment by total or partial gastrectomy is recommended for cases with persistent, debilitating symptoms or a risk of cancer.

Localized pseudomembranous gastritis associated with hepatic cirrhosis and portal hypertensive gastropathy: a case report.

Pseudomembranes in the large and small intestines are common in hospitalized patients that are immunosuppressed or on certain oral antibiotics. Pseudomembranous enterocolitis, histologically characterized by volcanic-like eruption of inflammatory cellular exudate from the mucosal surface, is mainly attributed to Clostridium difficile toxins and often presents with symptomatic diarrhea. Rarely, there are case reports of similar pseudomembranous lesions limited to the stomach in the absence of intestinal involvement. In this paper, we present a case of localized pseudomembranous gastritis in a 76-year-old patient with personal history limited to prior gastrointestinal bleed, liver cirrhosis, alcohol dependence, diabetes mellitus, and hypertension who was referred to the emergency department from his primary care physician's office due to low hemoglobin.

Case report: Fundic gland polyps caused by long-term omeprazole use in a Maltese dog.

Long-term use of proton-pump inhibitors can induce fundic gland polyps in the human stomach. However, this phenomenon has not been described in the veterinary literature. A 5-year-old intact female Maltese dog was referred to our hospital with chronic intermittent vomiting. The dog had been administered omeprazole (0.7-1.0 mg/kg PO q24 h) for the management of hydrocephalus for over 4 years; the omeprazole dose was increased to 10 mg/kg PO q24 h 8 months prior to presentation at referring hospital. Abdominal ultrasonography revealed marked thickening of the gastric wall with multi-lobulated, thickened folds. Subsequent endoscopy revealed marked polypoid lesions, and histological examination of the biopsy samples was consistent with the fundic gland polyps associated with proton-pump inhibitor use in humans. The lesions resolved after cessation of omeprazole, as assessed by ultrasonography. This report describes a case of fundic gland polyps following the long-term administration of omeprazole in a dog.

Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

BACKGROUND & AIMS: Metoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared with placebo in reducing symptoms of diabetic gastroparesis in women. METHODS: This US multicenter, randomized, double-blind, parallel group study enrolled women aged 18-75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy end point was change in mean daily Gastroparesis Symptom Assessment total score from baseline to Week 4. The Gastroparesis Symptom Assessment daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a 5-point ordinal scale. RESULTS: Two hundred and five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared with the placebo group from baseline to Week 4 (P = .881). However, subjects with moderate-to-severe symptoms at baseline had a significant treatment effect from Weeks 1 to 3 (P < .05) and experienced a significant reduction in nausea and upper abdominal pain for all 4 weeks versus placebo (P < .05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. CONCLUSIONS: Although the primary end point was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate-to-severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. (ClinicalTrials.gov identifier: NCT02025725.).

Upper gastrointestinal bleeding from gastric antral vascular ectasia following cocaine use: case presentation and review of literature.

Gastric antral vascular ectasia (GAVE), also known as "Watermelon stomach", is a rare cause of upper gastrointestinal bleeding (UGIB). It is characterized by an endoscopic appearance of flat red blood vessels traveling from the pylorus to the antrum. Patients often present with chronic blood loss resulting in iron deficiency anemia, or, less commonly, with acute gastropathy resulting in massive hemorrhage. The etiology of GAVE is unknown but the disorder has been more commonly observed in patients with cirrhosis, especially with portal hypertension, as well as in those with systemic sclerosis and other connective tissue disease. There is no definitive cure for GAVE, but the condition can be managed with a variety of endoscopic techniques, including heater probes, bipolar probes, plasma coagulators, laser therapy, and radiofrequency ablation. In rare cases, patients also require blood transfusions. Here we present an interesting case of upper GI bleeding resulting in symptomatic anemia in a 69-year-old female patient with GAVE following cocaine use. The patient was initially admitted for fatigue and shortness of breath and required multiple units of pRBCs. She was also found to have a urine drug screen positive for cocaine. Following stabilization, she underwent endoscopy which revealed the characteristic "watermelon stomach" appearance consistent with GAVE syndrome. The patient was discharged on an oral proton-pump inhibitor with instructions to follow-up outpatient with Gastroenterology. This case is presented as an example of a risk factor for acute exacerbation of a rare cause of UGIB. This patient presentation also represents an example of the importance of strict follow-up for those with risk factors for exacerbation of chronic GI conditions.

Hepatic encephalopathy due to cardiac cirrhosis.

Right-sided heart failure, including tricuspid regurgitation (TR), can cause cardiac cirrhosis. The pathophysiology is reduced arterial perfusion and passive congestion secondary to increased systemic venous pressure. However, hepatic encephalopathy due to cardiac cirrhosis is rare. This is the first case of hepatic encephalopathy with cardiac cirrhosis caused by persistent TR.

Endoscopic Follow-Up Between 3 and 7 Years After Sleeve Gastrectomy Reveals Antral Reactive Gastropathy but no Barrett's Esophagus.

BACKGROUND: The main concerns following sleeve gastrectomy (SG) include the risk of gastroesophageal reflux disease (GERD) and its complications, such as Barrett's esophagus (BE). However, there is conflicting data on esophageal conditions, and studies on alterations of gastric mucosa after SG are lacking, despite reported cases of gastric cancer. Our aim was to assess esophageal and gastric lesions after SG. METHODS: From November 2017, an upper gastrointestinal endoscopy (UGE) was proposed at least 3 years after SG to all patients operated on in our institution. Endoscopic results and gastric histological findings were analyzed. BE was defined as endoscopically suspected esophageal metaplasia with histological intestinal metaplasia. RESULTS: Between September 2008 and August 2018, 375 patients underwent SG at our institution, of which 162 (43%) underwent at least one UGE 3 years or more after SG (91% women, mean preoperative age: 43.3±10.3 years). Despite a significant increase in the prevalence of symptomatic GERD, hiatal hernia, and esophagitis after SG (p<0.001 vs. preoperatively), no cases of BE were detected. Gastric dysplasia was not found and the prevalence of gastric atrophy tended to decrease after SG. However, 27% of patients with gastric biopsies developed antral reactive gastropathy. CONCLUSIONS: At a mean follow-up of 54 months after SG, no BE or gastric dysplasia was identified. However, reactive gastric lesions appeared, and their long-term consequences need to be further clarified. Thus, the timing of endoscopic follow-up, starting as early as 3 years after SG should be reevaluated to improve patient adherence with long-term endoscopies.

The Impact of Partial Splenic Embolization on Portal Hypertensive Gastropathy in Cirrhotic Patients with Portal Hypertension.

This study investigated the impact of partial splenic embolization (PSE) on portal hypertensive gastropathy (PHG). We retrospectively analyzed endoscopic findings and the portal venous system of 31 cirrhotic patients with PHG. The improved group was defined as the amelioration of PHG findings using the McCormack classification. Child-Pugh scores of the improved group (18 of 31 patients) were significantly lower compared with those of the non-improved group (p = 0.018). The changes in the diameters of the portal trunk and those of the spleno-portal junction and spleen hilum in the splenic vein of the improved group were significantly larger than those of the non-improved group (p = 0.007, p = 0.025, and p = 0.003, respectively). The changes in the diameters of the portal vein and splenic hilum of the splenic vein showed significant correlations with Child-Pugh score (r = 0.386, p = 0.039; r = 0.510, p = 0.004). In a multivariate analysis of baseline factors related to the improved group, Child-Pugh grade A was significantly associated with the improvement of PHG (odds ratio 6.875, p = 0.033). PSE could be useful for PHG, especially in patients with Child-Pugh grade A, at least in the short term.

Trends of Chronic Liver Disease in a Tertiary Care Centre in the Eastern Part of India: A Retrospective Study.

AIM OF THE STUDY: To assess the relationship between the severity of liver cirrhosis and its outcomes based on laboratory parameters, Child-Turcotte-Pugh (CTP) score, and upper gastrointestinal (UGI) endoscopy findings. BACKGROUND:  Cirrhosis is the end stage of chronic liver disease (CLD) and is characterised by progressive liver fibrosis and distortion of the liver architecture. It is a major cause of morbidity and mortality all over the world. Cirrhosis is compensated in the initial stages and later progresses to the decompensated stage with various complications. The CTP scoring system predicts mortality in patients with cirrhosis. MATERIALS AND METHODS: This retrospective study was done in the Department of Medicine and Gastroenterology of Tata Main Hospital (TMH), Jamshedpur, Jharkhand, India. It was conducted over a period of two years between 1 January 2019 and 31 December 2020, on 150 confirmed cases of cirrhosis. RESULTS: The most common age group was 41-60 years (86, 57.33%) and the mean age ± standard deviation (SD) for all patients was 49.82 ± 11.63 years. In a total of 150 CLD cases, males were 96 (64%). The most common cause of CLD was alcohol (76, 50.67%). Based on presenting symptoms, most CLD patients presented with generalized weakness (144, 96.00%). The most common signs were icterus (68, 45.33%) and ascites (44, 29.33%). Most patients belonged to CTP class A (77, 51.33%), followed by CTP class B (44, 29.33%) and class C (29, 19.34%). The most common UGI endoscopy finding was portal hypertensive gastropathy (mild or severe) (135, 75%). Total deaths were 24 (16.00%), with 17 deaths (70.83%) in patients belonging to CTP class C. CONCLUSION: CLD is a common entity in eastern India with male preponderance and affects mostly people of the middle age group. Alcohol intake is a major cause of CLD, followed by non-alcoholic fatty liver disease and chronic hepatitis B and C. A significant rise in morbidity and mortality due to alcoholic liver disease (ALD) was observed in the study and needs urgent social and medical intervention. The incidence of ALD in our study was 50.67%.

Ischemic gastropathy with "leopard skin" stomach.

Ischemic gastropathy is a rare, underreported phenomenon that is associated with a poor prognosis. Patients often present with signs of shock, gastrointestinal bleeding, and anemia. We describe a patient with alcoholic cirrhosis who presented after a fall in hemorrhagic shock. Initial endoscopy revealed evidence of ongoing bleeding, with subsequent endoscopy revealing the "leopard skin" appearance in the stomach. The patient was treated supportively but eventually succumbed to his condition. Prompt diagnosis, treatment, and awareness of the delayed changes on upper endoscopy are imperative in diagnosing ischemic gastropathy. Patients with risk factors for the condition need to be given additional consideration for this diagnosis.

Diagnostic Principles for Chronic Gastritis Associated with Duodenogastric Reflux.

This article systematizes available data from the literature on biliary gastritis (BG) in order to increase the awareness of specialists about the latest possibilities for diagnosing the disease. BG occurs as a result of pathological duodenogastric reflux. In patients with a preserved duodenogastric junction, the dominant factor is represented by motor disorders of the upper digestive tract (primary biliary gastritis), while in patients recovering from surgical interventions it is represented by structural changes (secondary biliary gastritis). Progressive BG can lead to atrophy of the gastric mucosa, intestinal metaplasia, epithelial dysplasia, and eventually to gastric cancer. Diagnostic methods for BG are carried out to identify risk factors, exclude alarm symptoms and identify persistent motor disorders and pathological reflux (24 h pH-impedancemetry, hepatobiliary scintigraphy, 24 h monitoring of bilirubin content in the reflux using a Bilitec 2000 photometer), as well as to diagnose gastritis itself (esophagogastroduodenoscopy, morphological gastrobiopsy examination). The diagnosis of BG should be based on a multidisciplinary approach that combines a thorough analysis of a patient's complaints, an anamnesis of the disease, and the results of endoscopic and histological research methods.

[Severe cytomegalovirus-associated protein losing gastropathy in an immunocompetent adult]. / Entéropathie exsudative sévère compliquant une primo-infection à cytomégalovirus chez un adulte immunocompétent.

INTRODUCTION: Clinical expression of cytomegalovirus (CMV) infection is numerous and depends on the immune status of the host. In immunocompromised patients, CMV disease corresponds to reactivation of the virus with tissue damage responsible for significant morbidity and mortality. In immunocompetent adults, primary CMV infection is usually asymptomatic but may rarely result in severe organ damage. OBSERVATION: We report the case of a 28-year-old man, considered immunocompetent and without medical history, presenting with a primary CMV infection revealed by a severe protein-losing gastroenteropathy (serum albumin level: 18.9g/L). The CT scan showed a gastro-duodeno-jejuno-ileitis pattern. Upper intestinal endoscopy revealed diffuse ulcerated and congestive gastritis predominantly in the fundus. Histological analysis of the biopsies showed no viral inclusion and no immunohistochemical staining reaction, but a high viral load (5.61 log). Treatment was symptomatic associated with anticoagulation due to the major hypoalbuminemia. The patient slowly recovered, and normal clinical examination and blood tests were observed two months after the onset of symptoms. CONCLUSION: Severe CMV organ involvement in the immunocompetent patient is very rare but potentially serious. Digestive involvement complicated by exudative enteropathy is possible. Evolution is usually favorable without the need for antiviral treatment.

Injury patterns and potential diagnostic pitfalls associated with radiation and radio-chemotherapy in the stomach and gastroesophageal junction.

Chemoradiation-associated injury may cause marked epithelial and stromal changes in gastric specimens. We characterized these histologic features in a retrospective series of cases. Nineteen cases of radiochemotherapy-associated gastropathy were identified, including 16 from our institution and 3 from consultation material. Patient charts and hematoxylin and eosin-stained slides were reviewed. Most patients were men (79%) with a median age of 66 years. All patients had a documented history of radiation and 15 patients also received chemotherapy. The median time from treatment to biopsy or resection was 2.3 months. Gross and endoscopic findings included erythematous, hemorrhagic, or ulcerated mucosa. Mucosal eosinophilia was seen in 16 cases (84%) while 10 cases (53%) featured acute inflammation including neutrophilic microabscesses. Epithelial changes included increased apoptosis (6 cases, 32%) and marked epithelial atypia (10 cases, 53%), potentially mimicking malignancy in some cases. However, the atypical cells featured voluminous eosinophilic cytoplasm with low nuclear-to-cytoplasmic ratio, a clue to their benign nature. Neuroendocrine cell nests were seen in 4 cases (21%) and loosely aggregated in 1 case, potentially mimicking a well-differentiated neuroendocrine tumor or enterochromaffin-like (ECL) cell hyperplasia in autoimmune gastritis. Eleven cases (58%) featured vascular changes that included vessel dilation, hobnailed endothelial cells, and fibrin thrombi. Stromal changes were seen in 11 cases (58%) and included lamina propria hyalinization, submucosal fibrosis, and myofibroblast atypia. Injury associated with radiochemotherapy is histologically varied and may affect epithelial, stromal, and vascular compartments. Familiarity with these features is important as a subset of these findings may provoke concern for neoplasia.

p53 upregulated by HIF-1α promotes gastric mucosal epithelial cells apoptosis in portal hypertensive gastropathy.

BACKGROUND: Portal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of gastrointestinal bleeding. Mucosal apoptosis is an essential pathological feature of PHG. However, whether HIF-1α and p53 are involved in mucosal apoptosis and whether HIF-1α induces PHG by mediating p53 remains unclear. METHODS: Gastric mucosal injury and apoptosis were examined in PHG patients and animal models. The mechanisms of HIF-1α- and p53-mediated apoptosis were analyzed. The GES-1 cell line was used to elucidate the underlying mechanisms using siRNA knockdown of HIF-1α and p53 in a hypoxic environment in vitro. RESULTS: Epithelial apoptosis, HIF-1α, and p53 were markedly induced in the gastric mucosa of PHG. Apoptosis was attenuated in mice with HIF-1α- and p53-specific inhibitors. Apoptotic signaling factors were markedly induced in the gastric mucosa of PHG. Inhibition of p53 demonstrably attenuated the mucosal apoptosis; however, it did not affect HIF-1α expression. Conversely, targeted deletion of HIF-1α significantly inhibited p53 expression and attenuated the injury and p53-mediated apoptosis. Bax and Bcl-2 expression can be upregulated and downregulated by p53, respectively, to increasecleaved caspase-3 expression, which can be regulated by HIF-1α. CONCLUSIONS: These results indicate that HIF-1α regulates the p53-induced mucosal epithelial apoptotic signaling pathway and that HIF-1α and p53 are potential therapeutic targets for PHG.