Successful use of montelukast in eosinophilic gastroenteritis: a case report and a literature review.

BACKGROUND: Eosinophilic gastrointestinal disorders, also known as eosinophilic gastroenteritis, are rare inflammatory conditions characterized by eosinophilic infiltration of different parts of the gastrointestinal tract, along with peripheral eosinophilia in most cases. Other known causes for gut eosinophilic infiltration must be excluded to confirm the diagnosis of eosinophilic gastroenteritis. Symptoms of the disorder depend on the affected gastrointestinal tract segment and depth of involvement. Treatment includes systemic glucocorticoids and/or dietary therapy with an empiric elimination diet. Second line therapies include the leukotriene receptor antagonist montelukast, and other anti-allergy drugs such as mast cell stabilizers (including cromolyn and the H1-antihistamine ketotifen), suplatast tosilate which is a selective Th-2 cytokines (IL-4 and IL-5) inhibitor, and the monoclonal anti-IgE antibody omalizumab. We report a case of eosinophilic gastroenteritis who was successfully treated and achieved remission with montelukast as an initial monotherapy. Upon extensive literature review, this represents the second reported adult case of eosinophilic gastroenteritis who responds to montelukast alone as a first line therapy. CASE PRESENTATION: A 49-year-old female presented with recurrent abdominal pain, vomiting, diarrhea and unexplained eosinophilia. She was diagnosed with eosinophilic gastroenteritis and was successfully treated with montelukast monotherapy. After 7 days of therapy, the patient responded well and had complete resolution of her gastrointestinal symptoms and peripheral eosinophilia. Patient remained in remission on follow-up after 12 months. We reviewed the literature for leukotriene antagonist use in the treatment of eosinophilic gastroenteritis and included the cases treated with the leukotriene antagonist montelukast as an initial therapy or as a second line therapy for refractory disease. CONCLUSION: Montelukast may be an effective treatment for eosinophilic gastroenteritis, either alone or in combination with systemic steroids or ketotifen. Our patient is the second reported adult case of eosinophilic gastroenteritis who responded to montelukast alone as a first line therapy. Further studies and clinical trials are required to confirm efficacy compared to standard therapy.

Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and MyD88.

Gut-derived bacterial LPS plays an essential role in inducing intestinal and systemic inflammatory responses and have been implicated as a pathogenic factor in necrotizing enterocolitis and inflammatory bowel disease. The defective intestinal tight junction barrier was shown to be an important factor contributing to the development of intestinal inflammation. LPS, at physiological concentrations, causes an increase in intestinal tight junction permeability (TJP) via a TLR4-dependent process; however, the intracellular mechanisms that mediate LPS regulation of intestinal TJP remain unclear. The aim of this study was to investigate the adaptor proteins and the signaling interactions that mediate LPS modulation of intestinal tight junction barrier using in vitro and in vivo model systems. LPS caused a TLR4-dependent activation of membrane-associated adaptor protein focal adhesion kinase (FAK) in Caco-2 monolayers. LPS caused an activation of both MyD88-dependent and -independent pathways. Small interfering RNA silencing of MyD88 prevented an LPS-induced increase in TJP. LPS caused MyD88-dependent activation of IL-1R-associated kinase 4. TLR4, FAK, and MyD88 were colocalized. Small interfering silencing of TLR4 inhibited TLR4-associated FAK activation, and FAK knockdown prevented MyD88 activation. In vivo studies also confirmed that the LPS-induced increase in mouse intestinal permeability was associated with FAK and MyD88 activation; knockdown of intestinal epithelial FAK prevented an LPS-induced increase in intestinal permeability. Additionally, high-dose LPS-induced intestinal inflammation was dependent on the TLR4/FAK/MyD88 signal transduction axis. To our knowledge, our data show for the first time that the LPS-induced increases in intestinal TJP and intestinal inflammation were regulated by TLR4-dependent activation of the FAK/MyD88/IL-1R-associated kinase 4 signaling pathway.

Eosinophilic Gastroenteritis: An Underdiagnosed Condition.

BACKGROUND: Eosinophilic gastroenteritis (EOGE) is a rare idiopathic disease characterized by eosinophil-predominant inflammation of the stomach and/or intestines. Our aims are to determine the epidemiology, clinical features and outcomes of EOGE cases in a tertiary-care hospital. METHODS: Retrospective cohort study of patients with gastrointestinal eosinophilic infiltration from 2004 through 2014. All relevant specimens were reviewed by an expert pathologist. Significant eosinophilic infiltrate was defined as >25 eosinophils/HPF in the stomach or small intestine and >50 eosinophils/HPF in the colon. RESULTS: Three hundred and sixty-one charts were reviewed and 13 EOGE cases were identified, including nine adults and four pediatric cases. The majority (78 %) of adult cases were females. Clinical presentation was variable; most patients (62 %) had abdominal pain, followed by diarrhea (31 %) and nausea/vomiting (31 %). Atopy and food allergies were present in 54 and 38 % of patients, respectively. Weight loss and failure to thrive were present only in pediatric cases (50 vs 0 %; P = .01). Most EOGE cases (69 %) had peripheral eosinophilia, which was more prominent in patients with ascites compared to patients without ascites (37.3 ± 25.4 vs 9.3 ± 5.4 %; P = .01). Among patients who had long-term follow-up; 30 % had spontaneous remission, 60 % responded to steroids and/or restriction diet, and 10 % had refractory disease. CONCLUSION: EOGE is an underdiagnosed condition. In contrast to eosinophilic esophagitis; the disease might be female-predominant in adults. High index of clinical suspicion is required for diagnosis. Further studies about the long-term outcomes and the efficacy of restriction diet in adult patients are required.

Mechanism of IL-1ß modulation of intestinal epithelial barrier involves p38 kinase and activating transcription factor-2 activation.

The defective intestinal epithelial tight junction (TJ) barrier has been postulated to be an important pathogenic factor contributing to intestinal inflammation. It has been shown that the proinflammatory cytokine IL-1ß causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of the p38 kinase pathway and the molecular processes involved. In these studies, the in vitro intestinal epithelial model system (Caco-2 monolayers) was used to delineate the cellular and molecular mechanisms, and a complementary in vivo mouse model system (intestinal perfusion) was used to assess the in vivo relevance of the in vitro findings. Our data indicated that the IL-1ß increase in Caco-2 TJ permeability correlated with an activation of p38 kinase. The activation of p38 kinase caused phosphorylation and activation of p38 kinase substrate, activating transcription factor (ATF)-2. The activated ATF-2 translocated to the nucleus where it attached to its binding motif on the myosin L chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. Small interfering RNA induced silencing of ATF-2, or mutation of the ATF-2 binding motif prevented the activation of MLCK promoter and MLCK mRNA transcription. Additionally, in vivo intestinal perfusion studies also indicated that the IL-1ß increase in mouse intestinal permeability required p38 kinase-dependent activation of ATF-2. In conclusion, these studies show that the IL-1ß-induced increase in intestinal TJ permeability in vitro and in vivo was regulated by p38 kinase activation of ATF-2 and by ATF-2 regulation of MLCK gene activity.

Endoscopic-Assisted Percutaneous Sigmoidopexy: New Highlights on Technique and Outcomes.

Background: Sigmoid volvulus is primarily a disease of the elderly. Case Presentation: We describe a case of recurrent sigmoid volvulus in an elderly woman who refused surgery due to the high risk posed by general anesthesia and surgical intervention. She underwent endoscopic-assisted percutaneous sigmoidopexy using only three 2-shot anchor sets. No radiographic observation was necessary during the procedure. Some puncture sites were secured using endoscopic clips. Conclusion: Endoscopic-assisted percutaneous sigmoidopexy is increasingly used as an effective alternative to surgical sigmoidopexy when surgery under general anesthesia poses a high risk. Despite clinical improvement and resolution of the recurrent volvulus, after sigmoidopexy patients may continue to experience motility dysfunction and diffuse dilation of the colon for a few weeks, which may correlate with the episodes of obstruction experienced prior to fixation.

The Risk of Esophageal Food Impaction in Eosinophilic Esophagitis Patients: The Role of Clinical and Socioeconomic Factors.

Background: Eosinophilic esophagitis (EoE) patients present with dysphagia and often suffer from esophageal food impaction (EFI). EFI can lead to life-threatening perforation, and requires emergent endoscopic intervention. The aim of this study is to evaluate the risk factors for EFI in EoE patients. Methods: This is a retrospective study performed at a tertiary health-care system. Medical records and endoscopy images of EoE cases were reviewed. Clinical characteristics and outcomes including EFIs were documented. We used Zip-code median household income as a surrogate for patients' socioeconomic status. Results: A total of 291 EoE cases were included, mean age was 42 years. Most patients (65%) had classic EoE endoscopic findings including linear furrows and/or concentric rings; however, a significant proportion (47%) had findings suggestive of gastroesophageal reflux disease (GERD), such as the presence of erosive-esophagitis, a hiatal hernia or Schatzki's ring. Forty-eight patients (16%) developed one or more esophageal food impaction (EFI). The risk of EFI was less likely in the absence of furrows and/or rings; odds ratio (OR) = 0.28, 95% CI (0.11, 0.72) [P = 0.008]. Females had less EFI risk; OR = 0.42, 95% CI (0.19, 0.95) [P = 0.04]. The type of medical insurance and socioeconomic status was not associated with EFI risk. Conclusion: EFI risk is higher in EoE patients with esophageal furrows and/or rings and in men. Aggressive treatment might be required in this population. GERD and EoE can coexist in many patients. Further studies are required to examine the role of the socioeconomic status in EoE complications.

Gastric amyloidosis in a patient with dysphagia.

Dysphagia is a symptom with a broad differential diagnosis. Usually, the etiology of dysphagia is benign, but it is essential to rule out serious causes. It is also critical to think outside the box when the etiology is not obvious. Herein, we describe a case of multiple myeloma that initially presented with dysphagia. An 81-year-old male patient presented with dysphagia to solid food associated with anorexia and weight loss of 22 kg over the last 6 months. The patient looked chronically ill and cachectic. Upper endoscopy showed patchy erythema in the gastric antrum. Gastric biopsy was consistent with gastric amyloidosis. Although serum and urine protein electrophoresis did not show a monoclonal (M) band, immunofixation did show elevated free kappa light chains and elevated free Kappa/Lambda ratio. Bone marrow biopsy was consistent with multiple myeloma. Although gastrointestinal involvement is common in amyloidosis, it is unusual for amyloidosis to initially present in the gastrointestinal tract. Identification and treatment of the underlying condition, e.g., multiple myeloma, can lead to regression of gastrointestinal amyloidosis.

Acute Ischemic Colitis due to Oral Phenylephrine.

Oral phenylephrine is a commonly used over-the-counter nasal decongestant drug. It is usually taken for symptomatic relief (in combination drug products) for upper respiratory tract infections, allergic rhinitis, or sinusitis. Adverse cardiovascular effects of intravenous phenylephrine, including organ ischemia, are well known; however, oral phenylephrine is rarely associated with significant adverse effects. We describe the first case of acute ischemic colitis in a young patient due to over-the-counter oral phenylephrine, which was taken as a nasal decongestant. We reviewed the literature of colonic ischemia related to the use of systemic nasal decongestants phenylephrine and pseudoephedrine.

Outcomes of inflammatory bowel disease in patients with eosinophil-predominant colonic inflammation.

Background: Inflammatory bowel disease (IBD) is characterised by acute intestinal mucosal inflammation with chronic inflammatory features. Various degrees of mucosal eosinophilia are present along with the typical acute (neutrophil-predominant) inflammation. The effect of intestinal eosinophils on IBD outcomes remains unclear. Methods: This is a retrospective study. Archived intestinal mucosal biopsy specimens of treatment-naïve IBD patients were examined by two pathologists. The number of eosinophils per high-power field was counted, and the mucosal inflammation was classified according to the eosinophilic inflammatory patterns. Clinical outcomes during the follow-up period were recorded. Results: 142 treatment-naïve IBD patients were included. Mean age was 39 years. 83% of patients had ulcerative colitis, and median follow-up was 3 years. 41% of patients had disease flare(s) and 24% required hospitalisation. Eosinophil count was not associated with risk of disease flare or hospitalisation. Patients with neutrophil-predominant inflammation (>70% neutrophils) had greater risk of disease flare(s): 27(55%) versus 24(36%) and 7(28%) in patients with mixed and eosinophil-predominant inflammation, respectively (p=0.04). Overall, patients with neutrophil-predominant inflammation were more likely to have a disease flare; HR: 2.49, 95% CI (1.0 to 5.6). Hospitalisation rate was higher in patients with neutrophil-predominant inflammation: 17(35%) compared to 17(19%) in patients with eosinophil-rich inflammation (p=0.04). Kaplan-Meier analysis showed higher flare-free survival in patients with eosinophil-predominant inflammation compared to mixed and neutrophil-predominant inflammation. Conclusion: IBD patients with eosinophil-predominant inflammation phenotype might have reduced risk of disease flares and hospitalisation. Larger prospective studies to assess IBD outcomes in this subpopulation are warranted.

Investigating intestinal permeability and gut microbiota roles in acute coronary syndrome patients.

Background: Acute Coronary Syndrome (ACS) is a leading cause of morbidity and mortality. Perturbed gut- microbiota (dysbiosis) and increased intestinal permeability (leaky-gut) with translocation of bacterial antigens, play critical role in obesity and metabolic syndrome, which are also major ACS risk factors. Additionally, Trimethylamine-N-Oxide (TMAO), a metabolite produced by phylum Proteobacteria in gut is implicated in developing ACS. As Proteobacteria is a major source of translocated antigen lipopolysaccharides (LPS), we hypothesized that ACS patients have leaky-gut condition characterized by dysbiosis with increased Proteobacteria, leading to elevated blood levels of TMAO and LPS. Methods: In a pilot case-control study, we enrolled 19 ACS patients (within 72-h of cardiac events) and 19 healthy-controls. Gut barrier function was determined using lactulose-to-mannitol urinary excretion ratio (L/M ratio). Stool microbiome composition was examined using16S sequencing and predictive functional analysis for LPS biosynthesis pathway by PICRUSt tool. Serum TMAO and LPS levels were measured. Results: ACS patients had increased Gammaproteobacteria compared to controls:1.8 ±3.0 vs. 0.2 ±0.4% (P =0.04). Though Proteobacteria level was increased but not statistically significant: 4.1 ±3.8 vs. 2.1 ±1.7% (P =0.056). L/M-ratio was three times higher in ACS patients; 0.06 ±0.07 vs 0.023 ±0.02, (P =0.014). Surprisingly, there was no difference in the mean serum LPS or TMAO levels. However, PICRUSt analysis indicated increased Proteobacteria population increasingly contributed to LPS biosynthesis in ACS patients only. Conclusions: ACS patients likely to have leaky-gut and perturbed gut microbiota. Further studies are required to precisely define the role of dysbiosis in ACS.