Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.

Predictors for Celiac Disease in Adult Cases of Duodenal Intraepithelial Lymphocytosis.

BACKGROUND: Duodenal intraepithelial lymphocytosis (D-IEL) is an early marker for celiac disease (CD). However, the majority of cases are due to non-CD-related conditions. GOALS: To identify the predictors of CD when presented with D-IEL. METHODS: A total of 215 adult patients with D-IEL had undergone prospective and systematic evaluation for CD and other recognized associations.The gold-standard diagnosis of CD was based upon the presence of HLA-DQ2 and/or DQ8, persistence or progression of D-IEL following a gluten challenge, followed by symptomatic improvement on a gluten-free diet.Binary logistic regression models, adjusting for age and sex, were subsequently performed to compare presenting variables between CD and non-CD cases, and to determine their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: CD was diagnosed in 48 cases (22%) and non-CD in 167 cases (78%). There was no statistical difference in baseline demographics, clinical symptoms (ie, diarrhea, weight loss, abdominal pain), anemia, or hematinics between the CD and non-CD group.Patients with CD, in comparison with non-CD, were significantly more likely to have a positive family history of CD (21% vs. 3.6%, OR 6.73; PPV 62.5%, NPV 81%, specificity 96.4%), positive HLA-DQ status (100% vs. 49.1%; PPV 36.4%, NPV 100%, specificity 50.9%), and presence of endomysial antibody (EMA) (48% vs. 0%; PPV 100%, NPV 87%, specificity 100%); all P≤0.001.A normal tissue transglutaminase antibody (TTG) level was seen in 29.2% CD and 83.2% non-CD cases (OR 0.084, P<0.001; PPV 9.2%). There was no difference in the prevalence of TTG levels 1 to 2×upper limit of normal (ULN) between the groups (29.2% CD vs. 14.4% non-CD; PPV 33% to 38%). However, TTG levels between 3 and 20×ULN were significantly more prevalent in the CD group (33.3% vs. 2.4%, PPV 66.6% to 89%), whereas a TTG>20×ULN was exclusive to CD (8.3%, P<0.001, PPV 100%). CONCLUSIONS: In the setting of D-IEL, only the presence of a positive EMA or TTG>20×ULN at the outset can be used to make an immediate diagnosis of CD. Gastrointestinal symptoms, family history, anemia, or other celiac serology results do not reliably distinguish CD from non-CD without further investigations.

[Clinical and pathogenetic features of inflammatory and atrophic changes in the gastroduodenal zone in patients with varying severity of chronic heart failure associated with coronary artery disease].

AIM: To study the clinical features of inflammatory and atrophic changes (IAls) in the gastroduodenal zone (GDZ) in people with varying severity of chronic heart failure (CHF) associated with coronary artery disease (CAD) and to determine gastric secretion, local microcirculation, and the presence of Helicobacter pylori. SUBJECTS AND METHODS: Seventy-four patients with CHF and gastric duodenal (GD) IAls who were divided into 2 groups according to its severity were examined. The specific features of impaired gastric secretory function and blood flow in the GD mucosa and its contamination with H. pylori were elucidated. RESULTS: GD IAls were ascertained to be mainly focal in the patients with Stages I-Ila CHF and focal or diffuse in those with Stages IIb-III. According the clinical findings, these changes were generally shown in the concurrence of transient and unstable (in early- stage circulatory insufficiency) and prolonged and persistent (during severe congestive events) phenomena. The development of IAls in the GDZ was linked to its thrombohemorrhagic microcirculatory disorders, the severity of which increased as the symptoms of CHF progressed. In Stages I-Ila circulatory insufficiency, this was accompanied by the normal activity of acid-peptic factor, by the decreased production gastromucoproteins, and, in 58.3% of cases, by H. pylori. The patients with Stages IIb-III showed the suppressed production of all constituents of gastric secretion and H. pylori in 63.2% of cases. CONCLUSION: The clinical manifestations and mechanisms of GD IAIs in CHF associated with CAD have a number of substantial differences in relation to its severity, which should be kept in mind when elaborating therapeutic and diagnostic measures.

Immunoglobulin G4-related periaortitis complicated by aortic rupture and aortoduodenal fistula after endovascular AAA repair.

PURPOSE: To report a rare and complicated case of immunoglobulin (Ig) G4-related periaortitis involving both the aortic wall and the retroperitoneum without aneurysmal formation. CASE REPORT: A 79-year-old man with IgG4-related periaortitis suffered aortic rupture despite a normal caliber aorta after 6 months of steroid therapy (20 mg/d). Endovascular repair with an aortic cuff sealed the rupture. Steroid therapy was halted 2 weeks later due to infection. Four months later, a biopsy during esophagogastroduodenoscopy to investigate gastrointestinal bleeding suggested a relapse of IgG4-RD in the duodenum. Subsequent aortoduodenal fistula formation proved fatal. Generally, IgG4-related periaortitis does not result in such complications due to the absence of aneurysm formation and a thick aortic wall. CONCLUSIONS: Our report highlights a rare case of IgG4-related periaortitis where complications resulted following steroid therapy and surgical intervention, emphasizing the difficulties in dealing with IgG4-related cardiovascular lesions.

Intraepithelial lymphocyte distribution differs between the bulb and the second part of duodenum.

BACKGROUND: Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb.We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects. METHODS: The number of CD3+ IELs was determined in specimens from the second part of the duodenum and from the bulb in 34 non-celiac subjects. The numbers of IELs in the villus tip and sides were counted and the quotient tip/side was calculated. HLA DQ2/DQ8 and serum antibodies against transglutaminase were analysed. RESULTS: The mean number of IELs per 100 enterocytes (95% CI) in specimens was 14.7 (11.8-17.6) in the bulb, and 21.2 (17.0-25.5) in the second part of the duodenum (p<0.01). There was no difference in IEL count or distribution comparing patients carrying or lacking HLA DQ2/DQ8. CONCLUSIONS: IEL count in non-celiac, HLA DQ2/DQ8 positive or negative patients is significantly lower in the bulb than in the second part of the duodenum. These findings implicate that the site of biopsy should be taken into account when considering duodenal lymphocytosis.

Migration of eosinophils and CCR2-/CD68-double positive cells into the duodenal mucosa of patients with postinfectious functional dyspepsia.

OBJECTIVES: Recent studies have shown that postinfectious functional dyspepsia (FD) symptoms may persist after elimination of gastrointestinal (GI) infection as well as postinfectious irritable bowel syndrome accompanying colonic inflammation. However, it is unclear whether intestinal chronic inflammation can contribute to clinical symptoms of certain FD patients such as postinfectious FD. To determine the relationship between local inflammation of the duodenum and clinical symptoms, we evaluated the infiltration of several phenotypes of duodenal inflammatory cells as well as gastric motility using (13)C urea breath test in postinfectious FD patients. METHODS: We enrolled 136 consecutive patients diagnosed with FD according to Rome III criteria, and 20 healthy controls, after upper GI endoscopy. Gastric motility was evaluated by gastric emptying time (T-max) using the (13)C-acetate breath test. Upper abdominal symptoms including epigastric pain, epigastric burning, postprandial fullness, abdominal distension, and early satiety were assessed by questionnaire scores. We obtained biopsy specimens from the stomach and duodenum during upper GI endoscopy. Histological gastritis and duodenitis were assessed as mild, moderate, or severe according to previously described criteria. Characteristics of inflammatory cells and neuroendocrine cells were determined immunohistochemically with antibodies to CD3, CD68, CCR2, Vdelta1 TCR, and serotonin. RESULTS: Endoscopic duodenitis was observed in only 5.7% of postinfectious FD patients. However, the rates of histological duodenitis in duodenal biopsies of postinfectious FD patients were 17% for mild, 26% for moderate, and 57% for severe grades of duodenitis. The degree of histological duodenitis of postinfectious FD patients was significantly greater than that of healthy volunteers. There was a significant correlation between epigastric burning and the degree of duodenitis in postinfectious FD patients. There was no significant difference in histological duodenitis and T-max value in the postinfectious FD patients with or without Helicobacter pylori infection. In addition, CD68-positive cell number in postinfectious FD patients was significantly increased compared with the numbers in subjects with epigastric pain syndrome or postprandial distress syndrome and in healthy volunteers. CCR2-/CD68-double positive cell number in postinfectious FD patients was significantly (P=0.009) increased compared with those in healthy volunteers. CONCLUSIONS: Migration of inflammatory cells, in particular, duodenal CCR2-positive macrophages, may have an important function in the pathophysiology of postinfectious FD patients.

Radiographic and Endoscopic Features of Pancreaticoduodenal Malakoplakia.

Malakoplakia is a rare, granulomatous disorder that is typically triggered by infections in immunocompromised patients. Although it most commonly affects the urinary tract, cases may occasionally occur in the gastrointestinal tract. There are case reports of malakoplakia of the pancreas with associated pathologic description, but none with detailed imaging and endoscopic findings. In addition, description of magnetic resonance imaging characteristics of mass-forming malakoplakia in the literature is sparse. We present a case of pancreaticoduodenal malakoplakia in an immunocompromised patient, including detailed description of magnetic resonance imaging, computed tomography, and endoscopic findings with radiology-pathology correlation. Classic pathologic features of malakoplakia (eg, hypercellularity, inflammation, and mineralization of Michaelis-Gutmann bodies) lead to specific features on imaging, such as marked diffusion restriction, heterogeneous enhancement, calcification, and increased attenuation on nonenhanced computed tomography. These features may help differentiate malakoplakia from other more common lesions that occur in this location, especially if present in an immunocompromised patient.

Acute duodenal Crohn's disease successfully managed with low-speed elemental diet infusion via nasogastric tube: a case report.

Duodenal Crohn's disease is rare, and patients without obstruction are treated medically. We herein report one case whose duodenal Crohn's disease was successfully managed with low-speed elemental diet infusion through a nasogastric tube. A 28-year-old female developed acute duodenal Crohn's disease. Upper GI radiologic and endoscopic examinations showed a stricture in the duodenal bulb. Using the duodenal biopsy specimens, mucosal cytokine levels were measured; interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha levels were remarkably elevated. For initial 2 wk, powdered mesalazine was orally given but it was not effective. For the next 2 wk, she was treated with low-speed elemental diet therapy using a commercially available Elental(TM), which was infused continuously through a nasogastric tube using an infusion pump. The tip of the nasogastric tube was placed at an immediate oral side of the pylorus. The infusion speed was 10 mL/h (usual speed, 100 mL/h). After the 2-wk treatment, her symptoms were very much improved, and endoscopically, the duodenal stricture and inflammation improved. The duodenal mucosal cytokine levels remarkably decreased compared with those before the treatment. Although our experience was limited, low-speed elemental diet infusion through a nasogastric tube may be a useful treatment for acute duodenal Crohn's disease.

Suppression of extraintestinal and intestinal Nippostrongylus brasiliensis-induced eosinophilia by Eimeria nieschulzi.

Eosinophil responses in extraintestinal and intestinal tissues were examined in August and Sprague-Dawley rats infected with Nippostrongylus brasiliensis or Eimeria nieschulzi (or both), and in uninfected controls to test the hypothesis that E. nieschulzi suppresses the systemic N. brasiliensis-induced eosinophil response. Caudal vein blood, femoral bone marrow, bronchoalveolar lavage fluid, peritoneal lavage fluid, and duodenal and jejunal samples were collected on day 8 postinfection (PI) with E. nieschulzi, on day 16 PI of the N. brasiliensis infection, when these days coincided in the concurrently infected rats, and from uninfected controls. Differential white blood cell counts were made from blood smears and cytocentrifuged preparations, and duodenal and jejunal eosinophils per villus crypt unit were quantified. Eimeria nieschulzi significantly reduced N. brasiliensis-induced eosinophil levels in peripheral blood, lavage fluids, and duodenal and jejunal tissues in both rat strains. August and Sprague-Dawley rats monospecifically infected with N. brasiliensis and concurrently with both parasites demonstrated elevated eosinopoiesis compared with uninfected controls and rats infected with only E. nieschulzi; however, despite this, concurrently infected rats had a significantly greater level of eosinopoiesis than those infected with only the nematode. In addition, E. nieschulzi induced elevated neutrophil levels in both monospecifically and concurrently infected rats in all extraintestinal tissues examined in both rat strains, whereas lymphocyte counts decreased concomitantly. This study suggests that the intestinal coccidian E. nieschulzi has the ability to modulate the systemic inflammatory response to N. brasiliensis and that this is not a rat strain-specific phenomenon.

Cytokine mRNA quantification in duodenal mucosa from dogs with chronic enteropathies by real-time reverse transcriptase polymerase chain reaction.

The pathogenesis of inflammatory bowel disease (IBD) and antibiotic-responsive diarrhea (ARD) in dogs likely involves an interaction between the intestinal immune system and luminal bacterial or food antigens. German Shepherd Dogs (GSD) are particularly predisposed to both IBD and ARD. CD4+ T cells are important for the regulation of immune responses in the mucosa, and they exert their effects through the secretion of cytokines. The present study examined the role of cytokines in the pathogenesis of canine chronic enteropathies by quantification of mRNA encoding interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, interferon gamma, tumor necrosis factor-alpha, transforming growth factor-beta, and glyceraldehyde-3-phosphate dehydrogenase by real-time reverse transcriptase polymerase chain reaction in duodenal mucosal biopsies obtained from 39 dogs with chronic diarrhea and 18 control dogs. Contemporaneously collected biopsies were assessed for histologic changes with a 4-point grading system. No significant difference in the expression of cytokine mRNA (P > .01) was detected between dogs with and those without chronic diarrhea. Similarly, no significant differences in cytokine mRNA expression were observed between GSD and other breeds with chronic diarrhea, or between histologically normal duodenal mucosa and that with evidence of inflammatory change. Failure to detect a difference in mRNA expression does not rule out the possibility of a defect downstream at the level of translation or protein function. No conclusion can be drawn from these data as to the predominant CD4+ cell type in the pathogenesis of these canine chronic enteropathies.

Evolution of nonspecific duodenal lymphocytosis over 2 years of follow-up.

AIM: To assess the evolution of duodenal lymphocytosis (DL), a condition characterized by increased intraepithelial lymphocytes (IELs), over 2 years of follow-up. METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease (CD) were included. Evaluation of IELs infiltrate in duodenal biopsy samples was carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: IgG and IgA anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance imaging were performed when necessary. Risk factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR. RESULTS: Eighty-five patients (16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed IgG anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity (GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn's disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence. At multivariate analysis, the evolution towards CD was associated with an IELs infiltrate > 25 (OR = 1640.4) or 15-25 (OR = 16.95), human leukocyte antigen (HLA) DQ2/8 (OR = 140.85) or DQA1*0501 (OR = 15.36), diarrhea (OR = 5.56) and weakness (OR = 11.57). GS was associated with IELs 15-25 (OR = 28.59), autoimmune thyroiditis (OR = 87.63), folate deficiency (OR = 48.53) and diarrhea (OR = 54.87). CONCLUSION: DL may have a multifactorial origin but the IELs infiltrate and HLA are strong predictive factors for CD development and a clinical diagnosis of GS.

The pattern of involvement of the gastric mucosa in lymphocytic gastritis is predictive of the presence of duodenal pathology.

AIM: To determine whether the pattern of involvement of the gastric mucosa in lymphocytic gastritis is predictive of the presence or absence of duodenal pathology. METHODS: 50 cases (M:F, 26:24; median age 57 years) diagnosed as lymphocytic gastritis between 1986 and 1998 with concurrent duodenal (D2) biopsies were identified from a computer search of the pathology records and validated by counting gastric intraepithelial lymphocytes. Gastric and duodenal intraepithelial lymphocyte counts were performed on haematoxylin and eosin (H&E) and anti-CD3 stained sections. D2 biopsies were assessed for villous atrophy and chronic inflammatory cell infiltration by subjective grading, and gastritis was classified and graded according to the updated Sydney system. A case was designated corpus predominant when the corpus chronic inflammation grade exceeded that of the antrum. If it was less, then the case was antrum predominant, and if they were equal it was diffuse (pan-) gastritis. The ratio between the corpus and antral intraepithelial lymphocyte count in individual patients was calculated. RESULTS: Of 50 cases of lymphocytic gastritis, 21 were classified as corpus predominant. With one exception (a case of mild villous atrophy), all were accompanied by normal duodenal morphology. Cases with a corpus predominant gastritis had median duodenal intraepithelial lymphocyte counts of 19 (H&E) and 14.1 (CD3), whereas 29 subjects with an antrum predominant or diffuse gastritis had median counts of 39.9 (H&E) and 37.9 (CD3). Fifteen of these 29 cases (52%) showed villous atrophy; all were graded as moderate or severe. Patients with any degree of villous atrophy had a mean corpus/antrum intraepithelial lymphocyte ratio (H&E) of 0.59 (representing antral predominance), while those with normal duodenal morphology had a ratio of 2.39 (p < 0.0001). CONCLUSIONS: The pattern of involvement of gastric mucosa in lymphocytic gastritis is closely related to the associated duodenal pathology. Those with the corpus predominant form are unlikely to have duodenal pathology, while those with an antral predominant or diffuse form should have distal duodenal biopsies taken to exclude villous atrophy.

Mucosal interleukin-8 and Helicobacter pylori-associated gastroduodenal disease.

OBJECTIVE: To review the role of interleukin (IL)-8 in the immunopathology of Helicobacter pylori-associated gastroduodenal disease. METHOD: Literature review. RESULTS: In H. pylori infection, IL-8 secretion by the gastric mucosa is increased, particularly in patients with active neutrophilic gastritis. Immunoreactive IL-8 is evident in the epithelium of histologically normal gastric mucosa but epithelial IL-8 expression is increased in H. pylori-associated chronic gastritis. Gastric epithelial cell lines constitutively express IL-8 messenger (m)RNA and IL-8 message and protein secretion can be upregulated by the cytokines tumour necrosis factor-alpha, IL-1 alpha and IL-1 beta. H. pylori also directly induces epithelial IL-8 expression in a strain-specific manner. Cytotoxic strains expressing the CagA protein upregulate IL-8 mRNA and IL-8 protein secretion. CONCLUSION: IL-8 is an important chemotactic and activating factor for neutrophils. The secretion of IL-8 by epithelial cells is probably a key factor in host defences at mucosal sites, permitting a rapid polymorph response against infectious agents. If defence mechanisms fail and chronic infection results, continued upregulation of IL-8 and neutrophil activation could lead to mucosal damage and increased free radical formation. Mucosal IL-8 production in H. pylori infection may be an important factor in the immunopathogenesis of peptic ulcer disease and also be of relevance to gastric carcinogenesis.