Inflammatory responses in esophageal mucosa before and after laparoscopic antireflux surgery.

BACKGROUND: Currently, the primary treatment for gastroesophageal reflux is acid suppression with proton pump inhibitors, but they are not a cure, and some patients don't respond well or refuse long-term use. Therefore, alternative therapies are needed to understand the disease and develop better treatments. Laparoscopic anti-reflux surgery (LARS) can resolve symptoms of these patients and plays a significant role in evaluating esophageal healing after preventing harmful effects. Successful LARS improves typical gastroesophageal reflux symptoms in most patients, mainly by reducing the exposure time to gastric contents in the esophagus. Amelioration of the inflammatory response and a recovery response in the esophageal epithelium is expected following the cessation of the noxious attack. AIM: To explore the role of inflammatory biomolecules in LARS and assess the time required for esophageal epithelial recovery. METHODS: Of 22 patients with LARS (pre- and post/5.8 ± 3.8 months after LARS) and 25 healthy controls (HCs) were included. All subjects underwent 24-h multichannel intraluminal impedance-pH monitoring and upper gastrointestinal endoscopy, during which esophageal biopsy samples were collected using endoscopic techniques. Inflammatory molecules in esophageal biopsies were investigated by reverse transcription-polymerase chain reaction and multiplex-enzyme-linked immunosorbent assay. RESULTS: Post-LARS samples showed significant increases in proinflammatory cytokines [interleukin (IL)-1ß, interferon-γ, C-X-C chemokine ligand 2 (CXCL2)], anti-inflammatory cytokines [CC chemokine ligand (CCL) 11, CCL13, CCL17, CCL26, CCL1, CCL7, CCL8, CCL24, IL-4, IL-10], and homeostatic cytokines (CCL27, CCL20, CCL19, CCL23, CCL25, CXCL12, migration inhibitory factor) compared to both HCs and pre-LARS samples. CCL17 and CCL21 levels were higher in pre-LARS than in HCs (P < 0.05). The mRNA expression levels of AKT1, fibroblast growth factor 2, HRAS, and mitogen-activated protein kinase 4 were significantly decreased post-LARS vs pre-LARS. CCL2 and epidermal growth factor gene levels were significantly increased in the pre-LARS compared to the HCs (P < 0.05). CONCLUSION: The presence of proinflammatory proteins post-LARS suggests ongoing inflammation in the epithelium. Elevated homeostatic cytokine levels indicate cell balance is maintained for about 6 months after LARS. The anti-inflammatory response post-LARS shows suppression of inflammatory damage and ongoing postoperative recovery.

Roles of Cytokines in Pathological and Physiological Gastroesophageal Reflux Exposure.

Background/Aims: Gastroesophageal reflux disease is frequently observed and has no definitive treatment. There are 2 main views on the pathogenesis of gastroesophageal reflux disease. The first is that epithelial damage starts from the mucosa by acidic-peptic damage and the inflammatory response of granulocytes. The other view is that T-lymphocytes attract chemoattractants from the basal layer to the mucosa, and granulocytes do not migrate until damage occurs. We aim to investigate the inflammatory processes occurring in the esophageal epithelium of the phenotypes at the molecular level. We also examined the effects of these changes on tissue integrity. Methods: Patients with mild and severe erosive reflux, nonerosive reflux, reflux hypersensitivity, and functional heartburn were included. Inflammatory gene expressions (JAK/STAT Signaling and NFKappaB Primer Libraries), chemokine protein levels, and tissue integrity were examined in the esophageal biopsies. Results: There was chronic inflammation in the severe erosion group, the acute response was also triggered. In the mild erosion group, these 2 processes worked together, but homeostatic cytokines were also secreted. In nonerosive groups, T-lymphocytes were more dominant. In addition, the inflammatory response was highly triggered in the reflux hypersensitivity and functional heartburn groups, and it was associated with physiological reflux exposure and sensitivity. Conclusions: "Microinflammation" in physiological acid exposure groups indicate that even a mild trigger is sufficient for the initiation and progression of inflammatory activity. Additionally, the anti-inflammatory cytokines were highly increased. The results may have a potential role in the treatment of heartburn symptoms and healing of the mucosa.

Revisiting the Role of Esophageal Mucosal Dilated Intercellular Spaces in the Diagnosis and Pathophysiology of Heartburn.

Background/Aims: Dilated intercellular spaces (DISs) facilitate the diffusion of noxious agents into the deep layers of the esophageal epithelium. The role of DIS in heartburn pathogenesis is still controversial. Therefore, we aim to reinvestigate DIS in an extensively evaluated group of patients and healthy controls (HCs). Methods: We classified 149 subjects into the following groups: 15 HC, 58 mild erosive reflux disease (ERD), 17 severe ERD, 25 nonerosive reflux disease (NERD), 15 reflux hypersensitivity (RH), and 19 functional heartburn (FH). A total of 100 length measurements were performed for each patient's biopsy. Results: The overall intercellular spaces (ISs) value of gastroesophageal reflux disease (GERD) patients was higher than that of HC (P = 0.020). In phenotypes, mild ERD (vs HC [P = 0.036], NERD [P = 0.004], RH [P = 0.014]) and severe ERD (vs HC [P = 0.002], NERD [P < 0.001], RH [P = 0.001], FH [P = 0.004]) showed significantly higher IS. There was no significant difference between the HC, NERD, RH, and FH groups. The 1.12 µm DIS cutoff value had 63.5% sensitivity and 66.7% specificity in the diagnosis of GERD. There was a weak correlation (r = 0.302) between the IS value and acid exposure time, and a weak correlation (r = -0.359) between the IS value and baseline impedance. A strong correlation was shown between acid exposure time and baseline impedance (r = -0.783). Conclusions: Since the IS length measurement had better discrimination power only in erosive groups, it is not feasible to use in daily routine to discriminate other nonerosive phenotypes and FH. The role of DIS in heartburn in nonerosive patients should be reconsidered.

Epigenetic Alterations from Barrett's Esophagus to Esophageal Adenocarcinoma.

Barrett's esophagus (BE) is a disease entity that is a sequela of chronic gastroesophageal reflux disease that may result in esophageal adenocarcinoma (EAC) due to columnar epithelial dysplasia. The histological degree of dysplasia is the sole biomarker frequently utilized by clinicians. However, the cost of endoscopy and the fact that the degree of dysplasia does not progress in many patients with BE diminish the effectiveness of histological grading as a perfect biomarker. Multiple or more quantitative biomarkers are required by clinicians since early diagnosis is crucial in esophageal adenocancers, which have a high mortality rate. The presence of epigenetic factors in the early stages of this neoplastic transformation holds promise as a predictive biomarker. In this review, current studies on DNA methylations, histone modifications, and noncoding RNAs (miRNAs) that have been discovered during the progression from BE dysplasia to EAC were collated.

Psychometric tests, critical flicker frequency, and inflammatory indicators in covert hepatic encephalopathy diagnosis.

Background and Aim: Hepatic encephalopathy (HE) is a frequent complication of liver diseases. Systemic inflammation is key for HE pathogenesis. The main goal of the study was to investigate the role of psychometric tests, critical flicker frequency (CFF), and comparative evaluation of inflammatory indicators for the diagnosis of covert HE (CHE). Materials and Methods: The study was a prospective, nonrandomized, case-control study with a total of 76 cirrhotic patients and 30 healthy volunteers. The West Haven criteria were used to determine the occurrence of CHE in cirrhotic patients. Psychometric tests were applied to healthy and cirrhotic groups. CFF, venous ammonia, serum endotoxin, IL-6, IL-18, tumor necrosis factor alpha (TNF-α) levels, and hemogram parameters were evaluated for cirrhotic patients. Results: CFF values and psychometric tests were found to accurately discriminate CHE positives from CHE negatives (p<0.05). When the control group was excluded, the digit symbol test and the number connection A test failed, unlike CFF and other psychometric tests. Using CFF, a 45 Hz cutoff value had 74% specificity and 75% sensitivity. Basal albumin levels (p=0.063), lymphocyte-to-monocyte ratio (LMR) (p=0.086), and neutrophil-to-lymphocyte ratio (p 0.052) were significant, albeit slightly, among CHE groups. Basal albumin levels had 50% sensitivity and 71% specificity when 2.8 g/dL was used as a cutoff value to determine CHE. Conclusion: Both psychometric tests and CFF can be useful in diagnosing CHE. Using cytokine and endotoxin levels seems to be inadequate to diagnose CHE. Using LMR and albumin levels instead of psychometric tests for diagnosing CHE can be promising.

In Vitro and In Vivo Effects of Nonsteroidal Anti-inflammatory Drugs and Aspirin on Rabbit Esophageal Epithelium.

BACKGROUND: Gastroesophageal reflux disease has a high incidence of 23%, with 29% of those with gastroesophageal reflux disease consuming nonsteroidal anti-inflammatory drugs. There are insufficient data concerning the effects of nonsteroidal anti-inflammatory drugs on the esophageal tissue. We aimed to examine the effects of well-known nonsteroidal anti-inflammatory drugs using electrophysiologic criteria on the rabbit esophageal epithelium. METHODS: Esophageal epithelium mounted on Ussing chambers enabled in vitro investigation of the electrophysiological properties. Doses of 1 mg/mL, 2.5 mg/mL, 5 mg/mL ibuprofen, naproxen, and aspirin were dissolved in dimethyl sulfoxide and added to the luminal side. Esophagi were cannulated from both sides for the administration of high-dose ibuprofen in vivo, and the potential difference was monitored. RESULTS: Ibuprofen and aspirin inhibited tissue transport functions in a dose-dependent manner. pH 4 acid and 0.1 mg/mL ibuprofen alone were not harmful; however, the combination of these agents had an additive and significance effect: 78% decrease in the potential difference and 85% decrease in the short-circuited current (Isc). The change in the potential difference in the in vivo experiments (5 mg/mL ibuprofen) was similar (52 ± 7% decrease) with in vitro experiments in the first 30 minutes. CONCLUSION: Nonsteroidal anti-inflammatory drugs were harmful to the rabbit esophageal epithelium in both the in vitro and in vivo experiments. Even though aspirin and ibuprofen affected the transport mechanisms of the esophageal epithelium, the dose-dependent decrease of tissue potential difference and Isc with ibuprofen was more pronounced than those with aspirin. The combination of harmless doses of ibuprofen and acid demonstrated that even low acidic conditions can create a disruptive environment.

Pepsin and pH of Gastric Juice in Patients With Gastrointestinal Reflux Disease and Subgroups.

GOAL: The aim of this study was to investigate the pepsin values and pH results of gastric juice among the subtypes of gastroesophageal reflux disease (GERD) and functional heartburn. BACKGROUND: The major destructive agents of GERD on the esophageal epithelium are gastric acid and pepsin. No precise information about pepsin concentration in gastric juice exists. STUDY: Ninety patients with GERD, 39 erosive reflux disease (ERD) Los Angeles (LA) grade A/B, 13 ERD LA grade C/D, 19 nonerosive reflux disease (NERD), 8 esophageal hypersensitivity, 11 functional heartburn, and 24 healthy controls were included in the study. During endoscopy gastric juices from the patients were aspirated and their pH readings immediately recorded. Gastric juice samples were analyzed using Peptest, a lateral flow device containing 2 unique human monoclonal antibodies to detect any pepsin present in the gastric juice sample. RESULTS: The highest mean gastric pepsin concentration (0.865 mg/mL) and the lowest median gastric pH (1.4) was observed in the LA grade C/D group compared with the lowest mean gastric pepsin concentration (0.576 mg/mL) and the highest median gastric pH (2.5) seen in the NERD group. Comparing pH, the NERD patient group was significantly higher (P=0.0018 to P=0.0233) when compared with all other GERD patient groups. CONCLUSIONS: The basal gastric pepsin level in the healthy control group was comparable to literature values. There was good correlation and a significant linear relationship between the gastric pepsin level and gastric pH within the patient groups. The severity of the GERD disease is related to the lowest pH and the highest pepsin concentration in gastric juice.

Reference intervals of α-glycosidase, ß-glycosidase, and α-galactosidase in dried blood spot in a Turkish newborn population.

Inherited lysosomal storage diseases (LSDs) are rare, and diagnosis is often delayed for 7-10 years. Since the therapies have become available for a limited number of LSDs, (Fabry, Gaucher, Pompe, and MPS-1), early diagnosis of treatable LSDs can be lifesaving or ameliorating and allows timely treatment before irreversible damage occurs. Recently, the use of dried blood spot test (DBS) for newborn screening of LSDs has been proposed for newborn screening tests. They are noninvasive, sensitive, and specific assays with the further advantage of a fast turnaround time compared to measurement in leukocyte and/or fibroblast culture. We aimed to determine the reference intervals for lysosomal enzyme activities of newborn babies in our population and to investigate the effect of gestational week on enzyme activity. One hundred thirty healthy newborn babies (70 girls, 60 boys) were included into the study. α-Glycosidase, ß-glycosidase, and α-galactosidase activities in DBS samples of newborns were determined fluorometrically. Reference intervals were calculated using Dixon's rule and percentiles of 2.5-97.5. Cutoff limits (5 %) for α-glycosidase, ß-glycosidase, and α-galactosidase activities were 0.57, 0.92, and 2.18, respectively. α-Galactosidase activity was higher in girls compared to boys (p < 0.05). Interestingly, α-glycosidase and ß-glycosidase activities of newborns who were delivered before 38 weeks were significantly lower than those who were delivered at 39-40 weeks. Conclusion It is of utmost importance to define the reference intervals for lysosomal enzyme activities as well as cutoff limits for newborn babies with regard to gestational age and sex. More studies to clarify the reason for the change in enzyme activity by gestational week will be required.