Marker Of Gastroesophageal Reflux Disease Research Articles

Indicators of Mineral Metabolism in the Oral Fluid in Patients with Gastroesophageal Reflux Disease

Disruption of the digestive system in the gastrointestinal tract, namely in gastroesophageal reflux disease, leads to the development of pathological processes in the oral cavity, changing the homeostasis of the viscoelastic gel layer of the esophageal mucosa. Thus, it has been proven that there are reflex connections between the receptor apparatus of the esophageal mucosa and the efferent nerve fibers of the salivary glands, which can be disrupted in GERD. Therefore, saliva is involved in providing effective protection of the esophagus. As a result, the content of mineral components changes significantly: in particular, the level of calcium and enzyme composition.
 Aim to study the indicators of mineral metabolism: the content of calcium, alkaline, and acid phosphatases in mixed saliva in patients with gastroesophageal reflux disease.
 Methods 60 patients of various ages who underwent inpatient treatment at the IFNMU University Clinic were examined, where pH-metry was performed to determine acidity. The main group consisted of patients diagnosed with GERD, with decreased and increased acidity. The content of indicators of mineral metabolism in saliva was determined as follows: calcium (Ca) - photometric method with arsenase -111; acid phosphatase (AC) was determined by the Hillman method, alkaline phosphatase (AL) by hydrolysis of p-nitrophenyl phosphate at pH -10.4, release of p-nitrophenol and phosphate. The norm of indicators of mineral metabolism was established on 30 practically healthy volunteers. Statistical processing of data was carried out using the Microsoft Excel program by calculating the arithmetic mean.
 Conclusions thus, the results obtained indicate that in GERD there is a violation of mineral metabolism in the oral fluid. The oral fluid is the first to come into contact with the reflux agent. This leads to a violation of saliva neutralization, so the study of saliva mineral composition can be considered as an early diagnostic marker for gastroesophageal reflux disease.

Portable and Rapid Fluorescence Turn-On Detection of Total Pepsin in Saliva Based on Strong Electrostatic Interactions.

Salivary pepsin has been proposed as a promising diagnostic marker for gastroesophageal reflux disease (GERD). However, the activity of human pepsin is strongly influenced by pH, and the acidic condition (pH ∼ 2) is optimal, which is a contradiction for the pepsin detection kit based on its catalytic activity. Thus, its accurate quantification in saliva (neutral pH) by readily rapid tools with simplicity and low cost is still challenging. Herein, a convenient fluorescence assay has been developed for the rapid detection of pepsin at neutral pH based on its electrostatic interaction with SYBR Green (SG) rather than the bioactivity. At neutral pH, the positively charged SG fluorophore can be effectively adsorbed by the negatively charged pepsin due to the low isoelectric point (pI) and large molecular size of pepsin. Thus, the molecular rotation of SG is limited, and its fluorescence intensity is significantly increased. The strategy was further confirmed to have the same fluorescence response as that of normally active and inactivated pepsin. Due to the unique pI of pepsin, the fluorescence strategy is highly selective for pepsin compared to other proteins. On the basis of this strategy, a smartphone-based fluorescence capture device integrated with a programmed Python program was fabricated for both color recognition and the accurate detection of pepsin within 3 min. Under the optimal conditions, this turn-on sensor allowed for the on-site analysis of pepsin with a detection limit of 0.2 μg/mL. Moreover, this strategy was successfully used to assess salivary pepsin to aid in the noninvasive diagnosis of GERD.

CD8 T-Cell-Predominant Lymphocytic Esophagitis is One of the Major Patterns of Lymphocytic Inflammation in Gastroesophageal Reflux Disease.

Published reports have suggested an association of lymphocytic esophagitis (LyE) with gastroesophageal reflux disease (GERD) and primary motility disorders and have also shown that GERD and motility disorders frequently overlap. These findings make it difficult to determine the true relationship between LyE and GERD, which may be confounded by the presence of motility disorders with LyE. To characterize patterns of lymphocytic inflammation in patients with GERD who have no motility abnormalities. We identified 161 patients seen at our institution from 1998 to 2014 who were diagnosed with GERD, had normal esophageal motility, and available esophageal biopsies. LyE was defined as peripapillary lymphocytosis with rare or absent granulocytes. CD4 and CD8 immunophenotype of lymphocytes was evaluated using immunohistochemistry. We found increased intraepithelial lymphocytes in 13.7% of patients with GERD. Two major patterns and 1 minor pattern of lymphocytic inflammation were observed as follows: (1) LyE (in 6.8% [11 of 161] of patients and typically focal), (2) dispersed lymphocytes in an area of reflux esophagitis (in 5.6% [9 of 161] and typically diffuse), and (3) peripapillary lymphocytes in an area of reflux esophagitis (in 1.2% [2 of 161]). CD8 T cells significantly outnumbered CD4 T cells in 91% of patients with lymphocytic esophagitis and 100% of patients with dispersed lymphocytes (9 of 9) or peripapillary lymphocytes (2 of 2) in the area of reflux esophagitis. These findings suggest that LyE is one of the major patterns of lymphocytic inflammation in GERD. CD8 T-cell-predominant immunophenotype may be useful as a marker of GERD in the differential diagnosis of LyE.

Pepsin in Saliva as a Diagnostic Marker for Gastroesophageal Reflux Disease: A Meta-Analysis.

BackgroundGastroesophageal reflux disease (GERD) is very common. Salivary pepsin detection has previously been considered as a method for GERD diagnosis. We performed a meta-analysis to investigate the utility of salivary pepsin assay as a diagnostic tool of GERD.Material/MethodsPubMed, Web of Science, the Cochran Library, and EMBASE (from January 1980 to 23 October 2018) were searched for pepsin in saliva for GERD diagnosis. We summarized the retrieved specificity, sensitivity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), diagnostic odds ratio (DOR), and receiver operating characteristic (ROC) curves data in the meta-analysis.ResultsIn final analysis, a total of 5 studies were included. The summary sensitivity, specificity, NLR, and PLR were 0.60 (95% CI 0.41–0.76), 0.71 (95% CI 0.51–0.86), 0.56 (95% CI 0.34–0.93), and 2.1 (95% CI 1.1–4.1), respectively. The pooled DOR was 4 (95% CI 1.0–11.0) and area under the ROC was 0.70 (95% CI 0.66–0.74).ConclusionsThe meta-analysis showed that pepsin in saliva has moderate diagnostic value for GERD, and is not as helpful as previously thought.

Carditis: a relevant marker of gastroesophageal reflux disease. Data from a prospective central European multicenter study on histological and endoscopic diagnosis of esophagitis (histoGERD trial).

The columnar-lined mucosa at the gastroesophageal junction may contain an inflammatory infiltrate, commonly referred to as carditis (or cardia gastritis). The etiology of carditis is not entirely clear since published data are conflicting. Some authors believe it to be secondary to gastroesophageal reflux disease (GERD) and others to Helicobacter pylori gastritis. This prospective study aims at clarifying the relationship between carditis and the histological, clinical, and endoscopic findings of GERD, in a large cohort of individuals negative for H. pylori infection. Eight hundred and seventy-three individuals (477 females and 396 males, median age 53 years) participated in this study. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Reflux-associated changes of the esophageal squamous epithelium were assessed according to the Esohisto consensus guidelines. Grading of carditis was performed according to the Updated Sydney System, known from the histological evaluation of gastritis. In total, 590 individuals (67.5%) had chronic carditis. Of these, 468 (53.6%) had mild chronic inflammation, with 321 individuals (68.6%) showing no or minimal changes on endoscopic examination (Los Angeles Categories N and M). The presence of chronic carditis was associated with several GERD-related parameters of the esophageal squamous epithelium (P<0.0001), and data retained statistical significance even when analysis was restricted to individuals with mild chronic carditis and/or endoscopically normal mucosa. Chronic carditis was also associated with the presence of intestinal metaplasia (P<0.0001). In addition, chronic carditis had a statistically significant association with patients' symptoms of GERD (P=0.0107). This observation remained valid for mild chronic carditis in all patients (P=0.0038) and in those with mild chronic carditis and normal endoscopic mucosa (P=0.0217). In conclusion, chronic carditis appears to be the immediate consequence of GERD, correlating with patients' symptoms and endoscopic diagnosis. These results are valid in individuals with nonerosive reflux disease, which indicates a higher sensitivity of histological diagnosis. Our findings may impact the routine assessment of reflux patients.

Diagnosis of GERD in typical and atypical manifestations.

The manifestations of gastroesophageal reflux disease (GERD) have been recently classified into either esophageal or extra-esophageal syndromes. Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD. Endoscopy had a low sensitivity. Recently, the availability of multichannel intraluminal impedance and pH-monitoring (MII-pH) has modified the diagnostic approach towards atypical manifestations of GERD. There is a rising consensus that this technique should be considered as the gold standard for GERD diagnosis. Gastrin 17 (G-17) has been proposed as a non-invasive marker of GERD, due to the negative feedback between acid and the hormone. G17 levels seem able to identify patients with acid and non-acid reflux. (www.actabiomedica.it)

Esophageal chemical clearance and baseline impedance values in patients with chronic autoimmune atrophic gastritis and gastro-esophageal reflux disease

BackgroundThe factors influencing new markers of gastro-esophageal reflux disease detected by impedance-pH monitoring – mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index – need to be evaluated. AimTo compare endoscopy-negative heartburn with chronic autoimmune atrophic gastritis (CAAG). Materials and methods24 patients with CAAG, 25 with non-erosive reflux disease (NERD) and 25 with functional heartburn (FH) were included. In all patients the main impedance-pH monitoring parameters were calculated. ResultsCAAG and NERD patients had a number of reflux events (non-acid ones being more common among the former group) which was higher than that found in FH (p<0.001). MNBI decreased progressively in FH (>3000Ohm), CAAG (>2000Ohm) and NERD (<1000Ohm) patients (p=0.0046). The PSPW index was similar between CAAG and NERD patients but significantly lower in comparison to FH (p<0.0001). ConclusionPatients with CAAG have evidence of non-acid reflux based on the high number of reflux events and confirmed by low values of MNBI and PSPW index. MNBI is a strong marker of acid/non-acid reflux-induced mucosal damage, whereas the PSPW index can reliably discriminate patients with reflux from those with FH, independently of the acidity of refluxate.

Epithelial Thickness is a Marker of Gastroesophageal RefluxDisease.

Histologic criteria have been refined for the diagnosis of gastroesophageal reflux disease (GERD). We aimed to evaluate these criteria for the assessment of GERD and to measure interassessor agreement. We performed a post hoc analysis of data from the Diamond study (NCT 00291746), conducted in Europe and Canada on adults with frequent upper gastrointestinal symptoms who had not taken a proton pump inhibitor in the previous 2 months. GERD was diagnosed based on the presence of 1 or more of the following: reflux esophagitis, pathologic esophageal acid exposure, and/or positive symptom-acid association probability. Nonerosive reflux disease was defined as the presence of pathologic esophageal acid exposure and/or a positive symptom-acid association probability, but no reflux esophagitis. Biopsies collected from 336 patients from 0.5 cm and 2.0 cm above the Z line were evaluable; they were analyzed independently at pathology centers in Germany and Italy (biopsies from 258 and 195 patients, respectively). The primary outcomes were the accuracy of histologic criteria for the diagnosis of GERD, defined by endoscopy and pH monitoring, and interassessor agreement on histologic criteria. At the assessment site for basal cell layer thickness, total epithelial thickness was the best-performing criterion for diagnosis of investigation-defined GERD; it also identified nonerosive reflux disease, reflux esophagitis, and pathologic esophageal acid exposure at 0.5 cm and 2.0 cm above the Z line. Basal cell layer thickness and presence of dilated intercellular spaces did not identify patients with GERD. Among the criteria tested, the best agreement between assessments carried out at the 2 pathology centers was for total epithelial thickness at 0.5 cm and 2.0 cm above the Z line. Based on an analysis of 336 patients with frequent upper gastrointestinal symptoms, total epithelial thickness is a robust histologic marker for GERD.

Sa1305 Baseline Impedance Values Can Represent a Marker of Gastroesophageal Reflux Disease and Are Strongly Related With the Duration of the Disease

Sa1305 Baseline Impedance Values Can Represent a Marker of Gastroesophageal Reflux Disease and Are Strongly Related With the Duration of the Disease

Eosinophilic Gastrointestinal Disorders Affect More Than Just the Esophagus.

I n 1937, Dr R. Kaisjer provided the first description of eosinophilic gastroenteritis after reviewing surgical resections taken from various parts of the gastrointestinal (GI) tract (1). During the next few decades, other descriptions, again derived from whole tissue surgical specimens, followed. With the advent of flexible endoscopy in the 1960s, physicians were provided the necessary tools to procure mucosal biopsy samples from patients, escorting in a new era of defining the resident and pathological inflammatory cells of the intestinal mucosae. In the early 1980s, 2 publications identified eosinophils as markers of gastroesophageal reflux disease (2,3). The association of esophageal eosinophilia with gastroesophageal reflux disease held firm until the early 1990s when 3 publications provided the first descriptions of eosinophilic esophagitis (EoE) as a distinct disease entity (4,5,5a). Since then, 3 consensus recommendations and a European guideline have been published identifying and refining the diagnostic criteria for EoE (6–9). The emergence of EoE as an increasingly recognized distinct clinicopathological entity rekindled interest and raised questions about the role of the eosinophil in GI health and disease; for example, do eosinophils play a role in innate host defense and increase as a compensatory mechanism or is their increased presence a manifestation of a pathological inflammatory or allergic condition? (10,11). The latter explanation has certainly garnered more attention, and when tissue eosinophilia is seen in the context of organ-specific symptoms, with peripheral eosinophilia, without evidence of infection, and with resolution after steroid treatment, the diagnosis of an eosinophilic GI disease (EGIDs) is strongly considered.

The Status of Histopathology in the Diagnosis of Gastroesophageal Reflux Disease – Time for Reappraisal?

The histological diagnosis of gastroesophageal reflux disease is generally believed to be a tool of limited value. Recent data, however, indicate that histology may be useful for the management of patients with non-erosive reflux disease, who account for up to 60% of all patients with reflux symptoms. Early diagnosis of gastroesophageal reflux disease is crucial because chronic reflux esophagitis is a key risk factor for the development of Barrett´s esophagus, which predisposes to esophageal adenocarcinoma. Histologically, reflux esophagitis is characterized by basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory infiltration. These reflux-induced changes of the squamous epithelium are mainly related to the diagnosis of acute and/or active reflux. The chronic consequences of gastroesophageal reflux disease are mainly characterized by metaplatic mucosal replacement. The origin and significance of cardiac mucosa at the gastroesophageal junction are still controversial However, evidence is accumulating that injury and repair related to gastroesophageal reflux disease contribute to its development and/or expansion. Multilayered epithelium, defined as hybrid epithelium with characteristics of both squamous and columnar epithelium has been identified as a new sensitive marker of gastroesophageal reflux disease. This epithelium may be the precursor of metaplastic cardiac mucosa, and ultimately Barrett’s esophagus.

Dilated intercellular spaces in eosinophilic esophagitis.

Dilated intercellular spaces (DIS) in the esophageal epithelium can be induced by acid and reduced by proton pump inhibitors (PPI), and are thus considered a marker of gastroesophageal reflux disease (GERD). Over the years, however, DIS have also been reported in esophagitis unrelated to GERD. Because DIS have never been formally measured in eosinophilic esophagitis (EoE), we aimed at detecting and measuring DIS in EoE before and after nutritional or pharmacological therapy. In 22 children with EoE, DIS were measured by morphometry and transmission electron microscopy (TEM), before and after treatment with topical steroids (n = 16) and/or exclusion diet (n = 13). A total of 30 children undergoing upper gastrointestinal endoscopy with biopsy for nonesophageal disorders acted as controls. In controls, the mean (± standard deviation [SD]) number of esophageal eosinophils was 0.91 (± 0.47) and the mean DIS values were 0.62 (± 0.08) μm at morphometry and 0.33 (± 0.24) μm at TEM. In patients with EoE, the mean (± SD) number of esophageal eosinophils decreased from 31.8 (± 6.96) to 6.64 (± 5.01) (P < 0.0001), and the mean DIS values decreased from 2.26 (± 0.21) to 1.23 (± 0.20) μm at morphometry (P < 0.0001), and from 2.24 (± 0.28) to 0.98 (± 0.19) μm at TEM (P < 0.0001), respectively, before and after treatment. DIS are a prominent morphological feature of EoE, in which they can be significantly reduced by an appropriate non-PPI therapy.

Multilayered epithelium at the gastroesophageal junction is a marker of gastroesophageal reflux disease: data from a prospective Central European multicenter study (histoGERD trial)

Multilayered epithelium is defined as hybrid epithelium with characteristics of both squamous and columnar epithelia. Our aim was to evaluate the clinicopathological significance of the lesion by relating its presence to various histological and clinical and/or endoscopic features indicating gastroesophageal reflux disease (GERD). A total of 1,071 individuals participated in a prospective cross-sectional study (576 females and 495 males; median age 53 years). Biopsy material was systematically sampled from the gastroesophageal junction. The histological diagnosis of esophagitis was made according to the Esohisto consensus guidelines. The endoscopic diagnosis of esophagitis was made according to the modified Los Angeles classification and the diagnosis of Barrett's esophagus according to Prague's C & M criteria, respectively. Multilayered epithelium was identified in 103 (9.6 %) individuals, frequently within or adjacent to the ducts of esophageal glands. Its presence was associated with increasing age (p < 0.001), high BMI (p = 0.026), hiatal hernia (p < 0.001), and the endoscopic diagnoses of esophagitis (p = 0.002) and Barrett's esophagus (p < 0.001). Upon histology, multilayered epithelium was associated with features of the squamous epithelium indicating GERD, particularly intercellular space dilation (p = 0.005), and presence of cardiac mucosa (<0.001). For intestinal metaplasia, a trend was noted (p = 0.094). In conclusion, multilayered epithelium was observed in about every tenth individual undergoing upper gastrointestinal endoscopy. The association with histological and clinical features indicating GERD advocates the lesion as a promising new marker for reflux esophagitis. The association with cardiac mucosa and Barrett's esophagus suggests multilayered epithelium to be an intermediate step in the development of columnar metaplasia and, ultimately, Barrett's esophagus.

Rapid salivary pepsin test: Blinded assessment of test performance in gastroesophageal reflux disease

Pepsin lateral flow device (LFD) is a rapid noninvasive test to detect salivary pepsin as a surrogate marker for gastroesophageal reflux disease (GERD). We aimed to establish the test sensitivity, specificity, positive and negative predictive values (PPV, NPV) in patients with symptomatic and objective evidence of GERD compared to healthy controls. Prospective, blinded, controlled cohort study. A total of 230 samples were analyzed. In vitro bench testing was conducted on 52 gastric juice and 54 sterile water samples to assess test sensitivity and specificity. Saliva was collected from 58 patients with GERD and 51 controls. All patients with GERD underwent esophagogastroduodenoscopy (EGD) and wireless 48-hour pH monitoring off acid suppressive therapy. PPV and NPV were calculated based on disease definition of esophagitis and/or abnormal pH monitoring. Receiver operating characteristics analysis of in vitro samples found assay sensitivity and a specificity of 87%. There were 6/51 (12%) control subjects and 13/58 (22%) patients with GERD who tested positive for salivary pepsin (P = .25). There was a step-wise increase in the prevalence of positive salivary pepsin: esophagitis (55%), abnormal pH monitoring (43%), GERD symptoms only (24%) (P < .001). Salivary pepsin test showed a PPV of 81% and NPV of 78% for those with objective evidence of GERD (abnormal pH and/or esophagitis). Rapid LFD for salivary pepsin has acceptable test characteristics in patients with GERD. A positive salivary pepsin test in this group may obviate the need for more expensive diagnostic testing by EGD or pH monitoring.

E-Cadherin and the Esophagus

A molecular marker of gastroesophageal reflux disease might lead to early diagnosis and treatment.

Evaluation of Histologic Criteria for the Diagnosis of Gastroesophageal Reflux Disease

Background. Standardized criteria for the histologic assessment of gastroesophageal reflux disease (GERD) were recently developed and evaluated by an international working group, and showed promising levels of intraand inter-assessor agreement1. To gain clinical acceptance these criteria require appropriate validation2.Aim. To evaluate new criteria for histologic markers of GERD in a well characterized primary care population. Methods. The study included primary care patients from the Diamond study3 (ClinicalTrials.gov: NCT00291746) who had not previously taken proton pump inhibitors and who had upper gastrointestinal symptoms ≥ 2 times a week for ≥ 4 weeks, and at least mild symptoms on ≥ 3 days in the week before biopsy. GERD was diagnosed as any of the following: Los Angeles grade reflux esophagitis; distal esophageal pH 5.5% of 24 hours; ≥ 95% symptom association probability. Biopsies were collected at 0.5 cm and 2.0 cm above the Z-line and data were analyzed in a single-blind manner by one pathologist (MV). Variables assessed included total epithelial thickness (TET), papillary length (PL), basal cell thickness (all in μm), presence of dilated intercellular spaces (severity score: 0-2)1, number of inflammatory cells (in one high powered field), presence of necrosis, and presence of active or healed erosions. Logistic regression analysis of the histologic variables was performed for GERD versus non-GERD. Cut-off values for sensitivity, specificity, and predictive power (positive and negative) were calculated, and the receiver operating characteristic (ROC) curve was analyzed. Results. The analysis included 258 subjects: 138 (53%) GERD and 120 (47%) non-GERD. TET and PL (μm) at 0.5 cm and 2.0 cm were both significant predictors of GERD (p < 0.005), as was the presence of eosinophils at 2.0 cm (p < 0.05). The optimal efficiency based on the ROC analysis was observed for TET at 0.5 cm, with sensitivity and specificity values of 77% and 52%, and positive and negative predictive values of 65% and 66%, based on a cut-off of 390 μm. TET and PL were significant (p < 0.05) predictors of both reflux esophagitis and of pathologic esophageal pH. TET and PL were also significant predictors (p < 0.05) of non-erosive reflux disease versus non-GERD. Conclusions. Potential new criteria for the histologic evaluation of GERD showed good diagnostic properties when assessed in a well-characterized primary care population with upper gastrointestinal symptoms.

Refinement and Reproducibility of Histologic Criteria for the Assessment of Microscopic Lesions in Patients with Gastroesophageal Reflux Disease: the Esohisto Project

Standardized criteria for assessing microscopic esophageal lesions are required to test their utility as markers of gastroesophageal reflux disease (GERD). To finalize draft criteria for assessing microscopic esophageal lesions associated with gastroesophageal reflux and to test them for interobserver agreement. An international group of gastrointestinal pathologists was convened to finalize, using a consensus-based approach, draft criteria for recognizing microscopic esophageal lesions. Finalized criteria were retested for interobserver variability by four of the pathologists using 120 digitized esophageal biopsy slides from patients with GERD. The finalized criteria included further clarification on lesion definitions and new guidance on how to select the area for assessing each lesion. This latter refinement was guided by the high interobserver agreement observed when draft criteria were previously applied to biopsies where the assessment area was preselected. When finalized criteria were applied in the current study to digitized biopsies without a preselected assessment area, the pairwise agreement was 73-97% for basal cell hyperplasia, papillary elongation, intraepithelial eosinophil, neutrophil and mononuclear cell numbers, and active/healed erosions, with slightly lower agreement (64%) for dilated intercellular spaces (DIS). When a combined severity score was applied, the level of agreement was 77%. The mean kappa ranged from fair to high (0.26-0.77) for individual lesions and was high for the combined score (0.64). These levels of agreement are comparable with or higher than those for other accepted histologic definitions. Further steps include clinical validation of these criteria by correlating microscopic lesions with clinical variables such as esophageal acid exposure.

The feasibility of light microscopic measurements of intercellular spaces in squamous epithelium in the lower-esophagus of GERD patients

The study aims to determine whether light microscopy can be used to accurately measure the diameters of intercellular spaces between squamous epithelial cells in the lower esophagus, and whether changes in this outcome measure can be used as a diagnostic marker for gastroesophageal reflux disease (GERD). The study has two parts. Part 1 involves 42 asymptomatic controls and 119 patients with typical symptoms of GERD, including 58 with erosive esophagitis (EE), and 61 patients with nonerosive gastroesophageal reflux disease (NERD). All biopsies were taken from the lower esophagus. All samples were observed using an immersion objective, after which diameters were measured by computer-assisted morphometry. Part 2 involves 61 individuals who were randomly selected from part 1, including 19 controls, 13 with NERD and 29 with EE. Diameter measurements using both light microscopy and transmission electron microscopy (TEM) were performed for samples of 61 individuals. Samples from a total of 61 individuals (31 male, 30 female, mean age 44.3 ± 16.0 years) were observed using both light microscopy and TEM. Both methods showed significant differences between control and disease groups; the outcomes from the two methods had a certain correlation (r = 0.605, P = 0.000). Morphometric analysis of all 161 individuals (83 males, 78 females, mean age 41.4 ± 15.7) showed mean diameters from light microscopy to be 0.58 ± 0.16 µm for controls, 1.07 ± 0.30 µm for NERD, and 1.29 ± 0.20 µm for EE; differences between control and disease groups were significant (P<0.05). The optimal cut-off value from receiver operator characteristic analysis was 0.85 µm. Diagnoses were validated using the combination of symptoms of GERD, endoscopy, and 24 h ambulatory pH monitoring as the gold standard. At the optimal cutoff, sensitivity was 93.3% and specificity was 100%. The diameters of the intercellular spaces in squamous epithelium of lower esophagus from controls and in patients with GERD can be quantitatively measured using light microscopy. Dilated diameters can serve as a sensitive, specific, and objective indicator for diagnosis of GERD.

Variation of the Intercellular Space in the Esophageal Epithelium in Response to Hydrochloridric Acid Infusion in Patients with Erosive Esophagitis

ABSTRACT:The purpose of this study was to compare esophageal infusion with 0.1 N hydrochloridric acid (HCl) to esophageal infusion with saline in patients presenting with typical gastroesophageal reflux symptoms and erosive esophagitis.METHODS:Upper gastrointestinal endoscopy was performed on 44 prospective subjects, 29 of whom were included in the study. Eighteen patients presented with normal esophagi (Control Group “C”), nine of whom were infused with HCl and nine with saline. Eleven patients presented with erosive esophagitis (Lesion Group “L”), five of whom were infused with HCl and six with saline. Biopsies of the esophageal mucosa were collected before and after infusions.RESULTS:No statistically significant difference was found between the two types of infusions in terms of the dilation of the intercellular space of the esophageal epithelium, regardless of the status of the patient.CONCLUSIONS:Response to HCl infusion cannot be used as a marker for gastroesophageal reflux disease.

Multilayered Epithelium in Mucosal Biopsy Specimens From the Gastroesophageal Junction Region is a Histologic Marker of Gastroesophageal Reflux Disease

Barrett esophagus (BE) is defined as a columnar metaplasia of the distal esophagus that develops as a result of chronic gastroesophageal reflux disease (GERD). A distinctive type of multilayered epithelium (ME) that exhibits features of both squamous and columnar epithelium has been hypothesized to represent an early, or intermediate, phase in the development of BE. The aim of this prospective study was to evaluate the prevalence and specificity of ME in mucosal biopsies of the squamocolumnar junction (SCJ) from patients who had GERD, either with or without BE. During endoscopic examination of the esophagus, 2 biopsy specimens were obtained from across the SCJ from 27 patients with BE, 12 patients who had GERD without BE, and 14 controls who had no symptoms or endoscopic or histologic signs of GERD. ME was present at the SCJ in 33%, 33%, and 0% of BE, GERD, and control patients, respectively. Compared with control subjects, the prevalence of ME was significantly higher in both GERD and BE patients (P<0.05). In GERD patients without BE, ME was always detected adjacent to areas of cardia-type mucosa composed of mucous glands. ME from GERD patients and BE patients had a similar immunophenotype, showing expression of the intestinal markers MUC2 and cdx-2 in 38% and 77% of cases, respectively. The prevalence of expression of these markers in ME was significantly different from nongoblet epithelium in control patients. Our results provide further evidence that ME may represent an early, transitional form of columnar metaplasia, and that ME may be used as a histologic marker of reflux disease in mucosal biopsies from the gastroesophageal junction region.