Esophageal sensitivity to acid in patients with Barrett's esophagus is not related to preserved esophageal mucosal integrity.

BACKGROUND: Patients with Barrett's esophagus (BE) usually have severe gastroesophageal reflux. However, they often have surprisingly few reflux symptoms. We hypothesized that BE patients are less sensitive to acid than gastroesophageal reflux disease (GERD) patients without Barrett and that this is due to an unusual preservation of mucosal integrity of the squamous epithelium prohibiting transepithelial acid diffusion. METHODS: We prospectively analyzed esophageal sensitivity and esophageal mucosal integrity in GERD patients with and without BE and healthy subjects. An acid perfusion test was performed and mucosal integrity was assessed in vivo by electrical tissue impedance spectroscopy and ex vivo by Ussing chamber experiments with biopsy specimens. KEY RESULTS: Gastroesophageal reflux disease patients with BE were less sensitive to acid than GERD patients without BE, but more sensitive to acid than healthy controls (time to perception Barrett's 14.0 minutes, GERD 4.6 minutes, controls 17.5 minutes). However, extracellular impedance (6.2 and 5.7 vs 8.4×103  Ω/m) and transepithelial resistance (94.0 and 89 vs 118 Ω/cm2 ) was similar in BE and GERD patients and significantly lower than in healthy subjects. Transepithelial fluorescein flux was equally increased in GERD patients with and without BE (1.6 and 1.7×103 vs 0.6×103  nmol/cm2 /h). CONCLUSIONS & INFERENCES: Esophageal hypersensitivity to acid is less pronounced in BE patients than in GERD patients without Barrett. However, mucosal integrity of the squamous epithelium is equally impaired in GERD patients with and without Barrett, indicating that factors other than esophageal mucosal barrier integrity explain the difference in acid sensitivity between those with BE and those without.

Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn.

BACKGROUND: Patients with functional heartburn (FH) experience troublesome heartburn that is not related to gastroesophageal reflux. The etiology of the heartburn sensation in FH patients is unknown. In patients with reflux disease, esophageal hypersensitivity seems associated with impaired mucosal integrity. We aimed to determine esophageal sensitivity and mucosal integrity in FH and non-erosive reflux disease (NERD) patients. METHODS: In this prospective experimental study, we performed an acid perfusion test and upper endoscopy with biopsies in 12 patients with NERD and nine patients with FH. Mucosal integrity was measured during endoscopy using electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability. KEY RESULTS: Lag time to heartburn perception was significantly longer in FH patients (median 12 min) than in NERD patients (median 3 min). Once perceived, intensity of heartburn was scored equal with median visual analog scale 6.5 and 7.1 respectively. Esophageal mucosal integrity was also comparable between FH and NERD patients, both in vivo extracellular impedance and ex vivo transepithelial resistance and permeability were similar. CONCLUSIONS & INFERENCES: Patients with FH did not show acid hypersensitivity as seen in patients with NERD. However, once perceived, intensity of heartburn is similar. Esophageal mucosal integrity is similar between NERD and FH patients, and is therefore unlikely to be the underlying cause of the observed difference in esophageal acid perception.

Patients with refractory reflux symptoms often do not have GERD.

BACKGROUND: In patients with typical reflux symptoms that persist despite proton pump inhibitors (PPIs) it is sometimes overlooked that treatment fails due to the presence of other disorders than gastroesophageal reflux disease (GERD). The aim of this study was to determine the underlying cause of reflux symptoms not responding to PPI therapy in tertiary referral patients. METHODS: Patients with reflux symptoms refractory to PPI therapy who underwent 24-h pH-impedance monitoring were analyzed. Patients in whom a diagnosis was already established before referral, who had previous esophageal or gastric surgery, or who had abnormalities on gastroscopy other than hiatus hernia, were excluded. KEY RESULTS: In total, 106 patients were included. Esophageal manometry showed achalasia in two patients and distal esophageal spasm in another two. Twenty-four-hour pH-impedance monitoring revealed a total acid exposure time <6% in 60 patients (56.6%) of which 25 had a positive symptom association probability (SAP) while 35 showed a negative SAP. Sixty-nine patients ended up with a final diagnosis of GERD while 32 patients (30.2%) were diagnosed with functional heartburn (FH), two with functional chest pain, two with achalasia, and one with rumination. A trend toward an association with a final diagnosis of FH was found with the atypical symptom epigastric pain (p = 0.059) and with a secondary diagnosis of functional dyspepsia (p = 0.083). CONCLUSIONS & INFERENCES: Approximately one-third of the patients referred with refractory reflux symptoms suffer from disorders other than GERD, predominantly FH. This explains, at least partly, why many patients will not benefit from acid inhibitory treatment.

Normal values of esophageal motility after antireflux surgery; a study using high-resolution manometry.

BACKGROUND: Fundoplication is an effective therapy for gastroesophageal reflux disease (GERD), but can be complicated by postoperative dysphagia. High-resolution manometry (HRM) can assess esophageal function, but normal values after fundoplication are lacking. Our aim was to obtain normal values for HRM after successful Toupet and Nissen fundoplication. METHODS: Esophageal HRM was performed 3 months after Toupet or Nissen fundoplication in 40 GERD patients without postoperative dysphagia and with a normal barium esophagogram. Normal values for all measures of the Chicago classification were calculated as 5th and 95th percentile ranges. KEY RESULTS: The normal values (5th-95th percentiles) for integrated relaxation pressure (IRP) were higher after Nissen (5.1-24.4 mmHg) than after Toupet fundoplication (3.1-15.0 mmHg), and upper limit of normal was significantly higher after Nissen fundoplication than observed in the asymptomatic subjects that were described in the Chicago Classification. Distal contractile integral was significantly higher after Nissen (357-4947 mmHg*s*cm) than after Toupet (68-2177 mmHg*s*cm), and transition zone length was significantly shorter after Nissen (0-4.8 cm) than after Toupet fundoplication (0-12.8 cm). CONCLUSIONS & INFERENCES: HRM metrics for subjects after a Toupet fundoplication are similar to the normal values derived from healthy subjects used for the Chicago classification. However, after Nissen fundoplication a higher esophagogastric junction resting pressure and higher IRP are observed in asymptomatic subjects and this can be considered normal in the postoperative state. In addition, more vigorous contractions and less and smaller peristaltic breaks are normal after Nissen fundoplication.

Accuracy of hiatal hernia detection with esophageal high-resolution manometry.

BACKGROUND: The diagnosis of a sliding hiatal hernia is classically made with endoscopy or barium esophagogram. Spatial separation of the lower esophageal sphincter (LES) and diaphragm, the hallmark of hiatal hernia, can also be observed on high-resolution manometry (HRM), but the diagnostic accuracy of this finding has not yet been investigated. To determine the diagnostic value of HRM in the detection of hiatal hernia. METHODS: HRM recordings, endoscopy reports, and barium esophagograms of 90 patients were analyzed for the presence and size of a hiatal hernia. The diagnostic value of a hernia specific HRM pressure pattern was calculated, and the agreement of HRM with endoscopy and barium esophagogram for the assessment of hernia size. KEY RESULTS: HRM was found to be highly sensitive and specific for hiatal hernia detection, with a sensitivity of 92% and specificity of 95%, exceeding the sensitivity of endoscopy or radiography alone (both 73%). Patients with a hiatal hernia on HRM were manometrically characterized by an esophagogastric junction (EGJ) with partial or complete separation of the LES and crural diaphragm (CD), the latter being associated with significantly lower EGJ pressure. A cutoff value of spatial LES-CD separation on HRM of 1.85 cm yielded the optimal performance in identifying hiatal hernia. Agreement between HRM, endoscopy, and radiography for size of hiatal hernias was good (ICC [95% CI] 0.74 [0.65-0.82]). CONCLUSIONS & INFERENCES: With HRM, the presence or absence and size of a hiatal hernia can be assessed with greater sensitivity than with endoscopy or radiography alone.

Inter- and intrarater reliability of the Chicago Classification in pediatric high-resolution esophageal manometry recordings.

BACKGROUND: The Chicago Classification (CC) facilitates interpretation of high-resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software-based CC diagnosis in a pediatric cohort. METHODS: Thirty pediatric solid state HRM recordings (13M; mean age 12.1 ± 5.1 years) assessing 10 liquid swallows per patient were analyzed twice by 11 raters (six experts, five non-experts). Software-placed anatomical landmarks required manual adjustment or removal. Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL) and break size (BS), and an overall CC diagnosis were software-generated. In addition, raters provided their subjective CC diagnosis. Reliability was calculated with Cohen's and Fleiss' kappa (κ) and intraclass correlation coefficient (ICC). KEY RESULTS: Intra- and interrater reliability of software-generated CC diagnosis after manual adjustment of landmarks was substantial (mean κ = 0.69 and 0.77 respectively) and moderate-substantial for subjective CC diagnosis (mean κ = 0.70 and 0.58 respectively). Reliability of both software-generated and subjective diagnosis of normal motility was high (κ = 0.81 and κ = 0.79). Intra- and interrater reliability were excellent for IRP4s, DCI, and BS. Experts had higher interrater reliability than non-experts for DL (ICC = 0.65 vs ICC = 0.36 respectively) and the software-generated diagnosis diffuse esophageal spasm (DES, κ = 0.64 vs κ = 0.30). Among experts, the reliability for the subjective diagnosis of achalasia and esophageal gastric junction outflow obstruction was moderate-substantial (κ = 0.45-0.82). CONCLUSIONS & INFERENCES: Inter- and intrarater reliability of software-based CC diagnosis of pediatric HRM recordings was high overall. However, experience was a factor influencing the diagnosis of some motility disorders, particularly DES and achalasia.

Impact of spatial resolution on results of esophageal high-resolution manometry.

BACKGROUND: The Chicago classification for esophageal motility disorders was designed for a 36-channel manometry system with sensors spaced at 1 cm. However, many motility laboratories outside the USA use catheters with a lower resolution in the segments outside the esophagogastric junction. Our aim was to investigate the effect of spatial resolution on the Chicago metrics and diagnosis. METHODS: In 20 healthy volunteers and 47 patients with upper gastrointestinal symptoms, high-resolution manometric studies of the esophagus were retrospectively reanalyzed using the original 1-cm spacing in the segments outside the 7-cm esophagogastric junction segment, and again after manually increasing the spacing between sensors to 2, 3, and 4 cm (above the lower esophageal sphincter region). Measurements were analyzed in random order and the investigator was blinded to the outcome of the analyses performed in another resolution of the same patient. Intra-class correlation coefficients (ICC) and Kappa values were determined. KEY RESULTS: There was a very strong correlation between the 1-cm and 2-cm analysis for all Chicago metrics studied in healthy volunteers (ICCs: distal contractile integral 0.998; contractile front velocity (CFV) 0.964; distal latency 0.919; peristaltic break size 0.941). The 2-cm spacing analysis also correlated very well with the 1-cm analysis for the different Chicago diagnoses obtained in the patients (Kappa values ranging from 0.665 to 1.000). When the sensor spacing was increased to 3 and 4 cm, the correlation was reduced to moderate for the Chicago metrics, especially for break size and CFV of peristalsis. CONCLUSIONS & INFERENCES: The Chicago classification for esophageal motility disorders is still valid and the same normal values can be used when catheters with a slightly lower resolution are used (i.e., 2-cm vs 1-cm spacing). For larger sensor intervals, the classification and the normal values will need to be adjusted.

Normal values for solid-state esophageal high-resolution manometry in a European population; an overview of all current metrics.

BACKGROUND: Esophageal high-resolution manometry (HRM) allows accurate evaluation of esophageal motility. Normal values for HRM were established in the United States and several new parameters were introduced since. We aimed to provide a complete set of normal values for HRM obtained in a European population, including all current metrics used to describe the function of the upper esophageal sphincter (UES), the esophageal body, and the esophagogastric junction (EGJ). METHODS: Fifty healthy volunteers underwent esophageal HRM. Subjects swallowed 10 liquid boluses in supine position, after which UES, EGJ, and contraction wave parameters were evaluated. Mean and median values with 5-95th percentile ranges were calculated. KEY RESULTS: The normative thresholds (5-95th percentile) for the various parameters were; UES resting pressure 34.6-137.7 mmHg, UES residual pressure 0.0-8.5 mmHg, UES 0.2-s integrated relaxation pressure (IRP) 0.0-14.5 mmHg, EGJ length 3.1-6.3 cm, EGJ resting pressure 3.0-31.2 mmHg, EGJ 4-s IRP 2.0-15.5 mmHg, intrabolus pressure (IBP) 6.6-19.5 mmHg, distal contractile integral 178-2828 mmHg*s*cm, contractile front velocity (CFV) 2.9-5.9 cm s(-1) , distal latency 5.4-8.5 s, and transition zone length 0.0-8.2 cm. CONCLUSIONS & INFERENCES: Most HRM parameters assessed in this study resemble the previously described values on which the current criteria are based, supporting the widespread use of these criteria for clinical purposes. However, vigor of the esophageal contraction was lower and transition zone length larger than in previous reports. Peristaltic breaks occur frequently in healthy subjects.

Electrical tissue impedance spectroscopy: a novel device to measure esophageal mucosal integrity changes during endoscopy.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) have impaired esophageal mucosal integrity. Measurement of the mucosal integrity is complex and time-consuming. Electrical tissue impedance spectroscopy (ETIS) is a device that measures impedance of tissue in vivo during endoscopy. In this study, we aimed to validate ETIS as a measure of esophageal mucosal integrity. METHODS: Electrical tissue impedance spectroscopy measurements were performed during upper endoscopy in 12 GERD patients and 11 healthy controls after cessation of proton pump inhibition. During endoscopy biopsies of the distal esophagus were obtained for transmission electron microscopy to determine dilation of intercellular spaces (DIS) and for Ussing chamber experiments to determine transepithelial permeability and transepithelial electrical resistance. KEY RESULTS: Extracellular impedance measured in vivo by ETIS was significantly lower in GERD patients compared to controls [mean (SD) 5621 (3299) Ω.m and 8834 (2542) Ω.m, respectively, P < 0.05]. We found a strong inverse relation between extracellular impedance determined by ETIS and DIS (r = -0.76, P < 0.05), and between extracellular resistance in vivo and transepithelial permeability of esophageal biopsies (r = -0.65, P < 0.01). CONCLUSIONS & INFERENCES: Electrical tissue impedance spectroscopy is a new tool that can be used to evaluate esophageal mucosal integrity changes during endoscopy.

PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis.

BACKGROUND: Symptomatic response to proton pump inhibitor (PPI) therapy in patients with non-erosive reflux disease (NERD) is often reported as lower than in patients with erosive reflux disease (ERD). However, the definition of NERD differs across clinical trials. This meta-analysis aims to estimate the rate of symptom relief in response to PPI in NERD patients. METHODS: MEDLINE (1966-2010), Cochrane Comprehensive Trial Register (1997-2010) and EMBASE (1985-2010) databases were searched and manual searches from studies' references were performed. Randomized clinical trials were selected that included patients with heartburn, and analyzed the effect of short-term PPI treatment. The primary outcome of selected studies was defined as complete or partial heartburn relief. Two reviewers independently extracted data and assessed study quality of selected articles. Random effects models and meta-regression were used to combine and analyze results. KEY RESULTS: The pooled estimate of complete relief of heartburn after 4 weeks of PPI therapy in patients with ERD was 0.72 (95% CI 0.69-0.74) (32 studies), vs 0.50 (0.43-0.57) (eight studies) in empirically treated patients, 0.49 (0.44-0.55) (12 studies) in patients defined as non-erosive by negative endoscopy, and 0.73 (0.69-0.77) (two studies) in patients defined as non-erosive by both negative endoscopy and a positive pH-test. CONCLUSIONS & INFERENCES: In well-defined NERD patients, the estimated complete symptom response rate after PPI therapy is comparable to the response rate in patients with ERD. The previously reported low response rate in studies with patients classified as NERD is likely the result of inclusion of patients with upper gastrointestinal symptoms that do not have reflux disease.