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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.

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.

Increased esophageal sensitivity and impaired mucosal integrity have both been described in patients with gastroesophageal reflux disease, but the relationship between hypersensitivity and mucosal integrity is unclear. The aim of the present study was to investigate acid sensitivity in patients with erosive and nonerosive reflux disease and control subjects to determine the relation with functional esophageal mucosal integrity changes as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. In this prospective experimental study, 12 patients with nonerosive reflux disease, 12 patients with esophagitis grade A or B, and 11 healthy control subjects underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance, transepithelial permeability and gene expression of tight junction proteins and filaggrin. Patients with nonerosive reflux disease and esophagitis were more sensitive to acid perfusion compared with control subjects, having a shorter time to perception of heartburn and higher perceived intensity of heartburn. In reflux patients, enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. In conclusion, sensitivity to acid is enhanced in patients with gastroesophageal reflux disease, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Mucosal integrity of the esophagus is associated with the expression of filaggrin.

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.

In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.

Acid reflux episodes that extend to the proximal esophagus are more likely to be perceived. This suggests that the proximal esophagus is more sensitive to acid than the distal esophagus, which could be caused by impaired mucosal integrity in the proximal esophagus. Our aim was to explore sensitivity to acid and mucosal integrity in different segments of the esophagus. We used a prospective observational study, including 12 patients with gastroesophageal reflux disease (GERD). After stopping acid secretion-inhibiting medication, two procedures were performed: an acid perfusion test and an upper endoscopy with electrical tissue impedance spectroscopy and esophageal biopsies. Proximal and distal sensitivity to acid and tissue impedance were measured in vivo, and mucosal permeability and epithelial intercellular spaces at different esophageal levels were measured in vitro. Mean lag time to heartburn perception was much shorter after proximal acid perfusion (0.8 min) than after distal acid perfusion (3.9 min) ( P = 0.02). Median in vivo tissue impedance was significantly lower in the distal esophagus (4,563 Ω·m) compared with the proximal esophagus (8,170 Ω·m) ( P = 0.002). Transepithelial permeability, as measured by the median fluorescein flux was significantly higher in the distal (2,051 nmol·cm−2·h−1) than in the proximal segment (368 nmol·cm−2·h−1) ( P = 0.033). Intercellular space ratio and maximum heartburn intensity were not significantly different between the proximal and distal esophagus. In GERD patients off acid secretion-inhibiting medication, acid exposure in the proximal segment of the esophagus provokes symptoms earlier than acid exposure in the distal esophagus, whereas mucosal integrity is impaired more in the distal esophagus. These findings indicate that the enhanced sensitivity to proximal reflux episodes is not explained by increased mucosal permeability.

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

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.

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.

Water-perfused high-resolution manometry (HRM) catheters with 36 unidirectional pressure channels have recently been developed, but normal values are not yet available. Furthermore, the technique has not been validated and compared with solid-state HRM. We therefore aimed to develop normal values for water-perfused HRM and to assess the level of agreement between water-perfused HRM and solid-state HRM. We included 50 healthy volunteers (mean age 35 yr, range 21–64 yr; 15 women, 35 men). Water-perfused HRM and solid-state HRM were performed in a randomized order. Normal values were calculated as 5th and 95th percentile ranges, and agreement between the two systems was assessed with intraclass correlation coefficient (ICC) statistics. The 5th–95th percentile range was 3.0–6.6 cm/s for contractile front velocity (CFV), 141.6–3,674 mmHg·s·cm for distal contractile integral (DCI), 6.2–8.7 s for distal contraction latency (DL), and 1.0–18.8 mmHg for integrated relaxation pressure (IRP 4s). Mean (SD) and ICC for water-perfused HRM and solid-state HRM were 4.4 (1.1) vs. 3.9 (0.9) cm/s, ICC: 0.49 for CFV; 1,189 (1,023) vs. 1,092 (1,019) mmHg·s·cm, ICC: 0.90 for DCI; 7.4 (0.8) vs. 6.9 (0.9) s, ICC: 0.50 for DL; and 8.1 (4.8) vs. 7.9 (5.1), ICC: 0.39 for IRP 4s. The normal values for this water-perfused HRM system are only slightly different from previously published values with solid-state HRM, and moderate to good agreement was observed between the two systems, with only small differences in outcome measures.

BACKGROUND & AIMS: Patients with functional esophageal disorders present with symptoms of chest pain, heartburn, dysphagia, or globus in the absence of any structural abnormality. Visceral hypersensitivity is a feature of these functional disorders, and might be modulated by antidepressant therapy. We evaluated evidence for the efficacy of antidepressant therapy for symptoms associated with esophageal visceral hypersensitivity in patients with functional esophageal disorders or gastroesophageal reflux disease (GERD). METHODS: We performed a systematic search of the Cochrane Comprehensive Trial Register, MEDLINE, and EMBASE (through February 2014). We analyzed relevant randomized, placebo-controlled trials reporting the effect of antidepressant therapy on experimentally induced esophageal sensation or intensity, or frequency of heartburn, chest pain, dysphagia, or globus. RESULTS: The search strategy identified 378 articles; 15 described randomized controlled trials that were eligible for inclusion. In addition, 1 conference abstract and 2 case reports were included, providing the best available evidence on specific symptoms. Esophageal pain thresholds increased by 7% to 37% after antidepressant therapy. Antidepressant therapy reduced functional chest pain over a range from 18% to 67% and reduced heartburn in patients with GERD over a range of 23% to 61%. One study included patients with globus and none of the studies included patients with functional heartburn or functional dysphagia. CONCLUSIONS: Based on a systematic review, antidepressants modulate esophageal sensation and reduce functional chest pain. There is limited evidence that antidepressants benefit a subgroup of patients with GERD. More controlled trials are needed to investigate the effects of antidepressants on functional esophageal disorders.

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.

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.

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. 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. 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). Electrical tissue impedance spectroscopy is a new tool that can be used to evaluate esophageal mucosal integrity changes during endoscopy