Patrizia Zentilin

The Role of Nonacid Reflux in NERD: Lessons Learned From Impedance-pH Monitoring in 150 Patients off Therapy

INTRODUCTION:Nonerosive reflux disease (NERD) is the most common form of gastroesophageal reflux disease. While the role of acid reflux has been established, the relevance of nonacid reflux in generating symptoms in NERD is unknown.AIM: To evaluate the diagnostic utility of impedance-pH monitoring in NERD patients.METHODS: Patients with typical reflux symptoms (heartburn and/or regurgitation) and normal endoscopy (NERD) underwent a combined impedance-pH monitoring off proton pump inhibitor (PPI) therapy. Previously investigated 48 healthy volunteers served as controls. Distal esophageal acid exposure (% time pH < 4), number of acid and nonacid reflux episodes, 2-min window symptom index (SI; positive if ≥ 50%), and symptom association probability (SAP; positive if ≥ 95%) were calculated.RESULTS: Between June 2004 and June 2007, 150 NERD patients (82 women, mean age 48 yr, range 18–78 yr) reported symptoms during the impedance-pH monitoring. NERD patients had more reflux episodes (median [25th–75th percentile]) compared with healthy volunteers (total: 46 [26–65] vs 32 [18–43], P < 0.05; acid: 29 [14–43] vs 17 [8.5–31.0], P < 0.05; and nonacid: 20 [15–27] vs 18 [13.5–26.0], P= NS). Sixty-three (42%) patients had abnormal % time pH < 4. Among 87 patients with normal % time pH < 4., 22 (15%) had a positive SAP for acid, 19 (12%) for nonacid reflux, and 7 (5%) for both. Classifying patients with symptomatic nonacid reflux as having a hypersensitive esophagus reduced the number of patients with functional heartburn from 65 (43%) to 39 (26%).CONCLUSION: Monitoring for nonacid reflux in NERD patients reduces the proportion of patients classified as having “functional heartburn.” Studies assessing the clinical implications of these findings are warranted.

Reassessment of the Diagnostic Value of Histology in Patients with GERD, Using Multiple Biopsy Sites and an Appropriate Control Group

BACKGROUND:Histology is generally considered as a tool of limited value in the diagnosis of gastro-esophageal reflux disease (GERD).AIM:To reevaluate the diagnostic role of histological alterations in GERD, using multiple biopsy sites and an appropriate control group.METHODS:We studied 135 patients with typical and atypical symptoms of GERD. They underwent upper GI endoscopy and Los Angeles classification was used for grading cases with mucosal breaks. Biopsies were taken at the Z-line, 2 and 4 cm above it. Microscopic esophagitis was identified by necrosis/erosion, neutrophil/eosinophil intraepithelial infiltration, basal cell hyperplasia, elongation of papillae, dilation of intercellular spaces and a score (range: 0–2) was given for each lesion. Twenty-four-hour esophageal pH monitoring was performed in each patient. Twenty subjects without reflux symptoms, and with normal endoscopy and pH testing were considered as controls.RESULTS:Histological alterations were found in 100 of 119 GERD patients (84%) and in 3 of 20 controls (15%) with a significant difference (p < 0.00001). Histology was abnormal in 96% of patients with erosive esophagitis and in 76% of patients with nonerosive reflux disease (NERD). The sum of scores of microscopic lesions found in all biopsy sites ranged from 0 to 22 and we identified a cut-off value (score 2) that distinguished efficiently controls from GERD patients.CONCLUSIONS:In contrast with previous reports on the marginal role of histology in patients with GERD, our study shows that this technique can be a useful diagnostic tool, particularly in patients with NERD, when biopsies are taken at two sites including Z-line and 2 cm above it.

Functional Heartburn has more in common with Functional Dyspepsia than with Non-Erosive Reflux Disease

Introduction: Functional dyspepsia and non-erosive reflux disease (NERD) are prevalent gastrointestinal conditions with accumulating evidence regarding an overlap between the two. Still, patients with NERD represent a very heterogeneous group and limited data on dyspeptic symptoms in various subgroups of NERD are available. Aim: To evaluate the prevalence of dyspeptic symptoms in patients with NERD subclassified by using 24 h impedance-pH monitoring (MII-pH). Methods: Patients with typical reflux symptoms and normal endoscopy underwent impedance-pH monitoring off proton pump inhibitor treatment. Oesophageal acid exposure time (AET), type of acid and non-acid reflux episodes, and symptom association probability (SAP) were calculated. A validated dyspepsia questionnaire was used to quantify dyspeptic symptoms prior to reflux monitoring. Results: Of 200 patients with NERD (105 female; median age, 48 years), 81 (41%) had an abnormal oesophageal AET (NERD pH-POS), 65 (32%) had normal oesophageal AET and positive SAP for acid and/or non-acid reflux (hypersensitive oesophagus), and 54 (27%) had normal oesophageal AET and negative SAP (functional heartburn). Patients with functional heartburn had more frequent (p<0.01) postprandial fullness, bloating, early satiety and nausea compared to patients with NERD pH-POS and hypersensitive oesophagus. Conclusion: The increased prevalence of dyspeptic symptoms in patients with functional heartburn reinforces the concept that functional gastrointestinal disorders extend beyond the boundaries suggested by the anatomical location of symptoms. This should be regarded as a further argument to test patients with symptoms of gastro-oesophageal reflux disease in order to separate patients with functional heartburn from patients with NERD in whom symptoms are associated with gastro-oesophageal reflux.

Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring.

RATIONALE Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. OBJECTIVES To characterize GER (acid and nonacid) in patients with SSc with and without ILD. METHODS Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). MEASUREMENTS AND MAIN RESULTS Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. CONCLUSIONS Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.

Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy.

OBJECTIVES:We sought to compare reflux and symptom association patterns in patients with nonerosive reflux disease (NERD), erosive esophagitis (EE), and in healthy volunteers (HVs).METHODS:Patients with EE and NERD underwent combined impedance–pH monitoring. Normal values were defined on the basis of previously collected data from 48 HVs. We evaluated distal esophageal acid exposure time (AET), number and type of reflux episodes (acid, nonacid), acid and bolus clearance times, proximal extension of reflux episodes, and symptom association probability (SAP).RESULTS:Distal AET (percentage time, pH<4) was higher (P<0.01) in 58 EE patients (median 7.4%, 25–75th percentile 4.2–9.9%) compared with 168 NERD patients (4.2% (1.2–6.4%)) and 48 HVs (0.7% (0.2–1.4%)). Patients with EE and NERD had a higher (P<0.01) number of acid reflux episodes compared with HVs (51 (37–66) vs. 34 (22–51) vs. 17 (8–31); P<0.05), but a similar number of nonacid reflux episodes (22 (15–39) vs. 23 (15–38) vs. 18 (14–26); P=NS). The percentage of reflux episodes reaching the proximal esophagus was higher (P<0.01) in EE patients (57% (45–73%)) than in NERD patients (45% (36–60%)) and HVs (33% (19–46%)). A positive SAP for heartburn or regurgitation was found in 161 of 168 (96%) NERD and 54 of 58 (93%) EE patients (P=NS).CONCLUSIONS:Acid reflux episodes, volume, and acid clearance are important factors in the pathogenesis of reflux-induced lesions. Nonacid reflux contributes less to esophageal mucosa damage, but is involved in the development of reflux symptoms in both NERD and EE patients.

Partial regression of Barrett's esophagus by long-term therapy with high-dose omeprazole☆☆☆★

BACKGROUND Barretts esophagus is mainly regarded as an acquired condition related to increased gastroesophageal reflux. Thus it is conceivable that abolition of acid reflux would lead to its regression. The aim of this study was to assess whether long-term treatment with high-dose omeprazole (60 mg/day) produces a consistent control of gastric acid production and normalizes the esophageal acid exposure, thus reducing the length of Barretts epithelium. METHODS Fourteen patients (8 men and 6 women, mean age 52 years) with histologic diagnosis of columnar epithelium longer than 3 cm in the distal part of the esophagus were enrolled and began receiving 60 mg of omeprazole in a single daily morning dose. Before therapy and after 6 and 12 months of therapy, all patients had endoscopy with four-quadrant biopsies at 2 cm intervals. A 24-hour esophagogastric pH recording was performed at entry and after 10 days, 6 months, and 12 months of treatment in all patients. RESULTS The initial length of Barretts epithelium (4.5 +/- 1.9 cm) was significantly reduced after 6 months (3.1 +/- 1.1; p < 0.01) and 12 months (2.1 +/- 1.6; p < 0.005) of treatment. Values were significantly lower at 12 than at 6 months (p < 0.03). The 24-hour mean gastric pH after 10 days (5.89 +/- 0.58), 6 months (5.71 +/- 0.55), and 12 months (5.54 +/- 0.76) of therapy was always higher (p < 0.001) than the basal level (1.9 +/- 0.49). No significant difference in gastric pH was seen over the treatment period. The 24-hour mean percent of time in which pH in the esophagus was below 4.0 decreased significantly (p < 0.001) from a basal rate of 29.4% to 3.5%, 3.0%, and 4.9% in the various time intervals of therapy. There was a normalization of esophageal acid exposure in all patients but two. CONCLUSIONS It can be concluded that the antisecretory effect of 60 mg/day of omeprazole is consistent and is kept constant throughout the entire 1-year treatment period. The consequent normalization of esophageal acid exposure in almost all patients in our series led to a partial, but significant, regression in the length of Barretts epithelium.

The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease

INTRODUCTION Functional heartburn is defined by Rome III criteria as an endoscopy-negative condition with normal oesophageal acid exposure time, negative symptom association to acid reflux and unsatisfactory response to proton pump inhibitors. These criteria underestimated the role of non-acid reflux. AIM To assess the contribution of impedance-pH with symptom association probability (SAP) analysis in identifying endoscopy-negative patients with reflux disease and separating them from functional heartburn. METHODS Consecutive endoscopy-negative patients treated with proton pump inhibitors (n=219) undergoing impedance-pH monitoring off-therapy were analysed. Distal acid exposure time, reflux episodes, SAP and symptomatic response to proton pump inhibitors were measured. RESULTS Based on impedance-pH/SAP, 67 (31%) patients were pH+/SAP+, 6 (2%) pH+/SAP-, 83 (38%) hypersensitive oesophagus and 63 (29%) functional heartburn. According to pH-metry alone/response to proton pump inhibitors, 62 (28%) were pH+/SAP+, 11 (5%) pH+/SAP-, 61 (28%) hypersensitive oesophagus and 85 (39%) functional heartburn. In the normal-acid exposure population the contribution of impedance-pH/SAP compared to pH-metry alone/response to proton pump inhibitors in identifying patients with reflux disease and functional heartburn resulted to be 10%. In patients with abnormal-acid exposure, the contribution of impedance-pH/SAP increased by 3%. CONCLUSION Comparing impedance-pH testing with pH-metry alone plus the response to proton pump inhibitor therapy demonstrated that the latter ones cause underestimation of reflux disease patients and overestimation of functional heartburn patients.

Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients

The aim of the study was to characterise gastro-oesophageal reflux (GOR) in idiopathic pulmonary fibrosis (IPF). 40 consecutive IPF patients underwent pulmonary high-resolution computed tomography (HRCT) scan and impedance-pH monitoring while off antisecretory therapy. The presence of pulmonary fibrosis was assessed using validated HRCT scores. Reflux features included distal oesophageal acid exposure, number of acid/weakly acidic reflux episodes and their proximal migration. 40 consecutive patients with interstitial lung disease other than IPF (non-IPF patients) and 50 healthy volunteers were also enrolled. IPF patients had significantly higher (p<0.01) oesophageal acid exposure (median (interquartile range (IQR)) 9.25 (4.7–15.4)% versus 3.3 (1.4–7.4)% versus 0.7 (0.2–4.2)%, number of acid (median (IQR) 45 (23–55) versus 32 (19–44) versus 18 (10–31)), weakly acidic (median (IQR) 34 (19–43) versus 21 (11–33) versus 18 (15–28)) and proximal reflux (median (IQR) 51 (26.5–65.5) versus 20 (9.5–34.5) versus 9 (5–20)) events compared to non-IPF patients and healthy volunteers, respectively. Pulmonary fibrosis HRCT scores correlated well with reflux episodes in both the distal (r2=0.567) and proximal (r2=0.6323) oesophagus. Patients with IPF had more bile acids and pepsin (p<0.03) in bronchoalveolar lavage fluid (BALF) (62% and 67%, respectively) and saliva (61% and 68%, respectively) than non-IPF patients (25% and 25% in BALF, and 33% and 36%, respectively, in saliva) and controls (0% and 0% in BALF and saliva, respectively). Acid GOR is common in IPF, but weakly acidic GOR may also occur. Patients with IPF had a risk of pulmonary aspiration of gastric contents. Outcome studies with intense antireflux therapy are needed. Frequent acid/weakly acidic gastro-oesophageal reflux and high risk of pulmonary aspiration of gastric contents in IPF http://ow.ly/nSNv8

NERD: an umbrella term including heterogeneous subpopulations.

Nonerosive reflux disease (NERD) represents the more common phenotypic presentation of GERD and comprises patients who have typical symptoms without any mucosal breaks at endoscopy. However, these patients are markedly heterogeneous from a pathophysiological point of view and should be correctly classified by means of 24 h impedance–pH testing, which enables detection of both acidic and weakly acidic reflux and correlation with symptoms. This technique is able to identify two subsets of NERD (that is, patients with an excess of acid or with a hypersensitive oesophagus to both acid and weakly acidic reflux) and patients with functional heartburn (who do not have any kind of reflux underlying their symptoms and must be excluded from the realm of GERD). The mechanisms of symptom generation are not clear in patients with NERD, but the presence of microscopic oesophagitis, including the dilation of intercellular spaces, seems to have a relevant role. Patients with NERD in whom acid is the main pathogenetic factor respond successfully to PPI therapy, while those with hypersensitive oesophagus to weakly acidic reflux need to be treated with reflux inhibitors or surgery, although the experience in this field is very scant. Patients with functional heartburn should undergo therapy with pain modulators, but large placebo-controlled trials are necessary.

Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease.

Aliment Pharmacol Ther 2011; 34: 476–486