Veerle Mertens

Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection

Acid gastro-oesophageal reflux (GOR) and gastric aspiration have been labelled as risk factors for chronic rejection bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). The present study aimed to further characterise GOR (both acid and nonacid) and the degree of gastric aspiration in LTx recipients both with and without BOS. Impedance-pH recordings were used for GOR detection. Pepsin and bile acid levels were measured in bronchoalveolar lavage fluid (BALF). A total of 48% of patients had increased GOR, of which 27% had exclusively increased nonacid reflux. Cystic fibrosis patients had the highest prevalence of GOR. Pepsin was found in BALF of all patients and bile acids in BALF of 50% of the patients. Patients with BOS had neither increased GOR nor elevated pepsin in BALF. However, 70% of the patients with BOS had bile in BALF compared with 31% of stable patients. Proton pump inhibitor (PPI) treatment reduced acid reflux but did not affect nonacid reflux. Moreover, pepsin and bile levels in BALF were not reduced by PPI. One-half of the lung transplant patients had increased reflux, and nonacid reflux was common. Gastric aspiration occurred in most lung transplant patients. Pepsin was a more general marker and bile acids a more specific marker that might be associated with bronchiolitis obliterans syndrome. Proton pump inhibitor treatment did not prevent nonacid reflux and gastric aspiration.

Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough

Symptoms, oesophageal pHmetry and proton pump inhibitor treatment are used for diagnosing gastro‐oesophageal reflux‐related cough. Weakly acidic reflux is now increasingly associated with reflux symptoms such as regurgitation or chest pain.

Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces.

Background: Severe duodeno-gastro-oesophageal reflux (DGOR) is a risk factor for oesophagitis and Barrett’s oesophagus. Patients with non-erosive reflux disease (NERD) have a slight increase in DGOR. Patients with gastro-oesophageal reflux disease (GORD), who are taking proton pump inhibitors (PPIs), still have reflux but of weakly acidic pH and persistence of bile. In these two groups of patients, heartburn might be due to increased oesophageal mucosal permeability and dilated intercellular spaces (DIS). We aimed to assess whether experimental short exposure of the oesophageal mucosa to bile acids, in low concentrations (at acidic, weakly acidic and neutral conditions) can increase mucosal permeability and provoke DIS. Methods: Rabbit oesophageal mucosa was studied in diffusion and Ussing chambers. We assessed the effects of different solutions containing bile acids, applied to the mucosal side, on transepithelial electrical resistance (RT) and permeability to fluorescein. The diameter of intercellular spaces was assessed by using transmission electron microscopy. Results: Incubation of oesophageal mucosa with acidic solutions (pH 2.0) containing a range of bile acids (0.5–5 mmol/l) markedly decreased RT and increased mucosal permeability. Weakly acidic solutions (pH 5.0), and to some extent neutral solutions (pH 7.4), containing some bile acids also decreased RT and increased permeability, although the effects were much less marked and in some combinations no effect was seen. Exposure to bile acids provoked DIS in acid and weakly acidic conditions but not in neutral (pH 7.4) solutions. Conclusions: Experimental short exposure of the oesophageal mucosa to solutions with a bile acid concentration and acidity similar to that observed in the gastric contents of patients with NERD or ERD, and who are taking PPIs, may impair oesophageal mucosal integrity and even induce dilated intercellular spaces. Such a situation could, theoretically, underlie the occurrence and/or persistence of symptoms in these patients.

MICROSCOPIC VASCULAR INVASION IS THE MOST RELEVANT PROGNOSTICATOR AFTER RADICAL NEPHRECTOMY FOR CLINICALLY NONMETASTATIC RENAL CELL CARCINOMA

PURPOSE Although many factors have been considered to predict the outcome after radical nephrectomy, renal cell carcinoma continues to behave unpredictably. In a retrospective study the correlation between microvascular tumor invasion and disease-free survival after surgery for renal cell carcinoma was analyzed. MATERIALS AND METHODS Between 1980 and 1993, 180 patients (mean age 60 years) were followed for a mean of 52 months after radical or partial nephrectomy for clinically localized renal cell carcinoma. The relevance of microscopic vascular invasion was compared to classical tumor staging, grade and tumor diameter. RESULTS Microscopic vascular invasion was found in 51 patients (28.3%), including 20 (39.2%) with progression (mean interval to progression 72 months). Of 129 patients with no pathological evidence of microscopic vascular invasion only 8 (6.2%) showed progression at a mean interval of more than 160 months. The difference in disease-free survival as a function of microvascular invasion was statistically highly significant (log rank p < 0.00001) and on multivariate analysis this parameter was by far the most relevant predictor of progression. CONCLUSIONS In patients who underwent radical nephrectomy for clinically nonmetastatic renal cell carcinoma with microvascular invasion but without lymph node involvement or macroscopic vascular invasion the chance of disease progression is estimated at 45% within 1 year. Microvascular invasion is the single most relevant prognosticator after presumed curative radical nephrectomy for renal cell carcinoma.

Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique

Background Oesophageal intraluminal impedance is currently used for assessment of reflux in gastro-oesophageal reflux disease (GORD). Oesophageal mucosa integrity may have a key role in heartburn perception in non-erosive reflux disease (NERD). Severe erosive oesophagitis is associated with low impedance baseline. We hypothesised that impedance baseline measurements could be used to evaluate changes in oesophageal mucosa integrity in man. Methods We measured oesophageal impedance baseline before, during and after acid perfusion in rabbits and healthy subjects. Transepithelial resistance (TER) was determined and dilated intercellular spaces (DIS) were assessed in isolated rabbit oesophageal mucosa. Impedance baseline was measured retrospectively at different levels of the oesophagus in impedance-pH recordings from asymptomatic volunteers and patients with GORD. Results In healthy subjects and rabbits, impedance baseline dropped dramatically during perfusion of control solution (pH 7.2) but after perfusion, impedance recovered. In rabbits, after perfusion with saline pH 1.5 and 1.0 impedance values remained a 39.1±7.0% and 63.9±6.5% (p<0.05) lower respectively. There was a positive correlation between in vivo basal impedance and in vitro TER values (r=0.72, p=0.0021). Tissue showed no erosions but both acidic solutions induced DIS. In healthy subjects, after perfusion with saline pH 2.0 and 1.0 the impedance baseline remained lower a 21.9±6.5% and 52.7±5.0%, (p<0.0001) respectively. Patients with GORD have a lower impedance baseline than healthy volunteers at the distal oesophagus. Conclusions Impedance baseline measurements might be used to evaluate the status of the oesophageal mucosa and to study the role of the impaired mucosal integrity in acid-induced heartburn in healthy volunteers and in patients with GORD.

Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus

Background Oesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on ‘exposed’ and ‘non-exposed’ oesophageal mucosa and its relationship to symptoms in healthy subjects. Methods 14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale. Results (1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the ‘exposed’ oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the ‘exposed’ but also in the more proximal ‘non-exposed’ mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments. Conclusions The human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms.

GASTRO-OESOPHAGEAL REFLUX AND ASPIRATION OF GASTRIC CONTENTS IN ADULT PATIENTS WITH CYSTIC FIBROSIS

Background: Gastro-oesophageal reflux (GOR) is increased in cystic fibrosis (CF), but its prevalence, characteristics, association with gastric aspiration and respiratory impact are not well characterised. We investigated acid and weakly acidic reflux, aspiration and respiratory symptoms/function in adult CF patients. Methods: Thirty-three CF patients [19 men; 29 (18–55) years, [10 post-lung transplant (LTx)] underwent impedance–pH monitoring for detection of acid (pH<4) and weakly acid GOR (pH 4–7). In 16 patients cough was objectively recorded with oesophageal manometry, and the symptom association probability (SAP) was calculated. Saliva and bronchoalveolar lavage fluid (BALF) were tested for bile acids. Results: Twenty-eight patients had increased GOR (21 acid, 5 weakly acidic and 2 acid+weakly acidic) and 10 had a positive SAP for reflux cough. GOR parameters were similar in non-LTx and post-LTx CF patients. The sequence reflux cough was significantly more common than cough reflux. Sixteen of 38 patients had bile acids in saliva and 6/10 in BALF and this was almost exclusively observed in patients with genotype DF508/DF508. Only 12/28 with increased GOR and 9/22 with bile acids in saliva/BALF had typical reflux symptoms. There was a positive correlation (r = 0.53, p = 0.03) between oesophageal acid exposure and cough. SAP-positive patients with for reflux cough had a lower lung function than SAP-negative patients. Conclusion: Increased GOR is prevalent in CF and not secondary to cough. Acid GOR is common, but weakly acidic GOR may also occur. CF patients have a high risk of aspiration and reflux seems to be associated with more cough and poorer lung function. Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in CF progression.

Effects of Lesogaberan on Reflux and Lower Esophageal Sphincter Function in Patients With Gastroesophageal Reflux Disease

BACKGROUND & AIMS Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. METHODS In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal 45-60 minutes after morning doses. Ambulatory impedance-pH monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-pH monitoring was conducted for 4 hours after the third dose on day 2. RESULTS Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by approximately 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). CONCLUSIONS In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs.

Azithromycin Reduces Gastroesophageal Reflux and Aspiration in Lung Transplant Recipients

Azithromycin (AZI) is a macrolide antibiotic that improves lung function in lung transplant recipients (LTx). Gastroesophageal reflux (GER) has been implicated in the pathogenesis of chronic rejection after LTx. Macrolide antibiotics may affect GER by modifying esophageal and gastric motility. The purpose of this study was to evaluate the effect of AZI on GER and gastric aspiration after LTx. Acid and weakly acidic GER was measured with 24-h pH-impedance monitoring in 47 LTx patients (12 patients “on” AZI). Gastric aspiration was assessed in a separate group of 30 LTx patients before and after AZI by measurements of pepsin and bile acid in bronchoalveolar lavage fluid (BALF). Patients “on” AZI had a significant lower total number of reflux events [41 (30–61) vs. 22.5 (7–37.5)], number of acid reflux events [24 (16–41) vs. 8 (4–18)], esophageal acid exposure [2.9% (0.7–7.3) vs. 0.2% (0.1–2.0)], bolus exposure [0.73% (0.5–1.4) vs. 0.21% (0.12–0.92)], and proximal extent of reflux [14 (9–24) vs. 5 (2–7)]. AZI reduced the concentration of bile acids in BALF without affecting levels of pepsin. LTx patients “on” AZI have less GER and bile acids aspiration. This effect might be due to enhanced esophageal motility and accelerated gastric emptying.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

Objectives: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. Patients and Methods: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH ≥ 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. Results: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. Conclusions: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.