Increased acid and bile reflux in Barrett's esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy

OBJECTIVES: Barrett's metaplasia is an acquired condition resulting from longstanding gastroesophageal reflux disease. Approximately 10% of esophagitis patients develop Barrett's esophagus. There is increasing evidence that duodenogastroesophageal reflux plays a role in the progression of disease. We further analyzed the correlation of acid and biliary reflux with reflux esophagitis and Barrett's esophagus and tested the effects of proton pump inhibitor therapy. METHODS: Patients with either reflux esophagitis (group 1) or Barrett's esophagus (group 2) prospectively underwent simultaneous 24-h esophageal pH and bile reflux testing without any therapy affecting acid secretion or GI motility. A total of 16 patients in group 1 and 18 patients in group 2 were tested again under proton pump inhibitor therapy. RESULTS: Acid and bile exposure were significantly increased in Barrett's patients (n = 23) compared to 20 esophagitis patients (median percentage of time that pH was <4 was 24.6% vs 12.4%, p = 0.01, median percentage of time that bilirubin absorbance was >0.2 was 34.7% vs 12.8%, p < 0.05). During therapy, both acid and bile reflux decreased significantly in both groups. Median percentage of time that pH was <4 and bilirubin absorbance was >0.2 before and during therapy was 18.2%/2.3% and 29.8%/0.7% (p = 0.001 and p = 0.001) in Barrett's esophagus patients versus 14.5%/3.6% and 21.5%/0.9% (p = 0.002 and p = 0.011) in esophagitis patients. There was no significant difference between the groups. In two esophagitis patients, bile reflux increased during therapy. CONCLUSIONS: There is a good correlation of the duration of esophageal exposure to acid and bile with the severity of pathological change in the esophagus. Both acid and bile reflux is significantly suppressed by proton pump inhibitor therapy with exceptions among individual esophagitis patients. The prolonged simultaneous attack of bile and acid may play a key role in the development of Barrett's metaplasia.     

Pathophysiology of functional heartburn based on Rome III criteria in Japanese patients

AIM: To investigate the pathophysiology of functional heartburn (FH) in Japanese patients.METHODS: A total of 111 patients with proton pump inhibitor (PPI)-refractory non-erosive gastroesophageal reflux disease underwent intraesophageal pressure testing and 24-h multichannel intraluminal impedance-pH (24MII-pH) testing. The patients also completed several questionnaires while they were receiving the PPI treatment, including the questionnaire for the diagnosis of reflux disease (QUEST), the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), the gastrointestinal symptoms rating scale (GSRS), SF-36, and the Cornell Medical Index (CMI). The subjects were classified into FH and endoscopy-negative reflux disease (ENRD) groups based on the Rome III criteria.RESULTS: Thirty-three patients with esophageal motility disorder were excluded from this study, while 22 patients with abnormal esophageal acid exposure time (pH-POS) and 34 with hypersensitive esophagus (HE) were included in the ENRD group. The FH group included 22 patients with no reflux involvement. Sex, age, and body mass index did not differ significantly between the groups. The mean SF-36 values were < 50 (normal) for all scales in these groups, with no significant differences. The GSRS scores in these groups were not different and showed overlap with other gastrointestinal symptoms. The QUEST and the FSSG scores did not differ significantly between the groups. Neuroticism was diagnosed using the CMI questionnaire in 17 of the 78 included subjects within the pH-POS (n = 4), HE (n = 8), and FH (n = 5) groups, with no significant differences.CONCLUSION: Clinical characteristics of the FH and PPI-refractory ENRD groups were similar. Therefore, esophageal function should be examined via manometry and 24MII-pH testing to differentiate between them.     

Clinical symptoms of FSSG in gastroesophageal reflux disease are critical for PPI treatment: Japanese multi‐centers with 185 patients

Aim: The main aim of this study was to determine whether questionnaire evaluations of clinical symptoms in gastroesophageal reflux disease were useful to assess proton pump inhibitor therapy. Methods: A total of 185 Japanese patients (men, 88; women, 97; age: 55.7 ± 16.1 years) with gastroesophageal reflux disease were enrolled. The patients were divided based on the frequency scale for symptoms of gastroesophageal reflux disease: severe symptoms with scores ≥8 and mild symptoms with scores ≤7. Quality of life was evaluated with the Medical Outcomes Study 8‐Item Short‐Form Health Survey. All patients were treated with a proton pump inhibitor, rabeprazole (10 mg/day), for 8 weeks. Results: Patients were classified into four groups: reflux esophagitis with severe symptoms (n = 92, 49.7%); reflux esophagitis with mild symptoms (n = 17, 9.2%); non‐erosive reflux disease with severe symptoms (n = 66, 35.7%); and non‐erosive reflux disease with mild symptoms (n = 10, 5.4%). The dysmotility score was high in non‐erosive reflux disease with severe symptoms compared with reflux esophagitis with severe symptoms (9.1 ± 0.5 vs 6.8 ± 0.5, P < 0.05). The symptom score and quality of life in the severe symptoms groups for both reflux esophagitis and non‐erosive reflux disease were significantly improved by rabeprazole treatment. Only the reflux score was improved by rabeprazole in the reflux esophagitis with mild symptoms group; no therapeutic effect was observed for the non‐erosive reflux disease with mild symptoms group. Conclusions: Low scores on the frequency scale for the symptoms of gastroesophageal reflux disease indicate poor responsiveness to proton pump inhibitor treatment, and high scores indicate good responsiveness.     

抑酸剂对脑手术应激病人的胃酸影响

目的：探讨抑酸剂质子泵抑制剂和Ｈ２受体拮抗剂对颅脑围手术期患者胃酸分泌的影响。方法：（１）３０例患者随机分组;Ｈ２受体拮抗剂泰胃美组,质子泵抑制剂洛赛克组和对照组。（２）所有病例均于手术前４小时监测胃内ｐＨ至７２小时;（３）分析颅脑手术患者术前,术中,术后胃内平均ｐＨ及ｐＨ〈４时间百分率。     

Suppressive Effect of Antiulcer Agents on Granulocytes—A Role for Granulocytes in Gastric Ulcer Formation

Many clinicians have believed that H₂-blockers and proton pump inhibitors ameliorate gastric ulcers via their antacid function. We examined the effects of these antacids on granulocytes. Gastric ulcer patients were administered an H₂-blocker or proton pump inhibitor for a week and the number of granulocytes and the superoxide production were examined. To determine the trafficking of granulocytes, mice were exposed to restraint stress for 24 hr. The H₂-blocker decreased the number of granulocytes, while the proton pump inhibitor suppressed their superoxide production in humans and mice. The major function of H₂-blockers and proton pump inhibitors in curing gastric ulcers seems to be their suppressive effects on granulocytes. In this case, stress accelerates the trafficking of granulocytes from the bone marrow to the gastric mucosa. If we demonstrate a role for granulocytes in gastric ulcer formation, an gap in the acid–pepsin theory and the Helicobacter pylori theory is filled in.     

Predictors of clinical response of acid suppression in Chinese patients with gastroesophageal reflux disease

BackgroundUp to 40% of patients with gastroesophageal reflux disease fail to respond to proton pump inhibitor therapy.AimsTo determine predictors of clinical response of proton pump inhibitor therapy.MethodsConsecutive patients with gastroesophageal reflux disease were enrolled prospectively. All patients underwent upper endoscopy and 24-h multichannel intraluminal impedance and pH monitoring before receiving esomeprazole 20 mg b.i.d. for 2 months. Multivariate logistic regression analysis was used to determine the independent predictors of clinical response to proton pump inhibitor therapy.ResultsA total of 204 patients with typical reflux symptoms were recruited and screened. Among them 153 patients (mean age 46.3 ± 10.6 years, 51.0% female) completed all the examinations and were assigned to proton pump inhibitor therapy. Ninety-five patients (62.1%) responded to acid suppression after 2 months. Multivariate logistic analysis showed that the predictor for response was pathological distal esophageal acid reflux (P = 0.001). The factors associated with proton pump inhibitor therapy failure were the presence of irritable bowel syndrome alone (P = 0.006), depression (P = 0.005), and overlap of irritable bowel syndrome and functional dyspepsia (P = 0.002).ConclusionsThe clinical response of acid suppression on gastroesophageal reflux disease could be predicted by clinical and pH parameters rather than impedance data.     

A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough

OBJECTIVE: Recent studies suggest an association between chronic cough and gastroesophageal reflux. Our study aims were 1) to define the prevalence of acid reflux induced cough in the general community, 2) to examine the ability of esophageal testing to identify gastroesophageal reflux related cough, and 3) to assess the utility of omeprazole in a chronic cough algorithm. METHODS: Patients with chronic cough of unknown etiology, who were mostly from the community, were evaluated. Subjects underwent a chest x-ray, methacholine challenge test, and empiric trial of postnasal drip therapy, and completed daily cough symptom diaries subjectively evaluating cough frequency and severity on a graded scale of 0-4 (combined maximum 8). After excluding other causes of cough, the remaining patients underwent esophageal and pH testing. Those testing positive were randomized to omeprazole 40 mg b.i.d. or placebo for 12 weeks. Follow-up was 1 yr. RESULTS: A total of 71 patients were screened; 48 were excluded. Twenty-three patients were evaluated for gastroesophageal reflux disease; six (26%) were eventually determined to have an acid-related cough. Of these patients, 17 had a positive pH test, six (35%) of whom showed a striking improvement or resolution of their cough during omeprazole treatment which was sustained for up to 1 yr. Six had a negative pH test, none of whom responded to omeprazole therapy. No significant differences were seen between responders (n = 6) and nonresponders (n = 11) for demographic factors, baseline symptom frequency and duration, or physiological parameters (motility/pH). CONCLUSIONS: Acid-related chronic cough was present in 26% (six of 23) of patients evaluated for gastroesophageal reflux disease. Esophageal testing does not reliably identify patients with acid induced chronic cough responsive to proton pump inhibitor therapy. We suggest that the best diagnostic and therapeutic approach, after excluding asthma and postnasal drip syndrome, is empiric treatment for 2 wk with a high dose proton pump inhibitor.     

Endoscopy-negative reflux disease

Endoscopy-negative reflux disease (ENRD) is more prevalent than reflux esophagitis, especially in a primary care setting. Acid-sensitive esophagus (ie, reflux-related symptoms with normal acid exposure at 24-hour pH monitoring) is part of the gastroesophageal reflux disease spectrum. ENRD is not a mild disease (symptoms return frequently and have an impact on quality of life), but it rarely progresses to the erosive stage. In patients with atypical or extra-esophageal manifestations, pH monitoring remains useful, and symptom analysis (symptom index or symptom-associated probability) is of pivotal importance. A proton pump inhibitor (PPI) test may represent a cost-effective alternative to 24-hour pH monitoring. However, well-designed validation studies are necessary to assess the diagnostic value of PPI tests and improve specificity without reducing sensitivity. Management of ENRD is based on the same principles as that of reflux esophagitis. Restoration of quality of life is the major goal. Proton pump inhibitors are not more (and are sometimes even less) effective in non-erosive reflux disease than in reflux esophagitis. Different long-term strategies (continuous maintenance, intermittent or on-demand therapy) are available, depending on the needs of the patient. Antireflux surgery may be indicated in carefully selected patients. In the future, pharmacologic approaches targeted to transient lower esophageal sphincter relaxation or visceral perception should be developed.     

On-demand proton pump inhibitor therapy in patients with gastro-oesophageal reflux disease

On-demand therapy is an established modality in long-term therapy with histamine-2-receptor antagonists, in cases of mild non-erosive gastro-oesophageal reflux disease. In the literature, only a few studies have specifically addressed the problem of proton pump inhibitors on-demand treatment. The evidence, so far, available suggests that this might be an effective modality of long-term treatment in the majority of patients with non-erosive gastro-oesophageal reflux disease. This treatment modality appears to be the most cost-effective and the best tolerated medical regimen for gastro-oesophageal reflux disease. It also seems to be able to restore the impairment of health-related quality of life due to gastro-oesophageal reflux disease symptoms. Although the current standard of care for patients with non-erosive gastro-oesophageal reflux disease is maintenance therapy with daily administration of a proton pump inhibitor agent, on-demand therapy, with the same drug, may be a reasonable long-term choice. The ideal proton pump inhibitors for such treatment will be those with a more rapid onset of action, more profound acid inhibition, more predictable therapeutic effect and less drug-drug interactions. Newer proton pump inhibitors, like esomeprazole, the S-chiral isomer of omeprazole, are promising drugs for on-demand treatment of gastro-oesophageal reflux disease.     

Clinically distinct characteristics in patients younger than 40 years old with non-cardiac chest pain

Background and Aim: Little is known about non‐cardiac chest pain (NCCP) in young patients. We aimed to examine the proportion of gastroesophageal reflux disease (GERD) in young patients with NCCP compared to the average‐aged NCCP patients and to evaluate their symptomatic characteristics and the clinical efficacy of a 2‐week proton pump inhibitor (PPI) trial. Methods: Ninety‐six patients with NCCP ≥ 1/week were classified into the young‐aged (≤ 40 years, n = 38) and the average‐aged groups (> 40 years, n = 58). Typical reflux symptoms were assessed. The patients were defined into a GERD group and non‐GERD group according to reflux esophagitis on esophagogastroduodenoscopy and/or pathologic acid exposure on 24‐h esophageal pH monitoring. Then the patients were treated with 30 mg of lansoprazole bid for 14 days. Results: Nine patients (23%) in the young‐aged group and 22 patients (38%) in average‐aged group were diagnosed with GERD‐related NCCP (P = 0.144). The proportion of typical reflux symptoms was higher in the GERD group compared with the non‐GERD group in both age groups. A PPI test improved symptoms in the GERD group irrespective of age, but this improvement was not observed in non‐GERD group. Conclusions: In young NCCP patients, the prevalence of GERD was relatively low compared to average‐aged NCCP, but the difference was insignificant. The PPI test was very effective in diagnosing GERD in the NCCP patients in both age groups. Therefore, in young NCCP patients, if there is a negative response to a 2‐week PPI trial, the possibility of extra‐esophageal disease origin needs to be considered.     

Treatment of non-erosive reflux disease with a proton pump inhibitor in Chinese patients: a randomized controlled trial

Background  

Evidence suggests that rates of gastroesophageal reflux disease are increasing in the Asia–Pacific region, where patients tend to have predominantly non-erosive reflux disease as opposed to erosive (reflux) esophagitis. At present, data for the responsiveness of non-erosive reflux disease to proton pump inhibition are scant. We aimed to study esomeprazole for the treatment of non-erosive reflux disease in Chinese patients.     

The Value of Early Wireless Esophageal pH Monitoring in Diagnosing Functional Heartburn in Refractory Gastroesophageal Reflux Disease

Background and Aims

It is difficult to differentiate functional heartburn from proton pump inhibitor (PPI) failure. The aims of this study were to assess the role of early wireless esophageal pH monitoring in patients referred with gastroesophageal reflux disease (GERD) and to identify differences in the clinical spectrum among GERD subtypes.

Methods

We enrolled consecutive referred patients with suspected GERD. After endoscopy on the first visit, all underwent wireless esophageal pH monitoring when off the PPI.

Results

Two hundred thirty patients were enrolled. These patients were classified into a reflux esophagitis group (20, 8.7 %) and a normal endoscopic findings group (210, 91.3 %). Among the 210 patients in the normal endoscopic findings group, 63 (27.4 %) were diagnosed with pathological reflux, 35 (15.2 %) with hypersensitive esophagus, 87 (37.8 %) with normal acid exposure with negative symptom association, and 25 (10.9 %) with test failure. These groups did not differ in age, body mass index, smoking habit, alcohol consumption, symptom severity, quality of life, presence of atypical symptoms, overlap with irritable bowel syndrome, and the frequency of somatization, depression, and anxiety. PPI responses were evaluated in 135 patients. Fifty patients (37.0 %) were not responsive to the 4-week treatment; 26 (19.3 %) were diagnosed with refractory non-erosive gastroesophageal disease, and 24 (17.8 %) with functional heartburn. The demographics and clinical and psychological characteristics did not differ between the two groups.

Conclusions

Demographic characteristics and symptom patterns alone cannot differentiate functional heartburn from various subtypes of GERD. Wireless esophageal pH monitoring should be considered for the initial evaluation of GERD in the tertiary referral setting.     

Randomised comparison of the FerX Ella antireflux stent and the ultraflex stent: proton pump inhibitor combination for prevention of post-stent reflux in patients with esophageal carcinoma involving the esophago-gastric junction

Background and Aim: Metal stents placed across the gastroesophageal junction in patients with malignant dysphagia frequently present with reflux symptoms. We compared an antireflux stent with a standard open stent used in combination with proton pump inhibitor medication. Methods: Forty‐nine patients with dysphagia due to inoperable carcinoma in the lower third of the esophagus were randomly selected to receive either a antireflux valve stent (FerX‐Ella) (n = 22) or a covered standard open stent (Ultraflex), which was combined with proton pump inhibitors such as omeprazole (n = 26). The technical success, the presence of reflux, and complications were recorded. Results: Reflux was seen in 3/22 patients (13.6%) in the FerX‐Ella group and in 2/26 patients (7.7%) in the Ultraflex and proton pump inhibitor combination group (P‐value not significant). In both groups, a significant improvement in the dysphagia score was seen and no statistically significant difference was detected between the two groups (P = 0.84). The FerX‐Ella stents migrated more frequently (32%) than the Ultraflex stents (23%). This also necessitated surgical intervention more frequently in the FerX‐Ella group (2/22, 9.1%) compared to the Ultraflex group (1/26, 3.8%). Conclusion: The antireflux stent had no demonstrable advantages compared to the combination of standard open stent and proton pump inhibitor medication.     

Laparoscopic anti-reflux surgery to treat proton pump inhibitor-resistant non-erosive reflux disease

We performed surgery for proton pump inhibitor-resistant non-erosive reflux disease patients whose symptom index, confirmed by combined multichannel intraluminal impedance–pH monitoring, was positive. Laparoscopic Nissen fundoplication was performed in five patients and laparoscopic Toupet fundoplication in 3 patients. In 6 of 8 patients, non-acid or minor acid reflux caused the symptoms. Satisfaction percentages assessed 1 year postoperatively were 12.5 % (excellent) and 87.5 % (good).The number of total reflux events decreased to 28.5 ± 14.4 % postoperatively. The symptom index decreased from 63.8 to 20.8 %. It is controversial whether the surgery reduces weakly acidic reflux to the same degree as acid reflux. Previous reports discuss the effect of laparoscopic Nissen fundoplication on acid and weakly acidic reflux; however, the results of these studies are contradictory. In our cases, laparoscopic Toupet fundoplication as well as Nissen fundoplication improved symptoms, and reduced acid and non-acid reflux similarly. These findings strongly support the importance of surgical intervention in proton pump inhibitor-resistant non-erosive reflux disease patients.     

Impact of antisecretory treatment on respiratory symptoms of gastroesophageal reflux disease in children

The effect of antisecretory treatment on extraesophageal symptoms of gastroesophageal reflux disease was evaluated. Seventy‐eight children presenting with typical and extraesophageal symptoms of gastroesophageal reflux disease underwent a multichannel intraluminal impedance and pH monitoring (MII/pH). Children with a positive MII/pH were randomly treated with proton pump inhibitors (PPIs) or histamine H₂‐receptor antagonists (H₂RAs) during 3 months. At the end of the treatment period, all patients were recalled. A second treatment period of 3 months was given to those patients who were not symptom‐free after 3 months. Thirty‐five of the forty‐one (85.4%) children with a pathologic MII/pH presented with extraesophageal symptoms and were treated with PPIs (omeprazole; n:19) or H₂RAs (ranitidine; n:16) for 12 weeks. After 3 months, 11/19 (57.9%) PPI‐treated patients had a complete resolution of symptoms; 6/8 nonresponders were treated with PPI for another 3 months and became all symptom‐free. The other two underwent a Nissen fundoplication. Only 5/16 (31.2 %) patients treated with H₂RAs had a complete resolution of symptoms after 3 months; 1/11 was treated again with H₂RAs during 3 months, and 10/11 were changed to PPIs. In 3/10, a partial resolution of symptoms was achieved, while in 7/10, a complete remission was obtained (P < 0.05). Antisecretory reflux treatment improves extraesophageal reflux symptoms. The efficacy of PPIs is superior to that of H₂RAs in these children.     

Functional heartburn and non-erosive reflux disease

Gastroesophageal reflux disease (GERD) is a common disorder in Western countries. For many years our attention has been focused on patients with erosive esophagitis, but in recent times we have realized that endoscopy-negative reflux disease is the most common presentation of this illness, affecting up to 70% of these individuals. Patients with the non-erosive form (NERD) are a heterogeneous group including various subpopulations with different mechanisms for their main symptom of heartburn: reflux of acidic and non-acidic gastric contents, mucosal hypersensitivity, intraesophageal distension by gas, intraduodenal infusion of fat, muscle contractions and psychological abnormalities. As to esophageal acid exposure, patients with NERD can be subdivided into those with abnormal and normal pH testing. The latter group includes patients with a positive correlation between symptoms and reflux events, in whom heartburn can be controlled by proton pump inhibitor (PPI) therapy. According to the recent Rome III criteria, they are still in the realm of GERD. An additional group is called functional heartburn, because this typical symptom is associated neither with an abnormal pH test nor with a positive symptom index. Their response to PPIs is very disappointing. Therefore, there is an increasing consensus on the fact that they do not have GERD and should be treated with drugs other than PPIs.     

Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis

BackgroundThe pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied.AimsTo assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis.MethodsCases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index.ResultsThe median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P > 0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallow-induced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P = 0.003).ConclusionsRefractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation.     

The prokinetic effect of mosapride citrate combined with omeprazole therapy improves clinical symptoms and gastric emptying in PPI-resistant NERD patients with delayed gastric emptying

Background  

Previous studies have shown that non-erosive reflux disease (NERD) patients are less sensitive to proton pump inhibitor (PPI) treatment than patients with erosive reflux disease. The aim of this study was to investigate whether treatment with prokinetics in addition to omeprazole therapy would improve clinical symptoms, gastric emptying and esophageal peristalsis in PPI-resistant NERD patients with or without delayed gastric emptying.     

Increased frequency and enhanced perception of reflux in non-erosive reflux disease patients non-responders to proton pump inhibitors

BackgroundThe unsatisfactory response to medical treatment in non-erosive patients is becoming a real challenge for gastroenterologists. Non-responder patients, evaluated under treatment, present symptoms which are related to non-acidic, mixed and proximal reflux episodes.MethodsTo elucidate the reflux pattern and mechanisms related to persistence of symptoms despite treatment, oesophageal pH-impedance was performed in 55 non-erosive responder and 24 non-responder patients, studied off therapy. Ten responder and 10 non-responder patients underwent a repeated study during proton pump inhibitor treatment.ResultsNon-responders were characterised by a higher overall number and larger proportion of symptomatic reflux episodes. Non-responders were also characterised by an enhanced sensitivity to acidic, mixed and proximal refluxes. Weakly acidic reflux accounted for 29% of symptomatic refluxes in non-responders and 34% in responders. Proportions of acidic and weakly acidic reflux episodes were comparable both in responders and non-responders when analysed off and on treatment.ConclusionsAn increased overall number of reflux episodes and enhanced sensitivity to reflux are strongly associated with treatment failure. Treatment strategies aimed at decreasing transient lower oesophageal sphincter relaxations, pain modulators or anti-reflux surgery should be considered in non-responders in whom a significant relationship between symptoms and reflux has been confirmed.