Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

Abstract

Given the widespread use of potent acid suppressive therapies and primary caregivers' increasing comfort with prescribing these medications at high doses, the patient population presenting to gastroenterologists for symptoms of gastroesophageal reflux disease (GERD) has changed. Whereas previous consultation often revolved around the control of erosive disease and other mucosal manifestations of GERD, and terminated with the prescription of proton pump inhibitor (PPI) therapy, gastroenterologists often now only enter the scene after failure of PPI therapy, for symptoms either resistant or only partially responsive to these medications. Because of the high proportion of subjects with esophagitis who are healed with PPI,1Castell D.O. Kahrilas P.J. Richter J.E. et al.Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis.Am J Gastroenterol. 2002; 97: 575-583Google Scholar, 2Kahrilas P.J. Falk G.W. Johnson D.A. et al.The Esomeprazole Study InvestigatorsEsomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial.Aliment Pharmacol Ther. 2000; 14: 1249-1258Google Scholar upper endoscopy of such individuals is low yield,3Poh C.H. Gasiorowska A. Navarro-Rodriguez T. et al.Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment.Gastrointest Endosc. 2010; 71: 28-34Google Scholar with only a small minority demonstrating erosive disease. The care of such patients is challenging. High-quality evidence supporting useful diagnostic testing or alternative effective therapies is largely lacking. However, the number of subjects with GERD symptoms incompletely or nonresponsive to PPI therapies is high, and their utilization of healthcare resources is substantial. The purpose of this mini-review is to examine the definition and epidemiology of esophageal GERD symptoms incompletely responsive to PPI therapy, the potential pathophysiologic mechanisms behind these symptoms, the differential diagnosis and evaluation of such patients, and current and developing therapeutic options. Incomplete response of classic GERD symptoms, such as heartburn and regurgitation, to PPI therapy is common. A recent American Gastroenterological Association survey of >1000 subjects receiving PPI therapy for GERD symptoms demonstrated that 38% reported residual symptoms, and that more than half of those with residual symptoms took additional medication to control symptoms, most commonly over-the-counter antacids (47%).4AGAGERD patient study: Patients and their medications.http://www.gastro.org/user-assets/documents/13_Media/GERD_Survey_Final_Report_2.pdf,2008Google Scholar A systematic review of symptom control in trials of PPI therapy for GERD demonstrated that only a minority of subjects with GERD achieved complete symptom control on therapy.5Dean B.B. Gano Jr., A.D. Knight K. et al.Effectiveness of proton pump inhibitors in nonerosive reflux disease.Clin Gastroenterol Hepatol. 2004; 2: 656-664Google Scholar Interestingly, this analysis demonstrated that subjects entering GERD trials as nonerosive patients were less likely to achieve symptom control than were erosive patients (37% vs 57%; P < .001). Despite the common nature of incomplete control of GERD symptoms on PPI therapy, a universal definition for “PPI-refractory GERD” is lacking. Is a subject PPI refractory after incomplete control at once daily dosing? Should twice daily (BID) or other regimens be required before a subject is considered refractory? Previous work demonstrates that a substantial number of subjects (as high as 32%) on daily PPI continue to demonstrate abnormal distal esophageal acid exposures, and that this proportion can be lowered to single digits by increasing standard therapy to BID PPI.6Bajbouj M. Becker V. Phillip V. et al.High-dose esomeprazole for treatment of symptomatic refractory gastroesophageal reflux disease—a prospective pH-metry/impedance-controlled study.Digestion. 2009; 80: 112-118Google Scholar, 7Charbel S. Khandwala F. Vaezi M.F. The role of esophageal pH monitoring in symptomatic patients on PPI therapy.Am J Gastroenterol. 2005; 100: 283-289Google Scholar However, US Food and Drug Administration-approved dosing of these medications does not extend to BID therapy. Because BID therapy is commonly employed and has been recommended as a therapeutic trial in subjects refractory to once daily therapy,8Kahrilas P.J. Shaheen N.J. Vaezi M.F. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease.Gastroenterology. 2008; 135: 1392-1413Abstract Full Text Full Text PDF Scopus (342) Google Scholar for purposes of this discussion, refractory subjects will be considered as having troublesome symptoms despite BID PPI therapy. The Montreal classification defines GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.”9Vakil N. van Zanten S.V. Kahrilas P. et al.The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.Am J Gastroenterol. 2006; 101: 1900-1920Google Scholar Which symptoms are considered “troublesome” is left to the discretion of the patient. This classification further divides GERD into esophageal and extraesophageal syndromes, and subdivides esophageal syndromes as those manifest with esophageal injury, such as esophagitis, stricture, or Barrett's esophagus, and those manifest solely by troublesome symptoms. In such a scheme, a subject with heartburn and an incomplete response to PPI, who had no history of mucosal disease on or off therapy, in whom GERD was causing bothersome symptoms, would be classified as a nonerosive typical esophageal reflux patient. When patients have symptoms of ongoing reflux despite maximal PPI therapy, the main clinical question is: Are these symptoms related to gastroesophageal reflux? There is a broad differential diagnosis to consider, and potential etiologies may be gastrointestinal (GI) or non-GI related. The GI etiologies can be esophageal or nonesophageal, and the former may be reflux or non-reflux related. There are 3 major categories of reflux-related causes. First is reflux with ongoing acid exposure. Etiologies include incorrect medication dose timing, medication noncompliance, residual pathologic acid secretion, rapid PPI metabolism, a hypersecretory state, a significant anatomic abnormality like a large hiatal hernia, excess reflux during transient lower esophageal sphincter relaxations (tLESRs), or defective esophageal mucosal barrier function. Second is reflux of nonacid material from either the stomach or the duodenum (e.g., bile). Third is reflux of normal amounts of weakly acidic or alkaline contents into a hypersensitive esophagus. The non-reflux–related esophageal causes include dysmotility syndromes such as achalasia, esophageal spasm, or scleroderma; eosinophilic esophagitis; pill esophagitis; and infectious esophagitis. In the absence of structural, motility, or inflammatory causes, functional heartburn or function chest pain should be considered, depending on the primary symptom. It is beyond the scope of this mini-review to discuss the nonesophageal causes of reflux-type symptoms in detail, but typical conditions to consider include gallbladder disease, malignancy in the GI system or surrounding organs, cardiovascular disease, and musculoskeletal disease. The putative mechanisms of PPI-refractory GERD symptoms are illustrated in Figure 1. Similar to the differential diagnosis for symptoms, the mechanisms can be either reflux or non-reflux related. As noted, relatively few patients maintain pathologic levels of esophageal acid exposure despite appropriately administered BID therapy.6Bajbouj M. Becker V. Phillip V. et al.High-dose esomeprazole for treatment of symptomatic refractory gastroesophageal reflux disease—a prospective pH-metry/impedance-controlled study.Digestion. 2009; 80: 112-118Google Scholar, 7Charbel S. Khandwala F. Vaezi M.F. The role of esophageal pH monitoring in symptomatic patients on PPI therapy.Am J Gastroenterol. 2005; 100: 283-289Google Scholar There are several mechanisms to explain elevated esophageal acid exposures despite PPI therapy. First, there may be medication noncompliance. Only 60%–67% of PPI prescriptions are actually filled, and compliance with medication is <50% at 1 year after prescription.10El-Serag H.B. Fitzgerald S. Richardson P. The extent and determinants of prescribing and adherence with acid-reducing medications: a national claims database study.Am J Gastroenterol. 2009; 104: 2161-2167Google Scholar A related issue is whether the medication is taken correctly. The PPI must be activated within the parietal cell canaliculus for binding with the H-K ATPase.11Wolfe M.M. Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome.Gastroenterology. 2000; 118: S9-S31Google Scholar Because the greatest number of pumps are present in the preprandial state, the typical recommendation is to administer the medication before breakfast.11Wolfe M.M. Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome.Gastroenterology. 2000; 118: S9-S31Google Scholar, 12Robinson M. Review article: the pharmacodynamics and pharmacokinetics of proton pump inhibitors—overview and clinical implications.Aliment Pharmacol Ther. 2004; 20: 1-10Google Scholar Despite instruction, more than half of patients dose PPIs suboptimally.13Gunaratnam N.T. Jessup T.P. Inadomi J. et al.Sub-optimal proton pump inhibitor dosing is prevalent in patients with poorly controlled gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2006; 23: 1473-1477Google Scholar Another explanation may be related to PPI metabolism. Although individual PPIs are metabolized by different hepatic cytochrome isoenzymes, there is patient-level variability in drug metabolism. It is conceivable that a “rapid” PPI metabolizer might not achieve high enough serum levels for adequate acid suppression,14Furuta T. Shirai N. Sugimoto M. et al.Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies.Drug Metab Pharmacokinet. 2005; 20: 153-167Google Scholar, 15Klotz U. Impact of CYP2C19 polymorphisms on the clinical action of proton pump inhibitors (PPIs).Eur J Clin Pharmacol. 2009; 56: 1-2Google Scholar, 16Hunfeld N.G. Mathot R.A. Touw D.J. et al.Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians.Br J Clin Pharmacol. 2008; 65: 752-760Google Scholar but this is likely a small proportion of treatment failures. Nocturnal acid breakthrough is also related to PPI metabolism, and may be responsible for persistent symptoms in some patients,17Fass R. Sifrim D. Management of heartburn not responding to proton pump inhibitors.Gut. 2009; 58: 295-309Google Scholar but the correlation between symptoms and acid exposures is poor.18Nzeako U.C. Murray J.A. An evaluation of the clinical implications of acid breakthrough in patients on proton pump inhibitor therapy.Aliment Pharmacol Ther. 2002; 16: 1309-1316Google Scholar In the correct clinical context, for example if small bowel ulceration accompanies refractory reflux and diarrhea, a hypersecretory state such as Zollinger-Ellison syndrome could be considered. However, this remains an uncommon cause of refractory reflux, and PPIs are the recommended initial treatment for Zollinger-Ellison syndrome.19Osefo N. Ito T. Jensen R.T. Gastric acid hypersecretory states: recent insights and advances.Curr Gastroenterol Rep. 2009; 11: 433-441Google Scholar A final mechanism involves disruption of the antireflux barrier at the gastroesophageal junction, due to either a hiatal hernia or a hypotensive lower esophageal sphincter (LES). A number of medications and foods (eg, anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines, chocolate, caffeine, alcohol, peppermint) cause decreased LES pressures.20Kahrilas P.J. Clinical practice Gastroesophageal reflux disease.N Engl J Med. 2008; 359: 1700-1707Google Scholar, 21Tutuian R. Adverse effects of drugs on the esophagus.Best Pract Res Clin Gastroenterol. 2010; 24: 91-97Google Scholar tLESRs are the major mechanism of both physiologic and pathologic reflux.22Dodds W.J. Dent J. 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Criteria for objective definition of transient lower esophageal sphincter relaxation.Am J Physiol. 1995; 268: G128-G133Google Scholar Gastric distention, mediated by a vagal reflex arc, can prompt tLESRs, allowing for venting gas and, in patients with reflux disease, the reflux of gastric contents.24Pandolfino J.E. Zhang Q.G. Ghosh S.K. et al.Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry.Gastroenterology. 2006; 131: 1725-1733Abstract Full Text Full Text PDF Scopus (156) Google Scholar, 26Pandolfino J.E. Ghosh S.K. Zhang Q. et al.Upper sphincter function during transient lower oesophageal sphincter relaxation (tLOSR); it is mainly about microburps.Neurogastroenterol Motil. 2007; 19: 203-210Google Scholar PPIs do not have any effect on tLESRs; they are acid-suppressive medications, but do not inhibit the reflux of gastric contents. In patients where tLESRs are the predominant pathophysiologic mechanism of reflux, PPIs may neutralize gastric acid, but do not affect the underlying cause. The observation that tLESRs can be inhibited by gamma aminobutyric acid receptor type B (GABA) agonists, however, has opened new therapeutic possibilities (see below).27Lehmann A. Antonsson M. Bremner-Danielsen M. et al.Activation of the GABA(B) receptor inhibits transient lower esophageal sphincter relaxations in dogs.Gastroenterology. 1999; 117: 1147-1154Google Scholar, 28Lehmann A. Antonsson M. Holmberg A.A. et al.(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action.J Pharmacol Exp Ther. 2009; 331: 504-512Google Scholar PPIs convert acidic refluxate to nonacidic refluxate.29Vela M.F. Camacho-Lobato L. Srinivasan R. et al.Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole.Gastroenterology. 2001; 120: 1599-1606Google Scholar However, reflux of nonacidic fluid can also be associated with symptoms of reflux. Combined multichannel intraluminal impedance and pH monitoring allows detection of nonacid reflux.30Srinivasan R. Vela M.F. Katz P.O. et al.Esophageal function testing using multichannel intraluminal impedance.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G457-G462Google Scholar, 31Tutuian R. Vela M.F. Shay S.S. et al.Multichannel intraluminal impedance in esophageal function testing and gastroesophageal reflux monitoring.J Clin Gastroenterol. 2003; 37: 206-215Google Scholar, 32Vela M.F. Non-acid reflux: detection by multichannel intraluminal impedance and pH, clinical significance and management.Am J Gastroenterol. 2009; 104: 277-280Google Scholar This technology is able to characterize patients with ongoing reflux symptoms, but negative traditional pH testing because impedance monitoring can identify reflux of gas, mixed refluxate, and weakly or nonacid reflux.33Mainie I. Tutuian R. Shay S. et al.Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.Gut. 2006; 55: 1398-1402Google Scholar, 34Zerbib F. Roman S. Ropert A. et al.Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy.Am J Gastroenterol. 2006; 101: 1956-1963Google Scholar, 35Sharma N. Agrawal A. Freeman J. et al.An analysis of persistent symptoms in acid-suppressed patients undergoing impedance-pH monitoring.Clin Gastroenterol Hepatol. 2008; 6: 521-524Google Scholar Such reflux events may be promoted by tLESRs, hypotensive LES, a gastroesophageal junction anatomic defect, or a combination of these factors.36Richter J.E. Role of the gastric refluxate in gastroesophageal reflux disease: acid, weak acid and bile.Am J Med Sci. 2009; 338: 89-95Google Scholar Higher proximal extent of refluxate and reflux of mixed gaseous/liquid content are primary determinants of symptom generation.37Tutuian R. Vela M.F. Hill E.G. et al.Characteristics of symptomatic reflux episodes on Acid suppressive therapy.Am J Gastroenterol. 2008; 103: 1090-1096Google Scholar Bile acid reflux is also a potential cause of residual symptoms. Bile reflux can potentiate erosive esophagitis caused by an acidic refluxate, as well cause PPI-refractory reflux symptoms in the absence of acid exposure.38Tack J. Koek G. Demedts I. et al.Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or both?.Am J Gastroenterol. 2004; 99: 981-988Google Scholar, 39Siddiqui A. Rodriguez-Stanley S. Zubaidi S. et al.Esophageal visceral sensitivity to bile salts in patients with functional heartburn and in healthy control subjects.Dig Dis Sci. 2005; 50: 81-85Google Scholar Esophageal mechanoreceptors mediate stretch stimuli, and may be responsible for reflux symptoms.40Ang D. Sifrim D. Tack J. Mechanisms of heartburn.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 383-392Google Scholar In healthy volunteers, heartburn and chest pain can be induced through activation of mechanoreceptors by balloon distension41Patel R.S. Rao S.S. Biomechanical and sensory parameters of the human esophagus at four levels.Am J Physiol. 1998; 275: G187-G191Google Scholar in a process that can be independent of the presence of acid,42Fass R. Naliboff B. Higa L. et al.Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.Gastroenterology. 1998; 115: 1363-1373Google Scholar, 43DeVault K.R. Acid infusion does not affect intraesophageal balloon distention-induced sensory and pain thresholds.Am J Gastroenterol. 1997; 92: 947-949Google Scholar or exacerbated by it.44Peghini P.L. Johnston B.T. Leite L.P. et al.Mucosal acid exposure sensitizes a subset of normal subjects to intra-oesophageal balloon distension.Eur J Gastroenterol Hepatol. 1996; 8: 979-983Google Scholar Some patients with functional heartburn may have sensitization of these receptors as a mechanism of their symptoms.40Ang D. Sifrim D. Tack J. Mechanisms of heartburn.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 383-392Google Scholar, 42Fass R. Naliboff B. Higa L. et al.Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.Gastroenterology. 1998; 115: 1363-1373Google Scholar In addition, stimulation of mechanoreceptors may trigger a vagally mediated reflux arc that induces cough, bronchospasm, or other extraesophageal symptoms.36Richter J.E. Role of the gastric refluxate in gastroesophageal reflux disease: acid, weak acid and bile.Am J Med Sci. 2009; 338: 89-95Google Scholar, 45Canning B.J. Mazzone S.B. Reflex mechanisms in gastroesophageal reflux disease and asthma.Am J Med. 2003; 115: 45S-48SGoogle Scholar, 46Vaezi M.F. Atypical manifestations of gastroesophageal reflux disease.MedGenMed. 2005; 7: 25Google Scholar, 47Kollarik M. Brozmanova M. Cough and gastroesophageal reflux: insights from animal models.Pulm Pharmacol Ther. 2009; 22: 130-134Google Scholar The nonkeratinized, stratified squamous esophageal epithelium provides a robust physical barrier against material of wide-ranging temperature, pH, and osmolality. The ultrastructure of the esophageal mucosa has been well described, and although complexes of tight junctions are responsible for the majority of barrier function,48Orlando R.C. Lacy E.R. Tobey N.A. et al.Barriers to paracellular permeability in rabbit esophageal epithelium.Gastroenterology. 1992; 102: 910-923Google Scholar, 49Orlando R.C. Pathogenesis of gastroesophageal reflux disease.Am J Med Sci. 2003; 326: 274-278Google Scholar basolateral chloride/bicarbonate exchangers also rapidly normalize intracellular pH.50Tobey N.A. Reddy S.P. 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Tobey N.A. et al.Effect of ethanol on the structure and function of rabbit esophageal epithelium.Am J Physiol. 1998; 274: G819-G826Google Scholar A subset of patients with symptoms of reflux and normal upper endoscopies have normal esophageal acid exposures but a strong correlation between physiologic reflux events and symptoms.33Mainie I. Tutuian R. Shay S. et al.Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.Gut. 2006; 55: 1398-1402Google Scholar, 34Zerbib F. Roman S. Ropert A. et al.Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy.Am J Gastroenterol. 2006; 101: 1956-1963Google Scholar, 40Ang D. Sifrim D. Tack J. Mechanisms of heartburn.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 383-392Google Scholar Visceral hypersensitivity is likely the underlying mechanism,54Rao S.S. Gregersen H. Hayek B. et al.Unexplained chest pain: the hypersensitive, hyperreactive, and poorly compliant esophagus.Ann Intern Med. 1996; 124: 950-958Google Scholar although the exact pathophysiology is unknown. One candidate for local modulation of symptoms is an acid-sensing receptor in the transient receptor potential cation channel class.40Ang D. Sifrim D. Tack J. Mechanisms of heartburn.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 383-392Google Scholar In preliminary studies, the capsaicin or vanilloid receptor 1 is localized in sensory neurons, causes burning pain in response to an acid stimulus, and has been shown to have increased expression in esophagitis patients.55Caterina M.J. Julius D. The vanilloid receptor: a molecular gateway to the pain pathway.Annu Rev Neurosci. 2001; 24: 487-517Google Scholar, 56Matthews P.J. Aziz Q. Facer P. et al.Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus.Eur J Gastroenterol Hepatol. 2004; 16: 897-902Google Scholar If esophageal luminal clearance of noxious stimuli is impaired, then ongoing symptoms may result. In addition to gravity, the major mechanism of esophageal luminal clearance is peristalsis.49Orlando R.C. Pathogenesis of gastroesophageal reflux disease.Am J Med Sci. 2003; 326: 274-278Google Scholar Underlying etiologies to consider include aperistalsis, ineffective esophageal motility, and esophageal spasm.20Kahrilas P.J. Clinical practice Gastroesophageal reflux disease.N Engl J Med. 2008; 359: 1700-1707Google Scholar, 57Pandolfino J.E. Ghosh S.K. Rice J. et al.Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls.Am J Gastroenterol. 2008; 103: 27-37Google Scholar Similarly, if there is gastric dysmotility from gastroparesis of any etiology and the stomach does not empty in a timely fashion, not only can ongoing gastric distention trigger tLESRs, but the increased volume of gastric contents themselves may promote reflux.24Pandolfino J.E. Zhang Q.G. Ghosh S.K. et al.Transient lower esophageal sphincter relaxations and reflux: mechanistic analysis using concurrent fluoroscopy and high-resolution manometry.Gastroenterology. 2006; 131: 1725-1733Abstract Full Text Full Text PDF Scopus (156) Google Scholar In the absence of other mechanisms, it is common for reflux symptoms to be functional in nature. Indeed, in recent studies more than half of the PPI-refractory reflux symptom population did not have evidence of any gastroesophageal reflux on combined pH/impedance testing.33Mainie I. Tutuian R. Shay S. et al.Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring.Gut. 2006; 55: 1398-1402Google Scholar, 34Zerbib F. Roman S. Ropert A. et al.Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy.Am J Gastroenterol. 2006; 101: 1956-1963Google Scholar, 35Sharma N. Agrawal A. Freeman J. et al.An analysis of persistent symptoms in acid-suppressed patients undergoing impedance-pH monitoring.Clin Gastroenterol Hepatol. 2008; 6: 521-524Google Scholar The Rome III criteria for functional heartburn are (1) burning retrosternal discomfort or pain; (2) absence of evidence of that gastroesophageal acid reflux is the cause of the symptom; (3) absence of histopathology-based esophageal motility disorders; and (4) that the criteria are fulfilled for the last 3 months with symptom onset ≥6 months before diagnosis.58Galmiche J.P. Clouse R.E. Balint A. et al.Functional esophageal disorders.Gastroenterology. 2006; 130: 1459-1465Google Scholar Although the basis of these symptoms is unknown, it is believed that the pathophysiology involves visceral hypersensitivity and altered central nervous system pain modulation, often in the setting of psychologic comorbidity.58Galmiche J.P. Clouse R.E. Balint A. et al.Functional esophageal disorders.Gastroenterology. 2006; 130: 1459-1465Google Scholar, 59Rubenstein J.H. Nojkov B. Korsnes S. et al.Oesophageal hypersensitivity is associated with features of psychiatric disorders and the irritable bowel syndrome.Aliment Pharmacol Ther. 2007; 26: 443-452Google Scholar, 60Mizyed I. Fass S.S. Fass R. Review article: gastro-oesophageal reflux disease and psychological comorbidity.Aliment Pharmacol Ther. 2009; 29: 351-358Google Scholar For patients with esophageal reflux symptoms that persist on PPI therapy, the goal is to determine whether there is reflux disease, what the mechanism might be, and if there is not reflux disease, to perform other appropriate evaluation (Figure 2). After consideration of serious non-GI pathology and ensuring correct medication dosing, upper endoscopy is performed. It is important to recognize the yield of this procedure for structural disease is low, with only 0.2% of patients having esophageal cancer, <10% with persistent esophagitis, and 5%–10% with Barrett's esophagus.3Poh C.H. Gasiorowska A. Navarro-Rodriguez T. et al.Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment.Gastrointest Endosc. 2010; 71: 28-34Google Scholar, 17Fass R. Sifrim D. Management of heartburn not responding to proton pump inhibitors.Gut. 2009; 58: 295-309Google Scholar, 61Dickman R. Mattek N. Holub J. et al.Prevalence of upper gastrointestinal tract findings in patients with noncardiac chest pain versus those with gastroesophageal reflux disease (GERD)-related symptoms: results from a national endoscopic database.Am J Gastroenterol. 2007; 102: 1173-1179Google Scholar, 62Voutilainen M. Sipponen P. Mecklin J.P. et al.Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consecutive patients referred for endoscopy due to dyspeptic and reflux symptoms.Digestion. 2000; 61: 6-13Google Scholar It is also reasonable to perform at least five esophageal biopsies to exclude eosinophilic esophagitis, even if the esophageal mucosa seems to be normal.63Furuta G.T. Liacouras C.A. Collins M.H. et al.Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment.Gastroenterology. 2007; 133: 1342-1363Google Scholar, 64Dellon E.S. Farrell T.M. Bozymski E.M. et al.Diagnosis of eosinophilic esophagitis after fundoplication for ‘refractory reflux’: implications for preoperative evaluation.Dis Esophagus. 2009 Oct 26; ([Epub ahead of print])Google Scholar Eosinophilic esophagitis has been reported in 1%–8% of the PPI-refractory patient population undergoing upper endoscopy.3Poh C.H. Gasiorowska A. Navarro-Rodriguez T. et al.Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment.Gastrointest Endosc. 2010; 71: 28-34Google Scholar, 65Liacouras