Clinical manifestations, diagnosis, and treatment of non-acid reflux
- Radu Tutuian, MD
Radu Tutuian, MD
- Associate Professor, Gastroenterology
- University of Bern, Switzerland
- Donald O Castell, MD
Donald O Castell, MD
- AGA Peer Reviewer
- Professor of Medicine
- Director, Esophageal Disorders Program
- Medical University of South Carolina
Persistent symptoms in patients with suspected gastroesophageal reflux disease (GERD) who have been treated with proton pump inhibitors (PPIs) can be due to a variety of causes. A subset of these patients has symptoms related to continued reflux of non-acidic material. Advances in technology to evaluate esophageal function have clarified the role of non-acid reflux in the pathogenesis of persistent esophageal symptoms. Two developments have converged over the past 25 years to unmask the presence and prevalence of non-acid GERD symptoms. The availability of proton pump inhibitors in the late 1980s provided the opportunity to achieve maximal acid suppression. The development of ambulatory combined impedance-pH monitoring allowed identification of non-acid reflux episodes and their temporal relation to symptoms.
This topic review will summarize the clinical importance of non-acid reflux. A general approach to patients with suspected GERD who have persistent symptoms after taking PPIs is presented separately. (See "Approach to refractory gastroesophageal reflux disease in adults".)
Gastroesophageal reflux (GER) represents the retrograde flow of gastric content into the esophagus. It occurs even in healthy individuals and is regarded as "physiologic" as long as it does not induce esophageal mucosal abnormalities or symptoms.
Acid reflux is defined as the reflux of gastric contents with a pH <4.0. Non-acid reflux is reflux of gastric contents with a pH >4.0 (ie, above the threshold used by conventional pH monitoring to identify acid reflux).
Experts have suggested a new definition of GER episodes that defines reflux with a pH of 4.0 to 7.0 as "weakly acidic" reflux, and GER with a pH above 7.0 "weakly alkaline" . However, given the low prevalence of "weakly alkaline" reflux episodes we separate GER episodes into acid and non-acid using a cutoff value of 4.0, thereby grouping "weakly acidic" and "weakly alkaline" reflux into "non-acid" reflux.
- Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53:1024.
- Mainie 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.
- Zerbib 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.
- Iwakiri K, Kawami N, Sano H, et al. Acid and non-acid reflux in Japanese patients with non-erosive reflux disease with persistent reflux symptoms, despite taking a double-dose of proton pump inhibitor: a study using combined pH-impedance monitoring. J Gastroenterol 2009; 44:708.
- Sharma 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.
- Bredenoord AJ, Weusten BL, Curvers WL, et al. Determinants of perception of heartburn and regurgitation. Gut 2006; 55:313.
- Zerbib F, Duriez A, Roman S, et al. Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 2008; 57:156.
- Tutuian R, Vela MF, Hill EG, et al. Characteristics of symptomatic reflux episodes on Acid suppressive therapy. Am J Gastroenterol 2008; 103:1090.
- Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy. Am J Gastroenterol 2010; 105:1053.
- Vela MF, 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.
- Blonski W, Vela MF, Castell DO. Comparison of reflux frequency during prolonged multichannel intraluminal impedance and pH monitoring on and off acid suppression therapy. J Clin Gastroenterol 2009; 43:816.
- Sifrim D, Dupont L, Blondeau K, et al. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut 2005; 54:449.
- Tutuian R, Mainie I, Agrawal A, et al. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest 2006; 130:386.
- Poh CH, 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.
- Vela MF, Tutuian R, Katz PO, Castell DO. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003; 17:243.
- Koek GH, Sifrim D, Lerut T, et al. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003; 52:1397.
- Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABA B agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease. Gut 2003; 52:464.
- Zentilin P, Dulbecco P, Savarino E, et al. An evaluation of the antireflux properties of sodium alginate by means of combined multichannel intraluminal impedance and pH-metry. Aliment Pharmacol Ther 2005; 21:29.
- Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol 2012; 107:1662.
- del Genio G, Tolone S, del Genio F, et al. Total fundoplication controls acid and nonacid reflux: evaluation by pre- and postoperative 24-h pH-multichannel intraluminal impedance. Surg Endosc 2008; 22:2518.
- Mainie I, Tutuian R, Agrawal A, et al. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg 2006; 93:1483.
- Rosen R, Levine P, Lewis J, et al. Reflux events detected by pH-MII do not determine fundoplication outcome. J Pediatr Gastroenterol Nutr 2010; 50:251.