Non-Acidic Reflux Explains Lack of Response to H2 Blockers and PPIs

WASHINGTON, DC-Non-acidic reflux is a major cause of laryngeal inflammation, and patients with this disorder present with a constellation of symptoms that differ from classic gastroesophageal reflux (GERD). The most common symptom is chronic laryngitis. The mechanisms of injury and pathophysiology of this disorder are still being elucidated, and there is no gold standard for diagnosis. Non-acidic reflux is an area of active research and several hypotheses explaining how injury occurs are currently being explored. Pepsin and bile appear to be implicated, according to research discussed at a session during the recent AAO-HNS annual meeting.

Explore this issue:
February 2008

We are realizing that the non-acidic components of reflux are just as important as the acidic components. Non-response to acid suppression in some patients may indicate that the non-acidic components [bile and pepsin] are contributing to their symptoms. This message is important for otolaryngologists and for those patients who come in with symptoms that are not helped by acid suppression, said session chair Joel H. Blumin, MD, Associate Professor and Chief of the Division of Laryngology and Professional Voice at the Medical College of Wisconsin in Milwaukee.

Typical Scenario

The typical scenario is that patients come in with symptoms that appear to be related to GERD. They are treated with H2 blockers and/or proton pump inhibitors (PPI) and fail to respond, even if the dose of drug is increased or if H2 blockers are given at night, explained Jean Abitbol, MD, Ancien Chef de Clinique at the Faculty of Medicine of Paris. Postprandial symptoms are persistent and symptoms also occur at night.

Dr. Abitbol described three methods used to diagnose non-acidic reflux. pH testing shows that bile is not correlated with alkaline pH. pH testing alone cannot diagnose non-acidic reflux, he said. Impedance techniques are used to make the diagnosis. Bilirubin recording is a research tool that may prove useful. GABA-agonists, Baclofen, or surgery may be useful for management of non-acidic reflux, he said.

Clarence Sasaki, MD, Charles W. Ohse Professor and Chief of the Department of Otolaryngology at Yale University in New Haven, CT, who also spoke at the session, presented experimental data showing that bilirubin salts damage vocal cords of animal models, suggesting that bile plays a role in laryngeal injury in non-acidic reflux.

Role of Pepsin in Non-acidic Reflux

Recent research has implicated pepsin in causing damage in non-acidic reflux, explained Nikki Johnston, PhD, Assistant Professor in the Division of Research of the Department of Otolaryngology and Communication Sciences at the Medical College of Wisconsin, who has published in this area. Pepsin is detected in the laryngeal epithelium of patients with clinically diagnosed laryngopharyngeal reflux (LPR), but not in normal control subjects, she said.

In vitro experimental studies show that exposure to pepsin depletes protective proteins. Dr. Johnston and colleagues have found that human pepsin is maximally active at pH 2.0 and inactive at pH 6.5. Pepsin is inactive at neutral pH, but it remains stable. Pepsin is not irreversibly inactivated until pH 8.0. Dr. Johnston explained that this is clinically important, because pepsin-detected in the laryngopharynx of patients with reflux-attributed injury or disease-could sit inactive or dormant in the laryngopharynx and have the potential to be reactivated following a decrease in pH. In vitro studies show that pepsin is taken up by the laryngeal epithelial cells by receptor-mediated endocytosis. Thus, pepsin may be reactivated intraceullarly, causing depletion of protective proteins and damage to the mitochondria.

These findings suggest that pepsin inhibitors and pepsin antagonists may have clinical utility in patients with reflux attributed to laryngeal injury, Dr. Johnston said. Research efforts to develop drugs for non-acidic reflux are ongoing.


In diagnosing non-acidic reflux, a reflux finding score greater than 7 is considered significant, said Robert J. Toohill, MD, Professor in the Division of Laryngology and Professional Voice, Department of Otolaryngology and Communication Sciences at the Medical College of Wisconsin. The barium esophogram is a noninvasive test that is underutilized in diagnosing this disorder. The test is less invasive than other tests, takes up to 30 minutes to perform, and is less costly than other diagnostic techniques.

The barium esophogram will provide important information on duodenal gastroesophageal reflux [DGER] 60% to 70% of the time. It reveals the presence of motility and peristalsis problems, lower esophageal sphincter dysfunction, and spontaneous reflux, Dr. Toohill told listeners.

The 24-hour ambulatory pH study is considered the gold standard. The upper probe can be placed with an endoscope, which is preferable to a manometer, and this test can delineate upright or supine reflux. It provides useful information in 70% to 80% of cases. However, it is invasive, time-consuming, and expensive, he said.

Multichannel intraluminal impedance monitoring is another invasive, time-consuming, expensive test that is used to detect DGER. This test gives you reliable information, and if the probe reveals gastric contents in the upper esophagus, it is highly likely that the diagnosis is DGER, Dr. Toohill commented. Another advantage of multichannel intraluminal impedance monitoring is that it has built-in pH monitoring.

Transnasal esophagoscopy can be used to diagnose DGER in patients with GERD who have a poor response to acid suppression and for patients with cough and no diagnosis


Although dietary measures and lifestyle changes are important for relieving symptoms of GERD, they are not as important for DGER, Dr. Toohill said. Events related to DGER occur mostly when patients are in an upright position. The most important lifestyle change [to relieve symptoms of DGER] is to stop smoking, he commented.

H2 blockers and proton pump inhibitors (PPIs) are used to suppress acid in patients with GERD. H2 blockers are less expensive than PPIs and probably underutilized, he noted. H2 blockers may be safer than PPIs over the long term because PPIs interfere with calcium absorption. PPIs are expensive and probably overutilized, but these drugs are highly effective. PPIs should be given along with calcium supplementation to prevent hip fracture. Neither H2 blockers nor PPIs are helpful in non-acidic reflux, he commented.

Nissen fundoplication is the most effective treatment to prevent both acid and non-acidic reflux, but this is expensive and invasive, Dr. Toohill said. Nissen fundoplication can be done laparoscopically. Dr. Toohill cautioned that the procedure should be done by experienced surgeons, because there is a learning curve and complications can occur.

The Gaviscon Advance Raft is a new drug with a great deal of promise for non-acidic reflux, he said. This preparation is partly derived from seaweed and it forms an alginate raft that prevents gastric contents from backflowing. The oral drug is widely used in Europe but is not yet available in the United States. The side-effect profile is favorable and better than that with the Gaviscon liquid, he said.

To Reach ENToday

For Editorial, Permissions, or Publishing Matters:


Lippincott Williams & Wilkins 333 7th Avenue, 19th Floor New York, NY 10001 Phone: (646) 674-6544 Fax: (646) 674-6500

For Advertising Sales:

Michael Guire Lippincott Williams & Wilkins 1300 Virginia Drive, Suite 400 Ft. Washington, PA 19034 Phone: (215) 643-8140 Fax: (215) 643-3902

©2008 The Triological Society