PPI-refractory patients present diagnostic challenges

Gastroesophageal reflux disease (GERD) is the most common reason U.S. adults see a gastroenterologist and the leading indication for upper endoscopy. Although a majority of patients achieve satisfactory control with proton pump inhibitors (PPIs), 30 to 40 percent continue to experience symptoms despite treatment with these medications. An even greater number of patients with atypical symptoms attributed to GERD fail to respond to PPI therapy.

Thus, an important goal in evaluating patients with PPI-refractory symptoms is to distinguish those who have uncontrolled reflux from those whose symptoms are due to other, non-GERD etiologies, says Marcelo F. Vela, M.D., a gastroenterologist specializing in GERD at Mayo Clinic's campus in Arizona. This has become more challenging as the clinical presentations attributed to GERD have expanded beyond heartburn to include atypical manifestations such as asthma, laryngitis and chronic cough.

Evaluating patients with PPI-refractory symptoms

Before undertaking tests or other measures, physicians should ensure compliance and correct dosing of PPIs and encourage lifestyle modifications, including weight loss, elevating the head of the bed and waiting two to three hours before lying down, Dr. Vela says. He notes there is no strong evidence to support strict diets or liming chocolate, caffeine and spicy foods, but works with patients to assess diet on a case-by-case basis.

If symptoms persist, patients with typical GERD symptoms, such as heartburn and regurgitation, should undergo endoscopy, whereas patients with extraesophageal syndromes should be thoroughly assessed for non-GERD etiologies. When endoscopy is normal and ENT, pulmonary and allergy findings are negative, the next step is ambulatory reflux monitoring.

Whether reflux monitoring should be performed on or off PPI therapy and which technique should be used are matters of debate. Dr. Vela suggests basing the approach on a patient's clinical presentation and pretest likelihood of GERD as well as on available technology and expertise.

"If the probability of GERD is low — for example, patients with extraesophageal symptoms, a complete absence of response to PPI and no prior history of erosive esophagitis — then reflux monitoring can be performed seven days after stopping PPI," he says.

He notes that wireless pH capsule may be preferred for a test off-PPI, since it allows testing for 48 or even 96 hours and is more comfortable for patients. If reflux monitoring performed off PPI is negative, then the likelihood of GERD is very low, and diagnostic efforts can be directed toward other possible causes. A positive pH test off PPI confirms GERD, but doesn't provide much insight into the reasons for therapeutic failure.

When the possibility of GERD is higher — for instance, patients have typical symptoms, at least partial response to PPI, or prior esophagitis — testing should be performed on PPI with 24-hour impedance-pH monitoring to account for weakly acid or nonacid reflux. Systematic reviews have shown that weakly acid reflux is responsible for most reflux episodes in GERD patients who have persistent symptoms while on PPI therapy.

When patients test positive for acid reflux, nonacid reflux or both, therapy can be escalated to achieve better symptom control. If testing shows persistent acid reflux, strategies can focus on better acid suppression or on improving the function of the anti-reflux barrier. For patients with weakly acidic or nonacid reflux, further acid suppression isn't helpful, but enhancing the function of the anti-reflux barrier may be.

"We have to figure out a way to stop gastric contents from coming up — either with a surgical fundoplication, a magnetic sphincter augmentation device or pharmacologically, with the gamma-aminobutyric acid B receptor agonist, baclofen, which has been shown to reduce symptoms in all types of reflux in small studies," Dr. Vela explains. "Baclofen is not FDA-approved for GERD treatment and has a fairly high rate of side effects, so I use it only sparingly."

On the other hand, a negative test strongly suggests that ongoing symptoms aren't due to reflux, although determining the true cause can be challenging. PPIs should be stopped in patients in whom GERD is ruled out.

A more in-depth discussion along with an algorithm for the evaluation and management of patients with PPI-refractory is included in practice guidelines published in the March 2013 issue of The American Journal of Gastroenterology. Dr. Vela was senior author of the article.

For more information

Katz PO, et al. Guidelines for the diagnosis and management of gastroesophageal reflux disease. The American Journal of Gastroenterology. 2013;108:308.