REFILE-Reflux esophagitis may not be caused by chemical burn

Reuters Health Information: REFILE-Reflux esophagitis may not be caused by chemical burn

REFILE-Reflux esophagitis may not be caused by chemical burn

Last Updated: 2016-05-20

(Clarifies role of neutrophils in para 11; clarifies role of lymphocytes in para 12; corrects typo in "acid and bile" in para 15)

By Larry Hand

NEW YORK (Reuters Health) - Stopping proton pump inhibitor (PPI) therapy in patients successfully treated for gastroesophageal reflux disease (GERD) can quickly lead to the return of esophagitis, according to results of a small study.

But the way it happens may be "turning the pathogenesis of acute peptic esophagitis inside out," according to an editorial accompanying the study.

"If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine mediated rather than the result of chemical injury," the researchers said online May 17 in JAMA.

"Our study shows that acid is not damaging the esophagus directly. What it does is stimulate the cells that line the esophagus to make cytokines, and those cytokines are what draw inflammatory cells into the esophagus and that's what eventually causes the damage," senior author Dr. Stuart J. Spechler, of the University of Texas Southwestern Medical Center in Dallas, told Reuters Health in a phone interview.

Dr. Spechler and colleagues analyzed outcomes of 12 patients (mean age 58, 11 men) being treated for GERD at the Dallas Veterans Affairs Medical Center. The patients stopped taking PPIs, and the researchers assessed changes in esophageal inflammation for two weeks afterward.

At both one week and two weeks, biopsies showed significant increases in intraepithelial lymphocytes but few or no neutrophils or eosinophils. They also showed below-surface widening of intercellular spaces and development of basal cell and papillary hyperplasia.

Esophageal acid exposure increased from 1.2% at baseline to 17.8% at two weeks (p=0.0005). Mucosal impedance also decreased, and all patients had esophagitis.

"It has never been entirely clear when esophagitis would redevelop when you stop proton pump inhibitors. In this study, in our patients who started out with very severe reflux esophagitis, then healed with PPIs, within two weeks virtually all patients redeveloped esophagitis," Dr. Spechler said.

"I think it really changes our understanding of how reflux disease develops. This is an extremely common problem in this country. When stomach contents reflux back up into the esophagus it causes problems like heartburn, it can damage the lining of the esophagus. For almost a century we thought that the way that damage occurred is that acid from the stomach causes a chemical burn. But that's not what's happening," Dr. Spechler said.

"For the time being it's not going to change how we treat reflux disease, but I think it has a couple of important implications. It's important for physicians to have an accurate understanding of the mechanism of the disease that they are treating. And for the last 80 years our understanding of that has just been incorrect," he said.

The idea that reflux esophagitis develops "as an acid-peptic chemical injury has been largely unchallenged" since a 1935 JAMA paper about it, the researchers write. Neutrophils were thought to damage the esophagus surface.

The new research developed out of animal-model research, according to coauthor Dr. Rhonda Souza, also of the University of Texas Southwestern Medical Center. In those animal models lymphocytes caused damage beginning below the surface and eventually progressing to the surface.

"When we used the model, we noticed that after we did a surgery to induce reflux it actually took weeks for us to see ulcerations in the esophagus. So if it were just a simple burn to the esophagus, you would've thought that we would have seen that much faster," she told Reuters Health in a phone interview.

"We did a time-course study, one week all the way out to eight weeks. And that's when we started seeing that the injury seemed to be coming from the bottom. The inflammatory cells were the first on the scene. They were in the submucosa of the epithelium rather than the top. As they progressed over time the inflammatory cells seemed to make their way up toward the surface. The types of inflammatory cells were all different," she said.

"I think the next step would be to identify some of those key cytokines that the acid and bile seem to be triggering the release of. With people on proton pump inhibitors, you're still going to have some acid in bile reflux in the esophagus even with the current treatment. If we could figure out what are some of the key downstream cytokines are that cause the inflammation to occur, they would be our new target," Dr. Souza said.

Dr. Peter J. Kahrilas, of the Feinberg School of Medicine, Northwestern University, Chicago, wrote an accompanying editorial.

"Based on these findings," he notes, "perhaps the mantra for treating refractory GERD should be "divide and conquer," according to the clinical findings and this new information about the disease process. This is a heterogeneous patient group, and the therapeutic puzzle will only be solved piece by piece. (These researchers) may have just placed a very important piece."

The new research, Dr. Spechler concluded, "will really paint the way for research on new treatments for this disease, treatments that may target directly those cytokines and inflammatory cells."

The U.S. Department of Veterans Affairs and the National Institutes of Health supported this research.

SOURCE: http://bit.ly/1Oz9bi7 and http://bit.ly/1Tod6DK

JAMA 2016.

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