Otolaryngologists Research Role of Pepsin in Reflux, Lung Disease

When otolaryngologists consider the damaging effects of excess reflux of stomach contents, acid is usually thought to be the offending agent. Why, then, are researchers now looking at pepsin’s role in this process? The answer, to borrow a phrase from real estate, is location, location, location, according to experts in reflux disease.

Although acid is indeed one of the culprits in cases of gastroesophageal reflux disease (GERD), a growing body of evidence suggests that pepsin, an enzyme, is the substance that causes the most damage when the reflux extends beyond the upper esophagus and reaches the pharynx, larynx and lungs. Once present in sufficient amounts, studies have shown, pepsin can cause significant damage by adhering to laryngeal cells and breaking down proteins, among other injurious effects (published online November 10, 2011. Int J Otolaryngol. doi:10.1155/2012/646901). Thus, it’s not surprising that pepsin has been linked to serious lung disease, including acute exacerbations of idiopathic pulmonary fibrosis (Eur Respir J. 2012;39:352-358).

As for the theory that pepsin is a relatively unimportant local phenomenon—that is, something produced endogenously in the upper airways—“the literature is pretty clear on this: it shows that pepsin is produced only in the stomach,” Dr. Bishop said. “If you find it in the airways, you know that stomach contents, in some amount, are getting into those airways and potentially causing some damage.”

Assuming the recent work by Kerschner and colleagues linking pepsin to chronic pulmonary disease is confirmed in larger trials, the next question becomes, how should otolaryngologists treat a patient who has a positive pepsin test?

“I think such a result would make us refer patients not to increased acid suppression, but instead to antireflux surgery such as Nissen fundoplication, because remember, pepsin is not an acid—it’s an enzyme and is not affected by acid blocker therapy to any significant degree,” Dr. Bishop said.

Unfortunately, such surgery carries no guarantees of long-term success. “More than half of the patients in the Kerschner study who had undergone anti-reflux surgery actually had detectable levels of pepsin in their tracheas, presumably because those fundoplication wraps were breaking down over time and were not preventing reflux,” Dr. Bishop said. “So this is a definite challenge we all face in managing these patients.”

How about some type of treatment targeted to pepsin itself? That’s a somewhat tricky proposition, said Dr. Kerschner. “There’s really no ‘anti-pepsin’ medication that directly counteracts its effects, but evidence suggests that pepsin tends to be reactivated at lower pH levels, so counteracting those lower pHs with acid suppression therapy may actually have some beneficial effects.”