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.
Explore This IssueDecember 2013
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.”
Dr. Kerschner added, “We are also working in our lab on a more direct approach—that is, treatments that actually do counteract pepsin activation. But we’re quite a ways off from bringing that to fruition.”
Nancy Bauman, MD, a pediatric otolaryngologist at Children’s National Medical Center in Washington, DC, and an ENTtoday editorial board member, noted that regardless of where pepsin originates, “once it gets into the upper airway, the enzyme can do considerable damage.” Thus, the paper by Kerschner and colleagues “really has the potential to be seminal; this could bring about a significant change in how we view the role of extraesophageal reflux in chronic lung disease, how we diagnose the condition and, hopefully, how we treat it.”
Dr. Bauman still wonders if it is possible that the pepsin detected in this study could have come from a source other than the stomach. “We assume that pepsin arises only in the stomach, but I am not sure that we can exclude the possibility of airway epithelial metaplasia as a source of pepsin production. I also understand that some species of Aspergillus produce pepsin-like proteases but I assume that there would not be enough homology between such fungal proteases and human pepsin to be detected by the pepsin assay used in this study. Regardless of the source of pepsin, targeting inactivation of it will be the key to successfully treating these patients and the work of Dr. Kerschner and Dr. Nikki Johnston’s lab is very exciting.”—DB