Chronic PPI Use Could Lead to Esophageal Adenocarcinoma

Barrett’s esophagus (BE) is a condition in which tissue in the esophagus is replaced by tissue similar to that found in the intestinal lining, which predisposes a patient to esophageal adenocarcinoma (EAC).

How BE develops is unclear, but it’s been closely associated with chronic gastroesophageal reflux disease (GERD). Therefore, the prevailing theory is that GERD leads to BE, which in turn leads to EAC.

Alarmingly, EAC incidence has increased 600% over the past 25 years, suggesting that BE incidence has also increased. In a recent opinion piece, researchers from the Eastern Virginia Medical School in Norfolk, Virginia, proposed a new theory concerning the causal process behind BE. If proven, their theory may lead to changes in the way clinicians manage GERD.

Although most experts contend that chronic acid reflux causes BE, because most BE patients also have GERD, their thinking may be incorrect. Ever since proton pump inhibitors (PPIs) were introduced, EAC incidence has increased, so the Eastern Virginia Medical School researchers hypothesized that chronic PPI use might galvanize a metaplasia-dysplasia-carcinoma sequence.

Their rationale addressed 2 potential changes:

1. PPIs increase gastric pH temporally, and may allow bile salts to dissolve near the lower esophageal sphincter (LES) and enter the esophageal tract during reflux episodes.

2. If PPIs fail to suppress esophageal acid just briefly, then protonated bile salts may diffuse into the epithelial cells causing the mucosal metaplasia that could lead to BE.

While the researchers admitted that the role of bile and various bile acid salts in intestinal metaplasia is still unclear, they suggested that conjugated bile acids may induce it. Such bile salts are easily ionized in the increased intra-gastric pH environment experienced by patients with GERD and treated with PPIs.

Many BE patients are obese and consume high-fat diets, and bile salt production is a common response to high-lipid intake. PPIs improve intra-gastric pH control, allowing bile salts to ionize and migrate into the esophagus. Patients on long-term PPI treatment have impaired LES, which increases their risk for BE and EAC.

Regarding their second hypothesis, the researchers noted that many PPI-treated GERD patients have at least 1 reflux episode daily. Acid suppression is inconsistent, and pH rises above 4.

Trapped and ionized bile salts may become protonated, which can make those patients more hydrophobic and promote diffusion across their esophageal membrane.

In their conclusion, the researchers suggested that GERD patients chronically treated with PPIs may require tighter gastric pH control, especially if they are obese. Combining nonsteroidal anti-inflammatory drugs and PPI therapy is 1 way to decrease gastric pH below 4.