Image by Steven Fruitsmakk from Wikipedia

Over the last 30 years, the incidence of esophageal cancer has been steadily rising in spite of increased use of reflux medications. In fact, one can almost say that there is an inverse relationship between risk of esophageal cancer and reflux medication usage.

BUT, it is also a foregone conclusion that reflux increases the risk of esophageal and throat cancer too. So, why would there be an increased incidence of esophageal cancer when reflux is being better “controlled” now more than ever with medical acid suppression?

The answer might be bile… the substance made in the liver and secreted into the small intestine via the gallbladder. Bile is what helps the body digest dietary fat.

But when bile not uncommonly refluxes into the esophagus… bad things may happen, especially when acid production has been suppressed by reflux medications.

Disclaimer… The following is hypothetical and unproven.

Bile, if it happens to be in the esophagus or throat, is more destructive to the mucosal lining when acid is suppressed.

Bile salts/acids have fairly complicated acid-base properties, but an over-simplified explanation for the purpose of this blog is as follows.

Bile in a chemically unconjugated state has a pKa of 7. When such bile is in an acid environment (pH less than 6), it is insoluble and relatively harmless. However, when unconjugated bile enters a relatively alkaline environment (pH greater than 6), it becomes water soluble and “active” in its ability to damage mucosal linings.

As such, when acid suppression is induced by medications like zantac and prilosec, yes… the acid is suppressed but by the very fact that it raises the stomach and distal esophageal pH to a relative alkaline state, any bile that may be present now becomes activated and causes potentially just as much damage as acid.

And that’s why over a prolonged period of time repeated bile exposure in a relative alkaline environment may explain why esophageal cancer incidence seems to be increasing as the use of acid reflux medications has increased.

Proof?

Regardless of the “how,” does taking reflux medications actually increase risk of cancer???

In one study (2011), patients taking proton pump inhibitors were 61.3% to 81.5% more likely to develop esophageal pre-cancerous lesions or frank cancer (adenocarcinoma).

In another study published in the summer of 2013, it was found that patients with reflux were found to have a 78% increased risk of developing throat cancer. What researchers also found was that taking antacids for reflux (but NOT proton pump inhibitors or H2 blockers) seemed to protect against the development of throat cancer by 41% in patients with frequent heartburn.

To reiterate, antacids reduced risk of throat cancer… but NOT proton pump inhibitors like prilosec and H2 blockers like zantac.

Why? Because antacids work transiently to neutralize acid, but not suppress acid production whereas proton pump inhibitors and H2 blockers actually suppress acid production for a prolonged period of time.

The transient nature of acid neutralizers like TUMS allow for acid to still be produced thereby theoretically preventing bile from becoming soluble and damaging.

Prediction

So which is worse for you? Acid reflux or bile reflux? I’m not sure… but personally, I predict that once additional studies are performed that may ultimately strengthen the relationship between bile reflux and mucosal injury that may lead to cancer formation, reflux medications may go out-of-favor along with a class-action lawsuit. That’s a big if… I might end up being completely wrong.

Of course, that may be the reason why drug companies specify that such reflux medications should not be used longer than 2 months and prescribing information stress “short-term” treatment rather than long-term.

More Confusion

We can also throw more mud into this messy predicament… Pepsin, which is a stomach enzyme that breaks down proteins, can also damage esophageal and laryngeal mucosa. However, it is most active in an acidic environment. Once pH levels rise above 6.5, pepsin becomes inactivated. At pH 8.0, it becomes irreversibly inactivated.

As such, acid and pepsin cause damage in an acidic environment. Taking reflux medications to eliminate the acid creates an alkaline environment.

However, an alkaline environment than activates bile which can also cause damage.

Treatment

So what to do?

Ideally, given this no-win situation, the best way to treat reflux would be to keep bile where it is supposed to be (in the small intestine) and acid/pepsin in the stomach where it is supposed to be.

As such, I suspect that even more emphasis will be placed on lifestyle/dietary changes for reflux control. Medication-wise, use of antacids and barrier-type medications like alginate will become the main way of treating reflux long-term while medications that suppress acid will be prescribed only for short-term treatment spans.

Surgical management of reflux will become much more accepted and popular for patients who suffer from bad reflux to try and restore proper anatomical compartmentalization of bile, acid, and pepsin. Surgical management will include LINX, TIF, Nissen, etc. (more info)

At the very least, certainly caution should be present when placing a patient on long-term acid suppression with medications like prilosec and zantac, especially when such medications are already known to cause a whole host of other problems including bone fractures, clostridium difficile infections,  and malabsorption of vitamins and minerals. (more info)

Special thanks to Dr. Kevin Gillian who assisted in writing this blog.

References:
Bile Acid. Wikipedia

Gastroesophageal reflux disease symptom severity, proton pump inhibitor use, and esophageal carcinogenesis. Arch Surg. 2011 Jul;146(7):851-8. doi: 10.1001/archsurg.2011.174.

Gastric Reflux Is an Independent Risk Factor for Laryngopharyngeal Carcinoma. Cancer Epidemiology Biomarkers & Prevention. Published Online First May 23, 2013; doi: 10.1158/1055-9965.EPI-13-0183

The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991 Apr;101(4 Pt 2 Suppl 53):1-78.

Bile reflux gastritis and Barrett’s oesophagus: further evidence of a role for duodenogastro-oesophageal reflux?Gut 2001 Sep;49(3):359-63.

Acid and bile reflux in erosive reflux disease, non-erosive reflux disease and Barrett’s esophagus. Hepatogastroenterology. 55 (82-83), 442-7.

The role of bile acids in the neoplastic progression of Barrett’s esophagus – a short representative overview. Z Gastroenterol. 50 (9), 1028-34.