Do Reflux Medications Increase Risk of Esophageal and Throat Cancer?

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.

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Does Drinking Alkaline Water Help With Reflux?

Image by WJ Pilsak from Wikipedia

Treatment in some reflux-sufferers may require addressing not just the acid in reflux, but also the pepsin. In one tantalizing research paper, alkaline water (pH 8.8) was found to instantly and permanently inactivate pepsin in vitro (ie, in a test tube). Pepsin is a stomach enzyme that can cause inflammation and mucosal damage when in the throat area. This peptic enzyme can be deposited outside the stomach due to laryngopharyngeal reflux (LPR) and can cause symptoms of globus, burning, hoarseness, chronic cough, chronic throat clearing, etc.

With pepsin triggered symptoms, treatment to resolve can become exceedingly frustrating given standard treatment with zantac, prilosec, and other "reflux" medications do not work as well. Furthermore, human pepsin remains stable at pH 7.4 and can be repetitively reactivated by acid from any source (ie, orange juice).

BUT... keep in mind that test tube results in this research may not necessarily translate to actual improvement in humans. However, drinking a small amount of alkaline water a few times a day (just enough to coat the throat) can't hurt.

Keep in mind that most tap and bottled waters (typically pH 6.7 to 7.4) would not be expected to affect pepsin stability.

I should also mention that drinking alkaline water will not do much to help acid reflux as the alkaline water will only briefly neutralize any acid and is ineffective for long-duration acid suppression. For those suffering from acid reflux, stick with the traditional reflux medications which work extremely well.

Reference:
Potential benefits of pH 8.8 alkaline drinking water as an adjunct in the treatment of reflux disease. Ann Otol Rhinol Laryngol. 2012 Jul;121(7):431-4.

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Reflux Increases Risk of Throat Cancer by 78%

Brown University researchers found that frequent heartburn was an independent risk factor for not only esophageal cancer but also cancer of the throat and vocal cords. This conclusion was based on a large population study involving 631 patients with throat cancer and 1,234 without throat cancer as a control group.

The study group also did not heavily smoke, drink, or have HPV (other independent risk factors for throat cancer).

Individuals with frequent heartburn 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.

The explanation for how reflux can cause throat cancer is similar to how it can also cause esophageal cancer. With repetitive mucosal injury by gastric juices to the delicate lining of the throat, there is a cycle of healing and injury that may eventually trigger cancer development. Patients with reflux that reaches the throat level have a condition called LPR or laryngopharyngeal reflux. Although symptoms may be similar to the more common GERD, it is not unusual for patients to experience only throat symptoms without the heartburn. Such atypical symptoms include:

• Chronic cough
• Phlegmy throat
• Chronic throat clearing
• Vocal cord dysfunction
• Globus pharyngeus

It is also notable that it takes far less reflux episodes in the throat region compared to the esophagus in order to trigger mucosal damage... it takes fewer than THREE episodes per WEEK! [link]

In any case, more research is needed to determine at what point cancer risk increases in individuals with LPR, what type of reflux (acid?, non-acid?, pepsin?, bile?) triggers cancer concern, to what degree of reflux prevention is required to protect against cancer development.

Also more needs to be done to figure out why antacids help reduce cancer risk, but not other types of reflux medications.

References:
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.

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Does Milk Cause Increased Phlegm or Mucus Production?

For many individuals, milk and associated dairy products definitely seem to cause an increased production or thickening of mucus in the mouth and throat... the phlegmy throat. It certainly happens to me...

Of course, perception is not always supported by research...

"Milk and dairy product intake was not associated with an increase in upper or lower respiratory tract symptoms of congestion or nasal secretion weight. [...] We conclude that no statistically significant overall association can be detected between milk and dairy product intake and symptoms of mucus production in healthy adults, either asymptomatic or symptomatic, with rhinovirus infection." [link]

However, other research support the possibility that dairy products might increase mucus production only if the milk contains beta-CM-7 protein (not all milk contains this protein). [link]

I have a different hypothesis for why milk may cause the perception of increased mucus production. I should preface that I have no research study to quote to prove this hypothesis. Might be a good research project for a medical student???

In any case, milk contains a protein called casein. When the milk is not refrigerated, it causes bacteria to  metabolize lactose within the milk leading to lactic acid production as a byproduct. When acidity is present, the casein congregate in a process called curdling. That's the "chunks of milk" seen in milk gone bad.

Now, bacteria certainly will not be playing a role in lactic acid production after fresh milk is consumed, BUT, there IS acid present in the stomach which can initiate curdling.

Now what if a patient suffers from acid reflux... and what if some of the reflux episodes reach the throat level?

So, hypothetically speaking, if somebody who suffers from acid reflux drinks a lot of milk, two things might hypothetically happen (or drinks orange juice followed by milk):

1) Milk temperature goes up from body heat (which assists in curdling)
2) Acid present from the reflux will initiate curdling

If acid is present in the mouth and throat from reflux or secondary source (like recently drunk orange juice), curdling to some degree may occur from milk residue mixing with acid residue present leading to perception of mucus production.

Now does this actually happen???

I don't know and I hope some researcher looks into this hypothesis further!

However, in the end, if dairy avoidance helps with a phlegmy throat, than it can't hurt to avoid it! I should also point out that egg and wheat does cause a similar phlegmy problem in some patients.


Reference:
Relationship between milk intake and mucus production in adult volunteers challenged with rhinovirus-2. Am Rev Respir Dis. 1990 Feb;141(2):352-6.

Does milk increase mucus production? Med Hypotheses. 2010 Apr;74(4):732-4. doi: 10.1016/j.mehy.2009.10.044. Epub 2009 Nov 25.

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Reflux Medication Addiction

When a patient suffers from reflux, there is an astounding array of very effective medications to induce acid suppression for symptom relief.

Chief among the reflux medications are the proton pump inhibitors that include medications like prilosec, nexium, protonix, prevacid, dexilant, etc.

When such medications are taken by a patient, especially one who does not normally take proton pump inhibitors, effective acid suppression occurs. It works EXTREMELY well; even at low doses.

However, such medications should not be taken any longer than necessary and should be prescribed along with lifestyle changes to minimize persistence and/or recurrence.

Why?

In some ways, a patient suffering from reflux may become "addicted" to the reflux medication for continued symptom relief.

In other words, the reflux medication can induce the stomach to produce even more acid leading to the need for continued medical therapy... or increase dosages for continued symptom relief. Stopping the medication can cause even worse reflux... which leads the patient to resume the medication.

This "addiction"can occur in as little as 8 weeks in up to 40% of normal, healthy individuals. [link]

What happens?

The way proton pump inhibitors work is by blocking protein channels known as proton pumps in stomach cells (B) from producing acid (C).

The stomach cells realizing their proton pumps are being blocked, start revving up production of even MORE proton pump channels to fix its acid shortage which would in turn increase acid production and potentially lead to symptoms.

Sounds like a vicious cycle... because it is.

Although this "addiction" which is really an acid rebound phenomenon, is typically associated with proton pump inhibitors, it can also happen with H2-blockers (zantac, pepcid, etc), though not as severe.

Should you experience acid rebound after stopping a reflux medication, the unusually vigorous acid production and associated symptoms (the "withdrawal") go away if you can stand to wait it out. Since it takes time for the stomach to re-adjust, this wait can be significant:

• After stopping an H2-blocker, rebound symptoms usually start within two days and usually subside within 10 days.
• After stopping a proton pump inhibitor, rebound symptoms usually start after a week and continue for up to two months.

One can also slowly "taper" down the dosage of reflux medication and address any acid symptoms with an antacid.

Now, in certain circumstances, it is imperative that reflux medications be taken for months if not longer because the benefits outweigh the risks (gastric ulcer, Barrett's esophagus, vocal cord granuloma, etc). There is a specific reason for long-term treatment.

But if treatment is solely due to symptom relief alone, such medications should not be used daily indefinitely.

Talk to your doctor if you have concerns.


References:
Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009;137:80-87. Epub 2009 Apr 10.

Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology. 1999;116:239-247.

Systematic review: rebound acid hypersecretion after therapy with proton pump inhibitors. Aliment Pharmacol Ther. 2007;25:39-46.

Results of an intervention in an academic Internal Medicine Clinic to continue, step-down, or discontinue proton pump inhibitor therapy related to a Tennessee Medicaid formulary change. J Manag Care Pharm. 2009;15:344-350.

Safety of the long-term use of proton pump inhibitors. World J Gastroenterol. 2010;16:2323-2330.

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