Eight More Reasons to Avoid Proton Pump Inhibitors

on November 8, 2017 by Chris Kresser

Proton pump inhibitors are routinely used to treat acid reflux, peptic ulcers, and indigestion. Yet it seems that every week, a new study is published showing that PPIs have another nasty side effect. Read on to learn eight more reasons we should avoid using PPIs in clinical practice.

A little over a year ago, I wrote an article about PPIs and the dangers they pose to patients. Since then, I have been astounded by the growing evidence against PPIs. In fact, I could start a blog about the dangers of PPIs and have something to post every week!

While proton pumps are well known for their role in the stomach, they have a wide variety of functions. Proton pumps are present in just about every cell in the body and are essential for cellular energy production. The FDA has recognized the dangers of PPIs and has indicated that they should only be used for four or eight weeks, depending on the condition (1). Yet an estimated 15 million Americans take a PPI regularly to control symptoms of frequent acid reflux, and some have been on them for years or even decades (2).

In this article, I’ll review the latest research on PPIs and discuss several recent studies that were not included in my original article. If you haven’t already, be sure also to check out my articles on heartburn and antacids.

1) PPIs increase the risk of serious gut infections

When the pH of the stomach becomes more basic, microbes that would normally be destroyed in the acidic environment are able to pass unscathed into the small and large intestines. A 2016 study showed that use of PPIs was associated with a 1.7 times increased risk of Clostridium difficile and a 3.7 times increased risk of Campylobacter infection (3).

A 2016 Australian study of more than 38,000 adults over age 45 found that PPI use increased the risk of hospitalization for infectious gastroenteritis (4). Patients with chronic bowel problems who used PPIs had an even greater risk.

2) PPI use is associated with SIBO

A 2017 meta-analysis published in the Journal of Gastroenterology reviewed 19 articles and found that PPI use was associated with a 1.71 times greater prevalence of SIBO (5). They concluded that PPI use increased the risk of SIBO. Now, if you’ve read my articles on GERD, you probably know that I favor the hypothesis that heartburn is caused by increased intra-abdominal pressure. And the number one cause of intra-abdominal pressure? You guessed it: SIBO. So of course, it makes sense that those with SIBO would experience more reflux and be more likely to take PPIs in the first place.

However, PPI use could also exacerbate SIBO, since the acidity of chyme from the stomach entering the small intestine plays a key role in keeping microbial numbers in the small intestine down. Indeed, when the researchers looked only at studies that had compared the incidence of SIBO before and after PPI use in the same cohort of patients, they found a significant increase in SIBO (5). We’re likely looking at a vicious cycle, where SIBO causes reflux and increases the need for PPIs, and PPIs in turn lower stomach acid to exacerbate SIBO.

Need more reasons to avoid PPIs? Here you go.

3) PPIs alter the microbiota to exacerbate liver disease

Chronic liver disease is increasingly common in Western countries, with liver cirrhosis making the charts as the 12th leading cause of death worldwide (6). PPI use is particularly high in people with chronic liver disease, with 32 percent of patients with non-alcoholic fatty liver disease (NAFLD) and 67 to 72 percent of patients with cirrhosis taking acid-suppressing medications (7, 8, 9).

A study published just last week found that in mice, PPIs promote the growth of Enterococcus bacteria, which can translocate the liver to cause inflammation and exacerbate three distinct types of chronic liver disease: alcohol-induced liver disease, NAFLD, and non-alcoholic steatohepatitis.

The research team also looked at 4,830 human patients with alcoholic liver disease and found increased fecal concentrations of Enterococcus. Just two weeks of PPI therapy in healthy individuals was sufficient to increase Enterococcus. In alcoholics, the 10-year risk of liver disease was 8.3 percent higher for those actively using PPIs (10).

4) PPIs increase the risk of stroke

In a large cohort of more than 200,000 patients, PPI use increased the risk of first-time ischemic stroke, according to an abstract presented at the 2016 American Heart Association meeting. The researchers also found a positive dose-response relationship between PPI dose and stroke risk, such that those patients on higher doses were at the highest risk of stroke (11).

PPIs reduce production of nitric oxide, which promotes the dilation of blood vessels and improves blood flow (12). They also inhibit cellular lysosomes, which leads to aging of the blood vessel endothelial cells (13).

5) PPIs may cause an evolutionary mismatch

In my last article on PPIs, I touched on the effects of PPI use on nutrient status. In October 2016, a review was published that extensively discusses PPI use and micronutrient malabsorption (14). I particularly liked this excerpt that considers gastric acidity from an evolutionary perspective:

It is worth considering that the processes by which certain nutrients and minerals are absorbed faced evolutionary adaptation of their own over millennia, and such evolutionary adaptation occurred within the context of a gastric luminal pH in the range of 1–2. Along comes a medication such as PPIs that elevates gastroduodenal pH to 5.5–6.5, and it is not entirely surprising that absorption issues arise.

In other words, PPIs induce a highly unnatural physiological state that is misaligned with our human biology.

6) PPI use is associated with iron deficiency

Some micronutrients have been studied more than others in the context of PPI use. A case control study published in the March 2017 issue of Gastroenterology found that PPI users were significantly more likely to have iron deficiency. The use of PPIs was associated with a 2.49 times increased chance of developing iron deficiency. The association was even stronger for those taking high daily doses and was reduced after discontinuing acid-suppressing medication (15). Long-term iron deficiency can lead to iron-deficiency anemia.

7) PPI use during pregnancy may increase childhood asthma

PPI use may have detrimental effects during pregnancy as well. Heartburn is common in pregnancy due to hormonal changes and increasing pressure on the stomach from the growing fetus, and acid-suppressing medications are generally considered safe because they do not affect fetal development. However, a systematic review published in June 2017 found that children born to mothers who took acid-suppressing medications had a 1.3 times greater risk of developing asthma (16).

The potential link is not conclusive, but given the importance of the microbiota in the development of a child’s immune system, it certainly seems plausible. As a mother gets close to term, her vaginal microbiota begins to prepare for the delivery (17). The baby’s first major exposure to microbes is within the birth canal, and these seed the communities that will colonize the gut, skin, and other mucosal surfaces of the baby. An expecting mother who takes PPIs may perturb the preparation of her microbiota for passage to the baby. Of course, there could be a common factor that causes both heartburn during pregnancy and asthma in children, such as maternal gut dysbiosis. I look forward to seeing more research on this topic.

PPIs also interfere with protein digestion, which may increase the number of allergens that the fetus is exposed to through the placenta. Early exposure to allergens could induce Th2 immune dominance and sensitization of the immune system. In addition to demonstrating the potential dangers of PPIs, this research may suggest that adequate maternal stomach acid plays a protective role in child immune development.

8) PPIs increase the risk of death

A large scale observational cohort study of 3.5 million U.S. veterans found that PPI use was associated with a 1.23 times increased risk of death compared to non-use. Risk increased with time of use, and those who had used PPIs for over a year had a 1.5 times increased risk of death (18).

The authors of the study expressed significant concern about the widespread use of PPIs:

PPI are widely used by millions of people for indications and durations that were never tested or approved; they are available over the counter (without prescription) in several countries and generally perceived as safe class of therapeutics. They are often overprescribed, rarely deprescribed, and frequently started inappropriately during a hospital stay, and their use extended for long-term duration without appropriate medical indication.

What we should be doing instead

And there you have it: eight more evidence-based reasons to avoid PPIs. We can clearly see that a functional approach to treating these conditions would significantly improve patient outcomes. So to conclude, here are my recommendations for treating GERD without PPIs:

  • Switch the patient to a nutrient-dense, Paleo-type diet: many patients find that heartburn resolves simply from eliminating highly refined carbohydrates from their diet.
  • Test and treat SIBO: intra-abdominal pressure from SIBO is thought to be a major cause of lower esophageal sphincter dysfunction, which allows stomach contents to reflux back into the esophagus. Treating SIBO can relieve this pressure and often significantly reduces the frequency and severity of heartburn.
  • Look for nutrient deficiencies: iodine and choline, for example, are involved in the production and secretion of gastric acid.
  • Replace stomach acid to improve digestion: as I have explained in my previous articles, most patients with GERD have too little stomach acid, not too much.
  • Have your patient experiment with a low-carb diet: carbohydrate malabsorption can cause significant bloating, which exerts pressure on the lower esophageal sphincter to cause reflux. Some patients may find relief with a low-carb diet.

Now I’d like to hear from you. Had you seen these recent studies on PPIs? Have you had success in treating GERD without medication? Start the discussion in the comments below.

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