By Dr. Aylah Clark

Acid blocking medications such as proton pump inhibitors (PPIs) are ubiquitously used to control heartburn that can result from conditions like gastritis (inflammation of the stomach), esophagitis, and GERD (gastroesophageal reflux disease). They are very effective at controlling the symptom of heartburn but do not address the underlying causes and can have numerous negative health consequences when used long term. These unwanted long-term effects include increased allergies, reduced nutrient absorption, increased osteoporotic fractures, increased risk of kidney disease, negative effects on the gut microbiome, and increased risk of bacterial and viral infections.

Examples of PPIs:

• omeprazole (Prilosec, Prilosec OTC, Zegerid)
• lansoprazole (Prevacid)
• pantoprazole (Protonix)
• rabeprazole (Aciphex)
• esomeprazole (Nexium)
• dexlansoprazole (Dexilant)

Examples of Hydrogen Receptor Antagonists (H₂RAs):

• nizatidine (Axid)
• famotidine (Pepcid, Pepcid AC)
• cimetidine (Tagamet, Tagamet HB)
• ranitidine (Zantac)

Increased Allergies

In a study of 8.2 million people, those prescribed any type of acid-blocking medication had an increased risk of developing allergies. This association was not there with other medication classes such as those for cholesterol and blood pressure. The likely mechanism for this is that with lower acid we are unable to adequately break down proteins from food as well as other medications which increases their allergic potential. (1)

Several studies have further supported these findings and the underlying mechanisms. Omeprazole (Prilosec OTC) was shown to lower the threshold at which an antigen causes an allergic response. (2) Other acid lowering drugs have been shown to enhance the Th2 response, a branch of the immune system involved in allergy, asthma, and protection from foreign invaders like parasites.

Impaired Digestion & Reduced Nutrient Absorption

One of the more obvious concerns is impaired nutrient absorption. Gastric acid itself is important for helping your body break down food, but gastric acid secretions also activate pepsin and the release of enzymes from the pancreas. Pepsin helps break down proteins and pancreatic enzymes help break down fat, protein, and carbohydrates. Without these enzymes, your body cannot break down food and absorb the nutrients as well, even when you eat healthy foods.

Vitamin B12 deficiency is also a risk of long-term acid blocker use. Vitamin B12, or cobalamin, is released from food (primarily animal protein) in the stomach in the presence of gastric acid and pepsin. Intrinsic factor, which is released by parietal cells in the stomach and helps enable absorption of vitamin B12, is reduced by PPIs. Pancreatic enzymes are also part of the digestive process. Acid blockers therefore effect at least 4 key aspects of vitamin B12 absorption: the acid itself, pepsin, intrinsic factor, and pancreatic enzymes. In a study of 26,000 people over 15 years, those with a vitamin B12 deficiency were significantly more likely to have used PPIs or another type of acid blocker called a H₂RA (Hydrogen Receptor Antagonist) for ≥2 years. (3)

Other nutrient deficiencies that have been associated with acid blockers include vitamin C, magnesium, iron, and calcium. (4) It has been recommended to monitor micronutrient levels in patients on PPIs long term however this is not routine. (5)

Increased Osteoporosis-Related Fractures

Several studies have shown that long-term PPI use results in increased risk of osteoporosis and/or osteoporosis-related fractures. (6) (7) (8)

There are several mechanisms thought to be at play. Certainly, the low acid causing reduced absorption of vitamins and minerals needed for bone formation may contribute. Nutrient deficiencies may also contribute in less direct ways. For example, a vitamin B12 deficiency can elevate homocysteine, a marker often associated with vascular disease but is also predictive of fractures in osteoporosis. Homocysteine suppresses collagen cross-linking, a very important factor in quality bone formation. (9) (10) (11)

There is also evidence that there is unintended action of the medication itself on other receptors. Proton pump inhibitors work, as the name suggests, by inhibiting or blocking the proton pump, protons being hydrogen (H⁺). More specifically they inhibit the gastric H⁺-K⁺-ATPase pump. There are similar pumps (H⁺-ATPase) involved in bone metabolism specifically with cells called osteoclasts that break down bone. (12) (13)

Yet another possible mechanism in which PPIs effect bone health is mediated by gastrin. Gastrin is what stimulates gastric acid secretion. When we block these secretions with PPIs, gastrin levels rise as your body attempts to increase stomach acid. In animal studies, gastrin causes the parathyroid glands to grow and release more hormones. Your parathyroid glands are located in your neck and help control calcium levels. When blood levels of calcium are too low, parathyroid hormone signals your body to increase these levels and it gets this calcium in part from bone. Hyperparathyroidism is associated with low bone density due to calcium loss from bone. (14) (15)

Kidney Disease

PPI use has been associated with significantly increased risk of acute kidney injury (in a large study of 93,335 patients) and with chronic kidney disease (in a study of 84,600 patients). (16) Yet another large study of 572,661 patients showed a 5-fold increased risk of acute interstitial nephritis in current PPI users with greater risk in people over the age of 60. (17)

Previously, it was thought that the chronic kidney disease related to PPIs was only in people who had experienced prior acute kidney injury. Studies now show that this damage likely happens gradually with or without prior kidney injury. H₂ Blockers do not appear to have the same effect as illustrated by a study on veterans – those who took PPIs were 19% more likely to have low eGFR (a marker of kidney function) and 22% more likely to develop chronic kidney disease as compared to those on H₂ blockers. (18)

Though the exact method is unknown, the proposed mechanism for kidney injury with PPIs is through the immune system. Medication and microbial antigens (substances the body mounts an attack against) are thought to cause an immune reaction in the kidneys. (19)

Altered Microbiome and Dysbiosis

Your gut has its own ecosystem that functions best when the right conditions are present. Acid in your stomach is a normal part of the digestive system environment and when you block it, it changes the environment enough that it alters your microbiome. People who use PPIs have a less healthy microbiome including less diversity of gut bacteria and higher levels of Streptococcus, Staphylococcus, and Enterococcus bacteria. (20) This change in bacteria can have many downstream effects from changes to the immune system to symptoms like bloating, abdominal pain, diarrhea, and constipation.

SIBO (Small Intestine Bacterial Overgrowth)

In a meta-analysis of 11 studies, PPI use was shown to increase the risk of SIBO. Most of your gut bacteria is found in your large intestine, however in SIBO, there are abnormally high levels of bacteria in the small intestine resulting in a variety of symptoms, notably bloating due to fermentation of food by the bacteria. The studies that used the more accurate testing for SIBO (duodenal/jejunal aspirate) showed the largest correlation of 7.5 times the risk of SIBO with PPI use. (21)

Increased Risk of Bacterial & Viral Gastroenteritis

Not only is stomach acid one of your body’s first ways of digesting food, it is also one of your first defenses acting as a barrier to pathogens. PPI use has been associated with increased risk of a variety of gastrointestinal infections ranging from the imbalance of bacteria mentioned previously to viral gastroenteritis (stomach flu) (22) and some more serious infections like C. difficile and potentially pathogenic forms of E. coli (20)

Dementia

There have been mixed results of whether long term PPI use is associated with increased risk of dementia. One study of 3,076 patients found a 33% increased incidence of dementia and 44% increased risk of Alzheimer’s in patients using PPIs, (23)  and another study on 73,679 individuals similarly found a 44% increased risk of dementia. (24) Conversely, 2 other large studies (70,718 and 13,864 participants) (25) (26) found no association with PPIs and Alzheimer’s or cognitive function respectively.

Some possible connections between PPIs and cognitive decline include vitamin B12 deficiency as well as increased β-amyloid plaques which have been shown to occur in animal studies (while other studies contradict this).

What about using PPIs for Barrett’s Esophagus?

Many doctors are more adamant about continuing the use of PPIs in patients with Barrett’s Esophagus which is associated with a slight increased risk of esophageal cancer than the general population, but still low (0.1-0.4% per year by recent estimates). (27) Understandably, these doctors want to be conservative with treatment and will rarely advise patients to discontinue PPIs with this condition.

Acid blockers are certainly effective at reducing acid reflux and other characteristics associated with Barrett’s, however, the evidence is more theoretical whether acid-blocking medications reduce the progression of Barrett’s esophagus to cancer and the studies we do have show mixed results. (28) There is also no data on whether asymptomatic Barrett’s esophagus, in which the symptoms are well-controlled through other means, has a lower rate of progression.

Due to the very low incidence of progression of Barrett’s esophagus to cancer and low evidence that acid blockers are effective at reducing this progression further, some medical professionals are deprescribing PPIs in some cases.

Kayleen Hayes, PharmD from the University of Waterloo wrote a commentary on a 2019 JAMA article showing increased risk of viral gastroenteritis with PPI use and she advises limiting the prescription of PPIs for the “prevention of nonsteroidal anti-inflammatory drug-induced ulcers, severe esophagitis, Barrett esophagus, idiopathic chronic ulcer, refractory gastroesophageal reflux disease, pathological hypersecretory conditions (e.g. Zollinger-Ellison syndrome), and certain patients with history of gastrointestinal ulcer with bleeding.”

Furthermore, as stated in the 2008 American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease, evidence does not suggest that GERD will progress to Barrett’s esophagus if not treated with PPIs.

What Are My Other Options for Managing Heartburn/Acid Reflux?

We have seen there are some significant downsides to taking acid blocking medications. This doesn’t mean that there aren’t reasons to use them, but that for long-term control of heartburn and related symptoms alternatives should be pursued.

There are many effective alternatives that do not have the same side effects including dietary change, identifying sources of the inflammation such as food allergies and sensitivities, using treatments that actually heal the GI tract without blocking the acid, or addressing other underlying causes like dysfunction of the lower esophageal sphincter.

Naturopathic doctors are trained in helping identify underlying causes of symptoms like heartburn and gastrointestinal inflammation that are specific to each patient and are knowledgeable about safe treatments that work with the body to heal with lower risk of side effects. 

If you or someone you know suffers from any of these issues, schedule an appt at Third Stone Health to heal your digestive tract, prevent future disease, and optimize your health.

Works Cited

1. Anti‐acid medication as a risk factor for food allergy. Pali-Schöll, I and Jensen-Jarolim, E. s.l. : Allergy, 2011, Vol. 66, pp. 469-477.

2. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Angiolillo, DJ. s.l. : Clin Pharm Ther, 2011, Vol. 89, pp. 65-74.

3. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. Lam, JR. s.l. : JAMA, 2013, Vol. 310, p. 2435.

4. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Heidelbaugh, JJ. 3, s.l. : Ther Adv Drug Saf, 2013, Vol. 4, pp. 125-33.

5. PTU-112 Proton Pump Inhibitors – A Risk for Micronutrient Deficiency. But Are We Looking Out for This? El Menabawey, T, et al. A111, s.l. : Gut, 2016, Vol. 65.

6. Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Lin, SM, et al. 1, s.l. : Osteoporosis Int, 2018, Vol. 29, pp. 153-162.

7. Use of proton pump inhibitors and risk of osteoporosis-related fractures. Targownik, LE, et al. 4, s.l. : CMAJ, 2008, Vol. 179, pp. 319-26.

8. Acid-suppressive medications and risk of bone loss and fracture in older adults. Yu, EW, et al. 4, s.l. : Calcif Tissue Int, 2008, Vol. 83, pp. 251-9.

9. Homocysteine suppresses the expression of the collagen cross-linker lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation. Thaler, R, et al. 7, s.l. : J Biol Chem, 2011, Vol. 286, pp. 5578-88.

10. Homocysteine as a predictive factor for hip fracture in elderly women with Parkinson’s disease. Sato, Y, et al. 11, s.l. : Am J Med, 2005, Vol. 118, pp. 1250-5.

11. Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients. Zhu, Y, et al. s.l. : Clin Interv Aging, 2016, Vol. 11, pp. 1117-1121.

12. Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. Mizunashi, K, et al. 1, s.l. : Calcif Tissue Int, 1993, Vol. 53, pp. 21-5.

13. A Proton Pump Inhibitor’s Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study. Jo, Y, et al. 5, s.l. : Gut Liver, 2015, Vol. 9, pp. 607-614.

14. Growth of the parathyroid glands in omeprazole-treated chickens. Gagnemo-Persson, R, et al. 6, s.l. : Scan J Gastroenterol, 1994, Vol. 29, pp. 493-7.

15. Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake. Gagnemo-Persson, R, Samuelsson, A, Hakanson, R and Persson, P. 3, s.l. : Calcif Tissue Int, 1997, Vol. 61, pp. 210-5.

16. Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retrospective Cohort Study. Hart, E, et al. 4, s.l. : Pharmacotherapy, 2019, Vol. 39, pp. 443-453.

17. Proton Pump Inhibitors and CKD. Moledina, DG and Perazella, MA. 10, s.l. : JASN, 2016, Vol. 27, pp. 2926-28.

18. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Xie, Y, et al. 6, s.l. : Kidney Int, 2017, Vol. 91, pp. 1482-1494.

19. Acute interstitial nephritis. Praga, M and Gonzalez, E. 11, s.l. : Kidney Inter, 2010, Vol. 77, pp. 956-961.

20. Proton pump inhibitors affect the gut microbiome. Imhann, F, et al. s.l. : Gut, 2016, Vol. 65, pp. 740-748.

21. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Lo, WK and Chan, WW. s.l. : Clin Gastroenterol Hepatol, 2013, Vol. 11, pp. 483-490.

22. Association Between Acute Gastroenteritis and Continuous Use of Proton Pump Inhibitors During Winter Periods of Highest Circulation of Enteric Viruses. Vilcu, A, et al. 11, s.l. : JAMA Netw Open, 2019, Vol. 2, p. e196205.

23. Risk of dementia in elderly patients with the use of proton pump inhibitors. Haenisch, B, von Holt, K and Wiese, B. s.l. : Eur Arch Psychiatry Clin Neurosci, 2015, Vol. 265, pp. 419-428.

24. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. Gomm, W, von Holt, K and Thomé, F. s.l. : JAMA Neurol, 2016, Vol. 73, pp. 410-416.

25. No association between proton pump inhibitor use and risk of Alzheimer’s disease. Taipale, H, et al. 12, s.l. : Am J Gastroenterol, 2017, Vol. 112, pp. 1802-8.

26. Association between proton pump inhibitor use and cognitive function in women. Lochhead, P, et al. s.l. : Gastroenterology, 2017, Vol. 153, pp. 971-979.

27. Spechler, Stuart. Barrett’s Esophagus: Surveillance and Management. UpToDate.