In the late 1970s evidence began to emerge that a newly discovered pump, a H+/K+ ATPase in the gastric mucosa, was the final step in the process of acid secretion . With this discovery, further research demonstrated the ability to reduce gastric acid secretion by inhibiting these proton pumps . We now have drugs that do just that: the proton pump inhibitors (PPIs). Proton pump inhibitors have been used since 1989 to treat acid-related gastrointestinal disorders as well as in the evaluation of noncardiac chest pain [3, 4]. In 2011, the PPI omeprazole was the sixth most commonly dispensed prescription medication in the United States, with over 59 million prescriptions written .
Given the chronicity of many acid-related disorders, such as gastroesophageal reflux disease (GERD), many patients ultimately end up taking PPIs daily for many years. With this in mind, it is important to consider the potential side effects of PPIs and assess the costs and benefits of long-term PPI use.
One potential side effect of PPIs is the risk of malabsorption of vitamins and minerals, in particular vitamin B12. Vitamin B12 deficiency occurs as follows: gastric acid assists in the absorption of vitamin B12 by releasing the vitamin from the proteins to which it is bound when ingested so that it is available to bind to R-proteins and avoid degradation by acid in the stomach. In patients on PPIs, there is decreased production of gastric acid, which may contribute to malabsorption of the vitamin .
The risk of vitamin B12 deficiency secondary to antacid use has mostly been studied in the elderly population. With an increased prevalence of atrophic gastritis in elderly individuals, the absorption of protein-bound vitamin B12 is decreased . Multiple studies have shown an increased risk of vitamin B12 deficiency in patients over the age of 60 who have been on long-term PPIs [8, 9].
Until recently, there have been no large-scale studies looking at the risk of vitamin B12 deficiency across multiple age groups taking PPIs. However, a 2013 case-control study published in JAMA discussed the potential for vitamin B12 deficiency in individuals of varying ages taking acid-suppressing drugs for long periods of time . The study showed that having taken PPIs for 2 or more years was associated with an increased risk of vitamin B12 deficiency, with an odds ratio of 1.65 (95% CI, 1.58-1.73). Interestingly, the study showed a stronger association in younger age groups between vitamin B12 deficiency and PPI use for 2 or more years. The greatest association was seen in patients under the age of 30 (OR 8.12 [95% CI, 3.36-19.59]). With increasing age, the association actually decreased; for example, for patients older than 80 years old, the OR was 1.04 (95% CI, 0.96-1.13). Additionally, a stronger association was seen in women and in those taking higher dosages of PPIs.
PPIs are commonly used in emergency rooms and on inpatient floors as well as in outpatient medicine. One may wonder whether the malabsorption risk exists for patients being treated while they are in the hospital. One study assessing the risk of B12 deficiency in older adults on PPIs or H2 blockers showed no risk associated with past or short-term use . Additionally, a 2013 study by Lam and colleagues showed decreased risk of vitamin B12 deficiency once patients discontinued use of PPIs .
Long-term PPI use has also been associated with iron-deficiency anemia, malabsorption of magnesium and calcium, and increased risk of infection. States of hypochlorhydria have been known to cause iron-deficiency anemia; however the relationship between PPIs and iron-deficiency anemia has not been fully elucidated. In healthy individuals with normal iron levels, PPIs have not been shown to decrease iron levels significantly [11, 12]. However, some studies have shown that individuals with established iron deficiency may have a suboptimal response to oral iron replacement while on PPIs due to impaired absorption of nonheme iron, and therefore require treatment with high-dose iron replacement therapy for a longer duration or intravenously [13, 14].
In 2012 a systematic review was performed that looked at hypomagnesemia and long-term PPI use. The study found that this side effect occurred after a median of 5.5 years of PPI use and that discontinuation of the PPI resulted in fast recovery of normal magnesium levels . In 2011 the FDA issued a safety alert to warn providers of this potential side effect and recommended periodic magnesium levels for patients taking PPIs long-term .
In terms of calcium absorption, it has been suggested that the state of hypochlorhydria induced by PPIs may reduce absorption of calcium, thereby decreasing bone density. One study in 2006 found a significant increase in hip fracture risk in those patients prescribed long-term high-dose PPIs . Additionally, this study showed a plausible dose-response curve: an increased risk of hip fractures with increased duration of PPI therapy (adjusted odds ratio [AOR] for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<0.001 for all).
Overall, PPIs are one of the most prescribed drugs in the United States in both inpatient and outpatient settings. They are effective acid suppressants, providing many patients with relief of their symptoms. However, given the new data surfacing, it is crucial to assess the need for nutrient measurement and to weigh the costs and benefits of the PPIs.
Dana Zalkin is a 3rd year medical student at NYU School of Medicine
Peer reviewed by Michael Poles, MD, section editor, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Forte JG, Lee HC. Gastric adenosine triphosphatases: a review of their possible role in HCl secretion. Gastroenterology. 1977;73(4 Pt 2):921-926. http://www.ncbi.nlm.nih.gov/pubmed/20386
2. Fellenius E, Berglindh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase. Nature. 1981;290(5802):159-161.
3. Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology. 1998;115(1):42-49. http://www.nursing.unboundmedicine.com/nursingcentral/ub/citation/9649457/The_clinical_and_economic_value_of_a_short_course_of_omeprazole_in_patients_with_noncardiac_chest_pain_
4. Pandak WM, Arezo S, Everett S, et al. Short course of omeprazole: a better first diagnostic approach to noncardiac chest pain than endoscopy, manometry, or 24-hour esophageal pH monitoring. J Clin Gastroenterol. 2002;35(4):307-314.
5. IMS Institute for Healthcare Informatics. The use of medicines in the United States: Review of 2011. http://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf. Published April 2012. Accessed December 18, 2013.
6. Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr. 1997;66(4):750-759.
7. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.
8. Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008;9(3):162-167. doi: 10.1016/j.jamda.2007.10.004. http://www.ncbi.nlm.nih.gov/pubmed/18294598
9. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57(4):422-428.
10. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. doi:10.1001/jama.2013.280490. http://www.ncbi.nlm.nih.gov/pubmed/24327038
11. Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol. 1992;14(4):288-292.
12. Stewart CA, Termanini B, Sutliff VE, et al. Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther. 1998;12(1):83-98.
13. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J. 2004 ;97(9):887-889. http://www.ncbi.nlm.nih.gov/pubmed/15455980
14. Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole. Am J Ther. 2012;19(3):185-189.
15. Hess MW, Hoenderop JG, Bindels RJ, Drenth JP. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther. 2012;36(5):405-413. doi: 10.1111/j.1365-2036.2012.05201.x. Epub 2012 Jul 4.
16. Food and Drug Administration. Proton pump inhibitor drugs (PPIs): Drug safety communication. Low magnesium levels can be associated with long-term use. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245275.htm. Posted March 2, 2011. Updated February 12, 2014. Accessed March 17, 2014.
17. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):2947-2953. http://www.ncbi.nlm.nih.gov/pubmed/17190895