In the preceding article, the class of medications called the proton pump inhibitors (or PPIs) was shown to produce superior results for symptom control of heartburn over histamine-2 receptor antagonists (H2RAs). PPIs have become the gold standard agents for the long-term control of heartburn symptomatology. Overall, there are seven different PPI drugs that have 27 different formations (dosage and strengths) on the market today. Despite having equivalent efficacy for controlling heartburn, there are considerable variations in the costs of the PPIs. Although studies have shown similar efficacy for controlling heartburn across the seven different drugs, patients often respond differently to the PPIs.
There are four PPIs that are available as generic prescription drugs—lansoprazole, omeprazole (Prilosec), omeprazole/sodium bicarbonate (Zegerid®), and pantoprazole (Protonix®). Four of the seven PPIs are available over-the-counter (OTC) without a prescription: lansoprazole (Prevacid® 24HR and generics), omeprazole (Prilosec OTC and generics), (Nexium® OTC) and omeprazole/sodium bicarbonate (Zegerid® OTC). Table 1 displays the seven PPIs along with their brand names and whether prescription or non-prescription OTC generic equivalents are available to consumers.
|Generic||Name Brand||Available as a Prescription
|Available as a
Non-prescription Generic Drug
|Lansoprazole||Prevacid®, Prevacid® 24 hr. (a non-prescription version)||Yes||Yes|
|Omeprazole||Prilosec®, Prilosec® OTC||Yes||Yes|
|Omeprazole/Sodium Bicarbonate||Zegrid®, Zegrid® OTC||Yes||Yes (brand name only)|
Table 1: The Proton Pump Inhibitors (PPIs)
PPIs are powerful inhibitors of stomach acid, which allow the esophageal lining to heal and improve heartburn symptomatology. When used daily PPIs can produce superior results for long-term control of heartburn.
However, here is the problem: The Federal Drug Administration (FDA) has approved the use of OTC PPIs for heartburn to a 14-day course of treatment and further limited their use to just three times per year. Over the past six years, there have been several alerts by the FDA warning about potential dangers from this class of medication. Why exactly? Concerns over safety!
There are emerging concerns about the long-term safety of PPIs.
The next two articles will provide an evidence-based evaluation of the adverse effects of the PPIs in the medical literature. The first article will concentrate on the potential impairments of vitamin and mineral absorption due to PPI use while the second will provide information about the risks of infections, kidney damage, interference with cardiovascular medications, and susceptibility to events such as stroke and myocardial infarctions, bone fracture, and more.
Impairments in Vitamin and Mineral Absorption There is growing concern about the long-term ramifications of vitamin and mineral malabsorption from the lack of stomach acid in face of PPI use. There is evidence to suggest that those on chronic PPI medications may have an impaired availability of the minerals iron, calcium, magnesium, and vitamin B12.
Non-heme iron represents the vast majority of dietary iron, which is in the ferric form (Fe3+) and is not absorbable by the duodenal lining cells. Stomach acid, along with vitamin C, reduces ferric iron to the ferrous (Fe2+) form. PPIs, by virtually shutting down stomach acid production, keep the dietary non-heme iron in the ferrous form and decrease overall iron availability. A retrospective cohort study by Sarzynski E. et al., demonstrated that PPIs were attributed to the development of iron deficiency anemia.1 Furthermore, a case of iron deficiency anemia of unknown cause was shown to reverse within three months’ time after cessation of rabeprazole.2 Finally, Congenital dyserythropoietic anemia type I (CDA I) is a condition that is associated with impaired red blood cell production (erythropoiesis) and is associated with an increased absorption of iron. An open-labeled study using 20 mg daily of omeprazole for six months resulted in significantly lowered hemoglobin values and reduced iron indices.3 Dietary vitamin C can facilitate the conversion of non-heme ferric iron to the ferrous form, but studies have not been conducted to measure the impact of supplementation on the prevention of PPI-induced iron deficiency anemia. Interestingly, a study demonstrated that gastric juice levels of vitamin C are impaired while patients are taking PPIs.4 The absorption of zinc, a divalent trace mineral related to iron, has also been shown to be impaired by PPIs.5,6
Calcium. Stomach acid solubilizes calcium salts to release ionized calcium for absorption by the small intestine enterocytes. Over a long period, there is concern that a reduction of available ionized calcium could weaken bones and lead to a higher risk of fractures in vulnerable populations such as the elderly and post-menopausal females (Figure 1). Six studies have evaluated the impact of PPI medications on calcium absorption. Four7-10 of the six affirmed blunted post-ingestion plasma calcium, whereas two11,12 others could not confirm a blunted absorption of post-meal calcium in the setting of PPI therapy. The impact of PPIs on the risk of bone fracture is discussed in further detail in a subsequent article.
Figure 1: PPI Therapy Reduced Calcium Availability and Portents Towards Decreased Bone Strength. Reproduced with permission from Springer Health.
Magnesium. PPI-induced hypomagnesemia is a well-documented causative adverse effect from PPI medication use.13 There are dozens of cases of profound hypomagnesemia causing arrhythmia and other associated maladies that require hospitalization.13,14 A case series showed that the hypomagnesemia may occur within one year of therapy initiation and can have life- threatening consequences.15 Removal of the PPI is required for magnesium therapy to correct, and rechallenge with PPIs provokes the state of low magnesium status. The FDA has alerted the public about the potential development of life-threatening hypomagnesemia from the use of PPIs. Overall, the literature shows that this complication occurs in the setting of long-term use, good adherence, but is otherwise unpredictable. A recent study showed that H2RAs also blunted magnesium levels long-term but not to the same extents as the PPIs.16 The administration of loop diuretics in the setting of PPI use provokes a stronger risk for clinically significant hypomagnesemia.16 The mechanisms of action for the induction of hypomagnesemia by PPIs is unknown, but is not due to effects on the kidney—as even those on hemodialysis experience this complication. The FDA recommendation is to consider checking magnesium levels before starting PPI medications.
Vitamin B12. Gastric acid facilitates the release of vitamin B12 from dietary protein that binds to R proteins to form a B12-R protein complex, which is broken down in the duodenum by enzymes. Vitamin B12 binds to intrinsic factor and is passed down the small intestine to be absorbed by the terminal ileum. Low B12 status has been linked to a legion of adverse health conditions via impairments in methylation, which impact epigenetic regulation of cardiovascular physiology, inflammation, carcinogenesis, neurodegeneration, and much more. Long-term longitudinal studies are overall lacking in this area. However, Lam et al., published a case-controlled study in JAMA that was conducted within the Kaiser Permanente Northern California population, and 25,956 patients with new-onset of serum vitamin B12 deficiency were compared to 184,199 patients without B12 deficiency.17 Their results demonstrated that the use of either PPIs or H2RAs increased the risk of B12 deficiency. Taking more than 1.5 PPI pills daily was more strongly associated with vitamin B12 deficiency than were doses less than 0.75 pills per day. Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B12 deficiency.
Caveat. One problem with many of the studies that evaluate B12 status was that they relied only on serum B12 which is a late marker for impaired B12 status, whereas homocysteine (HCY) and methylmalonic acid (MMA) are early markers (Figure 2). A study by Hirschowitz et al. demonstrated that 10% of patients on PPI medications had low serum B12 but when screening for low B12 status using serum MMA and HCY, an additional 31% were discovered and all corrected with B12 supplementation.18
Figure 2. The amino acid methionine metabolism-produced homocysteine efficiently metabolizes to a harmless and most beneficial amino acid, cysteine, which is an important source of sulfur in human metabolism. The B vitamin folate, or folic acid, provides the methyl group(s) essential for amino acid methionine metabolism—with vitamin B12 as the required methionine metabolism coenzyme and vitamin B6 as the coenzyme necessary for further downstream cysteine production. Low B12, B6 or folate will result in high levels of homocysteine.
Conclusions. The use of long-term PPIs appears to raise the risk for the iron calcium, magnesium, and vitamin B12. If you are taking a PPI, be certain that you are being followed up on for the status of these micronutrients.
To Your Good Health,
- Sarzynski E, Puttarajappa C, Xie Y, Grover M, Laird-Fick H. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci. 2011;56(8):2349-2353.
- Hashimoto R, Matsuda T, Chonan A. Iron-deficiency anemia caused by a proton pump inhibitor. Intern Med. 2014;53(20):2297-2299.
- Shalev H, Quider AA, Harosh MB, Kapelushnik J. Proton pump inhibitors use suppresses iron absorption in congenital dyserythropoietic anemia. Pediatr Hematol Oncol. 2016;33(7-8):457-461.
- McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol. 2009;104 Suppl 2:S5-9.
- Ozutemiz AO, Aydin HH, Isler M, Celik HA, Batur Y. Effect of omeprazole on plasma zinc levels after oral zinc administration. Indian J Gastroenterol. 2002;21(6):216-218.
- Joshaghani H, Amiriani T, Vaghari G, et al. Effects of omeprazole consumption on serum levels of trace elements. J Trace Elem Med Biol. 2012;26(4):234-237.
- Graziani G, Como G, Badalamenti S, et al. Effect of gastric acid secretion on intestinal phosphate and calcium absorption in normal subjects. Nephrol Dial Transplant. 1995;10(8):1376-1380.
- Hardy P, Sechet A, Hottelart C, et al. Inhibition of gastric secretion by omeprazole and efficiency of calcium carbonate on the control of hyperphosphatemia in patients on chronic hemodialysis. Artif Organs. 1998;22(7):569-573.
- Graziani G, Badalamenti S, Como G, et al. Calcium and phosphate plasma levels in dialysis patients after dietary Ca-P overload. Role of gastric acid secretion. Nephron. 2002;91(3):474-479.
- O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med. 2005;118(7):778-781.
- Serfaty-Lacrosniere C, Wood RJ, Voytko D, et al. Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium, phosphorus, magnesium or zinc from food in humans. J Am Coll Nutr. 1995;14(4):364-368.
- Hansen KE, Jones AN, Lindstrom MJ, et al. Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res. 2010;25(12):2786-2795.
- Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM. 2010;103(6):387-395.
- Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol. 2011;27(2):180-185.
- Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis. 2010;56(1):112-116.
- Kieboom BC, Kiefte-de Jong JC, Eijgelsheim M, et al. Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study. Am J Kidney Dis. 2015;66(5):775-782.
- 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.
- Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2008;27(11):1110-1121.