Chronic use of proton pump inhibitors (PPI) has increased over the past decade due to their efficacy in treating a number of gastrointestinal conditions such as peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison Syndrome, helicobacter pylori infections, to name a few.  However, continuous use may expose the patient to adverse effects and/or clinically relevant drug-drug interactions.1  The current PPIs on the market include dexlansoprazole (Kapidex), esomeprazole (Nexium), omeprazole (Prilosec; Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (AcipHex).  One area of concern that has been discussed for decades is the need for adequate gastric acid or low pH for the absorption of nonheme-iron from food and non-food sources.  Since PPIs can significantly increase the pH for a long period of time throughout the day, there has been discussion about their ability to negatively influence oral iron absorption and thus prolong the time to effectively treat iron deficiency anemia. 

This topic is particularly pertinent for patients with bleeding ulcers who are also iron deficient and will need to be treated with both a PPI and oral iron replacement therapy.  In addition, it is known that approximately 10% of people in developed nations and 25-50% in developing nations are iron deficient for a number of reasons.2  Iron is an essential trace mineral that our bodies primarily utilize for carrying out cellular respiration (electron transport chain) and to carry oxygen to our tissue in the form of hemoglobin.3  Without adequate concentrations of iron, hemoglobin will not be adequately produced thereby resulting in the development of microcytic, hypochromic anemia (smaller and more pale red blood cells).2,3  While some patients can increase their iron stores through a proper diet, most will need iron replacement therapy.  The most common form of iron replacement in clinical practice is oral iron, or ferrous sulfate, at doses that provide 200 mg of elemental iron per day.4  Unfortunately, oral iron therapy is not only difficult to tolerate, but its absorption is influenced by a number of factors which include the type of iron product used, the presence of food or other medications, the anatomy of the stomach and small intestine, and the acidity of the environment in the areas of absorption.2,4-8  The influence of gastric acidity is the focus for this drug interaction. 

What is the normal process for absorption of oral iron and what role does gastric acidity have on this process?
Iron is available in several different forms with each form having a different bioavailability.  Iron in food can be in the form of either heme-iron or nonheme-iron (Fe3+; ferric iron) whereas the most common oral iron replacement is ferrous sulfate (Fe2+; ferrous iron).  Regardless of the type of iron ingested by mouth, the majority of iron is absorbed in the duodenum (the first segment of the small intestine).9,10  Heme-iron does not require any additional metabolism or chemical modification for absorption through the heme transporter on the luminal side of the enterocyte in the duodenum.2  Once absorbed, heme-iron is converted to mucosal ferritin for local storage or in preparation for secretion through the cell membrane transporter, ferroportin 1, as ferrous iron (Fe2+).2,5  This process is not as efficient for nonheme-iron (Fe3+; ferric iron).  In order for ferric iron (Fe3+) to be absorbed it must be converted from its oxidized state (Fe3+) to its reduced state (Fe2+; ferrous iron).2,5  This conversion is facilitated by the acidity of the stomach, initial intestinal contents and the presence of a cell membrane enzyme on the enterocyte called ferric-reductase or duodenal cytochrome B.2  Whether formed from ferric iron (Fe3+) in food or delivered directly via iron replacement, the ferrous (Fe2+) form of iron is more soluble and thus more easily absorbed into the intestinal enterocyte via divalent metal transporter-1 (DMT-1).  Once absorbed into the enterocyte, the majority of the ferrous iron is converted to mucosal ferritin.2  In a patient with iron deficiency, iron absorption into the basolateral side is increased because hepcidin (which is released from the liver) is decreased and thereby not able to inhibit ferroportin 1 activity.11  Interestingly, once ferrous (Fe2+) iron makes it into the basolateral side of the enterocyte, it is converted (or oxidized) back to the ferric (Fe3+) state with the help of hephaestin.2  When two of the newly formed ferric iron molecules bind to apotransferrin, transferrin is formed and functions to carry iron to the various storage sites in the body.  It is stored as ferritin and, when needed, will be utilized for hematopoiesis.

How do proton pump inhibitors (PPI) affect the absorption of oral iron replacement therapy?
It is well known that PPIs can increase the gastric pH through their inhibition of the H+/K+-ATPase pump on the parietal cell, thereby making the gastric environment more alkaline.  The greater degree of alkalinity facilitates the oxidation of ferrous (Fe2+) iron to the ferric state (Fe3+) which may negatively impact the bioavailability of iron in the duodenum.4,10  Once normal peristalsis moves the iron past this part of the intestine, it will not be absorbed.  It is for this reason that a patient's stool becomes black and tarry or they develop constipation while taking iron.

Is there any evidence that PPIs have the ability to reduce the absorption of iron in patients with iron deficiency anemia translates to an actual clinical reduction in absorption?
To our knowledge there are no human studies evaluating the impact of PPI use in patients with iron deficiency anemia who are also receiving oral iron replacement therapy.  However, there are a few studies that have evaluated the impact of PPIs on the overall absorption of oral iron in animals or patients without iron deficiency anemia.  One study in rats showed that omeprazole decreased absorption of iron in rats fed an iron-deficient diet, but did not affect rats fed a normal diet containing iron.12  There were also 2 studies done in non-iron deficient humans who were receiving PPIs for gastrointestinal conditions (primary reflux esophagitis and Zollinger-Ellison Syndrome) which did not reveal any abnormalities or deficiencies in iron body stores.13,14  It is important to note that none of the patients in either of these studies had iron deficiency anemia, gastrectomies, chronic inflammatory bowel diseases, or were known to have changed their dietary habits.  

Thus the relevance of this potential drug interaction is complicated by the fact that there are no prospectively designed studies that have determined the impact of PPI use in patients with iron deficiency anemia who are also being treated with oral iron therapy from non-food, nonheme sources of iron (such as ferrous sulfate).  This is a subtle point of observation, but may be significant since it is known that only the rate of absorption of iron is regulated, which is increased in states of iron deficiency.  The predominate use of the ferrous (Fe2+) iron dosage formulations in clinical practice has to do with the iron being in its reduced state (Fe2+) as well as its increased solubility in locations of the gastrointestinal tract where the pH is higher (> 3).12  

Due to all of these issues, it is relevant to consider other aspects of iron replacement so that delays in treatment are not unnecessarily prolonged.  For example, it is well known that if a patient were to take 200 mg of elemental iron per day on an empty stomach (for greatest absorption), it would take about 3 months of chronic therapy for replenishment of iron to occur.4  Given that most patients cannot tolerate oral iron on an empty stomach and/or may not be adherent with the multiple daily doses that is typically required, the replacement could actually be longer than 3 months.4  In addition, if other medications such as PPIs and/or histamine-2 receptor antagonists are inhibiting the bioavailability of iron in certain patients, it becomes evident why effective oral iron replacement can extend the time to replenishment even further.  To complicate things more, if the patient has or develops a chronic inflammatory disease state during this time, absorption can be further impaired since chronic inflammatory states result in the hepatic release of hepcidin, which can block the secretion of iron through the cell membrane transporter ferroportin into the basolateral compartment.10  Any delay in correcting iron stores may impair the effectiveness of erythropoietin replacement (if indicated), could affect the female patient who is pregnant or any patient known to have coronary artery disease and/or heart failure.  One method that can be used to determine the effectiveness of oral iron replacement therapy is look for an increase in the hemoglobin concentration by approximately 1 mg/dL per day starting after about 5-7 days of iron replacement.4

References:

1. Busti AJ, Herrington JD, Lehew DS, Daves BJ, McKeever GC.  Are there any differences among the proton pump inhibitors (PPIs) in their ability to inhibit the activation of clopidogrel (Plavix®) through the cytochrome P450 (CYP) enzyme system? Pharmacology Weekly 2010.
2. Aster JC.  Chapter 12: The Hematopoietic and Lymphoid System.  In:  Robbins Basic Pathology.  8^th Ed.  Kumar V, Abbas AK, Fausto N, Mitchell RN eds.  Saunders Elsevier; Philadelphia, PA.  2007:435-7.
3. Leiberman M, Marks AD.  Chapter 44:  Biochemistry of Erythrocytes and Other Blood Cells.  In:  Mark's Basic Medical Biochemistry A Clinical Approach.  3^rd Ed.  Lippincott Williams & Wilkins; Baltimore, MD.  2009:831-853.
4. Frewin R, Henson A, Provan D.  ABC of clinical haematology.  Iron deficiency anemia.  BMJ  1997;314:360-3.
5. Charlton RW, Bothwell TH.  Iron absorption.  Annu Rev Med  1983;34:55-68.
6. Esposito R.  Cimetidine and iron-deficiency and iron-deficiency anemia.  Lancet  1977;2:1132.
7. Walan A, Strom M.  Metabolic consequences of reduced gastric acidity.  Scand J Gastroenterol Suppl  1985;111:24-30.
8. Skikne BS, Lynch SR, Cook JD.   Role of gastric acid in food iron absorption.  Gastroenterology  1981;81:1068-71.
9. Wheby MS.  Site of iron absorption in man.  Scand J Haematol  1970;7:56-62.
10. Raffin SB, Woo CH, Roost KT et al.  Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase.  J Clin Invest  1974;54:1344-52.
11. Yeh KY, Yeh M, Glass J.  Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat.  Am J Physiol Gastrointest Liver Physiol  2004;286:G385-94.
12. Golubov J, Flanagan P, Adams P.  inhibition of iron absorption by omeprazole in rat model.  Dig Dis Sci  1991;36:405-8.
13. Koop H, Bachem MG.  Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy.  J Clin Gastroenterol  1992;14:288-92.
14. 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;12:83-98.

Proton Pump Inhibitors, PPI, Iron Supplements, Ferrous Sulfate Absorption, Iron Bioavailability