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.
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.
do proton pump inhibitors (PPI) affect the absorption of oral iron replacement
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.
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.
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
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
- 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.
- Aster JC. Chapter 12: The Hematopoietic and Lymphoid System. In: Robbins Basic Pathology. 8th Ed. Kumar V, Abbas AK, Fausto N, Mitchell RN eds. Saunders Elsevier; Philadelphia, PA. 2007:435-7.
- Leiberman M, Marks AD. Chapter 44: Biochemistry of Erythrocytes
and Other Blood Cells. In: Mark's Basic Medical Biochemistry A
Clinical Approach. 3rd Ed. Lippincott Williams & Wilkins; Baltimore, MD. 2009:831-853.
- Frewin R, Henson A, Provan D. ABC of clinical haematology. Iron deficiency anemia. BMJ 1997;314:360-3.
- Charlton RW, Bothwell TH. Iron absorption. Annu Rev Med 1983;34:55-68.
- Esposito R. Cimetidine and iron-deficiency and iron-deficiency anemia. Lancet 1977;2:1132.
- Walan A, Strom M. Metabolic consequences of reduced gastric acidity. Scand J Gastroenterol Suppl 1985;111:24-30.
- Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterology 1981;81:1068-71.
- Wheby MS. Site of iron absorption in man. Scand J Haematol 1970;7:56-62.
- Raffin SB, Woo CH, Roost KT et al. Intestinal absorption of
hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest
- 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.
- Golubov J, Flanagan P, Adams P. inhibition of iron absorption by omeprazole in rat model. Dig Dis Sci 1991;36:405-8.
- Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during
prolonged omeprazole therapy. J Clin Gastroenterol 1992;14:288-92.
- 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.