Iron is essential to the synthesis of hemoglobin, and its deficiency is the most common cause of anemia

around the world. The iron balance in normal individuals is maintained by absorption of the amount of iron
that is physiologically lost on a daily basis. This is usually 1 mg/d in men and 2 mg/d in menstruating
women. The average amount of dietary iron in the United States is approximately 10 to 20 mg, of which
10% (1-2 mg) is heme and 90% nonheme.[2] Although the heme component is absorbed independent of
gastric pH, the nonheme part requires an acidic pH for absorption. [3] When the daily loss of iron exceeds
that which can be absorbed, the body's iron stores are depleted, resulting eventually in iron deficiency
anemia. Once the primary cause is addressed, these patients require therapeutic iron replacement, which
usually takes the form of oral administration in doses that are well above the usual dietary intake.
Omeprazole is a potent gastric acid suppressant that works by inhibiting the mucosal proton pump
(Na+/K+ ATPase) and is taken by iron-deficient individuals as part of the treatment for upper GI tract
disorders that may or may not have been the primary cause of their anemia. It is well known that certain
conditions associated with hypochlorhydria, such as atrophic gastritis, vagotomy, and partial gastrectomy,
can lead to iron deficiency anemia.[4-6]
Interestingly, although omeprazole produces a profound hypochlorhydric state, clinical studies to date
have failed to associate it with iron deficiency even with prolonged use. [7] This may in part be due to the
compensation by dietary heme iron, which enables acid-independent absorption of the small amounts (12 mg/d) needed for homeostasis in the iron-replete individuals who typically participated in these studies,
which were not designed to look at response to oral iron in patients with established iron deficiency.
Unlike heme iron, however, nonheme iron depends on a low gastric pH to form soluble bivalent ferrous
iron for absorption in the duodenum.[4,8] Unless it is converted to this state, it cannot be absorbed. A
hypochlorhydric state, therefore, would impair predominantly the absorption of nonheme iron. Since
therapeutically administered oral iron is entirely nonheme in nature, its absorption may be drastically
curtailed by omeprazole. This may in turn lead to a state of unresponsiveness to oral iron replacement
with minimal or no improvement in anemia despite therapy that would be considered adequate for most
adults. Such individuals then may be able to maintain their hemoglobin levels in status quo because of
the acid-independent homeostasis provided by dietary heme iron, but are unlikely to achieve the
increment expected with oral (nonheme) therapeutic iron replacement.
We found this to be the case in each of the patients described above. After ongoing blood loss was
reasonably eliminated by appropriate studies, the possibility of iron malabsorption was considered and
patient 1 was screened with an oral iron-loading test as outlined previously. Although not in common
clinical use, such a test has been previously used for evaluation of iron absorption in the research setting,
and correlates well with the 59Fe whole body test.[1,9] The response of our patient was blunted on
omeprazole, suggesting malabsorption, but improved significantly after the cessation of omeprazole. In

the second patient, the prompt clinical response to the same oral dose and formulation of iron after the
cessation of omeprazole was considered adequate albeit indirect evidence of resolution of the
malabsorptive state.

3
In conclusion, our observations suggest that the profound hypochlorhydria induced by omeprazole may
impair the absorption of orally administered nonheme iron in iron-deficient individuals to the point of
making them poorly responsive or even refractory to such therapy. In addition, there is some preclinical
data suggesting a similar effect in a rat model.[10]Although both our patients were receiving omeprazole, it
is very likely that this phenomenon would apply equally to other PPIs. We believe these observations
deserve further study in a well-designed clinical trial with larger numbers of patients. In the meantime,
although such patients should still undergo appropriate diagnostic studies to rule out ongoing blood loss,
malabsorption as a result of omeprazole (or other PPI) should be considered in the differential diagnosis.
Once other causes are eliminated, cessation of the PPI may be the only intervention required to get the
appropriate clinical response to oral iron. If stopping the PPI were not an option because of the nature or
severity of the underlying disease, the next logical step for such patients would be to administer the iron
parenterally.