Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia.

Abstract: Hypochlorhydric states such as atrophic gastritis and partial gastrectomy have long been known to cause iron deficiency anemia. However, studies to date have failed to show a similar association with omeprazole, a proton pump inhibitor that also produces achlorhydria. These studies, however, have primarily involved nonanemic, iron-replete individuals. The effect of the drug has not been studied in patients with established iron deficiency, and to our knowledge the patients presented here are the first of their kind to be reported. Our observations support the probability that the profound hypochlorhydria induced by omeprazole may indeed impair the optimal absorption of orally administered iron in iron-deficient individuals, precluding them from obtaining therapeutically adequate amounts to establish the positive balance necessary for the resolution of anemia and the replenishment of stores. The possible explanations for this phenomenon are also discussed.

Key Words: iron deficiency, omeprazole, oral iron

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Clinicians treating iron deficiency are all too aware of patients who do not respond well to seemingly adequate doses of oral iron even in the absence of any objective evidence of persistent blood loss. If such a patient is also on a potent gastric acid suppressant such as omeprazole, it is often intuitively suspected as a possible explanation for the lack of response to the oral iron. Although this seems very plausible, to our knowledge there has been no published report describing it in the clinical setting. We discuss two patients who presented with iron deficiency anemia unresponsive to oral replacement therapy. Blood loss from the gastrointestinal (GI) tract had been determined to be the original cause for anemia in both patients. Continued bleeding was reasonably eliminated by appropriate clinical evaluation as a potential cause for persistence of the anemia. One common factor among these patients was that they were both receiving chronic omeprazole therapy. Malabsorption of the prescribed iron as a result of the hypochlorhydria induced by this drug was therefore considered as a possible explanation for the lack of improvement in the anemic state. A test for iron absorption was performed by administering three tablets of ferrous sulfate (325 mg each) and checking serum iron levels at 0, 30, 60, and 120-minute time points (Fig. 1). (1)

Case Reports

Patient 1

A 51-year-old woman was diagnosed with iron deficiency anemia, which on endoscopy was found to be a result of upper GI bleeding from "erosive gastritis." At the time of presentation, her hemoglobin was 10.2 g/dL and the mean corpuscular volume (MCV) was 76, which led to a presumptive diagnosis of iron deficiency by her treating physician. Helicobacter pylori was not detected, and the patient was placed on omeprazole 20 mg orally once a day together with ferrous sulfate (FeS[O.sub.4]) 325 mg orally three times a day. After six months of treatment, her anemia persisted with a hemoglobin of 9.9 g/dL and an MCV of 76. An evaluation for persistent GI bleeding including stool occult blood and upper and lower GI endoscopy was negative. She was then referred for hematology consultation, at which time malabsorption of iron as a result of the omeprazole was suspected. A test for iron absorption was performed by administering three tablets of ferrous sulfate (325 mg each), and checking serum iron levels at 0, 30, 60, and 120-minute time points. Malabsorption was suggested. Omeprazole was discontinued at this point; after 2 months of continued treatment with oral FeS[O.sub.4], the patient's hemoglobin improved to 11.5 g/dL and the MCV increased to 82. It is possible that the patient may have had some additional pathology such as anemia of chronic disease, which may explain the slightly subnormal hemoglobin value for her age even after 2 months of therapy. Although the hemoglobin did not "normalize" completely, the clear increment compared with the pretreatment value together with the resolution of microcytosis was believed to be adequate evidence of a responding iron-deficient state. The patient agreed to undergo a repeat Fe absorption test, the results of which are shown in Figure 1 alongside the absorption curve while receiving omeprazole.

Patient 2

An 83-year-old woman presented with fatigue and was found to be anemic, with a hemoglobin level of 9.3 g/dL and an MCV of 80. A GI endoscopic evaluation showed "gastric erosions" and was negative for Helicobacter pylori. The patient was started on omeprazole and oral iron. After 6 months of the above treatment, her hemoglobin failed to increase above 10 g/dL. Stool studies and repeat GI endoscopy did not show any clinically overt bleeding. A bone marrow evaluation performed at the time of initial hematology consultation was normal except for the absence of iron stores. Malabsorption of iron as a result of the omeprazole was suspected, and the proton pump inhibitor (PPI) was discontinued. Within 2 months, on the same dose and formulation of oral iron, the patient's hemoglobin improved to 11.8 g/dL with an MCV of 86. Confirmatory iron absorption testing was not performed in this case because of patient preference.

Discussion

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.

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Omeprazole is a potent gastric acid suppressant that works by inhibiting the mucosal proton pump ([Na.sup.+]/[K.sup.+] 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 (1-2 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 [.sup.59]Fe 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.

Conclusion

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.

The power of accurate observation is frequently called cynicism by those
who don't have it.
--George Bernard Shaw

Acknowledgments

We are grateful to Dr. Harry Carloss for providing clinical data on his patients and to Beverly Kirkpatrick for her assistance with the preparation of the manuscript.

Accepted October 22, 2003.

Please see Sucha Nand and Tawee Tanvetyanon's editorial on page 799 of this issue.

References

1. Schmid A, Jakob E, Berg A, et al. Effect of physical exercise and vitamin C on absorption of ferric sodium citrate. Med Sci Sports Exerc 1996;28:1470-1473.

2. Massey AC. Microcytic anemia: differential diagnosis and management of iron deficiency anemia. Med Clin North Am 1992;76:549-566.

3. Conrad ME. Iron absorption, in Johnson LR (ed): Physiology of the Gastrointestinal Tract. New York, Raven Press, 1987, ed 2, pp 1437-1453.

4. Schade SG, Cohen RJ, Conrad ME. Effect of hydrochloric acid on iron absorption. N Engl J Med 1968;279:672-674.

5. Hines JD, Hoffbrand AV, Mollin DL. The hematologic complications following partial gastrectomy: a study of 292 patients. Am J Med 1967;43:555-569.

6. Wheldon EJ, Venables CW, Johnston ID. Late metabolic sequelae of vagotomy and gastroenterostomy. Lancet 1970;1:437-440.

7. 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.

8. Bezwoda W, Charlton R, Bothwell T, et al. The importance of gastric hydrochloric acid in the absorption of nonheme food iron. J Lab Clin Med 1978;92:108-116.

9. Kaltwasser JP, Werner E, Schalk K, et al. Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis. Gut 1998;43:699-704.

10. Golubov J, Flanagan P, Adams P. Inhibition of iron absorption by omeprazole in rat model. Dig Dis Sci 1991;36:405-408.

RELATED ARTICLE: Key Points

* Several achlorhydric states are known to be associated with iron deficiency.

* Although proton pump inhibitors can cause profound achlorhydria, studies in iron-replete individuals have not shown a higher incidence of iron deficiency anemia.

* The cases presented suggest that omeprazole-induced achlorhydria may impair the response to oral iron therapy in patients with preexisting iron deficiency.

Vivek R. Sharma, MD, Mark A. Brannon, BS, PA-C, and Elizabeth A. Carloss, MD

From West Kentucky Hematology and Oncology, Paducah, KY; the Division of Medical Oncology/Hematology, University of Louisville, Louisville, KY; and Beth Israel Hospital, Harvard Medical School, Boston, MA.

Reprint requests to Vivek R. Sharma, MD, University of Louisville, 529 S. Jackson St., Louisville, KY 40202. Email: [e-mail]