Proton pump inhibitors and iron deficiency: is the connection real?

Iron therapy has been used for centuries, perhaps dating back to 1500 BCE, even though recognition of iron deficiency has been more recent. (1) The main causes of iron deficiency remain blood loss from the gastrointestinal and genitourinary tracts and, in poorer countries, lack of dietary iron. Gastrointestinal malabsorption of iron is a well-recognized but uncommon cause of this malady.

Many factors influence the absorption of iron, which takes place in the duodenum. Heme iron, derived from animal blood and muscle, is absorbed more readily than the nonheme iron found in plants and iron salts. Most nonheme iron is in the ferric form, which is poorly soluble and needs to be reduced to the ferrous form before its absorption. This is accomplished with the help of a ferric reductase protein, controlled by the gene for DCYTB (a duodenal protein that bears homology to b-type cytochromes). DCYTB localizes to the intestinal brush border and its expression is amplified during iron deficiency, ineffective erythropoiesis, and hypoxia. (2) Gastric acid also facilitates the conversion of ferric iron to ferrous form. In addition, the acid lowers the pH of upper duodenal contents, which improves iron absorption.

If acidic environment in the stomach is important for iron absorption, will a hypochlorhydric or achlorhydric state alone lead to iron deficiency? There are no clear-cut data to support this contention. Iron deficiency has been described in patients with partial or total gastrectomy, vagotomy, and atrophic gastritis, but these conditions are more than a simple lack of gastric acid. Wintrobe (3) stated in 1956 that "alone achlorhydria does not lead to iron deficiency." Proton pump inhibitors (PPIs) are powerful inhibitors of gastric acid secretion, but have not been shown to cause iron deficiency.

In this issue of the Southern Medical Journal, Sharma et al describe two patients with iron deficiency anemia from gastrointestinal bleeding. (4) Both patients received omeprazole to control their gastritis and oral iron for the anemia for six months. Their symptoms and bleeding resolved, but their hemoglobin levels failed to rise. Discontinuation of omeprazole therapy, however, rectified the situation, and hemoglobin levels improved to near normal. In one patient, iron absorption studies demonstrated a blunted response to oral iron during omeprazole therapy. Iron absorption improved after withdrawl of this agent. The authors suggest that omeprazole therapy may render iron replacement therapy ineffective if the patient is already iron deficient.

How does one explain these observations? Additional information would have been of help. Did the patients' diet provide enough heme iron? Why was omeprazole continued for six months? Both patients were given ferrous sulfate, hence the need for acid-facilitated conversion to ferrous form was obviated (although acidic milieu is important to maintain the ferrous state). It is possible that the PPIs impede iron absorption, but the effect is minimal and will not become easily apparent in iron-replete subjects. In such a scenario, longer duration of achlorhydria, for example lasting six months but not two months, could prolong (or perhaps cause) iron deficiency. The PPIs may also have resulted in a higher pH in the duodenum affecting absorption of iron.

A definitive answer about the relationship between PPI therapy and iron absorption can be provided only through a large, controlled trial with simultaneous studies of iron absorption. If such an association is confirmed, the findings of Sharma et al may influence clinical practice, and patients with iron deficiency anemia requiring long-term acid-suppressive therapy may need parenteral iron supplementation.

Accepted December 8, 2003.

Please see "Effect of Omeprazole on Oral Iron Replacement in Patients with Iron Deficiency Anemia" on page 887 of this issue.

References

1. Beutler E, Fairbanks VF, Fahey JL. Clinical Disorders of Iron Metabolism. New York, Grune and Stratton, 1963, pp 1-18.

2. McKie AT, Barrow D, Latunde-Dada GO, et al. An iron regulated ferric reductase associated with the absorption of dietary iron. Science 2001; 291:1755-1759.

3. Wintrobe MM. Clinical Haematology, London, Kimpton, 1956, ed 4, p. 134.

4. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J 2004;97:887-889.

Sucha Nand, MD, and Tawee Tanvetyanon, MD

From the Loyola University Medical Center, Maywood, IL

Reprint requests to Sucha Nand, MD, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Division of Hematology/Oncology, 2160 South First Avenue, Maywood, IL 60153.