A 69-year-old man is evaluated for fatigue. He undergoes a colonoscopy and is found to have a right-sided colon cancer. His hematocrit is 33 with an MCV of 72. His ferritin level is 3. What do you recommend to help with his iron deficiency?

A. Ferrous sulfate 325 mg daily.

B. Ferrous sulfate 325 mg b.i.d.

C. Ferrous sulfate 325 mg t.i.d.

Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).1 This dosing regimen has considerable gastrointestinal side effects. Recent research into iron absorption suggests that the higher the dose of iron given, the more absorption may be hindered. In a study of 54 women who had low ferritin levels, lower daily doses of iron – and not giving it multiple times a day – led to better iron absorption.2

In a study of elderly patients with iron deficiency, 90 hospitalized elderly patients older than 80 years with iron deficiency anemia were randomized to receive elemental iron as 15 mg or 50 mg of liquid ferrous gluconate, or 150 mg of ferrous calcium citrate for 60 days.3 Two months of iron treatment raised hemoglobin and ferritin levels to a similar degree in all groups, with no significant differences between the 15-mg, 50-mg, and 150-mg groups.

There was a significant difference in abdominal discomfort, with much less (20%) in the patients who received 15 mg of ferrous gluconate, compared with 60% in those who received 50 mg and 70% in those receiving 150 mg (P less than .05 comparing 15 mg with 50 mg and 150 mg). Statistically significant differences were also seen for nausea/vomiting, constipation, and dropout, with much lower rates seen in the low-dose (15-mg) group.

In a study of iron supplementation in individuals undergoing blood donation, a single daily dose of iron was used (37.5 mg of elemental iron) in half of the subjects, with the rest of the subjects receiving no iron.4 The mean age of the participants was 48 years.

Subjects who received the once-daily low-dose iron recovered much more quickly toward predonation hematocrit than did those who did not receive the low-dose iron (time to 80% hemoglobin recovery, 32 days vs. 92 days in the non–iron treated patients, P = .02). The effect was more dramatic in subjects who started with a low ferritin level (defined as less than 26), where time to 80% hemoglobin recovery was 36 days in the iron-treated patients vs. 153 days for the no-iron group.

The results of this study are in line with what we know about avid iron absorption in iron deficient patients, and the success of low doses in a younger patient population is encouraging.

In a small study looking at two different doses of elemental iron for the treatment of iron deficiency, 24 women (ages 18-35 years) with iron deficiency were randomized to 60 mg or 80 mg of elemental iron or placebo for 16 weeks.5 There was no difference in normalization of ferritin levels in the women who received either dose of iron. There was also no difference in side effects between the groups.

This study is small and had minimal difference in iron dose. In addition, the dosing was given once a day for both groups. I suspect that the lack of difference in side effects was due to both the small size of the study and the minimal difference in iron dose.

What does this all mean? I think that the most appropriate dosing for oral iron replacement is a single daily low-dose iron preparation. Whether that dose is 15 mg of elemental iron to 68 mg of elemental iron (the amount in a 325-mg ferrous sulfate tablet) isn’t clear. Low doses appear to be effective, and avoiding high doses likely decreases side effects without sacrificing efficacy.


1. Fairbanks V.F., Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed. Beutler E., Coller B.S., Lichtman M.A., Kipps T.J., eds. (New York: McGraw-Hill; 2001, pp. 460-2).

2. Blood. 2015 Oct 22;126(17):1981-9 .

3. Am J Med. 2005 Oct;118(10):1142-7.

4. JAMA. 2015 Feb 10;313(6):575-83 .

5. Nutrients. 2014 Apr 4;6(4):1394-405 .

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at dpaauw@uw.edu.