14th November 2020, Dr Chee L Khoo
We all know how difficult it is to treat iron deficiency anaemia (IDA) with oral iron supplements. Oral iron supplements not only cause constipation in many patients but they take forever to reverse the iron deficiency anaemia. Gastrointestinal absorption is a problem no matter how many iron tablets you take a day. Taking oral iron supplements every morning with lots of vitamin C is often suggested to maximise the absorption. Are these scientifically based recommendations? Or are they factoids – statements quoted often enough that it is accepted as facts?
Iron preparations available on the market vary widely in dosage, compound, cost and bioavailability. Ferrous iron is the preferred form because of its high Commonly-used ferrous iron compounds include the salts ferrous fumarate, ferrous sulfate, ferrous gluconate, and the amino acid chelate, ferrous bisglycinate. In general, the bioavailability of ferrous iron compounds is similar and their side effect profile and efficacy to regenerate haemoglobin (Hb) are also comparable, as long as sufficient iron is given. However, they vary in their elemental iron content. Iron bioavailability from ferric iron preparations is typically 3 to 4 times lower than that of ferrous sulfate.
Many multivitamin/mineral preparations usually contain low doses of iron that are insufficient to correct iron deficiency and may contain other minerals (such as zinc) that interfere with iron absorption. There is no good evidence that inclusion of other nutrients, such as the B-vitamins or vitamin A, improves iron bioavailability. Antacids and proton-pump inhibitors should not be taken with iron, because an increased gastric pH reduces iron dissolution and absorption. Controlled- or slow-release preparations of iron have no clear therapeutic advantage, are usually poorly absorbed and should not be used.
Iron released from supplements can form non-absorbable complexes with various food components in the gut lumen. For example, whole grains and pulses are rich in phytic acid, which is a strong inhibitor of iron absorption at even low levels. Coffee, black tea, herbal teas, red wine and hot chocolate contain polyphenols, which also impair iron absorption. Taking iron supplements in an empty stomach may improve absorption but may also upset the stomach.
Traditionally, the recommended daily dose is 100–200 mg iron per day given as three or four divided doses of ferrous salts: e.g., a 325 mg ferrous sulfate tablet contains 65 mg of elemental iron; three tablets per day will provide 195 mg of iron. However, lower doses may be just as efficacious but may have less side GI side effects.
Does Vitamin C help?
Iron occurs predominantly in the duodenum and upper jejunum, where ferrous iron can be transported into small intestine mucosal epithelial cells. When taken orally, iron is always oxidised to the Fe3+ state from its original form. It requires an acidic gastrointestinal environment to be dissolved adequately for absorption. Theoretically, vitamin C can create a more acidic environment in the stomach and prevent the oxidisation of ferrous iron to ferric iron (1). However, in a series of 12 individuals treated with iron during intake of a regular or vitamin C–supplemented diet (2) the effect of vitamin C on promoting iron absorption from a complete diet was far less pronounced than that from a single meal. The facilitating impact of vitamin C with food on iron status is minimal (2, 3).
In a 2-year, open-label, single-centre, RCT conducted at Huashan Hospital, Fudan University, Shanghai, China, 440 adults (96.8% women) with newly diagnosed IDA were randomised to receive either 300mg oral iron tablet (ferrous succinate) with 600mg vitamin C daily or 300mg oral iron supplement alone (5). Patients were treated for 3 months and assessed with a complete blood count every 2 weeks for 2 months; iron metabolism was measured at week 8. The primary outcome was the change in haemoglobin level from baseline to the 2-week follow-up.
Oral iron supplements alone were just as efficacious as oral iron supplemented with vitamin C in patients with IDA. These results challenge the recommendation to take vitamin C supplements with oral iron to improve the efficacy and speed up the recovery from anaemia.
Daily supplement vs alternate day supplement
In 1943, an absorption study in dogs showed a reduction in iron absorption when iron was given after a preceding iron dose (5). Subsequent investigations confirmed the blocking effect of high doses of iron on iron absorption from a subsequent dose.
The primary regulator of body iron homeostasis is hepcidin. During iron deficiency, hepcidin expression is switched off through multiple mechanisms (6). Circulating hepcidin levels fall, ferroportin and the divalent metal transporter (DMT)-1 are fully expressed on enterocytes, and intestinal iron absorption increases (6).
Plasma hepcidin also follow a circadian rhythm and typically increases over the day (7-9). Thus, oral iron doses should be given in the morning. Further, oral iron doses ≥60 mg in non-anaemic women with iron deficiency and ≥100 mg in women with IDA trigger an increase in circulating hepcidin that persists 24 h after the dose, but subsides by 48 h. In a series of small experiments, in iron-depleted women, providing iron supplements on alternate days and in single doses optimizes iron absorption and might be a preferable dosing.
In summary, oral iron supplements should be given in the morning on alternate days to maximise absorption. It really doesn’t matter whether vitamin C is given or not as it doesn’t help absorption. The supplements should be given in an empty stomach as there are too many things that can interfere and affect absorption.
- da Silva Rocha D, Capanema FD, Netto MP, Noguiera de Almeida CA, do Carmo Castro Franceschini S,
- Lamounier JA. Effectiveness of fortification of drinking water with iron and vitamin C in the reduction of anemia and improvement of nutritional status in children attending day-care centers in Belo Horizonte, Brazil. Food Nutr Bull. 2011;32(4):340-346. doi:10.1177/156482651103200405
- Cook JD, Reddy MB. Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet. Am J Clin Nutr. 2001;73(1):93-98. doi:10.1093/ajcn/73.1.93
- Hunt JR, Gallagher SK, Johnson LK. Effect of ascorbic acid on apparent iron absorption by women with low iron stores. Am J Clin Nutr. 1994;59(6):1381-1385. doi:10.1093/ajcn/59.6.1381
- Li N, Zhao G, Wu W, Zhang M, Liu W, Chen Q, Wang X. The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial. JAMA Netw Open. 2020 Nov 2;3(11):e2023644. doi: 10.1001/jamanetworkopen.2020.23644. PMID: 33136134; PMCID: PMC7607440.
- Hahn, P.F., et al., 1943. Radioactive iron absorption by gastro-intestinal tract. J. Exp. Med. 78 (3), 169–188.
- Sangkhae, V., Nemeth, E., 2017. Regulation of the iron homeostatic hormone hepcidin. Adv Nutr 8 (1), 126–136