Iron

James Meschino DC, MS, ROHP

General Features

In a healthy adult, there are 3-5 mg of Iron.  Of this, 60-70 percent is present in hemoglobin, 30 percent is stored, and the remainder functions as a component of various substances, in particular the cytochrome enzymes of the electron transport system and myoglobin which provides intracellular transfer and storage of oxygen within muscle cells.

As an essential component of hemoglobin, Iron binds oxygen when it passes through the blood vessels in the lungs, which it later releases to the tissue.  Thus, Iron plays a vital role in oxygen transport through the body.

In turn, oxygen’s delivery to the cells of the body enables them to continuously generate ATP energy through aerobic metabolism (electron transfer chain, also known as oxidative phosphorylation).  As well, DNA synthesis, thyroid hormone synthesis, synthesis of several neurotransmitters and healthy immune system function, all require adequate Iron nutritional status.  Iron deficiency is considered to be the most common nutritional deficiency in North American.  Even marginal deficiencies of Iron may result in fatigue, weakening of the immune system, impaired immune function and impaired neurotransmitter and thyroid hormone synthesis.

Absorption and Metabolism

There are two forms of dietary Iron, heme Iron in the form of hemoglobin and myoglobin, and non-heme Iron.  Heme Iron is absorbed into the mucosal cells as the intact porphyrin complex (as occurs in animal foods) and is little affected by the composition of the meal.  Hence, Iron absorption is generally about 25 percent, whereas non-heme Iron absorption (from plant foods) is often only 5 percent.  Non-heme Iron absorption is affected by meal composition.  Factors that increase non-heme Iron absorption include ascorbic acid, meat, fish and poultry, acid medium, calcium (binds to phosphates and oxalates, allowing more Iron to be absorbed instead of bound to these common plant-based components), intrinsic factor (enhances Iron absorption as well as being necessary for vitamin B₁₂ absorption), and increased Iron need (pregnancy, anemia, periods of growth, etc.).

Once absorbed from the intestinal tract into the mucosal cells of the gut, both heme and non-heme Iron form a common Iron pool.  Within the mucosal cell, Iron combines with apoferritin to form ferritin.  Iron is then released to the circulation in accordance with the body’s needs. In times of need, transferrin in the blood is less saturated with Iron and, as it passes through the gut blood vessels, Iron passes from the intestinal mucosal cells to transferrin.  Transferrin then transports it through the bloodstream to the target tissue.

If blood transferrin is already adequately saturated with Iron (one-third of its total Iron-binding capacity – TIBC), less Iron is absorbed from the mucosal cells to transferrin and the remaining mucosal Iron cannot be absorbed.  These mucosal cells are sloughed off every two to three days and the Iron within them is excreted via the feces.  This elaborate system is in place to guard against an Iron overload, which carries serious health implications.  It can, however, become overwhelmed by excessive Iron intake leading to hemochromatosis where excessive Iron is stored in the liver, heart, pancreas, skin and other organs.  This leads to increased free radical damage to this tissue and is linked to cancer, heart disease, arthritis, diabetes and possibly psychiatric illnesses.

Hereditary forms of hemochromatosis exist in which the body lacks the ability to limit Iron absorption from the gut and stores greater than normal amounts.  Chronic alcoholism can also lead to hemochromatosis.¹

The evidence from many scientific studies suggest that high Iron levels (above 200 mcg per litre blood), may lead to an increase in the risk of cardiovascular disease.  The increased risk is thought to be due to increased oxidative (free radical) damage to the heart, blood vessels and LDL-cholesterol.  Once oxidized LDL-cholesterol is more inclined to participate in the atherosclerotic process, narrowing arteries.^2,3

On the other hand, adequate Iron levels are necessary as every second 2.5 million erythrocytes (RBC), 20,000 white blood cells, and 5 million platelets are sent into the circulation.  Each red blood cell contains over 250 million hemoglobin molecules, which means that a single RBC can transport to the body more than a billion molecules of oxygen from their entry point in the lungs.

RBCs have an average life span of 120 days.  As they die, their Iron is recycled very efficiently by the body.  So efficient is the recycling system that very little Iron is excreted on a daily basis – less than 0.1 mg in the urine, 0.5 mg from the intestine and even less by perspiration and sloughed skin.  Most of the Iron present in feces represents unabsorbed dietary Iron and exfoliated mucosal cells, to a lesser degree.¹

Overall, men lose about 1 mg of Iron per day.  Women lose about 1.8 mg per day on average, during their childbearing years (blood loss during menstruation accounts for significantly more Iron loss than occurs in men).

Assuming Iron absorption is about 10 percent, men require 10 mg per day of Iron intake and women require 18 mg per day of Iron intake to replenish the daily Iron losses.

Most men can achieve this level of intake, but many women fail to consume 18 mg of Iron per day from food and consequently, Iron deficiency is more common in women.¹

Recommended Daily Allowance (Iron)

Iron Deficiency

Iron deficiency is the most common nutrient deficiency in the United States.  The groups at highest risk are infants under 2 years of age, teenage girls, pregnant women, and the lower-income elderly.  Studies have found evidence of Iron deficiency in 30-50 percent of people in these groups.  In fact, 35-58 percent of young, healthy women have Iron deficiency.  During pregnancy, the number is even higher.^1,4  In elderly persons, Iron absorption is reduced due to less gastric acidity.⁵

Iron deficiency can lead to anemia, excessive menstrual loss, learning disabilities, impaired immune function or decreased energy levels and physical performance.^1,4,6

Iron deficiency is the most common cause of anemia, however, anemia is the last stage of Iron deficiency (microcytic hypochromic).  A low level of serum ferritin is an early marker of sub-optimal Iron status.  A deficiency is indicated by a blood level of 12 mcg per litre or less.  Normal range is 40-160 mcg per litre.  A level of 30 mcg per litre or less should demand attention from a health practitioner.^4,8

Marginal Iron deficiency can occur without anemia, producing such symptoms as fatigue, behavioural problems (decreased alertness and attention span), muscle weakness and increased susceptibility to infections.⁷

Supplementation, Studies and Clinical Applications

1. Correction of Iron-Deficiency Anemia

The usual dose is 180 mg per day of Iron in adults and 2 mg per kg of body weight per day in children.

Usually ferrous sulfate, 325 mg, three times per day is given, which yields 180 mg of Iron (about 10-20 mg is absorbed).

Symptoms of Iron deficiency anemia include easy fatigability, tachycardia, palpitations and tachypnea on exertion.

Blood tests must be monitored during Iron supplementation at these high doses to ensure adequate replenishment and the prevention of Iron overload.  It may take one to two months to correct anemia with further supplementation to replenish Iron stores.⁸

2. Restless Leg Syndrome

Some evidence suggests that Iron supplementation (even in the absence of anemia) can effectively treat restless leg syndrome, at doses of 200 mg ferrous sulfate, three times daily.  Blood monitoring is vital at this level of supplementation.⁹

3. Cognitive Ability

An important study in the Lancet (1996) demonstrated that adolescent girls given low dose Iron supplementation improved their cognitive ability, memory and concentration after eight weeks relative to girls given the placebo.  Serum Iron levels rose in the supplemented group (within normal range) and there was no blood level change in Iron occurrence in the placebo group.  There was a direct relationship between how much the blood Iron levels rated and the ability to learn.¹⁰

Dosage Ranges

Iron-Deficiency Anemia:  325 mg ferrous sulfate, three times per day (requires appropriate monitoring).⁸

Side Effects and Toxicity

Large doses of Iron can cause damage to the intestinal tract lining, vomiting and diarrhea, liver damage, abdominal and joint pain, weight loss, fatigue, excess thirst and hunger.  In children a one time dose of Iron at 3000 mg can cause death (several deaths a year occur from accidental Iron overdose in children).

With Iron supplementation, constipation is the most common side effect.

Single Iron supplements should not be given in cases of peptic ulcers and inflammatory bowel disease as Iron can have a corrosive effect and exacerbate these conditions, if the dose is too high.  Patients with hereditary hemochromatosis, hepatitis and thalassemia should not take Iron supplements indiscriminately and require medical supervision of their Iron status.¹¹

Drug-Nutrient Interactions

Iron may also decrease the absorption of carbidopa, levodopa and it binds to warfarin, decreasing the absorption of this anti-coagulant drug – if present in the gut at the same time.

Iron-supplements should not be taken at the same time as chlorhexidine, used in the treatment of gingivitis as teeth staining may result.

Women using oral contraceptives may reduce their Iron loss and, therefore, their Iron blood levels should be monitored.

Desferoxamine is used to remove excess Iron from the body and, therefore, concurrent Iron supplementation will counter its effectiveness.^11,12

The following drugs have been shown to reduce Iron absorption or deplete Iron stores in various ways:

1. Bile Acid Sequestrants (colestipol, cholestyramine)^13,14
2. H-2 Receptor Antagonists (antacids)¹⁵
3. Penicillamine¹⁶
4. Tetracyclines – Iron binds to tetracyclines reducing absorption of the drug and the mineral^17,18
5. Quinolone Antibiotics – Iron binds to these drugs reducing the absorption of the drug and the mineral¹⁹
6. Salicylates – due to damage to the GI-tract²⁰
7. Indomethacin – due to damage to the GI-tract^21,22
8. Neomycin – due to damage to the GI-tract²³
9. Stanozolol²⁴

Nutrient-Nutrient Interactions

1. Calcium: high calcium intake may reduce Iron absorption.²⁵
2. Magnesium: high magnesium intake may reduce Iron absorption.²⁶
3. Manganese: high manganese intake may reduce Iron absorption.²⁷
4. Zinc: high zinc intake may reduce Iron absorption.²⁸
5. Ascorbic Acid (Vitamin C): high Vitamin C intake increases Iron absorption.^29,30
6. Phosphorous: Iron can bind to phosphorous in the intestinal tract, reducing the absorption of both nutrients.³¹

1. Standard Textbooks of Nutritional Science:

– Shils M, Shike M, Olson J, Ross C.  Modern Nutrition in Health and Disease. 9^th ed.  Baltimore, MD: Lippincott Williams & Wilkins; 1993.

– Escott-Stump S, Mahan LK, editors.  Food, Nutrition and Diet Therapy. 10^th ed.  Philadelphia, PA: W.B. Saunders Company; 2000.

– Bowman B, Russell RM, editors. Present Knowledge in Nutrition, 8^th ed.  Washington, DC:.ILSI Press; 2001.

– Kreutler PA, Czajka-Narins DM, editors. Nutrition in Perspective. 2^nd ed.  Upper Saddle River, NJ: Prentice Hall Inc.; 1987.

2. Tzonou A, Lagiou P, Trichopoulou A, Tsoutsos V, Trichopoulos D. Dietary iron and coronary heart disease risk: a study from Greece.  Am J Epidemial 1998;147(2):161-6.
3. Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F. Body Iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck Study.  Circulation 1997;96(10):3300-7.
4. Fairbanks VF, Beutler E.   In:  Shills ME, Young VR, editors.  Modern Nutrition in Health and Disease. 7^th ed.  Philadelphia, PA: Lea and Febiger; 1988.  p. 193-226.
5. Jacobs AM, Owen GM. The effect of age on Iron absorption.  J Gerontol 1969;24:95-6.
6. Cook JD, Lynch SR. The liabilities of Iron deficiency.  Blood 1986;68:802-9.
7. Hendler S. The Doctors’ Vitamin and Mineral Encyclopedia.  New York, NY: Simon and Schuster; 1990.  148-56.
8. Tierney LM Jr., McPhee SJ, Papadakis MA, Current medical diagnosis and treatment.  33^rd ed.  Stamford, Conn: Appleton and Lange; 1994.  p. 415-7.
9. O’Keeffe ST, Gaavin K, Lavan JN. Iron status and restless legs syndrome in the elderly.  Age Ageing 1994;23:200-3.
10. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomized study of cognitive effects of Iron supplementation in non-anemic Iron-deficient adolescent girls.  Lancet 1996;973(348):992-6.
11. Reavley N. The New Encyclopedia of Vitamins, Minerals, Supplements & Herbs.  New York, NY: M Evans and Company Inc.; 1998.  249-62.
12. Healthnotes 1998-2002. Available from: URL: http://www.healthnotes.com.
13. Leonard JP, Desager JP, Beckers C, Harvengt C. In vitro binding of various biological substances by two hypocholesterolaemic resins.  cholestyramine and colestipol.  Arzneimittelforschung 1979;29(7):979-81.
14. Thomas FB, et al. Inhibition of Iron absorption by cholestyramine. Demonstration of diminished Iron stores following prolonged administration.  Am J Dig Dis 1972;17(3):263-9.
15. Aymard JP, Aymard B, Netter P, Bannwarth B, Trechot P, Streiff F. Haematological adverse effects of histamine H2-receptor antagonists.  Med Toxicol Adverse Drug Exp 1988;3(6):430-48.
16. Harkness JA, Blake DR. Penicillamine nephropathy and Iron.  Lancet 1982;2(8312):1368-9.
17. Neuvonen PJ. Interactions with the absorption of tetracyclines.  Drugs 1976;11(1):45-54.
18. Heinrich HC, Oppitz KH, Gabbe EE. Inhibition of Iron absorption in man by tetracycline.  Klin Wochenschr 1974;52(10):493-8.
19. Lomaestro BM, et al. Absorption interactions with fluoroquinolones. 1995 Update.  Drug Saf 1995; 12(5):314-33.
20. Leonards JR, Levy G, Niemczura R. Gastrointestinal blood loss during prolonged aspirin administration.  N Engl J Med 1973;289(19):1020-2.
21. Gaginells TS. Drug-induced malabsorption.  Drug Therapy 1975:88.
22. Jallad NS, Cattan A, Weidler DJ. Efficacy of misoprostol in controlling indomethacin induced fecal blood loss in arthritic patients.  Int J Clin Parmacol Ther Toxicol 1993;31(8):376-81.
23. Jacobson ED, Faloon WW. Malabsorptive effects of neomycin in commonly used doses.  J Am Med Assoc 1961;175:187-90.
24. Taberner DA. Iron deficiency and stanozolol therapy.  Lancet 1983;1(8325):648.
25. Hallberg L, Brune M, Erlandsson M, et al. Calcium: effect of different amounts on nonheme- and heme-Iron absorption in humans.  Am J Clin Nutr 1991; 53(1):112-9.
26. Disch G, Classen HG, Haubold W, Spätling L. Interactions between Magnesium and Iron. In vitro studies.  Arzneimittelforschung 1994;44(5):647-50.
27. Rossander-Hulten, L, Sandstrom, BM, Hallberg, LB. Competitive inhibition of Iron absorption by Manganese and Zinc in humans.  Am J Clin Nutr 1991;54(1):152-6.
28. Crofton RW, Gvozdanovic D, Gvozdanovic S, Khin CC, Brunt PW, Mowat NA, et al. Inorganic Zinc and the intestinal absorption of ferrous Iron.  Am J Clin Nutr 1989;50(1):141-4.
29. Hallberg L, Brune M, Rossander-Hulten L. Is there a physiological role of Vitamin C in Iron absorption.  Ann N Y Acad Sci 1987;498:324-32.
30. Lynch SR, Cook JD. Interaction of Vitamin C and Iron.  Ann N Y Acad Sci 1980;355:32-44.
31. Hsu CH, Patel SR, Young EW. New phosphate binding agents: ferric compounds.  J Am Soc Nephrol. 1999;10(6):1274-80.