Almost everyday, I have a patient coming in with a main concern of Fatigue.

Fatigue is one of the top 10 presenting concerns in primary care. It can be the presenting symptom of almost any disease [1,2,3].

The cause could be functional (depression, anxiety, somatoform), or organic (involving organ or tissue dysfunction)[2]. Add that to the fact that often multiple causes of fatigue may be present, and we’ve got a case!

Hey doc, got a quick natural remedy for fatigue? No Big Deal.

Consider those statements a clause: when you read about a condition that lists  fatigue as a symptom, take into account that there are hundreds of other conditions out there that also list fatigue as a symptom.

Instead of bombarding you with how to diagnose your fatigue – Let your doctor piece the puzzle together –  I want to bring your attention to just one mineral: Iron.

Why did I funnel from Fatigue to Iron? Mostly because I’ve seen basic Iron Deficiency as the cause of fatigue in more patients than I would like to.  Where did all the iron go? Is Iron deficiency a epidemic? Or am I a magnet for it? (That’s some good punning, right?)

All of this background, because I want to give you the low down on Iron without suggesting that you too, have Iron Deficiency Fatigue.  All that to cover my ass, really. If you are feeling tired, don’t take iron – Instead, talk to your healthcare team, they might have a better idea.

IRON: It is the world’s most common, preventable, nutritional deficiency [4,5,6,7]. 

Iron is an essential micro-mineral, also called a trace mineral. Your body requires a small amount everyday.  Everyday, body iron content is being moved around, transformed and recycled, with a small amount being lost [6].

Iron is present in every cell in your body. It is stored in your liver, bone marrow, spleen and used in your blood and muscles [6].

The human body contains 2-4 g of iron (38 mg/kg in Females, 50 mg/kg in Males) 65% is found in hemoglobin, 10% in myoglobin, 1-5% as part of enzymes, remaining as blood or storage [6].

Iron is required for oxygenation of tissues, energy creation, immune response, cognitive performance, neurotransmitter synthesis and metabolism in the liver [6].

Too little dietary iron can cause a dangerous condition called Iron Deficiency Anemia. (Different than other types of anemia)[7].

Too much dietary iron causes a lethal condition called Hemochromatosis or Hemosiderosis [8].

There are TWO types of iron:

• HEME IRON – attached to a protein (globin) in blood cells, that delivers oxygen. It is found only in meat, fish and poultry (MFP) and is highly absorbable. In MFP, ~50-60% of the iron content is heme, the rest is non-heme.

• Must be hydrolyzed from globin, via proteases in the Stomach & Small Intestine.
• Is in a porphyrin ring, and remains soluble in the presence of the amino acids & peptides from the degraded globin.
• Is readily absorbed into the Small Intestine (mostly the duodenum) [6]

• NON-HEME IRON – attached to components in fruit, vegetables, nuts, grains, and MFP.

• Is released by Hydrochloric Acid and pepsin.

• Releases as Fe3+ (ferric iron), soluble in acidic environment.

• Is an insoluble complex if in the alkaline distal duodenum, with Pancreatic buffers – decreasing bioavailabilty.
• Non-heme absorption depends on body status. Chelators (small organic ligand compounds that complex w/ metal ions) help.
• Integrin is a small intestine membrane protein that helps absorption of Iron & Zinc across brush border of the small intestine. [6]

Normal Losses[6]:

Iron that is not transported across the mucosal cell for release in to the blood, may be incorporated into Apoferritin, (Ferritin) stored as ferric, and reduced back to ferrous if needed. If not needed, the iron remains as ferritin and is excreted by the mucosal cells (within 2-3 days), and sloughed off from the GI tract. [6]

• Accumulated losses from GI, Skin and Kidney: Males 0.9 – 1.0 mg/day, Non-Menstrual Females 0.7 – 0.9 mg/day

• Menstruating females – 0.5 – 1.3-1.4 mg/day during menses. Avg blood loss is 35 ml (with an normal upper  limit of 80 ml) [6]

Absorption[6]:

Iron absorption is anywhere between 2-35% of the consumed iron, depending on body stores, illness, life stage, type of iron and inhibitors/enhancers. On average 8-18% of dietary iron is absorbed. Dietary recommendations take this absorbability into account.

If we eat 12-15 mg/day, most of us absorb 0.6-1.5 mg, though absorption varies on many factors. When stores are high, absorption can be as little as 0.5 mg, and up to 3-6 mg when stores are low. Most prepared foods are fortified with iron, to combat this variability.  [6]

Enhancers of Iron Absorption [6]:

• Ascorbic Acid (forms chelate, acts as a reducing agent, at an acidic pH)
• Citric, Lactic, Tartaric Acid
• Sugars (fructose and sorbitol)
• MFP factor  – actin & myosin components of muscle tissue & peptides w/ cysteine.
• Mucin – endogenously made small protein made by gastric and intestinal cells. Gastric mucin, aka gastrogerrin binds and maintains solubility in both acid and alkaline conditions.
• Fermentation of grains helps to reduce phytates.

Inhibitors of Iron Absorption[6,10,11]:

• Excess alkalinization (antacids)
• Rapid intestinal transit
• Small intestine tissue damage (Celiac Disease)
• Achylia (Reduced Gastric Juices)
• Tannins (Tea) (reduces absorption by over 60%)
• Coffee consumption after a meal (reduces absorption by 40%)
• Oxalic acid (spinach, chard, berries, chocolate, tea)
• Phytates (whole grains, legumes)
• Phosvitin (Phosphorylated Serine in egg yolks)
• Co-consumption w/ Calcium, Calcium Phosphate, Zinc, Manganese, Nickel
• EDTA

Strong stomach acid, citrus fruit and certain animal proteins assist absorbability. By including small amounts (only 75mg ~ 1 medium size orange) of fruit sugar, Vitamin C, lemon/lime juice, or meat protein during meals, you can enhance non-heme absorption from 2% up to 8% (maybe even 20%, if you are deficient).

75 mg of MFP  or Acid maximizes iron absorption (more doesn’t do more).

Terms:

Ferritin is iron in a storage form – consists of Apoferritin protein & Ferric (Fe3+) Iron.  Iron molecules deposit in Apoferritin and are constantly being degraded and re-synthesized [6].

• Serum ferritin is an index of body stores; 1 ng/ml ferritin = 10 mg/ml of body stores [6].

• Normal adult serum ferritin is usually higher than 12ng/ml. Below 12 ng/ml indicates Iron Deficiency Anemia [4,6,7,9]
• Ferritin is also a positive acute phase protein (APP). Ferritin rises to inhibit the iron uptake of microbes [12,13].

Transferrin – A protein that  binds and transports iron that has been transported across mucosal membrane, but also transports iron that has been released from iron containing compounds in body.

• The oxidized ferric state (Fe3+) of iron is  the form that is transported attached to a protein.
• Transferrin’s 1/2 life is 7-10 days.
• Transferrin is a negative acute phase protein (Transferrin lowers in inflammation to conserve protein for production of other APPs ) [12,13].

Serum Iron – the amount of Iron circulating in the blood, that is attached to Transferrin.

• Normal Serum iron; Males: 55 – 165 ug/dl; Females: 40 – 155ug/dl

TIBC (Total Iron Binding Capacity) – reflection of Iron stores, via the saturation of Transferrin. TIBC increases when stores are low, and decreases when stores are high.

• Normal TIBC is 250-400 ug/dl; over 400 indicates deficiency.

Transferrin Iron Saturation Percentage – Can be calculated by: (Serum iron concentration x 100 ) / TIBC

• In Iron  Deficiency Anemia, Transferrin saturation decreases to <16%; normally 33% [6].

Hemoglobin – amount of iron in found hemoglobin, but last to change.

Why you might need extra Iron:

Iron Deficiency Anemia diagnosis, GI bleeding, Hypo/Achlorhydria, Vegetarian/Vegan diets, Heavy menstruation, Alcoholism, Elderly, Pregnancy, Antacid Use, Renal Failure, Diets with excessive: tea tannins, phytates in fibre, calcium in milk, phosphate carbonation.

A less unrecognized (& possibly more relevant) source of iron deficiency:

Menstruating females who choose not give birth/delay pregnancy into later years.

Extended years with monthly menstruation increases the likelihood of developing of an iron deficiency (18). Women lose anywhere from 30 – 180ml of fluid per menstrual shedding cycle (2-12 Tbsp). Typically ~35 ml of fluid is shed with 1.3 mg/day of iron loss. At ~45ml, iron losses are at 1.6mg/day while menstruating. If menstrual losses are between 60-80ml consistently, iron losses are upwards of 2mg/day and can cause significant depletion of iron stores(18). Ferritin stores begin dropping at 60ml, and clinical symptoms begin to appear at 80ml (19). Heavy menstruation (menorrhagia) is only diagnosed if losses are above 80ml (20).

Some online and academic resources claim that for every millilitre of menstrual loss, there is 0.5 mg of iron lost. This is inaccurate and can insinuate upwards of 20-40mg of iron lost every cycle. If these losses were accurate, a normal menstruating woman would be lying on the floor, barely breathing at the end of each period. These numbers are an uninformed extrapolation of venous blood iron concentrations and transposed into assumptions about menstrual fluid. Menstrual fluid is made of blood, water, mucus, endometrial fluid and glandular tissue.

Regular menstruation has about equal blood: fluid ratio, IUD users lose more blood:fluid & oral contraceptive users lose less blood:fluid (21). More accurate calculations within an average 4-5 day menstrual cycle are more likely 5-7mg of iron loss; at 90ml it would bring about 13-16mg of iron loss.

How I have interpreted & reverse engineered the calculations:

# of mls of menstrual fluid x 0.25 (half the fluid is blood, and 0.5mg of iron per ml of blood) = Average amount of iron lost over ~7 days (which is typically the medically assumed length of a period)

Amount of iron lost over 7 days/7 = usually stated amount lost per day of period x 4 or 5 (more realistic timeline for losses during periods).

How it looks in real life:

40ml x 0.25mg/ml = 10mg

10mg/7days= 1.4mg/day (which is the commonly claimed healthy amount to be lost per day of menstruation).

1.4mg/day x 4 or 5 days = 5 – 7mg iron lost in an average length, regular menstrual shedding.

or

90ml x 0.25mg/ml = 22.5 mg

22.5mg/7days = 3.21mg/day (heavy iron losses)

3.21mg/day x 4 or 5 days = 13-16mg iron lost in an average length heavy menstrual shedding.

I could be completely incorrect, but when I look at the research out there, they aren’t doing much better in estimations, so I thought I’d give it a good math club, solve for ‘x’ try.

Generally all humans lose ~1mg iron per day on any given day. When we begin lose ~2mg  or higher per day, iron stores will begin to deplete. Every 21 days, menstruation repeats and has the potential to drain just a little more each cycle, particularly if coupled with any of the above reasons that iron malabsorption is occurring.

In my clinical practice with the specific group of long term consistently menstruating women, I have found that the aside from using cessation-based oral contraceptives to halt monthly shedding, an established iron deficiency is intractable even with high dose elemental iron supplements. Heme iron supplements help but menstrual cessation is the most efficient therapy that shows significant objective results and clinical changes in symptoms. Through supplements these changes can take up to one year.

This light on iron deficiency in my research has shifted the way I approach iron deficiency in this subgroup. I promote and identify with women’s choices for choosing not to bear children and continue menstruation, but I now emphasize the impact of monthly bleeding and have become focused and streamlined in solutions for managing this form of iron deficiency.

Recommended Intake [6]

• Age 1-3 ::                                             3 – 7 mg/day
• Age 4-8 ::                                            4.1 – 10 mg/day
• Males Age 9 -13 & 19 + ::                     6 – 8 mg/day
• Males 14-18 ::                                       7.7 – 11 mg/day
• Non-menstruating females 9 +            5.7 – 8 mg/day
• Menstruating females 9 +                    7.9 – 18 mg/day
• Pregnancy                                           23 – 27 mg/day
• Lactation                                              7 – 10 mg/day

Below is a list of non-fortified, iron-rich foods, from highest to lowest [14,15]:

Amount of Iron

21 mg

11 mg

8.8 mg

7-8mg

6.6 mg

5.7 mg

5.2 mg

5.2 mg

5.0 mg

5.0 mg

3.8 mg

3.1 mg

12.8 mg

2.3 mg

2.0 mg

1.8 mg

1.7 mg

1.6 mg

1.5 mg

1.4 mg

1.3 mg

1.1 mg

Food

Clams 2.5 oz

Chicken Liver 3 oz

Soybeans 1 cup

Wild Duck 2.5 oz/75g

Lentils (cooked) 1 cup

Oysters (canned) 3 oz/85g

Beef liver  3 oz/85g

Kidney Beans 1 cup

Molasses (blackstrap) 1 tbsp

Baked Beans 1 cup

Venison 3 oz/85g

Braised Beef 3 oz/85g

Baked Potato with skin 

Prune Juice 6 oz cup

Turkey, dark meat 3 oz/85g

Ground Beef 3 oz/85g

Apricot (dried halves) 10

Oats (cooked) 1 cup

Spinach (raw) 1 cup

Cocoa powder 2 tbsp

Peas (frozen, cooked) 1/2 cup

Turkey, light meat 3 oz/85g

Breast milk has a special protein, Lactoferrin that allows for high levels of iron absorption from breast milk. All other dairy products are not iron-rich [6].

Medications [7,9, 16]:

Total Iron = amount in product

Elemental = amount available for absorption.

Total/Elemental Iron per dose in mg (Absorption)

150 Total/150 elemental (100%) – Though 1 study shows low absorption [17]

33 Total/33 elemental (100%) 

100 Total/ 100 elemental (100%)

100 Total/35 elemental (35%)

300 Total/100 elemental (33%)

300 Total /60 elemental (20%)

300 Total /36 elemental (12%)

Source of Supplementation

Polysaccharide iron complex 

Bovine Heme Iron Polypeptide

Carbonyl Iron

Ferrous Succinate

Ferrous Fumarate

Ferrous Sulfate

Ferrous Gluconate

Now: Questions I have about iron, because you can't be a scientist without questions.            

1. If Iron specifically enhances microbe growth, then why is Ferritin an APP? (Which included Inflammation & Illness). Shouldn’t it only rise in bacterial infection?

2. How is Hepcidin involved in Iron sequestration/ (a liver protein – released when Iron stores are high – that regulates transporter protein synthesis). Is Hepcidin a reliable surrogate marker for anything?

3. In Iron Deficiency Anemia, is it possible to increase iron stores with food only, within similar time frames as medication?

References:

1. Ponka, D., Kirlew, M. (2007) Top 10 differential diagnoses in family medicine. Can Fam Physician. May; 53(5): 892.

2. Allan, F. N. (1944). The differential diagnosis of weakness and fatigue. N Engl J Med. 231(12); 414-418.

3. Rosenthal, T.C., Majeroni, B.A., Pretorious, R., Malik, K. (2008). Fatigue: An Overview. Amer Fam Physician. 78(10); 1173-1179.

4. Goddard AF, McIntyre AS, Scott BB. (2000). Guidelines for the management of iron deficiency anaemia. Gut. 46(Suppl IV):iv1-iv5.

5. Mahan, K., Escott-Stump, S. (2004). Krause’s Food Nutrition and Diet Therapy 11th Ed. Philadelphia: Elsevier

6. Gropper, S.S., Smith, J.L., Groff, J.L. (2005). Advanced Nutrition and Human Metabolism 4th Ed. Toronto:Wadsworth

7. BC Ministry of Health (2010) – Iron Deficiency – Investigation and Management. Clinical Practice Guidelines

8. BC Ministry of Health (2006) – Iron Overload – Investigation and Management. Clinical Practice Guidelines

9. Stang J, Story M. eds. (2005) Guidelines for adolescent nutrition services. Minneapolis, MN: Center for Leadership, Education and Training in Maternal and Child Nutrition, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota. Chapter 9:101-108

10. Rockey, D.C, Cello, J.P. (1993).  Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med. 329:1691-1695.

11. Fasano, A., Catassi, C. (2012). Celiac Disease. N Engl J Med.  367; (25):2419-2426.

12. Jurado, R.L. (1997). Iron, Infections, and Anemia of Inflammation. Clinical Infectious Diseases. 25:888–95

13. Gruys, E, Toussaint M.J.M., Niewold T.A., Koopmans S.J. (2005). Acute phase reaction and acute phase proteins. J Zhejiang Univ SCI. 6B(11):1045-1056

14. Office of Dietary Supplements. (2007). Iron Fact Sheet. National Institutes of Health.http://ods.od.nih.gov/factsheets/Iron-HealthProfessional/

15. Linus Pauling Institute (2009). Iron. Oregon State University. http://lpi.oregonstate.edu/infocenter/minerals/iron/

16.  Comparison of oral iron supplements. (2008). Pharmacist’s Letter/Prescriber’s  Letter. 24(8):240811.

17. Glahn, R.P., Rassier, M., Goldman M.I., Lee, O, Cha, J. (2000).  A comparison of iron availability from commercial iron preparations using an in vitro digestion/ caco-2 cell culture model. J Nutr Bio. 11(2): 62-68.

18. Ofojekwo, M.J., Nnanna, O.U., Okelie, C.E., Odewumi, I.O.U., Lugos, M.D. (2013).Hemoglobin and serum iron concentrations in menstruating nulliparous women in Jos, Nigeria. Lab Medicine 44(2): 121-124.

19. Andrade, A.T., Souza, J.P., Shaw, S.T. Jr., Belsey, E.M., Rowe, P.J. (1991). Menstrual blood loss and body iron stores in Brazilian women. Contraception.Mar; 43 (3): 241-249.

20.  Napolitano, M., Dolce, A., Celenza, D. Grandone, E., Perilli, M.G., Siragusa, S., Carta, G., Orecchioni, A., Mariani, G. (2014). Iron-dependent erythropoiesis in women with excessive menstrual blood losses and women with normal menses. Ann. Hematol. Apr; 93(4): 557-563.

21. Fraser, I.S., McCarron, G., Markham, R., Resta, T. (1985). Blood and total fluid content of menstrual discharge. Obstet Gynecol. Feb; 65(2):194-198.

22. Fraser., I.S., Warner, P. Marantos, P.A., (2001). Estimating menstrual blood loss in women with normal and excessive mentrual fluid volume. Nov; 98(5) Part 1:806-814