Iron supplementation on paper, appears to be the easiest intervention for restoring low iron values. Simply observing the blood values of iron in the serum or ferritin values usually is enough to make up a doctors mind to dish out the old iron tablets or recommend iron infusions to remedy the situation. But what if a low iron value is simply not reflective of the true iron deficient anaemic state?

Iron is a necessary metal that participates in many aspects of function and anaemia is very possible from a number of sources like a bad cut and blood loss, menorrhagia, microscopic intestinal bleeds and a diet very low in Iron. However iron excess is also easily achieved. It’s ubiquity from food stuffs like meat, vegetables and the well-recognised “fortification” of iron in many flours and cereals can contribute to iron
overload. An excess of iron can lead to poor metabolism, constipation, accumulation of iron within the central nervous system and contributing to the ever increasing findings of dementia and cardiovascular disease. Iron participates in the Fenton reaction which produces hydroxyl radicals or reactive oxygen species which can damage the mitochondria and optimal energy production.

Iron is also a key component of the thyroid gland and production of TPO (thyroid peroxidase) which is instrumental in the process of thyroxine (T4) production. Hypothyroidism is also well positioned to mimic the states of anaemia which can include fatigue and therefore related blood tests can help to dial in on whether anaemia is really present.

To determine if iron is indeed either deficient or excessive, running the following tests would be useful.

Thyroid panel with temperature and pulse evaluation (already covered in other seminars)

Serum iron
TIBC, Ferritin, % Transferrin saturation RBC/blood chemistry,  Vitamin A, Copper

Serum Iron

The serum iron test is of little diagnostic value when tested in isolation, primarily because most of the body’s iron is carried on the protein haemoglobin, which is also responsible for carriage and supply of both oxygen and carbon dioxide.

Reference range Optimal
Alarm

30-170 ug/dl or 5.30 - 30.45 μmol/L 50-100 μg/dl or 8.96 - 17.91 μmol/L <4.5 or > 35.82

Ferritin

Ferritin is essentially the main storage form of iron found in the body. Ferritin is indeed a useful tool for detecting iron status but like many other compartmentalised markers can be influenced by many things which include thyroid function, vitamin A values, and the obvious intake of iron that is ubiquitous. Most flours and cereals are still fortified with iron, and iron cookware also has the capacity to increase both iron and ferritin values. High ferritin values can also be associated with hemochromatosis and iron overload, kidney and liver disease.

Ferritin may be below 33ng/ml in men and 10ng/ml in females

Males 33-236 ng/ml Alarm <8ng/DL >500ng/dL Females 10-122ng/ml
PM females 10-263 ng/ml

TIBC - Total Iron binding capacity

TIBC is an approximate value of of transferrin levels, the protein responsible for carrying iron within the blood and can help identify a a true iron deficiency anaemia. A high value above the reference range below with low iron, ferritin, percentage ferritin would implicate anaemia. Additional factors like MCV and MCH would also support this finding.

The TIBC tends to be the opposite of ferritin and iron and therefore if this test is low both hemochromatosis, nutritional deficiencies, inflammatory disease, liver dysfunction or gastrointestinal bleeds is suggested.

Optimal 250-350 ug/dL or 44.8-62.7 umol/L

% Transferrin saturation

The percentage of transferring saturation can be calculated by
% transferrin saturation =( Iron x 100)/ TIBC and can be a better index of iron saturation that purely transferrin.

Conventional - 16-60% Optimal - 20-35% Alarm - <5% >70%

Hematopoiesis is the production of red blood cells (RBC) and during hypothyroidism bone marrow repression can be responsible for decreased red blood cell production, and consequently changes to RBC markers is well known. The following tests are useful adjuncts to thyroid and iron evaluation;

RBC Red blood cell HGB -Hemoglobin HCT - Hematocrit

Females: 4.0 -4.5 Males 4.2-4.9 x 1012 /L Females: 135-145g/L Males 140-150 g/L

0.37-0.44 0.40-0.48

MCV - Mean Corpuscular volume 82-89.9 fL
MCHC Mean corpuscular haemoglobin concentration 28.0 -31.9 pg RDW Red blood cell distribution width 11-15%

A common theme of both anaemia and low thyroid function is a decreased HGB and HCT in addition to low serum, ferritin and increased TIBC and RDW.

Thyroid and iron status

I’ve written many times on the role of thyroid and systemic optimal function. Hypothyroidism tends to have a profile almost identical to anaemia. As you can see from the study table below. Those with a TSH of 5 miU/L had decreased serum iron, %transferrin saturation, HGB and an increased TIBC. Another key component of thyroid related blood chemistries is the increase of the RDW. Increased RDW has been associated with increased acute coronary syndrome, myocardial infarction, ischemic cerebrovascular disease, peripheral artery diseases, atrial fibrillation and hypertension (Danese et al 2015). In essence it sounds like the correlation of hypothyroidism and these aspects of cardiovascular and neurovascular disease are indeed strong, and are abundantly supported by a large body of literature. Some studies suggest that many parameters like Iron, HGB and others might not change substantially but an ever increasing RDW might be a useful marker to help differentiate hypothyroidism over anaemia.

A useful indicator for iron need might be, that upon starting thyroid hormone replacement therapy and a failure to change parameters like heat production and fatigue, or even TSH values which might not move as a true iron deficiency would not allow production of T4 within the thyroid gland.

Vitamin A and anaemia

I’ve written in another lesson about the benefits of eating liver for retinol compared to excess beta carotenoids. Vitamin A is of benefit for many reasons from skin health ( and melanoma protection) to hormone conversion.

The WHO classifies a vitamin A deficiency that warrants a public health problem at 0.7 umol/l or below and if occurs within 20% of the population , with severe implications to increased disease, decreasing immunity, infections and increased child mortality. In much the same vein as thyroid function, reductions in vitamin A, in addition to increased infections, also lend themselves to decreased hematopoiesis. Therefore vitamin A deficiency is also associated with decreased haemoglobin, and hematocrit that reverses with supplemental vitamin A (Semba and Bloom 2002).

Depletion of Vitamin A from an older study suggested 359-771 days (Hodges et al 1978) however in conditions where need is higher such as high UV areas, summer time and increased infections in winter Vitamin A need would certainly increase. During illness and again in tandem with thyroid values a depletion of vitamin A can occur, which also correlates with non-thyroidal illness where T3 is low. This low state of T3 is usually a combination of increased inflammation production of glucocorticoids like cortisol, suppression of oxidative glucose of metabolism and thyroid function at large. The anaemia of infection can be correlated with the decreasing availability of vitamin A which has a dual effect of decreasing available stored iron and is associated with the suggested process of the cell danger response, which allows partitioning of iron stores to prevent damage during illness. Optimal Vitamin A values would allow for the optimal transport of iron to occur.


Depending on how chronic the infection could lead to a concomitant hypothyroid/low vitamin A state that becomes harder to diagnose. It’s quite likely that both serum iron, ferritin, T3, TSH and haemoglobin would appear low and may respond favourably to liver consumption, beta carotenoids in moderation and or supplementation.

Vitamin A - Retinol reference range

0.29 mg/L or 2.56 umol - 1.05 mg/L or 9.2 umol

Copper and Anemia

Copper is an essential component of iron absorption and much like all the other factors mentioned above is also implicated in optimal metabolism through cytochrome C/C oxidase in the aerobic or electron transport chain. Copper deficiency will cause an anaemic like state impacting key proteins like haemoglobin and hematocrit that should improve with supplemental copper use

Malabsorption of copper
Gastric surgery, including gastric bypass or gastrectomy
Enteropathies such as inflammatory bowel disease, cystic fibrosis, and celiac disease Excessive use of copper chelators
Zinc supplement overuse, parenteral overdosing, denture cream ingestion.
Wazir and Ghobrial 2017

Copper optimal lab value 70-125 ug/dL Ceruloplasmin is a copper transport protein and ideal ranges are 25-30mg/dl

As we know with many other metals there exists a fine line between necessary, inadequate and excessive. Iron has several interactions with both endogenous and exogenous influences and the ageing spots called lipofuscin is a product of such relationships which involve many factors.

“ In a vitamin E deficiency , unsaturated oils are oxidised in a way that produces “age pigment,” also called ceroid pigment or lipofuscin. This pigment consumes both oxygen and fuel, bit produces no useable energy. Estrogen excess synergies with a deficiency of vitamin E to intensify the formation of this pigment. Partly this might be because estrogen is a powerful stimulant of iron absorption, and iron is involved in the peroxidation that produces the pigment.”

Ray Peat’s input

Interestingly, in Ray Peat’s latest newsletter from July 2021 he mentions the effects of estrogen’s capacity to increase iron by inhibiting the formation of hepcidin ( Peat citing Balbouj et al 2018). Hepcidin controls the absorption of iron from the gastrointestinal tract and in studies using IVF treatment (exogenous estrogens), showed increased C reactive protein (CRP), decreased ferritin, and hepcidin but this did not affect the iron value per se (Lehtihet et al 2016). If Hepcidin suppression is chronic the increasing likelihood of iron absorption, mediated both by circulating estrogen’s and external environmental xenoestrogens that can act as both receptor agonists, and influence cellular swelling and alter mitochondrial function. The double whammy of excess estrogen and iron overload could be a substantial pathway in diseases like diabetes, cancer their progression.

The erroneous suggestion that estrogen is always low due to gradual loss of ovarian steroidal hormones, still leads many to think that there’s a need to supplement estrogen. Yet estrogen is often increased in post-menopausal women and some studies suggest that any BMI > 25 is associated with increased aromatase production and ultimately higher local levels of estrogen that have been implicated in breast cancer (Brown et al 2015). This could be induced by a convergence of factors which include poor dietary/lifestyle habits and environmental pollutants that could also lead to reduced hepcidin and iron accumulation.

Of course, still, an emphasis by many is that failure of estrogen production, can decrease hepcidin and can lend itself to iron accumulation but many often fail to entertain the idea that a lack of progesterone, allows increases to estrogen via aromatase (in post-menopausal women mainly or with those with increased fat mass) and facilitates iron absorption. Studies do show that hepcidin does increase marginally in post-menopausal subjects but that increase could also occur from steadily increasing oestrogen levels and decreased progesterone values. Low Hepcidin has been associated with higher iron values and increased incidence of osteoporosis and high hepcidin is associated with hypothyroidism that lowers with treatment.

In females, the idea that vast amounts of blood are lost with each cycle is erroneous and many old studies detailed that often only a few milligrams might even be lost. Heavy cycles or menorrhagia, often induced by estrogen excess could lead to an increased iron need but assessing serum iron with ferritin % transferrin, TINC and a red blood cell count would give a great overview of real need.

Lowering Iron values and accumulation

Hemochromatosis can of cause be a problem and if chronic can lead to a toxic overload of iron accumulation in both organs and disrupt cellular metabolism. In this state blood donations are often well recommended. The obvious avoidance of iron rich foods, especially with combinations of vitamin C rich foods is useful. Regular coffee, tea and calcium rich food consumption especially with iron rich foods like red meat, vegetables and fortified products can help to minimise absorption of iron. Keeping an adequate intake of both calcium and zinc can also play their part in keeping iron levels at an optimal value. It becomes prudent to recommend increased vitamin E need with excess iron and I think an additional 100IUs per day is always helpful. In his book Health Preserver by Wilfred E. Shute, he documented doses of vitamin E of up to 1600 IUs per day to ameliorate the symptoms of both diabetes and heart disease. As Hemochromatosis is well documented to progress to diabetes and states of cardiovascular disease, experimenting with dosage may be the most prudent course of action.

Increasing Iron Values

I think as a general rule of thumb, eating iron rich foods with foods that are high in vitamin C should improve anaemia if it does exist, as opposed to taking specific iron supplements. Often I’ve found clients who got constipated when previously prescribed iron supplementation, and I think this is usually a good symptom of unnecessary or excessive iron supplementation.

To recap: An iron and ferritin result that is low does not equate to a true iron deficiency. Assessing other blood values like TIBC, haemoglobin, RDW and others and with a good evaluation of vitamin A, copper and thyroid status can give you a better idea of what you truly need, without increasing unnecessary doses of iron. Steak anyone?

This blog is taken from an old coaching lesson in the members area and is expanded in an hours video in the functional hormones and nutrition seminars.

References:

Brown KA, Iyengar NM, Zhou XK, et al. Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab. 2017;102(5):1692-1701. doi:10.1210/jc.2016-3606

Demirtas S, Karahan O, Yazici S, Guclu O, Caliskan A, Yavuz C, Kucuker A, Mavitas B. The relationship between complete blood count parameters and Fontaine's Stages in patients with peripheral arterial disease. Vascular. 2014 Dec;22(6):427-31. doi: 10.1177/1708538114522227. Epub 2014 Feb 12. PMID: 24522438.

Danese E, Lippi G, Montagnana M. Red blood cell distribution width and cardiovascular diseases. J Thorac Dis. 2015;7(10):E402-E411. doi:10.3978/j.issn.2072-1439.2015.10.04

Hernik, A., Szczepanek-Parulska, E., Filipowicz, D. et al. The hepcidin concentration decreases in hypothyroid patients with Hashimoto’s thyroiditis following restoration of euthyroidism. Sci
Rep 9, 16222 (2019). https://doi.org/10.1038/s41598-019-52715-3

Khatiwada, S., Gelal, B., Baral, N. et al. Association between iron status and thyroid function in Nepalese children. Thyroid Res 9, 2 (2016). https://doi.org/10.1186/s13044-016-0031-0

Lehtihet M, Bonde Y, Beckman L, et al. Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans. PLoS One. 2016;11(2):e0148802. Published 2016 Feb 11. doi:10.1371/ journal.pone.0148802

Ray Peat’s 2021 Newsletter Estrogen, Iron, degenerative ageing, and progesterone.

Semba, R., Bloem, M. The anemia of vitamin A deficiency: epidemiology and pathogenesis. Eur J Clin Nutr 56, 271–281 (2002). https://doi.org/10.1038/sj.ejcn.1601320

Wazir SM, Ghobrial I. Copper deficiency, a new triad: anemia, leucopenia, and myeloneuropathy. J Community Hosp Intern Med Perspect. 2017;7(4):265-268. Published 2017 Sep 19. doi: 10.1080/20009666.2017.1351289

Wunderer F, Traeger L, Sigurslid HH, Meybohm P, Bloch DB, Malhotra R. The role of hepcidin and iron homeostasis in atherosclerosis. Pharmacol Res. 2020;153:104664. doi:10.1016/j.phrs.2020.104664

https://www.who.int/vmnis/indicators/retinol.pdf