Iron

Synonym(s): Aspergillus oryzea gluconat, curry leaf, iron gluconat, ferric oxide, ferric gluconate, iron bisglycinate, iron gluconate, ferrous sulphate, Murraya koenigii, Colostrum, VegyFerrin

Nutrient group: Minerals & trace elements

Sources and physiological effects

Dietary sources
Iron is widely found in vegetable and animal foods. While animal foods mainly provide hemoglobin- or myoglobin-bound iron and to a lesser extent hemic enzymes, vegetable foods contain inorganic iron compounds. For example, veal, pork liver, legumes and oat flakes are considered rich in iron. However, how well a food is able to provide iron does not depend on its absolute iron content, but on the binding form of the iron and on the presence of absorption and promoting substances.
Physiological effects
Blood	Component of hemoglobin and myoglobin Central role in oxygen transport
Acid-base balance	Hemoglobin is involved in the removal of CO₂ and thus also plays an important role in acid-base metabolism.
Energy metabolism	Component of the enzyme cytochrome oxidase, which is involved in the electron transfer of the respiratory chain.
Hormone production	Synthesis of the thyroid hormone L-thyroxine Involvement in the formation of L-dopa

EFSA Health Claims

Health Claims		EFSA Opinion
Iron	Contributes to reducing fatigue and fatigue
Iron	Contributes to normal cognitive function Contributes to a normal metabolism Contributes to normal formation of red blood cells and haemoglobin Contributes to normal oxygen transport in the body Contributes to a normal function of the immune system Has a function in cell division

Recommended intake

D-A-CH reference values for the intake of iron (Reference values EFSA and NHI )
	Alter	Iron (mg/d)
Infants (months)
	0-4	0,5
	4-12	8
Children (years)
	1-4	8
	4-7	8
	7-10	10
	10-13	13,5
	13-15	13,5
Teenagers/adults (years)		Women/td>	Men
	15-19	15	12
	19-25	15	10
	25-51	15	10
	51-65	10	10
	> 65	10	10
Pregnant woman	30
Breast-feeding woman	20
Group with increased needs	Childhood, growth, pregnancy, lactation, endurance sports, vegan diet, frequent blood donation, blood loss (occult gastrointestinal bleeding, hemorrhoids, esophageal varices, endoparasites), malabsorption through high coffee/tea consumption, chronic intestinal inflammation, short bowel syndrome, phenylketonuria
Special group at risk of deficiency	Children, pregnant women, nursing mothers, vegans, recurrent gastroenteritis, short bowel syndrome, etc.
Advice	EFSA recommends 15-20 iron mg/d for women of childbearing age.

Recommended intakes according to food labelling regulations		Iron
(=100 % TB marking on label)		14 mg
Nutrient safety
UL	Long-term daily intake, at which no negative health effect are to be expected	45 mg/d (according to NIH)
NOAEL	Maximum intake, with no observed adverse effect	65 mg/d
Advice	It is often heard that high ferritin levels increase the risk of cardiovascular disease. There is a group of people who have genetically higher ferritin levels than the average (heterozygous hemochromatosis). The data are inconsistent: however, the majority of studies show no connection with an increased risk of CHD. Persons with homozygous hemochromatosis, i.e. those suffering from iron storage disease, must not take extra iron (rarely occurs).

Detailed information

Physiological function

As a central component of hemoglobin, iron is responsible for the transport of oxygen in the blood and thus for the cellular energy supply. Part of it is present as myoglobin and serves as an oxygen reservoir for the muscle. Iron-containing enzymes have many functions, for example in the electron transfer in the respiratory chain, in neurotransmitter synthesis, collagen formation and carnitine production. Other iron-dependent functions include immune defense, DNA synthesis and the breakdown of fatty acids. With the help of the transport protein transferrin, iron reaches the target cells. Transferrin also prevents free iron ions from having an oxidative effect and thus having a toxic effect (1). Iron is stored after binding to the proteins ferritin and hemosiderin in the liver, spleen and bone marrow. If there is an increased demand for iron, the deposits are mobilised.

Iron deficiency and its symptoms

Although iron deficiency is the most common nutrient deficiency in the world, this situation is rarely encountered in industrialized nations. Nevertheless, undersupply can occur at any time in various phases of life or in connection with illness. A subclinical or clinical deficiency often occurs in pregnancy (2), athletes (3), heavy menstruation, gastrointestinal bleeding or digestion and absorption disorders (4) . The symptoms are unspecific. The reduced oxygen transport in the blood leads to an impaired supply of organs and tissues. This causes general complaints such as fatigue, exhaustion and fatigue. Early symptoms of iron deficiency include cracks in the corners of the mouth, chapped, brittle and dry skin, disorders in hair and nail growth and an increased susceptibility to infection caused by an impaired immune response (4). Latent iron deficiency symptoms are characterized in that the iron reservoirs are largely emptied. This does not yet lead to a failure of iron-dependent functions, but there are also no reserves for times of increased demand. . Iron deficiency ultimately leads to hypochromic microcytic anaemia, which manifests itself in the formation of hemoglobin-poor, small erythrocytes (1). A distinction must be made between megaloblastic anemia caused by vitamin B₁₂- and/or folic acid deficiency. About 17% of women and about 32% of men are affected (5). Excessive levels of iron in the body can also be detrimental to health. An increased ferritin level seems to increase the formation of free radicals. In healthy persons, an intake of up to 65 mg/day is not associated with undesirable side effects (1).

Women of childbearing age: risk groups for iron deficiency

Women of childbearing age are considered a particular risk group for iron deficiency (6). With the onset of puberty and up to menopause, women lose iron monthly due to menstruation. Blood loss is about 30 ml per month, resulting in a loss of about 15 mg iron. In women with heavy periods, the iron losses go beyond this. The risk of female iron deficiency is also increased by pregnancy and breastfeeding (3), teenage growth spurts, exercise (7), certain medications or digestion and absorption disorders (8). An internal screening conducted by found serum ferritin levels of maximum 30 ng/ml in 50% of women between 16 and 44 years of age. These values correspond to empty or scarce iron stores and are regarded as an indicator of a prelatent deficiency. The results confirmed women of childbearing age as a particular risk group for iron deficiency (9). Women of childbearing age often show subclinical signs of deficiency such as skin disorders, exhaustion, fatigue or lassitude. A manifest iron deficiency is clinically characterized by increased transferrin concentrations and lowered ferritin levels (hypochromic microcytic anemia) (10).

Different absorption of iron salts and plant iron

Iron supplementation is possible in the form of iron salts and vegetable iron. Previously available animal sourced hematopoietic preparations are currently not on the market. Iron salts contain the trace element iron in a divalent and trivalent form. The biological properties of iron salts are based on their ability to change valence and their ability to form compounds with both anionic and neutral molecules. Although iron is widespread in food, its absorption rates into the body are strongly influenced by various factors. Inorganic iron compounds in divalent and trivalent form are only absorbed very poorly, as they tend to form complexes that are difficult to dissolve, especially in the weakly alkaline environment of the upper small intestine. Iron compounds from plant sources also show a deteriorated bioavailability in the presence of plant-typical complexing agents such as phytic acids, oxalic acid or tannins (11). Other plant components such as vitamin C and possibly the carotenoids, on the other hand, improve absorption. Iron salts should therefore be taken fasting and in combination with vitamin C to improve absorption.
Iron compounds from plant sources are in principle absorbed just as well as iron salts. In plants iron is partly present in the cytochrome B structure, which contains iron protoporphyrin (12), and in the storage form ferritin (13). The clever selection of plant iron sources can therefore achieve the same high bioavailability as animal heme iron (14). Initial observational studies have shown a 20 % higher bioavailability of plant curry leaf iron (MoFerrin®21) compared to iron gluconate (15). It has also been proven that iron from plant sources remains intact in its protein structure (nanocage) when it is absorbed into the intestinal cell and is first – broken down in the enterocytes, similar to the heme protein –. Absorption as a complete ferritin molecule prevents oxidative damage to the intestinal cell caused by iron ions. The absorption is slower than via the known mechanisms, which means that the downstream control mechanisms for iron absorption are more effective. Through the separate absorption pathway, plant iron could also be a way of treating “non-responders“ where conventional oral iron preparations do not improve iron status (13) (14).

Better tolerance of plant iron

Oral supplements with iron salts show poor gastrointestinal tolerance. Side effects are expected in about 20% of users (flatulence, pain, constipation and nausea) and lead to an abortion rate of 5% for study participants. Supplementation with porphyrin-bound iron from plants, on the other hand, shows a higher tolerance rate. Vegetable iron from curry leaves also has a significantly reduced tendency to form radicals compared to iron gluconate and ferric sulphate. On the one hand, this could be due to a special iron complex typical of curry leaf and/or to the increased concentration of accompanying plant antioxidants. These lower prooxidative effects ensure good tolerability and make Moferrin® a gentle and long-term safe iron therapy without oxidative stress. (15)

Iron from curry leaf extract (Murraya koenigii)

Natural plant iron from the curry leaf extract (Murraya koenigii) is now available for the first time in Europe as a plant iron preparation with a high active ingredient content and high bioavailability. The curry leaf tree grows all over the Indian subcontinent. Unlike most people think, the curry leaf is not identical to the “curry“ spice. The leaves of Murraya koenigii are used in Indian cuisine as fresh herbs and are used to enhance the flavor of many traditional dishes. By chance, the curry leaf was discovered as an excellent source of vegetable iron. However, only the gradual development of a special extraction and standardization process enables the use of curry leaf extract as a natural iron supplement in the prevention and therapy of iron deficiency diseases. An intervention study has shown that the herbal iron supplement Moferrin® can significantly increase serum ferritin levels in women with empty or scarce iron stores (< 30 ng/ml). After a 3-week supplementation with 105 mg iron from the curry leaf extract, the participants almost doubled their serum ferritin levels (7). In a comparative iron absorption test MoFerrin® showed a better bioavailability than synthetic iron gluconate. The single application of 90 mg iron shows a 20 % higher increase after 4 hours in Moferrin® compared to iron gluconate (16).

Reference values

Parameter	Substrate	Description
Iron	Serum (µg Iron/dl)	The sole determination of iron in blood serum is not sufficient for the diagnosis of iron deficiency.
	Whole Blood (mg Iron/l)	Iron is predominantly (99 %) erythrocytically bound. Hematocrit-correlated whole blood analysis enables the correct interpretation of the supply status.
Transferrin	Serum (mg/dl)	Iron is absorbed by the intestine and bound in the blood to the transport protein transferrin.
Ferritin	Serum (µg/l)	Iron is present in the organs in the form of ferritin.
Transferrin saturation	%	=Iron (serum)/transferrin

Reference values	Women	Men	Interpretation
Iron (Serum)	40 - 150 µg/dl	40 - 160 µg/dl	Decreased values: For iron deficiency (with simultaneously reduced ferritin) and chronic inflammations, infections or tumors, Hemolytic serum samples Increased values: Hereditary or secondary hemochromatosis
Iron (whole blood)	420 - 460 mg/l	440 - 500 mg/l
Transferrin	200 - 310 mg/dl	210 - 340 mg/dl	Decreased values: In hemochromatosis, infections, chronic inflammation, renal and enteral protein loss, reduced protein synthesis Increased values: With manifest iron deficiency, partly also with latent iron deficiency
Ferritin	10 - 140 µg/l	20 - 360 µg/l	Decreased values: In case of latent and manifest iron deficiency Increased values: For iron overload disorders, chronic or malignant diseases, liver parenchyma damage, erythropoietin therapy
Transferrin saturation	16 - 45 %		Helps in combination with altered ferritin and iron values to distinguish an iron surplus from iron distribution disorders

Change in iron status
Iron deficiency	Iron levels low Transferrin increased (reactive additional production by the liver in iron deficiency) Ferritin reduced (emptying of the storage iron) Transfer saturation low
Iron surplus	Iron levels increased Transferrin decreased Ferritin increased Transferrin saturation increased
Inflammations, tumors	Iron levels reduced Transferrin decreased Ferritin normal or increased Transfer saturation normal

Deficiency symptoms

Impact on	Symptoms
General health	Fatigue, reduced performance, sensitivity to cold
Blood	Iron deficiency anemia (hypochromic microcytic anemia) Increased lactate levels
Skin and mucous membranes	Paleness Corner of the mouth rhagades Glossitis, dysphagia (swallowing disorders)
Hair and nails	Brittle nails, diffuse hair loss
Children	Growth disturbances
Cardiovascular system	Stress dyspnea, dizziness

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	Prevention of iron deficiency in women of childbearing age	14 - 30 mg/d
	With increased iron demand in pregnancy & lactation, in growth and in performance sports	50 - 200 mg/d
	Complementary therapy for digestion and absorption disorders such as diarrhea, stomach or intestinal diseases to ensure sufficient supply	100 - 200 mg/d




Pharmacological effects at a high intake	Therapeutic for high blood loss after surgery, gastrointestinal bleeding or heavy menstrual bleeding	100 - 300 mg/d
	Therapeutic for iron deficiency anemia	100 - 300 mg/d

Administration

General mode of administration
When	Iron salts: For optimal absorption iron salts should be taken fasting or 1 hour after meals. Absorption can be improved by combining with vitamin C. Vegetable iron: Alternative ways of absorption are assumed for plant iron and strict, fasten intake does not therefore seem to be necessary. However, due to the lack of knowledge of absorption disorders caused by other micro and macro nutrients, fasting is also recommended for plant iron.
Side effects
Iron salts: Nausea, vomiting, diarrhea, constipation, dark stool. Iron should be taken in low doses to improve gastrointestinal tolerance. Free iron ions can contribute to the release of free oxygen radicals, therefore the combination with antioxidants is recommended. Plant iron: No side effects have been described so far.
Contraindications
Haemochromatosis (iron storage disease), severe liver and kidney diseases, hemolytic anemia, lead anemia

Interactions

Drug interactions
Antacids (PPI, H₂-blockers, Al/Mg containing)	Impair the absorption of non-hemic iron.
Bisphosphonates (e.g. alendronate, ibandronate)	Impair absorption through complex formation.
NSAID's (v.a. ASS, Diclofenac)	Long-term NSAID intake can lead to iron loss due to GI bleeding.
Antibiotics (gyrase inhibitors, tetracyclines, cephalosporins)	Impair absorption through complex formation.
Estrogens	Oral contraceptives increase iron serum levels.
Antiparkinson drugs (L-dopa, carbidopa)	May lead to complex formation (important to leave time between ingestions).
Thyroid hormones (L-thyroxine)	Reduced iron absorption due to complex formation (important to leave time between ingestions).
Immune stimulants (e.g. interferon alpha)	Iron impairs the effectiveness of immune stimulants Contraindicated during hepatitis therapy.
Sulphusalazines (e.g. mesazalin)	May lead to complex formation (important to leave time between ingestions).
Nutrient interactions
Trace elements	Calcium, magnesium, manganese, zinc, phosphorus and copper impair iron absorption.
Vitamins	Vitamin C converts trivalent iron into more absorbable bivalent iron. Folic acid, vitamin A, B₂ and B₆ improve the absorption and mobilization of iron.
Amino acids	Lysine, methionine and cysteine improve iron absorption.
Taurine	Iron improves the taurine plasma level.

Description and related substances

Description

Trace elements

Related substances

Various iron compounds are approved in NEM:

Iron carbonate, iron citrate, iron ammonium citrate, iron gluconate, iron fumarate, iron sodium diphosphate, iron lactate, iron sulphate, iron diphosphate (iron pyrophosphate), iron saccharate, elemental iron, iron bisglycinate, iron L-pidolate, iron phosphate, iron (II) -taurate.

The solubility of divalent iron (Fe²⁺) is better than that of trivalent iron (Fe³⁺), therefore the bioavailability of compounds with Fe²⁺ is usually better.

References

1) Hahn, A. et al. 2005. Ernährung. Physiologische Grundlagen, Prävention und Therapie.

2) Hara, K. et al. 2001. Iron supplementation in pregnancy – evidence and controversies. Acta Obstet Gynecol Scand. 80(8):683-8

3) Beard, J., Tobin, B. 2000. Iron status and exercise. AmJ Clin Nutr. 72(2Suppl):594S-7S

4) Schümann, K., Weiss, G. 2002. Vitamine Spurenelemente und Mineralstoffe. Prävention und Therapie mit Mikronährstoffen.

5) Elmadfa, I. 2012. Österreichischer Ernährungsbericht 2012. B. f. Gesundheit, Bundesministerium für

Gesundheit.

6) Bundesforschungsinstitut für Ernährung und Lebensmittel. 2008. Nationale Verzehrsstudie.

7) Fäth-Neubauer, B., Viebahn, I. 2012. Biogena Eisen-Interventionsstudie: Pflanzliches Eisen füllt Eisenspeicher. Biogena Naturprodukte GmbH.

8) Niestroj, I. 2000. Praxis der Orthomolekularen Medizin. Physiologische Grundlagen, Therapie mit Mikro-Nährstoffen.

9) Hunt, J. R. 2003. Bioavailability of iron, zinc, and other trace minerals from vegetarian diets. Am J Clin Nutr. 78(3 Suppl):633S-639S

10) Karlson, P. 1977. Kurzes Lehrbuch der Biochemie.

11) Lönnerdal, B. 2009. Soybean ferritin: implications for iron status of vegetarians. Am J Clin Nutr. 89(5):1680S-1685S

12) mehrere Anwendungsbeobachtung durch GanzImmun, 2009

13) Theil, E.C. et al. 2012. Absorption of Iron from Ferritin is Independent of Heme Iron and Ferrous Salts in Women and Rat Intestinal Segments. Journal of Nutrition.

14) Martius, F. 2009. Eisenmangel ohne Anämie. Curriculum Schweiz.Med.9(15-16):294-299

15) Greilberger, J. 2011. Curryblatt-Eisen günstiger als Eisensalze durch geringere pro-oxidative Effekte. Biogena Naturprodukte GmbH.

16) Martin, M. 2009. Pflanzenbasiertes Eisen (MoFerrin®) im Vergleich zu einem herkömmlichen Eisenpräparat (Eisen-II-Gluconat mit Ascorbinsäure). GanzImmun Diagnostics AG.

References Interactions:
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.

Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.

Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.