Iron - Rachel Arthur Nutrition
Transcription
Iron - Rachel Arthur Nutrition
nutrition notes Iron One of the most researched micronutrients, iron still fosters new discoveries about its homeostasis and physiological role. Rachel Arthur explains groups at risk of deficiency and supplementation considerations. Rachel Arthur, BHSc, ND, is a practising naturopath and lecturer in naturopathic nutrition and a research assistant at NatMED Research in the School of Health and Human Sciences, Southern Cross University The Editor thanks Surinder K Baines, BSc, PhD, GradDipDiet, APD, Lecturer in Nutrition and Dietetics, University of Newcastle, for her kind assistance in the peer review of this article Summary • • • • • • • 36 Although haem iron exhibits superior bioavailability, per capita red-meat consumption in Australia has continued to decline, leaving us heavily reliant on the non-haem form There are several groups at risk of iron deficiency in Australia, with third-trimester pregnant women and children from some ethnic minorities exhibiting the highest rates of deficiency Although Australian rates of iron-deficiency anaemia (IDA) remain low in comparison to other countries, a great many more individuals suffer from iron depletion The human body exhibits sophisticated regulation of iron levels, including an extraordinary capacity for recycling iron that is partly protective in those with borderline iron status but may contribute to unhealthy iron accumulation in others Hereditary haemochromatosis, estimated to affect ~0.33–0.5%8 of Australians, is a genetic iron-metabolism disorder with a low phenotypic penetrance that can result in increased morbidity and mortality due to unregulated uptake of iron from the GI tract Iron supplementation may be beneficial in some children’s behavioural disorders New research investigating iron supplementation practices, including forms, dose and dosage regimes, have been substantially revised Complementary Medicine May / june 2007 iron nutrition notes T he last few decades have seen iron research develop from the singular concern of deficiency (chlorosis or anaemia) to an appreciation of its potential toxicity and the body’s mechanisms for minimising such risks. Dietary sources and bioavailability While iron is widely distributed in food, the average Western diet contains only about 5–7 mg per 1000 kcal.1 There are two types of dietary iron: haem iron (hFe) in the form of haemoglobin and myoglobin, the predominant type found in flesh foods (50–60 per cent), and non-haem iron (n-hFe), which is the major form in plant and dairy foods.1,2 Iron fortificants added to some cereal products, yeast extracts and legumebased meat substitutes3 are n-hFe and can be any number of iron salts (e.g. ferrous fumarate, ferrous lactate, reduced iron) with elemental amounts restricted to <3.5 mg per serve.3 Iron bioavailability is dependent upon the form found in food, with hFe providing the highest absorbable percentage (20–30 per cent4,5). Non-haem iron bioavailability varies dramatically (2–20 per cent), dependent upon a range of extrinsic factors6,7 [see ‘Dietary and digestive factors affecting iron absorption’ table, p 38]. Consequently, flesh foods are considered preferable sources of iron, including highly concentrated examples such as offal and clams.8,9 The Australian diet, however, typically has a hFe:nhFe of about 1:12.4, and these specific foods are not commonly consumed.7 In fact, Australian meat consumption has declined significantly since the 1970s, coupled with a small increase in per capita vegetable consumption.10 The major dietary sources of iron consumed by Australians in 1998 were cereal and cereal products (40 per cent), followed by meat (17–22 per cent) and fruits and vegetables (about12 per cent).8 Dietary sources of iron9 Source Fe content (serving size) (mg/serve) Clams (100 g) 27.96 Lamb kidneys (130 g) 15.60 Lamb liver (130 g) 13.00 Chicken livers (130 g) 11.70 Mussels (12=120 g) 8.06 Oysters (12=120g) 6.94 Soya bean (100 g) 5.14 Lamb sirloin chop (100 g) 2.34 Lean beef sirloin, roasted (100 g) 1.70 Dried figs (4=80 g) 1.62 Mung beans (100 g) 1.17–1.4 Dried peach (25 g) 1.01 A smaller study made similar findings and identified fortified breakfast cereals alone as contributing a staggering 15 per cent of total daily iron in both omnivorous and vegetarian women.7 While the fractional absorption of iron fortificants vary, they are reported to provide ≤0.33 mg per 100 g11 of product consumed. Improved outcomes of iron fortification are hampered by the insolubility of metallic iron and the negative interactions between soluble iron compounds and the food matrix in terms of palatability, shelf life, etc.4 Another consideration is the potential interaction between the fortificant and components of the whole meal. With breakfast cereals a key source of dietary iron7,12, consumption with milk1 may reduce their absorbable iron content. See ‘Dietary sources of iron’ table, above. Absorption The absorption and bioavailability of iron is dichotomous as a consequence of its major dietary presentations as hFe or n-hFe. Each form undertakes distinct pathways of digestion and absorption and is subject to contrasting degrees of regulation12 [see ‘Regulation of haem and non-haem iron through alterations in uptake’ table, p 40]. May / june 2007 Complementary Medicine 37 nutrition notes iron Inhibit absorption Enhance absorption Dietary and digestive factors affecting iron absorption Factor Type of Fe affected Mechanism Acids e.g. ascorbic, n-hFe citric, lactic, malic and tartaric 2,16,17 Act as reducing agents to produce Fe2+ and form a chelate, increasing solubility in small intestine Consumption of 75 mg vitamin C (e.g. ½ glass orange juice or 1 medium kiwi fruit) maximises bioavailability of Fe (e.g. from 2% to 8%)1 Flesh foods e.g. meat, poultry and fish n-hFe, hFe Digestion of contractile proteins produces cysteine-containing peptides that form bioavailable chelates and stimulate intestinal secretions that may further ↑ uptake Consuming 75 g cooked meat with iron-rich vegetables will maximise absorption of n-hFe in both (from 2% to 8%)1 Hypo- or achlorhydria n-hFe Acidic environment required to reduce Fe3+ to more bioavailable Fe2+ or to maintain solubility as Fe3+ Foods and supplements that may help maintain a low pH in the stomach (e.g. lemon juice, apple cider vinegar) may enhance absorption. Hypo- and achlorhydria have been implicated in Fe deficiency Polyphenols e.g. tea, coffee, wine n-hFe Polyphenols form non-absorbable complexes with Fe within intestinal lumen18 If tea or coffee are consumed during or within an hour of a n-hFe meal/supplement, n-hFe absorption can be ↓ ≥60%.12 This is dose-dependent and may be only of significance in those already at risk19 Oxalic acid e.g. tea, spinach, parsley, rhubarb, chocolate n-hFe Oxalates readily bind n-hFe to form an Despite high iron content, spinach, parsley and other insoluble chelate high-oxalate foods do not represent good sources of n-hFe9 Phytates e.g. whole-grains and legumes n-hFe (±hFe)13 Phytates bind with n-hFe to form insoluble chelates, increased ingestion of Fe will not overcome this effect1,16 Fermentation of grains or sprouting of legumes will increase Fe bioavailability from these foods Other divalent cations i.e. calcium, phosphorous, zinc, manganese and nickel n-hFe, hFe Competition for shared transporters, inhibition of basolateral transfer12 or formation of insoluble chelates mean that high consumption of these nutrients can ↓ Fe absorption and vice versa Consuming n-hFe with milk or a Ca supplement (providing ≥300 mg elemental Ca) can reduce Fe absorption by 70%.1 This partly explains the higher deficiency rates evident in children who consume a high-dairy diet.13–15 One small study did not demonstrate impaired Fe absorption, however, both sample size and amount of Ca were small12 Haem iron is a metalloporphyrin found in flesh foods (e.g. haemoglobin and myoglobin). Digestion of this molecule is complete following hydrolysis of the globin portion, the haem porphyrin ring absorbed intact. This means free iron does not dissociate at any stage within the lumen and therefore is resistant to unfavourable chelation. Although the mechanism is yet to be completely elucidated, it appears largely impervious to the regulatory influences affecting the protein carriers responsible for n-hFe uptake. In contrast to this, n-hFe is released from food producing either ferrous (Fe2+) or predominantly ferric (Fe3+) ions. As Fe3+, the iron is soluble only in an acidic environment and, upon mixing with the alkaline secretions of the pancreas, commonly forms the insoluble ferric 38 Example Complementary Medicine May / june 2007 hydroxide compound. Fe3+ can undergo reduction within the intestinal lumen to facilitate uptake or bind to solubilising chelators in order to overcome this.1 The overall contribution of Fe3+ to absorbable iron, while not fully quantified, is speculated to be small.2 Fe2+, however, when favourably chelated, is released and readily absorbed across the brush border by protein-carrier transporters, including the divalent cation or mineral transporter 1 (DMT1). Despite this, fractional absorption of n-hFe remains relatively low in most instances, principally the result of interactions between n-hFe, negative chelating agents and other antagonistic competitors such as divalent cations1,13–15 co-presenting in the GI tract [see ‘Dietary and digestive factors affecting iron absorption’ table, above]. Distribution, storage, recycling and ‘excretion’ Transferrin carries almost all of the absorbed and recycled iron around the body and is typically one-third saturated with iron.1,16 Due to the bone marrow’s high erythropoietic iron demand, 70–90 per cent is delivered here, facilitated through transferrin receptors found on the plasma membrane.16 The amount of iron taken up by cells is influenced by transferrin saturation, with higher iron content promoting increased uptake and the cells’ receptor numbers, which in turn is directly proportionate to the cells’ iron demand. The liver parenchyma is the primary iron storage site (about 60 per cent). The remaining 40 per cent occurs in the reticuloendothelial cells (RE) of liver, spleen, bone marrow and possibly between iron nutrition notes May / june 2007 Complementary Medicine 39 nutrition notes iron muscle fibres.1 The main storage form is ferritin, a dynamic molecule which is constantly undergoing synthesis and degradation, providing an intracellular pool of available iron. Ferritin levels correlate directly with the amount of iron stored and, consequently, are used as a first-line indicator of iron status.12,17 Release of iron from ferritin requires reduction of Fe3+ via reducing agents (e.g. vitamin C, riboflavin, niacin and possibly sulphide).2 When the iron-binding capacity of ferritin is exceeded, as in iron overload, iron binds to haemosiderin. Healthy iron stores for males, which peak in their 30s to 40s, are 50 mg/kg, while women have less due to both smaller body size and altered iron status as a result of pregnancy and menstruation. Women’s peak concentrations occur at the age of 60.2,20,21 The human body possesses an extraordinary recycling capacity for iron, with about 40–60 per cent of iron salvaged from the degradation of ferritin and haemoglobin being reused for haemoglobin synthesis within 12 days, and the remainder entering storage.2,16 For haemoglobin, this occurs in the RE system of phagocytes of the liver, bone marrow and spleen and provides about 20–25 mg iron per day1, while ferritin breakdown occurs in the tissues, with amounts sufficient to meet any shortfall in intake. Excluding menstruating females, there are no actual excretory pathways for iron22 and losses in healthy people remain extremely low. The little iron that is lost occurs primarily in the GIT via minute blood loss, bile products and desquamated mucosal cells.1 Other sources of iron loss include the skin (through cell sloughing) and urine. Urine concentrations should remain low due to the large size of most iron-containing molecules, which prevent glomerular filtration except in renal pathology.1,2 Homeostasis/regulation of levels Iron absorption, in particular n-hFe, increases with low iron status and decreases in replete individuals.1,8 The GIT is considered to be the primary site for overall iron regulation. In spite of this, iron deficiency is common, therefore this adaptation is not absolute.20 The evidence points to three key regulators of Fe absorption: stores, erythropoietic demand and dietary intake23 [see ‘Regulation of haem and non-haem through alterations in uptake’ table, below]. Another important player in iron metabolism is inflammation. Inflammatory stimuli rapidly trigger hepcidin release, which then inhibits iron recycling in macrophages. This can cause a substantial (about 30 per cent) drop in serum iron and, if continued long term, results in the anaemia of chronic disease.16,22 This is believed to be an important part of the acute-phase response, limiting the use of iron by invading pathogens.1,16,22 Deficiency prevalence Estimates of worldwide prevalence of iron deficiency vary, with figures ranging from 700 million to two billion, depending on definitions and cut-off points used.4,32,33 Australian research confirms the significance of this issue and identifies at-risk groups similar to most countries. Rates of IDA (overt irondeficiency anaemia) have been reported to be at most five per cent in children aged between six months and five years in Australia and New Zealand34–36, with evidence of increased prevalence in some ethnic minorities.13,37,38 It is important to remember, however, that rates of IDA, the end-stage deficiency, present an oversimplified view of the problem because they don’t take into account individuals exhibiting iron depletion. When these figures are combined, the true magnitude of the problem becomes apparent. For Regulation of hFe and n-hFe iron through alterations in uptake7,9,13,14,30 Regulator Mechanism Type of Fe Hepcidin Key regulator secreted by bone marrow and liver, whose release is triggered by high Fe stores and inflammation. In response to elevated hepcidin, enterocytes stimulate degradation of ferroportin and therefore inhibit Fe efflux into portal blood. Conversely, when hepcidin levels ↓ as a result of anaemia or hypoxemia, together with low cellular Fe uptake, the same transport proteins can be upregulated within 24–48 hours. May also ↓ DMIT1 expression hFe and n-hFe. The absorption of both hFe and n-hFe are affected by body stores. However, n-hFe shows the greatest adaptive response (10–15-fold vs. 2–3fold)20–21 Fe-rich meal and ↑ Fe concentration in enterocytes16,20,21,23 A bolus of Fe enterally administered results in enterocyte resistance to additional absorption for several days. This trapped Fe is then lost with the rapid turnover of mucosal cells (2–3 days). There is additional evidence of redistribution and ↓ expression of DMIT1 hFe and n-hFe Aconitase hydratase and related protein2 Detects ↓ cytosolic concentration and binds to Fe-responsive elements (IRE) of ferritin, ferroportin and transferrin genes to increase storage, impair the transfer of iron across the basolateral membrane of the enterocyte and slow the transfer of iron from the GIT and from Fe stores hFe and n-hFe. n-hFe is affected to a larger extent Unknown erythropoietic regulator23 When the erythropoietic drive is high in relation to Fe supply, Fe absorption ↓. Mediated potentially through increasing transferrin receptors n-hFe 22,24,25 40 Complementary Medicine May / june 2007 Key interactions54 Interaction Drug/medicine Solution Fe ↓ drug absorption • ACE inhibitors Separate doses by ≥2 hours • Cimetidine • L–dopa and carbidopa • Quinoline antibiotics • Thyroxine Drug ↓ Fe absorption • Antacids • Cholestyramine, colestipol Separate doses by ≥2 hours and monitor Fe levels • H2-receptor antagonists • Proton pump inhibitors ↓ Fe and ↓ drug absorption when co-administered • Penicillamine ↓ Fe levels independent of absorption • Haloperidol Separate doses by ≥2 hours • Sulfasalazine • Tetracylcines Increased iron intake may be required during long term treatment Additive pharmacological effect • Erythropoietin example, in one study of six- to 24month-old children in New Zealand, 4.3 per cent of the sample were found to be anaemic, while an additional 33.5 per cent were diagnosed as either iron deficient or having low iron stores, bringing the real figure to 37.8 per cent.34 Vegetarians and vegans Exclusive consumption of n-hFe results in an overall iron bioavailability of 10 per cent compared to 18 per cent for an omnivorous diet. This suggests that vegetarians would need to consume 80 per cent more n-hFe, increasing total daily requirements from 8 mg in men and 18 mg in women to 14.4 mg and 32.4 mg respectively.1,16,17 There is evidence, however, of longterm adaptation to diets with low Fe bioavailability and, accordingly, some researchers argue that these figures are probably an overestimation.21 Although studies have demonstrated increased n-hFe absorption following long-term (10-week) consumption of a vegetarian diet by men, later studies in women found Beneficial interaction possible the adaptation was not sufficient for those with low iron stores.39 Australian male40 and female7 lactoovo-vegetarians and vegans demonstrate significantly lower ferritin levels and higher rates of iron depletion than their omnivorous counterparts, in spite of higher iron intakes. Surprisingly, rates of anaemia do not differ in women.7 Children Iron deficiency is most prevalent worldwide in preschool-aged children.4,11,16,36,41 This apparent susceptibility is multifactorial, including the rapid growth evident in the first year, depletion of maternal and infant iron stores at six months post-partum28 and the low bioavailable iron content of most complementary foods.23,42,43 The only national survey investigating rates of IDA reported an incidence of 2–3.3 per cent among preschoolers36, peaking among two-year-olds.35 However, the reported percentages affected by suboptimal iron in Australian and New Zealand range from 14.4 per cent35 to March / April 2007 Complementary Medicine 41 nutrition notes iron 40 per cent.34 These figures increase again within several subgroups: • low birth-weight and premature infants due to inadequate gestational iron accrual33,44 • prolonged exclusive breastfeeding23,44 • consumption of meat less than four times per week35 • young vegetarian children with a reduced stomach capacity, preventing the 80 per cent increase in iron-containing foods necessary to compensate for reduced iron bioavailability.1,14,17 Australian data indicate that about two per cent of children are vegetarians45 • over-reliance on milk and milk products (≥650 mL/day) in children >12 months13,14,37,46 • Aboriginal children in rural but not urban areas36 • recent maternal immigration47 potentially associated with inadequate maternal iron, poverty, reduced food diversity and subsequent over-reliance on cow’s milk.13,44 Hereditary haemochromatosis – when Fe regulation goes wrong Hereditary haemochromatosis (HH) is one of a number of genetic iron-metabolism disorders that particularly affects individuals with northern European, western and southern German or Spanish ancestry. Estimations of the percentage of Australians with this condition range between about 0.33–0.5%8, increasing to 1.2% of men ≥58 years of age.26 HH is a human leukocyte antigen (HLA)-linked autosomal recessive disorder caused by a single nucleotide polymorphism in the HFE gene16, with the majority of symptomatic individuals being homozygotes (80–100%).27–29 The loss of normal HFE protein expression on enterocyte cell membranes results in impaired sensing of body iron stores.29 This stimulates increased expression of DMIT1, increasing GIT iron absorption. A recent discovery has been the partial hepcidin deficiency characteristic of HH and considered to be as central to its pathogenesis as insulin is to diabetes.22,24,29,30 Ultimately, this annuls the ‘stores regulator’, producing ongoing increased absorption (≥ x 2)16 in the face of elevated ferritin. Over time, transferrin and ferritin become saturated22 and excess iron is stored as haemosiderin, deposited in the liver, heart and endocrine glands, increasing the risk of malfunction and damage.6,8 The liver is the primary target and 30% of deaths from HH are due to hepatocellular carcinoma.6,29 Individuals can also be heterozygous for HH, with an incidence approximating 10% of Americans.6 Heterozygotes, although potentially displaying abnormal iron status, don’t demonstrate the same upregulation of iron absorption28 or develop organ failure.1 Even HH homozygotes are typically asymptomatic due to the low penetrance of the clinical phenotype. Only 60% of homozygotes eventually develop iron overload27, and results from a large American study suggest that <1% develop frank haemochromatosis, although this remains controversial.16 Clinical features of HH may take decades to appear, typically presenting midlife, and show substantial inter-individual variation. Most notably, the age of onset is delayed in females and regular blood donors, and accelerated in patients with existing comorbidities, e.g. viral hepatitis.6,31 While restriction of both dietary Fe and supplemental vitamin C and tea consumption to impair iron uptake is a sensible first step in the management of HH, those homozygotes with high ferritin +/- increased transferrin saturation should have regular venesection. If undertaken prior to the development of cirrhosis, this can reduce morbidity and mortality.27,29 42 Complementary Medicine May / june 2007 The demonstrated negative relationship between excess dairy consumption and poor iron status is controversial but has attracted a number of explanations, such as milk’s poor iron content and substitution for other iron-rich foods, calcium’s potential to inhibit iron uptake and possible microscopic GIT blood loss.14 Adolescent girls48 A rapid growth spurt, together with menarche and a trend for declining redmeat consumption in this age group, increase the likelihood of a shortfall between requirements and intake.49 Additional exacerbating factors include high menstrual losses, strenuous exercise, frequent blood donation or other sources of blood loss (e.g. epistaxis), pregnancy, low socio-economic status and ethnicity.49 While one study estimated that about eight per cent of Australian teenage girls have low iron stores, with a quarter of these suffering IDA14, substantially higher figures have been reported by other authors (12 per cent low ferritin and seven per cent IDA).49 Women7 A number of contributing factors merge to place women at an increased risk of iron deficiency. Most notable is menstrual blood loss (30 to >80 mL per cycle)1, 50 equivalent to about 13.5–36 mg per month.2 Such direct iron loss is exacerbated in IUD users5,50 who experience 30–50 per cent greater blood loss, and is moderated in women on oral contraception. In addition to this, women demonstrate a number of dietary patterns that also compromise intake, consuming less overall iron than men each day (11.1 mg vs. 15.2 mg)8, as well as a reduced hFe: n-hFe.8 Restricted calorie consumption may also play a part.14 The Australian Longitudinal Study of Women’s Health estimates that one in three women have been diagnosed with iron deficiency by the age of 45–50.51 Other than vegetarianism, risk factors for women include: iron nutrition notes •m ultiparity — risk is increased with parity, with a threefold greater risk for those women with two or three children and almost four times greater risk for those with four or more50; • regular strenuous exercise — longdistance running in particular is associated with increased iron losses through sweat, faeces and intravascular haemolysis (namely footstrike), as well as a dilutional pseudoanaemia.52–54 Together, these produce a 20 per cent faster rate of whole-body iron loss in female athletes than in non-athletes.15 Compounding this is consistent evidence of energy underconsumption by female athletes, which often results in compromised iron intake52,53; •p regnancy — the total iron cost of pregnancy is reported to be in the vicinity of 700–1400 mg.4,32,55 This is required for the growth and maintenance of both foetus and mother, with allowances made for losses at delivery. Increased requirements begin in the second trimester and have increased eightfold by the third.4 Accordingly, rates of anaemia follow similar step-wise increases, from about 6.7 per cent in the first trimester to 45.6 per cent in the third, indicative of the widening gap between demand and consumption.50 A comparison between the current RDI (27 mg/day) and the average dietary intake of iron by Australian pregnant women (12 mg/d) makes plain the principle cause.56 Some authors state that unless preconception iron stores are ≥500 mg, the high iron requirements of pregnancy necessitate supplementation.4 This position is supported by a study of over 2000 unsupplemented pregnant women, whose haemoglobin levels remained low throughout gestation and at one year postpartum.4 This suggests that iron depletion in pregnancy can have longlasting effects for the mother. The suggested consequences of inadequate maternal iron during Features of acute and chronic iron deficiency1,4,5,15,16,59 Acute deficiency (early indicators) Chronic deficiency (late indicators) • Listlessness, fatigue and lethargy • Pallor of mucous membranes • Glossitis • Angular stomatitis • Reversible gastric atrophy • Increased susceptibility to infection • Increased lead absorption • Delayed psychomotor development in infants and children • Impaired work performance and productivity in adults • Pica: geophagia (dirt) and pagophagia (ice) • Parasthesias in hands and feet • Cold extremities • Impaired thyroid function • Diminished menstrual flow • Hyperactivity and possibly ADHD • Microcytic hypochromic anaemia • Pale blue sclera • Koilonchyia (spoon-shaped nails) • Slow tooth growth • Poor tooth integrity with increased caries • Salivary gland dysfunction • Irreversible learning impairment in children • Increased maternal morbidity, premature labour and LBW babies • Oesophageal webbing (Plummer-Vinson syndrome) • Exertional dyspnoea • Tachycardia • Palpitations • Angina • Claudication • Night cramps • Cardiac bruits • Cardiomegaly • Cardiac failure • Spleen enlargement gestation (e.g. low birth weight, premature labour and increased perinatal mortality) remain controversial. Comorbidities Comorbidities associated with increased blood loss place other individuals at risk of a secondary iron deficiency, including any form of haemorrhage, renal disease, steatorrhoea, some GIT parasite infestations1, coeliac and IBD and menorrhagia.50 In addition to this, factors associated with compromised absorption of iron may also precipitate a secondary deficiency, such as protein calorie malnutrition, hypo- or achlorhydria [see JCM 2007;6(1):55–7], Helicobacter pylori infections or infestations of certain parasites, e.g. hookworm.1 Signs of deficiency Early indicators of iron depletion are generalised, due partly to the rapid compromise of the Kreb’s cycle Fe metalloenzymes and ETC cytochromes, which are essential to the production of cellular energy. Consequently, patients classically present with listlessness and fatigue. A diminished oxygen-carrying capacity can result in the pallor often described as the key clinical feature of iron deficiency. However, this can often be hard to detect in patients of varying skin tones and is best observed in the mucous membranes57, e.g. inside lower eyelid or mouth. Other features are listed in the ‘Features of acute and chronic iron deficiency’ table, above. Indications for iron Prevention and treatment of IDA Studies in anaemic children have demonstrated that ferrous sulphate 300 mg weekly dosing was successful in increasing both haemoglobin and IQ.54 Prophylactic iron supplementation (40 mg/d) from 18 weeks’ gestation prevented iron deficiency in 90 per cent of women and anaemia in 95 per cent, and these benefits carried through into the post-partum period.59 An Australian study found comparable results with 20 mg/d from 20 weeks’ gestation.56 Fatigue without anaemia Braun and Cohen54 report that iron supplementation (80 mg/d) is useful for May / june 2007 Complementary Medicine 43 nutrition notes iron some fatigued women in the absence of abnormal iron studies, reducing fatigue by 29 per cent over four weeks. However, this was only true for those with baseline ferritin <50 mcg/L. ADHD Iron has attracted attention as a potential contributor in ADHD due to the similarities between some of the disease features and the deficiency presentation. Development of this theory includes the recent finding that IDA potentially alters blood–brain barrier permeability, allowing a range of substances normally blocked to pass through, such as [beta] endorphin, which is associated with poor learning and memory.60 Links have also been made with the delayed maturation of the frontal cortex and low thyroid levels also evident in IDA. Building on this hypothesis, one study demonstrated that a staggering 84 per cent of children with ADHD were iron depleted (ferritin <30 ng/mL) compared to only 18 per cent of controls. Ferritin levels correlated with the severity of the cognitive impairment.61 Other studies have produced similar results.62 Unfortunately, the only clinical trial to date was a small open-label study of iron-replete boys supplemented with iron. Although there was some cognitive and behavioural improvement, trials in ID or IDA ADHD sufferers are warranted.63 Suboptimal iron has also been linked to juvenile delinquency and aggression and conduct disorders in children.64 Breath-holding Some studies suggest an association between iron deficiency and breathholding spells, with supplementation significantly reducing the frequency of episodes.65 However, potential mechanisms have not been explained.65 Choosing a supplement While some researchers suggest that supplements are required for those 44 Complementary Medicine May / june 2007 patients with confirmed suboptimal status49, others argue that although more slow to correct ferritin levels (at least nine months), dietary treatment of mild iron deficiency is preferable.51 This argument is convincing because dietary modification may also prevent subsequent IDA through addressing dietary causes. Additionally, more sustained improvements have been demonstrated with dietary treatment in comparison to short-term supplementation. However, in severe iron depletion IDA or patient non-compliance, supplementation is vital. All oral iron supplements (e.g. ferrous sulphate, lactate and fumarate) are n-hFe and, as such, their bioavailability can be significantly improved with the inclusion of 75 mg of vitamin C in each tablet.1 Ferrous sulphate is the least expensive and most frequently prescribed form, providing between 80 mg (FGF) and 105 mg (FerroGradumet) elemental iron per tablet.66 One of the major complaints about this preparation is GIT side-effects, including abdominal cramps and constipation. However, researchers argue that all iron salts when given at an equivalent dose have comparable adverse events.4 This is not surprising given that these amounts far exceed the established tolerable upper levels of intake16 and, as such, have received much criticism for being routinely recommended by some in pregnancy.4,56,67 As with most minerals, to optimise uptake, iron should be taken on an empty stomach. However, this exaggerates side-effects and can create additional GIT discomfort in the form of reflux and nausea. It is therefore recommended that patients start on a lower dose (~30 mg ferrous sulphate), increasing gradually over time, and consume their supplements with foods, excluding those that negatively affect iron absorption i.e. tea, to maximise compliance.4 Although daily dosing is frequently recommended, a number of studies have revealed weekly dosing to have comparable effects.54,68 An increasing number of studies show improved success with low-dose (≤20 mg) long-term supplementation (at least six months) in many patients including children and pregnant women.33,56,67 Certain clinical situations necessitate parenteral administration, including:4 • impaired iron absorption • poor tolerance or non-compliance of oral iron supplements • inflammatory bowel conditions • chronic GIT blood loss non-responsive to oral treatment • haemodialysis patients who cannot achieve a positive iron balance with oral treatment alone. Administered intravenously, iron polymaltose (Ferrum H Injection) has been associated with anaphylactic reactions in susceptible patients. However, for many it remains the method of choice, as intramuscular injection produces increased discomfort and allergic reactions in a larger patient population.66 Ferric sodium gluconate and iron sucrose were recently approved in the US and reportedly have improved safety profiles.4 A response to iron therapy is evidenced by a clinical benefit and characterised by a haemoglobin rise of about 1 g/dL per week. Patients with IDA require supplemental iron for a minimum of six months4 to one year1 to replenish stores. Other areas under investigation concerning supplementation include improved athletic performance15, 53, cognition and haemodialysis.54 Contraindications, toxicity and adverse reactions Accidental excess consumption of iron supplements is the most common cause of poisoning in infants, producing vomiting, upper abdominal pain, pallor, cyanosis, diarrhoea, drowsiness, shock and death.2,57 The human body goes to enormous lengths to avoid excess iron accumulation. Consequently, iron supplementation should always be iron nutrition notes May / june 2007 Complementary Medicine 45 nutrition notes iron conservative and restricted to cases of demonstrable deficiency. Supplemental iron is contraindicated in any form of haemochromatosis or iron-loading anaemias (thalassemia, sideroblastic anaemia). Iron increases, either elevated ferritin and/or unbound iron, may increase the risk of: • oxidative stress via the generation of the hydroxyl radical exacerbated in those individuals with low baseline anti-oxidant nutrition/status1,33 • oxidative stress in pregnancy implicated in pre-eclampsia and gestational diabetes69 • abnormal offspring behaviour of mothers routinely supplemented during pregnancy67 • infection and morbidity from infectious diseases in children in developing countries33,70 • gallstone disease in men (increased hFe consumption)71 • colorectal cancer with long-term high consumption of hFe from red and processed meats72–74 • type 2 diabetes on both healthy and HH populations (increased hFe consumption from red meat and elevated ferritin)75–77 • results from studies investigating links between hFe consumption and iron stores and cardiovascular risks have been equivocal78–80 • possible links with neurodegenerative conditions such as Friedrich’s ataxia, Huntington’s, Alzheimer’s and Parkinson’s disease, as well as amyotrophic lateral sclerosis and atypical parkinsonian syndromes.2,82,83 It remains possible, however, that this is due to a genetic iron dyshomeostasis rather than an overt excess.84,85 Conclusion The balance between adequacy and excess in the case of iron is subtle and individual but must be paramount in the practitioner’s mind. In contrast to most other micronutrients, we are likely to see both 46 Complementary Medicine May / june 2007 deficiency and overload in our patients. As such, we need to be as competent in recognising and managing iron excess as we have become in our daily encounters with its deficiency. Future developments in understanding iron dyshomeostasis will advance our knowledge further regarding the metabolism of this extraordinary mineral, and potentially offer new treatments for a range of chronic conditions associated with iron accumulation. ◗ References 1 Gropper S, et al. Advanced Nutrition and Human Metabolism, 4th edn. California: Thomson Wadsworth, 2005. 2 Kohlmeier M. Nutrient Metabolism. London: Academic Press, 2003. 3 Australia New Zealand Food Standards Code. Barton: FSANZ, 2006. Report No. 90. 4 Chitambar C, et al. Nutritional Aspects of Hematologic Diseases. In: Shils M, et al. Modern Nutrition in Health and Disease. 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