Download 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. Baltimore: Lippincott Willians & Wilkins, 2006:1436–61.
5 Hallberg L, et al. AJCN 1991;54:1047–58.
6 Whitlock E, et al, Annals Int Med
2006;145(3):209–23.
7 Ball M, et al. Am J Clin Nutr 1999;70(3):353–8.
8 Jones G. Minerals. In: Wahlqvist M (ed). Food
& Nutrition. 2nd edn. Sydney: Allen & Unwin,
2002:271–82.
9 US Department of Agriculture ARS. USDA
National Nutrient Database for Standard
Release, Release 18.
10 Australian Bureau of Statistics. 4306.0 Apparent
consumption of foodstuffs Australia 1997–98 and
1998–99. Canberra: ABS, 25/10/2000.
11 Uauy R, et al. Food-Based Dietary Guidelines for
Healthier Populations: International Considerations. In: Shils M, et al (eds), op cit.
12 Roughead Z, et al. AJCN 2002;76:419–25.
13 Karr M, et al. MJA 2001;174:165–74.
14 Rutishauser I. Childhood and Adolescence. In:
Wahlqvist M (ed), op cit.
15 Beard J, et al. AJCN 2000;72(suppl.):594S–7.
16 Wood R, et al. Iron. In: Shils M, et al. Op cit.
17 NHMRC. Nutrient Reference Values for Australia
And New Zealand Including Recommended
Dietary Intakes. Australian Government Department of Health and Ageing National Health and
Medical Research Council, 2006.
18 Morck T, et al. AJCN 1983;37:416–20.
19 Mennen L, et al. Eur J Clin Nutr 2007, Epub
ahead of print.
20 Hallberg L, et al. AJCN 1997;66:347–56.
21 Hunt J, et al. AJCN 2000;71:94–102.
22 Ganz T, et al. AJP Gastrointest Liver Physiol
2006;290:G199–G203.
23 Domellof M, et al. AJCN 2002;76:198–204.
24 Nemeth E, et al. Annu Rev Nutr
2006;26:323–42.
25 Wessling-Resnick M. AJP Gastrointest Liver
Physiol 2006;290:G1–G6.
26 Elliot R, et al. Aust NZ J Med 1986;16(4):491–5.
27 Gertig D, et al. MJA 2003;179(10):517–8.
28 Roe M, et al. AJCN 2005;81;814–21.
29 Limdi J, et al. QJM 2004;97:315–24.
30 Pietrangelo A. Annu Rev Nutr 2006;26:251–70.
31 Robertson I, et al. Asia Pacific J Clin Nutr
2006;15(3):S131.
32 O’Brien K, et al. AJCN 2003;77:924–20.
33 Iannotti L, et al. AJCN 2006;84(6):1261–6.
34 Soh P, et al. Eur J Clin Nutr 2004;58(1):71–9.
35 Karr M, et al. Aust NZ J Public Health
1996;20:618–22.
36 Mackerras D, et al. Asia Pacific J Clin Nutr
2004;13(4):330–5.
37 Nguyen N, et al. J Paediat Child Health
2004;40(8):414–9.
38 Heath A, et al. Asia Pacific J Clin Nutr
2002;11(4):251–7.
39 Hunt J. AJCN 2003;78:1168–77.
40 Wilson A, et al. Eur J Clin Nutr 1999;53:189–94.
41 Walker S, et al. Lancet 2007;369(9556):145–57.
42 Krebs N, et al. AJCN 2007;85(2):639S–45S.
43 Szymlek-Gay E, et al. Asia Pacific J Clin Nutr
2006;15(Suppl 3):S81.
44 Couper R, et al. MJA 2001;174:162–5.
45 Cashel K. MJA 2000;173(suppl 7):S4–5.
46 Oti-Boateng P, et al. J Paediatr Child Health
1998;34:250–3.
47 Tiong A, et al. MJA 2006;185(11/12):602–6.
48 English R, et al. MJA 1990;152(11):582–6.
49 Gibson R, et al. Asia Pacific J Clin Nutr
2002;11(Suppl 3):S543–52.
50 Scholl T. AJCN 2005;81(suppl):1218S–22.
51 Patterson A, et al. AJCN 2001;74:650–6.
52 Akabas S, et al. AJCN 2005;81(15):1246S–51S.
53 Read R, et al. Nutrition for activity, sport and
survival. In: Wahlqvist M, ed. Op cit.
54 Braun L, Cohen M. Herbs & Natural Supplements: an evidence based guide. 2nd edn.
Sydney: Elsevier, 2007.
55 Turner R. Nutrition During Pregnancy. In: Shils
M, et al (eds). Op cit.
56 Makrides M, et al. AJCN 2003;78:145–53.
57 Heimburger D, et al. Clinical manifestations of nutrient deficiencies and toxicities: a
resume. In: Shils M, et al (eds). Op cit.
58 DePaola D, et al. Nutrition and Dental Medicine.
In: Shils M, et al (eds). Op cit.
59 Millman N, et al. Acta Obstet Gynecol Scand
2004;84(3):238–47.
60 Yehuda S, et al. J Paediar Gastro Nutr
2006;43(Suppl 3):S22–5.
61 Konofal E, et al. Arch Pediatr Adolesc Med
2004;158(12):1113–5.
Iron continued on page 66>>