Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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iron atoms, while the iron atoms are linked to the rest

of the protein via the sulfur atoms of cysteines. In each

of these three types of iron–sulfur protein each iron

atom is tetrahedrally surrounded by four sulfur

atoms. Compounds containing more than one iron

atom show complex redox behavior as each iron

atom can be either iron(II) or iron(III).

Environment

0012 Terrestrial The earth’s core is composed of metallic

iron, and iron compounds form 1.5% of the litho-

sphere, making iron the eighth most abundant

element. The most common iron mineral is hematite

(Fe

), with magnetite (Fe

), siderite (FeCO

limonite (FeO(OH)) and iron pyrites (Fool’s gold,

FeS

) also widely distributed. At neutral pH, aerial

oxygen readily oxidizes iron(II) in solution to iro-

n(III). To be stable, iron(II) compounds must, like

iron pyrites, be insoluble.

Protein

fig0009 Figure 9

Protein

bundles

surrounding

core

Mineral

core

fig0010Figure 10

fig0011Figure 11

Protein

fig0008 Figure 8

CH CH

−

fig0007 Figure 7

Cys

fig0012Figure 12

3370 IRON/Properties and Determination

0013 Aquatic Sea water contains low concentrations of

iron (0.002–0.02 ppm) complexed by chloride ions.

Fresh water, with pH around 7, can contain suspen-

sions of hydrated iron(III) oxide, or iron complexed

to organic material.

Losses/Gains during Food Processing

(Including Changes in Speciation)

0014 Iron compounds in foods are not appreciably volatile

so iron cannot be lost by vaporization during normal

processing. As iron compounds occur naturally asso-

ciated with proteins, the iron compounds found in

foods are generally changed on heating, so that the

tertiary structure of the protein is destroyed. This will

cause the iron compound to lose its functionality.

Thus, after heating, myoglobin will no longer revers-

ibly bind oxygen – the iron(II) is irreversibly oxidized

to iron(III). Normal cooking will not break the pep-

tide links in the protein, or free iron from its coordin-

ation shell.

0015 In principle, foods cooked or processed in iron or

steel vessels could potentially pick up significant

amounts of iron. However, as commercial processing

is now largely carried out in equipment constructed

of stainless steel, this is not a major problem. The

most likely situation where significant iron pick-up

may occur is with acidic foods or those containing

high levels of chloride ions. In domestic situations

where cast iron pots are used, iron uptake may

be appreciable, in relation to the amounts naturally

present.

0016The levels of iron resulting from contamination are

unlikely to be significant from a toxicological (or

even nutritional) point of view. However, they may

lead to metallic taints in some foods and they

may accelerate formation of rancidity by acting as a

catalyst of lipid oxidation.

Iron Fortification of Foods

0017Iron compounds used for fortification of foods are

varied. These additives are still widely referred to by

their older (ferrous/ferric) names. Iron(II) (ferrous)

sulfate is the cheapest iron source, and iron intro-

duced this way is well absorbed. Iron absorption

depends on the nature of the food. Sources of ascorbic

acid enhance iron absorption from additives, while

tea inhibits absorption. Choice of fortificant is a

balance between using iron in a form which is well

absorbed, while not causing unacceptable color or

taste changes in the food. Many countries add iron

compounds to flour and cereals to counteract iron-

deficiency anemia. Flour is fortified to iron levels of

between 16.5 ppm (UK) and 44 ppm (US).

0018Dependent on the liquidity of the product, one

can use soluble compounds with good iron bioavail-

ability (iron(II) (ferrous) sulfate, iron(II) (ferrous)

gluconate, iron(II) (ferrous) lactate, iron(III) (ferric)

saccharate, iron(III) (ferric) ammonium citrate,

soluble iron(III) (ferric) pyrophosphate). Care has to

be taken to avoid unpleasant taste, undesirable

coloring and catalysis of fat oxidation. Less soluble

iron sources (iron(II) (ferrous) fumarate, iron(II) (fer-

rous) succinate, iron(III) (ferric) pyrophosphate,

elemental iron, sodium iron(III) pyrophosphate, iro-

n(III) (ferric) orthophosphate) may be better with

more solid foods.

Analysis: Isolation and Extraction

0019It is relatively easy to analyze food samples for their

iron content. The method of analysis depends on the

nature both of the samples, and of the detection tech-

nique selected. It is usual to remove the organic part

of foods from the inorganic constituents before analy-

sis. This can be done by wet digestion or dry ashing

methods.

Wet digestion

0020Many wet analytical techniques require the iron to be

present as uncomplexed iron(II) or iron(III) ions in

the analyte with absence of organic residues. A uni-

versal method to achieve this is to heat the sample

with a digestion mixture containing concentrated

nitric, perchloric and sulfuric acids in a Kjeldahl

flask for some hours. All organic matter is oxidized

SFe

Cys

fig0014 Figure 14

Cys

fig0013 Figure 13

IRON/Properties and Determination 3371

to water and carbon dioxide, while metal ions are left

behind as uncomplexed ions (the anions from these

acids are poor ligands). While not necessary for

oxidation, the presence of sulfuric acid insures that

samples do not dry out to an explosive perchlorate.

After digestion, the sample is diluted appropriately.

Dry Ashing

0021 The simplest way to remove organic matter from a

sample prior to analysis is by aerial oxidation at red

heat in a silica, porcelain, or platinum crucible.

Samples (1–10 g) are normally dried carefully at

100–110



C before heating in a muffle furnace. All

iron is oxidized to Fe

, and organic matter present

is oxidized to carbon dioxide and water vapor. At

high temperatures, iron porphyrin compounds and

others may volatilize before oxidation and iron may

be lost, so ashing temperatures must be kept as low as

possible – temperatures of 500–550



C are generally

used. Dry ashing methods must be tested for iron

recovery before routine use. After ashing, the cooled

ash is dissolved in dilute hydrochloric acid.

Analysis: Spectroscopic and

Electrochemical Methods

0022 The simplest way to assay the iron content of the

solutions resulting from ashing is to reduce all iron

to iron(II) using metallic zinc, and then to titrate the

iron(II) with potassium permanganate.

Spectroscopic Methods

0023 Instrumental methods, mainly spectroscopic, are now

widely used.

0024 UV/Visible Absorbance Both iron(II) and iron(III)

form colored complexes, which can be used to assay

iron. Samples from ashing normally contain iron as

iron(III). Addition of thiocyanate produces a blood-

red color of [Fe(H

SCN]

2þ

, which can be spectro-

photometrically measured at 480 nm. Normally

samples are reduced to iron(II) with a reductant

such as ascorbic acid, or hydroxylamine hydro-

chloride, the complexing ligands 1,10-phenanthro-

line (phen) or 2,2

-dipyridyl (dipy) added, and

absorbances of the colored complex ions

[Fe(phen)

]

2þ

or [Fe(dipy)

]

2þ

measured at 505–

510 nm.

0025 Atomic Absorbance Spectrophotometry Atomic ab-

sorption spectrophotometry (AAS) has been widely

used to assay for iron. Solutions containing iron(II) or

iron(III) are introduced as an aerosol into the flame

where atomization takes place. The method has a

detection limit of 0.003 ppm, and is easily automated

for the analysis of many samples. Interference from

other metals in the sample is minimal. Normally only

a single element, e.g. iron, can be analyzed for at a

time on each sample.

0026Inductively Coupled Plasma Optical Emission Spec-

trophotometry (ICPOES) Solutions containing iro-

n(II) or iron(III) are introduced into a plasma as an

aerosol, and the emissions from atomic transitions

specific to iron are measured in a suitable spectropho-

tometer. This technique has a similar sensitivity to

AAS, but is more convenient for multielement assays.

As atomic transitions are detected, the technique is

sometimes referred to as Inductively Coupled Plasma

Atomic Emission Spectrophotometry (ICPAES).

0027Spark Emission Spectroscopy This works in a simi-

lar way to ICPOES. The liquid sample is placed so

that sparks are formed between the solution and an

inert electrode. In the sparks, iron atoms are excited

to high energy levels, and emissions at wavelengths

specific to iron are measured.

Electrochemical Methods

0028Spectroscopic methods are now widely used for iron

analysis. Electrochemical methods, though effective,

are of secondary importance. Iron-containing solu-

tions may be reduced to convert all iron to iron(II)

which can be titrated with ceric sulfate, and the end-

point detected potentiometrically. Low concentra-

tions of iron may be determined by polarography,

but advanced polarographic techniques such as

differential pulse polarography generally give better

results.

See also: Iron: Properties and Determination;

Spectroscopy: Atomic Emission and Absorption; Visible

Spectroscopy and Colorimetry

Further Reading

Clydesdale FM and Weimer KL (1985) Iron Fortification of

Foods. Orlando, FL: Academic Press.

Cotton FA, Wilkinson G, Murillo CA and Bochmann M

(1999) Advanced Inorganic Chemistry, 6th edn. New

York: Wiley-Interscience.

Cunniff P (1995) Official Methods of Analysis, 16th edn.

Arlington: Association of Official Analytical Chemists.

Greenwood NN and Earnshaw A (1997) Chemistry of the

Elements, 2nd edn. Boston: Butterworth-Heinemann.

Holland B, Welch AA, Unwin ID, Bun DH and Paul AA

(1991) McCance and Widdowson’s The Composition of

Foods, 5th edn. Cambridge: Royal Society of Chemistry.

Hughes MN (1987) Coordination compounds in biology.

In Wilkinson G, Gillard RD and McLeverty JA (eds)

Comprehensive Coordination Chemistry, vol. 6.

Oxford: Pergamon.

3372 IRON/Properties and Determination

Kaim W and Schwederski B (1994) Bioinorganic Chemis-

try: Inorganic Elements in the Chemistry of Life. Wiley:

Chichester.

Neilson SS (1998) Food Analysis, 2nd edn. Aspen: Gaithers-

berg.

Pare

JRJ and Be

langer JMR (1997) Instrumental Methods

in Food Analysis. Amsterdam: Elsevier.

Reilly C (1991) Metal Contamination of Food, 2nd edn.

London: Elsevier.

Sigel A and Sigel H (1998) Metal Ions in Biological Systems,

vol. 35. Iron Transport and Storage in Microorganisms,

Plants and Animals. New York: M Dekker.

Physiology

S R Lynch, Eastern Virginia Medical School, Norfolk,

Virginia, VA, USA

Introduction

0001 Iron plays a central role in metabolic processes in-

volving oxygen transport and storage as well as oxi-

dative metabolism and cellular growth. The fact that

it readily serves as an electron donor or acceptor

accounts both for its critical metabolic role and its

potential toxicity. Iron-containing compounds func-

tion as carriers for oxygen and electrons and as cata-

lysts for oxidation and hydroxylation reactions. Ionic

iron can also participate in reactions that produce

toxic free radicals. Free radicals may in turn damage

cellular constituents. It is therefore not surprising that

body iron content is controlled within narrow limits,

and that the metal itself is transported and stored as a

component of specific iron-binding proteins rather

than as the free cation.

0002 This article reviews the functional role of iron in

the body, the physiological processes responsible for

the control of internal exchange and balance, and the

consequences of iron deficiency and excess. Some

aspects of the physiology of iron that are specifically

related to iron-deficiency anemia are discussed later.

(See Anemia (Anaemia): Iron deficiency Anemia.)

Body Iron Distribution

0003 The normal human body contains 3–4 g of iron

(40–50 mg per kg of body weight; Table 1), 75%

(approximately 36 mg kg

1

) of which is present in

metabolically active compounds. The remainder is

contained in a storage pool (approximately 10 mg

1

in men and 5 mg kg

1

in menstruating women)

which is readily available if metabolically active iron

is depleted for any reason.

Functional Iron Compartment

Heme Proteins

0004Most of the functional iron in the body is present in

the form of heme proteins, i.e., proteins with an iron

protoporphyrin IX prosthetic group.

0005Hemoglobin, which is made up of four globin

chains, each with an attached heme group, transports

oxygen to the tissues. It is quantitatively the most

important heme protein and contains 80% of all

functional iron.

0006Myoglobin is found in the sarcoplasm of muscles.

It has a structure similar to hemoglobin but contains

only one globin chain attached to a single heme group

and accounts for a further 10% of functional iron.

Myoglobin acts as an oxygen store, insuring an

adequate oxygen supply during muscle contraction.

(See Exercise: Muscle.)

0007Despite its vital metabolic role, all other tissue iron

represents only a small fraction of total body iron.

The cytochromes are a group of heme-containing

electron transport enzymes that are essential for the

oxidative metabolism necessary to generate adeno-

sine triphosphate (ATP) as well as for the oxidative

degradation of drugs and endogenous substrates.

Catalase and peroxidase are involved in the reduction

of endogenously generated hydrogen peroxide.

Nonheme Tissue Iron

0008In mitochondria, nonheme compounds account for

more iron than do those containing heme. This

group of enzymes includes the metalloflavoproteins,

the iron sulfur proteins, and ribonucleotide reductase.

In addition, iron is necessary in a loosely bound form

for the activity of other enzymes, such as those re-

sponsible for the hydroxylation of proline and lysine

in protocollagen, during the synthesis of collagen.

(See Coenzymes.)

0009All functional iron compounds are constantly being

degraded and replaced by newly synthesized material.

tbl0001Table 1 Distribution of iron in adult human beings

Men: total

body content

Women

:total

bodycontent

mg mg kg

1

mg mg kg

1

Functional

Hemoglobin 2300 31 1700 28

Myoglobin 320 4 180 3

Heme enzymes 80 1 60 1

Nonheme enzymes 100 1 76 1

Storage

Ferritin 540 7 200 3

Hemosiderin 235 3 100 2

Age range 18–44 years.

IRON/Physiology 3373

Internal iron exchange therefore plays a crucial

role in preserving normal iron-dependent metabolic

processes.

Iron Transport and Storage

0010 Iron entering the plasma is rapidly bound to the

specific iron transport protein, transferrin. The

iron-free protein apotransferrin is a single-chain

glycoprotein (mol wt 79 570) with two nonidentical

iron-binding sites that have a high affinity for ferric

iron under physiological conditions (effective stabil-

ity constant, 10

mol l

1

). Plasma apotransferrin is

synthesized predominantly in the liver. It exists in the

plasma in the iron-free form or as monoferric or

diferric transferrin since iron loading at each binding

site is a random process.

0011 Iron delivery from plasma transferrin to the tissues

is mediated by a specific transferrin receptor which

is a transmembrane glycoprotein dimer composed

of two identical subunits (each with mol wt 94 000)

linked by a disulfide bond. Transferrin receptors are

expressed on the surfaces of all cells in proportion to

their iron requirements. Large numbers are present in

tissues with high requirements, e.g., developing red

blood cells and placenta.

0012 At the pH of plasma and extravascular fluid

bathing cell surfaces, receptors have very little affinity

for apotransferrin and the highest affinity for diferric

transferrin (2–710

9

mol l

1

). Once bound, the

transferrin–transferrin receptor complex, together

with its attached iron, is internalized by the cell in a

clathrin-coated pit that closes to form an endosome.

The endosome then fuses with an acidic vesicle

(pH < 5.5). The fall in pH results in release of iron

from the transferrin. The iron is transferred across the

endosomal membrane into the cell. Natural resistance-

associated macrophage protein 2 (Nramp 2, now also

called divalent metal transporter 1, DMT-1) has re-

cently been identified as the putative transmembrane

iron transport protein that transfers iron out of the

endosome. The rat isoform of Nramp 2 is a divalent

cation transporter (DCT-1) with a broad substrate

range that includes ferrous iron. The transferrin re-

ceptor remains intact. Its affinity for apotransferrin

increases, becoming equal to that for diferric trans-

ferrin, because of the lower pH. The complex is

transported back to the cell surface, where the apo-

transferrin is released back into the circulating

plasma.

0013 Any iron entering a cell that is not immediately

used for the synthesis of metabolically active com-

pounds is stored in the form of ferritin. Apoferritin

is a hollow, spherical protein shell composed of 24

subunits that may be of two types, differing slightly

in molecular weight – L (mol wt 19 700) and H

(mol wt 21 100). Each complete apoferritin molecule

can store as many as 4500 iron atoms within its

central core as ferric hydroxyphosphate. Iron enters

and leaves the intact protein through channels in the

shell.

0014Catabolism of cellular ferritin may result in the

formation of a second type of iron storage protein,

hemosiderin, which is water-insoluble. It has both

a higher iron content and a slower turnover than

ferritin.

0015The acquisition and storage of iron by cells is regu-

lated by the translational control of the synthesis of

transferrin receptors and of apoferritin. Two iron-

regulatory proteins (IRP-1 and IRP-2) that both

sense and adjust cellular iron supply have been iden-

tified. They are cytoplasmic RNA-binding proteins

that modulate the expression of messenger RNA

(mRNA) for transferrin receptor and apoferritin by

binding to iron-responsive elements (IREs) on the 3

and 5

untranslated regions of the mRNAs for trans-

ferrin receptors and the H- and L-chains of ferritin

respectively. Low cellular iron levels favor increased

binding of the IRPs to the IREs, repressing the syn-

thesis of ferritin, but stabilizing transferrin receptor

mRNA against cellular ribonucleases, thereby in-

creasing transferrin receptor expression and cellular

iron uptake. High cellular iron leads to decreased IRP

binding with a decrease in iron uptake and increased

ferritin synthesis and iron storage.

0016The two IRPs are functionally similar, but are regu-

lated in different ways. In iron-replete cells IRP-1 has

been identified as cytosolic aconitase, an iron-sulfur

protein that mediates the enzymatic interconversion

of citrate to isocitrate in the tricarbocylic acid cycle.

Low cellular iron results in reversible conversion of

enzymatically active aconitase to a form with high

RNA-binding affinity and no enzymatic activity.

Transferrin receptor synthesis is enhanced, apoferri-

tin formation is suppressed, and functional iron

homeostasis is restored. IRP-2 is functionally similar

to IRP-1, but lacks aconitase activity. Unlike IRP-1,

the binding of IRP-2 to the IREs is regulated by

degradation of the protein when cells are iron-replete.

0017The above description characterizes iron transport

and storage in most cells of the human body. How-

ever, erythroid cells have very high iron requirements

and appear to possess mechanisms for regulating iron

uptake at a transcriptional level that can override

posttranscriptional control. Iron transport and stor-

age by the macrophages of the spleen, bone marrow,

and liver are also different. These are cells primarily

involved in processing hemoglobin derived from

senescent red blood cells. At the end of their life

span, erythrocytes are phagocytosed by macrophages,

3374 IRON/Physiology

predominantly in the spleen. The heme is separated

from the globin and rapidly catabolized by the

enzyme, heme oxygenase. Iron is released and either

returned to the plasma within a few hours or incorp-

orated into the storage compartment of the cell with a

more gradual return to the plasma (half-life about 7

days). Normally, two-thirds of the iron is released

immediately, but this fraction may be either increased

when demands are high or reduced when less iron is

required.

Internal Iron Exchange

0018 The development of radioiron tracers made it possible

to quantify the processes involved in the internal iron

exchange described above. Since 80% of the body’s

functional iron is in the hemoglobin of the circulating

red blood cells, measurements of internal iron ex-

change are dominated by the requirements of this

compartment (Figure 1). Complete exchange of the

iron in the circulating red blood cell compartment

occurs every 4 months. This involves rapid transfer

of iron by plasma transferrin. Only 3–4 mg iron is

found in the plasma at any one time, but 35 mg is

transported through this compartment each day.

Most of it comes from hemoglobin catabolism in

macrophages. Two-thirds (24 mg day

1

) is delivered

to erythroid precursors in the bone marrow for the

synthesis of new hemoglobin. While there is some

iron loss owing to ineffective red cell production or

the removal of iron not used for hemoglobin synthesis

from red cell precursors, most of the iron (70%) is

returned to the circulation as hemoglobin in erythro-

cytes. Erythrocytes have a life span of about 120 days.

The senescent cells are catabolized in the macro-

phages of the liver, spleen, and bone marrow, com-

pleting the cycle.

0019Most of the iron lost during red cell production and

the iron derived from senescent red cells is processed

by macrophages. Thus a quantity of iron equivalent

to about 1% of the functional hemoglobin iron in the

circulating red cell compartment (22 mg iron) enters

the macrophages each day with a corresponding

quantity being released to the plasma.

0020A smaller but quantitatively significant daily ex-

change occurs between the plasma iron and storage

iron in hepatocytes. The rate of exchange and direc-

tion of net flow is dependent on serum iron concen-

tration and transferrin saturation. A high serum iron

concentration favors the accumulation of iron in the

liver.

0021Finally, a minor fraction of the daily iron turnover

(about 3 mg day

1

) is transferred between the plasma

and the extravascular transferrin compartment and

approximately two-thirds of this (2 mg day

1

) ex-

changes with the tissues, supplying iron to heme and

nonheme iron-dependent enzymes.

Iron Absorption and Excretion

0022The total body iron content of healthy human beings

is held within narrow limits. This is primarily a con-

sequence of the fact that most of the iron is located

in tightly regulated functional compartments. Iron

stores usually account for only 15–30% of total

body iron. The size of the storage compartment may

vary 25-fold without any apparent physiological

impairment.

Red blood cell

hemoglobin

Bone

marrow

Macrophage

Iron

store

Iron

store

Plasma

Transferrin

Tissues

Myoglobin

Liver

(hepatocytes)

Gastrointestinal

tract

Absorption

Uterus

Gastrointestinal

tract

Skin, sweat

Kidney, urine

Iron loss

fig0001 Figure 1 Body iron exchange.

IRON/Physiology 3375

Iron Loss

0023 In contrast to the dynamic transfer of iron between

body compartments, exchange with the external en-

vironment is minimal. No adjustable excretory mech-

anism exists, but a small obligatory loss occurs with

the physiological turnover of skin epithelium and

the cells of the gastrointestinal and urinary tracts

(Figure 1). Low concentrations of iron are also pre-

sent in sweat, bile, and urine. In addition, the feces

contain small quantities of blood. Finally, menstru-

ation accounts for a significant proportion of the iron

lost by women of child-bearing age.

0024 In normal men the loss of iron from the body is

about 1 mg day

1

. This is balanced by an equivalent

absorption. Complete iron exchange with the envir-

onment in a normal man would therefore be expected

to take about 10 years. In women menstrual losses

account for an extra 0.5 mg day

1

. The higher iron

loss is matched by a higher rate of absorption.

Iron Absorption

0025 Typical western diets contain approximately 1.5 mg

iron MJ

1

. From the point of view of absorption,

food iron may be considered to exist in one of three

forms. Ten percent or less is present as heme derived

chiefly from hemoglobin and myoglobin in meat.

Heme iron is readily absorbed and little affected by

dietary factors. This small fraction may supply a third

of the iron requirements of individuals eating a mixed

meat-containing diet. The remainder of the iron

(90% or more in western diets and often virtually

100% in the diets of developing countries) must be

solubilized for absorption. If solubilized, nonheme

iron derived from all dietary sources enters a common

pool in the lumen of the upper small intestine before

absorption. A variable proportion of nonheme iron is

insoluble and unavailable for absorption. This iron

is generally regarded as contaminant iron. Much of it

enters food products during storage or processing,

particularly in developing countries. (See Meat:

Nutritional Value.)

0026 Absorption of soluble nonheme iron from the

common pool is quite variable. It is governed both

by the body’s requirement and the balance between

enhancing and inhibiting ligands in the diet that either

promote uptake by mucosal cells (increase bioavail-

ability) or render the iron in the pool unavailable for

absorption. Enhancing factors include ascorbic acid,

other organic acids, and meat and fish tissue. Low

gastric luminal pH resulting from hydrochloric acid

secretion by the stomach or from the ingestion of

acidic foods also promotes nonheme iron absorption.

The most powerful inhibitors are found in vegetable

foods and include phytates, polyphenols, and vege-

table proteins. (See Bioavailability of Nutrients.)

0027Absorption of both heme and nonheme iron is

maximal in the duodenum, partly because the luminal

conditions (particularly lower pH) favor solubiliza-

tion and absorption of nonheme iron, but also be-

cause cells in his region show the greatest ability to

respond to changes in body iron needs.

0028Absorption may be considered to occur in three

phases: first, uptake across the mucosal cell brush

border; second, a phase that involves either rapid

transfer of iron through the mucosal cells or its reten-

tion in the cellular ferritin store; and third, transfer

from the mucosal cell to plasma transferrin. Most of

the iron retained in the cell is lost when the cell exfoli-

ates. The absorption of both heme and nonheme iron

is regulated by the size of the body iron stores.

0029Heme iron enters the mucosal cell through a path-

way different from that for nonheme iron. It is taken

up as the intact heme moiety. Once within the cell,

iron is released from heme by the enzyme, heme

oxygenase. It joins an absorption pathway common

to both heme and nonheme iron.

0030Percentage absorption from the small heme pool

varies about twofold. The primary adaptation to

changes in iron requirements occurs in the adjustment

of absorption from the larger nonheme pool. Percent-

age absorption is inversely correlated with the size of

the body iron stores and may vary as much as 20-fold.

Regulation occurs both during mucosal iron uptake

by the enterocyte and during release of iron from the

cell to circulating transferrin. Mucosal uptake is the

rate-limiting step.

0031Despite years of research, the precise molecular

mechanisms involved in the uptake of elemental iron

into mucosal cells and its transfer to the plasma

remain a subject of controversy. However, it was

recently discovered that two isoforms of Nramp 2

(DMT-1) are expressed at the brush borders of the

apical poles of enterocytes in the duodenum, the site

of maximal iron absorption. Dietary iron starvation

leads to a marked upregulation of Nramp 2 isoform

1 in proximal duodenal enterocytes. Cells in the rest

of the small intestine are not affected. Nramp 2

mRNA has an IRE in its 3

untranslated region.

0032It has been postulated that the iron status of duo-

denal enterocytes is determined by their iron uptake

from the circulation during development in the duo-

denal crypts. They only become functional iron-

absorbing cells 48 h later when they reach the

duodenal villous tips. According to the theory the

cells are programmed to regulate iron absorption

during this period of time by an IRP–IRE mechanism.

In the face of iron deficiency, enterocytes acquire less

iron from the plasma during their early development.

3376 IRON/Physiology

DMT-1 is upregulated and apoferritin synthesis

limited. The cells absorb and transfer dietary iron

through the basolateral membrane to circulating

plasma transferrin efficiently. If the individual is

iron-sufficient, the enterocytes acquire more iron

during early development. They will express less

DMT-1, take up less iron from the duodenal lumen,

and store some of the absorbed iron intracellularly as

ferritin. Very little of the iron stored as ferritin reen-

ters the absorptive pathway at a later stage. Most of it

is lost when the cell exfoliates.

Iron Deficiency

0033 In western countries iron deficiency occurs most often

when there is a relatively sudden increase in iron

requirements or iron losses, e.g., during pregnancy

or in association with pathological blood loss.

0034 The physiological importance of both the storage

iron compartment and the capacity for the rapid trans-

fer of iron through the plasma in preventing overt

functional iron deficiency is illustrated by the effect

of blood loss. In response to significant anemia caused

by bleeding, individuals with an iron store of 1000 mg

can mobilize 40 mg day

1

, allowing rapid restoration

of the functional deficit. On the other hand, an indi-

vidual who lacks storage iron and depends on absorp-

tion from an average diet for the additional iron will

increase delivery to the bone marrow by only 2–

4 mg day

1

. Red cell production increases by a small

margin. Thus, loss of iron from the major functional

compartments is rapidly corrected when stores are

adequate, but very slowly replaced by absorption,

even when dietary iron bioavailability is relatively

high. If meal iron bioavailability is low, positive bal-

ance may not be achieved, leading to chronic iron-

deficiency anemia. Low bioavailability diets also

lead to iron deficiency when requirements are in-

creased by rapid growth or menstruation.

0035 Negative iron balance leads to a reduction in the

iron content of all functional compartments. Anemia

caused by reduced hemoglobin synthesis is the most

easily documented. Nevertheless, the availability of

iron to support metabolic systems in the tissues is

reduced concurrently. The physiological conse-

quences of iron deficiency therefore result both from

impaired oxygen delivery and functional abnormal-

ities in the tissues. However it is noteworthy that

clinically significant tissue iron deficiency does not

appear to occur in the absence of anemia.

Effects of Iron Deficiency

0036 The clinical manifestations of moderate to severe

anemia are well known and include pallor, fatigue,

weakness, dizziness, and reduced maximal work cap-

acity. The consequences of anemia per se and the

adverse effects of iron-deficiency anemia on the out-

come of pregnancy are dealt with in the section on

iron-deficiency anemia. (See Anemia (Anaemia):

Iron-deficiency Anemia.)

0037Several additional consequences are thought to

result primarily from the associated tissue iron defi-

ciency. From the epidemiological point of view, the

most important are developmental delay and cogni-

tive impairment in childhood and impaired work

performance at all ages.

Mental and Motor Development

0038Iron-deficiency anemia is associated with impaired

mental development and physical coordination in

children under the age of 2 years, difficulty with

visual discrimination tests, and the ability to maintain

selective attention in preschool children and poor

school achievement in later childhood. Short-term

memory and emotional health may also be affected.

These functional abnormalities are thought to be the

result of the effects of iron deficiency on brain neuro-

transmitters, but their biochemical basis is poorly

understood. In older children they appear to be re-

versible by successful iron supplementation.

Skeletal Muscle Dysfunction

0039Significant limitation of the ability to perform endur-

ance physical activity has emerged as an important

consequence of chronic iron deficiency. Animal stud-

ies conducted by Finch and coworkers demonstrated

that iron-deficient rats show marked impairment of

running ability which is unrelated to hemoglobin

level. It results from impaired oxidative metabolism

in iron-depleted muscles. Field studies from many

developing countries suggest that a similar disability

reduces an iron-deficient individual’s ability to carry

out prolonged physical work.

Immunity and Infection

0040Several laboratory tests of immune function are

abnormal in patients with iron-deficiency anemia.

Lymphocyte proliferation in response to the mito-

gens, phytohemagglutinin, and concanavalin A is

reduced, demonstrating defective T-cell immunity.

Intracellular bacterial killing by polymorphonuclear

leukocytes is impaired. The clinical importance of

these laboratory observations is uncertain, although

some studies have suggested that the administration

of iron to iron-deficient children may reduce the

prevalence of enteritis and influenza-like illnesses.

Iron deficiency also appears to be a predisposing

factor in chronic mucocutaneous candidiasis.

IRON/Physiology 3377

Miscellaneous Liabilities

0041 Angular stomatitis, glossitis, postcricoid webbing

of the esophagus associated with painful dysphagia

(Patterson–Kelly or Plummer–Vinson syndrome),

atrophic gastritis, and koilonychia (spoon-shaped

finger nails) have all been attributed to tissue iron

deficiency. These clinical findings appear to be less

common in recent years and a marked geographic

variation in prevalence has frequently been noted,

suggesting that factors other than iron deficiency

may play an important role.

0042 An intriguing sensory disturbance encountered in

both children and adults who are iron-deficient is the

perversion of taste leading to the consumption of

nonfood items (pica) or compulsive ice eating (pago-

phagia). The specificity of pagophagia as a symptom

of iron deficiency has been confirmed by the study of

patients in whom iron deficiency was induced by

phlebotomy alone, making the contribution of con-

founding nutritional and social factors unlikely. It is

corrected by iron repletion.

0043 Iron deficiency may also lead to impaired thermo-

genesis as well as abnormalities in thyroid metab-

olism and catecholamine turnover. Finally, lead

absorption may be enhanced, increasing the risk of

lead toxicity, particularly in children.

Iron Toxicity

Acute Iron Toxicity

0044 The ingestion of large quantities of elemental iron can

cause acute iron poisoning. This occurs most often in

young children who may eat iron tablets as ‘candy.’

The pathological consequences include a severe nec-

rotizing gastroenteritis as well as disseminated intra-

vascular coagulation, liver and cardiac injury. Death

may ensue if the dose is large or treatment is not

instituted immediately.

Chronic Iron Toxicity

0045 More important from the nutritional point of view is

the gradual accumulation that occurs when the quan-

tity of iron entering the body exceeds requirements by

even a small margin. The body has no means of

increasing iron excretion significantly, making a posi-

tive iron balance inevitable if regulation of absorption

is impaired, or if the diet contains a quantity of avail-

able iron that overwhelms the absorptive control

mechanisms. Excess iron can also be introduced

through the parenteral route (blood transfusion, par-

enteral iron administration).

0046 Impaired regulation of absorption Hereditary he-

mochromatosis is the commonest cause of iron

overload resulting from the impaired regulation of

iron absorption, and the commonest form of iron

overload in the USA, western Europe, and Australia.

It is an autosomal recessive disorder with a gene

frequency reported to be as high as 1 in 10 in people

of northern European descent. One in 300 are homo-

zygous and at risk for developing severe iron overload

with its associated pathological consequences. A

single G-to-A mutation resulting in a cysteine-

to-tyrosine substitution (C282Y) in the HFE gene

has recently been shown to be responsible for the

majority of cases of human leukocyte antigen

(HLA)-linked hereditary hemochromatosis. The HFE

gene is located on the short arm of chromosome 6 and

is tightly linked to the HLA locus. It has been identi-

fied in between 60% and 100% of patients depending

on whether their ethnic origin was southern or north-

ern Europe. A second mutation, H63D, has been

linked to an additional 1–10% of cases, especially

when present with C282Y in the compound hetero-

zygous form. The mechanisms by which mutations in

the HFE gene lead to tissue iron overload have not yet

been established.

0047HFE-associated hemochromatosis is characterized

by a rate of iron absorption that is inappropriately

high for the size of body iron stores. Downregulation

of nonheme iron absorption in the face of rising stor-

age iron is impaired and heme iron absorption

virtually unregulated. Equally important to the

pathogenesis of the condition is the presence of an

abnormally high serum iron and transferrin satur-

ation associated with disordered iron distribution

within the body, favoring iron accumulation in the

parenchymal cells of organs such as the liver, heart,

and pancreas. Comparatively less iron is located in

the normal macrophage iron store.

0048Although the defective control of absorption is an

inborn error of metabolism manifest from birth, the

prevalence of the clinical syndrome is highest in men

over the age of 40 years. Excess iron is accumulated

slowly because maximal absorption from the average

western diet is only 3–5 mg day

1

. Once the total

body iron load has increased to 15 g or more (a pro-

cess which takes 15–20 years), organ damage be-

comes evident.

0049The exact mechanism by which the iron injures

tissues has not been established, but lipid peroxida-

tion in membranes and subcellular organelles, as well

as iron-induced lysosomal disruption, are probably

involved. The clinical consequences include increased

skin pigmentation, cirrhosis of the liver associated

with an increased risk of developing liver cancer,

congestive cardiac failure and cardiac arrhythmias,

diabetes mellitus, and hypogonadism owing both to

end organ and pituitary dysfunction. In addition,

3378 IRON/Physiology

patients with hemochromatosis often suffer from an

arthropathy characterized by chondrocalcinosis and

a predilection for involvement of the second and

third metacarpophalangeal joints of the hand.

0050 If HFE-associated hemochromatosis is identified

before significant iron overload has occurred, all of

the clinical findings may be averted by iron removal.

Therapeutic phlebotomy is usually employed. Un-

checked progressive iron overload is associated with

severe irreversible morbidity and a significantly

shortened life span.

0051 Excessive iron absorption from a normal diet may

also occur in association with certain iron-loading

anemias, chronic liver disease, and porphyria cutanea

tarda.

0052 Dietary iron overload is a form of chronic iron

toxicity unique to the indigenous population of sev-

eral countries in southern Africa (subSaharan iron

overload). Traditional acidic fermented beverages

brewed in containers made from iron become

contaminated with iron at concentrations of 15–

40 mg l

1

. The beer has a low alcohol content and

the large volumes consumed may supply 50–100 mg

of available dietary iron per day. Total body iron

burdens comparable to those encountered in heredi-

tary hemochromatosis are encountered. Organ

damage with progression to cirrhosis and the devel-

opment of diabetes mellitus occur. However in the

earlier stages cellular iron distribution tends to be

different from that seen in HFE-associated hereditary

hemochromatosis with greater accumulation in the

macrophages of the spleen, liver, bone marrow, and

muscle. Two other clinical conditions are commonly

associated with the presence of excess iron – ascorbic

acid deficiency and osteoporosis. Ascorbic acid defi-

ciency results from accelerated catabolism in patients

with severe iron overload, often in association with a

low dietary intake. The factors responsible for the

osteoporosis remain poorly understood.

0053 SubSaharan dietary iron overload was originally

believed to be solely a consequence of excessive iron

consumption. Recent investigations have challenged

this belief. Family studies suggest that iron loading

occurs only when iron intake is excessive and a puta-

tive non-HLA-linked iron-loading gene is present.

See also: Anemia (Anaemia): Iron-deficiency Anemia;

Bioavailability of Nutrients; Coenzymes; Exercise:

Muscle; Immunology of Food; Meat: Nutritional Value