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

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given adequate supplies of iodine. Another explan-

ation for the hyperthyroidism is that thyroid nodules

of iodine deficiency become autonomous of normal

control and produce excess thyroid hormone when

iodine becomes available. High levels of iodine

appear to interfere with the synthesis of thyroid

hormones. This is referred to as the Wolff–Chaikoff

effect. The block is usually temporary, but it persists

in some subjects and leads to development of goiters.

0019 Individuals who are sensitive to iodine may react

to even small quantities of this element with fever,

salivary gland enlargement, ioderma, visual prob-

lems, and/or other symptoms. Ioderma (dermatoses)

resulting from iodine sensitivity vary from acne-type

eruptions, rashes and urticaria, to eruptions described

as bullous vesicular, purpuric hemorrhagic, pustular,

or tuberous fungating. Deaths from these more severe

forms of ioderma have been reported. Acute re-

sponses to the ingestion or injection of large doses of

an iodine-containing solution have included cardio-

vascular collapse, convulsions, asthma attacks, and

death.

Assessment of Iodine Status

0020 Assessment of iodine status for an individual may be

done by a physician checking for the presence of

goiter, by measuring serum T

and TSH, by measur-

ing urinary iodine, and by checking for other signs

and symptoms of iodine deficiency or excess (e.g.,

level of fatigue, blood pressure, heart rate). Urinary

iodine alone is not sufficient for determining the

iodine status of an individual because it is a ‘short-

term’ measure of iodine status reflecting the previous

day’s iodine intake, which may not be consistent with

long-term measures of iodine intake. Individuals

should also be asked about their usual diet, use of

iodized salt, and use of dietary supplements that

might contain iodine. Dietary assessment may be

inaccurate due to the difficulty of obtaining precise

information about iodine used as indirect or direct

food additives (e.g., in milk, salt, bread) and in

supplements.

0021 Assessment of the iodine status of population

groups requires methods that are both rapid and in-

expensive. The methods used include the rate of palp-

able and/or visible goiter, urinary iodine excretion,

and blood T

and TSH. In countries where assessment

of iodine status is especially important for public

iodine supplementation programs, iodine status may

be measured by assessing the level of TSH in neonatal

blood. Even though urinary iodine is a short-term

measure of iodine status, it gives a useful indication

of the distribution of iodine intakes for a population.

Urinary iodine levels of <20 mgl

1

are considered to

reflect severe deficiency, 20–49 mgl

1

are moderate

deficiency, and 50–99 mgl

1

are mild deficiency.

Urinary iodine levels between 100 and 200 mgl

1

are considered satisfactory.

See also: Children: Nutritional Requirements;

Goitrogens and Antithyroid Compounds; Hormones:

Thyroid Hormones; Infants: Nutritional Requirements;

Iodine: Iodine-deficiency Disorders

Further Reading

Bogden JD and Klevay LM (2000) Clinical Nutrition of the

Essential Trace Elements and Minerals. Totowa, NJ:

Humana Press.

Hetzel BS (1989) The Story of Iodine Deficiency: An

International Challenge in Nutrition. Oxford: Oxford

University Press.

Hetzel BS and Clugston GA (1999) Iodine. In: Shils ME,

Olson JA, Shike M and Ross AC (eds) Modern Nutrition

in Health and Disease, 9th edn. Baltimore, MD: Wil-

liams & Wilkins.

Pennington JAT (1988) Iodine. In: Smith K (ed.) Trace

Minerals in Foods. New York: Marcel Dekker.

Pennington JAT (1990) A review of iodine toxicity reports.

Journal of the American Dietetic Association 90: 1571–

1581.

Iodine-deficiency Disorders

E N Pearce and S L Lee, Boston Medical Center,

Boston, MA, USA

Introduction

0001Iodine is a chemical element found in trace amounts in

the human body (15–20 mg). Iodine is stored almost

entirely within the thyroid gland. The amount of

iodine found in extrathyroidal tissues is minute and,

therefore, it is considered a ‘trace element’ or a ‘micro-

nutrient.’ The only function for iodine in human

physiology is in the synthesis of thyroid hormones.

Severe iodine deficiency will result in impairment of

thyroid hormone synthesis that is necessary for

normal childhood growth and adult metabolic func-

tion. Population effects of severe iodine deficiency

include endemic goiter (enlarged thyroid gland),

cretinism, decreased fertility rate, increased infant

mortality, and mental retardation. The term iodine

deficiency disorders (IDD) refers to the full clinical

spectrum of disease caused by iodine deficiency.

3360 IODINE/Iodine-deficiency Disorders

Iodine Deficiency

0002 Worldwide, there are large geographic areas with soil

deficient in iodine. Human iodine intake is derived

approximately 90% from food and 10% from water.

The iodine content of foods and water generally

reflects the iodine content of the local soil in which

the food is grown. Current calculations by the Inter-

national Council for Control of Iodine Deficiency

Disorders (ICCIDD) have suggested that 29% of the

world’s population, or approximately 1.6 billion

people, live in areas of iodine deficiency and are at

risk for IDD. Those people at highest risk for IDD are

located primarily in mountainous regions such as the

Himalayas, the European Alps, the Andes, and

the mountains of China. Iodine in the soil at these

locations has been washed away by millions of

years of glaciation and flooding. Iodine deficiency

also occurs in lowland regions which are far from

the oceans, such as central Africa and eastern Europe.

Human iodine intake is obtained only through the

diet. Crops grown in iodine-deficient areas will have

decreased iodine concentrations. Animals in these

areas will also be deficient, which may lead to

decreased yields of meat, milk, and wool. In all

these areas, those who consume only locally pro-

duced foods are at risk for IDD.

0003 The dietary iodine requirement for normal thyroid

physiology in adults is 100–150 mgday

1

. Two simi-

lar sets of recent recommendations from the US Na-

tional Academy of Sciences, UNICEF (United

Nations Childrens Fund), ICCIDD, and the World

Health Organization (WHO) for different popula-

tions are shown in Tables 1 and 2.

0004 In areas where iodine is not added to food products

meant for humans or domesticated animals the pri-

mary sources of dietary iodine are saltwater fish and

seaweed, because of the high iodine concentration in

the oceans. Trace amounts are also found in grains

and vegetables.

0005 In countries such as the USA and the UK, iodine

deficiency has been eliminated by means of ‘silent

prophylaxis.’ Iodine has been voluntarily sup-

plemented in table salt (* 70 g kg

1

). After initial

success in the 1920s to 1960s, areas that became

iodine-sufficient after voluntary dietary supplementa-

tion have had a measurable decrease in iodine intake.

Data collected for the first US National Health and

Nutrition Examination Survey (NHANES I), con-

ducted from 1971 to 1974, showed that the average

urinary iodine concentration was 293.3 mgg

1

creati-

nine, reflecting adequate dietary iodine intake. By

the time of NHANES III in 1988–94, however, the

average urinary iodine had fallen to 124.6 mgg

1

creatinine. In particular, between the two surveys,

the risk for insufficient dietary iodine intake of

women of child-bearing age (15–44 years) increased

3.8 times.

0006It is not clear why iodine intake has fallen again in

these areas but the etiology is likely multifactorial.

This decrease in dietary iodine may be a result of

reduced intake of eggs and salt, decreased iodate

conditioners in bread, decreased use of iodized salt

in manufactured foods, and poor education about

the use of iodized salt. Currently in the USA only

50% of the salt sold in supermarkets is iodized. Non-

iodized salt contains little or no iodine. Another

major source of dietary iodine in industrialized coun-

tries is egg yolks, because of iodine supplementation

of chicken feed. Dairy products and meats have vari-

able amounts of iodine, as some dairy cows and cattle

are fed extremely high levels of iodine in supplements

to maintain fertility and prevent hoof root. Levels of

iodine in cows’ milk reflect the animal’s iodine

oral intake. It has been often erroneously concluded

that iodine in milk is from the iodophors used in

the dairy industry to cleanse cows’ teats. Small pub-

lished studies suggest that, when properly used and

rinsed off the cows’ teats, very little iodine is trans-

ferred from iodophors into milk. Starting in the

1940s, iodate had been used as a bread stabilizer by

tbl0001 Table 1 WHO/UNICEF/ICCIDD recommended daily iodine

intake

Population Recommended daily intake

(m/day)

Children

0–59 mo 90

6–12 yr 120

Adults > 13 yr 150

Pregnant and lactating women 200

WHO/UNICEF/ICCIDD (2001).

tbl0002Table 2 US National Academy of Sciences recommended daily

iodine intake

Population Recommended daily allowance (RDA)

(m/day)

Infants

0–6 mo 110 AI

7–12 mo 130 AI

1–8 yr 90

9–13 yr 120

Children 6–12 yr 120

Adults > 13 yr 150

Pregnant women 220

Lactating women 290

US National Academy Sciences Food and Nutrition Board and Institute of

Medicine (2002).

RDA not established for infants. These are values are adequate intake

(AI) for infants based on the minimal iodine intake of infants exclusively

fed human milk.

IODINE/Iodine-deficiency Disorders 3361

the commercial baking industry; this practice was

abandoned in the USA in the 1960s but has re-

appeared in some breads in the US. One particular

type of red dye, erythrocine (US Food, Drug and

Cosmetic (FD&C) no.3), contains large amounts of

iodine. This dye was commonly used until the 1960s

in candy and breakfast cereals in the USA and is still

found in some medications. In most other countries,

iodination of salt, bread, or drinking water is man-

dated by law, and is performed under government

supervision.

Prevalence

0007 More than 13% of the world’s population has some

form of IDD. In 1990, at least 1.572 billion people

worldwide were at risk for IDD. These included

710 million people in Asia, 60 million in Latin Amer-

ica, 227 million in Africa, and 20–30 million in

Europe. Of these, 655 million were known to have

goiter, and 11.2 million had cretinism. IDD is known

to affect 50 million children: 100 000 cretins are born

each year. The ICCIDD maintains a database of

iodine nutrition in different countries (CIDDS data-

base) available at the website: http://www.med.virgi-

nia.edu/*jtd/iccidd.

Pathophysiology of IDD

0008 Dietary iodine is readily taken up through the gut in

the form of iodide. From the circulation, it is concen-

trated in the thyroid gland by means of an energy-

dependent sodium-iodate symporter. In the follicle

cells of the thyroid gland, four atoms of iodine are

incorporated into each molecule of l-thyroxine (l-T

)

and three atoms into each molecule of triiodothyro-

nine (T

). These hormones are essential for neuronal

development, sexual development, and growth, as

well as for regulating metabolic rate, body heat, and

energy.

0009 When dietary iodine intake is inadequate, the

serum T

level initially falls, and a number of physio-

logical processes occur to restore adequate thyroid

hormone production. The pituitary gland detects

low T

levels and releases more thyroid-stimulating

hormone (TSH). TSH stimulates the growth, iodine

uptake, and metabolic activity of thyroid follicular

cells. TSH stimulates the thyroid to increase iodine

uptake, thyroid hormone synthesis, and thyroid hor-

mone secretion into the circulation. Increased TSH

and the reduction of iodine stores within the thyroid

result in an increased ratio of T

to T

production. T

is 20–100 times biologically more potent than T

and requires fewer atoms of iodine, so this tends to

conserve iodine stores and maintain normal thyroid

function. In addition, thyroid hormones are deiodi-

nated in the liver and the iodine is released

back into the circulation for reuptake and reuse

by the thyroid gland. Under these circumstances

of an efficient reutilization process, approximately

100–150 mg of iodine daily is passively lost in

the urine, with additional small losses from biliary

secretion into the gut, and must be replaced by

dietary intake.

0010Enlargement of the thyroid gland is a normal adap-

tive reaction to low iodine intake. Iodine deficiency

is the most frequent cause of endemic goiter, which is

defined as a goiter prevalence of > 10% in a popula-

tion. Thyroid gland volume measured by the sensitive

and accurate method of ultrasonography shows that

at any age the glands of an iodine-sufficient popula-

tion are smaller than an iodine-deficient population.

Iodine-deficiency goiter is initially diffuse with homo-

geneous hyperplasia. With time, the hyperplasia be-

comes nonuniform and interspersed by areas of

regression or degeneration and fibrosis, resulting in

nodular changes. Some nodules may become autono-

mous and secrete excess thyroid hormone regardless

of the TSH level. Autonomous thyroid nodules in

areas of iodine deficiency frequently contain TSH

receptor-activating mutations that keep the TSH re-

ceptor in the activated or ‘on’ state, regardless of

TSH ligand binding. With time (years to decades),

growth and accumulation of the autonomous nodules

may result in mild thyrotoxicosis. When a goiter

is associated with hyperthyroidism, it is called a

toxic multinodular goiter. In addition, autonomous

nodules in goiters of euthyroid patients subsequently

exposed to normal or high iodine levels may also lead

to thyrotoxicosis. Depending on the exposure time

and severity of the iodine deficiency, goiters may

enlarge sufficiently to cause tracheal and esophageal

narrowing and obstruction. Generally, treatment

with iodine supplementation or T

therapy will not

decrease the size of large nodular goiters in adults but

will shrink small diffuse goiters of young children

with iodine deficiency.

0011If iodine deficiency is extremely severe, thyroid hor-

mone production will fall, and patients will become

hypothyroid. Adults will have the usual signs and

symptoms of hypothyroidism with goiter. Hypothy-

roidism in the fetus, neonates, and in young children

prevents central nervous system maturation, espe-

cially neuronal myelination, leading to permanent

mental retardation. In the most severe form, the con-

stellation of mental retardation and growth abnor-

malities is called cretinism.

0012The severity of iodine deficiency in a population

can be estimated by several measurements that can be

obtained in the field, as shown in Table 3.

3362 IODINE/Iodine-deficiency Disorders

0013 Dietary iodine intake is not the sole determinant

of goiter development. Even in areas of severe iodine

deficiency, there can be substantial variations in

the incidence of goiter. One reason for this is the

presence of goitrogens in the diet. The clinical dis-

orders of iodine deficiency are magnified in the pres-

ence of dietary goitrogens. Goitrogens are substances

that decrease the bioavailability of iodine or interfere

within the thyroid hormone biosynthethic pathway.

The presence of these substances was first established

through animal experiments in the 1920s. Thiocya-

nates inhibit the thyroid gland’s iodine-concentrating

mechanism. Vegetables of the genus Brassica, which

include cabbage, Brussels sprouts, broccoli, cauli-

flower, turnips, rape and rapeseed, and horseradish,

all contain thioglucosides which are converted to

thiocyanate after ingestion. Foods that contain cy-

anogenic glucosides release cyanide when digested;

this is detoxified in the body to become thiocyanate.

These goitrogenic foods include many major dietary

staples of the developing world, such as cassava,

maize, sweet potatoes, pearl millet, and lima beans.

Finally, flavonoids (polyphenols), organic com-

pounds found in many food plants, including millet

species, also have antithyroid activity that inhibit

thyroid hormone synthesis. Additionally, the clinical

disorders of iodine deficiency tend to be more pro-

found in geographic areas with coexisting selenium

and vitamin A deficiencies, or protein-calorie malnu-

trition. Generally, the foods listed here by themselves

do not contain sufficient goitrogens to be clinically

important for thyroid physiology until the intake

constitutes a major portion of the diet or is combined

with iodine or other dietary deficiencies.

Clinical Manifestations

0014 Affected patients come from geographic regions where

IDD is endemic. The first sign of iodine deficiency is

diffuse thyroid enlargement, which becomes nodular

or multinodular with time. If a goiter is large enough,

individuals may complain of compressive symptoms

such as hoarseness, shortness of breath, or dysphagia.

Goiters can be assessed by palpation and can be graded

from 0 to 2, as shown in Table 4.

0015Thyroid size, determined by ultrasound, has re-

cently been shown to reflect the iodine sufficiency of

a population. Unlike size estimates determined by

palpation alone, ultrasound measurements are repro-

ducibly accurate to within 10%. When goiter appears

in > 5% of a regional population, iodine deficiency

should be considered (Table 3).

0016Iodine requirements increase during pregnancy, in

part because of fetal requirements but also because

of the mother’s increase in total body volume. This

increased iodine requirement will increase maternal

goiter size in areas of mild, moderate, or severe iodine

deficiency. Even in areas of borderline iodine intake,

up to 10% of women may develop goiter during

pregnancy. This pregnancy-related increase in thyroid

volume has been carefully documented by ultrasound

scans and may not be fully reversible after pregnancy,

so goiter may increase in size in the mother after each

pregnancy.

0017Patients with hypothyroidism due to severe iodine

deficiency may experience fatigue, weight gain, cold

intolerance, dry skin, constipation, or depression.

Signs on physical exam may include dry skin, perior-

bital edema, and delayed relaxation phase of the deep

tendon reflexes. Neonates and young infants are

much more severely affected by iodine deficiency

than are adults, and are more likely to become overtly

hypothyroid.

0018Children are profoundly affected by iodine defi-

ciency. In addition to the risk of goiter formation,

neurological development and linear growth are

critically dependent on prenatal and postnatal

iodine intake and thyroid hormone sufficiency.

Significant neuronal maturation and myelination

tbl0003 Table 3 Measures of iodine deficiency disorder severity in populations

None Mild Moderate Severe

Urinary iodine,

median (mgdl

1

)

> 100 50–99 20–49 < 20

Goiter prevalence < 5% 5–20% 20–30% > 30%

Neonatal thyroid-stimulating

hormone > 5 mlU ml

1

whole blood

< 3% 3–20% 20–40% > 40%

Cretinism 0 0 þ þþþ

Adapted from WHO-UNICEF-ICCIDD (1993).

tbl0004Table 4 Clinical grades of thyroid enlargement

Grade 0 No visible or palpable goiter

Grade 1 Enlarged thyroid that is palpable but not visible

when the neck is in the neutral position

Grade 2 Enlarged thyroid swelling that is

palpable and visible when the neck is in a

neutral position

Reproduced from Delange FM and Utiger RD (eds) (2000) In: Werner &

Inbgar’s The Thyroid, 8th edn. Philadelphia: Williams & Wilkins, with

permission.

IODINE/Iodine-deficiency Disorders 3363

occur postnatally. Cretinism is the most extreme

manifestation of IDD. It is rare, but is still seen in

regions of severe iodine deficiency in southern and

eastern Europe, Asia, Africa, and Latin America.

Despite efforts by many international health organ-

izations, including the WHO, 100 000 cretins are

born each year. Cretinism can be divided into neuro-

logic and myxedematous subtypes, although these

subtypes have considerable clinical overlap, as

shown in Table 5. Neurologic cretinism is more

common and is thought to be caused by maternal

hypothyroidism secondary to iodine deficiency

during pregnancy (especially between gestational

weeks 12 and 30). Myxedematous cretinism is

found primarily in Nepal, western China, and Zaire.

It is considered a result of iodine deficiency and hypo-

thyroidism in the fetus during late pregnancy or in the

neonatal period. Both conditions can be prevented by

adequate maternal and childhood iodine intake.

0019 Although overt cretinism is rare, populations in

which severe iodine deficiency is prevalent are at

risk for lower IQ and mental retardation, sometimes

known as IDD developmental retardation. In fact,

iodine deficiency is the leading cause of preventable

mental retardation worldwide. This decrease in

mental acuity in afflicted communities, combined

with decreased agricultural yields of meat, milk, and

wool from iodine-deficient animals, can have a dev-

astating impact on local economies.

0020 Severely iodine-deficient women are more likely to

experience infertility, and pregnancy in this group is

more likely to result in miscarriage or congenital

anomalies. Children born to these women are more

likely to have low birth weights, and to suffer infant

mortality. Recent studies in the USA suggest that

infants born to mothers with untreated hypothyroid-

ism have a small reduction in intelligence as measured

by standardized tests.

0021 Finally, it is unclear whether iodine deficiency in-

creases the incidence of thyroid cancer. There are

clearer data that iodine intake affects the histiological

subtypes of thyroid cancers. In areas where iodine

deficiency is endemic there is a higher proportion of

more aggressive thyroid cancers (follicular and ana-

plastic thyroid carcinoma) and an increased thyroid

cancer mortality rate. Iodine prophylaxis has been

demonstrated to reduce the proportion of follicular

thyroid carcinomas and increase the proportion of the

less aggressive form of thyroid cancer, papillary

thyroid carcinoma.

Laboratory Data

0022The kidneys excrete approximately 90% of ingested

iodine. The best diagnostic test for IDD, therefore, is

a 24-h urine iodine collection. Based on this, IDD

can be classified as mild (3.5–5 mgldl

1

), moderate

(2.0–3.5 mgldl

1

), or severe (< 2.0 mgldl

1

). If a 24-h

urine collection is not practical, a random urine

iodine-to-creatinine ratio can be substituted. In this

case, 50–100 mglg

1

creatinine is consistent with mild

iodine deficiency, 20–49 mglg

1

creatinine with mod-

erate deficiency, and < 20 mglg

1

creatinine with

severe deficiency.

0023Population studies have shown that neonates with

IDD will have elevated TSH levels at birth but normal

levels when evaluated weeks later. The extent of their

transient hypothyroidism correlates with the severity

of the iodine deficiency (Table 2). Blood from the

umbilical cord or from a heelstick can be saved on

filter paper and sent to a laboratory for screening

within the first few days of life. Neonatal TSH screen-

ing is used widely in Europe, Japan, and North Amer-

ica. In areas of adequate iodine intake, about one in

4000 infants will be hypothyroid. In iodine-deficient

areas, by contrast, hypothyroidism may be present in

up to 10% of newborns. Early treatment of these

hypothyroid infants with exogenous thyroid hor-

mone can reduce the risk for developmental delays

and mental retardation. Unfortunately, neonatal TSH

screening is difficult and expensive and is not done in

much of the developing nonindustrialized world.

0024Thyroid function studies are usually within the

normal range in the presence of mild iodine insuffi-

ciency. In euthyroid patients with iodine deficiency,

however, serum TSH levels may be normal to in-

creased, T

levels normal or slightly elevated, and T

levels normal or decreased. Only in very extreme

iodine deficiency does hypothyroidism develop; in

this setting serum TSH will be elevated and both T

and T

decreased.

0025Twenty-four-hour radioactive iodine uptake is used

in developed countries to help distinguish between

different types of thyroid disease. Uptakes will

be substantially increased in the presence of IDD

due to increased TSH stimulation and reduction

in the nonisotopic iodine pool. Therefore, thyroid

uptake values in iodine-sufficient areas such as the

USA are significantly lower than in areas with iodine

deficiency such as western Europe.

0026Thyroid size as determined by ultrasound reflects the

iodine sufficiency of a population. When goiter appears

in > 5% of a regional population, iodine deficiency

tbl0005 Table 5 Neurologic and myxedematous cretinism

Neurologic

cretinism

Mental retardation, abnormal

gait, and deaf-mutism, but not goiter

or hypothroidism

Myxedematous

cretinism

Mental retardation, short stature,

goiter, and hypothyroidism

3364 IODINE/Iodine-deficiency Disorders

should be considered (Table 3). Ultrasound scans of a

goiter can be used to document size, volume, and

normal size of individual nodules within the gland.

Medical Treatment

0027 Prophylactic iodine replacement therapy will prevent

IDD, including goiter, hypothyroidism, and cretin-

ism, and is indicated for the entire population within

an area of iodine deficiency. Once IDD has been

established, long-term dietary iodine replacement

may decrease the size of small diffuse goiters of

short duration in infants, young children, and preg-

nant women. The supplementation of iodine will not

reverse cretinism or reduce the size of large nodular

endemic goiters.

0028 Otherwise, patients do not routinely require spe-

cific therapy unless goiter is large enough to cause

compressive or obstructive symptoms (for example,

tracheal obstruction, thoracic inlet occlusion, or

hoarseness). Radioactive iodine (I-131) has been

used, primarily in Europe, to decrease thyroid volume

of euthyroid goiters by up to 40–60%. Exogenous

(l-T

) can also be used to decrease goiter size, but is

generally not effective in adults and older children.

Supplemental l-T

, when added to T

and T

secre-

tion by the autonomous nodules in the endemic

goiter, may cause thyrotoxicosis. Long-term l-T

therapy that results in the suppression of TSH to

below-normal levels may have deleterious effects on

cardiac and bone health and, therefore, is no longer

routinely given to patients with goiter.

0029 Surgical treatment by thyroidectomy may be indi-

cated for compressive symptoms of a large goiter.

Prevention

0030 At a population level, IDD can be prevented by the

iodination of food products or the water supply.

Optimal supplements should provide physiologic

iodine levels, must be able to reach all of the affected

population, and must be affordable. Different

approaches have been required in different areas of

the world.

0031 Iodized salt was first instituted in the USA and

Switzerland in the 1920s. In practice, the iodination

of salt has proved to be the best method of iodine

supplementation. Everyone needs salt, it is consumed

at the same rate throughout the year, and there is little

variation in patterns of salt use with differences in

socioeconomic status. Salt can be used in animal feeds

as well as in table salt for human consumption. Add-

itionally, in most areas salt comes from a limited

number of production centers. The technology in-

volved in salt iodination is relatively straightforward.

The iodine does not affect the appearance or the taste

of the salt. Either iodide or iodate can be used; the

iodate is more stable in tropical climates. Salt iodin-

ation programs cost US$0.05 per person annually.

Iodine dose recommendations for each region are

based on the average salt intake of the local popula-

tion, local iodine requirements, and average losses of

iodine during salt transportation and storage. Despite

the relative simplicity of this approach, salt iodin-

ation can take years to reach the most severely

affected areas of an iodine-deficient region.

0032An alternative to salt iodination in some develop-

ing countries has been the periodic use of iodized

oil supplements. This is frequently used as an interim

measure while iodized salt programs are being

implemented, and is especially used for women of

child-bearing age and for children. The iodized oil

can be given as an intramuscular injection of 0.5 ml

(240 000 mg iodine) during the first year of life or

1.0 ml (480 000 mg iodine) thereafter. A single dose

is effective for 3–5 years. However, the injections

require individual contact with a skilled caregiver.

There is also a risk of disease transmission if sterile

syringes and needles are not readily available. There-

fore, oral iodized oil administration has been gaining

favor instead. One oral administration can be effect-

ive for up to a year, although it does not provide the

constant levels attained by injection. The usual oral

dose is 0.1–0.25 ml (about 380 000 mg iodine).

0033Iodized bread has been used with some success

in several countries, including the Netherlands,

Tasmania, Russia, and Australia. Iodination of other

substances such as tea and sugar has also been tried,

though these substances tend to be consumed in

variable quantities. An alternative approach is the

iodination of drinking water. Relatively constant

daily amounts of iodine can be added to either house-

hold or school water supplies. However, this is gener-

ally more expensive than large-scale iodized salt

programs and requires a significant amount of moni-

toring and oversight. In some remote areas of China,

where other approaches were not feasible, the iodin-

ation of irrigation and well water was highly effective

over several years. This intervention was shown to

decrease infant mortality by about 50%. This ap-

proach was extremely cost-effective, improving not

only human health but livestock production.

0034Education of government officials and of affected

populations is a critical component of any iodine

supplementation program. It is important for the

public to understand the importance of using iodized

salt, especially in countries such as the USA and the

UK, where iodination of salt is not mandated by law

(only 50% of salt sold in US supermarkets and 2.5%

of salt sold in the UK is iodized).

IODINE/Iodine-deficiency Disorders 3365

Complications of Iodine Treatment

0035 The primary complication of iodine prophylaxis for

IDD is the development of hyperthyroidism. This is

known as the Jod–Basedow phenomenon, or iodine-

induced hyperthyroidism (IIH). The presentation of

hyperthyroidism may be subtle. Typical symptoms

include anxiety, heat intolerance, palpitations, weight

loss, increased appetite, tremor, and menstrual dis-

turbances. IIH is caused by the hyperfunctioning

areas of autonomy that tend to develop in long-

standing iodine-deficient goiters. It tends to be ob-

served in patients over age 45 during the early phase

of IDD prevention programs. It has been seen in

almost all iodine supplementation programs world-

wide. Well-documented IIH epidemics occurred in the

USA from 1924 to 1928, in Tasmania in the 1960s,

and, more recently, in Zaire and Zimbabwe. The

outbreaks in Zaire and Zimbabwe were thought to

be due to iodine overload secondary to insufficient

monitoring of salt iodination programs. IIH occurs,

however, even with physiologic iodine supplementa-

tion levels (100–200 mg day

1

). IIH is usually benign

and easily treatable, but in rare cases severe cardio-

vascular complications can lead to fatalities. For this

reason, iodized oil administration is not recom-

mended for adults over age 45. In general, doses of

up to 1100 mg of iodine per day are considered safe

for adults.

Eliminating IDD: Worldwide Progress

0036 At the United Nations World Summit for Children in

1990, a plan was adopted for the elimination of IDD

by the year 2000. Although substantial progress has

been made toward this goal, it has not been achieved.

According to WHO data, the proportion of the world

population at risk for IDD dropped from 28.9% in

1994 to 13.7% in 1997. The proportion of the popu-

lation in developing countries regularly consuming

iodized salt increased from only 5% in 1990 to 60%

in 1994. Currently 68% of the 5 billion people

residing in countries with iodine deficiency have

access to iodized salt. Rates of goiter, cretinism, and

mental retardation are decreasing worldwide. How-

ever, programs must be continually monitored, and

must be sustainable.

See also: Hormones: Thyroid Hormones; Iodine:

Properties and Determination; Physiology

Further Reading

Delange FM (2000) Iodine deficiency. In: Braverman LE

and Utiger RD (eds) Werner & Ingbar’s The Thyroid,

8th edn, pp. 295–316. Philadelphia: Lippincott Williams

& Wilkins.

Delange F and Hetzel BS (2002) The iodine deficiency dis-

orders. Available at: http://www.thyroidmanager.org/

Chapter20. Endocrine Education Inc., Boston, MA.

Dunn JT (ed.) IDD Newsletter. International Council for

Control of Iodine Deficiency Diseases.

Dunn JT and Van der Har F (1990) A Practical Guide to the

Correction of Iodine Deficiency. The Netherlands:

ICCIDD.

Hetzel BS (1989) The Story of Iodine Deficiency: An Intel-

lectual Challenge in Nutrition. New York: Oxford Uni-

versity Press.

Hollowell JG, Staehling NW, Hannon WH et al. (1998)

Iodine nutrition in the United States: trends and

public health implications: iodine excretion data from

the National Health and Nutrition Surveys I and III

(1971–1974 and 1988–1994). Journal of Clinical Endo-

crinology and Metabolism 83: 3401–3408.

International Council for the Control of Iodine Deficiency

Disorders (ICCIDD) Database of iodine nutrition in

different countries (CIDDS database). Available online

at http://www.med.virginia.edu/

jtd/iccidd.

Lee K, Bradley R, Dwyer J and Lee SL (1999) Too much

versus too little: the implications of current iodine intake

in the United States. Nutrition Reviews 57(6): 177–181.

United States National Academy of Sciences (2002) Dietary

reference intakes for vitamin A, vitamin K, arsenic,

boron, chromium, copper, iodine, iron, manganese,

molybdenum, nickel, silicon, vanadium, and zinc. Chap-

ter 8, pp. 258–289.Washington, DC: A joint Food and

Nutrition Board and Institute of Medicine publication.

WHO Nutrtion Unit (1994) Indicators for assessing iodine

deficiency disorders and their control through salt iod-

ization. Geneva: WHO.

WHO/UNICEF/ICCIDD (1993) Indicators for assessing

iodine deficiency disorders and their control pro-

grammes. Report of a joint WHO/UNICEF/ICCIDD

consultation. Geneva: WHO.

WHO/UNICEF/ICCIDD (2001) Assessment of the iodine

deficiency disorders and monitoring their elimination.

Geneva: WHO.

3366 IODINE/Iodine-deficiency Disorders

IRON

Contents

Properties and Determination

Physiology

Biosynthesis and Significance of Heme (Haem)

Properties and Determination

J R Chipperfield, University of Hull, Hull, UK

Physical and Chemical Properties

0001 The element iron (Latin ferrum), atomic number 26,

relative atomic mass 55.85, has an electronic configur-

ation [Ar] 3d

. Iron normally occurs in one of three

oxidation states iron(0) (metallic iron), iron(II) and

iron(III). Iron(II) and iron(III) compounds were for-

merly called ‘ferrous’ and ‘ferric’ respectively. Iron

oxides are high-melting-point solids. Iron(II) oxide

(FeO), is black, whereas iron(III) oxide (Fe

)is

orange-red. Both iron(II) and iron(III) form many

ionic salts, such as halides (FeCl

and FeCl

), sulfates

(FeSO

and Fe

(SO

)

), and nitrates (Fe(NO

)

and Fe

(NO

)

). Iron(II) sulfate, iron(II) gluconate, and iron

(II) fumarate are used medicinally for oral iron supple-

mentation. In acidic solution these salts dissolve to give

the aquated cations [Fe(H

]

2þ

, and [Fe(H

]

3þ

(Figure 1). These octahedral aquated ions are also

found in solid hydrated salts such as hydrated iron(II)

sulfate (FeSO

.7H

O), and hydrated iron(III) sulfate,

(Fe

(SO

)

.9H

O). As pH increases, insoluble hydrox-

ides Fe(OH)

and Fe(OH)

precipitate, the latter being

so insoluble that, at pH 7, the equilibrium concentra-

tion of iron(III) in solution is only 10

9

mol dm

3

Solutions of iron(III) salts are strongly acidic due to

hydrolysis of the [Fe(H

]

3þ

cation (eqn 1).

½FeðH

OÞ



3þ

þ H

O Ð½FeðH

OÞ

ðOHÞ

2þ

þ H

ð1Þ

The pK

of [Fe(H

]

3þ

is around 2, similar to that of

phosphoric acid, and therefore solutions of iron(III)

salts are as acidic as a solution of phosphoric acid of

the same molarity.

0002Both iron(II) and iron(III) form complexes with

many ligands. Simple monodentate ligands such as



and CN



give complex ions such as tetrahedral

[FeCl

]

2

and [FeCl

]



(Figure 2) and octahedral

[Fe(CN)

]

4

and [Fe(CN)

]

3

(Figure 3). Chelating

ligands such as phen (1,10-phenanthroline), (Figure 4),

and dipy (2,2

-dipyridyl), (Figure 5), give the

chelated complex ions [Fe(phen)

]

2þ

,[Fe(phen)

]

3þ

[Fe(dipy)

]

2þ

, and [Fe(dipy)

]

3þ

(Figure 6).

n = 2[iron(II)] or 3[iron(III)]

fig0001 Figure 1

n −

n = 2[iron(II)] or 1[iron(III)]

fig0002Figure 2

n −

n = 4 [iron(II)] or 3[(iron(III)]

fig0003Figure 3

1,10-phenanthroline (phen)

fig0004Figure 4

IRON/Properties and Determination 3367

0003 In the absence of ligands, aerial oxygen will readily

oxidize solutions of iron(II) compounds to iron(III).

When ligands are present they most commonly (e.g.,



) stabilize iron(III) more than iron(II), or

more rarely (e.g., phen) stabilize iron(II) relative to

iron(III) such that aerial oxidation of iron(II) to iro-

n(III) is prevented. Iron(II) has the electron configur-

ation [Ar] 3d

, and in octahedral complexes the six 3d

electrons may be found in two configurations – high-

spin, with four unpaired electrons, or low-spin, with

no unpaired electrons. The presence of unpaired

electrons imparts paramagnetism to high-spin iron(II)

compounds. Iron(III) is similarly found in a high-spin

(five unpaired electrons) or low-spin (one unpaired

electron) configuration. The nature of the ligands

determines whether complexes are high- or low-spin.

0004 In Pearson’s terminology of ‘hard’ and ‘soft’ acids

and bases, iron(III) is a ‘hard’ acid and forms its most

stable complexes and compounds with ‘hard’ ligands

(i.e., those containing oxygen or nitrogen donor

atoms). Iron(II) is ‘softer’ than iron(III) and, as well

as bonding to both oxygen and nitrogen donor atoms,

is also found bonded to ‘soft’ ligands such as sulfur

donor ligands.

0005 In life processes, iron(II) complexes are needed

which are not irreversibly oxidized to iron(III) by

aerial oxidation.

Occurrence and Speciation in Foods and

in the Environment

Foods

0006 Iron is found in foods derived from both animals and

plants. Table 1 shows typical concentrations of iron

found in a variety of common foods. The iron may be

present either as heme-based compounds or as non-

heme compounds.

0007Heme compounds In mammals the two main iron-

containing compounds are the heme proteins hemo-

globin and myoglobin, which are used to transport

oxygen. Heme proteins consist of an iron–porphyrin

unit (Figure 7) and a protein unit. The porphyrin unit

coordinates to the iron in a plane. In myoglobin and

hemoglobin the fifth coordination position of the iron

is occupied by a nitrogen atom (from a histidine

residue) which is linked to the protein chain, and the

sixth position is occupied by a water or oxygen mol-

ecule. This is shown diagrammatically in Figure 8.

Other heme proteins are the cytochromes in which,

as part of redox reactions, the iron atoms shuttle

between iron(II) and iron(III). They have a similar

porphyrin–iron core to that shown above, but both

the fifth and sixth coordination positions of the iron

are linked to the protein chain (Figure 9).

0008Although most familiar in animals, photosynthesis

in plants involves similar heme proteins.

0009Nonheme proteins Nonheme proteins in animals

and plants are used to store and transport iron. The

most abundant in mammals is ferritin. This consists

of an iron-containing core surrounded by a protein

sheath (Figure 10). The core may contain up to 4500

iron atoms (as iron(III)), and has a structure some-

what similar to the hydrated iron(III) oxide ferrihy-

drite 5Fe

.9H

O. The surrounding protein sheath

consists of 24 similar subunits. Another iron trans-

port protein, transferrin, is a glycoprotein containing

a single polypeptide chain folded into two lobes. Each

protein can strongly bond two iron(III) ions and each

iron(III) ion has a carbonate or bicarbonate anion

associated with it. The iron(III) atoms are octahed-

rally coordinated.

0010A variety of microorganisms produce and release

siderophores. These are powerful chelating agents

which bond to iron atoms through oxygen atoms,

and yield neutral molecules which can pass through

cell walls. One particular example is ferrichrome

(Figure 11) which is a cyclic hexapeptide containing

three hydroxamate groups.

0011Iron–sulfur proteins These are widely distributed

and encompass rubredoxins, ferredoxins, and high-

potential iron proteins (HIPIPs). Rubredoxins

(Figure 12) contain a single iron atom bonded

through four tetrahedrally arranged sulfur atoms to

the rest of the protein. Ferredoxins can have two iron

atoms (Figure 13), or four iron atoms (Figure 14). In

each case there are sulfur atoms bridging between the

2,2'-dipyridyl (dipy)

fig0005 Figure 5

n = 2[iron(II) or 3[iron(III)]

phen or dipy

fig0006 Figure 6

3368 IRON/Properties and Determination

tbl0001 Table 1 Iron content of common foods

Cereals Iron content

(mgFe per100 g)

Milk products Iron content

(mgFe per100 g)

Meat, fish Iron content

(mgFe per100 g)

Vegetables Ironcontent

(mgFe per100 g)

Miscellaneous Iron content

(mgFe per100 g)

White plain flour 1.5 Whole milk 0.06 Bacon (raw, lean) 1.2 Potatoes (new) 0.3 Raisins 3.8

Whole meal flour 3.9 Cheddar cheese 0.3 Ham (canned) 1.2 Lentils (dried) 11.1 Currants 1.3

Savory rice (cooked) 0.5 Yogurt 0.1 Beef (raw, lean) 2.1 Peas (raw) 2.8 Mixed nuts 2.1

White spaghetti (boiled) 0.5 Dairy icecream 0.1 Lamb (raw, lean) 1.6 Cabbage (raw) 0.7 White sugar trace

Brown bread 2.2 Eggs and fats Veal (raw) 1.2 Swede (raw) 0.1 Honey 0.4

White bread 1.6 Chicken egg 1.9 Chicken (raw) 0.7 Tomato 0.5 Instant coffee 4.4

Cornflakes 6.7 Butter 0.2 Liver (pig, raw) 21.0 Mushroom 0.6 Coffee (infusion) trace

Christmas pudding 1.5 Margarine 0.3 Cod (raw) 0.3 Apples 0.1 Tea (infusion) trace

Olive oil 0.4 Herring (raw) 0.8 Bananas 0.3 Beer (canned) 0.01

Prawns (boiled) 1.1 Plum 0.4 Red wine 0.9

Data abstracted from 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.