Chapter 10

Iodine

Introduction

--Iodine is a constituent of the thyroid hormones thyroxine (T₄) and triiodothyronine(T₃)

--Iodine deficiency disorders (IDD) is the term used instead of goiter to denote effects of I on growth and development

--Iodine deficiency is now accepted as the most common cause of preventable mental defects in the world today (Hetzel and Wellby, 1997)

--Almost every country of the world has had problems

History

--I is one of the oldest elements in terms of recognition of importance in animal and human functions

--3000 B.C., Chinese emperor Shen-Nung, noted seaweed prevented goiter

--2000 B.C., Hindu literature refers to goiter

--1500 B.C., goiter treated surgically in Egypt

--460-370 B.C., Hippocrates noted burnt sponges and seaweed relieved goiter

--Many factors blamed for goiter, e.g., humidity, temperature, lack of sunshine, poverty, lack of sanitation, alcoholism and consanguinity

--In Europe, believed goiter related to effect of moon

--In Ecuador customary to rub goiters with saliva at time of new moon.

--1811, Courtois isolated I from ash of seaweed

--1816, I used to treat goiter

--Soon, opposition to use of I due to toxic side-effects

--~1900, I recognized as component of thyroid

--Boussingault first suggested iodization of salt

--1922-1924 mass prophylaxis with salt in Switzerland and Michigan

--In Switzerland widespread occurrence, form of mental deficiency and deaf-mutism (endemic cretinism)

--After 5 years of iodized salt in Michigan, goiter rate fell from 38.6% to 9%

--Livestock also used iodized salt

--1959, use of injections of iodized oil in New Guinea

--From 1959-1972 cretinism and goiter prevented in this region

Chemical Properties and Distribution

--Iodine is a halogen that is volatilized by sunlight and heat

--Minimize volatilization by maintaining I in an alkaline mixture and use K iodate vs. K iodide

--I not required by plants

--I in air increased by pollution

--Seawater contains most in form of iodates

--Solar light oxidizes and I escapes into the air

--Atmospheric I then deposited on land by rain and snow

--Many soils of the world low in I, related to three factors

1. Recent glaciation

2. Distance from the sea

3. Low annual rainfall

Metabolism

Absorption -- In feeds and water, I is largely as inorganic iodide and it is absorbed throughout G.I. tract and transported by plasma proteins

--I also readily absorbed in the lungs, through the skin following application of tincture of I, iodophors, or organic I-containing compounds

--I secreted in saliva, other G.I. tract fluids, and breakdown of I from hormones is reabsorbed in the digestive tract

--For ruminants, 70-80% of I absorbed in rumen and additional 10% in abomasum (or true stomach)

--Iodothyronine and other iodinated amino acids absorbed intact

--Intestinal parasitic infestations interfere with I absorption (Furnee et al., 1997)

Tissue uptake and distribution

--In plasma, I is transported to the thyroid

--If I status is good 10% or less of absorbed I taken up by thyroid, but if deficient, more than 80% (Stanbury, 1996)

--Thyroxine is synthesized by step wise iodination of thyroglobulin

--Thyroglobulin is the main storage form in the thyroid

--I is present in thyroid as:

a. inorganic I

b. monoiodotyrosine

c. diiodotyrosine

d. triiodothyronine (T₃)

e. tetraiodothyronine (thyroxine, T₄)

--The gland produces and releases thyroxine when stimulated by the pituitary thyroid stimulating hormone (TSH)

--TSH acts on tyrosine-rich thyroglobulin to make tyrosine available for iodination

--TSH stimulates the thyroid to release thyroxine which is transported to all body cells

--Thyroxine is carried into the cell and deiodinated to triiodothyronine

--The enzyme catalyzing this reaction is 5'-deiodinase, a Se-containing enzyme

--Se deficient rats became I deficient with growth reduction and osteopenia suggesting that adequate Se status should be ensured before measures to correct I deficiency (Moreno-Reyes et al., 2006)

--Triiodothyronine is the active form of the hormone having at least 10 times the activity of thyroxine (Berdanier, 1998)

--Failing thyroid function (e.g., I deficiency) leads to hyperplasia of the follicular cells and enlargement of the thyroid gland (e.g., goiter)

--Se deficiency, a role in control of thyroid hormone metabolism

--The deiodinating enzyme, which produces T₃, type I iodothyronine 5'-deiodinase is a selenoenzyme with most of activity occurring in liver, kidney and thyroid

--Deiodination of T₄ is also catalyzed by type II 5' deiodinase, which produced T₃ for local use

--Also, a type III enzyme that is thought to protect the brain from toxic effects of T₃ (conversion of T₃ to T₂)(Brody, 1999)

--Se also plays an indirect role in control of thyroid hormone synthesis via Se dependent glutathione peroxidase (GSH-Px)

--High I intake when Se is deficient may iniciate thyroid tissue damage as a result of low thyroidal GSH-Px activity during thyroid stimulation (Hotz et al., 1997)

--Fe deficiency anemia impairs thyroid metabolism, reducing both T3 and T4 (Hess et al., 2002). Fe deficiency lowers thyroid peroxidase activity, Heme-containing enzyme needed for initial steps for thyroid hormone synthesis

--I crosses the placenta freely and through the mammary gland

--For laying hens, the ovaries absorb I readily, and high dietary I results in eggs high in the mineral

--Transfer of thyroxine to the fetus occurs most readily in latter stage of pregnancy

Storage -- Iodide ions resemble Cl ions in that they permeate all tissues, but 70-80% is concentrated in thyroid (70-80%)

Excretion -- Excreted as organic I in feces or as free I in urine

--Most I excretion is in urine with smaller amounts in feces and sweat (urinary loss 40 times greater than fecal loss)

--No renal threshold for I as losses continue in urine even in deficiency

--In tropical areas, loss in sweat can be significant

--Amount secreted in milk depends on body status

--Colostrum is 4 to 5 times higher than later produced milk

--Temperature affects I transfer to milk, goat milk had 6 times more I at 33°C vs. 5°C (Lengemann, 1979)

Goitrogen and Other Iodine Antagonists

--Goitrogenic substances may be of equal or greater importance than is dietary I

--Feed goitrogens may increase I requirement 2-4 fold

--Goitrogen can interfere with thyroid hormone synthesis

--The gland grows in response to TSH, to increase thyroxin production

--Goitrogen sources are cassava, cabbage, disulfids of saturated and unsaturated hydrocarbons from organic sediments in drinking water, products from E. coli, soybean, cottonseed, flaxseed, peas, peanuts, and I excess in seaweed and kelp

--Babassu (Orbignya phalerata), palm-tree coconut fruit, resulted in high goiter in Brazil (Gaitan et al., 1994)

--Two varieties of millet were goitrogenic (Elnour et al., 1997)

--Smoking of tobacco 2 fold ↑ in goiter (Foo et al., 1994)

--10 to 100 times requirement of I ingested ↑ goiter 6-12% in Japan

--Goitrogens inhibit conversion iodide to iodine, (needed iodination of tyrosine), inhibit iodination of monoiodothyrosine; or inhibit coupling of diiodotyrosine molecules to form thyroxine

--Cruciferous plants contain goitrogens that reduce hormonogenesis in the thyroid (only partly reversible with I)

--Many pasture plants contain cyanogenetic glycosides, thiocyanate inhibits I concentrations in the thyroid

--Modern varieties of white clover have very high levels of goitrogens, have resulted in high lamb mortalities (Sargison and West, 1998)

--Soybean meal, cottonseed meal, and linseed meal can produce goiter

--High cassava (cyanogenic glucosides) results in goiter (Abuye et al., 1998)

--Brassica species (kale, cabbage, broccoli, rutabagas, cauliflower, turnip, Brussel sprouts and rape) produce active goitrogens. They are glucosinoletes (also called thioglucosides), 100 different kinds exist (Stoewsand, 1995)

--High intake of corn silage results in goiter in calves

--Goitrogens in the milk of cows consuming cruciferous plants ↑ likelihood of I deficiency in calves and humans

--Other antagonists to I

a. High As, F, Ca

b. deficient or high dietary Co

c. low Mn

--High goiters in town of S. Africa where water high in F (Jooste et al., 1999)

Physiological Functions

--Only known role of I is for synthesis of thyroxine and triiodothyronine. Thyroxine contains 65% I

--Multiple functions as regulator of cell activity and growth

--Crosses placental barrier early in embryonic life, prior to embryonic thyroid functioning

Thyroid hormones active roles in:

a. Thermoregulation

b. Intermediate metabolism

c. Reproduction

d. Growth and development (e.g., cell differentiation)

e. Circulation

f. Muscle function

g. Oxidation of cells

--↑thyroid hormones, ↑ basal metabolic rate (BMR)

Hyperthyroidism - weight loss

Hypothyroidism - weight gain

--With hypofunctioning thyroid (e.g., goiter), energy exchange and quality of heat liberated by tissues is reduced and ↓ BMR

--Thyroid hormones also:

1. Influence mental and physical growth and differentiation or maturation of tissues (Mediated by gene expression, Brody, 1999)

2. Effects other glands (e.g., gonads)

3. Neuromuscular functioning

4. Hair and feathers

5. Influence metabolism of nutrients (e.g, minerals and water)

--Triiodothyronine can turn on or off the activity of genes involved in synthesis of specific m-RNA, which controls synthesis or inhibition of particular proteins involved in cell function (Refetoff et al., 1993)

--Nuclear receptors of vitamin A (retinoic acid) interact with steroid and thyroid hormone receptors (Lang et al., 1994)

--Receptors in cell nuclei are functionally analogous for steroid hormones, triiodothyronine, 1,25 (OH)₂D and retinoic acid

--The super family of nuclear proteins interacts with specific genes and regulates their transcription

--Retinoic acid has been found to stimulate, synergistically with triiodothyronine, the production of growth hormone

--Triiodothyronine and retinoic acid control over-lapping net works of genes

Requirements

--I requirements for growth may not be the same for reproduction, lactation, or for thyroid structure integrity (Underwood and Suttle, 1999)

e.g., normal growth chickens 0.07 ppm vs 0.3 ppm normal thyroid

--About 10% of I intake excreted in milk

--Different breeds of turkeys, different requirements and amount of I in eggs dependent on individual hens (Rys et al., 1997)

--Climate and environment effect thyroid hormone secretion, during summer for cattle, sheep and goats

--The gland enlarges to improve "trapping" I from blood stream

--I requirement greatly affected by goitrogenic feeds

--If diet contains as much as 25% strongly goitrogenic feeds (e.g., Brassica forages, rape and turnips), supplemental I should be doubled

--Thiocyanate-type goitrogen counteracted by additional I, but thiouracil types only partially suppressed

--Human requirements are 40-120 µg, highest requirement for pregnancy and lactation

Natural Sources

--I is widely distributed, content in water reflects concentrations in food

--Water from goitrous areas in India and Ceylon was 0.1-0.2 µg/L vs 0.9 µg/L in a nongoitrous area of Delhi

--However, water itself does not contribute a significant proportion of daily I intake

--Oilseed meals may contain 0.11-0.20 ppm while grain from the same area range from 0.04-0.10 ppm

--Milk, eggs and meat contain more I than plants

--Fish are particularly rich in I

--Fertilizer application can increase, Chilean nitrate can double or triple I content of crops

--Applying seaweed can increase I in crops 10-100 times

--Plant species may be more important in determining forage I content than soil or season

--13 ryegrass plants in New Zealand ranged from 184-2470 ppb

--Plant maturity a factor, a 4-5 fold decrease in I with advancing maturity

--Liming ↓ forage I

--I can be ↑ in eggs (yolk) by 100 fold with supplementation

Supplemental I (mg/d)	Milk I (µg/L)
0	8
40	361
81	895
162	1559
405	2036
810	2393

--Dairy products provide 38-50% of I for adults and 56-85% for young children

--An organic form of I (EDDI) is a therapeutic measure for footrot and lumpy jaw, this greatly ↑ milk I

--Other sources (Hamper et al., 1997)

a. iodophor for udder washes, teat dips, milking machines, washing tanks

b. erythrosine (58% I), a widely used food dye (red color)

c. potassium iodate, a dough conditioner for bread making

d. iodized salt for product seasoning

Deficiency

--Iodine deficiency disorder (IDD) including goiter in both animals and man, occurs in almost every country

--More likely in animals since they receive feeds locally produced

--Allman and Hamilton (1949) suggested that I deficiency is the most widespread of all mineral deficiencies

--Not true today because of iodized salt

--Most notorious IDD regions are high mountain regions (Alpine valleys, the Pyrenees, slopes of the Himalayas and Cordillera of the Andes)

--But also, low-lying areas, in interior of countries where wind or rainfall are unable to carry traces of I from the sea to the soil

--Also, soils leached by heavy I-poor rains or where there is little rainfall

Swine

--Reproductive failure the main effect

--Birth of dead or hairless pigs

--Also, weak pigs that appear unusually large and fat, because of a bloated condition

--Hypothyroidism including shortening of leg bones, a dwarfed appearance, goiter and extreme sluggishness

--An inherited congenital goiter found in swine

Poultry

--Deficiency results in poor growth, ↓ egg production and egg size, decreased hatchability and thyroid enlargement in embryos

--Lack of I or goitrogen (e.g., thiouracil) decreased egg production, hens were fat and growth of abnormally long, lacy feathers (Scott et al., 1982)

--Testes can remain small and free of spermatozoa, and male plumage may be lost

--Can be a problem in pet birds such as Budgerigars, goiter resulted from a diet based on millet

Ruminants

--Deficiency manifested by goiter, general weakness, and animals born blind, hairless or dead

--Goiter may be a clinical sign of a less severe deficiency than lack of hair or wool

--Retardation of fetal brain seen in lambs

--Reduced quantity or quality of wool growth associated with goiter

--Irregularity or suppression of estrus periods

--Fetal development may be arrested at any stage, resulting in early death and resorption, abortion and stillbirth or weak young born and retained placenta

--Sheep receiving I improved reproductive performance by either 14 or 21% over a two-year period

--In goats, infertility and abortion main effects

--I-deficient goats gave birth to kids that were hairless, had skin edema, very shortened limbs and goiter

--In an I-deficient region of Canada, feeding I greatly improved first-service conception rate in cattle

--In I-deficient bulls and stallions, a decline in libido and deterioration in semen quality

--Goitrous goats had abnormal electrocardiographs, suggesting abnormal cardiovascular function. Overall improvement with supplemental I (Singh et al., 2002)

Horses

--Goiter usually appears at birth, other signs include weakness persistent hypothermia, respiratory distress and high neonatal mortality

--There is an increased susceptibility to infectious diseases and respiratory infections

--Foals may be stillborn or exhibit extreme weak-ness at birth (e.g., inability to stand and suckle)

--I-deficient mares, have abnormal estrus cycles and males reduced libido and reduced semen

Other Animal Species

Laboratory Animals - Goiter in newborn rats and inhibited reproduction

--I-deficient rats had more coarse and less dense hair

--For mice, thyroid 3 times normal size, pituitaries twice normal size

--In hamsters, a genetic influence on goiter

--Cats - goiter, alopecia, fetal resorption and death. Estrus and libido unaffected

--Dogs - goiter main sign of I deficiency, cretinism reported in regions with endemic goiter

--Fish -- goiter and increased mortality

--Rabbits - Growth and social behaviors affected, rabbits not receiving I had more aggressive behavior (scratching and biting)

Humans

--Globally > 1.9 billion persons, including 285 million children, have inadequate I intake (Zimmermann et al., 2006)

--¼ to ⅓ of world's population subsists on I-deficient diets, vast majority in developing countries (Ramakrishan, 2002)

--At risk for IDD, which include goiter and a wide spectrum of mental, psychomotor and growth abnormalities

--Even mild I deficiency related to hearing impairment and reduced intelligence quotient (Remer et al., 2006)

--Currently, an estimated 655 million cases of goiter and 26 million cases of preventable mental deficiency including 5.7 million cases of cretinism (WHO, 1991)

--Up to ⅓ of people in China are at risk for IDD

--In N. China subclinical prenatal I deficiency negatively affects infant development (Choudhury and Gorman, 2003)

--Endemic goiter in all Latin American countries

--In Asuncion, at one time, there was goiter in almost every home (Langer, 1960)

--In Ceylon and Nigeria among females, goiter was 56 and 72%, respectively

--Endemic cretinism is generally < 20 µg I/d and affects up to 10% of populations in severely I-deficient regions in India, Indonesia and China (Tai et al., 1982)

--A number of surveys in Afghanistan show goiter in more than 20% of children and women (Oberlin et al., 2006)

--In India, estimated 270 million people are at risk of IDD, 79 million have goiter and 2.2 million suffer from cretinism (Ramachandran, 2002)

--Three levels of IDD severity

1. Mild - 5-20% of school children (urine iodine 3.5-5 µg/dl)

2. Moderate IDD - goiter, 30% (urine iodine 2.0-3.5 µg/dl)

3. Severe - 30+% goiter, with 1-10% endemic cretinism (urine I < 2.0 µg/dl)

--Goiter 20-30 times more common in women than men, most common in young girls at puberty

--Considerable impact of I deficiency on brain development and function, particularly in the fetus and in early childhood

-- ↓ Intelligence scores in affected communities > 10

--A mean I.Q. of 30.8 ± 8.8 of 112 cretins in Thailand (Rajatanavin et al., 1997)

--Mild to moderate intellectual impairment, an important consequence of I deficiency

--Mathematical tests in Russian school children improved 46.7% after I supplementation (Benade et al., 1997)

--Women with goiter in India reproduction problems

--I-deficiency ↑ fetal death, congenital defects, deaf mutism and spastic diplegia

--Children's hearing inferior in endemic deficient regions

--From apparently normal subjects in Iran, there was mild to moderate growth retardation and neurological auditory and psychomotor impairments in a I-deficient area (Azizi et al., 1995)

--Goiter is the most visible evidence of IDD, it is the "tip of the iceberg," which includes lower I.Q., ↑ fetal, infant and child mortality, poor growth and birth defects

--Misconception that I deficiency has been virtually eliminated because of salt iodination, unfortunately, this is not true

--Incidences of I deficiency reported in various regions since 1992

a.	Malaysia	42.8%	e.	Tunisia	49.5%
b.	South Africa	17.5%	f.	Chad	63.0%
c.	Saudi Arabia	22.0%	g.	Namibia	34.5%

--Greatest factor affecting prevalence of IDD is isolation of populations and sole dependence on locally grown foods low in I

--IDD is usually prevalent in remote locations from the sea

Assessment of Status

--Diagnosed by presence of goiter

--< 4 g serum thyroxine/dl is prejudicial to brain development

--Serum protein-bound I and I content of thyroid tissue can reveal the status

--Evaluating T₃ and T₄ in blood

--Cattle milk < 10-20 µg/L indicates low intake

--Urine I and blood thyroid stimulating hormone (TSH) are good status indicators (Zimmerman et al., 2005)

--TSH testing in newborns is useful to identify I status

Supplementation

--I deficiency has declined in recent years due to iodized salt and other preventive measures

--However, still a serious health problem in developing countries

--Prior to I supplementation in Montana an annual loss of thousands of pigs

--Addition of 0.0076% I is effective level of I in salt

--Mix I with salt in a mineral mixture or concentrate mixture

--In inaccessible areas, salt blocks containing I dropped by planes

--Available sources of I of relatively equal value are K iodide, Na iodide and ethyleneadiamine dihydroiodide (EDDI), these forms are available but I will leach or evaporate under hot, humid tropical conditions

--Calcium iodate and pentacalcium orthoperiodate are also highly available but have greater physical stability and are not so rapidly lost from a free-choice mineral mixture

--Heat and sunlight favor loss of I by volatilization

--Use K iodate or a stabilized iodide form vs. K iodide to prevent volatilization

--Under adverse climatic conditions in 18 months, 40% of I was lost

--Other methods to provide include oral dosing, intramuscular injections of iodized oil and intraruminal devices

--Good results in both animals and humans with injectable I

--Iodized poppy seed oil was given to breeding goats in Yogyakarta, Indonesia. One injection lasted 2 years or until the third kidding (Lebdosoekojo, 1981)

--Slow release intraruminal devices have lasted six years (Judson, 1996)

--Millions of children will never achieve their full potential due to learning disabilities from I deficiency

--Iodized salt has done much to improve life, but difficulties are encountered in production of iodized salt and maintaining its quality

--Cost in Asia to provide is 3-5¢ per person per year (Hetzel and Wellby, 1997)

--In China (Xinjiang and Inner Mongolia), people preferred a desert salt (low I) and would not consume the iodized salt

--In Haiti iodized salt was combined with diethylcarbamazine to control both IDD as well as a parasite (Beach et al., 2001)

--I supplementation improved cognition in I deficient school children in Albania (Zimmermann et al., 2006)

--For humans, a single injection of iodized oil protected for 3-5 years

--Oral iodized oil lasts only half as long

--Indirect method, provide more I to livestock so that more I is in milk and eggs

--I has also been added to candy (Mexico) and to sugar (Sudan) and water in several locations

--Recent data from the US, a sharp decline in I intake during last 20 years (Lee et al., 1999)

Toxicity

--Maximum tolerable levels are:

a. sheep and cattle 50 ppm

b. swine 400 ppm

c. poultry 300 ppm

d. horses 5 ppm

--Horses are considerably less tolerant to excess (Wehr et al., 2002)

--Goiter can develop (due to excess) in both mares and foals with as little as 40 mg I/d

--Excess I inhibits T₃ and T₄ so more TSH

--For mares receiving 100 mg I daily for last 3 months of pregnancy, foals were weak, lethargic, abnormal bone growth and high mortality

--Toxicosis signs in cattle include depressed appetite, dull listless appearance, excessive tears and sloughing of skin, a cough and excessive nasal discharge

--Excessive I may impair immune system, and reduce the ability of antibodies to respond

--For sheep, depression anorexia, hypothermia and poor weight gain

--For laying hens, reduced egg production, egg size and hatchability

--For swine, depressed gain, F.I.

--For human, 2 mg/d is harmful

--Inhabitants of coastal regions of both Japan and China consume large amounts of seaweed which can result in 50-80 mg/d. This has resulted in goiter

--Excess I inhibits organic I formation in hypothyroidism, feedback inhibits T₃ synthesis

--High I intake ↑ risk of thyroid papillary cancer in humans (Goldhaber, 2003)

Hyperthyroidism (Thyrotoxicosis)

--Hyperthyroidism is defined as an over activity of thyroid function, with elevated T₃ and T₄ plasma levels

--Graves disease (an autoimmune disorder): hyperthyroidism, opthalmopathy and infiltrative dermopathy

--Thyroidectomy and oral antithyroid drugs are treatments