CENSO NACIONAL ECONÓMICO

Distribution of iodine in human body

The normal adult human body contains 1 5 - 2 0 mg of iodine and the thyroid gland contains 70-80% of it (Lloyd et al., 1978; Delange, 1995).

Iodine in thyroid gland

The normal adult thyroid weighs only 15 - 40 g or about 0.03% of the whole body weight with unique concentration powers for iodine (Berne & Levy, 1993). However, the total amount of iodine in the thyroid varies with intake, age and glandular activity.

H,0,

Fi g. 2 . 2 .1 .1 . Th e ‘i o d i d ep u m p’ a n dio d i n em e t a b o l i s m

F ig.2 .2 .1 .1 .show s that the thyroid gland concentrates iodide from the circulation norm ally 100 tim es and in case o f iodine deficiency up to 500 tim es (Griffiths, 1974) by an active transport m echanism called the ‘iodide trapping m echanism ’ or ‘iodide pum p’. The thyroid iodine pool has a slow turnover o f about 1% daily (Griffin, 1992; Berne & Levy, 1993; Rhodes & Tanner, 1995; Guyton & H all, 1996).

W ithin thyroid gland, iodine is found in the inorganic iodide form and is rapidly oxid ised and bound to about one-sixth o f the 140-tyrosine residues in thyroglobulin, a glycoprotein with a m olecular w eight o f 6 5 0 KD containing about 90% o f the total iodine in the gland. In the thyroid gland, iodine and tyrosine are the major substrates to form the thyroid horm ones. Thyroid peroxidase and hydrogen peroxide (H2O2) are

the enzym es involved in the oxidation and binding o f iodide. The iodotyrosines, m ono- and di-iodothyronine (MIT & DIT) are then in v o lv ed in ‘coupling reactions’ to form triiodothyronine (T3) and thyroxine (T4). In the normal adult human thyroid, the average distribution o f the various iodinated com pounds are 23% MIT, 33% DIT, 7% T3, and 35% T4. Traces o f reverse T3 (rT3) and other com ponents that vary with the

supply o f iodine to the thyroid gland are also found as these are probably formed by condensation o f DIT and MIT (R oche et al., 1955; Stanbury, 1977;R hodes & Tanner,

1995; Guyton & H all, 1996).

The human thyroid secretes about 80 pg (103 nm ol) o f T4, 4 pg (7 nm ol) o f T3, and 2 p g (3.5 nm ol) o f rT3 per day (Berne & Levy, 1993; G uyton & Hall, 1996).

Iodine in extra thyroid tissues

About 20-30% of the total amount of iodine in human body is present in the extra thyroid tissues. The highest concentration (in pg I/g wet weight) is found in periorbital fats and orbicularis oculii muscles of the eye (0.25). The amount in other organs (Hamilton et al., 1973) in diminishing order are as follows: the liver, hair, pituitary and salivary glands (0.20 ± 0.06), the lungs and ovaries (0.07 ± 0.03), the kidneys (0.04 ± 0.01), the lymph nodes (0.03 ± 0.01), the brain and testes (0.02 ± 0.003), and the muscles (0.01 ± 0.001). Iodine in tissues occurs in both the free inorganic (0.01 pg/g) and the bound organic form - mainly as T4, together with small amounts of other

compounds, such as T3 (Salter, 1950; Griffin, 1992).

iodine in blood

Iodine exists in both inorganic and organic forms in the blood. The normal range of plasma inorganic iodide (PH) is 0.1 - 0.6 pg/100 mL; values <0.1 indicate EID and those >1 point to exogenous iodine administration (Wayne et al., 1964). The organic iodine in blood is present mainly as T4. Up to 10% of plasma organic iodine is made up of iodinated substances including T3 and DIT and minute concentrations of tissue

metabolites of T4 (Gross & Rivers, 1952; Roche et al., 1955). Thyroglobulin is the

major thyroid protein and a small amount is normally secreted into circulation. Iodotyrosines appear in the peripheral circulation following TSH stimulation and in hyperthyroidism (Taurog et al., 1956).

Physiological iodine requirement of man

Iodine is essential for normal growth, development and well being of humans (Hetzel , 1989; Griffin, 1992; Berne & Levy 1993; Guyton & Hall, 1996). Estimation of physiological iodine requirement in man is difficult.

However, it must be at least equal to the daily amount of hormonal iodine degraded in peripheral tissues and unrecovered by the thyroid. This is about 40 - 100 pg/day. Therefore, only 100 - 150 pg I/day is the recommended daily allowance (RDA) (Wayne et al., 1964, WHO, 1979, Hetzel & Dunn, 1989; Guthrie, 1989; Hetzel, 1989; Lamberg, 1993). Three reviews on the RDA for iodine (Delange et al., 1988) are particularly useful.

Allowing for the renal and faecal iodide loss, the minimum iodine requirement is 120 [ig/day in adults and the safe figures are 150 jxg/day, 175 M-g/day, and 200 lig/day during adolescence, pregnancy and lactation respectively (Wayne et ah, 1964; Goodman & Gillman, 1985).

The Food and Nutrition Board of the National Academy o f Sciences at the National Research Council, USA, recommended a daily iodine intake o f 35 pg/day for children aged 0 - 6 months; 45 pg/day for 6 - 1 2 months old; 6 0 - 1 1 0 pg/day for 1 - 1 0 years old; and 100 - 115 pg/day from 11 years upwards (Mitchell, 1974). A recent review on observational studies recommended an initial dose of 11 pg/Kg/day for the neonatal period, then 8 - 1 0 pg/Kg/day for 1 - 6 months, 6 - 8 pg/Kg/day for 6 - 1 2

months, and 5 - 6 pg/Kg/day for 1 - 5 years of age (Xue-Yi et al., 1994).

The WHO and ICCIDD now recommend an iodine intake of 90 pg/day from birth through 6 years, 120 pg/day for 7 - 1 2 years old children, 150 pg/day for adults, and

2 0 0 pg/day for pregnant and lactating women.

Absorption and excretion of iodine

Iodine in food largely exists as inorganic iodide and orally administered iodine is rapidly and almost completely absorbed from all levels of the gastrointestinal tract. Inorganic iodine is reduced to iodide in intestinal mucosa prior to absorption (Guyton & Hall, 1996). Iodine is excreted mainly in urine, with smaller amounts appearing in faeces and sweat (Underwood, 1977). Complete glomerular filtration and passive reabsorption of iodine results in a renal iodide clearance o f 30 - 40 mL/min, which is independent of the blood iodine levels (Griffin, 1992).

A UIE of <40 pg/day is suggestive of ID in man provided the renal iodide clearance is normal (Koutras, 1968). A UIE <50 pg/day or 50 pg/g Cr in random specimens from a population sample indicates the existence of endemic goitre in a community (Stanbury et al., 1974).

Faecal iodine excretion is mostly in the organic form and is comprised of T4 and its

metabolites. In Greece, the range of mean faecal iodine concentration in normal adults was 5 - 4 2 pg/day. In a goitre endemia of Greece, faecal iodine concentration increased from 5 - 6 pg/day to 18 - 30 pg/day after salt iodisation (Koutras, 1968).

Bioconversion of iodine

Bioconversion is the efficiency (or fractional rate) of the enzymatic conversion of a compound of interest, such as iodine in the IPSO to a derivative compound of metabolic importance, for example iodide. It is presumed that bioconversion of iodine occur in intestinal mucosa cells.

Physiology of the thyroid giand

The main output of the thyroid gland is T4 (93%), a prohormone that converts to

the metabolically active T3 (7%) that is four times more potent. The normal thyroid

gland secretes only a small proportion of the daily T3 requirement and the remainder

comes from T3 deiodination. The thyroid produces relatively more T3 in

hypothyroidism and hyperthyroidism. The thyroid hormone secretion is regulated by a negative feedback mechanism of TSH in pituitary gland called ‘thyrotrophin’ and its secretion is stimulated by thyrotrophin releasing hormone (TRH) produced by the hypothalamus of the brain. Thyrotrophin virtually regulates all the steps in the biosynthesis of the thyroid hormones provided enough iodine is present (Guyton & Hall, 1996).

Fig. 2.2.1.2. The ‘th y ro id p h y s io io g y ’

Source: Greenspan & Rappoport, 1991

I ’O f U A L ' S Y S T E M i I I

TSH

Transport and metabolism of the thyroid hormones

Both the T4 and T3 are largely bound to 3 plasma proteins. 70% of both the TT4 and TT3 are bound to thyroxine binding globulin (TEG), 20% of the TT4 is bound to thyroxine binding pre-albumin (TBPA), and about 10% of the TT4 is bound to the albumin fraction. In contrast, very little T3 is bound to the TBPA and about 10% of

the TT3 are bound to the albumin fraction. The ‘free T4’ (FT4) fraction (i.e., proportion circulating in non protein-bound biologically active form) is <0.03% (2 ng/dL) of the TT4 concentration and the ‘free T3’ (FT3) fraction is only 0.3% (0.3 ng/dL) of the plasma TT3 concentration (0.15 p-g/dl). T4 binds more tightly on the plasma proteins than the T3 resulting in a lower metabolic clearance rate and longer serum or biologic

half-life (7 days) than T3 that has a half-life of <l-day. However, T3 being 4 times

more potent has faster tissue action time than T4 (Rhodes & Tanner, 1995; Guyton &

Hall, 1996).

The free plasma thyroid hormones are in equilibrium with the protein bound hormones in the tissues (Griffin, 1992; Guyton & Hall, 1996). The estrogens during pregnancy markedly increase the TEG levels. The half-life of the TBPA, the TEG, and the albumin are 2, 5, and 13 days respectively. There is very little T4 in the urine

(DTE, 1994). The alternate mono-deiodination product of about a third of the secreted T4 formed by the extra thyroidal removal of an inner ring iodine, is 3,3’,5’-T3 or rT3

with little or no biological activity. The serum rT3 concentrations are less than the T3

concentrations because of the more rapid metabolic clearance. The rT3 binds to the

TEG (Rhodes & Tanner, 1995; Guyton & Hall, 1996).

Extra thyroidal metabolism of the thyroid hormones

At normal rates of thyroid hormone synthesis and secretion in the adult, about 120 |ig I/day enter the thyroid gland that secretes 80 pg I/day in the form of the T3 and T4

(metabolised in the liver, kidneys and many other tissues as the sulphates and glucuronide conjugates). Approximately 35% T4 is converted to T3 by outer phenolic

ring mono-deiodination catalysed by the enzyme 5 ’-deiodinase (Type 1 found in liver and kidneys and Type 2 found in pituitary gland). About 45% T4 is converted to rT3 by

inner ring deiodination catalysed by the enzyme 5-deiodinase (Type 3) having Se as an essential constituent in its moiety. The remaining 20% T4 is metabolised by non-de-

The thyroid hormone derivatives are excreted in bile, and a proportion of these are reabsorbed by entero-hepatic circulation. The total amount of iodine entering the ECF is 600 pg I/day of which 16% enters the thyroid, 80% is excreted in the urine and the remaining 4% is excreted in the faeces (Griffin, 1992; Arthur, 1992; Berne & Levy,

1993; Rhodes & Tanner, 1995; Guyton & Hall, 1996).

Functions of the thyroid hormones

The thyroid hormones have several functions including the enhancement of carbohydrate, fat, protein and vitamin metabolism (Griffin, 1992; Berne & Levy, 1993; Rhodes & Tanner, 1995; Guyton & Hall, 1996).

Calorigenic action

Thyroid hormones increase the basal metabolic rate (BMR) associated with increased oxygen (O2) consumption and heat production and play a role in body

temperature maintenance and adaptation to cold environments in all the tissues except the brain, spleen, and reproductive glands (Durham, 1989; Lippold & Cogdell, 1991).

Effects on the nervous system

In hypothyroidism, the mental processes are slow. In hypothyroid rats, the brain- specific cell membrane glyco-proteins are distorted and may lead to permanent functional impairments because they do not permit an orderly catch-up in the developing brain (Patel et al., 1985). If neonatal hypothyroidism is not corrected within the first two weeks after birth, there is always a risk of permanent brain damage. In ID, the toxic effects of thiocyanate (SCN) are increased. In hypothyroid infants, an abnormal development of the synapses, a defective myelination and a seriously retarded mental development may be found. Several studies suggested that the absolute level of the T4 at diagnosis is a predictor of brain damage (Hetzel &

Pandav,1994).

Effects on the heart

The thyroid hormones increase the number and affinity of the P-adrenergic receptors in the heart and consequently increase its sensitivity to the inotropic (force of contraction) and chronotropic (heart rate) effects of the catecholamines (Zilva et al.,

Effects on growth and development

Thyroid hormones are essential for cellular replication, differentiation and growth and hence for normal growth, skeletal maturation, mental development and sexual maturation. In hypothyroid children, bone growth is slow and epiphyseal closure is delayed. Thyroid hormones also potentiate the effect of growth hormone on several tissues. Congenital hypothyroidism is often associated with mal-development of gonads and reproductive failure (Rhodes & Tanner, 1995; Guyton & Hall, 1996).