Iodine

I.  Physiological Role

1. Iodine is a component of the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃)
2. Frogs and salamanders need thyroid hormone only for larval metamorphesis; in the adult animal, the thyroid has no evident endocrine function
3. The primary function of T₃ and T₄ is to stimulate 0₂ consumption of almost all metabolically active tissues
   1. Exceptions are adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary
   2. T₄ actually depresses 0₂ consumption of the anterior pituitary, presumably because it inhibits TSH secretion
4. The action of T₃ and T₄ to increase 0₂ consumption by tissues has secondary effects
   1. Heat production for maintenance of constant body temperature
   2. A slight rise in body temperature activates heat dissipating mechanisms
   3. Catabolism of endogenous protein and fat stores (with increased nitrogen excretion)
      1. Thyroid excess
         1. If food intake is not increased, endogenous protein and fat stores are catabolized, resulting in weight loss
         2. Thyrotoxic myopathy results when severe catabolism of skeletal uric acid
         3. Hypercalcemia and hypercalciuria With some degree of osteoporosis may occur
            Thyroid deficiency results in myxedema, a puffiness of the skin due to accumulated protein complexes which promote water retention
   4. Increased cardiac output due to combined action of thyroid hormones and catecholamines on the heart
      1. Actions of thyroid hormones and catecholamines are intimately interrelated
         1. Effects of thyroid hormone on the heart resemble those of b-adrenergic stimulation
         2. Thyroid hormones increase the number of b-adrenergic receptors
   5. Increased bone marrow metabolism and absorption of vitmain B₁₂ from the intestine (In absence of thyroid hormones a moderate anemia occurs)
   6. Thyroid hormones are necessary for hepatic conversion of carotene to vitamin A.  Accumulation of carotene in the blood is responsible for yellowish tint of skin in hypothyroidism)
   7. Increased activity of nervous system
      1. Effects on the nervous system are rapid mentation, irritability, and restlessness (since only traces of thyroid hormones cross the blood-brain barrier, effects are probably secondary to increased responsiveness to catecholamines)
   8. Thryoid hormones increase rate of absorption of carbohydrate from the gastrointestinal tract. (In hyperthyroidism, blood glucose rises rapidly and may exceed the renal threshold but it falls rapidly and increased catabolism and increased action of epinephrine keep liver glucogen depleted)
   9. Thyroid hormones lower circulating cholesterol
   10. Thyroid hormones are essential for normal growth and skeletal maturation
       1. In hypothyroid children, bone growth is slowed and epiphyseal closure is delayed
       2. Growth hormone secretion may be depressed in hypothyroidism and thyroid hormones potentiate the effect of growth hormone on the tissues
5. Phagocytosing leucocytes take up inorganic iodide and fix it to ingested particles or organisms. This iodination reaction may play a microbicidal role

II.  Tissue Distribution (J. Dairy Sci. 58:1578, 1975)

1. The thyroid contains more iodine than the entire remaining body
   1. Adult human thyroid weighs 20-25 g and contains 8-10 mg I
   2. About 95% of thyroid I is bound to thyroglobulin
   3. Average distribution of iodinated amino acids:
      1. Thyroxine (T4)         45 %
      2. Triiodothyronine (T3)             3%
      3. Iodotyrosines (MIT & DIT)  42%
      4. Reverse triiodothronine (rT3)                trace
2. Digestive tract contents may account for up to 40% of total body iodine
   1. Distribution of iodine in the bovine
      

      Item	Relative Weight	Relative I Content
      	% of total body
      Thryoid Gl tract contents Muscle Blood Skeleton Internal organs Skin, hair, hoof etc.	6.5 x 10-3 20 30 6 15 15 6	55 40 5 5 5 5 5	1.0 1.2 0.7 1.3 0.8

   2. Relative radioiodine concentrations in bovine tissues
      

      Blood plasma Skeletal muscle Bone Eyeball Liver Spleen Heart Hoof Adrenal Uterus Thyroid gland

      100 14 28 28 32 34 34 37 41 83 400,000

      Pancreas Salivary gland Lymph node Kidney Lung Mammary gland Ovary Skin and hair Cartilage Bile

      44 47 55 62 64 65 66 66 70 91

   3. Concentrations of I in milk, blood plasma, and tissues of cows fed different levels of I (E. W. Swanson)
      

      	I Supplement (ppm)
      	Basal	1	2	4
      Dietary I intake (ppm) Blood plasma I (mg/ml) *Milk I (ng/ml)   Liver I (ng/g) Heart I (ng/g) Kidney I (ng/g) Muscle I (ng/g)   Thyroid I (mg/g)	0.80 144a 184 a 154 a 168 a 195 a 162 a 1,672 a	1.94 167 a 502 b 175 a 179 a 225 a 169 a 1,653 a	2.9 192 a 631 b 166 a 194 a 243 b 170 a 1,915 a	4.88 239 c 838 c 213 b 218 b 303 c 199 b 1,936 a

      ^a,b,cValues within the same line not bearing the same superscript differ (P< .05)

III.  The Thyroid Gland

1. Thyroid hormone synthesis and release
   (See Ganong 1981. Review of Medical Physiology loth ed. Lange Medical Publications, Los Altos, CA. Thyroid hormone synthesis and release. In: The Thyroid. A Fundamental and Clinical Text. 4th ed. 1978. Harper and Row, New York, NY)
   1. I is actively transported from the circulation into thyroid cells, then it diffuses into the colloid
      1. Transport mechanism is stimulated by TSH and depends on Na⁺, K⁺ -ATPase
      2. Normal I concentration in the thyroid cell is 30-40X that in plasma.
      3. Amount of radioiodine taken up is iversely related to stable I intake Goitrogens inhibit I uptake
   2. I diffuses into the colloid. Amino acids are iodinated still attached to thyroglobulin
   3. In the gland, I is rapidly oxidized and bound to the 3 position of tyrosine molecules which are bound to thyroglobulin
      1. Binding is blocked by antithyroid drugs such as thiouracil
      2. The enzyme thyroid peroxidase is responsible for oxidation and binding of I with H₂0₂ accepting the electrons
   4. Monoidotyrosine is next iodinated in the 5 position to form diiodotryosine
      1. This iodination is also facilitated by thyroid peroxidase
   5. Two diiodotyrosine molecules undergo oxidative condensation to form T₄, still in peptide linkage. (The concensation is energy requiring and catalyzed by thyroid peroxidase)
      thyroxine (T₄, tetraiodothyronine)
   6. T₄ may be considered as a prohormone which is further processed in the thyroid as well as in peripheral tissues. Most of the T₃ results from deiodination of T₄
      1. Deiodination in the outer ring to the active 3,5,3'-triiodothyronine (T₃)
      2. Deiodination in the inner ring to metabolically inactive 3,3',5'- triiodothyronine (rT₃)
   7. Some T₃ is probably also formed by condensation of monoiodotyrosine with diiodotyrosine
   8. 3,5,3' triiodothyronine (T₃)
      1. A small amount of reverse T₃ is also formed, probably by condensation of diiodotyrosine with monoiodotyrosine.  3,3',5'-triiodothyronine (rT₃)
         rT₃ has no thyroid hormone activity
      2. Diet composition composition influences thyroid hormone levels and thermogenesis in man (Clin. Endocrinol. Metab. 5:377, 1976)
      3. Effects of high carbohydrate diets
         – Increase T₃ and elevate thermogenesis
         – Reduce synthesis of reverse T₃
         – Is reverse T₃, which has no thyroid hormone activity, a mechanism to control metabolic rate?
         – To lower metabolic rate, T₃ could be reduced as reverse T3 increases
      4. Relationship between diet, plasma thyroid hormones, and thermogenesis in man
         

         Diet	T3	rT3	T4	Thermogenesis
         High CHO Low CHO High fat	­ - no change	- ­ no change	no change no change no change	no data

      5. Relationship between diet, T₄, T₃, and rT₃ in dairy cows (J. Dairy Sci. 68:1148-1154, 1985)
         – Restricted energy intake can result in higher rate of production of rT₃ and decrease serum concentration of T₃ without altering thyrotrophin-thyrotrophin releasing hormone secretion.
         – Slight changes of energy balance might be indicated readily by reverse T₃ concentration in blood serum
      6. Effects of food restriction on net conversion of T₄ to 3,5,3' triiodothyronine (T₃) or 3, 3'5'-triiothyronine (rT₃) in growing pigs (J. Endocr. 95:349-355, 1982)
         – Fasting decreases deiodination of T₄ to T₃ by liver and kidney
         – Conversion of T₄ to rT₃ was reduced in liver but not in kidney
         – Serum T₄ and T₃ decreased during fasting
         – rT₃ incresed during fasting
2. Thyroid hormone secretion
   1. Thyroid cells ingest colloid by endocytosis
   2. In the cells, globules of colloid merge with lysosomes
   3. Peptide bonds between iodinated residues and thyroglobulin broken by proteases in the lysosomes
   4. T₃, T₄, DIT and MIT are liberated into the cytoplasm
   5. DIT and MIT are deiodinated by iodotyrosine dehaloqenase, (which does not attack iodinated thyronines). I is reutilized
   6. T₃ and T₄ pass on into the circulation
   7. Thyroid uptake of iodide and secretion of thyroid hormones are regulated by the TSH feedback system
      1. TSH binds to receptors in thyroid cell membranes
      2. Resultant increase in intracellular cyclic AMP produces the changes
      3. Prolonged TSH stimulation enlarges the thyroid (goiter). Growth hormone, corticosteroids and insulin are also required
   8. In plasma, thyroid hormones are bound to albumin, thryoxine-binding prealbumin, and thryoxine-binding globulin
      1. Total T₄ approx. 8 mg/dl, 99.98% bound
      2. Total T₃ approx. 0.15 mg/dl, 99.8% bound
3. Mechanism of action of thyroid hormones
   1. Thyroid hormones enter cells
      1. T₃ binds to receptors in cell nuclei.
      2. T₄ is converted to T3 in cytoplasm.
   2. T₃ acts on DNA to increase synthesis of messenger RNA
   3. Messenger RNA dictates formation of proteins which presumably act as enzymes to modify cell function
      1. Activity of membrane-bound Na + K+-ATPase in increased
      2. Increased energy consumption associated with increased Na⁺ transport may contribute to increased metabolic rate
      3. Mitochondrial protein synthesis is increased

IV.  The Mammary Gland

1. Iodide is the form of iodine which moves in either direction between the blood and mammary gland
2. Milk iodine content of cows milk increases in direct proportion to intake up to 160 mg daily (table below)
3. Above this, the percentage of total intake entering milk is reduced

V.  Absorption and Excretion (J. Dairy Sci. 58:1578, 1975)

1. Iodine appears to be absorbed primarilyy by simple diffusion
2. Essentially all iodine in the diet is absorbed
3. Iodine is excreted in both urine and feces
   1. In humans, I is excreted primarilyy in urine; fecal excretion of I is negligible
   2. Urine is also a primary excretory route for I in ruminants (~40% of intake) but fecal I of endogenous origin is appreciable (~ 25% of intake)
      1. With increasing iodine intake or when goitrogens are consumed, the proportion of I excreted in urine increases
4. Sites of absorption of I
   1. I is absorbed throughout the intestinal tract
   2. In ruminants, between 70% and 80% of daily I intake is absorbed from the rumen and an additional 10% from the omasum
   3. Re-entry of circulating I into the digestive tract predominates in the gastric stomach

VI.  Homeostatic Control

1. Urinary excretion is the primary regulating mechanism
   1. Urinary I excretion is reduced when I intake is limited
   2. Excess dietary I is excreted in urine
2. Abomasal recycling may conserve I, particularly when intake is limited
   1. Abomasal excretion transfers I from vascular to extravascular spaces
   2. This protects I from excessive excretion in urine
   3. I excreted into abomasum is available for reabsorption from the intestines
3. More total I is secreted in milk with increasing intake, but percentage of intake secreted in milk decreases

VII.  Interactions with Other Dietary Constituents

1. Thyroid uptake of I is reduced by:
   1. Arsenic
   2. Iron
   3. Cobalt
   4. Goitrogens such as thiocyanate

VIII.  Iodine Requirements

1. Calculation of theoretical dietary I requirements. (Values assumed by Dr. Swanson for dairy cow)
   1. Feed intake - 2.5% of body weight
   2. Thyroid uptake efficiency - 30% of dietary intake
   3. Daily thyroxine secretion rate - 0.2 to 0.3 mg/100 kg BW
   4. Amount of thyroxine I recycled - 15%
   5. Since T₄ contains 60% I, 0.2 - 0.3 mg T₄ = .14 to .2 mg I per 100 kg BW
   6. With thyroid uptake efficiency of 30%, .2 + .3 = .67 mg I per 100 kg BW needed. (.2 mg I per 100 kg BW + 30% I uptake)
   7. 0.67 mg + 2.5 kg feed = .27 mg/kg = .27 ppm
   8. since recycling = 15%, .27 ppm can be reduced to .25 ppm.
2. Recommended daily allowances:
   1. Bustad and Fuller have calculated I requirements of most animals to be between 1 and 2 mg/100 kg body weight
   2. Dairy cattle (Swanson, Nutrient Requirements of Dairy Cattle, 5th ed.
      1978)
      1. Growing; nonlactating - .25 ppm in feed dry matter
      2. Lactating; pregnant - .5 ppm in feed dry matter
   3. Human (adult and children ~4 yr) 150 mg/day
   4. Amounts should be increased when diets contain goitrogenic substances

IX.  Dietary Sources

1. Reliable published values are scarce because of analytical problems
   Most analyses indicate 0.25 ppm will usually be attained in most feeds except in areas where I is deficient in soil and water
2. Diets are usually supplemented by addition of iodized salt containing Nal, KI, KIO₃, calcium iodate, pentacalcium orthoperiodate, or ethylene-diamine-dihydriodide
   1. Physical availability of I - present in a form not lost by volatilization, leaching or migration into the center of a salt block. (Nal and KI not always physically available)
   2. Nutritional availability depends - present in a form that can be absorbed and
      utilized efficiently for formation of thyroid hormone.
   3. DIS is nutritionally available to nonruminants but not to ruminants
      1. DIS and milk protein bound iodine may be absorbed from the rumen in combinations metabolized differently from iodide
   4. PCOP appears to be nutritionally available to ruminants but its absorption is delayed until after it has dissolved in the gastric stomach (same for calcium iodate)
   5. Nal, KI, KIO₃, calcium iodate, PCOP, and EDDI all appear to be nutritionally available to both ruminants and nonruminants

X.  Deficiency

1. Deficiency is a geographical problem. Occurs when:
   1. Feeds and water are low in iodine
   2. Goitrogenic substances are present in feed
   3. Thiocyanate and perchlorate block thyroid uptake of iodine
   4. Thiouracil blocks organification of iodine
2. Deficiency signs
   1. Deficiency signs are more likely in newborn
   2. Goiter - thyroid hypertrophy under continued stimulation by TSH
   3. Hairlessness in newborn pigs and calves
   4. Long-term deficiencies may result in decreased milk yields and some signs of hypothyroidism
   5. An extended period (more than a year) often required before deficiency signs are noticed
3. Cretanism – failure of thyroid gland to function normally for some reason during development
   1. Myxedema – puffiness of the skin due to accumulated protein complexes which promote water retention
   2. Yellowish tint of skin from accumulation of carotene due to deficiency of thyroid hormone necessary for hepatic conversion or, carotene to vitamin A
   3. Reduced mentality
   4. Reduced bone growth and delayed epiphyseal closure

XI.  Toxicity

1. May result when animals receive I from multiple sources
   1. Trace mineralized salt containing I
   2. EDDI as prophylactic measure against mycotic infection
      1. As part of mineral mixture fed free choice
      2. As part of protein supplement
2. Toxicity may occur when the diet consistently contains 50-100 ppm of I
   1. Signs of I toxicity
   2. Goiter
      1. Excess I inhibits thyroid hormone synthesis at all steps, starting with iodination of tyrosyl residues up to the formation of T₄ and T₃
      2. This is another example of a deficiency and an excess of an element producing the same symptoms
      3. An escape from or adapl~ation to this mechanism usually occurs after 48 hours
         – A drop in intrathyroide I concentration causes a more efficient hormone synthesis
         – The drop in intrathyroidal I concentration is due to a persistent reduction of I transport into the thyroid cell
      4. Excess I can inhibit secretion of thyroid hormone by preventing hydrolysis of thyroglobulin
   3. The safety range is very wide, near 100 times requirement
   4. Toxicity could result from pharmacological doses given in treatment of foot rot or lumpy jaw
      1. Excessive tears and salivation
      2. Watery nasal discharge
      3. Tracheal congestion causing coughing
      4. Subnormal feed intake and growth
      5. Birth of weak or dead young
   5. Rapid recovery follows removal of excess iodine

Iodine — I (atomic number 53)

A halogen the thyroid uses to build T3 and T4. Too little causes goiter; too much can also disturb the thyroid.

Vitamins, Major Elements, Trace Elements, Toxic Elements

Vitamins

Vitamin A	Vitamin B1 (Thiamin)	Vitamin B2 (Riboflavin)	Vitamin B3 (Niacin)
Vitamin B5 (Pantothenic Acid)	Vitamin B6	Vitamin B12	Vitamin C
Vitamin D	Vitamin E	Vitamin K	Biotin
Folic Acid

Major Elements

Calcium	Magnesium	Phosphorus	Sodium, Potassium, Chloride
Sulfur (Sulfer)

Trace Elements

Boron	Chromium	Cobalt	Copper
Fluorine	Iodine	Iron	Manganese
Molybdenum	Nickel (Nickle)	Selenium	Silicon
Tin	Vanadium	Zinc	Ultra Trace

Toxic Elements

Aluminum	Arsenic	Cadmium	Lead
Mercury