3)

Deiodination in the inner ring to metabolically inactive 3,3',5'- triiodothyronine (rT₃)

Some T₃ is probably also formed by condensation of monoiodotyrosine with diiodotyrosine

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

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

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 primarily 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 primarily 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

Trace Elements

• Boron
• Chromium
• Cobalt
• Copper

• Fluorine
• Iodine
• Iron
• Manganese

• Molybdenum
• Nickel
• Selenium
• Silicon

• Tin
• Vanadium
• Zinc
• Ultra Trace Elements

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