Thyroid hormone

🥼 Practice and Clinical
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Increase ATPase activity mainly includes [[Thyroxine T4]] (also called thyroxine), [[Triiodothyronine T3]], [[Reverse triiodothyronine rT3]] T4 has a high content, T3 has strong activity. The thyroid first synthesizes T4, then…

Increase ATPase activity
Mainly includes

  • [[Thyroxine T4]] (also called thyroxine)
  • [[Triiodothyronine T3]]
  • [[Reverse triiodothyronine rT3]]

T4 content is high, T3 is highly active
The thyroid first synthesizes T4, then metabolizes it into T3 in peripheral tissues (mainly T3, but also a small amount of rT3)
If T4 to T3 conversion is insufficient, it results in [[Low T3 syndrome]] (at this time mainly converted to rT3)

Synthesis and Metabolism#

  1. Follicular iodine uptake: Iodine absorbed from the intestine exists in the blood as I^- with a concentration of 250 μg/L (< approximately 20-50 times that in the thyroid). About one-third is actively transported into the thyroid by thyroid epithelial cells. The thyroid’s iodine uptake depends on the “iodine pump” on the follicular wall epithelial cell membrane (actually the Na⁺/K⁺-ATPase pump transporting iodine), which transports iodine against the electrochemical gradient by secondary active transport. The iodine pump activity can be inhibited by thiamazole (methimazole) to suppress iodine uptake and treat hyperthyroidism. Clinically, the ability to uptake radioactive iodine is often used to monitor thyroid function — [[Iodine 131 uptake rate]].
  2. Activation of I^- occurs at the border between follicular epithelial cells and follicular lumen. Activation is a prerequisite for tyrosine iodination. Congenital deficiency of [[Thyroid peroxidase TPO]] results in inability to activate → thyroid hormone synthesis disorder → goiter (thyroid hormones cannot be released; the anterior pituitary perceives insufficient [[Thyroid-stimulating hormone TSH]] release, and continues to release TSH to stimulate thyroid growth, attempting to increase thyroid hormone secretion).
  3. Tyrosine iodination: Thyroglobulin (TG), synthesized by ribosomes in follicular epithelial cells, is stored in the follicular lumen at the junction of follicular epithelial cells and the lumen.
  4. Coupling (condensation) of iodotyrosines: MIT and DIT couple to form thyroid hormones.

The above activation, iodination, and coupling (condensation)

  • Are all catalyzed by the same TPO enzyme, whose activity is regulated by TSH. Drugs inhibiting TPO activity (such as [[Thionamides]]) block T4 and T3 synthesis, thereby treating hyperthyroidism.
  • All occur on the same TG molecule, so TG contains various components. The ratio of T4 to T3 is approximately 20:1, influenced by iodine content; iodine deficiency causes increased MIT and thus increased T3.

Storage, Release, Transport, Metabolism#

  1. Storage: Synthesized T3 and T4 remain bound to the TG molecule and are stored in the follicular lumen. The storage capacity is large (T4 storage > T3), sufficient for body use for 2–3 months; therefore, antithyroid drugs require a longer treatment duration to be effective.
  2. Release: When the thyroid is stimulated by TSH, follicular cells phagocytose TG in the follicular lumen into the cell, where it fuses with lysosomes. Under lysosomal proteases, T3 and T4 are separated and released into the bloodstream. [[Monoiodotyrosine MIT]] and [[Diiodotyrosine DIT]] are deiodinated by deiodinase, and the released iodine is recycled for thyroid hormone production.
  3. Transport: After release into the blood, T3 and T4 are transported in bound form (bound to 3 plasma proteins) and free form. T4 mainly exists in the bound form (>99%), while T3 mainly circulates in free form. Only free form is biologically active, with T3’s biological activity about 5 times that of T4. Bound and free forms can interconvert, maintaining stable concentrations of free T4 and T3 in the blood. Normal adult serum T4 concentration is 51~142 nmol/L, T3 concentration is 1.2~3.4 nmol/L.
  4. Metabolism: The half-life of T3 is 1.5 days, and T4 is 7 days.
    1. 20% of T3 and T4 are deiodinated in the liver; 80% are deiodinated in target tissues by deiodinases. T4 is converted to T3 (45%) and rT3 (55%); T3 and rT3 are further deiodinated to MIT, DIT, and iodide-free thyronine.
    2. Pregnancy, starvation, stress, metabolic disorders, liver disease, and renal failure can increase T4 deiodination to rT3 (because rT3 has low biological activity, its thermogenic effect is only about 5% of T4), affecting T4’s biological effect on tissues — [[Low T3 syndrome]].

Physiological Functions of Thyroid Hormones#

The characteristics of thyroid hormone action are extensive, slow, and long-lasting.
Their main effects are: promoting metabolism and heat production ↑, promoting growth and development, enhancing nervous system excitability, and promoting cardiovascular activity (thyrotoxic heart disease, prone to atrial fibrillation, etc.)

Effects on metabolism (promoting metabolism and increasing heat production)#

  1. Energy metabolism
    1. The most significant effect of T3 and T4 is to accelerate energy metabolism in most body cells, increasing oxygen consumption and heat production, thereby raising basal metabolic rate (BMR).
    2. The thermogenic effect is mainly related to increased Na^+-K^+-ATPase activity; secondarily related to promoting fatty acid oxidation producing abundant heat.
    3. Hyperthyroidism: heat intolerance and excessive sweating, BMR exceeding normal by 50~100%.
    4. Hypothyroidism: heat preference and cold intolerance, BMR lower than normal by 30~45%.
  2. Protein, fat, and carbohydrate metabolism
    1. Protein metabolism
      1. Physiological doses promote protein synthesis; high doses promote protein breakdown (skeletal muscle protein breakdown → muscle weakness; bone protein breakdown → osteoporosis, increased blood calcium).
      2. Hyperthyroidism: weight loss, weakness, increased urinary nitrogen and calcium, negative nitrogen balance.
      3. Hypothyroidism: reduced protein synthesis, muscle weakness, increased mucopolysaccharide (normally used for intracellular protein synthesis) accumulation, leading to myxedema.
    2. Fat metabolism
      1. T3 and T4 promote fatty acid oxidation, enhancing glucagon’s lipolytic and fatty acid oxidation effects.
      2. Although they promote cholesterol synthesis, their more prominent effect is accelerating cholesterol degradation in the liver. Therefore, hyperthyroidism results in decreased blood cholesterol; hypothyroidism causes increased blood cholesterol.
    3. Carbohydrate metabolism
      1. Physiological doses of T3 and T4 lower blood sugar by promoting intestinal mucosal glucose absorption, glycogen synthesis, and breakdown, accelerating glucose uptake and utilization by peripheral tissues like fat and muscle.
      2. High doses of T3 and T4 raise blood sugar by promoting glycogen breakdown and enhancing the hyperglycemic effects of adrenaline, glucagon, cortisol, and GH. Hence, hyperthyroidism leads to elevated blood sugar.
  3. Growth and development (promotion)
    1. Promote tissue differentiation, growth, and maturation (especially brain and long bones), with the greatest effect from embryonic period to 4 months after birth.
    2. Induce synthesis of certain growth factors, promote formation of N-type axons and dendrites, and growth of myelin sheath and glial cells.
    3. Promote long bone growth and development.
    4. Promote anterior pituitary secretion of DH, which permits GH function.
    5. Thyroid hormone deficiency in infants causes cretinism; prevention should start from pregnancy.

Effects on various organ systems#

  1. Nervous system (promoting nervous system excitability)
    1. Enhance excitability of CNS and sympathetic nervous system.
    2. Hyperthyroidism: irritability, agitation, poor sleep with many dreams, muscle tremors.
    3. Hypothyroidism: expressionless, slow behavior, memory decline, somnolence all day.
  2. Cardiovascular system (promoting cardiovascular activity)
    1. Increased heart rate, cardiac contraction, and cardiac output.
    2. Increase the number of β receptors on myocardial cell membranes (β-blockers can also be used to treat hyperthyroidism), enhance adrenaline stimulation of cAMP production inside myocardial cells, promote Ca2+ release from sarcoplasmic reticulum, and strengthen myocardial contractility.
    3. In hyperthyroidism, heart rate accelerates and strengthens, systolic pressure increases, diastolic pressure slightly decreases (due to increased tissue oxygen consumption causing relative hypoxia, vasodilation of small vessels, and decreased peripheral resistance), causing increased pulse pressure.
  3. Increase gastrointestinal motility and secretion of digestive glands.
  4. Permissive effect on NE-induced lipolysis and GH-stimulated long bone growth.
  5. Maintain normal menstruation and lactation.