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• The thyroid is a butterfly shaped gland. It possesses one of the highest rates of blood flow in the body. It is composed of follicles; each follicle surrounds a cavity full of colloid material (thyroglobulin). Parafollicular cells, lie in between the follicles.

• The thyroid gland is made up of a left lobe and a right lobe connected by an isthmus.

• An ascending pyramidal lobe is present in ∼ 50% of the population.

• The thyroid gland is encapsulated by:

  • Pretracheal fascia (false/surgical capsule)

  • Internal capsule (true capsule)

    • Inner connective tissue covering that cannot be separated from the gland
    • Forms septae, dividing the gland into lobes and lobules.

  • Vasculature and innervation of the thyroid.

  • Thyroid cells (characteristics and functions)

  <aside> 🧠 The inferior thyroid artery runs close to the recurrent laryngeal nerve and the superior thyroid artery close to the superior laryngeal nerve. Both nerves are at risk during thyroid surgery.

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  Thyroid hormones.

  • The normal thyroid gland uses a sodium iodine symporter (NIS) in an energy-dependent process, known as "iodine trapping", to absorb iodine against a concentration gradient. After dietary, inorganic iodine enters the thyroid follicular cells, it is oxidized to organic iodide by the enzyme thyroid peroxidase. Following oxidation, iodine binds to tyrosine residues in thyroglobulin to form monoiodotyrosine, leading to several possible combinations.

  • Either two monoiodotyrosines can combine to form diiodotyrosine, which can then unite with another diiodotyrosine to form thyroxine (T4), or a monoiodotyrosine can link with a diiodotyrosine to make triiodothyronine (T3).

  • The thyroid follicular cells then engulf thyroglobulin, which contains all the iodinated tyrosine compounds (mono and diiodotyrosine, triiodothyronine, and thyroxine), by pinocytosis.

  • In the thyroid cytoplasm, the iodinated tyrosine residues are removed from the rest of the thyroglobulin, then secreted from the basolateral border of the thyroid follicular cells.

  • To summarize, thyroid peroxidase is responsible for the oxidation of inorganic iodine, the formation of mono and diiodotyrosine, and the coupling that forms T3 and T4.

  • There is an equilibrium between bound and free circulating thyroid hormone in the bloodstream. About 70% of the circulating thyroid hormone is bound to thyroid-binding globulin (TBG). The remainder of the bound protein is attached to thyroxine-binding prealbumin (transthyretin) and albumin.

  • TBG decreases in hepatic failure due to a decrease in globulin synthesis by the liver, while TBG increases in pregnancy or with oral contraceptive use (estrogen increases TBG).

  • Estrogen affects thyroid hormones, causing an increase in total T4, but thyroid function remains normal. Similar changes are seen in the hyper-estrogenic state of pregnancy.

  • Over 99% of circulating thyroid hormones are bound to plasma proteins. The main protein responsible for binding circulating thyroid hormone is thyroid binding globulin (TBG). Estrogen use increases TBG levels because the catabolism of TBG decreases when estrogen is present.

  • An increase in TBG levels leads to an increase in total T4 (bound T4 plus free T4) and total T3. However, the level of free thyroid hormones stays normal, so patients remain euthyroid and have normal TSH levels.

  

  

  

  • Thyroglobulin (TG) is produced in the rough endoplasmic reticulum of the follicular cells. In the Golgi apparatus, TG is packed in vesicles and released into the colloid via exocytosis.
  • Iodide (I-) is taken up in the follicular cells via the basolateral Na+/I- symporter, which is driven by Na+/K+-ATPase. Iodine diffuses to the apex of the cell and is transported into the colloid via the Pendrin transporter.
  • The enzyme thyroid peroxidase (TPO) catalyzes the biosynthesis of the thyroid hormones T3 and T4 and their precursors monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are all attached to the TG molecule stored in the colloid.
  • For the release of thyroid hormones, TG is taken up by the follicular cells via endocytosis. Following fusion with a lysosome, proteolytic enzymes cleave TG to release T3, T4, DIT, and MIT. T3 and T4 are released into the blood (via the MCT8 transporter). Deiodinase removes the iodine from the MIT and DIT; iodine is then re-added to the intracellular I- pool.
  • Thyroid-stimulating hormone (TSH) from the pituitary gland stimulates the basolateral uptake of iodine, as well as the biosynthesis and release of thyroid hormones.

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  • The thyroid gland predominantly produces the thyroid hormone T4. T3 is the most active form, four times as potent as T4. Reverse T3 (rT3) is an inactive form of thyroid hormone.
  • In peripheral tissues, deiodinase enzymes convert T4 to T3 and rT3 (specific isoforms prefer T4 conversion into either T3 or rT3). However, T3 cannot be converted into T4 or rT3.
  • T4 has a higher affinity for binding proteins than T3, resulting in a longer half-life. Most circulating thyroid hormone is T4, usually 50 times more than T3.
  • The plasma half-lives of T4, T3, and rT3 are 7 days, 1 day, and less than one day, respectively. They are cleared from circulation by glucuronidation in the liver.
  • T3 isn't typically prescribed to hypothyroid patients due to its short half-life and rapid gastrointestinal absorption, which can lead to significant fluctuations in plasma levels throughout the day.
  • T3 and T4 bind to the same nuclear receptor, but T3 binds with 10 times more affinity, making it the more active form of thyroid hormone.
  • Some consider T4 to be a circulating prohormone of T3, with most peripheral activity resulting from the conversion of T4 to T3 by 5' monodeiodinase. However, there is still substantial evidence of inherent biological activity for T4.
  • Many target tissues can regulate the conversion of T4 to either T3 or rT3, thereby locally controlling hormone activity. Although the thyroid releases some T3 into circulation, most circulating T3 is derived from the peripheral conversion of T4 into T3 and its release back into circulation (e.g., liver, kidney, and skeletal muscle).

  

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  Physiologic action and regulation of thyroid hormones.

  • Notes.
  • Thyroid hormones do not primarily indicate or inhibit specific cellular processes in many tissues. However, numerous processes only function optimally when the correct amounts of thyroid hormones are present, highlighting their permissive nature.
  1. Metabolic rate: Thyroid hormones increase the metabolic rate by enhancing Na+/K+-ATPase activity, as evidenced by increased oxygen consumption, increased respiratory rate, and heat production.
  2. Growth and Maturation: Without sufficient thyroid hormones during the perinatal period, the nervous system's maturation quickly develops abnormalities. These include abnormal synapses development, decreased dendritic branching and myelination, leading to mental retardation. These neural changes are irreversible and result in cretinism unless replacement therapy starts soon after birth.
  3. Lipid Metabolism: Thyroid hormone speeds up cholesterol clearance from the plasma. It is necessary for converting carotene to vitamin A, hence hypothyroid individuals may suffer from night blindness and skin yellowing.
  4. Cardiovascular Effects: Thyroid hormones have a positive impact on the heart in two ways. They increase the force of the heart's contractions (inotropic effect) and speed up the heart rate (chronotropic effect). The increased contractility is partly direct and partly indirect, as they increase the number and affinity of beta-adrenergic receptors in the heart, increasing sensitivity to catecholamines. They also directly increase heart rate by acting on the SA node. Cardiac output, heart rate, and stroke volume are all increased, while systolic pressure increases due to increased stroke volume, and diastolic pressure decreases due to decreased peripheral resistance. Optimum cardiac performance requires thyroid hormones within the normal range.
  5. Bone growth: Thyroid hormones work in synergy with Growth Hormone (GH).
  6. Gut motility: Thyroid hormones increase gut motility.

  T3 functions (4 B’s):

  • Brain maturation.
  • Bone growth.
  • β-adrenergic effects.
  • Basal metabolic rate.

  Regulation of thyroid hormones.

  • TRH from the hypothalamus stimulates thyrotrophs in the pituitary gland to secrete TSH, which in turn stimulates follicular cells to secrete thyroid hormones.
  • The release of thyroid hormone is regulated through negative feedback inhibition by T3 on hypothalamic TRH-secreting neurons and thyrotroph cells of the anterior pituitary.
  • T3 acts upon the paraventricular nucleus to decrease the synthesis and release of TRH.
  • Increasing concentrations of T3 also cause downregulation of thyrotroph cell TSH gene transcription and internalization of their TRH receptors, which reduces their responsiveness to TRH.
  • Thus, T3 is the main regulator of TSH secretion. Regulatory T3 concentrations partially arise from the systemic conversion of T4 to intracellular T3 by the 5' deiodinase enzyme present within the cells of the hypothalamus and pituitary gland. However, systemic circulating T3 levels also contribute to the total intracellular T3; thus, exogenously administered T3 contributes to the feedback inhibition of TSH.
  • Exogenous T3 supplementation would reduce circulating levels of TSH, leading to decreased secretion of T4 from the thyroid gland. This could also lead to decreased peripheral rT3 conversion.