Endocrine System: Thyroid Gland Function

Endocrine - Thyroid

• The presentation covers the cellular biology and homeostasis of the endocrine system, specifically focusing on the thyroid gland.
• VP 2025 and Clara Camargo, DVM, Cert AqV are associated with this material.

Learning Objectives

• Locate the thyroid glands and briefly describe both its macro and microanatomy.
• Describe the regulation, synthesis, secretion, transport, and metabolic clearance of thyroid hormones.
• Describe the effects of the thyroid hormones on target tissues.
• Understand the symptoms of the main pathologies related to the thyroid hormones, including hyperthyroidism, hypothyroidism, and goiter.

Endocrine Glands

• Key endocrine glands include the hypothalamus, pineal gland, parathyroid, adenohypophysis, thyroid, pancreas, adrenal glands, ovaries, and testicles.
• The thyroid produces T3, T4, and calcitonin

Hormone Chemical Structure

• Amines are hormones derived from the modification of amino acids and are generally hydrophilic, except for thyroid hormones, which are hydrophobic.
• Thyroid hormones (T3 and T4) are derived from the amino acid tyrosine, as are catecholamines (dopamine, norepinephrine, epinephrine).
• The half-life of epinephrine is about 1 minute, while thyroxine (T4) has a half-life of 7-10 days.
• T3 and T4 require carrier proteins like thyroxine-binding globulin (TBG) and albumin for transport in the blood.
• Catecholamines bind to cell membrane receptors, whereas thyroid hormones bind to nuclear receptors.

Thyroid Gland Anatomy

• The thyroid gland is a butterfly-shaped gland located caudal to the trachea, typically at the level of the first or second tracheal ring in most mammals.

Thyroid Gland Microanatomy

• Thyroid tissue consists of numerous sac-like structures called thyroid follicles, which vary in size and have follicular epithelial cells arranged in a circular pattern that synthesize thyroid hormones.

Thyroid Gland Colloid

• The follicles are filled with colloid, a viscous liquid rich in protein (thyroglobulin, which is a glycoprotein) produced by the follicular epithelial cells.
• Thyroid hormones are stored in the colloid, which allows mammals to withstand periods of iodine deprivation without immediate effects on thyroid hormone production.

Thyroid Gland Parafollicular or C-Cells

• Parafollicular cells, or C-cells, are located outside the follicles, and secrete calcitonin, a peptide hormone involved in the regulation of calcium and phosphate metabolism.
• Calcitonin secretion is primarily regulated by blood calcium levels and is not directly controlled by the HP axis.
• When blood calcium levels are high, calcium sensors on the parafollicular cells trigger the release of calcitonin to help reduce calcium levels.

HPT Axis

• The hypothalamus responds to various stimuli, including cold weather, leptin (produced by adipose tissue during TAG gain), and lactation.
• The most important regulator of TRH secretion is thyroid hormone itself.
• Thyroid hormones also provide negative feedback directly on the adenohypophysis, causing reduced secretion of TSH.
• The concentration of T4 and T3 in blood and brain creates a negative feedback loop to the hypothalamus and anterior pituitary.

Thyroid Hormone Synthesis

• Tyrosine, a component of thyroglobulin.
• Iodine (I²) is essential.
• Thyroglobulin is synthesized within the follicle epithelial cells.
• Tyrosine combines with iodine to form thyroid hormones.

Thyroid Hormone Synthesis - Iodide

• Iodine (I²) comes from the diet and is converted to iodide (I-) in the intestinal tract before being transported to the thyroid follicle cells.
• Thyroid follicle cells trap iodide (I-) via a secondary active transport process using a Na+/I- cotransporter, where sodium provides the driving force to bring iodide into the cell.
• Intracellular iodide concentration is 25 – 200 times higher than outside the cell.

Thyroid Hormone Synthesis - Thyroid Peroxidase

• Oxidation of iodide to elemental iodine (l- → l²)
• Tyrosine iodination (Iodine combines to the tyrosine residue on thyroglobulin protein with the help of thyroid peroxidase)
• If 1 l² molecule attaches = MONOIODOTYROSINE (MIT)
• If 2 l² molecules attach = DIIODOTYROSINE (DIT)

Thyroid Hormone Synthesis - Fusion

• Fusion of two iodinated tyrosines
• 1 DIT + 1 DIT = T4 or Tetraiodothyronine or Thyronine or Thyroxine (4 iodine molecules)
• 1 MIT + 1 DIT = T3 or Triiodothyronine (3 iodine molecules)

Thyroid Hormone Storage

• T3 and T4 remain attached to thyroglobulin molecules and are stored in the colloid until secretion, offering a unique storage that allows the thyroid to maintain a large hormone reserve.
• T4 is preferentially produced by the thyroid follicle cells when iodine is sufficient; normally, the thyroid hormone is synthesized at a ratio of 4:1 (T4/T3)
• During iodine deficiency, the ratio may shift to 1:3 (T4/T3).
• A major source of T3 is peripheral deiodination of T4 in target tissues via enzyme-dependent deiodinases.

Thyroid Hormone Secretion

• TSH, secreted by the anterior pituitary, stimulates the secretion of thyroid hormones.
• Iodinated thyroglobulin is endocytosed back into the follicular epithelial cells and undergoes proteolysis, liberating both T4 and T3.
• Lysosomes fuse to thyroglobulin vesicles, leading to enzymes cleaving T3 and T4.
• Iodine atoms on iodinated tyrosine residues of thyroglobulin are efficiently recycled within the follicle cell to iodinate new thyroglobulin molecules.
• T3 & T4 freely pass through the thyroid follicle cell membrane into the surrounding capillaries due to their lipophilic nature.

Thyroid Hormone Transport

• Thyroid hormones are transported in the blood plasma attached to proteins, specifically thyroxine-binding globulin (TBG) and albumin, both synthesized in the liver.
• Only a small amount of hormone is free in the blood plasma.
• Free T4 and T3 are available to diffuse into the target cells
• Once free T4 enters the target cell, most of it is converted to T3 by iodothyronine deiodinases in the target cell cytosol.
• Reverse T3 (rT3) can be formed depending on the position of iodine; this is an inactive form of the hormone produced in high amounts in peripheral tissues during disease states.

Thyroid Hormone Transport - Equilibrium

• The equilibrium between free and bound hormone in the blood plasma is shifted by physiological, pharmacological, or pathological conditions such as catabolism during pregnancy and the use of certain drugs.
• Adjustments to maintain a normal amount of free hormone occur rapidly with declines in the rate of metabolism or stimulation of thyroid hormone secretion through the release of TSH.
• Reference values of free T4 and T3 vary for different species.

Hormone Clearance

• T4 and T3 hormones are cleared from the plasma through conjugation (formation of sulfates and glucuronides, mainly in the liver) and deiodination (metabolic breakdown by tissues, mainly in the liver, skeletal muscle, and kidneys).
• Conjugation involves the formation of sulfates and glucuronides majorly in the liver.
• Metabolites are excreted via the liver into bile (subsequently in feces) or via the kidney into the urine.
• A decreased metabolic clearance rate can lead to an excessively high concentration of thyroid hormones in the blood, potentially causing symptoms of hyperthyroidism, such as in liver disease.

Thyroid Hormone Actions

• They are primary factors for the control of cellular metabolism.
• Binds to nuclear receptors and initiate mRNA transcription.
• Important for the normal activity of all tissues.
• The mechanism of action is not fully understood but is being investigated through pathological conditions (hypo or hyperthyroidism).

Thyroid Hormone cellular actions

• There is an increase in the quantity of mitochondria and rate of synthesis.
• BMR is the minimal rate of energy expenditure per unit time at rest.
• Cellular enzymes increase activity in response to thyroid hormones.
• There is an increase in O2 consumption and heat production.
• Weight loss in hyperthyroidism, weight gain in hypothyroidism

Actions of thyroid hormones - metabolism

• There is an increase in absorption of glucose
• Facilitates the movement of glucose into fat and muscle tissues
• Increases lypolysis and mobilises fat, for fatty acids to become available for B-oxidation.
• Stimulates a reduction in plasma cholesterol and liver fat.
• Can cause hyperlipidemia

Thyroid Hormone Action

• Thyroid hormones affect gastrointestinal (GI) functions, increasing appetite, food intake, and GI motility; hyperthyroidism can cause diarrhea due to hypermotility.
• Skin integrity is maintained by thyroid hormones.
• Hypothyroid animals often exhibit hair loss, changes in skin and hair color, and are predisposed to developing skin infections.

Action of thyroid hormones - Growth

• Influence occurs through the nervous system (CNS). Reduced quantities may reduced mental abilities and lethargy in animals.
• GH can lead to dwarfism through hypothyroidism.
• Increase blood flow and cardiac output through the use of catecholamines.
• Increases the numbers of beta adrenergic receptors on a heart
• Improves heart rate and heart excitability.
• Can induce metamorphosis in amphibians and fish larvae.

Thyroid Pathologies

• Hyperthyroidism is most common in cats and is caused by hyperplasia or tumors (adenomas) of the thyroid gland, typically affecting middle-aged to older cats.
• It is characterized by autonomous growth of thyroid follicles due to abnormalities in the signal transduction of the thyroid cell.
• Hypermetabolism causes increased heart rates, weight loss, increased appetite (polyphagia), increased thirst/urination (polydipsia/polyuria), vomiting/diarrhea, shedding, unkempt appearance, and hyperactivity.

Thyroid Pathologies cont.

• Hypothyroidism is more common in dogs and causes a general reduction in metabolic rate, characterized by slow heart rate, decreased body temperature, infertility, weight gain, and slower mental ability. Primary causes of hypothyroidism in dogs include:
  • lymphocytic thyroiditis (inflammation).
  • congenital thyroid dysgenesis (inherited defects in the hypothalamic-pituitary-thyroid axis).
  • T4 transport defects.
  • goitrogens.
  • iodine deficiency.
  • autoimmune thyroiditis. Secondary causes include:
  • pituitary tumors.
  • radiation therapy.
  • glucocorticoids.

Hypothyroidism

• Lethargy and obesity
• Reproductive disorders
• Bradycardia
• Fatigue
• Cold intolerance

Iodine deficiency

• Caused by Inadequate dietary intake and consumption of feeds that cause intereferences with the thyroid gland (Goitrogens)
• Goitrogens are brassicas, white clover pastures.
• It is most prevalent in cattles sheep and goats

Iodine deficiency effects

• In severe cases the organ is unable to cope.
• Animals becaome inappetant, and display a slow heart rate
• Animals undergo reduces fertility and fetus' become hypothyroid.
• Enlargement of the thyroid
• Calves and lambds can be born hairelss and weak

Thyroid Diagnosis

• Total T4 and T3
• Free T4 and T3
• T3 suppression test
• Reverse T3
• Antibodies (T3 and T4, thyroglobulin)
• TRH and TSH
• Genetic test (TPO gene mutation)
• Drugs affecting the thyroid hormones
• Understanding these points help in diagnosis:
• Chemical structure of the hormones
• Synthesis and regulation
• How do they travel in the blood circulation
• Signal transduction
• Hormone clearance