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The Normal Thyroid and its Biologic Action

by Andrea Jensen
Fall 2006


Introduction

In the past three decades, a dramatic increase in the incidence of thyroid dysfunction among middle-aged to geriatric cats has been observed.  A number of factors could be contributing to this apparent rise, including the simple fact that cats are living longer and receiving medical evaluation more frequently than in prior years.  As both veterinarians and guardians learn more about the feline patient, recognition of the clinical syndrome of hyperthyroidism increases.  Along with recognition, our ability to confirm diagnosis with sensitive assays for thyroid hormones and related factors has increased.  Because of these advancements, it is difficult to assess whether or not environmental or genetic factors are influencing the incidence of the disease.  It has been suggested that several environmental factors may have caused an increase in feline susceptibility to hyperthyroidism.  Some of these factors include an increase in indoor only pets, which often results in a diet of strictly commercial cat foods, many of which contain iodine based food dyes.  In addition, some cases of hyperthyroidism are caused by cancerous tumors, which may have increased in incidence as carcinogens have increased in our environment.  Regardless of the cause, hyperthyroidism has become one of the most common endocrine diseases afflicting aged cats today.

The prominence of hyperthyroidism in geriatric feline medicine has been a driving force for research in this area.  In order to fully understand dysfunction, it is critical to understand the mechanisms of action involved in the normal animal.  The purpose of this discussion is to outline the normal structure, function, and biologic action of the thyroid gland and its hormones.

Histology, Synthesis, and Secretion

Thyroid hormones are synthesized by a unique mechanism in the thyroid gland.  In fact, the histology of the gland itself is exceptional.  Contained within the thyroid gland are numerous thyroid follicles, which can each be considered thyroid hormone factories operating independent of each other.  Each follicle consists of a spherical border of follicular cells surrounding a central lumen where thyroid hormone is synthesized.  The follicular lumen is made up of a colloid matrix, primarily thyroglobulin protein, which is the necessary scaffold for building both triiodothyronine (T3) and tetraiodothyronine (T4) and is synthesized within the follicular cells and transported to the lumen.  Throughout the gland, a rich vascular supply of interfollicular capillaries provides the necessary components for thyroid hormone, such as iodine and amino acids, which travel through the follicular cells and enter the lumen.  The thyroid gland receives more blood flow per unit volume of tissue than virtually any other organ in the body.

Follicular cells are stimulated by thyroid stimulating hormone (TSH) released from the pituitary gland, which itself is stimulated by thyroid releasing hormone (TRH) from the hypothalamus.  Both the hypothalamus and the pituitary are under negative feedback control by the presence of T4 and T3 in the blood and the subsequent release of somatostatin, a TSH inhibitor, from the hypothalamus.  This feedback mechanism is commonly referred to as the hypothalamic-pituitary-thyroid axis.  When blood concentrations of T4 and T3 are low, TSH is uninhibited and signals the follicular cells of the thyroid gland to become active.  The follicular cells respond by expanding from low cuboidal to columnar, and organelles such as rough endoplasmic reticulum, Golgi apparatus, and lysosomal bodies become more pronounced.

The action of TSH on follicular cells influences all processes associated with both synthesis and secretion of thyroid hormones.  On the exterior surface of the follicular cells, an active transport system for iodide uptake called the sodium-iodide symporter is stimulated by TSH, which directly increases the amount of iodide taken up from the blood and made available for thyroid hormone synthesis.  Iodide (I-), in addition to necessary amino acids and other factors, are actively transported by the Golgi apparatus of the follicular cells through the cell and into the lumen of the follicle.  Once the iodide has passed into the lumen, it is immediately oxidated to iodine (I2) by the critical enzyme thyroperoxidase.  Tyrosyl residues and thyroglobulin are iodinated to form T4 and T3, and may remain stored until more thyroid hormone is needed in circulation.  The synthesis phase can be interrupted with drug therapies, such as methimazole, which specifically inhibits the action of thyroperoxidase.

To stimulate secretion from the follicular lumen, TSH upregulates basolateral receptors of follicular cells.  The activation of these receptors activates adenylate cyclase within the cell membrane and the subsequent generation of intracellular cAMP, leading to a cascade of events by kinases and other enzymes, with the eventual stimulation of microvilli on the lumenal surface of the follicular cells.  Microvilli elongate, reach further into the colloid matrix, and phagocytize "handfuls" of thyroid hormone containing colloid to bring into the cell for processing and release.  This endocytosis is an early step in response to TSH stimulation.  The colloid droplet, which is now contained within the cytoplasm of the follicular cell, fuses with intracellular lysosomes to form a phagolysosome.  The significance of this step is in the contents of the lysosome.  Proteolytic enzymes of the lysosome process the thyroid hormone complex, breaking down thyroglobulin and releasing free T4 and T3 into the cytosol.  T4 and T3 are hydrophobic and freely diffuse out of the cell and into circulation, where they become protein bound to increase stability in circulation.

In Circulation

Although the ratio of T4 to T3 released from the thyroid gland is approximately 2 to 1, the concentration is rapidly altered to approximately 20 to 1 by the time it reaches peripheral tissues.  T3 is the more biologically active form on target cells with a plasma half life measured in hours, while T4 is the primary circulating form with a half life measured in days.  T4 binds with high affinity to thyroxine-binding globulin (TBG) produced in the liver.  Protein bound hormone is protected from breakdown and does not easily enter target cells, and can therefore remain in circulation longer.  T3 loosely binds to transthyretin or albumin, and can easily free itself to gain access to target cells or be cleared from the body.  Certain drug therapies, such as diphenylhydantoin, o,p'-DDD, or salicylates can selectively displace T4 from TBG, making T4 more susceptible to degradation and clearance from the body.

Protein bound T4 in circulation may be released from TBG and converted to active T3, converted to inactive T3, or cleared from the body.  Conversion from T4 to active T3 for use by target cells is via the enzyme 5'-Deiodinase in the liver, kidney, or peripheral tissues.  This is the typical reaction the body uses to rapidly produce more biologically active thyroid hormone as needed.  In some cases, conversion to inactive T3 (reverse T3 or rT3) by a related enzyme, 5-Deiodinase, takes place.  This enzyme removes an iodine from a different position on the molecule, rendering it inactive.  When the body needs a mechanism to attenuate the overall metabolic effects of thyroid hormone, such as during protein malnutrition, starvation, or febrile illness, this mechanism is a valuable way to preserve resources.  However, there are also environmental factors that can cause the body to increase the activity of 5-Deiodinase simply by blocking the action of 5'-Deiodinase.  Food color red number 3, found in some foods is an example of a 5'-Deiodinase inhibitor.  Any drugs or foods exceptionally high in iodine can have the same effect.  The reduction in active T3 reduces the amount of negative feedback on the hypothalamus and pituitary gland, resulting in an increase in TSH circulation, which may over-stimulate thyroid follicular cells.

The primary clearance mechanism of excess thyroid hormone is in the liver, but some is cleared by the kidney.  Excess T4 undergoes glucuronidation, which is relatively poor in the cat compared to other species.  T3 undergoes sulphation in the liver.  The conjugation process with glucuronic acid is facilitated by the enzyme T4 UDP-glucuronyl transferase.  This enzyme attaches a glucuronic acid to a specific position on the phenolic ring of T4, which increases the solubility of the hormone and allows it to enter the bile and be cleared from the body.  Due to entero-hepatic recycling, 1/3 of the metabolites in bile are reabsorbed.  Since cats are relatively poor conjugators of phenolic compounds, it is useful to note that drug therapies such as butazoladine and phenobarbitol increase T4 clearance by inducing T4 UDP-glucuronyl transferase activity.

Target Cells

Thyroid hormone targets virtually every cell in the body to activate mitochondrial energy metabolism by increasing oxygen consumption, which increases basal metabolic rate (BMR), respiratory rate, and calorie generation.  Thyroid hormone also upregulates gene expression of structural proteins for growth and dozens of enzymes needed for intermediator metabolism.  T3 and T4 that are free of carrier protein are both able to enter target cells, but T3 acts with significantly higher affinity within the cell.  Free T4 in peripheral tissues, as mentioned previously, may undergo monodeiodination by 5'-Deiodinase to form active T3.  Active T3, in the unbound form, is hydrophobic and passes freely into target cells.  It immediately binds to cytosolic binding protein (CBP) to stabilize it intracellularly and prevent it from diffusing back out of the cell.  CBP binding is a low affinity reaction, and T3 readily frees itself to gain access to the mitochondria or the nuclear receptors within the cell.  Binding to the inner mitochondrial membrane activates oxidative phosphorylation and ATP synthesis.  Binding to nuclear receptors increases mRNA transcription leading to an increase in protein synthesis.

T3 hormone increases the rate at which the body uses carbohydrates and fats, increasing breakdown and decreasing storage, to make more glucose available for the energy demands generated by increased BMR and protein catabolism.  Specifically, T3 increases glycolysis, gluconeogenesis, intestinal glucose absorption with increased intestinal motility, and decreases the rate of glycogen storage in the muscle and liver.  In adipose tissue, lypolysis is greatly enhanced, sensitivity to other metabolic hormones is increased, cholesterol excretion is increased, and oxidation of free fatty acids is increased.

Such dramatic increases in energy demand and oxygen use creates a need for higher blood flow and delivery to tissues.  T3 hormone directly increases blood flow by stimulating heart rate and cardiac output.  This has great significance in feline patients because the increased work load on the heart can lead to cardiac hypertrophy, particularly in the left ventricle, to handle not only the increased heart rate, but also the increased demand for a larger stroke volume.  As the muscle mass increases, it becomes less efficient and susceptible to total heart failure.

Virtually every tissue in the body is responsive to thyroid hormone.  Liver tissue, kidney, lung, intestine, adipose tissue, heart, and skeletal muscle are all susceptible to its effects.  In addition, the central nervous system responds to thyroid hormone.  As might be expected, increases in BMR ncludes an increase in neural transmission, which is particularly critical in early neuronal development of young animals.  In adult cats with hyperthyroidism, this increase in neural impulse transmission may be part of the cause of irritability and hyperactivity in chronic patients, combined with the overall imbalance of metabolism as a whole.

Thyroid research in the feline patient has been very successful in elucidating very specific mechanisms involved from the time of dietary iodine intake to that of synthesis and release of biologically active thyroid hormone in the body and in target cells.  What is especially encouraging is the knowledge we have, and are still gaining, regarding the unique characteristics of the cat and how we can best handle the direct and indirect effects caused by dysfunction.


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