Thyroid Function

J. Jerry Kaneko

Department of Pathology, Microbiology, and Immunology
School of Veterinary Medicine
University of California, Davis
Davis, California

Disorders of the thyroid gland are the most common endocrine disorders in humans, and extensive historical and scientific literature is available. Among the domestic animals, thyroid function and its diseases are well known in companion animals but less so in other animals, domestic or wild. In livestock, nutritional iodine deficiencies have been of greater importance than thyroid gland diseases, particularly in the iodine-deficient areas of the world. The importance of thyroid function and its diseases has also become progressively more important as the longevity of companion animals such as the dog and the cat has increased.

Advances in thyroid physiology, pathogenesis of its diseases, and the continued development and refinement of methods of testing thyroid function have added impetus to the study of thyroid disease in all animals. This chapter reviews the anatomy and physiology of the thyroid gland and its diseases as a corollary to the understanding of the pathophysiology of the thyroid gland in disease. Emphasis is placed on the physiological bases of a variety of thyroid function tests, most of which are now readily available to the veterinary clinician.

Accessory or extrathyroidal tissue is commonly observed in the dog, particularly near the thoracic inlet though they may be found anywhere along the esophagus. This accessory tissue is fully functional physiologically, synthesizes hormone, and can be located by its uptake of radionuclides. This is a particularly important consideration for the dog when thinking about surgical intervention for treatment of hyperthyroidism resulting from a thyroid tumor.

The thyroid gland is a highly vascularized tissue with a large blood flow. The functional unit of the thyroid gland is the thyroid follicle, which can be envisioned as a spherical structure composed of an outer monolayer of follicular cells surrounding an inner core of colloid. Colloid is a thyroglobulin-hormone complex that is the storage reservoir of thyroid hormone in the thyroid gland. The colloid stored in the lumen is a clear, viscus fluid. The individual follicular cells vary from 5 to 10 μm in height, and the entire follicle may vary from 25 to 250 μm in diameter. The size of the follicles and the height of their follicular cells vary according to the functional state of the gland. The cells may vary from an inactive squamous cell to the highly active, tall columnar cell. Interspersed between the follicles are the thyroid “C” cells, the source of calcitonin, the hypocalcemic hormone associated with calcium metabolism. A third type of hormonal tissue, the parathyroid, is imbedded within the thyroid or located in close proximity to it. The parathyroids are the source of parathormone, the hypercalcemic hormone. Removal of the parathyroids is virtually unavoidable during surgical thyroidectomies so that post-surgical hypocalcemias are important consequences to be considered.

The thyroid gland is unique among the endocrine glands in that an integral part of its hormone, L-thyroxine (T₄), is a trace mineral, iodine, which is available to the animal in only limited amounts. Marine plants are known to be good sources of iodine, but on land, iodine is limited and many regions of the world are known to be iodine deficient. The recommended daily requirement is 35 μg/kg bw (276 nmol/kg bw) for the adult dog and 70 μg/kg bw (551.6 nmol/kg bw) for the growing puppy. For most animals, nutrient requirements are given in mg/Kg dry diet or ppm and range from 0.1 to 1.0 mg, including cats and horses. Milk is a poor source of hormonal iodide contributing only about 4% to 7% of the maintenance requirements for hormone (Akasha and Anderson, 1984).

The small requirements are compensated for by an efficient intestinal absorption mechanism and conservation and recycling of internal iodine. Little iodine is lost from the body by the various excretory routes such as urine, saliva, tears, milk, sweat, and feces. Also, whereas most endocrine glands store little of their hormones, the thyroid manages to store large quantities of hormone sufficient for 1 to 3 weeks depending on the species. The thyroid gland contains about 20% of the total body iodine. Its iodine content and size vary with iodine intake and the state of thyroid function, but it usually contains 10 to 40 mg (78.8 to 315.2 μmol) iodine/100 gm tissue or 4 to 16 mg (31.5 to 126.1 μmol) iodine in a 20-kg dog.

Iodine can be absorbed in any of its soluble chemical forms, but in the intestines it is usually absorbed in the form of iodides (I^–), iodates (IO₄^–), or as the hormonal forms. Iodides may be absorbed from any moist body surface, including the mucus membranes, and it is absorbed easily through broken epithelia. Normally, the chief route of entry into the general circulation is by absorption through the mucosal cells of the small intestine. The I^– in the circulation is trapped almost exclusively by the thyroid gland, with small amounts being trapped by the salivary gland and minimal amounts by the gastric mucosa, placenta, and mammary gland. In the ruminant, 70% to 80% of an oral dose is absorbed in the rumen and 10% in the omasum.

The main route of excretion of I^– is by the kidneys through which almost all the I^– that was not trapped by the thyroid is lost in the urine. A small but significant amount is lost in the saliva, and minimal amounts are lost in tears, feces, sweat, and milk. A minute amount of free hormone, that fraction not bound to serum proteins, is also lost in the urine. These routes of excretion are especially important considerations when patients are being treated with radioiodine.

FIGURE 20-1 Pathways of iodine metabolism and thyroid hormone synthesis. Goitrogenic blocking agents are shown in brackets.

1. Trapping of Iodide

FIGURE 20-2 Chemical structures of the major iodinated compounds of the thyroid gland.

2. Synthesis of Thyroid Hormones

After trapping, there is an oxidation of I^–catalyzed by a peroxidase and the product is a highly active form of iodine, most likely a free radical, I^*. This reaction is inhibited by thyrotoxic agents such as the thiouracils or thioureas and stimulated by TSH. Propylthiouracil is commonly used in the treatment of hyperthyroidism. The I^* almost instantaneously binds to the phenyl groups of the tyrosine moieties of thyroglobulin at the 3 or 5 position to form a monoiodotyrosine (MIT) or a diiodotyrosine (DIT). This iodination occurs while the tyrosines remain in polypeptide linkage within the thyroglobulin molecule. Next, the iodinated phenyl groups of the tyrosines are coupled by the oxidative condensation of an iodinated phenyl group of one DIT to another DIT to form T₄ or of an MIT group to a DIT to form T₃. These iodination reactions occur mainly at the follicular cell membrane-colloid interface. These iodination reactions are energy requiring and sensitive to blocking by sulfa drugs, thioureas, and paraaminobenzoic acid (PABA).

3. Storage of Hormone

4. Release of Hormone

TSH stimulation of the release of hormones is the second of its two principal sites of action. Within a few minutes after giving TSH, small packets of colloid are taken up by the follicular cell membrane, and vesicles are formed and taken into the follicular cell by endocytosis. The vesicles merge with lysosomes within the cell, and the lysosomal proteases hydrolyze the colloid and release their MIT, DIT, T₃, and T₄. The released MIT and DIT are enzymatically degraded by microsomal tyrosine deiodinases, and their iodine is recycled within the follicular cell. The T₄ and T₃ are released into the circulation by a simple diffusion process. Of the total hormone released, about 90% is T₄ and 10% is T₃. Within the gland, there is also some deiodination of the T₄ of the inner phenyl group to form rT₃, but most of this deiodination occurs in the peripheral tissues. This rT₃ is the inactive form of thyroid hormone and is on a degradation pathway.

In the cat, rabbit, rat, mouse, guinea pig, pigeon, or chicken, TBG is absent and most of the hormone is transported by albumin. The albumin binding constant is about 10⁵ liter/mole for T₄ or T₃ but with an unlimited binding capacity. In these species without TBG, albumin transports between 50% and 80% of the hormones. T₃ (and likely rT₃) appears to bind to these transport proteins in parallel with T₄ binding.

Protein binding has several functions. Protein binding solubilizes these lipid soluble hormones for transport in the aqueous plasma. The bound forms also do not readily pass through the renal glomerular membrane, so they minimize urinary loss of hormones, whereas the free hormones pass and are lost. The bound forms also serve as a large and readily accessible reservoir of the active hormones for delivery to the target organs and cells. Finally, the protein binding equilibrium is the fundamental basis for protein or immunoprotein binding assays of hormone and the indirect assay of TBG.

The molecular basis of thyroid hormone action at the cellular level has been frequently reviewed, and a multifaceted concept of its action has evolved. For many years, the mitochondrion was considered to be the site of thyroid hormone action. Uncoupling of oxidative phosphorylation (ox-phos) in the mitochondria was a viable hypothesis for many years. Under normal conditions, 3 moles of ATP (P) are synthesized per atom of oxygen (½ 0₂ = 0) used in the cytochrome oxidase system; hence, P:0 ratio equals 3. If less than 3 moles of ATP are formed per unit 0 in a system in the presence of a compound such as the thyroid hormone, the system is said to be uncoupled (i.e., P:0 ratio is less than 3). In this event, more O₂ would be needed to generate an equivalent amount of ATP, and O₂ consumption would increase. T₄ has repeatedly been shown to uncouple oxidative phosphorylation in in vitro systems, but it does so only in large, unphysiological amounts. These findings were extended to the whole animal to explain the increased oxygen consumption by T₄. The large amounts of oxidative energy not incorporated into ATP increased body temperature and were dissipated as heat. Thus, T₄ action was theorized to be the result of the uncoupling of oxidative phosphorylation.

Another now well-known effect of thyroid hormone is the stimulation of cellular protein synthesis (Tapley, 1964; Tata et al., 1963), and this occurs during the latent period when the calorigenic effect of thyroid hormone occurs. T₃ is now known to stimulate messenger RNA (mRNA) transcription, increasing translation and protein synthesis and accounting for the anabolic effects of thyroid hormones. This also means that the site of action is at the cell nucleus.

Another action of thyroid hormone is to stimulate the “sodium pump” (Na-K-ATPase) at the cell membrane, an action that would increase O₂ consumption (Edelman, 1974). Ouabain, an inhibitor of Na-K-ATPase, also inhibits the increased O₂ consumption induced by T₄ or T₃. Thus, stimulation of the sodium pump is an important way in which thyroid hormones stimulate increased oxygen consumption and accounts for almost half of the increase.