Thyroid Function

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OrgansHormonesThyroid Function

The function of the thyroid is to secrete hormones which control metabolic pathways and thereby control various physiological functions. The thyroid gland operates in concert with the hypothalamus and the pituitary, which is commonly referred to as the "hypothalamic-pituitary-thyroid axis." In addition to the stimulatory cascade leading to thyroid hormone secretion, the axis is also subject to feedback inhibition by the circulating thyroid hormones.

The Thyroid

The thyroid is a small (25 grams) butterfly-shaped gland located at the base of the throat. The largest of the endocrine glands, it consists of two lobes joined by the isthmus. The thyroid hugs the trachea on either side at the second and third tracheal ring, opposite of the 5th, 6th and 7th cervical vertebrae. It is composed of many functional units called follicles, which are separated by connective tissue.
Thyroid follicles are spherical and vary in size. Each follicle is lined with epithelial cells which encircle the inner colloid space (colloid lumen). Cell surfaces facing the lumen are made up of microvilli and surfaces distal to the lumen lie in close proximity to capillaries.
The thyroid is stimulated by the pituitary hormone TSH to produce two hormones, thyroxine (T4) and triiodothyronine (T3) in the presence of iodide. Hormone production proceeds by six steps:
  1. Dietary iodine is transported from the capillary through the epithelial cell into the lumen.
  2. Iodine is oxidized to iodide by the thyroid peroxidase enzyme (TPO) and is bound to tyrosine residues on the thyroglobulin molecule to yield monoiodotyrosine (MIT) and diiodotyrosine (DIT).
  3. TPO further catalyzes the coupling of MIT and DIT moieties to form T4 and/or T3.
  4. The thyroglobulin molecules carrying the hormones are taken into the epithelial cells via endocytosis in the form of colloid drops.
  5. Proteolysis of the iodinated hormones from thyroglobulin takes place via protease/peptidase action in lysosomes and the hormones are released to the capillaries.
  6. Any remaining uncoupled MIT or DIT is deiodinated to regenerate iodide and tyrosine residues.
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The Pituitary

The pituitary is located at the base of the brain and consists of two lobes, denoted the anterior and posterior lobes. This endocrine gland produces several metabolic hormones that direct crucial functions throughout the body, including regulation of growth, reproduction and metabolism. The pituitary is closely associated with the hypothalamus, which regulates the secretion of pituitary hormones through the release of various neurohormones.
The anterior pituitary is crucial for proper thyroid function through the production and secretion of thyroid stimulating hormone (TSH). TSH secretion is positively regulated by a neurohormone known as thyrotropin releasing hormone (TRH) from the hypothalamus.
The Hypothalamus

The hypothalamus is located at the base of the brain as part of the diencephalon. The hypothalamus directs many corticodiencephalic processes which coordinate peripheral autonomic mechanisms, endocrine activities and many somatic functions, including regulation of water balance, body temperature, sleep, sexual development and food intake. The hypothalamus secretes several neural hormones which regulate secretion of various pituitary hormones. The neuropeptide TRH is secreted by the hypothalamus and acts to stimulate TSH production in the anterior pituitary
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Thyrotropin releasing hormone is produced by the hypothalamus and functions to stimulate the anterior pituitary to release TSH. TRH is a small tripeptide that acts in conjunction with somatostatin and dopamine to regulate the synthesis and release of TSH in a dose dependent manner. Dysfunction at this stage in the stimulatory cascade results in decreased TSH production and hence hypothyroidism, termed a tertiary thyroid disorder. While thyroid hormones T4 and T3 down-regulate TSH in a classic feedback inhibition scheme, TRH production is also inhibited the these thyroid hormones, albeit to a lesser degree, in the hypothalamus.
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Thyroid stimulating hormone (TSH) or thyrotropin is a glycoprotein with a molecular weight of approximately 28,000 daltons, synthesized by the basophilic cells (thyrotropes) of the anterior pituitary. TSH is composed of two noncovalently linked subunits designated alpha and beta. Although the alpha subunit of TSH is common to luteinizing hormone (LH), follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG ), the beta subunits of these glycoproteins are hormone specific and confer biological as well as immunological specificity. Both alpha and beta subunits are required for biological activity. TSH stimulates the production and secretion of the metabolically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3), by interacting with a specific receptor on the thyroid cell surface. T3 and T4 are responsible for regulating diverse biochemical processes throughout the body which are essential for normal development and metabolic and neural activity.
The synthesis and secretion of TSH is stimulated by the hypothalamic tripeptide thyrotropin releasing hormone (TRH) in response to low levels of circulating thyroid hormones. Elevated levels of T3 and T4 suppress the production of TSH via a classic negative feedback mechanism. Recent evidence also indicates that somatostatin and dopamine exert inhibitory control over TSH release, suggesting that the hypothalamus may provide both inhibitory and stimulatory influence on pituitary TSH production. Failure at any level of regulation of the hypothalamic-pituitary-thyroid axis will result in either underproduction (hypothyroidism) or overproduction (hyperthyroidism) of T4 and/or T3.
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Thyroxine (T4) is an iodine-containing hormone which has a molecular weight of approximately 777 daltons and is secreted by the thyroid gland. T4 and its associate thyroid hormone T3 are responsible for regulating diverse biochemical processes throughout the body which are essential for normal metabolic and neural activity. Although T3 has greater biologic potency, T4 is normally present in human serum in approximately 50 fold excess of circulating T3, and accounts for more than 90 percent of the circulating protein-bound iodine. T4 is 99.9 percent bound to serum thyroxine binding proteins (TBP). The hormone is transported bound primarily to thyroxine binding globulin (TBG) and secondarily by thyroxine binding prealbumin (TBPA) and albumin. Less than 0.03 percent of the total circulating T4 is unbound and therefore biologically active.

Clinically, T4 measurements have long been recognized as an aid in the assessment and diagnosis of thyroid status. Elevated T4 values are characteristically seen in patients with overt hyperthyroidism, while T4 levels are generally depressed in patients with overt hypothyroidism. Normal T4 levels accompanied by high T3 values are seen in patients with T3-thyrotoxicosis. T4 levels are altered by physiological or pathological changes in TBP capacity. Thyroxine binding globulin (TBG) capacity has a pronounced effect on the concentration of thyroid hormones. Consequently, T4 levels may be elevated with increased concentrations of TBG, such as in pregnancy, administration of oral contraceptives or estrogen, infectious and chronic active hepatitis, biliary cirrhosis or congenital increase in TBG levels. Conversely, when TBG levels are decreased, such as in nephrotic syndrome, androgen therapy, glucocorticoid therapy, major systemic illness or congenital decrease of TBG, T4 may be reduced.
Drugs which compete for protein binding sites, such as phenylbutazone, diphenylhydantoin or salicylates, can result in a depressed T4 measurement. Serum T4 levels in neonates and infants are higher than values in the normal adult, due to the increased concentration of TBG in neonate serum. While in many cases T4 values give good indications of thyroid status, T4 values should be normalized for individual variations in thyroxine binding protein (TBP) capacity. The Free Thyroxine Index (FTI) is conventionally used to achieve this measurement. To ensure maximum diagnostic accuracy, the final definition of thyroid status should be determined in conjunction with other thyroid function tests such as TSH, FT4, Total T3, FTI and clinical evaluation by the physician.
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Triiodothyronine (T3) was first identified in human serum in 1952 by Gross and Pitt-Rivers. Since that time, the physiologic effects of T3 have been widely investigated and appreciation of its clinical significance has greatly increased. T3 and its associate thyroid hormone, thyroxine (T4), are responsible for regulating diverse biochemical processes throughout the body which are essential for normal development and metabolic and neural activity. T3 has a molecular weight of 651 daltons and contains 58 percent iodine. The majority of serum T3 is derived enzymatically from 5’-deiodination of T4 in the peripheral tissues rather than directly from the thyroid. Approximately one-third of all T4 secreted is deiodinated to yield T3. T3 is bound to thyroxine binding globulin (TBG), prealbumin and albumin. The actual distribution of T3 among these binding proteins is controversial as estimates range from 38 percent to 80 percent for TBG, 9 percent to 27 percent for prealbumin and 11 percent to 35 percent for albumin. The binding of these proteins is such that only 0.2 percent to 0.4 percent of the total T3 is present in solution as unbound or free T3 (FT3). This free fraction represents the physiologically active thyroid hormone. There is evidence that T3 is the metabolically active hormone with T4 serving as a "prohormone" for T3 just as thyroglobulin is for T4. The metabolic effectiveness of T4 is decreased by agents that inhibit T3 formation, indicating that much of the T4 activity stems from formation of T3. This is further supported by the differences in TBG binding affinity and half-life. T4 has a half-life of 6.7 days while T3 has a half-life in serum of only 1.5 days. It has become apparent in recent years that T3 plays an important role in the maintenance of the euthyroid state.

Serum T3 measurements can be a valuable component of a thyroid screening panel in diagnosing certain disorders of thyroid function, as well as conditions caused by iodide deficiency. Clinically, measurements of serum T3 concentration are especially valuable in diagnosing hyperthyroidism and in following the course of therapy for this disorder. Under conditions of strong thyroid stimulation, the T3 measurement provides a good estimation of thyroid reserve. Recognition of a thyroid dysfunction called T3-thyrotoxicosis, associated with an increased serum T3 level but normal T4, free T4 and in vitro Uptake results have further highlighted the importance of serum Total T3 measurements. Dietary iodide deficiency results in inadequate production of thyroid hormones despite the presence of normal thyroid tissue. In these cases, the serum T4 concentration is often low while the TSH concentration is elevated. Elevated TSH associated with low T4 is normally indicative of hypothyroidism. However, in iodine deficiency, these results together with a normal or slightly elevated serum T3 are indicative of euthyroid status in most individuals.
T3 levels are also affected by conditions which affect TBG concentration. Slightly elevated T3 levels may occur in pregnancy or during estrogen therapy. Depressed levels may occur during severe illness, malnutrition, in renal failure and during therapy with the antithyroid drugs propranolol, propylthiouracil and salicylates. In patients with severe or chronic illnesses, many abnormalities of thyroid hormone balance occur. T4 production and the extent of serum thyroid hormone binding may be independently abnormal, resulting in low, normal or high free T4 estimate. Serum T3 concentrations are often low; TSH levels may be normal or slightly elevated. Total T3 measurements may be valuable when hyperthyroidism is suspected and the free T4 estimate is normal.
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