Hypothyroidism denotes an underactive thyroid, an endocrine gland located in the front of the neck, just below the larynx (voice box). The thyroid, via its production of thyroid hormones (T4 and T3), activates over 100 cellular enzymes responsible for a multitude of functions in every cell of the body. Virtually every metabolic process is affected by thyroid hormones.
When secretion of thyroid hormones is excessive, the metabolic rate can increase up to 100% above normal. If no thyroid hormone is secreted, metabolic activity can quickly drop 40%. In hypothyroidism, thyroid function usually drops only slightly, but even this causes cellular functions to slow down and metabolic wastes to build up throughout the body. Hypothyroidism can range from a barely detectable (subclinical) drop in thyroid hormone production and/or activity to a severe drop that results in life-threatening state called myxedema.
The functioning of the thyroid gland is affected by an interactive web of body systems in which it plays a part. Other primary participants in this web include: the hypothalamus, the pituitary, the liver, the kidneys, the adrenal glands, and hormone-like substances called cytokines. If the activity of any of these components is impaired, this disruption in normal function can result in low thyroid activity.
The thyroid produces two main hormones: T4, the least active form, and T3, a much more active hormone primarily responsible for regulating cellular metabolic activities. The production of both T4 and T3 is carefully controlled by the thyroid’s overseers, the pituitary and hypothalamus, two endocrine glands located in the brain. As T3 levels drop in the blood, the hypothalamus secretes TRH (thyrotropin-releasing hormone), a signaling hormone that notifies the pituitary to secrete TSH (thyroid-stimulating hormone). As its name implies, TSH stimulates the thyroid gland to produce T4 by combining iodine with the amino acid tyrosine. This results in the production of approximately 90% of the body’s T4 and 10% of its T3. (T4 is tyrosine plus 4 iodine molecules, while T3 is tyrosine plus three iodine molecules.) If the hypothalamus fails to secrete TRH, the pituitary's fail-safe system takes over. The pituitary checks up on the hypothalamus by sampling the amount of T3 passing through its own circulation as it converts inactive T4 into T3. If its T3 levels drop, the pituitary gland secretes TSH, which triggers the thyroid to produce and release T4, thus quickly rectifying the situation.
Once T4 is in the blood, another part of the body's network takes over, using cortisone, a hormone secreted by the adrenal gland, to convert T4 to T3 in the peripheral tissues, primarily the liver and kidneys, from which T3 is sent into the bloodstream.
Although now circulating to cells throughout the body, T3 has still not reached its final target, the interior of the cells where T3 affects metabolic functions. To complete its job, T3 must pass through the cellular membranes and connect with the right receptor sites to gain entry into the mitochondria (the tiny energy production factories within each cell) and/or the cell’s nucleus.
Finally, effective thyroid function faces one other potential internal roadblock: cytokines. Hormone-like substances secreted by various types of cells, cytokines direct immune responses and act as messengers in cell-to-cell communication. Some cytokines directly affect the hypothalamic-pituitary-thyroid axis and are capable of blocking the conversion of T4 to T3.
Conditions outside the body can also affect thyroid function. When the diet does not contain adequate amounts of iodine, the thyroid cannot produce T4. When this occurs, the thyroid enlarges, swelling into a goiter, the typical sign of hypothyroidism in the developing world where iodine deficiency is common. Long-term stress, which depletes the adrenal glands’ stores of cortisone, can also cause a problem. Even if the thyroid gland produces sufficient amounts of T4, so blood tests of T4 levels (the test commonly used to evaluate thyroid activity) appear normal, if insufficient cortisol is available in the liver and kidneys where it is used to convert T4 to T3, metabolism will slow down. High levels of cytokines may also play a role here since certain cytokines prevent the conversion of T4 to T3.
If a blood test finds low levels of T4 along with low levels of TSH, this suggests that the pituitary is not doing its job. If, however, blood levels of TSH are elevated and T4 levels are still low, this indicates that the pituitary has responded properly, but the thyroid gland is not following the directions provided by TSH.
If T3 levels are adequate, this suggests one of three possibilities. Cellular membranes could be malfunctioning, which would prevent T3 from gaining entry into the cells. T3 could be just slightly malformed, in which case it would have difficulty entering the cell and, if it could manage to get inside, might not be able to attach to the appropriate receptor sites. Finally, the receptor sites inside the cells might not be functioning properly.
To sum up this complex array of possibilities, hypothyroidism may be due to:
Although experts estimate that some disorder in thyroid function affects approximately 13 million Americans, more than half are undiagnosed since many people mistake the signs of hypothyroidism for aging-associated declines. Mild thyroid failure occurs in 4% to 17% of women and 2% to 7% of men, with the risk increasing with age. The elderly are most susceptible, but hypothyroidism can affect people of all ages, even infants. One out of every 4,000 infants is born with congenital hypothyroidism.
If blood levels of T4 are used as the only diagnostic criterion, between 1-4% of the adult population has moderate to severe hypothyroidism, and another 10-12% has mild hypothyroidism. If, in addition to blood thyroid (T4) levels, medical history, physical examination, and basal body temperature are used, the true incidence of hypothyroidism ranges somewhere near 25% of the population. Of this 25%, women comprise 20%, and men, 5%.