The thyroid gland secretes the hormones T4 (thyroxine) and T3 (triiodothyronine) which then control metabolism. These hormones act on a wide variety of tissues and in each organ may have slightly different effects. Thyroid hormone secretion is under the control of thyrotropin (a thryoid-stimulating hormone, TSH) which is secreted by the pituitary gland. The normal serum Thyroxine/Triiodothyronine levels and the activation of thyroid hormone receptors inversely regulate Thryoid-stimulating hormone secretion; the higher the level of thyroid hormones in the blood, the lower the Thryoid-stimulating hormone level and vice versa. The hallmark of underactive thyroid (primary hypothyroidism), therefore, is an elevated Thryoid-stimulating hormone level. Occasionally, thyroid hormone levels are within the normal range and the Thryoid-stimulating hormone is elevated, yet these patients are still appropriately considered to have hypothyroidism. Similarly, hyper-thyroidism is characterized by a decreased (usually undetectable) Thryoid-stimulating hormone level.
The thyroid gland traps the important chemical iodine and through a series of biochemical reactions synthesizes Thyroxine and Triiodothyronine. If there is inadequate iodine available (e.g., iodine deficiency), then lack of thyroid hormone synthesis and secretion may result in increased Thryoid-stimulating hormone secretion and possibly thyroidal enlargement.
Tissues contain specific nuclear receptors that bind VTriiodothyronine. These receptors cause a variety of proteins to be formulated which enhance metabolism. Each organ or tissue may have varying amounts of Thyroxine/Triiodothyronine receptors and different specific proteins and actions may result from receptor activation.
THYROID FUNCTION TESTS
Thyrotropin (Thryoid-stimulating hormone)
Serum Thryoid-stimulating hormone is the best indicator of thyroid hormone levels at the tissue level. All abnormal Thryoid-stimulating hormone concentrations must be investigated even if the serum Thyroxine and Triiodothyronine levels are within the normal range.
In the past, total Thyroxine measurements and indirect assessment of binding proteins had been used as had Free Thyroxine estimates. These tests, however, were imperfect and now have been replaced by a direct “free Thyroxine” measurement. Free Thyroxine measurements are more accurate and reliable. Free Thyroxine measurements, nonetheless, are still imperfect and their use during pregnancy, for example, has been somewhat problematic.
Free Triiodothyronine assays have not become widely available as a routine test. Serum Triiodothyronine concentrations need not be performed routinely but may be especially helpful in the evaluation and treatment of hyperthyroid patients.
Substances produced in the blood which activate the immune system (antibodies) against specific types of thyroid components (thyroglobulin and thyroid peroxidase) develop in patients with autoimmune thyroid disease. These antibody levels (titers) are typically elevated in patients with some types of autoimmune diseases which affect the thyroid gland such as Hashimoto’s thyroiditis, and may be elevated in patients with Graves’ disease (autoimmune thyroid disease), but usually at a lower titer.
A radioactive iodine uptake (RAIU) test (normal range about 8-30%) is useful to help diagnose hyper-thyroidism, as the test should be elevated. A very low RAIU test (less than 5%) is also useful when seen in a patient with hyperthyroidism as this suggests the presence of (less severe) subacute, silent, or postpartum thyroiditis. An RAIU test cannot be used in a pregnant or breast-feeding woman.
Thyroid scans are not used often now and the older practice of using them to determine if a thyroid lump (nodule) was “cold” or nonfunctional (suggesting a higher risk of being cancerous) has fallen into disfavor because of the advent of fine needle aspirations (FNA; using a fine needle to remove a small amount of thyroid tissue for testing). On the other hand, it is relevant to perform an isotope (specialized imaging technique) scan to assess whether a thyroid nodule is “hot” or autonomous. A “hot” nodule concentrates most of the isotope and the remaining extranodular tissue (tissue outside of the nodule) concentrates little, if any, isotope. Isotope scans are recommended in patients with solitary nodules (and in some patients with multi-nodular goiters) with a low Thryoid-stimulating hormone.
Thyroid sonograms, another specialized imaging technique to evaluate the consistency of the thyroid gland, are important to help diagnose the presence and size of thyroid nodules and are used to follow changes in the nodule(s) over time.
Hyperthyroidism clinically is typically associated with signs or symptoms of anxiety, nervousness, weight loss, palpitations, tachycardia, warm, moist skin, hand tremor, sweating, and heat intolerance. The most common cause in young women is Graves’ disease. Graves’ disease is caused by the formation of specific Thryoid-stimulating hormone receptor antibodies that stimulate thyroid hormone synthesis and secretion resulting in increased serum free Thyroxine, Triiodothyronine, and, as a result, an undetectable Thryoid-stimulating hormone. One unusual aspect of Graves’ disease is that some of its manifestations may be a result of the antibodies, rather than a direct consequence of thyroid hormone excess. Eye findings and pretibial myxedema (swelling seen in thyroid disease) are two such disorders. Possible ophthalmic manifestations include lid lag, proptosis (protruding eyes), conjunctivitis, diplopia (double vision), and rarely impaired visual acuity.
Treatment of Graves’ disease hyperthyroidism can be either long-term antithyroid agents in an effort to induce a remission, surgery, or radioactive iodine. Specific antithyroid medications (e.g., propylthiouracil [PTU] or methimazole) can be used in an effort to induce a permanent remission. This treatment is very effective in normalizing thyroid function tests but only infrequently produces a long-lived remission when they are discontinued. Patients must be carefully monitored for potential adverse effects of PTU or methimazole including skin rash, hepatotoxicity (liver toxicity), arthralgias (joint pains), and bone marrow suppression. Pregnant women who are definitively diagnosed as having Graves’ hyperthyroidism can be treated with low-dose PTU. The goal is to maintain the free Thyroxine in the upper normal range for pregnancy with the Triiodothyronine within the normal range. Because of the potential side effects of antithyroid agents and the low likelihood that they will induce a long-lived remission when discontinued, most clinicians use antithyroid agents to cause normal thyroid function in the short term, but then utilize a more permanent definitive therapy such as radioactive iodine.
The most commonly utilized treatment for Graves’ hyperthyroidism is radioactive iodine (RAI) therapy. RAI therapy is safe and effective. Rarely, it may worsen ophthalmopathy (eye problems). The goal of RAI therapy is to render the patient hypothyroid (lowered thyroid functioning) so that lifelong thyroid supplement therapy is then prescribed with periodic monitoring. Efforts to administer a dose of RAI sufficient to render the patient euthyroid (normal thyroid functioning), rather than hypothyroid, are difficult to achieve routinely due to differing thyroid gland sensitivity, and unless the patient is rendered hypothyroid, the persistent presence of detectable Thryoid-stimulating hormone receptor antibodies may result in recurrent hyperthyroidism. RAI must not be used in pregnant or lactating women. Women of childbearing potential should delay becoming pregnant until at least 6 months after receiving RAI therapy.
Surgery is rarely used as the primary treatment modality for Graves’ hyperthyroidism except in patients with suspicious thyroid nodules and in patients who desire surgery, after discussion of the therapeutic options. The decision as to which treatment modality to employ should be jointly reached with the health care team and the patient and family.
Other Causes of Hyperthyroid
Patients with multinodular goiters (multiple nodules) and solitary autonomous nodules (single nodules) also may be hyperthyroid. Definitive treatment for these patients generally is surgery or RAI therapy but antithyroid agents may restore euthyroidism (normal thyroid functioning). Patients with inflammation of the thyroid gland or thyroiditis, typically evolve through phases of hyperthyroidism and hypothyroidism. Occasionally, permanent thyroid function abnormalities may persist. Taking L-thyroxine (thyroid supplementation) may be associated with abnormal thyroid function (either too high or too low) and these patients should have frequent thyroid hormone evaluations. Elderly patients may present with very subtle findings suggestive of hyperthy-roidism, and the sole manifestation could be a cardiac arrhythmia, such as atrial fibrillation (a type of irregular heart rate). Other manifestations could be congestive heart failure, muscle weakness, or a flat affect. Taken together, this presentation is referred to as “apathetic hyperthyroidism.”
Subclinical hyperthyroidism is defined as a Thryoid-stimulating hormone that is decreased below the normal range in conjunction with a normal serum free Thyroxine and Triiodothyronine. Subclinical hyperthyroidism is part of a continuum of hyperthy-roidism and usually, but not always, the signs and symptoms are less severe than in patients with overt hyperthyroidism (suppressed Thryoid-stimulating hormone, elevated free Thyroxine/Triiodothyronine). Subclinical hyperthyroidism has been found to be associated with an increased risk of atrial fibrillation (a type of irregular heart rate) and with enhanced bone loss, especially in patients over about age 50 years.
Hypothyroidism may manifest as signs or symptoms of lethargy, cold intolerance, difficulty concentrating, slowed thinking (mentation) and reflexes, dry skin, slowed heart rate (bradycardia), hair loss, and constipation. Primary hypothyroidism is characterized by an elevated Thryoid-stimulating hormone in conjunction with a low free Thyroxine and Triiodothyronine. The most common causes of primary hypothyroidism include types of autoimmune disorders that affect the thyroid gland such as Hashimoto’s thy-roiditis, deliberate destruction of the thyroid gland (e.g., RAI, surgery), and congenital abnormalities. The thyroid gland itself may or may not be enlarged depending upon the etiology. Hypothyroidism may be associated with reproductive abnormalities and blood lipid (cholesterol/fat) elevations. Symptoms of hypothy-roidism may be nonspecific and frequently patients will attribute subjective symptoms of tiredness, for example, to hypothyroidism, when, in fact, thyroid hormone is not playing a role. Other autoimmune disorders such as diabetes mellitus, Addison’s disease (adrenal insufficiency), premature ovarian failure, and pernicious anemia (anemia due to reduced red blood cell production) may also occur in increased frequency in patients who have autoimmune thyroid disease (Hashimoto’s thyroiditis).
Chronic or severe hypothyroidism may present as severe lowered body temperature (hypothermia), mental confusion, and perhaps even coma (usually in conjunction with several of the more routine signs and symptoms noted above).
Patients being evaluated for thyroid disease should also have a thorough physical examination and a routine laboratory testing to include complete blood count (CBC) and comprehensive metabolic profile. Patients with primary hypothyroidism may require a thyroid sonogram to assess thyroid structure. Thyroid antibody measurements may help to diagnose autoimmune thyroid disease as the etiology.
In routine patients, l-thyroxine therapy is used for the treatment of most patients with primary hypothy-roidism with an equilibrium period of 4-6 weeks. A slower initiation schedule may be used in elderly patients or those with cardiac disease in order to avoid an increase in cardiac arrhythmias or worsen angina pectoris.
Subclinical hypothyroidism is defined by an elevated Thryoid-stimulating hormone level with a normal Free Thyroxine concentration. This condition is part of a continuum of mild hypothyroidism to overt hypothyroidism (elevated Thryoid-stimulating hormone with decreased Free Thyroxine). The signs and symptoms of sub-clinical hypothyroidism vary, but, in general, are subtle in comparison to patients with more overt disease. Patients with subclinical hypothyroidism should have a thorough history and physical examination and laboratory studies to include CBC, comprehensive metabolic profile, and probably a lipid profile.
THYROID NODULES AND GOITER
The critical issue with regard to thyroid nodules is to try to discern nodules that harbor malignancy from those that are benign. About 80-90% of all thyroid nodules are benign. The approach to thyroid nodules is controversial and varies between physicians. Thyroid nodules larger than approximately 1 cm usually require evaluation and monitoring. An FNA interpreted by an experienced specialist in cell disorders (cytologist) should be performed. Clinical findings such as family or personal history of thyroid cancer, radiation exposure to the neck area, identifiable or palpable cervical lymph nodes, a nodule that is very firm or adherent to surrounding tissue, hoarse voice, male gender and age greater than 40, nodule growth and probably nodule size greater than 3-4 cm increase concern that the nodule harbors thyroid cancer. These comments are guidelines and clinical findings are important and may, for example, suggest a thyroidectomy (thyroid removal) be performed even in the context of a benign aspiration. Thyroid function tests, CBC, and comprehensive metabolic profile should be obtained routinely in a patient being evaluated for a thyroid nodule.
A thyroid aspiration interpretation can be read as either benign, suspicious, malignant, or indeterminate. A patient with a benign aspiration can be followed with baseline and periodic examination and repeated sono-grams to assess nodule changes. The false-negative rate of a benign aspiration is about 2-5% so a repeat aspiration is recommended in 3-12 months helping confirm the original diagnosis. Nodules larger than 3-4 cm have a higher false-negative rate. A suspicious aspiration usually requires surgery. The chance of a nodule harboring thyroid cancer when the aspiration is suspicious is probably about 20%, although this depends on the individual cellular (cytologic) characteristics as well as the experience of the cytologist. Sometimes the clinical findings are sufficiently worrisome that surgery should be recommended even if the aspiration is benign. If the nodule is relatively small and the patient has few worrisome clinical features, then the patient may be followed with periodic neck exams and sonograms until it is clear that the nodule is benign. If a nodule grows while a patient is being followed, a repeat thyroid aspiration is usually indicated. If the FNA shows malignancy, then a near-total or total thyroidectomy should usually be performed. An indeterminate cytology should be repeated, perhaps with sonographic guidance.
The term “goiter” refers to diffuse enlargement of the thyroid gland usually noted on physical examination and confirmed by specialized imaging studies, such as sonogram. Occasionally, thyroid function tests are abnormal in patients with goiter, but usually they are normal. Functional abnormalities, of course, must be addressed.
Although still controversial, it is believed that each nodule in a patient with a multinodular (multiple nodules) goiter has the same chance of harboring malignancy as does a solitary thyroid nodule. Practically speaking, every nodule larger than 1 cm may not be able to be aspirated, even if sonographic guidance is used. One approach is to perform sonograms on most patients with goiters and to try to aspirate (usually under sonographic guidance) nodules larger than 1 cm. However, judgment must be utilized. Interpretation of the FNA and the clinical approach is similar to that noted for patients with thyroid nodules. It is important to monitor patients with goiters (and benign aspirates) with periodic examinations and sonograms. If a nodule is enlarging, repeat aspiration should be performed, when possible. Possible indications for surgery in patients with a goiter include: suspicious or malignant aspiration, enlarging nodules or goiter, tracheal (windpipe) compression, impingement on the nerves in the neck (recurrent laryngeal nerve), or additional worrisome features. In large goiters, it may be helpful to obtain additional tests such as pulmonary function tests, swallowing studies, and/or chest computerized tomo-gram (CT). These tests help to define size, location of nodules, and compression of other organs and may be used to monitor the individual over time.
There are some reports of using RAI therapy to treat euthyroid goiter patients. This treatment is still undergoing investigation. Most euthyroid patients with goiters do not have indications for treatment (e.g., abnormal thyroid function tests, compression) so they can be followed with periodic examination and radio-logic studies with FNAs as appropriate.
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