Hyperthyroidism:A Comprehensive Review
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Endocrine Nurse Practitioner, Carl T Hayden VAMC, Phoenix. Arizona
James V. Felicetta
MD, FACP
Chief, Medical Service, Carl T Hayden VAMC, Phoenix, Arizona Associate Clinical Professor of Medicine, University of Arizona
Hyperthyroidism is an endocrine disorder encountered in adult primary care clinics. This article reviews normal thyroid physiology as well as the pathophysiology, diagnosis, clinical signs and symptoms, and diagnostic tests and treatment for the most common clinical hyperthyroid entities. Current research is also discussed as it relates to clinical practice.
S e v e r a l distinct pathophysiologic entities can result in hyperthyroidism. By far, the most common is Graves’ disease. Other entities encountered with some frequency include toxic multinodular goiter, subacute thyroiditis, toxic adenoma, and thyrotoxicosis factitia. Clinicians need to be familiar with the signs and symptoms of hyperthyroidism and understand the clinical use of thyroid function tests. This will allow accurate, rapid diagnosis, followed by appropriate therapy. Hyperthyroidism is an endocrine disorder encountered in adult primary care clinics. This article reviews normal thyroid physiology as well as the pathophysiology, diagnosis, clinical signs and symptoms, and diagnostic tests and treatment for the most common clinical hyperthyroid entities. Current research is also discussed as it relates to clinical practice.
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NORMAL THYROID PHYSIOLOGY ~~
T h e normal adult thyroid gland is an anterior structure located on both sides of the trachea. It consists of two encapsulated lobes, with a horizontal isthmus connecting these two lobes at the level of the cricoid cartilage (Utiger, 1987). T h e production of thyroid hormone is regulated by an important feedback loop involving the pituitary and the thyroid glands. T h e pituitary gland secretes thyroid-stimulating hormone (TSH) when it detects a n inadequate circulating blood level of thyroid hormone. In response to this TSH, the thyroid gland then synthesizes and secretes its hormones, primarily thyroxine (called T4,because it contains four iodine atoms) but also lesser amounts of triiodothyronine (called T,, with three iodine atoms).
JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
Iodine plays a critical role in the production of thyroid demands imposed by stimulation from excess levels of hormones. A minimum amount of dietary iodide intake, thyroid hormone (Utiger, 1987). Common symptoms 50-70 pg daily, is needed to allow normal hormone of hyperthyroidism include nervousness, anxiety, synthesis. The average daily intake of iodide in the increased sweating, heat intolerance, palpitations, IJnitedStates is 150 pg, attributable to widespread iodide tremors, increased heart rate, diarrhea, menstrual supplementation of salt and bread (Utiger, 1987). dysfunction, cardiac problems, fatigue, weakness, and Although iodine deficiency is uncommon in the United weight loss (Housten & Hay, 1990). Typical physical States today, i t remains the most common cause of findings in hyperthyroidism include tachycardia, moist hypothyroidism in the world. skin, rapid speech, or generalized hyperkinesis, with Most of the circulating T, is not secreted directly by or without thyroid enlargement (Housten & Hay, 1990; the thyroid gland, but instead derives from peripheral Utiger, 1987; Waldstein, 1980). breakdown o f TIoutside the gland. This process occurs Several distinct pathophysiologic entities can result in a number of sites, the liver and kidneys being the in hyperthyroidism. By far, the most common is Graves’ most important (Waldstein, 1980). Thyroid hormones disease, sometimes known as toxic diffuse goiter. do not circulate freely for the most part, but rather in However, other entities are also encountered, which asroc iation with certain hormone-binding proteins. For must be distinguished from Graves’ disease. These example, roughly 99.95% of circulating T4 is bound to include toxic multinodular goiter, subacute thyroiditis, these proteins, leaving only the other .05%free. Roughly toxic adenoma, and thyrotoxicosis factitia (McFarland 80% o f the bound hormone is carried by thyronine- & Saleeby, 1988). T h e following discussion defines each binding globulin (TBG), 15%by thyronine-binding pre- of the common clinical entities and emphasizes recent albumin, and the remaining 5% by albumin (Utiger, research findings as they relate to current treatment 1987). Only the free, or unbound hormone, has any options. metabolic activity, however. This is critical to remember when interpreting- thyroid function tests, because the . total level of T4may be elevated or depressed, even when CLINICAL ENTITIES the level of the free, metabolically active hormone remains normal. Thyroid hormones affect essentially every metabolic GRAVES’ proccss in the human body. An understanding of the Graves’ disease is classified as an autoimmune disease. normal function of thyroid hormones provides a It is believed to be caused by antibodies that stimulate rationale for the symptoms that clients experience with excess synthesis and secretion of T, and T4 from the excessive hormone secretion. T h e effects of thyroid thyroid gland, which results in diffuse thyroid hor mone secretion in the human body include, but are hyperplasia (5%-10%of clients have no palpable thyroid not limited to, production of growth hormone, enlargement). It occurs at all ages and in both genders, stimulation of thermogenesis, and synthesis of many but is most classically seen in younger women structural proteins, enzymes, and hormones, and (Waldstein, 1980). It runs in families and often is metabolism of cholesterol and triglycerides. Therefore, associated with specific human lymphocyte antigen the function of thyroid hormones is necessary for normal serotypes that increase genetic susceptibility to the growth and development and tissue function (Utiger, disease. Having Graves’ disease also increases the relative 1987). risk of contracting other related autoimmune diseases, such as pernicious anemia, gonadal insufficiency, and Addison’s disease (Waldstein, 1980). Clients with Graves’ disease typically have a diffuse, PATH0PHYSIOLOGY symmetrically enlarged goiter, with varying signs and symptoms of hyperthyroidism (McFarland & Saleeby, Hyperthyroidism is a condition in which excessive 1988). One specific physical finding for Graves’ disease levels of thyroid hormone are circulating, either because is a thyroid bruit associated with an increased blood of a n exogenous source such as surreptitious self- supply to the gland in this disease. Graves’ disease also administration or prescribing error or, more typically, has typical eye signs such as exophthalmos; conjuctival because of excess hormone production by the thyroid injection; proptosis; chemosis (edema of the ocular gland (Waldstein, 1980). Because hormones secreted by conjunctiva); and lid retraction, which can be very the thyroid gland have a stimulatory function, typical serious because it can compress the optic nerve, leading symptoms reflect either increased organ function or the to blindness (McFarland & Saleeby, 1988). A common inability of a particular organ to keep u p with the concern with Graves’ eye disease is the potential for
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corneal abrasion, resulting from irritation by airborne to produce thyroid hormones without the usual stimulation of TSH. Toxic multinodular goiter is dust and lint and the inability to have complete lid closure. Clients are often advised to tape their eyelids uncommon in younger clients, but it is seen frequently in the elderly. Clients typically report progressive shut at night. Another occasional finding , pretibial thyroid enlargement with multiple palpable thyroid myxedema, is an unusual skin lesion not seen in any other type of hyperthyroidism. It consists of an area nodules. Symptoms of hyperthyroidism usually develop of orange-brown thickening over the tibia, which can gradually. Clients with toxic multinodular goiter do be cosmetically disfiguring, particularly in a young not have ophthalmopathy or pretibial myxedema (Nordyke, Gilbert, & Harada, 1988),two features unique female. Some clients with Graves’ disease may not demon- to Graves’ disease. It has been speculated that this entity strate the classic indicators of the disease. Their may be caused by intermittent iodine deficiencies early symptoms may be subtle and nonspecific, such as fatigue in life (Kabadi, 1982).The underlying etiology of toxic and nervousness. These nonspecific symptoms are multinodular goiter remains unknown, despite the frequently encountered in elderly subjects (Federman, speculation concerning iodide deficiency early in life. 1991).A prospective study of 880 hyperthyroid patients seen during a 24-year period showed that weight loss SUBACUTE THYROIDITIS Another important entity that can cause hyperthyand atrial fibrillation are the most common findings in elderly patients (Nordyke, Gilbert, & Horada, 1988). roidism is subacute thyroiditis. This name is somewhat But the same study also suggested that older patients misleading, since subacute thyroiditis is actually an show considerably fewer clinical findings such as acute disease process. There are two basic variants, thyroid enlargement, heat intolerance, increased painful (classic) thyroiditis and the more recently perspiration, irritability, increased appetite, or weight described painless thyroiditis. Both entities result from an acute antibody-mediated inflammatory process changes (Nordyke, Gilbert, & Harada, 1988). The prevalence of thyroid enlargement decreases with within the thyroid itself, producing damage to the gland age, from 95% in patients aged 50 or less, to only 73% and subsequent release of preformed hormone (Utiger, in patients aged 70-83 (Nordyke, Gilbert, & Harada, 1987; Waldstein, 1980). Clients having painful thyroi1988). Other common symptoms in elderly clients ditis often have a recent history of upper respiratory include depression, lethargy, apathy and anorexia, a infection. This infection is believed to stimulate the constellation of symptoms known as “masked” or immune system in a way that leads to the production “apathetic hyperthyroidism” (Kabadi, 1989; Sowers & of antibodies destructive to the thyroid gland. Overt Felicetta, 1988). No one knows the exact mechanism hyperthyroid symptoms occur in about half the clients; for this constellation (Jadresic, 1990), although it has however, these symptoms may be overshadowed by been postulated that i t is a consequence of the body’s nonspecific symptoms or by a painful, tender thyroid blunted ability to respond to adrenergic stimuli, (Utiger, 1987).Most clients with hyperthyroidism caused resulting in symptoms similar to those seen in clients by thyroiditis recover completely and become euthyroid again, often after a transient intervening hypothyroid receiving beta-blockers. Clients may also have symptoms indicative of end- period while the thyroid gland struggles to repair itself. organ failure caused by the inability of a given organ A minority of clients go from hyperthyroidism through to compensate for increased thyroid hormone stimu- euthyroidism to a state of permanent hypothyroidism. In painless thyroiditis, the symptoms of hyperthylation. As a result, Graves’ disease should be considered as a possible underlying factor in clients having new- roidism are typically mild and of relatively abrupt onset, onset atrial fibrillation, angina, or congestive heart usually without a typical history of upper respiratory infection. The thyroid is not tender, and thyroid failure (Ladenson, 1990; Kabadi, 1989). enlargement is modest. The symptoms may persist for TOXIC MULTINODULAR GOITER several weeks or months, followed by either immediate A less common, but still very important, cause of recovery or by a transient period of hypothyroidism hyperthyroidism is toxic multinodular goiter, or (Utiger, 1987).Clients with painless thyroiditis are more Plummer syndrome. This is a slowly progressing entity likely to experience recurrent episodes of transient that begins with isolated areas of hyperplasia within hyperthyroidism than are clients with painful thyroithe thyroid gland and progresses to the development ditis. Both entities are seen with increased frequency of discrete, palpable, multiple thyroid nodules. Many, in the 6 months postpartum, which is a time of immune but certainly not all, of these clients go on to develop rebound from the relative immunosuppression of overt hyperthyroidism when nodular areas develop an pregnancy. autonomous (independent) ability to take u p iodide and It is important for the clinician to recognize the
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JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
symptoms of subacute thyroiditis and distinguish it from Hashimoto’s thyroiditis, a common cause of hypothyroidism. T h e clinical course of Hashimoto’s thyroiditis may include a transient period of hyperthyroidism, but the disorder eventuates into permanent hypothyroidism (Utiger, 1987).
TOXIC ADENOMA Another cause of hyperthyroidism is a single toxic adenoma, an isolated, benign tumor of the thyroid gland. Typically seen in younger individuals, clients have characteristic signs and symptoms of hyperthyroidism. A single nodule in the thyroid can typically be palpated on physical examination. A radioactive thyroid scan usually shows heavy uptake of the isotope in the nodule, but virtually no uptake in the surrounding thyroid tissue (Dorfman, 1977). T h e lack of uptake in surrounding tissue reflects suppression of T S H by the excess hormone produced by the autonomous nodule. It is not known why toxic adenomas are able to produce thyroid hormone autonomously without benefit of TSH stimulation.
THYROTOXICOSIS FACTlTlA (FACTITIOUS HYPERTHYROIDISM) Excessive consumption of exogenous thyroid hormone can result in symptoms of hyperthyroidism and in serum T4 elevations. This entity is typically seen in clients receiving excessive doses of 1-thyroxine, usually 0.3 mg per day or more (Utiger, 1987; Greer, 1986). Symptoms usually abate after the hormone dose is lowered appropriately. Although dosing errors by prescribers or pharmacists do occur, excessive consumption of exogenous hormone is far more commonly caused by surreptitious self-administration of thyroid hormone. Typical clients are health care professionals and others who have ready access to medications. A desire to lose weight often motivates such an individual to self-dose with excessive amounts of thyroid hormone.
LABORATORY TESTS T h e classic laboratory findings in hyperthyroidism include a n elevated serum T 4 , as measured by radioimmunoassay, and an elevated T3 resin uptake (RU) in clients with normal amounts of binding sites (Surks, Chopra, Mariash, Nicoloff, & Solomon, 1990). In clients with normal quantities of binding proteins, the severity of the clinical symptoms usually correlates roughly with the degree of T4elevation (Utiger, 1987). The T4radioimmunoassay measures the total amount of thyroxine, both bound and free, in the serum. However, the fraction of T4 bound to serum-binding
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proteins can be altered in a variety of both acute and chronic nonthyroidal illnesses (so-called euthyroid sick syndrome). Additionally, since estrogen increases the quantity of TBG, clients receiving estrogen replacement or oral contraceptives will have increased levels of bound Tz4, while the free T4,which is the metabolically active fraction, remains normal (Felicetta, 1983). Similarly, exogenous androgens lower T B G levels, so that clients receiving androgens have low total T4levels, reflecting the reduced amount of bound T4, but normal free T4 levels. Problems with binding proteins are clarified through the T3RU test, which should always be obtained along with the total T4measurement. T h e total T4measurement is essentially meaningless if it is not accompanied by a TSRU. T3RU measures the number of available (empty) serum-binding sites for thyroid hormones. In the T3RU test, there is competition between the client’s serum with a n unknown number of available binding sites and a fixed number of binding sites on the resin. T h e resin and serum are mixed together with a small amount of labeled (radioactive) T, added. After a few minutes of equilibration, the serum and resin are separated, and the radioactive T3 that is bound to the resin is counted. Women with increased estrogen levels, as in pregnancy or oral contraceptive usage, have increased binding sites caused by increased levels of TBG. These clients, therefore, have a low resin uptake. In other words, their sera have relatively more free binding sites available than does the resin. Clients with hyperthyroidism usually have a n elevated T4 and an elevated T3RU, since the serumbinding sites are saturated with thyroid hormone. The resin, therefore, experiences relatively little competition from the small number of unoccupied serum-binding sites (Felicetta, 1983). In clients with alterations in the quantity of binding proteins rather than true disturbances in thyroid status, the T4 and the resin uptake typically move in opposite directions. Clients with true disturbances in thyroid state, however, have T4 and T 3 R U values that move i n the same direction: hypothyroid clients have low T4and low T3RU values, whereas hyperthyroid clients have elevated T4and T3RU values. One calculated value that may be helpful in some instances is the serum-free thyroxine index, which is derived by multiplying together the T, and the T3RU. This test is helpful in healthy outpatients who have normal quantities of thyroid-binding proteins, unlike clients taking estrogens or androgens or those clients with a hereditary excess or deficiency of TBG. In clients with normal binding proteins, the serum-free thyroxine index does correlate reasonably well with the true thyroid state (Felicetta, 1983). I n the setting of 11
physiologic stress or illness, however, the serum-free thyroxine index can be very misleading. Typically it is artificially low in the presence of acute illness or physiologic stress. Another test occasionally helpful in confirming suspected hyperthyroidism is the thyrotropin-releasing hormone ( T R H ) stimulation test. A baseline T S H is first measured, and then intravenous T R H is injected, followed by repeat TSH measurements at regular intervals. TSH normally rises to a peak 30 minutes after T R H administration. In hyperthyroidism, however, the pituitary has already been exposed to high levels of rirrulating T3 and T, and is therefore largely unresponsive to the administered T R H , resulting in a flat T S H response. T h i s test is especially useful i n confirming mild or subtle hyperthyroidism, where the thyroid function tests alone may not allow a definitive diagnosis. A final laboratory test useful in evaluating hyperthyroidism is the 24-hour radioactive iodine uptake. This test is very important in distinguishing Graves’ disease from other possible causes of hyperthyroidism. The client swallows a radioactive capsule containing sodium iodide and then returns after 24 hours to place his or her neck under a counter. T h e uptake is the percentage of the radioactive iodide dose found over the thyroid gland after 24 hours. A typical value for 24-hour uptake is 5%-25%;the uptake is usually greater than 35% (and often far higher) in clients with hyperthyroidism caused by Graves’ disease (Waldstein, 1980). T h e 24-hour radioactive iodine uptake is very helpful in differentiating between Graves’ disease and subacute thyroiditis because the uptake in subacute thyroiditis is very low, because of suppression of T S H by the release of large quantities of preformed hormone. Clients consuming excessive amounts of exogenous hormone also have a very low uptake, again because of suppression of T S H by the high circulating levels of the hormones (Felicetta, 1983). Clients whose hyperthyroidism is caused by toxic multinodular goiter or toxic adenoma typically have 24-hour radioactive uptake values that are either at the upper limits of normal or only modestly increased. Clients whose uptake values are in this gray zone usually need to have a thyroid scan performed to try to confirm a suspected diagnosis of toxic multinodular goiter or single toxic adenoma. Thyroid scans using radioactive tracers are useful in differentiating certain thyroid entities for the purpose o f prescribing appropriate treatment as well as ruling out cancer. Thyroid scans define the size of the gland, presence and number of nodules, and degree of iodide uptake by the gland and any nodules. Hot nodules take u p isotope more avidly than normal tissue, whereas
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warm nodules take u p iodide with a n affinity equal to that of normal tissue. Cool nodules take u p iodide less avidly than normal tissue, whereas cold nodules do not take u p tracer at all. Hot or warm nodules usually carry n o risk of malignancy, whereas cool or cold uptake by nodules indicates some risk of cancer, with one in four cool/cold nodules being malignant. A cool or cold nodule requires further evaluation, either by fine needle aspiration biopsy or by surgical exploration (Sowers & Felicetta, 1988).
TREATMENT T h e available therapeutic modalities for the management of hyperthyroidism include antithyroid drugs, beta-blockers, radioactive iodine, and surgery. T h e antithyroid drugs block multiple steps in the synthesis of thyroid hormone within the gland. T h e two most commonly prescribed antithyroid drugs are propylthiouracil and methimazole. T h e benefits of antithyroid drugs include a relatively rapid onset of effect (within 10 days to 2 weeks), and the lack of any permanent damage to the thyroid. However, the side effects of antithyroid therapy may be severe on occasion and can include agranulocytosis, skin rashes, severe (fatal, on rare occasion) hepatotoxicity, a n d transplacental delivery to the fetus (Werner, Romaldini, Bromberg, Werner, & Farah, 1989). Treatment strategies may include attempting to discontinue the drug when the client becomes euthyroid, or simply giving the drug for a predetermined period of 1 to 2 years. In a recent study, Edan and co-workers evaluated the optimum duration of antithyroid therapy by monitoring the serum thyroid antibodies in hyperthyroid patients to determine the onset of remission (Edan el al., 1989). They observed 56 patients for u p to 2 years after withdrawal of therapy. Treatment was discontinued when the serum thyroid stimulating antibody ceased being detected. Treatment duration ranged from 3-18 months, although 12 patients continued to have antibody present in their serum after 18 months of treatment. Propranolol, a beta-adrenergic blocker, is widely used in the management of hyperthyroidism. Beta-blockers do not cure hyperthyroidism, but they are very effective in ameliorating the symptoms because of the potentiating effect of thyroid hormones on beta-adrenergic receptors. Beta-blockers combat this potentiation and result in lower heart rates, less nervousness, and less tremulousness. French investigators evaluated 26 patients with Graves’ disease who were treated with 160320 m g a day of propranolol for 1 to 21 months and
JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
observed for u p to 5 years to evaluate the efficacy of propr;inolol. Eight patients experienced remissions that lasted 30-48 months after propranolol withdrawal, while 18 patients did not improve or relapse and were treated conventionally (Codaccioni et al., 1988). LJnfortunately, the authors were unable to predict which patients would benefit from propranolol therapy, or whether remission was achieved spontaneously or berause of the propranolol. Regardless, propranolol’s sympathetic blocking mechanism offers symptomatic relief to clients who are not candidates for other conventional therapy. The typical dosage of propranolol in the management of hyperthyroidism is 10-40 mg, four times a day (Waldstein, 1980). Another major method employed in the modern management of certain types of hyperthyroidism is therapeutic radiation treatment with radioactive iodine (1”’r). Radioiodine damages functioning thyroid tissue and typically reduces symptoms of hyperthyroidism within 6 weeks to 3 months after treatment. A single dose of 4-10 mCi is generally effective in two thirds of clients, although roughly 20%require a second dose, arid the remainder three or more doses (Waldstein, 1980). In a recent study, the investigators found that the optimal dose for eliminating hyperthyroidism in Graves’ disease was 10 mCi (Nordyke & Gilbert, 1991). It can take as long as 6 months to see the full effects o f radioiodine; therefore the concomitant use of antithyroid drugs and propranolol is often indicated during that time. When goiter size decreases and thyroid hormone levels drop, the antithyroid drug and the betablorker ran be tapered. T h e most common side effect of radioiodine is the eventual obliteration of functional thyroid tissue, which renders the client hypothyroid and in need of life-long replacement therapy. Sridama and co-workers found that 1 1% of the patients they had treated with radiation were rendered hypothyroid by the end of the first year, but fully 76% by the eleventh year (Sridama, McCormick, Kaplan, Fauchet, & DeGroot, 1984). One can reduce the prevalence of hypothyroidism by waiting for the full effects of the first dose of 1311 before administering the second dose, with an interval between doses of 6 months to 1 year. Hyperthyroid clients who have received radiation should be seen at least biannually to detect signs and symptoms of possible hypothyroidism (Sterling, 1975). Radiation therapy is contraindicated in pregnant women because of its potential harmful effects on the fetus. Surgery is a final therapeutic option in the management of certain types of hyperthyroidism, including Graves’ disease (Falk, 1990). However, the number of surgeries has declined dramatically in recent years because of advances in medical treatment. Thyroidec-
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tomy is indicated when antithyroid drugs and radioiodine have not been successful, or when a client categorically rejects the standard treatment options. T h e procedure involves resecting part or all functioning thyroid tissue. There are a number of potentially serious complications of surgery. These include transient or permanent hypocalcemia caused by damage to the four parathyroid glands embedded in the thyroid gland, vocal cord dysfunction, and hypothyroidism. T h e incidence of hypothyroidism is between 25% to 75% in the first year after surgery (Ozoux et al., 1988; Utiger, 1987).
SPECIFIC THERAPY Treatment options for Graves’ disease include antithyroid drugs, radioactive iodine, or surgery, depending on the severity of the disease, age, and treatment preference of the client (McFarland & Saleeby, 1988). In general, most U. S. practitioners favor radioiodine for most of their clients because of the ability to deliver effective single-shot therapy. However, some practitioners do like to offer a trial of antithyroid drugs before moving to radioiodine therapy. In addition to therapy for reversing the hyperthyroidism, clients experiencing Graves’ ophthalmopathy need local treatment to protect the cornea, such as local ointments and shields, as well as treatment with systemic steroids in those few clients whose vision is endangered (Waldstein, 1980). Clients with toxic multinodular goiter need to be treated with large doses of l31I, because there is typically no spontaneous remission in this entity. Toxic goiters are somewhat less radiosensitive than thyroid tissue in Graves’ disease; therefore, larger doses of radioiodine must be given. 1311 doses may range from 20 to 70 mCi, with some clients requiring repeat doses before they are rendered euthyroid (Kabadi, 1982). Clients with cardiac manifestations of hyperthyroidism should be placed on antithyroid drug therapy before radioiodine. Hypothyroidism after radioiodine therapy in this entity is relatively rare. T h e management of single toxic adenomas follows along similar principles. Single subacute thyroiditis is usually transient and mild; it is not appropriate to use antithyroid medications or 1311. Many clients may not need any treatment other than aspirin for local pain, because the entity is selflimiting. A short course of corticosteroid therapy may be appropriate for those with more severe pain and tenderness over the thyroid. For those clients who are symptomatic with hyperthyroidism, propranolol in a dosage of 10 to 20 mg four times a day is the drug of choice.
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Finally, a very small fraction of clients with hyperthyroidism may develop a serious, life-threatening complication known as thyroid storm. This is usually found in clients who are already hyperthyroid and then develop an additional nonthyroidal illness or infection, or experience an injury or procedure. It can also occur after 1311 therapy if adequate pretreatment with betablockers has not been done. Symptoms include fever, tachycardia, anorexia or vomiting, mental status changes, and hypotension caused by cardiovascular collapse. Practitioners encountering hyperthyroid clients who manifest these symptoms should immediately refer them for appropriate treatment, which includes large doses of propylthiouracil, propranolol, corticosteroids, and iodide to block the further release of thyroid hormone from the gland (Utiger, 1987).
Hyperthyroidism includes several common entities seen in primary care clinics. Recent research has contributed a better understanding of symptoms, laboratory indicators, and treatment protocols. Clinicians need to be familiar with the symptoms of hyperthyroidism, both classic and subtle, and to understand the clinical use of thyroid function tests. This will aid them in accurately and quickly diagnosing this entity, and in prescribing the appropriate therapy, thereby enhancing the client's safety and comfort.
ACKNOWLEDGMENTS
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The authors acknowledge the efforts of Dr. Udaya Kabadi and the Carl T. Hayden VAMC library, medical media, and research staff for their contributions to this manuscript.
References Codaccioni,J., Orgiazzi, J., Blanc, P., Pugeat, M., Roulier, R., & Carayon P. (1988). Lasting remission in patients treated for Graves' hyperthyroidism with propranolol alone: A pattern of spontaneous evolution of the disease. Journal of Clinical Endocrinology and Metabolism, 67(4), 656-662. Dorfman. S. G. (1977). Hyperthyroidism: Usual and unusual causes. Archives lnternal Medicine, 7 37, 995-996. Edan, G., Massart, C , Hody, B . Poirer. J., Le Reun, M.. Hespel, J,, Leclech, G., & Simon, M. (1989). Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves' disease.British Medical Journal, 298,359361. Falk, S A (1990). The management of hyperthyroidism: A surgeon's perspective. Ofolaryngolog,c Cfinics of North America, 23(3). 361380. Federman, D. D. (1991). Hyperthyroidism in the geriatric population. Hospital Pracfice, 61 -76. Felicetta, J. V. (1983). How to make thyroid function tests work for you. Modern Medicine, 116-1 30. Greer, M. A. (1986). Thyrotoxicosis without hyperthyroidism. In S. H. lngbar & L. E. Braverman (Eds.), Werner's: The thyroid (5th ed.). Philadelphia: Lippincott. Housten, M. S., & Hay, I. D. (1990). Practical management of hyperthyroidism. American Family Physician,47 (3), 909-916. Jadresic, D. P. (1990). Psychiatric aspects of hyperthyroidism.Journal of Psychosomatic Research, 34(6),603-615. Kabadi, U. M.(1982). Laboratory tests for evaluating thyroid therapy. American Family Physician,26(3). 183-188. Kabadi, U. M. (1989). Thyroid diseases and the elderly. Comprehensive Therapy, 7 5(6), 53-65. Ladenson, P. W. (1990). Recognition and management of cardiovascular disease related to thyroid dysfunction.The American Journal of Medicine, 88,638-641. McFarland, K. F., & Saleeby, G. (1988). Graves' disease. Postgraduate
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Medicine, 83(4), 275-282. Nordyke, R. A,, & Gilbert, F. I. (1991). Optimal iodine-131 dose for eliminating hyperthyroidismin Graves' disease. Journal of Nuclear Medicine, 32(3), 41 1-415. Nordyke, R. A,, Gilbert, F. I., & Harada, A. S. (1988). Graves' disease: Influence of age on clinical findings. Archives lnternal Medicine, 148,626-631. Ozoux, J., de Calan, L.,Portier, G., Rivallain, B., Favre, J., Robier. A., Goga, D., & Brizon, J. (1988). Surgical treatment of graves' disease. American Journal of Surgery, 156, 177-181. Sowers, J. R., & Felicetta, J. V. (Eds.). (1988). Endocrinology of aging. New York: Raven Press. Sridama, V., McCormick, M., Kaplan, E., Fauchet, R., & DeGroot, L. (1984). Long-term follow-up study of compensated low-dose '311 therapy for Graves' disease. New England Journal of Medicine, 31 7(7),426-432. Sterling, K. (1975). Radioactive iodine therapy. Medical Clinics of North America, 59(5),1217-1220. Surks, M. I., Chopra, I. J., Mariash, C. N., Nicoloff, J. T., & Solomon, D. H. (1 990). American thyroid association guidelines for use of laboratory tests in thyroid disorders. Journal of the American Medical Association, 263(11), 1529-1532. Utiger, R. D. (1987). The thyroid: Physiology, hyperthyroidism, hypothyroidism, and the painful thyroid. In P. Felig, J. D. Baxter, A. E. Broadus, & L. A. Frohman (Eds.), Endocrinology and metabolism (2nd ed.). New York: McGraw-Hill. Waldstein, S. S. (1980). The assessment and management of hyperthyroidism.Otolaryngologic Clinics of North America, 7 3(1), 13-27. Werner, M. C., Romaldini. J. H., Sromberg, N., Werner, R. S., & Farah, C. S. (1989). Adverse effects related to thionamide drugs and their dose regimen.American Journal of MedicalSciences,297(4), 216-219.
JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
rll
Endocrine Nurse Practitioner, Carl T Hayden VAMC, Phoenix. Arizona
James V. Felicetta
MD, FACP
Chief, Medical Service, Carl T Hayden VAMC, Phoenix, Arizona Associate Clinical Professor of Medicine, University of Arizona
Hyperthyroidism is an endocrine disorder encountered in adult primary care clinics. This article reviews normal thyroid physiology as well as the pathophysiology, diagnosis, clinical signs and symptoms, and diagnostic tests and treatment for the most common clinical hyperthyroid entities. Current research is also discussed as it relates to clinical practice.
S e v e r a l distinct pathophysiologic entities can result in hyperthyroidism. By far, the most common is Graves’ disease. Other entities encountered with some frequency include toxic multinodular goiter, subacute thyroiditis, toxic adenoma, and thyrotoxicosis factitia. Clinicians need to be familiar with the signs and symptoms of hyperthyroidism and understand the clinical use of thyroid function tests. This will allow accurate, rapid diagnosis, followed by appropriate therapy. Hyperthyroidism is an endocrine disorder encountered in adult primary care clinics. This article reviews normal thyroid physiology as well as the pathophysiology, diagnosis, clinical signs and symptoms, and diagnostic tests and treatment for the most common clinical hyperthyroid entities. Current research is also discussed as it relates to clinical practice.
8
NORMAL THYROID PHYSIOLOGY ~~
T h e normal adult thyroid gland is an anterior structure located on both sides of the trachea. It consists of two encapsulated lobes, with a horizontal isthmus connecting these two lobes at the level of the cricoid cartilage (Utiger, 1987). T h e production of thyroid hormone is regulated by an important feedback loop involving the pituitary and the thyroid glands. T h e pituitary gland secretes thyroid-stimulating hormone (TSH) when it detects a n inadequate circulating blood level of thyroid hormone. In response to this TSH, the thyroid gland then synthesizes and secretes its hormones, primarily thyroxine (called T4,because it contains four iodine atoms) but also lesser amounts of triiodothyronine (called T,, with three iodine atoms).
JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
Iodine plays a critical role in the production of thyroid demands imposed by stimulation from excess levels of hormones. A minimum amount of dietary iodide intake, thyroid hormone (Utiger, 1987). Common symptoms 50-70 pg daily, is needed to allow normal hormone of hyperthyroidism include nervousness, anxiety, synthesis. The average daily intake of iodide in the increased sweating, heat intolerance, palpitations, IJnitedStates is 150 pg, attributable to widespread iodide tremors, increased heart rate, diarrhea, menstrual supplementation of salt and bread (Utiger, 1987). dysfunction, cardiac problems, fatigue, weakness, and Although iodine deficiency is uncommon in the United weight loss (Housten & Hay, 1990). Typical physical States today, i t remains the most common cause of findings in hyperthyroidism include tachycardia, moist hypothyroidism in the world. skin, rapid speech, or generalized hyperkinesis, with Most of the circulating T, is not secreted directly by or without thyroid enlargement (Housten & Hay, 1990; the thyroid gland, but instead derives from peripheral Utiger, 1987; Waldstein, 1980). breakdown o f TIoutside the gland. This process occurs Several distinct pathophysiologic entities can result in a number of sites, the liver and kidneys being the in hyperthyroidism. By far, the most common is Graves’ most important (Waldstein, 1980). Thyroid hormones disease, sometimes known as toxic diffuse goiter. do not circulate freely for the most part, but rather in However, other entities are also encountered, which asroc iation with certain hormone-binding proteins. For must be distinguished from Graves’ disease. These example, roughly 99.95% of circulating T4 is bound to include toxic multinodular goiter, subacute thyroiditis, these proteins, leaving only the other .05%free. Roughly toxic adenoma, and thyrotoxicosis factitia (McFarland 80% o f the bound hormone is carried by thyronine- & Saleeby, 1988). T h e following discussion defines each binding globulin (TBG), 15%by thyronine-binding pre- of the common clinical entities and emphasizes recent albumin, and the remaining 5% by albumin (Utiger, research findings as they relate to current treatment 1987). Only the free, or unbound hormone, has any options. metabolic activity, however. This is critical to remember when interpreting- thyroid function tests, because the . total level of T4may be elevated or depressed, even when CLINICAL ENTITIES the level of the free, metabolically active hormone remains normal. Thyroid hormones affect essentially every metabolic GRAVES’ proccss in the human body. An understanding of the Graves’ disease is classified as an autoimmune disease. normal function of thyroid hormones provides a It is believed to be caused by antibodies that stimulate rationale for the symptoms that clients experience with excess synthesis and secretion of T, and T4 from the excessive hormone secretion. T h e effects of thyroid thyroid gland, which results in diffuse thyroid hor mone secretion in the human body include, but are hyperplasia (5%-10%of clients have no palpable thyroid not limited to, production of growth hormone, enlargement). It occurs at all ages and in both genders, stimulation of thermogenesis, and synthesis of many but is most classically seen in younger women structural proteins, enzymes, and hormones, and (Waldstein, 1980). It runs in families and often is metabolism of cholesterol and triglycerides. Therefore, associated with specific human lymphocyte antigen the function of thyroid hormones is necessary for normal serotypes that increase genetic susceptibility to the growth and development and tissue function (Utiger, disease. Having Graves’ disease also increases the relative 1987). risk of contracting other related autoimmune diseases, such as pernicious anemia, gonadal insufficiency, and Addison’s disease (Waldstein, 1980). Clients with Graves’ disease typically have a diffuse, PATH0PHYSIOLOGY symmetrically enlarged goiter, with varying signs and symptoms of hyperthyroidism (McFarland & Saleeby, Hyperthyroidism is a condition in which excessive 1988). One specific physical finding for Graves’ disease levels of thyroid hormone are circulating, either because is a thyroid bruit associated with an increased blood of a n exogenous source such as surreptitious self- supply to the gland in this disease. Graves’ disease also administration or prescribing error or, more typically, has typical eye signs such as exophthalmos; conjuctival because of excess hormone production by the thyroid injection; proptosis; chemosis (edema of the ocular gland (Waldstein, 1980). Because hormones secreted by conjunctiva); and lid retraction, which can be very the thyroid gland have a stimulatory function, typical serious because it can compress the optic nerve, leading symptoms reflect either increased organ function or the to blindness (McFarland & Saleeby, 1988). A common inability of a particular organ to keep u p with the concern with Graves’ eye disease is the potential for
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corneal abrasion, resulting from irritation by airborne to produce thyroid hormones without the usual stimulation of TSH. Toxic multinodular goiter is dust and lint and the inability to have complete lid closure. Clients are often advised to tape their eyelids uncommon in younger clients, but it is seen frequently in the elderly. Clients typically report progressive shut at night. Another occasional finding , pretibial thyroid enlargement with multiple palpable thyroid myxedema, is an unusual skin lesion not seen in any other type of hyperthyroidism. It consists of an area nodules. Symptoms of hyperthyroidism usually develop of orange-brown thickening over the tibia, which can gradually. Clients with toxic multinodular goiter do be cosmetically disfiguring, particularly in a young not have ophthalmopathy or pretibial myxedema (Nordyke, Gilbert, & Harada, 1988),two features unique female. Some clients with Graves’ disease may not demon- to Graves’ disease. It has been speculated that this entity strate the classic indicators of the disease. Their may be caused by intermittent iodine deficiencies early symptoms may be subtle and nonspecific, such as fatigue in life (Kabadi, 1982).The underlying etiology of toxic and nervousness. These nonspecific symptoms are multinodular goiter remains unknown, despite the frequently encountered in elderly subjects (Federman, speculation concerning iodide deficiency early in life. 1991).A prospective study of 880 hyperthyroid patients seen during a 24-year period showed that weight loss SUBACUTE THYROIDITIS Another important entity that can cause hyperthyand atrial fibrillation are the most common findings in elderly patients (Nordyke, Gilbert, & Horada, 1988). roidism is subacute thyroiditis. This name is somewhat But the same study also suggested that older patients misleading, since subacute thyroiditis is actually an show considerably fewer clinical findings such as acute disease process. There are two basic variants, thyroid enlargement, heat intolerance, increased painful (classic) thyroiditis and the more recently perspiration, irritability, increased appetite, or weight described painless thyroiditis. Both entities result from an acute antibody-mediated inflammatory process changes (Nordyke, Gilbert, & Harada, 1988). The prevalence of thyroid enlargement decreases with within the thyroid itself, producing damage to the gland age, from 95% in patients aged 50 or less, to only 73% and subsequent release of preformed hormone (Utiger, in patients aged 70-83 (Nordyke, Gilbert, & Harada, 1987; Waldstein, 1980). Clients having painful thyroi1988). Other common symptoms in elderly clients ditis often have a recent history of upper respiratory include depression, lethargy, apathy and anorexia, a infection. This infection is believed to stimulate the constellation of symptoms known as “masked” or immune system in a way that leads to the production “apathetic hyperthyroidism” (Kabadi, 1989; Sowers & of antibodies destructive to the thyroid gland. Overt Felicetta, 1988). No one knows the exact mechanism hyperthyroid symptoms occur in about half the clients; for this constellation (Jadresic, 1990), although it has however, these symptoms may be overshadowed by been postulated that i t is a consequence of the body’s nonspecific symptoms or by a painful, tender thyroid blunted ability to respond to adrenergic stimuli, (Utiger, 1987).Most clients with hyperthyroidism caused resulting in symptoms similar to those seen in clients by thyroiditis recover completely and become euthyroid again, often after a transient intervening hypothyroid receiving beta-blockers. Clients may also have symptoms indicative of end- period while the thyroid gland struggles to repair itself. organ failure caused by the inability of a given organ A minority of clients go from hyperthyroidism through to compensate for increased thyroid hormone stimu- euthyroidism to a state of permanent hypothyroidism. In painless thyroiditis, the symptoms of hyperthylation. As a result, Graves’ disease should be considered as a possible underlying factor in clients having new- roidism are typically mild and of relatively abrupt onset, onset atrial fibrillation, angina, or congestive heart usually without a typical history of upper respiratory infection. The thyroid is not tender, and thyroid failure (Ladenson, 1990; Kabadi, 1989). enlargement is modest. The symptoms may persist for TOXIC MULTINODULAR GOITER several weeks or months, followed by either immediate A less common, but still very important, cause of recovery or by a transient period of hypothyroidism hyperthyroidism is toxic multinodular goiter, or (Utiger, 1987).Clients with painless thyroiditis are more Plummer syndrome. This is a slowly progressing entity likely to experience recurrent episodes of transient that begins with isolated areas of hyperplasia within hyperthyroidism than are clients with painful thyroithe thyroid gland and progresses to the development ditis. Both entities are seen with increased frequency of discrete, palpable, multiple thyroid nodules. Many, in the 6 months postpartum, which is a time of immune but certainly not all, of these clients go on to develop rebound from the relative immunosuppression of overt hyperthyroidism when nodular areas develop an pregnancy. autonomous (independent) ability to take u p iodide and It is important for the clinician to recognize the
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JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
symptoms of subacute thyroiditis and distinguish it from Hashimoto’s thyroiditis, a common cause of hypothyroidism. T h e clinical course of Hashimoto’s thyroiditis may include a transient period of hyperthyroidism, but the disorder eventuates into permanent hypothyroidism (Utiger, 1987).
TOXIC ADENOMA Another cause of hyperthyroidism is a single toxic adenoma, an isolated, benign tumor of the thyroid gland. Typically seen in younger individuals, clients have characteristic signs and symptoms of hyperthyroidism. A single nodule in the thyroid can typically be palpated on physical examination. A radioactive thyroid scan usually shows heavy uptake of the isotope in the nodule, but virtually no uptake in the surrounding thyroid tissue (Dorfman, 1977). T h e lack of uptake in surrounding tissue reflects suppression of T S H by the excess hormone produced by the autonomous nodule. It is not known why toxic adenomas are able to produce thyroid hormone autonomously without benefit of TSH stimulation.
THYROTOXICOSIS FACTlTlA (FACTITIOUS HYPERTHYROIDISM) Excessive consumption of exogenous thyroid hormone can result in symptoms of hyperthyroidism and in serum T4 elevations. This entity is typically seen in clients receiving excessive doses of 1-thyroxine, usually 0.3 mg per day or more (Utiger, 1987; Greer, 1986). Symptoms usually abate after the hormone dose is lowered appropriately. Although dosing errors by prescribers or pharmacists do occur, excessive consumption of exogenous hormone is far more commonly caused by surreptitious self-administration of thyroid hormone. Typical clients are health care professionals and others who have ready access to medications. A desire to lose weight often motivates such an individual to self-dose with excessive amounts of thyroid hormone.
LABORATORY TESTS T h e classic laboratory findings in hyperthyroidism include a n elevated serum T 4 , as measured by radioimmunoassay, and an elevated T3 resin uptake (RU) in clients with normal amounts of binding sites (Surks, Chopra, Mariash, Nicoloff, & Solomon, 1990). In clients with normal quantities of binding proteins, the severity of the clinical symptoms usually correlates roughly with the degree of T4elevation (Utiger, 1987). The T4radioimmunoassay measures the total amount of thyroxine, both bound and free, in the serum. However, the fraction of T4 bound to serum-binding
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proteins can be altered in a variety of both acute and chronic nonthyroidal illnesses (so-called euthyroid sick syndrome). Additionally, since estrogen increases the quantity of TBG, clients receiving estrogen replacement or oral contraceptives will have increased levels of bound Tz4, while the free T4,which is the metabolically active fraction, remains normal (Felicetta, 1983). Similarly, exogenous androgens lower T B G levels, so that clients receiving androgens have low total T4levels, reflecting the reduced amount of bound T4, but normal free T4 levels. Problems with binding proteins are clarified through the T3RU test, which should always be obtained along with the total T4measurement. T h e total T4measurement is essentially meaningless if it is not accompanied by a TSRU. T3RU measures the number of available (empty) serum-binding sites for thyroid hormones. In the T3RU test, there is competition between the client’s serum with a n unknown number of available binding sites and a fixed number of binding sites on the resin. T h e resin and serum are mixed together with a small amount of labeled (radioactive) T, added. After a few minutes of equilibration, the serum and resin are separated, and the radioactive T3 that is bound to the resin is counted. Women with increased estrogen levels, as in pregnancy or oral contraceptive usage, have increased binding sites caused by increased levels of TBG. These clients, therefore, have a low resin uptake. In other words, their sera have relatively more free binding sites available than does the resin. Clients with hyperthyroidism usually have a n elevated T4 and an elevated T3RU, since the serumbinding sites are saturated with thyroid hormone. The resin, therefore, experiences relatively little competition from the small number of unoccupied serum-binding sites (Felicetta, 1983). In clients with alterations in the quantity of binding proteins rather than true disturbances in thyroid status, the T4 and the resin uptake typically move in opposite directions. Clients with true disturbances in thyroid state, however, have T4 and T 3 R U values that move i n the same direction: hypothyroid clients have low T4and low T3RU values, whereas hyperthyroid clients have elevated T4and T3RU values. One calculated value that may be helpful in some instances is the serum-free thyroxine index, which is derived by multiplying together the T, and the T3RU. This test is helpful in healthy outpatients who have normal quantities of thyroid-binding proteins, unlike clients taking estrogens or androgens or those clients with a hereditary excess or deficiency of TBG. In clients with normal binding proteins, the serum-free thyroxine index does correlate reasonably well with the true thyroid state (Felicetta, 1983). I n the setting of 11
physiologic stress or illness, however, the serum-free thyroxine index can be very misleading. Typically it is artificially low in the presence of acute illness or physiologic stress. Another test occasionally helpful in confirming suspected hyperthyroidism is the thyrotropin-releasing hormone ( T R H ) stimulation test. A baseline T S H is first measured, and then intravenous T R H is injected, followed by repeat TSH measurements at regular intervals. TSH normally rises to a peak 30 minutes after T R H administration. In hyperthyroidism, however, the pituitary has already been exposed to high levels of rirrulating T3 and T, and is therefore largely unresponsive to the administered T R H , resulting in a flat T S H response. T h i s test is especially useful i n confirming mild or subtle hyperthyroidism, where the thyroid function tests alone may not allow a definitive diagnosis. A final laboratory test useful in evaluating hyperthyroidism is the 24-hour radioactive iodine uptake. This test is very important in distinguishing Graves’ disease from other possible causes of hyperthyroidism. The client swallows a radioactive capsule containing sodium iodide and then returns after 24 hours to place his or her neck under a counter. T h e uptake is the percentage of the radioactive iodide dose found over the thyroid gland after 24 hours. A typical value for 24-hour uptake is 5%-25%;the uptake is usually greater than 35% (and often far higher) in clients with hyperthyroidism caused by Graves’ disease (Waldstein, 1980). T h e 24-hour radioactive iodine uptake is very helpful in differentiating between Graves’ disease and subacute thyroiditis because the uptake in subacute thyroiditis is very low, because of suppression of T S H by the release of large quantities of preformed hormone. Clients consuming excessive amounts of exogenous hormone also have a very low uptake, again because of suppression of T S H by the high circulating levels of the hormones (Felicetta, 1983). Clients whose hyperthyroidism is caused by toxic multinodular goiter or toxic adenoma typically have 24-hour radioactive uptake values that are either at the upper limits of normal or only modestly increased. Clients whose uptake values are in this gray zone usually need to have a thyroid scan performed to try to confirm a suspected diagnosis of toxic multinodular goiter or single toxic adenoma. Thyroid scans using radioactive tracers are useful in differentiating certain thyroid entities for the purpose o f prescribing appropriate treatment as well as ruling out cancer. Thyroid scans define the size of the gland, presence and number of nodules, and degree of iodide uptake by the gland and any nodules. Hot nodules take u p isotope more avidly than normal tissue, whereas
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warm nodules take u p iodide with a n affinity equal to that of normal tissue. Cool nodules take u p iodide less avidly than normal tissue, whereas cold nodules do not take u p tracer at all. Hot or warm nodules usually carry n o risk of malignancy, whereas cool or cold uptake by nodules indicates some risk of cancer, with one in four cool/cold nodules being malignant. A cool or cold nodule requires further evaluation, either by fine needle aspiration biopsy or by surgical exploration (Sowers & Felicetta, 1988).
TREATMENT T h e available therapeutic modalities for the management of hyperthyroidism include antithyroid drugs, beta-blockers, radioactive iodine, and surgery. T h e antithyroid drugs block multiple steps in the synthesis of thyroid hormone within the gland. T h e two most commonly prescribed antithyroid drugs are propylthiouracil and methimazole. T h e benefits of antithyroid drugs include a relatively rapid onset of effect (within 10 days to 2 weeks), and the lack of any permanent damage to the thyroid. However, the side effects of antithyroid therapy may be severe on occasion and can include agranulocytosis, skin rashes, severe (fatal, on rare occasion) hepatotoxicity, a n d transplacental delivery to the fetus (Werner, Romaldini, Bromberg, Werner, & Farah, 1989). Treatment strategies may include attempting to discontinue the drug when the client becomes euthyroid, or simply giving the drug for a predetermined period of 1 to 2 years. In a recent study, Edan and co-workers evaluated the optimum duration of antithyroid therapy by monitoring the serum thyroid antibodies in hyperthyroid patients to determine the onset of remission (Edan el al., 1989). They observed 56 patients for u p to 2 years after withdrawal of therapy. Treatment was discontinued when the serum thyroid stimulating antibody ceased being detected. Treatment duration ranged from 3-18 months, although 12 patients continued to have antibody present in their serum after 18 months of treatment. Propranolol, a beta-adrenergic blocker, is widely used in the management of hyperthyroidism. Beta-blockers do not cure hyperthyroidism, but they are very effective in ameliorating the symptoms because of the potentiating effect of thyroid hormones on beta-adrenergic receptors. Beta-blockers combat this potentiation and result in lower heart rates, less nervousness, and less tremulousness. French investigators evaluated 26 patients with Graves’ disease who were treated with 160320 m g a day of propranolol for 1 to 21 months and
JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS
observed for u p to 5 years to evaluate the efficacy of propr;inolol. Eight patients experienced remissions that lasted 30-48 months after propranolol withdrawal, while 18 patients did not improve or relapse and were treated conventionally (Codaccioni et al., 1988). LJnfortunately, the authors were unable to predict which patients would benefit from propranolol therapy, or whether remission was achieved spontaneously or berause of the propranolol. Regardless, propranolol’s sympathetic blocking mechanism offers symptomatic relief to clients who are not candidates for other conventional therapy. The typical dosage of propranolol in the management of hyperthyroidism is 10-40 mg, four times a day (Waldstein, 1980). Another major method employed in the modern management of certain types of hyperthyroidism is therapeutic radiation treatment with radioactive iodine (1”’r). Radioiodine damages functioning thyroid tissue and typically reduces symptoms of hyperthyroidism within 6 weeks to 3 months after treatment. A single dose of 4-10 mCi is generally effective in two thirds of clients, although roughly 20%require a second dose, arid the remainder three or more doses (Waldstein, 1980). In a recent study, the investigators found that the optimal dose for eliminating hyperthyroidism in Graves’ disease was 10 mCi (Nordyke & Gilbert, 1991). It can take as long as 6 months to see the full effects o f radioiodine; therefore the concomitant use of antithyroid drugs and propranolol is often indicated during that time. When goiter size decreases and thyroid hormone levels drop, the antithyroid drug and the betablorker ran be tapered. T h e most common side effect of radioiodine is the eventual obliteration of functional thyroid tissue, which renders the client hypothyroid and in need of life-long replacement therapy. Sridama and co-workers found that 1 1% of the patients they had treated with radiation were rendered hypothyroid by the end of the first year, but fully 76% by the eleventh year (Sridama, McCormick, Kaplan, Fauchet, & DeGroot, 1984). One can reduce the prevalence of hypothyroidism by waiting for the full effects of the first dose of 1311 before administering the second dose, with an interval between doses of 6 months to 1 year. Hyperthyroid clients who have received radiation should be seen at least biannually to detect signs and symptoms of possible hypothyroidism (Sterling, 1975). Radiation therapy is contraindicated in pregnant women because of its potential harmful effects on the fetus. Surgery is a final therapeutic option in the management of certain types of hyperthyroidism, including Graves’ disease (Falk, 1990). However, the number of surgeries has declined dramatically in recent years because of advances in medical treatment. Thyroidec-
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tomy is indicated when antithyroid drugs and radioiodine have not been successful, or when a client categorically rejects the standard treatment options. T h e procedure involves resecting part or all functioning thyroid tissue. There are a number of potentially serious complications of surgery. These include transient or permanent hypocalcemia caused by damage to the four parathyroid glands embedded in the thyroid gland, vocal cord dysfunction, and hypothyroidism. T h e incidence of hypothyroidism is between 25% to 75% in the first year after surgery (Ozoux et al., 1988; Utiger, 1987).
SPECIFIC THERAPY Treatment options for Graves’ disease include antithyroid drugs, radioactive iodine, or surgery, depending on the severity of the disease, age, and treatment preference of the client (McFarland & Saleeby, 1988). In general, most U. S. practitioners favor radioiodine for most of their clients because of the ability to deliver effective single-shot therapy. However, some practitioners do like to offer a trial of antithyroid drugs before moving to radioiodine therapy. In addition to therapy for reversing the hyperthyroidism, clients experiencing Graves’ ophthalmopathy need local treatment to protect the cornea, such as local ointments and shields, as well as treatment with systemic steroids in those few clients whose vision is endangered (Waldstein, 1980). Clients with toxic multinodular goiter need to be treated with large doses of l31I, because there is typically no spontaneous remission in this entity. Toxic goiters are somewhat less radiosensitive than thyroid tissue in Graves’ disease; therefore, larger doses of radioiodine must be given. 1311 doses may range from 20 to 70 mCi, with some clients requiring repeat doses before they are rendered euthyroid (Kabadi, 1982). Clients with cardiac manifestations of hyperthyroidism should be placed on antithyroid drug therapy before radioiodine. Hypothyroidism after radioiodine therapy in this entity is relatively rare. T h e management of single toxic adenomas follows along similar principles. Single subacute thyroiditis is usually transient and mild; it is not appropriate to use antithyroid medications or 1311. Many clients may not need any treatment other than aspirin for local pain, because the entity is selflimiting. A short course of corticosteroid therapy may be appropriate for those with more severe pain and tenderness over the thyroid. For those clients who are symptomatic with hyperthyroidism, propranolol in a dosage of 10 to 20 mg four times a day is the drug of choice.
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Finally, a very small fraction of clients with hyperthyroidism may develop a serious, life-threatening complication known as thyroid storm. This is usually found in clients who are already hyperthyroid and then develop an additional nonthyroidal illness or infection, or experience an injury or procedure. It can also occur after 1311 therapy if adequate pretreatment with betablockers has not been done. Symptoms include fever, tachycardia, anorexia or vomiting, mental status changes, and hypotension caused by cardiovascular collapse. Practitioners encountering hyperthyroid clients who manifest these symptoms should immediately refer them for appropriate treatment, which includes large doses of propylthiouracil, propranolol, corticosteroids, and iodide to block the further release of thyroid hormone from the gland (Utiger, 1987).
Hyperthyroidism includes several common entities seen in primary care clinics. Recent research has contributed a better understanding of symptoms, laboratory indicators, and treatment protocols. Clinicians need to be familiar with the symptoms of hyperthyroidism, both classic and subtle, and to understand the clinical use of thyroid function tests. This will aid them in accurately and quickly diagnosing this entity, and in prescribing the appropriate therapy, thereby enhancing the client's safety and comfort.
ACKNOWLEDGMENTS
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The authors acknowledge the efforts of Dr. Udaya Kabadi and the Carl T. Hayden VAMC library, medical media, and research staff for their contributions to this manuscript.
References Codaccioni,J., Orgiazzi, J., Blanc, P., Pugeat, M., Roulier, R., & Carayon P. (1988). Lasting remission in patients treated for Graves' hyperthyroidism with propranolol alone: A pattern of spontaneous evolution of the disease. Journal of Clinical Endocrinology and Metabolism, 67(4), 656-662. Dorfman. S. G. (1977). Hyperthyroidism: Usual and unusual causes. Archives lnternal Medicine, 7 37, 995-996. Edan, G., Massart, C , Hody, B . Poirer. J., Le Reun, M.. Hespel, J,, Leclech, G., & Simon, M. (1989). Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves' disease.British Medical Journal, 298,359361. Falk, S A (1990). The management of hyperthyroidism: A surgeon's perspective. Ofolaryngolog,c Cfinics of North America, 23(3). 361380. Federman, D. D. (1991). Hyperthyroidism in the geriatric population. Hospital Pracfice, 61 -76. Felicetta, J. V. (1983). How to make thyroid function tests work for you. Modern Medicine, 116-1 30. Greer, M. A. (1986). Thyrotoxicosis without hyperthyroidism. In S. H. lngbar & L. E. Braverman (Eds.), Werner's: The thyroid (5th ed.). Philadelphia: Lippincott. Housten, M. S., & Hay, I. D. (1990). Practical management of hyperthyroidism. American Family Physician,47 (3), 909-916. Jadresic, D. P. (1990). Psychiatric aspects of hyperthyroidism.Journal of Psychosomatic Research, 34(6),603-615. Kabadi, U. M.(1982). Laboratory tests for evaluating thyroid therapy. American Family Physician,26(3). 183-188. Kabadi, U. M. (1989). Thyroid diseases and the elderly. Comprehensive Therapy, 7 5(6), 53-65. Ladenson, P. W. (1990). Recognition and management of cardiovascular disease related to thyroid dysfunction.The American Journal of Medicine, 88,638-641. McFarland, K. F., & Saleeby, G. (1988). Graves' disease. Postgraduate
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Medicine, 83(4), 275-282. Nordyke, R. A,, & Gilbert, F. I. (1991). Optimal iodine-131 dose for eliminating hyperthyroidismin Graves' disease. Journal of Nuclear Medicine, 32(3), 41 1-415. Nordyke, R. A,, Gilbert, F. I., & Harada, A. S. (1988). Graves' disease: Influence of age on clinical findings. Archives lnternal Medicine, 148,626-631. Ozoux, J., de Calan, L.,Portier, G., Rivallain, B., Favre, J., Robier. A., Goga, D., & Brizon, J. (1988). Surgical treatment of graves' disease. American Journal of Surgery, 156, 177-181. Sowers, J. R., & Felicetta, J. V. (Eds.). (1988). Endocrinology of aging. New York: Raven Press. Sridama, V., McCormick, M., Kaplan, E., Fauchet, R., & DeGroot, L. (1984). Long-term follow-up study of compensated low-dose '311 therapy for Graves' disease. New England Journal of Medicine, 31 7(7),426-432. Sterling, K. (1975). Radioactive iodine therapy. Medical Clinics of North America, 59(5),1217-1220. Surks, M. I., Chopra, I. J., Mariash, C. N., Nicoloff, J. T., & Solomon, D. H. (1 990). American thyroid association guidelines for use of laboratory tests in thyroid disorders. Journal of the American Medical Association, 263(11), 1529-1532. Utiger, R. D. (1987). The thyroid: Physiology, hyperthyroidism, hypothyroidism, and the painful thyroid. In P. Felig, J. D. Baxter, A. E. Broadus, & L. A. Frohman (Eds.), Endocrinology and metabolism (2nd ed.). New York: McGraw-Hill. Waldstein, S. S. (1980). The assessment and management of hyperthyroidism.Otolaryngologic Clinics of North America, 7 3(1), 13-27. Werner, M. C., Romaldini. J. H., Sromberg, N., Werner, R. S., & Farah, C. S. (1989). Adverse effects related to thionamide drugs and their dose regimen.American Journal of MedicalSciences,297(4), 216-219.
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