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Management of thyrotoxicosis. (Featured CME Topic: Thyroid Dysfunction/Disease).

THE TERM THYROTOXICOSIS refers to the clinical and biochemical manifestations of exposure to excessive quantities of thyroid hormones, whereas hyperthyroidism implies that these hormones have originated in the thyroid gland. (1) Whichever term is used, it follows logically that treatment must proceed from an understanding of the cause of the condition, as well as the age and general health of the patient and the severity of disease. Obviously, therapy for a toxic multinodular goiter in an elderly woman would differ from that for a young woman with the usually transient thyrotoxicosis associated with postpartum thyroiditis. One convenient way of thinking about this is to divide the varieties of thyrotoxicosis into 2 groups, those associated with high radioactive iodine uptake (RAIU) and those associated with low RAIU (Table 1).

THYROTOXICOSIS ASSOCIATED WITH HIGH RAIU

GRAVES' DISEASE

Graves' disease accounts for up to 80% of hyperthyroid cases. It most commonly occurs in persons under 40 years of age, and is seen up to 10 times more frequently in women than in men. Until the middle of the 20th century, it was assumed that Graves' disease was the result of excessive secretion of thyrotropin from the pituitary, but it is now realized that this is an extraordinarily rare cause of thyrotoxicosis. (2) In 1956, Adams and Purves, using a bioassay for thyroid-stimulating hormone (TSH), reported finding a substance in the serum of patients with Graves' disease that behaved differently from TSH, which they named the long-acting thyroid stimulator, or LATS. (3) In due time, this was identified as a gamma globulin' or antibody, which attaches to the thyrotropin receptor on thyroid follicular cells. These thyroid-stimulating immunoglobulins (TSIs) thus mimic the action of TSH, binding to and activating the thyrotropin receptor, producing not only excess secretion of thyroid hormones, but hypertrophy and hyperplasia of the thyroid follicles. (5) The mechanism by which this occurs is not fully understood, but it is known that the production of these TSIs are dependent upon T cells, and that multiple epitopes in the extra-cellular domain of the TSH receptor are recognized by circulating T cells. (6) The TSH receptor is a member of the G protein-coupled family of receptors, (7) mutations of which may lead to constitutive activation in rare instances (see Toxic Adenoma).

Extrathyroidal Manifestations of Graves' Disease

Clinically evident infiltrative ophthalmopathy occurs in about 50% of patients with Graves' disease, but can be detected in almost all patients by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). (8) Ophthalmic pathology occurs in Graves' disease due to edema and inflammation involving the extraocular muscles, as well as increased orbital fat and connective tissue. The infiltration of muscle and connective tissue by macrophages and lymphocytes and the increase in volume of the retrobulbar tissue may result in protrusion of the eyes (exophthalmos/proptosis) and paresis of extraocular function that may be accompanied by diplopia. Like Graves' hyperthyroidism itself, the associated ophthalmopathy appears to be of autoimmune origin in response to antigens from the thyroid gland and the orbit. Recently, Bahn and colleagues (9) reported that a preadipocyte subpopulation of orbital fibroblasts expressed the thyrotropin receptor, which could be the putative common antigen, although other po ssible autoantigens have been suspected. (10) Another extrathyroidal manifestation, less common than ophthalmopathy, is a skin lesion or dermopathy. This may vary from scarcely detectable patches of thickened skin, most commonly in the pretibial area, to an elephantiasic involvement of the entire lower leg and foot secondary to lymphocytic infiltration of the dermis and the accumulation of glycosaminoglycans. (11) In one series of 150 patients with Graves' dermopathy reported from the Mayo Clinic, only 1 patient did not have accompanying ophthalmopathy. (12)

Pathogenesis of Graves' Disease

Genetic, environmental, and constitutional factors interact through unknown mechanisms to bring about this autoimmune disease. No single gene appears to be involved, and the concordance in identical twins is only about 20%. (13) While there is an association with human leukocyte antigen (HLA) alleles that varies with racial groups, the risk of Graves' disease in HLA-identical siblings of an affected individual is less than the risk of a monozygotic twin, implying the involvement of non-HLA-related genes. (13) Females have as much as a 10-fold greater incidence of Graves' disease, perhaps due in part to estrogen effects on the immune system. It has long been suggested that certain life-altering events, especially those involving loss or bereavement, might trigger the disease, but this is far from certain. (14) Smoking is strongly associated with ophthalmopathy, but only weakly with Graves' hyperthyroidism. (15) In iodine-deficient environs, exposure to supplemental iodine may trigger Graves' disease in some pe rsons, the so-called jodbasedow phenomenon. (16) Lithium therapy, most commonly associated with the production of goiter and hypothyroidism, has been reported to induce thyrotoxicosis in a few patients, some of whom had diffuse toxic goiters. (17) Reports of Graves' disease resulting from interferon-[beta] therapy (18) have not been substantiated by prospective studies. (19)

Diagnosis

In most instances, the diagnosis of Graves' disease can be readily made from the clinical signs and symptoms (Table 2) and by measurement of thyroid function. A sensitive assay for TSH is an excellent screening test for thyrotoxicosis, since very small increments in thyroid hormone production suppress circulating TSH levels. (20) If the TSH level is suppressed, measurement of free-thyroxine ([FT.sub.4]) level is indicated and, for economy of time, both should be measured during the same visit when the diagnosis is first suspected. If the TSH level is low but the [FT.sub.4] level is normal and thyrotoxicosis is clinically suspected, a free triiodothyronine ([FT.sub.3]) level should be measured, since, in rare instances, patients will have only excess triiodothyronine ([T.sub.3]) production. The presence of antibodies to thyroglobulin, and especially to thyroid peroxidase (TPO), (21) is further confirmation of autoimmune thyroid disease, though not specific for Graves' disease. An iodine 131 uptake and scan is usually not needed unless radioiodine treatment is planned or other causes of thyrotoxicosis, such as thyroditis, are suspected. Measurement of thyroid receptor antibodies/thyroid-stimulating immunoglobulin (TRAb/TSI) in the diagnosis and management of Graves' disease has been available since Davies et al report in 1977, (22) but there is continuing controversy concerning its usefulness. This may be in part due to the insensitivity of older assays, and this has been overcome by newer techniques using human recombinant-TSH receptors. (23) Expense is another factor, with current assays costing around $150 to $225 per sample. Thus, assay for TRAb, at least in the United States, has generally been limited to special situations, such as during pregnancy, when exophthalmos is unilateral, or when the diagnosis is otherwise in question.

Treatment

The following comments will be directed toward the treatment of Graves' disease, but will apply in varying measure to the treatment of all forms of thyrotoxicosis. Although attempts have been made to treat the autoimmune production of thyroid-stimulating antibodies, none have proven successful to date. (24,25) Conversely, autoimmune hyperthyroidism has been reported in patients who were undergoing immunosuppressive therapy, indicating the probable heterogeneity of the immune response. (26,27) Thus, all treatments are directed at the thyroid gland or at the manifestations of excess production of thyroid hormones. Surgery, radioactive iodine (RAI), and antithyroid drugs are used by physicians in various parts of the world in accordance with their experience and local custom. In North America, RAI is preferred by a majority of endocrinologists, whereas antithyroid drug therapy is predominant in Europe and Japan, with surgery being employed by all for only narrow indications. (28)

Antithyroid Drugs

In the United States, two thionamide drugs, methimazole (Tapazole) and propylthiouracil (PTU), are available for therapy of Graves' disease, as well as other causes of thyrotoxicosis. Both act by inhibiting thyroid hormone synthesis and, additionally, PTU in high concentration blocks the 5'-deiodinase enzyme that converts thyroxine to triiodothyronine. This effect may be advantageous in patients who are very toxic, but in patients who are less ill, the longer half-life of methimazole, which permits less frequent dosing, may make it of greater utility. Furthermore, patients treated with PTU who are subsequently given RAI treatment may have a less satisfactory response than those previously treated with methimazole. (29) Between 30% and 40% of patients treated with antithyroid drugs go into a remission lasting 10 years or longer. (5) While there is no entirely reliable predictor, patients with large goiters, ophthalmopathy, or young age are less likely to have a lasting response. PTU is usually initiated at a dose of 100 mg to 150 mg every 8 hours, and the dose reduced to 50 mg three times daily (tid) or twice daily (bid) after a euthyroid state is reached. Methimazole is usually started at 5 mg to 15 mg bid, but up to 30 mg bid in patients who are very toxic, with maintenance doses of 5 mg to 10 mg daily. Some thyroid specialists prefer to give a fixed dose of antithyroid drug (eg, methimazole, 30 mg) along with thyroxine to prevent hypothyroidism (the block-replace regimen vs the titration regimen). Using the block-replace method in the United Kingdom, Weetman et a1 (30) found an insignificant difference in remission rate one year after cessation of thionamide therapy, whether given for 6 or 12 months (59% vs 65%). A recent prospective, randomized trial of the titration method indicated that there was no increase in the rate of remission when treatment was continued beyond 18 months. (31) One interesting report from Japan, indicating a striking increase in remission of Graves' hyperthyroidism (98% vs 65%) and re duction in TRAb when thyroxine was added during and after methimazole treatment, (32) could not be confirmed by several subsequent investigators for reasons that are not apparent. (33-36) Common complications of thionamide drug treatment include abnormal sense of taste, pruritus, urticaria, fever, and arthralgias. Serious complications are rare, but include cholestatic jaundice, thrombocytopenia, lupus-like syndrome, hepatitis, and agranulocytosis. Methimazole typically causes cholestatic jaundice, while PTU causes cytotoxic hepatitis, but the reason remains unknown. (37) Both usually resolve with drug withdrawal, but the PTUrelated hepatitis may be fatal even after medication is discontinued, especially if the patient remains thyrotoxic (38) Agranulocytosis is, fortunately, quite rare; it is estimated to be on the order of 1 in 400 patients (39) (although one study placed the incidence as low as 3 cases per 10,000 patient years). (40) The great majority of patients recover if medication is promptly stopped a nd appropriate antibiotic therapy given. Patients taking thionamides must be instructed to stop taking the medication immediately and contact their physician for leukocyte and differential counts should they develop a sore throat, fever, or malaise. It should be noted that granulocytopenia may be observed in untreated Graves' disease, so only if the absolute granulocyte count is low should medication be discontinued. If total granulocyte counts are low they should be followed serially, and medication stopped if the trend is downward. The longstanding recommendation has been to avoid routine white blood cell (WBC) counts in patients treated with thionamide, since agranulocytosis is idiosyncratic and can occur without warning within a few hours, most commonly within the first few weeks of treatment. This advice has been called into question by Tajiri et al, (41) who followed 15,398 patients with Graves' disease over a 12-year period; 55 (0.4%) of the patients developed agranulocytosis on antithyroid drug therap y. Only 12 of the 55 were symptomatic, with the remainder being discovered during routine screening. In any event, a baseline WBC count should be obtained before initiation of treatment. Despite these caveats, thionamide treatment is usually well tolerated, and seldom must be withdrawn because of side effects.

Radioactive Iodine Treatment

Experience with RAI therapy for thyrotoxicosis extends for more than half a century now in hundreds of thousands of patients, and its safety, efficacy, and cost effectiveness are seldom disputed. (42) A survey of North American endocrinologists found that 69% of them favored RAI over thionamides for initial treatment of adults. (43) At one extreme, some specialists recommend that the first episode of Graves' disease treatment should be with thionamides, limiting the use of RAI to patients aged 50 years or older because of the risk of atrial fibrillation in this age group. (5) Others have advocated using RAI even in children, conceding that the risk of thyroid cancer in children after iodine 131 treatment is unknown, but thought to be very low. (44) In fact, the frequency of thyroid cancer, which is reported to be more common in Graves' disease patients than in the general population, is said, on the basis of surveys, to be higher in patients treated with antithyroid drugs than in those treated with surgery o r RAI This may reflect the fact that an effective dose of RAI interferes with subsequent cell replication and that more thyroid tissue remains after drug therapy. (45) Nevertheless, it would seem prudent to avoid using radioiodine in younger children, especially in view of the striking increase in thyroid cancer in children under 15 years of age exposed to radioisotope fallout from the Chernobyl accident. (46 47) RAI should never be used in pregnant women or those who are breast feeding. Exacerbation of ophthalmopathy may follow RAI therapy, especially in smokers, but may be prevented by glucocorticoids (eg, prednisone 40 mg/day) given concomitantly and tapered over a period of 2 to 3 months. (48)

In a survey of 46,988 patients receiving (131) I for diagnostic purposes or to treat hyperthyroidism or thyroid cancer, Hall et al (49) found no significant increase in the incidence of leukemia. Several reports have commented on an increased mortality rate in patients treated with RAI (50 51) but, as noted by one of these authors, the hyperthyroidism itself, rather than treatment with (131) I, appeared to be the principal explanation for the elevated mortality rate. This conclusion is borne out by a retrospective cohort study of more than 3,000 women treated between 1946 and 1964 for hyperthyroidism at the Mayo Clinic with either (131) I (n = 1,005) or surgery (n = 2,124); the mortality rates in the two groups were identical. (52) Patients who are mildly to moderately thyrotoxic can be given RAI without any thionamide pretreatment, but with sufficient doses of [beta]-blockers (eg, propranolol 20 mg-80 mg orally every 6 to 8 hours) to prevent exacerbation of increased heart rate and other adrenergic symptoms . In very toxic patients, especially older ones with comorbid conditions, it is wiser to begin with full-dose thionamide treatment for several weeks to months in order to bring them to or near a euthyroid state before RAI treatment. The drug can then be stopped 5 to 7 days before the RAI is administered. As noted earlier, treatment with PTU before RAI may result in diminished effectiveness of the RAI, so methimazole is the preferred medication. (29) If symptoms of thyrotoxicosis are significant and persistent after RAI treatment, thionamide therapy may be started, but that may decrease the cure rate, especially if begun sooner than 2 weeks after an RAI dose of <370 megabequerels (10 mCi). (53)

Many attempts have been made to determine a dose of RAI that would provide an optimal cure rate with minimal development of hypothyroidism. That goal has proven to be elusive, and hypothyroidism is the principal side effect of RAI therapy. (54) The incidence of hypothyroidism is largely dependent on the dose of RAI. reaching around 20% or higher in the first couple of years posttreatment, and continuing at a rate of 3% to 5% per year thereafter. One retrospective report of 260 patients noted that, of 67 patients who developed hypothyroidism during the 12 months following (131) I therapy, 39 (58%) spontaneously became euthyroid. (55) In another group of 31 patients with Graves' disease treated with (131) I, it was observed that those with persistent hyperthyroidism had less reduction in the size of their thyroid glands than those who became euthyroid (12.9%) or hypothyroid (77.4%) after one year, implying a lesser degree of thyroid damage. Furthermore, the persistently hyperthyroid group had significantly gre ater pretreatment levels of thyroid-stimulating antibodies. (56) It is important to emphasize to patients the likely development of hypothyroidism and the necessity for indefinite followup. It is of note that the most common cause of hypothyroidism in the US is RAI therapy for thyrotoxicosis. (1)

Surgical Treatment

As indicated previously, surgery for Graves' disease is currently employed in a small minority of patients. Indications include thyrotoxic individuals who are allergic to thionamides and unable to take radioiodine because of pregnancy, youth, massive thyromegaly with compressive symptoms, (57) or personal choice. While it is preferable to prepare the patient with antithyroid drugs preoperatively so that they are euthyroid (or more nearly so), that may not be possible. Excellent results have been obtained by using propranolol alone (58) or in combination with potassium iodide (59) to prepare patients for operation. In addition to permanent hypothyroidism, complications of surgery include a very low incidence of mortality (<1% in most centers) and a somewhat higher incidence of recurrent laryngeal nerve damage and permanent hypoparathyroidism. Transient hypocalcemia is reported to occur in up to 25% of post-thyroidectomy patients, (60) and must be dealt with by oral calcium supplementation and vitamin D prepar ations when ionized calcium levels are <1.12 mmol/L. When hypocalcemia is symptomatic or ionized calcium is <1.0 mmol/L, intravenous calcium should be given. (61) Serum calcium levels will usually normalize after a few weeks to months, with the spontaneous recovery of parathyroid function. If hypoparathyroidism persists after a year, it must be considered permanent. (62) The incidence of complications of thyroid surgery is related, not surprisingly, to the skill of the surgeon, and therein lies the rub; since thyroid operations are less common than in previous times, fewer surgeons gain the requisite experience.

TOXIC MULTINODULAR GOITER

After Graves' disease, toxic multinodular goiter (TMG) is the most common cause of hyperthyroidism, accounting for 5% to 15% of cases. (63) It occurs most often in patients aged 50 years or older and, as in Graves' disease, is far more common in women. Toxic multinodular goiter arises from nontoxic multinodular goiter when the nodules become autonomous, usually over a long period of time. Abrupt onset is occasionally seen after exposure to iodine, called the jodbasedow phenomenon. (16) There is no associated ophthalmopathy or dermopathy, but the goiters tend to be large, and compressive symptoms are not uncommon. Most patients are only mildly thyrotoxic, but cardiac manifestations, such as atrial fibrillation, are seen more often than in Graves' disease, perhaps due to the older population at risk. (61) A number of etiologic factors may contribute to the formation of a multinodular goiter that becomes autonomous and eventually toxic. Inherent functional heterogeneity of thyroid nodules, growth factors, goitr ogens, availability of iodine, and genetic abnormalities may all play a role. (65) As with solitary adenomas, some (but not all) nodules may be monoclonal in origin and contain cells that exhibit TSFI-receptor mutations that are constitutively activated. (66)

Diagnosis

The diagnosis of TMG is usually clinical, supported by laboratory data. Patients are often asymptomatic or very mildly toxic, but found to have a goiter on physical examination, or perhaps with abnormal results on a laboratory test. Initial laboratory studies may show only a suppressed TSH level, with normal [FT.sub.4] and [T.sub.3] levels. When the diagnosis is in doubt, nuclear scans, RAIU, and, occasionally, fine-needle thyroid aspiration may be used (the latter would be used only if there was a dominant nodule suspicious for malignancy, and is not indicated for the diagnosis of TMG). Radioiodine uptake is indicated in order to estimate the therapeutic dose when treatment with (131) I is contemplated, or if thyroiditis is suspected. Other imaging modalities, such as CT or MRI, are more expensive and, like ultrasound,' provide no indication of function, so offer no advantage over nuclear scanning.

Treatment

Therapy for TMG includes radioiodine ablation, surgical removal, or treatment with thionamides.

Radio iodine Ablation

Most patients with TMG are treated with RAI, with 1311 being the isotope of choice. (67) Unless symptoms are very mild, it is best to pretreat with thionamides until a euthyroid state is achieved. The 24-hour RAIU is usually lower and the goiter larger in patients with TMG than in those with Graves' disease, with a corresponding need for higher doses of RAI to achieve success. Intake of a low-iodine diet for a minimum of 3 to 5 days before and during treatment is recommended to maximize the uptake and therapeutic effect. If the patient has been on thionamide therapy, that can be discontinued at the time the low-iodine diet is begun. While some physicians base the dosimetry on a number of factors, including the estimated size of the gland, the uptake, and the desired radiation per gram of thyroid, others give an empiric dose. (68,69) As with Graves' disease treated with RAI, hypothyroidism is a common occurrence, but often not until many years after treatment.

Surgical Treatment

If the TMG gland is large and causing compressive symptoms or if the patient refuses radioiodine treatment, thyroidectomy may be indicated. (67) Total thyroidectomy is advocated by some, (70) while others recommend only partial removal. (71) Preoperative treatment with thionamides is recommended, but not treatment with cold iodine, which has the potential of exacerbating the thyrotoxicosis. As noted with Graves' disease, it is important to find a surgeon who has had experience with thyroid operations in order to decrease mortality and morbidity. (72)

Antithyroid Drug Treatment

While Graves' disease may go into remission during thionamide therapy, this cannot be expected with TMG. Thus, antithyroid medication treatment is generally used to bring the patient into a euthyroid state before PAL or surgery. In an occasional older patient with comorbidities and very mild thyrotoxicosis (see Subclinical Hyperthyroidism), a small dose of methimazole (5 mg - 10 mg) given once daily may be preferred, but most such patients will eventually require definitive treatment. Potential side effects of thionamides were noted previously.

TOXIC ADENOMA

Autonomously functioning thyroid adenomas are a rare cause of thyrotoxicosis. Apparently they are found more often in Europe than in the US, perhaps due to a greater incidence of iodine deficiency there. (65) Hamburger (73) reported that <1% of patients referred to his clinic had autonomously functioning thyroid nodules. In his report of 349 patients followed over 18 years, there were 287 nontoxic and 62 toxic solitary adenomas. Toxic lesions were seen in 56.5% of patients over 60 years of age, but in only 12.5% of the younger patients. Triiodothyronine toxicosis was observed in 46% of those patients with hyperthyroidism. All but four of the toxic adenomas measured [greater than or equal to]3 cm in diameter. Toxic adenomas are monoclonal expansions of thyroid follicular cells (65); these adenomatous cells have an inherent increased ability to trap iodine and to make hormone, independent of TSH. In some adenomas, there is a constitutive activation of the TSH second-messenger cascade. (74) In others, there is a somatic mutation in the gene encoding the stimulatory [alpha]-subunit of the G protein, Gs-[alpha]. (75)

Diagnosis

The great majority of toxic adenomas are [greater than or equal to]3 cm, so most will be readily palpable. Once the nodule's production of thyroid hormone exceeds the normal level, the TSH level will be suppressed. A total or free-[T.sub.3] level should be measured, since the nodule may be secreting primarily [T.sub.3], and the [T.sub.4] or FT4 level may be normal or even low. (76) Although a fine-needle thyroid aspiration (FNTA) is recommended as the initial step in evaluating a solitary thyroid nodule, (77) a radionuclide scan should be the first test performed if it is known that the TSH level is suppressed. A toxic adenoma will appear as warm or hot and the risk of malignancy is virtually nonexistent, so FNTA need not be performed. (65)

Treatment

Treatment options are the same as for other forms of hyperthyroidism, namely thionamides, RAI, or surgery. In addition, injection of the adenoma with alcohol has evolved as another therapeutic possibility. As is the case in TMG, thionamides represent only a temporizing measure, and will not provide definitive therapy. Iodine 131 has been used successfully to treat hot nodules for many years, but the dose of radiation remains controversial. Some advocate a higher dose to decrease the incidence of recurrent hyperthyroidism, (73) whereas others have reported that low-dose treatment (mean dose, 10.3 mCi) was effective. (78) In one long-term follow-up (median, 8 years) of patients treated with (131)I for a toxic solitary nodule, 50% had a persistent hot nodule, despite normal TSH levels. (79) It is not clear whether or not such patients have a continued risk of recurrent hyperthyroidism. Although the incidence of thyroid cancer in patients exposed to therapeutic doses of (131)I appears to be very low, (89) use in younger patients may be questioned. For these reasons, along with the possibility of hypothyroidism after RAI, many advocate surgical removal of toxic adenomas. In one recent series of 324 patients treated surgically, only 0.3% exhibited recurrent hyperthyroidism, but there was an 8% incidence of hypothyroidism, so long-term monitoring of patients remains necessary. (81) The same authors have reported their experience with ultrasound-guided injection of sterile 95% ethanol without anesthesia into toxic nodules. An average of 4 to 8 sessions were required, with 58.7% of 387 cases demonstrating a complete cure. Over a 5-year period of observation, there were no recurrences and only a 0.3% incidence of hypothyroidism. In addition to the inconvenience of multiple treatments, side effects include local pain, hematomas, fever, transient (but at times) marked exacerbation of the thyrotoxicosis, and temporary dysphonia, apparently due to recurrent laryngeal nerve damage from ethanol leakage out of the thyroid.

THYROTOXICOSIS ASSOCIATED WITH LOW RAIU

Although use of RAIU for diagnosis is neither desirable nor necessary in many cases, there are several causes of thyrotoxicosis in which it will be low. In each instance the uptake is low, often <1% in 24 hours, because the hypothalamic-pituitary-thyroid axis is suppressed by either endogenous hormone released from the thyroid gland (thyroiditis), by ectopic thyroid tissue (struma ovarii or metastatic thyroid cancer), or by exogenous thyroid hormone (thyrotoxicosis factitia). In addition, a large intake of nonradioactive iodine may dilute the test dose of radioiodine and produce a falsely low result.

THYROIDITIS

SUBACUTE THYROIDITIS

This entity which is known by many names, including de Quervain's thyroiditis, painful thyroiditis, giant cell thyroiditis, and granulomatous thyroiditis, is caused by a viral infection of the thyroid and often appears after an upper respiratory tract infection. (82) Onset can be sudden or gradual, with pain that may radiate to the ear (simulating otitis), the jaw, or the occipital area. The thyroid is usually very tender, and pain may be brought on by head movement or swallowing. Systemic symptoms are common and may include malaise, fever, myalgias, and lassitude. The condition is more common in women than in men, and is rare in children and the elderly, with the peak incidence occurring in the fourth and fifth decades of life. A minority of patients will have associated thyrotoxicosis, with the usual clinical symptoms. (83)

Diagnosis

When the classic signs and symptoms are present, the diagnosis is easily suspected on clinical grounds, although it possibly could be confused with the early stages of acute suppurative (bacterial) thyroiditis. (81) Occasional patients will not have the typical pain and tenderness, and the condition may resemble "silent" thyroiditis. (85) The erythrocyte sedimentation rate is almost always elevated during the acute phase of the disorder, often to very high values. A fine-needle aspiration will usually produce the characteristic giant cells.

Treatment

Aspirin or other nonsteroidal drugs will often bring relief from pain, but glucocorticoid therapy may be necessary if pain is severe. The usual regimen is a prednisone dose of 40 mg to 60 mg once daily for a week, then rapid dose reduction and termination after about 4 weeks. If withdrawn too early, however, symptoms may return. Relief of pain should begin within 1 to 2 days and if pain is not alleviated after 72 hours, the diagnosis should be questioned. The thyrotoxicosis resolves spontaneously, and no treatment is needed other than [beta]-blockers for symptomatic relief.

HASHIMOTO 'S THYROIDITIS

Hashimoto's thyroiditis, like Graves' disease, is an autoimmune disease of the thyroid gland. Most patients remain euthyroid or become hypothyroid, but some will develop transient thyrotoxicosis (Hashitoxicosis). Following the thyrotoxic phase, which may last for a few months, about 40% will pass through a hypothyroid period, but most will return to a euthyroid condition. (80) This has been called silent thyroiditis to distinguish it from the painful thyroiditis described above.

Diagnosis

As with other forms of thyrotoxicosis, suppression of TSH, and increased levels of circulating thyroid hormones are found. Inflammation of the thyroid causes release of antigens into the circulation, to which antibodies will develop in many patients. These antibodies are not the cause of the autoimmune inflammatory process, but rather a reflection of the damage. Antithyroid peroxidase (TPO) antibodies will be elevated in more than half of patients, and antithyroglobulin antibodies in about one fourth of patients. As with Graves' disease, there is a strong female preponderance. Although there is an increased incidence of the disorder, as well as other autoimmune diseases, in relatives of patients, no direct gene linkage has been uncovered to date. (87) Most patients will present with a goiter which classically is firm, rubbery, freely movable, and nontender. The diagnosis is made on clinical grounds. When biopsy or fine-needle aspiration is performed, Hashimoto's disease is histologically distinct, with focal lymphocytic infiltration in contrast to the intrafollicular giant cells seen in de Quervain's thyroiditis.

Treatment

When thyrotoxicosis occurs with Hashimoto's disease it is transient and requires no therapy other than propranolol or other [beta]-blockers for symptomatic relief. If symptoms persist beyond 3 to 4 months, further tests should be done to exclude Graves' disease or TMG.

POSTPARTUM THYROIDITIS

According to Stagnaro-Green, postpartum thyroiditis (PPT) is the most common endocrinologic disease, occurring in 5% to 10% of all women. (88) By his definition, the following triad must be present for the diagnosis to be made: 1) there must be no history of thyroid hormonal abnormalities, either before or during pregnancy; 2) there must be a documented abnormal TSH level (either suppressed or elevated) during the first year postpartum; and 3) the woman cannot be TSH-receptor antibody positive (thus excluding Graves' disease) or have a toxic nodule. The classic presentation of PPT begins with a transient hyperthyroid phase occurring between 6 weeks and 6 months postpartum. This is followed by a hypothyroid phase, and, finally, a euthyroid state by the end of the first postpartum year. A majority of women (38%) present with hyperthyroidism alone, or hypothyroidism alone (36%), with only 26% exhibiting the classic picture. (88)

Diagnosis

The symptoms of thyrotoxicosis in the postpartum woman are often incorrectly attributed to the stress of pregnancy, delivery, and motherhood, so physicians need to be alert to the possibility of this condition in order to make a correct diagnosis. A screening TSH level is the most cost-effective initial test, and if that is abnormal, further testing should be done as indicated to determine thyroid status. An episode of PPT in the first pregnancy was followed by a 69% recurrence rate in the second pregnancy in one prospective study. (89) Thyroid ultrasound hypoechogenicity and positive test for TPO antibodies correlate well with lymphocytic infiltration and thyroid dysfunction in women with PPT. (90) All evidence points to PPT being an autoimmune disease, and the classification of PPT as distinct from Hashimoto's thyroiditis is perhaps arbitrary.

Treatment

Just as with other forms of thyroiditis, the thyrotoxicosis observed with PPT is transient and of limited severity. Antithyroid drugs have no place in treatment. Treatment with [beta]-blockers is used in symptomatic patients as necessary. Since nearly one fourth of women with PPT may eventually develop permanent hypothyroidism, (91) annual screening of TSH levels is indicated.

FACTITIOUS THYROTOXICOSIS

Self-administration of thyroid hormone for secondary gain is occasionally seen. Patients are often medical personnel, or individuals who have been prescribed thyroid hormone for legitimate reasons but take excessive amounts. Most will have an underlying psychiatric disorder. Some may be taking thyroid hormone unknowingly as part of an unscrupulous diet medication. In the 1980s, an epidemic of thyrotoxicosis occurred in the mid-western United States due to contamination of hamburger meat with bovine thyroid glands. (92) The clinical picture will depend upon the amount and duration of hormone ingestion. The TSH level should be suppressed, along with the radioiodine uptake. Circulating levels of thyroxine may be elevated above the normal range, but could be suppressed if [T.sub.3] were taken rather than thyroxine. Quantitative thyroglobulin measurements may be low and serve as evidence of an exogenous source of thyroid hormone. (93)

STRUMA OVARII

An extremely rare cause of thyrotoxicosis associated with a low RAIU may be seen when an ovarian teratoma contains functioning thyroid tissue. Uptake of RAT over the mass could confirm the diagnosis. (94) These are potentially malignant tumors; surgical removal is the treatment of choice, and will cure the thyrotoxicosis. (95)

METASTATIC THYROID CANCER

Another very rare cause of thyrotoxicosis associated with a low RAIU is metastatic thyroid cancer, especially to the lung, (96) although functioning metastases to liver (97) and bone (98) have been described. Radioiodine uptake in the metastases may be effective therapy, but usually only after total thyroidectomy.

IODINE INGESTION

Approximately 150 [micro]g of iodine daily are required for thyroid hormone synthesis. Ordinarily, the thyroid gland can maintain normal function even in the presence of a large excess iodine exposure. Individuals at risk for development of iodine-induced hyperthyroidism include persons with iodine-deficient goiters (rare in the US where iodine is plentiful), individuals with nontoxic multinodular goiters, and euthyroid patients previously treated for Graves' disease with antithyroid drugs. (99) Amiodarone is especially prone to causing thyroid dysfunction, with a daily dose of 400 mg containing 150 mg of iodine, approximately 10% of which is released as free iodide. Two mechanisms are responsible for the production of amiodarone-induced thyrotoxicosis (AIT). (100) Type I AIT is seen in susceptible patients due to the large amount of excess iodine; type II AIT may be noted in patients with normal thyroid glands because of a dose-dependent cytotoxic effect on thyroid follicles with release of preformed thyroi d hormones, as seen in thyroiditis. (101) Many of the type I AIT patients develop a refractory form of thyrotoxicosis, and therapy may be difficult. Radioiodine is ineffective due to the large iodine load and low uptake, and thionamides may be ineffective. Thyroidectomy may be the only treatment, obviously a risky undertaking in these critically ill patients.

SPECIAL PROBLEMS

THYROID STORM

An acute exacerbation of thyrotoxicosis, called thyroid storm or thyrotoxic crisis, is a life-threatening condition demanding prompt treatment, since without aggressive treatment the mortality rate is [greater than or equal to]50%. The condition is characterized by fever, accelerated tachycardia (often greater than 140 beats/mm), marked agitation, and even delirium or psychosis that may proceed to stupor or coma. (64) The condition may be seen in a patient with undiagnosed thyrotoxicosis, most often Graves' disease, or in one in whom the diagnosis is known but in whom treatment has been inadequate. Precipitating causes include infection, trauma, general anesthesia, myocardial infarction, and pulmonary embolus, and many others. Blood for diagnostic studies (thyroid function, culture, etc) should be drawn, but treatment should not await laboratory confirmation. A suggested treatment algorithm is found in Table 3. Note that sodium iodide, which works immediately to block the release of preformed thyroid hormone s, should be given only after PTU treatment has been started, in order that new hormone synthesis is stopped. Propylthiouracil is preferred to methimazole in this case, since in high doses it blocks the conversion of [T.sub.4] to [T.sub.3], as do high doses of glucocorticoids. Cardiac complications are treated conventionally with digitalis, antiarrhythmic drugs, and diuretics. Fluid deficits are potentially very large from both gastrointestinal and insensible fluid losses, and vigorous replacement is mandatory. Precipitating causes must be identified and treated.

THYROTOXICOSIS DURING PREGNANCY

Hyperthyroidism in the pregnant woman poses special problems in management. Graves' disease is a very important cause of maternal and fetal morbidity. (102) Whenever possible, it is advisable for hyperthyroid women desiring pregnancy to achieve a euthyroid state before conception. When that is not the case, thionamides or surgery are the only options for treatment, since RAI is contraindicated. Fetal goiter and hypothyroidism may be caused by excessive PTU or methimazole, so these drugs should be carefully titrated to the minimum dose necessary to achieve control. Both appear to be equally effective, and neither has been associated with birth defects. (103) Dosage of antithyroid drugs is adjusted frequently during the course of pregnancy, with a goal of maintaining the free hormone levels in the upper one third of the normal range. (104) Surgery is reserved for those women who are allergic to thionamides or who fail treatment because of noncompliance. (102) Preoperative preparation with iodides is contraindi cated because they cross the placenta and may cause neonatal goiter and hypothyroidism, (105) but [beta]-blockade can be used. A TSI titer should be obtained, since high titers are suggestive for the development of neonatal hyperthyroidism. (106)

HYPEREMESIS GRAVIDARUM

Transient hyperthyroidism of hyperemesis gravidarum (THHG) is characterized by severe nausea, vomiting, dehydration, ketonuria, weight loss of more than 5% of body weight by 6 to 9 weeks' gestation, and thyroid tests in the hyperthyroid range. (107) THHG appears to result from a thyrotropic effect of human chorionic gonadotropin (hCG), which, like TSH, is a glycoprotein and shares a common alpha-subunit. (108) Thionamide treatment is poorly tolerated because of the nausea and vomiting, and even with normalization of thyroid test values the vomiting persists. (109) Management is supportive, with intravenous rehydration, and symptoms usually resolve along with the hyperthyroxinemia by 16 to 20 weeks of gestation, although the TSH level may remain suppressed for a longer time. It should be noted that a suppressed TSH level may be seen in women with less severe vomiting, in those with multiple gestations, and even in normal pregnancy. (102) Unlike patients with Graves' disease, those with THHG generally have no signs or symptoms of hyperthyroidism before pregnancy.

TROPHOBLASTIC TUMORS

Hydatidiform mole is seen in approximately 1 in 2,000 pregnancies in the US, and incidence is reported to be 10 times greater in Asian and Latin American countries. Choriocarcinoma occurs in about 1 in 60,000 pregnancies, with some 40% of cases occurring in women previously diagnosed with hydatidiform moles. These tumors secrete large amounts of hCG, and when the serum level exceeds approximately 200 IU/mL, hyperthyroidism is likely to occur. (110) While the prevalence of associated hyperthyroidism varies, it has been reported to be >50% in some series. (111) Surgical excision of the mole or appropriate chemotherapy of the choriocarcinoma cures the hyperthyroidism.

THYROTOXICOSIS IN THE ELDERLY

Older patients may not exhibit the typical signs and symptoms of thyrotoxicosis, a situation sometimes referred to as apathetic hyperthyroidism. One recent study compared 19 classic signs of hyperthyroidism between older patients (34 patients; mean age, 80.2 years) and younger patients (50 patients; mean age 37.4 years). A goiter was present in 94% of the younger group, but only 50% of the older patients. Anorexia and atrial fibrillation were significantly more common in the older patients (P < .001), whereas 7 signs were found significantly less frequently in older patients: hyperactive reflexes, increased sweating, heat intolerance, tremor, nervousness, polydypsia, and increased appetite. Three signs that were highly associated with thyrotoxicosis in older patients compared to older controls were apathy, tachycardia, and weight loss. The results suggest the need for routine screening for thyroid disease in older individuals. (112)

SUBCLINICAL HYPERTHYROIDISM

Since the development of sensitive assays for TSH with a threshold for detection that is [less than or equal to]0.1 mU/L, it has become increasingly common to see individuals with suppressed values for TSH, but normal levels of serum thyroxine and triiodothyronine. This is known as subclinical hyperthyroidism, and it presents a problem. Should patients be treated for a low TSH level if they are asymptomatic and all other tests of thyroid function are normal? Several authors have pointed out potential undesirable associations of subclinical hyperthyroidism: it is a risk factor for atrial fibrillation in older individuals, (113) correlates with markers of increased bone turnover in Graves' disease, (114) and may affect cardiac morphology (significant increases in left ventricular mass) and function (increase in fractional shortening and mean velocity of heart-rate-adjusted circumferential fiber shortening), as well as quality of life in young and middle-aged patients. (115) As Toft (116) points out in a recent review of the subject, in the absence of clinical thyroid disease, it may be difficult to decide whether the suppressed TSH level is the result of nonthyroidal illness and medication, autonomous thyroid function, or the initial phase of thyroiditis, even after obtaining additional studies, such as radioisotope uptake and imaging, and measurement of TSI. He suggests that if after 8 weeks the TSH level has normalized or is now elevated, it may be assumed that the patient is recovering from nonthyroidal illness or had the hyperthyroid phase of thyroiditis. If the original pattern is still present, then the choice would be between a trial of antithyroid drugs or continued close clinical follow-up.

CONCLUSION

Graves' disease is the most common cause of thyrotoxicosis, followed by toxic multinodular goiter. There are, however, many additional conditions to be considered when a patient is encountered with thyrotoxicosis, and accurate diagnosis is essential for appropriate therapy.
TABLE 1.

Varieties of Thyrotoxicosis

 Associated With Associated With
Elevated Radioiodine Uptake Depressed Radioiodine Uptake

Graves' disease Thyroiditis
Multinodular goiter Thyrotoxicosis factitia
Toxic adenoma Iodine ingestion
Hyperemesis gravidarum Struma ovarii
Trophoblastic tumors Metastatic thyroid cancer
TABLE 2.

Common manifestations of Thyrotoxicosis

Symptoms Signs

Heat intolerance Goiter
Excessive sweating Hyperkinesis
Palpitations Hyperreflexia
Hyperdefecation Tachycardia
Hyperphagia Lid retraction
Nervousness Lid lag
Weakness Ophthalmopathy
Weight loss Dermopathy
 Onycholysis
 Velvety skin
 Tremor
 Warm, moist palms
 Gynecomastia
 Proximal muscle weakness
TABLE 3.

Treatment of Thyroid Storm


1. Begin propylthiouracil, 200 mg given
 orally or by nasogastric tube,
 every 6 hours; wait at least
 30 minutes, then go to the next steps.
2. Start sodium iodide, 0.5 g by slow IV
 drip over 24 hours; alternatively, give 15
 drops of saturated solution of potassium
 iodide (SSKI) or 30 drops of Lugol's solution
 per day orally in 3 or 4 divided doses.
3. Propranolol, 40 mg every 6 hours orally.
4. Dexamethasone 0.5 mg every 6 hours orally;
 alternatively, Solucortef, 100 mg IV by
 continuous drip every 12 hours.
5. Vigorous correction of fluid deficits and
 electrolyte imbalance.
6. Treatment of infection or other precipitating causes.

IV = Intravenous.


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From the Department of Medicine, University of Tennessee Health Science center, Memphis, Tenn.

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Author:Fisher, Joseph N.
Publication:Southern Medical Journal
Geographic Code:1USA
Date:May 1, 2002
Words:9981
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