Hypothyroidism
The primary treatment of hypothyroidism is hormone replacement therapy. In primary hypothyroidism, thyroid-stimulating hormone (TSH) concentrations can be used to monitor this treatment. Free T4 is an insensitive indicator and may be within the normal range when TSH is inhibited. However, measurement of free T4 is warranted in secondary hypothyroidism when TSH release is impaired. The goals of therapy include correction of hypothyroidism to a euthyroid state (reduction of symptoms and normalization of TSH secretion), reduction in goiter size, and/or prevention of thyroid cancer recurrence.
Synthetic Thyroxine (T4: Levothyroxine)
Synthetic thyroxine (T4) is the treatment of choice for primary hypothyroidism. In the peripheral tissues, T4 is deiodinated to form triiodothyronine (T3; the active form of thyroid hormone) (Fig. 39-1). In young healthy patients, initial doses range from 50 to 200 µg per day. Although formulations of T4 (Synthroid, Levoxyl, generic preparations) may have minor differences in bioavailability, one study suggests that bioequivalence among formulations may be equivalent.1,2 Doses may be decreased in older patients and increased during pregnancy.3,4 Because T4 has a half-life of 7 to 10 days, hypothyroid patients can miss several days of T4 without adverse consequences. If the patient is unable to eat for more than a week, parenteral T4 (80% of the patient’s oral dose) can be administered.
T3 Formulations (Liothyronine)
Liothyronine is the levorotatory isomer of T3 and is 2.5 to 3.0 times as potent as levothyroxine. Its rapid onset and short duration of action preclude the use of liothyronine for long-term thyroid replacement. T4-T3 combination therapy may improve symptoms in a small subgroup of patients with a polymorphism in type 2 deiodinase, which converts T4 to T3.5
Hyperthyroidism
The treatments for hyperthyroidism are antithyroid drugs, radioiodine, and/or surgery. TSH levels are useful for the diagnosis of hyperthyroidism, but not for determining its degree of severity. Therefore, measuring free T3 and T4 is necessary to assess the efficacy of treatment. Once steady state is achieved, TSH can be used to assess the efficacy of therapy.
A large number of substances interfere with the synthesis of thyroid hormones or reduce the amount of thyroid tissue. These compounds include (a) thionamides, (b) inhibitors of the iodide transport mechanism, (c) iodide, and (d) radioactive iodine.
Thionamides (Methimazole, Propylthiouracil, Carbimazole)
Thionamides are antithyroid drugs that inhibit the formation of thyroid hormone by inhibiting thyroid peroxidase to prevent incorporation of iodine into tyrosine residues of thyroglobulin (Fig. 39-2). Thionamides exert immunosuppressive effects via a reduction in concentrations of antithyrotropin-receptor antibodies. In addition to blocking hormone synthesis, propylthiouracil also inhibits the peripheral deiodination of T4 and T3.6 Antithyroid drugs are useful in the treatment of hyperthyroidism before elective thyroidectomy.
Serum levels of thionamides peak 1 to 2 hours after ingestion.6 Thionamides are not available as parenteral preparations. The half-life of methimazole (4 to 6 hours, dosed once daily) is longer than the half-life of propylthiouracil (75 minutes, dosed several times per day). Drug-induced decreases in excessive thyroid activity usually require several days, because preformed hormone must be depleted before symptoms begin to wane. In a few patients, especially those with severe hyperthyroidism, definite improvement is evident in 1 to 2 days.
Side Effects
Minor side effects of thionamide therapy are observed in approximately 5% of patients and include urticarial or macular skin rash, arthralgias, and gastrointestinal discomfort.6 Granulocytopenia and agranulocytosis are serious but rare side effects that are most likely to occur in the first 3 months of therapy with an antithyroid drug.6 Periodic white blood cell counts, although helpful for detecting gradual decreases in the leukocyte count, should not be relied on to detect agranulocytosis because of the rapidity with which this complication can develop. Fever or pharyngitis may be the earliest manifestation of the development of agranulocytosis. Recovery is likely if the antithyroid drug is discontinued at the first sign of this side effect. Hepatic toxicity has been reported with thionamide use, particularly propylthiouracil.7,8 Methimazole crosses the placenta and appears in breast milk. Placental passage, however, is limited for propylthiouracil, making it the preferred drug for use in the parturient.6
Iodine (Saturated Potassium Iodide Solutions, Potassium Iodide-Iodine [Lugol’s Solution])
Iodide is the oldest available therapy for hyperthyroidism, providing a paradoxical treatment that is effective for reasons that are not fully understood. The response of the patient with hyperthyroidism to iodide is acute and often discernible within 24 hours, emphasizing that release of hormone into the circulation is quickly interrupted. Indeed, the most important clinical effect of high doses of iodide is inhibition of the release of thyroid hormone. This may reflect the ability of iodide to antagonize the ability of TSH and cyclic adenosine monophosphate to stimulate hormone release.
Iodide is particularly useful in the treatment of hyperthyroidism before elective thyroidectomy. Indeed, the combination of oral potassium iodide and propranolol is a recommended approach.9 The vascularity of the thyroid gland is also decreased by iodide therapy.10 Chronic treatment with iodide, however, is often associated with a recurrence of previously suppressed excessive thyroid gland activity.11
Allergic reactions may accompany treatment with iodide or administration of organic preparations that contain iodide. Angioedema and laryngeal edema may become life-threatening.
Radioactive Iodine
Radioiodine is commonly administered as the therapy of choice for Graves’ hyperthyroidism.12 Many practitioners administer radioactive iodine therapy to patients after euthyroidism is achieved via thionamides. Among the radioactive isotopes of iodine, 131I is the most frequently administered. This isotope is rapidly and efficiently trapped by thyroid gland cells, and the subsequent emission of destructive β rays acts almost exclusively on these cells, with little or no damage to surrounding tissue. It is possible to completely destroy the thyroid gland with 131I within 6 to 18 weeks.13 Indeed, hypothyroidism occurs in about 10% of treated patients in the first year after 131I administration and increases about 2% to 3% each year thereafter. For this reason, iatrogenic hypothyroidism must be considered preoperatively in any patient who has previously been treated with 131I.
Hyperthyroidism is treated with orally administered 131I, with symptoms of excessive thyroid gland activity gradually abating over a period of 2 to 3 months. One-half to two-thirds of patients are cured by a single dose of isotope, and the remainder require an additional one to two doses. The use of 131I is contraindicated during pregnancy because the fetal thyroid gland would concentrate the isotope. Most thyroid cancers except for follicular cancer accumulate little radioactive iodine. As a result, the therapeutic effectiveness of 131I for treatment of thyroid cancer is limited.
References
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2. American Thyroid Association, Endocrine Society, American Association of Clinical Endocrinologists. Joint statement on the U.S. Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid. 2004;14:486.
3. Sawin CT, Herman T, Molitch ME, et al. Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med. 1983;75:206–209.
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5. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab. 2009;94:1623–1629.
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7. Cooper DS. The side effects of antithyroid drugs. Endocrinologist. 1999;9:457–476.
8. Williams KV, Nayak S, Becker D, et al. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab. 1997;82:1727–1733.
9. Feek CM, Stewart J, Sawers A, et al. Combination of potassium iodide and propranolol in preparation of patients with Grave’s disease for thyroid surgery. N Engl J Med. 1980;302:883–885.
10. Erbil Y, Ozluk Y, Giris M, et al. Effect of lugol solution on thyroid gland blood flow and microvessel density in the patients with Graves’ disease. J Clin Endocrinol Metab. 2007;92:2182–2189.
11. Philippou G, Koutras DA, Piperingos G, et al. The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement. Clin Endocrinol. 2002;36:573–578.
12. Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Clin Endocrinol Metab. 2012;97:4549–4558.
13. Franklyn JA. The management of hyperthyroidism. N Engl J Med. 1994;330:1731–1738.