A number of compounds are capable of interfering, directly or indirectly, with the synthesis, release, or action of thyroid hormones (Table 39–4). Several are of great clinical value for the temporary or extended control of hyperthyroid states. The major inhibitors may be classified into four categories:
Anti-thyroid drugs, which interfere directly with the synthesis of thyroid hormones;
Ionic inhibitors, which block the iodide transport mechanism;
High concentrations of iodine, which decrease release of thyroid hormones from the gland and also may decrease hormone synthesis;
Radioactive iodine, which damages the thyroid gland with ionizing radiation.
Table 39-4Anti-thyroid Compounds ||Download (.pdf) Table 39-4 Anti-thyroid Compounds
|PROCESS AFFECTED ||EXAMPLES OF INHIBITORS |
|Active transport of iodide ||Complex anions: perchlorate, fluoborate, pertechnetate, thiocyanate |
|Iodination of thyroglobulin || |
Thionamides: propylthiouracil, methimazole, carbimazole
Aniline derivatives; sulfonamides
|Coupling reaction || |
All other inhibitors of iodination
|Hormone release || |
|Iodotyrosine deiodination ||Nitrotyrosines |
|Peripheral iodothyronine deiodination || |
Oral cholecystographic agents
|Hormone excretion/inactivation ||Inducers of hepatic drug-metabolizing enzymes: phenobarbital, rifampin, carbamazepine, phenytoin |
|Hormone action || |
Binding in gut: cholestyramine
Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis. These drugs include inhibitors of the peripheral deiodination of thyroxine to the active hormone, triiodothyronine, β adrenergic receptor antagonists, and Ca2+ channel blockers. The anti-thyroid drugs have been reviewed by Cooper (2005). Adrenergic receptor antagonists are discussed more fully in Chapter 12 and Ca2+ channel blockers in Chapter 27.
The anti-thyroid drugs that have clinical utility are the thioureylenes, which belong to the family of thionamides. Propylthiouracil may be considered as the prototype.
History. Studies on the mechanism of the development of goiter began with the observation that rabbits fed a diet composed largely of cabbage often developed goiters. This result was probably due to the presence of precursors of the thiocyanate ion in cabbage leaves. Later, two pure compounds were shown to produce goiter: sulfaguanidine, a sulfanilamide antimicrobial used to treat enteric infections, and phenylthiourea.
Investigation of the effects of thiourea derivatives revealed that rats became hypothyroid despite hyperplastic changes in their thyroid glands that were characteristic of intense thyrotropic stimulation. After treatment was begun, no new hormone was made, and the goitrogen had no visible effect on the thyroid gland following hypophysectomy or the administration of thyroid hormone. This suggested that the goiter was a compensatory change resulting from the induced state of hypothyroidism and that the primary action of the compounds was to inhibit the formation of thyroid hormone. The therapeutic possibilities of such agents in hyperthyroidism were evident, and the substances so used became known as anti-thyroid drugs (Astwood, 1945).
Structure–Activity Relationship. The two goitrogens found in the early 1940s proved to be prototypes of two different classes of anti-thyroid drugs. These two, with one later addition, made up three general categories into which most of the agents can be assigned:
Thioureylenes include all the compounds currently used clinically (Figure 39–9);
Aniline derivatives, of which the sulfonamides make up the largest number, embrace a few substances that have been found to inhibit thyroid hormone synthesis;
Polyhydric phenols, such as resorcinol, which have caused goiter in humans when applied to abraded skin.
Anti-thyroid drugs of the thiamide type.
A few other compounds, mentioned briefly later, do not fit into any of these categories.
Thiourea and its simpler aliphatic derivatives and heterocyclic compounds containing a thioureylene group make up most of the known anti-thyroid agents that are effective in humans. Although most of them incorporate the entire thioureylene group, in some a nitrogen atom is replaced by oxygen or sulfur so that only the thioamide group is common to all. Among the heterocyclic compounds, active representatives are the sulfur derivatives of imidazole, oxazole, hydantoin, thiazole, thiadiazole, uracil, and barbituric acid.
l-5-Vinyl-2-thiooxazolidone (goitrin) is responsible for the goiter that results from consuming turnips or the seeds or green parts of cruciferous plants. These plants are eaten by cows, and the compound is found in cow's milk in areas of endemic goiter in Finland; it is about as active as propylthiouracil in humans.
As the result of industrial exposure, toxicological studies, or clinical trials for various purposes, several other compounds have been noted to possess anti-thyroid activity (Miller et al., 2009). Thiopental and oral hypoglycemic drugs of the sulfonylurea class have weak anti-thyroid action in experimental animals. This is not significant at usual doses in humans. However, anti-thyroid effects in humans have been observed from dimercaprol and lithium salts. Polychlorinated biphenyls bear a striking structural resemblance to the thyroid hormones and may function as either agonists or antagonists of thyroid hormone action (Zoeller et al., 2000). Amiodarone, the iodine-rich drug used in the management of cardiac arrhythmias, has complex effects on thyroid function (Basaria and Cooper, 2005). In areas of iodine sufficiency, amiodarone-induced hypothyroidism due to the excess iodine is not uncommon, whereas in iodine-deficient regions, amiodarone-induced thyrotoxicosis predominates, whether because of the excess iodine or the thyroiditis induced by the drug. Amiodarone and its major metabolite, desethylamiodarone, are potent inhibitors of iodothyronine deiodination, resulting in decreased conversion of thyroxine to triiodothyronine. In addition, desethylamiodarone decreases binding of triiodothyronine to its nuclear receptors. Recommendations have been made as to screening methods to identify chemicals that may alter thyroid hormone action or homeostasis (Diamanti-Kandarakis et al., 2009).
Mechanism of Action. The mechanism of action of the thioureylene drugs has been thoroughly reviewed (Cooper, 2005). Anti-thyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; they also inhibit the coupling of these iodotyrosyl residues to form iodothyronines. This implies that they interfere with the oxidation of iodide ion and iodotyrosyl groups. The drugs are thought to inhibit the peroxidase enzyme, thereby preventing oxidation of iodide or iodotyrosyl groups to the required active state (Taurog et al., 1996). The anti-thyroid drugs bind to and inactivate the peroxidase only when the heme of the enzyme is in the oxidized state. Over a period of time, the inhibition of hormone synthesis results in the depletion of stores of iodinated thyroglobulin as the protein is hydrolyzed and the hormones are released into the circulation. Only when the preformed hormone is depleted and the concentrations of circulating thyroid hormones begin to decline do clinical effects become noticeable.
There is some evidence that the coupling reaction may be more sensitive to an anti-thyroid drug, such as propylthiouracil, than is the iodination reaction. This may explain why patients with hyperthyroidism respond well to doses of the drug that only partially suppress organification.
When Graves' disease is treated with anti-thyroid drugs, the concentration of thyroid-stimulating immunoglobulins in the circulation often decreases, prompting some to propose that these agents act as immunosuppressants. Perchlorate, which acts by an entirely different mechanism, also decreases thyroid-stimulating immunoglobulins, suggesting that improvement in hyperthyroidism may reduce thyroid antibodies.
In addition to blocking hormone synthesis, propylthiouracil partially inhibits the peripheral deiodination of T4 to T3. Methimazole does not have this effect; although the quantitative significance of this inhibition has not been established, it provides a rationale for the choice of propylthiouracil over other anti-thyroid drugs in the treatment of severe hyperthyroid states or of thyroid storm, where a decreased rate of T4→T3 conversion would be beneficial.
Absorption, Metabolism, and Excretion. The anti-thyroid compounds currently used in the U.S. are propylthiouracil (6-n-propylthiouracil) and methimazole (1-methyl-2-mercaptoimidazole; tapazole, others). In Great Britain and Europe, carbimazole (neo-mercazole), a carbethoxy derivative of methimazole, is available, and its anti-thyroid action is due to its conversion to methimazole after absorption. Pharmacological properties of propylthiouracil and methimazole are shown in Table 39–5.
Table 39-5Selected Pharmacokinetic Features of Anti-thyroid Drugs ||Download (.pdf) Table 39-5 Selected Pharmacokinetic Features of Anti-thyroid Drugs
| ||PROPYLTHIOURACIL ||METHIMAZOLE |
|Plasma protein binding ||∼75% ||Nil |
|Plasma t1/2 ||75 minutes ||∼4-6 hours |
|Volume of distribution ||∼20 liters ||∼40 liters |
|Concentrated in thyroid ||Yes ||Yes |
|Metabolism of drug during illness |
| Severe liver disease ||Normal ||Decreased |
| Severe kidney disease ||Normal ||Normal |
|Dosing frequency ||1-4 times daily ||Once or twice daily |
|Transplacental passage ||Low ||Low |
|Levels in breast milk ||Low ||Low |
Measurements of the course of organification of radioactive iodine by the thyroid show that absorption of effective amounts of propylthiouracil follows within 20-30 minutes of an oral dose and that the duration of action of the compounds used clinically is brief. The effect of a dose of 100 mg of propylthiouracil begins to wane in 2-3 hours, and even a 500-mg dose is completely inhibitory for only 6-8 hours. As little as 0.5 mg of methimazole similarly decreases the organification of radioactive iodine in the thyroid gland, but a single dose of 10-25 mg is needed to extend the inhibition to 24 hours.
The t1/2 of propylthiouracil in plasma is ∼75 minutes, whereas that of methimazole is 4-6 hours. The drugs are concentrated in the thyroid, and methimazole, derived from the metabolism of carbimazole, accumulates after carbimazole is administered. Drugs and metabolites appear largely in the urine.
Propylthiouracil and methimazole cross the placenta equally (Mortimer et al., 1997) and also can be found in milk. The use of these drugs during pregnancy is discussed later.
Untoward Reactions. The incidence of side effects from propylthiouracil and methimazole as currently used is relatively low. The overall incidence as compiled from published cases by early investigators was 3% for propylthiouracil and 7% for methimazole, with 0.44% and 0.12% of cases, respectively, developing the most serious reaction, agranulocytosis.
Agranulocytosis usually occurs during the first few weeks or months of therapy but may occur later. Because agranulocytosis can develop rapidly, periodic white cell counts usually are of little help, although a baseline white blood cell count and differential should be obtained before anti-thyroid drug treatment is initiated. Patients should be instructed to immediately report the development of sore throat or fever, which are often signs of the presence of leukopenia. If these signs or symptoms occur, patients should discontinue their anti-thyroid drug and obtain a granuloctye count. Agranulocytosis is reversible upon discontinuation of the offending drug, and the administration of recombinant human granulocyte colony-stimulating factor may hasten recovery (Magner and Snyder, 1994). Mild granulocytopenia, if noted, may be due to thyrotoxicosis or may be the first sign of this dangerous drug reaction. Caution and frequent leukocyte counts are then required.
The most common reaction is a mild, occasionally purpuric, urticarial papular rash. It often subsides spontaneously without interrupting treatment, but it sometimes calls for the administration of an antihistamine, corticosteroids, and changing to another drug (cross-sensitivity between propylthiouracil and methimazole is uncommon). Other less frequent complications are pain and stiffness in the joints, paresthesias, headache, nausea, skin pigmentation, and loss of hair. Drug fever, hepatitis, and nephritis are rare, although abnormal liver function tests are not infrequent with higher doses of propylthiouracil. Although vasculitis was previously thought to be a rare complication, antineutrophilic cytoplasmic antibodies (ANCAs) have been reported to occur in ∼50% of patients receiving propylthiouracil and rarely with methimazole (Sato et al., 2000; Sera et al., 2000).
Propylthiouracil-associated hepatic failure has been increasingly recognized, especially in children and pregnant women (Cooper and Rivkees, 2009). There are 47 published reports of propylthiouracil-associated liver failure in adults and children, and 23 liver transplants between 1990 and 2007 due to propylthiouracil-associated liver failure. Methimazole may cause cholestatic dysfunction, but it is not associated with hepatocellular necrosis, and there are no reports of liver transplants due to methimazole-associated liver toxicity. There is increasing concern about using propylthiouracil as a first-line treatment, except in severe thyrotoxicosis when the inhibition of T4 to T3 is desired, and possibly in the first trimester of pregnancy. The FDA has added a "black box" warning to propylthiouracil because of liver failure, recommending close monitoring of liver function during its use. Propylthiouracil should not be used in children except in the case of methimazole allergy.
Therapeutic Uses. The anti-thyroid drugs are used in the treatment of hyperthyroidism in the following three ways:
as definitive treatment, to control the disorder in anticipation of a spontaneous remission in Graves' disease
in conjunction with radioactive iodine, to hasten recovery while awaiting the effects of radiation
to control the disorder in preparation for surgical treatment (Cooper, 2003)
Methimazole is the drug of choice for Graves' disease; it is effective when given as a single daily dose, has improved adherence, and is less toxic than propylthiouracil. Methimazole has a relatively long plasma and intrathyroidal t1/2, as well as a long duration of action. The usual starting dose for methimazole is 15–40 mg per day. The usual starting dose of propylthiouracil is 100 mg every 8 hours. When doses >300 mg daily are needed, further subdivision of the time of administration to every 4-6 hours is occasionally helpful. Failures of response to daily treatment with 300-400 mg of propylthiouracil or 30-40 mg of methimazole are most commonly due to nonadherence but can be seen with very severe disease. Delayed responses also are noted in patients with very large goiters or those in whom iodine in any form has been given beforehand. Once euthyroidism is achieved, usually within 12 weeks, the dose of anti-thyroid drug can be reduced, but not stopped, lest an exacerbation of Graves' disease occur (see later section on remissions).
Response to Treatment. The thyrotoxic state usually improves within 3-6 weeks after the initiation of anti-thyroid drugs. The clinical response is related to the dose of anti-thyroid drug, the size of the goiter, and pretreatment serum T3 concentrations. The rate of response is determined by the quantity of stored hormone, the rate of turnover of hormone in the thyroid, the t1/2 of the hormone in the periphery, and the completeness of the block in synthesis imposed by the dosage given. When large doses are continued, and sometimes with the usual dose, hypothyroidism may develop as a result of overtreatment. The earliest signs of hypothyroidism call for a reduction in dose; if they have advanced to the point of discomfort, thyroid hormone in full replacement doses can be given to hasten recovery; then the lower maintenance dose of anti-thyroid drug as discussed earlier is instituted for continued therapy. Despite initial suggestions to the contrary, there is no demonstrated benefit of combination levothyroxine and methimazole therapy on either remission rates (Rittmaster et al., 1998) or on changes in serum concentrations of thyroid-stimulating immunoglobulins.
After treatment is initiated, patients should be examined and thyroid function tests (serum FT4 and total or free triiodothyronine concentrations) measured every 2-4 months. Serum TSH will often remain suppressed for several months after a patient has been hyperthyroid, so the circulating thyroxine and triiodothyronine concentrations are the most reliable assessment of thyroid status (Uy et al., 1995). Once euthyroidism is established, follow-up every 4-6 months is reasonable.
Control of the hyperthyroidism usually is associated with a decrease in goiter size. When this occurs, the dose of the anti-thyroid drug should be significantly decreased and/or levothyroxine can be added once hypothyroidism is confirmed by laboratory testing.
Remissions. There is no highly reliable way of predicting before treatment which patients will eventually achieve a lasting remission and which will relapse. A favorable outcome is unlikely when the disorder is of long standing, the thyroid is quite large, serum T3 concentration is high relative to serum T4 concentration, or various forms of treatment have failed. To complicate the issue further, remission and eventual hypothyroidism may represent the natural history of Graves' disease.
During treatment, a positive sign that a remission may have taken place is reduced size of the goiter. The persistence of goiter often indicates failure, unless the patient becomes hypothyroid. Another favorable indication is continued freedom from all signs of hyperthyroidism when the maintenance dose is small. Finally, a decrease in thyroid-stimulating immunoglobulins is associated with remission, although the clinical features and improvement in thyroid function tests are usually sufficient to make this assessment.
The Therapeutic Choice. Because anti-thyroid drug therapy, radioactive iodine, and subtotal thyroidectomy all are effective treatments for Graves' disease, there is no worldwide consensus among endocrinologists about the best therapeutic approach. Prolonged drug therapy of Graves' disease in anticipation of a remission is most successful in patients with small goiters or mild hyperthyroidism. Those with large goiters or severe disease usually require definitive therapy with either surgery or radioactive iodine (131I). Radioactive iodine remains the treatment of choice of many endocrinologists in the U.S.
Many investigators consider coexisting ophthalmopathy to be a relative contraindication for radioactive iodine therapy because worsening of ophthalmopathy has been reported after radioactive iodine (Bartalena et al., 1998a), although this remains controversial. Others suggest that development of hypothyroidism, regardless of the treatment, is the strongest risk factor for progression of ophthalmopathy. Smoking is a risk factor for worsening ophthalmopathy (Bartelena et al., 1998b). In older patients, depleting the thyroid gland of preformed hormone by treatment with anti-thyroid drugs is advisable before therapy with radioactive iodine, thus preventing a severe exacerbation of the hyperthyroid state during the subsequent development of radiation thyroiditis. Subtotal thyroidectomy is advocated for Graves' disease in young patients with large goiters, children who are allergic to anti-thyroid drugs, pregnant women (usually in the second trimester) who are allergic to anti-thyroid drugs, and patients who prefer surgery over anti-thyroid drugs or radioactive iodine. Radioactive iodine or surgery is indicated for definitive therapy in toxic nodular goiter.
Thyrotoxicosis in Pregnancy. Thyrotoxicosis occurs in ∼0.2% of pregnancies and is caused most frequently by Graves' disease (Chan and Mandel, 2007). Anti-thyroid drugs are the treatment of choice; radioactive iodine is clearly contraindicated. Historically, propylthiouracil has been preferred over methimazole because transplacental passage was thought to be lower; however, as noted earlier, both propylthiouracil and methimazole cross the placenta equally (Mortimer et al., 1997). Methimazole is also very rarely associated with aplasia cutis and an embryopathy that can include choanal atresia and other anomalies (Diav-Citrin and Ornoy, 2002). Current data suggest that either may be used safely in the pregnant patient (Momotani et al., 1997; Mortimer et al., 1997), although the concern for propylthiouracil-associated liver failure in pregnancy may favor the use of methimazole, especially after organogenesis in the first trimester (Cooper and Rivkees, 2009). Carbimazole is used in the EU during pregnancy and is rarely associated with congenital gut abnormalities (Barwell et al., 2002).
The anti-thyroid drug dosage should be minimized to keep the serum FT4 index in the upper half of the normal range or slightly elevated. As pregnancy progresses, Graves' disease often improves, and it is not uncommon for patients either to be on very low doses or off anti-thyroid drugs completely by the end of pregnancy. Therefore the anti-thyroid drug dose should be reduced, and maternal thyroid function should be frequently monitored to decrease chances of fetal hypothyroidism. Relapse or worsening of Graves' disease is common after delivery, and patients should be monitored closely. Methimazole up to 20 mg daily in nursing mothers reportedly has no effect on thyroid function in the infant (Azizi et al., 2003), and propylthiouracil is thought to cross into breast milk even less than methimazole.
Adjuvant Therapy. Several drugs that have no intrinsic anti-thyroid activity are useful in the symptomatic treatment of thyrotoxicosis.
β Adrenergic receptor antagonists (Chapter 12) are effective in antagonizing the sympathetic/adrenergic effects of thyrotoxicosis, thereby reducing the tachycardia, tremor, and stare, and relieving palpitations, anxiety, and tension. Either propranolol, 20-40 mg four times daily, or atenolol, 50-100 mg daily, is usually given initially. Propranolol or esmolol can be given intravenously if needed. Ca2+ channel blockers (diltiazem, 60-120 mg four times daily) can be used to control tachycardia and decrease the incidence of supraventricular tachyarrhythmias (Chapters 27 and 29). These drugs, however, should be used as an adjunct to anti-thyroid drug therapy for more rapid improvement of adrenergic-related symptoms and not as the only treatment for hyperthyroidism. Usually only short-term treatment with β adrenergic receptor antagonists or Ca2+ channel blockers is required, 2-6 weeks, and it should be discontinued once the patient is euthyroid.
Other drugs that are useful in the rapid treatment of the severely thyrotoxic patient are agents that inhibit the peripheral conversion of thyroxine to triiodothyronine. Dexamethasone (0.5-1 mg, two to four times daily) and the iodinated radiological contrast agents iopanoic acid (500-1000 mg once daily) and sodium ipodate (oragrafin) (500-1000 mg once daily) are effective in preoperative preparation; neither iopanoic acid nor sodium ipodate is available in the U.S. Cholestyramine has been used in severely toxic patients to bind thyroid hormones in the gut and thus block the enterohepatic circulation of the iodothyronines (Mercado et al., 1996). Immunotherapy has been used for Graves' hyperthyroidism and ophthalmopathy. The B-lymphocyte depleting agent rituximab, when used with methimazole, prolongs remission of Graves' disease (El Fassi et al., 2009). A novel approach that has been successful only in vitro uses low-molecular-weight antagonists of the TSH receptor (Neumann et al., 2008). This approach has the potential to provide a rapid and targeted treatment for Graves' disease.
Preoperative Preparation. To reduce operative morbidity and mortality, patients should be rendered euthyroid before subtotal thyroidectomy as definitive treatment for hyperthyroidism. It is possible to bring almost all patients to a euthyroid state with a normal range serum T4 and T3 concentration. The serum TSH concentration will be suppressed below normal for several months after serum T4 and T3 is normalized, so it is not required that the serum TSH concentration be normal before surgery. The operative mortality in these patients in the hands of an experienced thyroid surgeon is extremely low. Prior treatment with anti-thyroid drugs usually is successful in rendering the patient euthyroid for surgery. Iodide is added to the regimen for 7-10 days before surgery to decrease the vascularity of the gland, making it less friable and decreasing the difficulties for the surgeon. In the patient who is either allergic to anti-thyroid drugs or is noncompliant, a euthyroid state usually can be achieved by treatment with iopanoic acid (not available in the U.S.), dexamethasone, and propranolol for 5-7 days before surgery. All of these drugs should be discontinued after surgery.
Thyroid Storm. Thyroid storm is an uncommon but life-threatening complication of thyrotoxicosis in which a severe form of the disease is usually precipitated by an intercurrent medical problem (Nayak and Burman, 2006). It occurs in untreated or partially treated thyrotoxic patients. Precipitating factors associated with thyrotoxic crisis include infections, stress, trauma, thyroidal or non-thyroidal surgery, diabetic ketoacidosis, labor, heart disease, and, rarely, radioactive iodine treatment.
Clinical features are similar to those of thyrotoxicosis but more exaggerated. Cardinal features include fever (temperature usually >38.5°C) and tachycardia out of proportion to the fever. Nausea, vomiting, diarrhea, agitation, and confusion are frequent presentations. Coma and death may ensue in up to 20% of patients. Thyroid function abnormalities are similar to those found in uncomplicated hyperthyroidism. Therefore thyroid storm is primarily a clinical diagnosis.
Treatment includes supportive measures such as intravenous fluids, antipyretics, cooling blankets, and sedation. Anti-thyroid drugs are given in large doses. Propylthiouracil is preferred over methimazole because it also impairs peripheral conversion of T4→T3. The recommended initial dose of propylthiouracil is 200-400 mg every 6-8 hours (Nayak and Burman, 2006). Propylthiouracil and methimazole can be administered by nasogastric tube or rectally if necessary. Neither of these preparations is available for parenteral administration in the U.S.
Oral iodides are used after the first dose of an anti-thyroid drug has been administered. The agents mentioned earlier as adjuvant therapies of thyrotoxicosis may be usefully applied. Hydrocortisone (100 mg intravenously every 8 hours) can be used in the setting of hypotension both as an inhibitor of conversion of thyroxine to triiodothyronine and as supportive therapy of possible relative adrenal insufficiency (Nayak and Burman, 2006). Finally, treatment of the underlying precipitating illness is essential.
The term ionic inhibitors designates substances that interfere with the concentration of iodide by the thyroid gland (Diamanti-Kandarakis et al., 2009). The effective agents are anions that resemble iodide: thiocyanate, perchlorate, and fluoroborate, all monovalent hydrated anions of a size similar to that of iodide.
The most studied example, thiocyanate, differs from the others qualitatively; it is not concentrated by the thyroid gland but in large amounts may inhibit the organification of iodine. Thiocyanate is produced following the enzymatic hydrolysis of certain plant glycosides. Thus, certain foods (e.g., cabbage) and cigarette smoking result in an increased concentration of thiocyanate in the blood and urine, as does the administration of sodium nitroprusside. Indeed, cigarette smoking has been reported to worsen both subclinical hypothyroidism (Müller et al., 1995) and Graves' ophthalmopathy (Bartalena et al., 1998b). Dietary precursors of thiocyanate may be a contributing factor in endemic goiter in certain parts of the world, especially in Central Africa, where the intake of iodine is very low.
Among other anions, perchlorate (ClO4–) is 10 times as active as thiocyanate (Wolff, 1998). The various NIS inhibitors, perchlorate, thiocyanate, and nitrate, are additive in inhibiting iodine uptake (Tonacchera et al., 2004). Perchlorate blocks the entrance of iodide into the thyroid by competitively inhibiting the NIS. Perchlorate is transported by NIS using a different stoicheiometry, electroneutral, compared with that seen with transport of iodine (Dohan et al., 2007). Although perchlorate can be used to control hyperthyroidism, it has caused fatal aplastic anemia when given in excessive amounts (2-3 g daily). Perchlorate in doses of 750 mg daily has been used in the treatment of Graves' disease and amiodarone-iodine–induced thyrotoxicosis (National Academy of Sciences/National Research Council [NAS/NRC], 2005). Perchlorate can be used to "discharge" inorganic iodide from the thyroid gland in a diagnostic test of iodide organification. Other ions, selected on the basis of their size, also have been found to be active; fluoroborate (BF4–) is as effective as perchlorate.
Ammonium perchlorate is an essential oxidizer in the production of rocket fuel, and water supplies have been contaminated with perchlorate derived from the sites of production. A National Academy of Sciences Committee recommended a reference dose of perchlorate exposure of 0.0007 mg/kg per day that would produce no adverse effect. This level of no effect is much higher than that found in most water supplies, indicating a low risk of perchlorate exposure influencing thyroid function (NAS/NRC, 2005). The reference dose was primarily derived from a 2-week study in normal volunteers that determined the daily dose of perchlorate that produced no effect on thyroid function or 123I uptake (Greer et al., 2002). There remain concerns that accumulated perchlorate exposure from multiple sources and combined exposure to other iodine uptake inhibitors may impair thyroid function, especially as it might affect pregnant women and young children (Miller et al., 2009). A study in the U.S. showed a correlation between perchlorate exposure and an increase in serum TSH (still within the normal range), only among women with low iodine intake (Blount et al., 2006). Men and women with adequate iodine intake did not show any influence of perchlorate on thyroid function. Others have argued that the risk of thyroid dysfunction from perchlorate exposure is extremely low and there is little evidence to support this view (Charnley, 2008). A study among pregnant women living in areas of very high natural perchlorate contamination showed no effect on maternal thyroid function or pregnancy outcome for mother or infant (Tellez et al., 2006). Although reassuring, the high iodine content in this region may limit the effects of perchlorate. Because the primary mode of toxicity of perchlorate is inhibition of iodine uptake, the best approach to reduce susceptibility is to maintain adequate iodine intake, especially during pregnancy (Becker et al., 2006).
Lithium has a multitude of effects on thyroid function; its principal effect is decreased secretion of thyroxine and triiodothyronine (Takami, 1994), which can cause overt hypothyroidism in some patients taking Li+ for the treatment of mania (Chapter 16).
Iodide is the oldest remedy for disorders of the thyroid gland. Before the anti-thyroid drugs were used, it was the only substance available for control of the signs and symptoms of hyperthyroidism. Its use in this way is indeed paradoxical, and the explanation for this paradox is still incomplete.
Mechanism of Action. High concentrations of iodide appear to influence almost all important aspects of iodine metabolism by the thyroid gland. The capacity of iodide to limit its own transport was mentioned earlier. Acute inhibition of the synthesis of iodotyrosines and iodothyronines by iodide also is well known (the Wolff-Chaikoff effect). This transient 2-day inhibition is observed only above critical concentrations of intracellular rather than extracellular concentrations of iodide. With time, "escape" from this inhibition is associated with an adaptive decrease in iodide transport and a lowered intracellular iodide concentration, associated with a decrease in NIS mRNA and protein (Eng et al., 1999).
An important clinical effect of high [I–]plasma is inhibition of the release of thyroid hormone. This action is rapid and efficacious in severe thyrotoxicosis. The effect is exerted directly on the thyroid gland and can be demonstrated in the euthyroid subject as well as in the hyperthyroid patient. Studies in a cultured thyroid cell line suggest that some of the inhibitory effects of iodide on thyrocyte proliferation may be mediated by actions of iodide on crucial regulatory points in the cell cycle (Smerdely et al., 1993).
In euthyroid individuals, the administration of doses of iodide from 1.5-150 mg daily results in small decreases in plasma thyroxine and triiodothyronine concentrations and small compensatory increases in serum TSH values, with all values remaining in the normal range. However, euthyroid patients with a history of a wide variety of underlying thyroid disorders may develop iodine-induced hypothyroidism when exposed to large amounts of iodine present in many commonly prescribed drugs (Table 39–6), and these patients do not escape from the acute Wolff-Chaikoff effect (Roti et al., 1997). Among the disorders that predispose patients to iodine-induced hypothyroidism are treated Graves' disease, Hashimoto's thyroiditis, postpartum lymphocytic thyroiditis, subacute painful thyroiditis, and lobectomy for benign nodules. The most commonly prescribed iodine-containing drugs are certain expectorants (e.g., potassium iodide), topical antiseptics (e.g., povidone iodine), and iodinated radiological contrast agents.
Table 39-6Commonly Used Iodine-Containing Drugs ||Download (.pdf) Table 39-6 Commonly Used Iodine-Containing Drugs
|DRUGS ||IODINE CONTENT |
|Oral or local || |
|Amiodarone ||75 mg/tablet |
|Calcium iodide syrup ||26 mg/mL |
|Iodoquinol (diiodohydroxyquin) ||134-416 mg/tablet |
|Echothiophate iodide ophthalmic solution ||5-41 μg/drop |
|Hydriodic acid syrup ||13-15 mg/mL |
|Iodochlorhydroxyquin ||104 mg/tablet |
|Iodine-containing vitamins ||0.15 mg/tablet |
|Idoxuridine ophthalmic solution ||18 μg/drop |
|Kelp/seaweed ||0.15 mg/tablet |
|Lugol's solution ||6.3 mg/drop |
|PONARIS nasal emollient ||5 mg/0.8 mL |
|KI, saturated solution (KISS) ||38 mg/drop |
|Topical antiseptics || |
|Iodoquinol cream (diiodohydroxyquin) ||6 mg/g |
|Iodine tincture ||40 mg/mL |
|Iodochlorhydroxyquin cream ||12 mg/g |
|Iodoform gauze ||4.8 mg/100 mg gauze |
|Povidone–iodine ||10 mg/mL |
|Radiology contrast agents || |
|Diatrizoate meglumine sodium ||370 mg/mL |
|Propyliodone ||340 mg/mL |
|Iopanoic acid ||333 mg/tablet |
|Ipodate ||308 mg/capsule |
|Iothalamate ||480 mg/mL |
|Metrizamide (undiluted) ||483 mg/mL |
|Iohexol ||463 mg/mL |
Response to Iodide in Hyperthyroidism. The response to iodides in patients with hyperthyroidism is often striking and rapid. The effect usually is discernible within 24 hours, and the basal metabolic rate may fall at a rate comparable to that following thyroidectomy. This provides evidence that the release of hormone into the circulation is rapidly blocked. Furthermore, thyroid hormone synthesis also is mildly decreased. In the thyroid gland, vascularity is reduced, the gland becomes much firmer, the cells become smaller, colloid reaccumulates in the follicles, and the quantity of bound iodine increases, as though an excessive stimulus to the gland has been removed or antagonized. The maximal effect is attained after 10-15 days of continuous therapy when the signs and symptoms of hyperthyroidism may have greatly improved.
Unfortunately, iodide therapy usually does not completely control the manifestations of hyperthyroidism, and after a variable period of time, the beneficial effect disappears. With continued treatment, the hyperthyroidism may return in its initial intensity or may become even more severe than it was at first.
Therapeutic Uses. The uses of iodide in the treatment of hyperthyroidism are in the preoperative period in preparation for thyroidectomy, and in conjunction with anti-thyroid drugs and propranolol, in the treatment of thyrotoxic crisis.
Before surgery, iodide is sometimes employed alone, but more frequently it is used after the hyperthyroidism has been controlled by an anti-thyroid drug. It is then given for 7-10 days immediately preceding the operation. Optimal control of hyperthyroidism is achieved if anti-thyroid drugs are first given alone. If iodine also is given from the beginning, variable responses are observed; sometimes the effect of iodide predominates, storage of hormone is promoted, and prolonged anti-thyroid treatment is required before the hyperthyroidism is controlled. These clinical observations may be explained by the capacity of iodide to prevent the inactivation of thyroid peroxidase by anti-thyroid drugs (Taurog et al., 1996).
Another use of iodide is to protect the thyroid from radioactive iodine fallout following a nuclear accident, military exposure, or large scale radioiodination procedures in laboratories. Because the uptake of radioactive iodine is inversely proportional to the serum concentration of stable iodine, the administration of 30-100 mg of iodide daily will markedly decrease the thyroid uptake of radioisotopes of iodine. Following the Chernobyl nuclear reactor accident in 1986, ∼10 million children and adults in Poland were given stable iodide to block the thyroid exposure to radioactive iodine from the atmosphere and from dairy products from cows that ate contaminated grass (Nauman and Wolff, 1993).
The dosage or form in which iodide is administered bears little relationship to the response achieved in hyperthyroidism, provided that not less than the minimal effective amount is given; this dosage is 6 mg of iodide per day in most, but not all, patients.
Strong iodine solution (Lugol's solution) is widely used and consists of 5% iodine and 10% potassium iodide, which yields a dose of 8 mg of iodine per drop. The iodine is reduced to iodide in the intestine before absorption. Saturated solution of potassium iodide (SSKI) also is available, containing 50 mg per drop. Typical doses include 16-36 mg (2-6 drops) of Lugol's solution or 50-100 mg (1-2 drops) of SSKI three times a day. A potassium iodide product (thyroshield) is available over the counter in the U.S. to take in the event of a radiation emergency and block the uptake of radioiodide into the thyroid gland. The adult dose is 2 mL (130 mg) every 24 hours, as directed by public health officials, with specific dose recommendations in children and infants based on age and weight.
Untoward Reactions. Occasional individuals show marked sensitivity to iodide or to organic preparations that contain iodine when they are administered intravenously as a supplement (e.g., sodium iodine [iodopen]) during total parental nutrition therapy. The onset of an acute reaction may occur immediately or several hours after administration. Angioedema is the outstanding symptom, and laryngeal edema may lead to suffocation. Multiple cutaneous hemorrhages may be present. Also, manifestations of the serum-sickness type of hypersensitivity—such as fever, arthralgia, lymph node enlargement, and eosinophilia—may appear. Thrombotic thrombocytopenic purpura and fatal periarteritis nodosa attributed to hypersensitivity to iodide also have been described.
The severity of symptoms of chronic intoxication with iodide (iodism) is related to the dose. The symptoms start with an unpleasant brassy taste and burning in the mouth and throat as well as soreness of the teeth and gums. Increased salivation is noted. Coryza, sneezing, and irritation of the eyes with swelling of the eyelids are commonly observed. Mild iodism simulates a "head cold." The patient often complains of a severe headache that originates in the frontal sinuses. Irritation of the mucous glands of the respiratory tract causes a productive cough. Excess transudation into the bronchial tree may lead to pulmonary edema. In addition, the parotid and submaxillary glands may become enlarged and tender, and the syndrome may be mistaken for mumps parotitis. There also may be inflammation of the pharynx, larynx, and tonsils. Skin lesions are common and vary in type and intensity. They usually are mildly acneform and distributed in the seborrheic areas. Rarely, severe and sometimes fatal eruptions (ioderma) may occur after the prolonged use of iodides. The lesions are bizarre; they resemble those caused by bromism, a rare problem, and as a rule involute quickly when iodide is withdrawn. Symptoms of gastric irritation are common, and diarrhea, which is sometimes bloody, may occur. Fever is occasionally observed, and anorexia and depression may be present.
Fortunately, the symptoms of iodism disappear spontaneously within a few days after stopping the administration of iodide. The renal excretion of I– can be increased by procedures that promote Cl– excretion (e.g., osmotic diuresis, chloruretic diuretics, and salt loading). These procedures may be useful when the symptoms of iodism are severe.
Chemical and Physical Properties. Iodine has several radioactive isotopes, although the primary ones used for the diagnosis and treatment of thyroid disease are 123I and 131I. The short-lived radionuclide of iodine, 123I, is primarily a γ-emitter with a t1/2 of only 13 hours and is used in diagnostic studies to measure 24-hour iodine uptake and for thyroid imaging. In contrast, 131I has a t1/2 of 8 days and emits both γ rays and β particles. More than 99% of its radiation is expended within 56 days. It is used therapeutically for thyroid destruction of an overactive or enlarged thyroid and in thyroid cancer for thyroid ablation and treatment of metastatic disease.
Effects on the Thyroid Gland. The chemical behavior of the radioactive isotopes of iodine is identical to that of the stable isotope, 127I. 131I is rapidly and efficiently trapped by the thyroid, incorporated into the iodoamino acids, and deposited in the colloid of the follicles, from which it is slowly liberated. Thus the destructive β particles originate within the follicle and act almost exclusively on the parenchymal cells of the thyroid, with little or no damage to surrounding tissue. The γ radiation passes through the tissue and can be quantified by external detection. The effects of the radiation depend on the dosage. When small tracer doses of 131I are administered, thyroid function is not disturbed. However, when large amounts of radioactive iodine gain access to the gland, the characteristic cytotoxic actions of ionizing radiation are observed. Pyknosis and necrosis of the follicular cells are followed by disappearance of colloid and fibrosis of the gland. With properly selected doses of 131I, it is possible to destroy the thyroid gland completely without detectable injury to adjacent tissues. After smaller doses, some of the follicles, usually in the periphery of the gland, retain their function.
Therapeutic Uses. Radioactive iodine finds its widest use in the treatment of hyperthyroidism and in the diagnosis of disorders of thyroid function. Sodium iodide 131I (hicon, others) is available as a solution or in capsules containing essentially carrier-free 131I suitable for oral administration. Sodium iodide 123I is available for scanning procedures. Discussion here is focused on the therapeutic uses of 131I.
Hyperthyroidism. Radioactive iodine is a valuable alternative or adjunctive treatment of hyperthyroidism (Brent, 2008). Stable iodide (non-radioactive) used as treatment for hyperthyroidism, however, may preclude treatment and imaging with radioactive iodine for weeks after the stable iodide has been discontinued. A urinary iodine measurement can be performed to monitor the iodine load. In those patients exposed to stable iodide, a 24-hour radioiodine measurement of a tracer dose of 123I should be performed before 131I administration to ensure there is sufficient uptake to accomplish the desired ablation.
Dosage and Technique. 131I, 7000-10,000 rads per gram of thyroid tissue, is administered orally. The effective dose for a given patient depends primarily on the size of the thyroid, the iodine uptake of the gland, and the rate of release of radioactive iodine from the gland subsequent to the nuclide's deposition in the colloid. Comparison studies have shown little advantage of a standard individualized dose, based on gland weight and radioactive iodine uptake, over a fixed dose (Jarl⊘v et al., 1995). For these reasons, the optimal dose of 131I, expressed in terms of microcuries taken up per gram of thyroid tissue, varies in different laboratories from 80-150 μCi. The usual total dose is 4-15 mCi.
The lower doses produce a lower incidence of hypothyroidism in the early years after treatment; however, many patients with late hypothyroidism may go undetected, and the ultimate incidence of hypothyroidism is probably no less than with the larger doses. In addition, relapse of the hyperthyroid state, or initial failure to alleviate the hyperthyroid state, is increased in patients receiving lower doses of 131I. Thus, many endocrinologists recommend initial treatment with thyroid ablative doses of 131I, with subsequent treatment for hypothyroidism. There also is evidence that pretreatment with an anti-thyroid drug reduces the therapeutic efficacy of 131I. The medication, therefore, should be discontinued ∼1 week before the therapeutic dose of 131I therapy and only resumed 3 days after 131I (Walter et al., 2007). If the anti-thyroid drug cannot be discontinued, the effect can be overcome by adjusting to a higher radioiodine dose.
Course of Disease. The course of hyperthyroidism in a patient who has received an optimal dose of 131I is characterized by progressive recovery. Beginning a few weeks after treatment, the symptoms of hyperthyroidism gradually abate over a period of 2-3 months. If therapy has been inadequate, the necessity for further treatment is apparent within 6-12 months. It is not uncommon, however, for the serum TSH to remain low for several months after 131I therapy, especially if the patient was not rendered euthyroid before receiving the radioactive iodine. Occasionally, this delayed recovery of the hypothalamic-pituitary-thyroid axis results in a picture of central hypothyroidism, with low circulating thyroid hormones. Thus, assessing radioactive iodine failure based on TSH concentrations alone may be misleading and should always be accompanied by determination of free T4 and usually serum T3 concentrations. Furthermore, transient hypothyroidism, lasting up to 6 months, may occur in up to 50% of patients receiving a dose of 131I calculated to result in euthyroidism (Aizawa et al., 1997). This is less of a problem if the patient receives a higher, ablative dose of 131I because hypothyroidism occurs far more frequently and persists.
Depending to some extent on the dosage schedule adopted, 80% of patients are cured by a single dose, ∼20% require two doses, and a very small fraction require three or more doses before the disorder is controlled. Patients treated with larger doses of 131I almost always develop hypothyroidism within a few months.
β Adrenergic antagonists, anti-thyroid drugs, or both, or stable iodide, can be used to hasten the control of hyperthyroidism while awaiting the full effects of the radioactive iodine.
Advantages. The advantages of radioactive iodine in the treatment of Graves' disease are many. No death as a direct result of the use of the isotope has been reported. There have been reports of increased mortality from cardiovascular and cerebrovascular disease in the first year after radioactive iodine therapy (Franklyn et al., 1998); however, there is no evidence that the increased mortality was related to the radioactive iodine itself, and long-term follow-up of radioactive iodine therapy for Graves' disease has demonstrated no increase in overall cancer mortality in patients treated with 131I (Ron et al., 1998). In the non-pregnant patient, no tissue other than the thyroid is exposed to sufficient ionizing radiation to be detectably altered. Nevertheless, continuing concern about potential effects of radiation on germ cells prompts some endocrinologists to advocate anti-thyroid drugs or surgery in younger patients who are acceptable operative risks. Hypoparathyroidism is a small risk of surgery. With radioactive iodine treatment, the patient is spared the risks and discomfort of surgery. The cost is low, hospitalization is not required in the U.S., and patients can participate in their customary activities during the entire procedure, although there are recommendations to limit exposure to young children.
Disadvantages. The chief consequence of the use of radioactive iodine is the high incidence of delayed hypothyroidism. Even when elaborate procedures are used to estimate iodine uptake and gland size, most patients become hypothyroid.
Several analyses of groups of patients treated ≥10 years previously suggest that the eventual rate may exceed 80%. However, it now appears that the incidence of hypothyroidism also increases progressively after subtotal thyroidectomy or after anti-thyroid drug therapy, and such failure of glandular function is probably part of the natural progression of Graves' disease, no matter what the therapy. Although cancer death rate is not increased after radioiodine therapy, there is a small but significant increase shown in specific types of cancer, including stomach, kidney, and breast (Metso et al., 2007). This finding is especially significant because these tissues all express the iodine transporter NIS and may be especially susceptible to radiation effects.
It is essential that patients treated with radioiodine understand that the resulting hypothyroidism will require lifelong treatment and monitoring. Because there are variations in the interval of time from treatment to the development of hypothyroidism, patients must have regular thyroid function testing after radioiodine. Also, once diagnosed, it is difficult to ensure that patients who need the hormone actually take it. Because the health risks of untreated subclinical hypothyroidism are becoming increasingly evident (Biondi and Cooper, 2008), hypothyroidism, either subclinical or overt, requires long-term follow-up to ensure adequate thyroid hormone status and optimal replacement therapy.
Another disadvantage of radioactive iodine therapy is the long period of time that is sometimes required before the hyperthyroidism is controlled. When a single dose is effective, the response is most satisfactory; however, when multiple doses are needed, it may be many months or a year or more before the patient is well. This disadvantage can be largely overcome if the initial dose is sufficiently large. Other disadvantages include possible worsening of ophthalmopathy after treatment (Bartalena et al., 1998a). Radioactive iodine treatment can induce a radiation thyroiditis, with release of preformed thyroxine and triiodothyronine into the circulation. In most patients, this is asymptomatic, but in some there can be worsening of symptoms of hyperthyroidism and rarely cardiac manifestations, such as atrial fibrillation or ischemic heart disease and very rarely thyroid storm. Pretreatment with anti-thyroid drugs should reduce or eliminate this complication and is indicated especially in those with underlying cardiac disease or the elderly. Finally, salivary gland dysfunction may be seen, especially after the higher doses used for the treatment of thyroid cancer (Mandel and Mandel, 2003). Sialogogic agents to hasten the transit of radioiodine through the salivary glands are used by many clinicians but have unproven efficacy. Salivary gland damage is most strongly linked to the cumulative dose of radioiodine.
Indications. The clearest indication for this form of treatment is hyperthyroidism in older patients and in those with heart disease. Radioactive iodine also is the best form of treatment when Graves' disease has persisted or recurred after subtotal thyroidectomy and when prolonged treatment with anti-thyroid drugs has not led to remission. Finally, radioactive iodine is indicated in patients with toxic nodular goiter because the disease does not go into spontaneous remission.
The risk of inducing hypothyroidism is less in nodular goiter than in Graves' disease, perhaps because of the normal progression of the latter and the preservation of nonautonomous thyroid tissue in the former. Usually, larger doses of radioactive iodine are required in the treatment of toxic nodular goiter than in the treatment of Graves' disease. Radioactive iodine has been used to decrease the size of large nontoxic multinodular goiters that are causing compressive symptoms in patients who are otherwise poor operative risks. Although surgery remains the treatment of choice for patients with compressive multinodular goiters, radioactive iodine therapy may benefit elderly patients, especially those with cardiopulmonary disease. The uptake in multinodular goiters may be low, so some have increased radioiodine uptake by administration of exogenous recombinant human TSH (thyrotropin alfa [thyrogen]) (Duntas and Cooper, 2008), but caution should be exercised because this treatment may induce transient elevations in serum thyroxine and triiodothyronine that could result in excessive stimulation of the heart.
Contraindications. The main contraindication for the use of 131I therapy is pregnancy. After the first trimester, the fetal thyroid will concentrate the isotope and thus suffer damage; even during the first trimester, radioactive iodine is best avoided because there may be adverse effects of radiation on fetal tissues. The risk of causing neoplastic changes in the thyroid gland has been an ongoing concern since radioactive iodine was first introduced, and only small numbers of children have been treated in this way. Indeed, many clinics have declined to treat younger patients for fear of causing cancer and have reserved radioactive iodine for patients older than some arbitrary age, such as 25 or 30 years. Because experience with 131I is now vast, these age limits are lower than they were in the past. The most recent report by the Cooperative Thyrotoxicosis Therapy Follow-up Study Group shows no increase in total cancer mortality following 131I treatment for Graves' disease (Ron et al., 1998). Furthermore, there was no increase in the occurrence of leukemia following large-dose 131I therapy for thyroid cancer, although there was an increase in colorectal cancers in this population (de Vathaire et al., 1997). These data strongly suggest that laxatives be given to all patients receiving 131I therapy for treatment of thyroid cancer to decrease the risk of future digestive tract malignancies. Transient abnormalities in testicular function have been reported following 131I therapy for treatment of thyroid cancer, but no long-term effects on fertility in either men or women have been demonstrated (Dottorini et al., 1995; Pacini et al., 1994). Patients with allergies to iodine contrast agents or to topical iodide-containing products should not have any adverse reaction to 131I. The amount of elemental iodine contained in the treatment is not greater than that contained in iodized salt or flour that is part of regular dietary intake.
Diagnostic Uses. Measurement of the thyroidal accumulation of a tracer dose is helpful in the differential diagnosis of hyperthyroidism and nodular goiter. The response of the thyroid to TSH-suppressive doses of thyroid hormone can be evaluated in this way. Following the administration of a tracer dose, the pattern of localization in the thyroid gland can be depicted by a special scanning apparatus, and this technique is sometimes useful in defining thyroid nodules as functional ("hot") or non-functional ("cold") and in finding ectopic thyroid tissue and occasionally metastatic thyroid tumors.
Thyroid Carcinoma. Because most well-differentiated thyroid carcinomas accumulate very little iodine, stimulation of iodine uptake with TSH is required to treat metastases effectively. Currently, endogenous TSH stimulation is evoked by withdrawal of thyroid hormone replacement therapy in patients previously treated with near-total thyroidectomy with or without radioactive ablation of residual thyroid tissue. Total-body 131I scanning and measurement of serum thyroglobulin when the patient is hypothyroid (TSH >35 mU/L) help to identify metastatic disease or residual thyroid bed tissue. Depending on the residual uptake or the presence of metastatic disease, an ablative dose of 131I ranging from 30 mCi to >150 mCi is administered, and a repeat total body scan is obtained 1 week later. The precise amount of 131I needed to treat residual tissue and metastases is controversial. Thyrotropin alfa (recombinant human TSH) is now available to test the ability of thyroid tissue, both normal and malignant, to take up radioactive iodine and to secrete thyroglobulin (Haugen et al., 1999). Thyrogen allows assessment of the presence of metastatic disease, without the necessity for patients to stop their suppressive levothyroxine therapy and become clinically hypothyroid. Thyrotropin alfa is approved for diagnostic scanning and for thyroid remnant ablation after thyroidectomy in thyroid cancer patients, but not for treatment of metastatic disease. (Duntas and Cooper, 2008; Pacini and Castangna, 2008).
TSH-suppressive therapy with levothyroxine is indicated in all patients after treatment for thyroid cancer. The goal of therapy usually is to keep serum TSH levels in the subnormal range, although relaxing the degree and duration of suppression, especially for stage 1 and 2 cancers, is now recommended (Burmeister et al., 1992; Cooper et al., 2006). Follow-up evaluation every 6 months is reasonable, along with determination of serum thyroglobulin concentrations (Spencer and LoPresti, 2008). Patients with a rise in thyroglobulin but no detectable disease on whole-body scan require additional imaging and consideration of alternative treatments including surgery and external radiation (Kloos, 2008). A rise in serum thyroglobulin concentration is often the first indication of recurrent disease. The prognosis in patients with thyroid cancer depends on the pathology and size of the tumor and is generally worse in older individuals. Overall, the vast majority of patients with thyroid cancer will not die of their disease. Papillary cancer is usually not aggressive; the 10-year survival rate exceeds 80%. Follicular cancer is more aggressive and can metastasize via the bloodstream. Still, prognosis is fair and long-term survival is common. Even in patients with metastatic, differentiated thyroid cancer, 131I therapy is very effective and may be even curative (Cooper et al., 2006). Anaplastic cancer is the exception: It is highly malignant with survival usually <1 year. Medullary thyroid carcinomas do not accumulate I– and cannot be treated with 131I.
Chemotherapy in Thyroid Cancer
Advanced and metastatic poorly differentiated papillary and follicular thyroid cancer often does not concentrate iodine sufficient for therapy with 131I (Kloos, 2008). There have been significant advances in targeted chemotherapy for thyroid cancer (Sherman, 2009). Recent advances in the molecular genetics of thyroid cancer have resulted in the identification of oncogenic mutations in the BRAF and RAS genes, known to activate the MAPK signaling pathway. Medullary thyroid carcinoma is associated with mutations in the RET gene, which also enhance MAPK signaling. These findings have led to a number of successful clinical trials in poorly differentiated papillary and follicular thyroid cancer and medullary thyroid cancer. Treatment with inhibitors of receptor tyrosine kinases, vascular endothelial growth factor (VEGF), and the VEGF receptor have produced partial response rates in the range of 30%. Agents studied include axitinib, gefitinib, imatinib, motesanib, sorafenib, sunitinib, and vandetanib (Sipos and Shah, 2010). Single agents in poorly differentiated thyroid cancer have most commonly produced disease stabilization, although combining agents to target multiple growth-promoting pathways may improve the disease response.