Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function. However, the major etiologies of thyrotoxicosis are hyperthyroidism caused by Graves’ disease, toxic MNG, and toxic adenomas. Other causes are listed in Table 405-7.
Graves’ disease accounts for 60–80% of thyrotoxicosis. The prevalence varies among populations, reflecting genetic factors and iodine intake (high iodine intake is associated with an increased prevalence of Graves’ disease). Graves’ disease occurs in up to 2% of women but is one-tenth as frequent in men. The disorder rarely begins before adolescence and typically occurs between 20 and 50 years of age; it also occurs in the elderly.
TABLE 405-7Causes of Thyrotoxicosis ||Download (.pdf) TABLE 405-7 Causes of Thyrotoxicosis
|Primary Hyperthyroidism |
|Graves’ disease |
|Toxic multinodular goiter |
|Toxic adenoma |
|Functioning thyroid carcinoma metastases |
|Activating mutation of the TSH receptor |
|Activating mutation of GSα (McCune-Albright syndrome) |
|Struma ovarii |
|Drugs: iodine excess (Jod-Basedow phenomenon) |
|Thyrotoxicosis Without Hyperthyroidism |
|Subacute thyroiditis |
|Silent thyroiditis |
|Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma |
|Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue |
|Secondary Hyperthyroidism |
|TSH-secreting pituitary adenoma |
|Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis |
|Chorionic gonadotropin-secreting tumorsa |
|Gestational thyrotoxicosisa |
As in autoimmune hypothyroidism, a combination of environmental and genetic factors, including polymorphisms in HLA-DR, the immunoregulatory genes CTLA-4, CD25, PTPN22, FCRL3, and CD226, as well as the TSH-R, contribute to Graves’ disease susceptibility. The concordance for Graves’ disease in monozygotic twins is 20–30%, compared to <5% in dizygotic twins. Indirect evidence suggests that stress is an important environmental factor, presumably operating through neuroendocrine effects on the immune system. Smoking is a minor risk factor for Graves’ disease and a major risk factor for the development of ophthalmopathy. Sudden increases in iodine intake may precipitate Graves’ disease, and there is a threefold increase in the occurrence of Graves’ disease in the postpartum period. Graves’ disease may occur during the immune reconstitution phase after highly active antiretroviral therapy (HAART) or alemtuzumab treatment.
The hyperthyroidism of Graves’ disease is caused by TSI that are synthesized in the thyroid gland as well as in bone marrow and lymph nodes. Such antibodies can be detected by bioassays or by using the more widely available TBII assays. The presence of TBII in a patient with thyrotoxicosis implies the existence of TSI, and these assays are useful in monitoring pregnant Graves’ patients in whom high levels of TSI can cross the placenta and cause neonatal thyrotoxicosis. Other thyroid autoimmune responses, similar to those in autoimmune hypothyroidism (see above), occur concurrently in patients with Graves’ disease. In particular, TPO antibodies occur in up to 80% of cases and serve as a readily measurable marker of autoimmunity. Because the coexisting thyroiditis can also affect thyroid function, there is no direct correlation between the level of TSI and thyroid hormone levels in Graves’ disease. In the long term, spontaneous autoimmune hypothyroidism may develop in up to 15% of patients with Graves’ disease.
Cytokines appear to play a major role in thyroid-associated ophthalmopathy. There is infiltration of the extraocular muscles by activated T cells; the release of cytokines such as IFN-γ, TNF, and IL-1 results in fibroblast activation and increased synthesis of glycosaminoglycans that trap water, thereby leading to characteristic muscle swelling. Late in the disease, there is irreversible fibrosis of the muscles. Orbital fibroblasts may be particularly sensitive to cytokines, perhaps explaining the anatomic localization of the immune response. Though the pathogenesis of thyroid-associated ophthalmopathy remains unclear, there is mounting evidence that the TSH-R may be a shared autoantigen that is expressed in the orbit; this would explain the close association with autoimmune thyroid disease. Increased fat is an additional cause of retrobulbar tissue expansion. The increase in intraorbital pressure can lead to proptosis, diplopia, and optic neuropathy.
Signs and symptoms include features that are common to any cause of thyrotoxicosis (Table 405-8) as well as those specific for Graves’ disease. The clinical presentation depends on the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient’s age. In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis.
Thyrotoxicosis may cause unexplained weight loss, despite an enhanced appetite, due to the increased metabolic rate. Weight gain occurs in 5% of patients, however, because of increased food intake. Other prominent features include hyperactivity, nervousness, and irritability, ultimately leading to a sense of easy fatigability in some patients. Insomnia and impaired concentration are common; apathetic thyrotoxicosis may be mistaken for depression in the elderly. Fine tremor is a frequent finding, best elicited by having patients stretch out their fingers while feeling the fingertips with the palm. Common neurologic manifestations include hyperreflexia, muscle wasting, and proximal myopathy without fasciculation. Chorea is rare. Thyrotoxicosis is sometimes associated with a form of hypokalemic periodic paralysis; this disorder is particularly common in Asian males with thyrotoxicosis, but it occurs in other ethnic groups as well.
TABLE 405-8Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency) ||Download (.pdf) TABLE 405-8 Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency)
|Symptoms ||Signsa |
Hyperactivity, irritability, dysphoria
Heat intolerance and sweating
Fatigue and weakness
Weight loss with increased appetite
Oligomenorrhea, loss of libido
Tachycardia; atrial fibrillation in the elderly
Warm, moist skin
Muscle weakness, proximal myopathy
Lid retraction or lag
The most common cardiovascular manifestation is sinus tachycardia, often associated with palpitations, occasionally caused by supraventricular tachycardia. The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur and can lead to worsening of angina or heart failure in the elderly or those with preexisting heart disease. Atrial fibrillation is more common in patients >50 years of age. Treatment of the thyrotoxic state alone converts atrial fibrillation to normal sinus rhythm in about half of patients, suggesting the existence of an underlying cardiac problem in the remainder.
The skin is usually warm and moist, and the patient may complain of sweating and heat intolerance, particularly during warm weather. Palmar erythema, onycholysis, and, less commonly, pruritus, urticaria, and diffuse hyperpigmentation may be evident. Hair texture may become fine, and a diffuse alopecia occurs in up to 40% of patients, persisting for months after restoration of euthyroidism. Gastrointestinal transit time is decreased, leading to increased stool frequency, often with diarrhea and occasionally mild steatorrhea. Women frequently experience oligomenorrhea or amenorrhea; in men, there may be impaired sexual function and, rarely, gynecomastia. The direct effect of thyroid hormones on bone resorption leads to osteopenia in long-standing thyrotoxicosis; mild hypercalcemia occurs in up to 20% of patients, but hypercalciuria is more common. There is a small increase in fracture rate in patients with a previous history of thyrotoxicosis.
In Graves’ disease, the thyroid is usually diffusely enlarged to two to three times its normal size. The consistency is firm, but not nodular. There may be a thrill or bruit, best detected at the inferolateral margins of the thyroid lobes, due to the increased vascularity of the gland and the hyperdynamic circulation.
Lid retraction, causing a staring appearance, can occur in any form of thyrotoxicosis and is the result of sympathetic overactivity. However, Graves’ disease is associated with specific eye signs that comprise Graves’ ophthalmopathy (Fig. 405-8A). This condition is also called thyroid-associated ophthalmopathy, because it occurs in the absence of hyperthyroidism in 10% of patients. Most of these individuals have autoimmune hypothyroidism or thyroid antibodies. The onset of Graves’ ophthalmopathy occurs within the year before or after the diagnosis of thyrotoxicosis in 75% of patients but can sometimes precede or follow thyrotoxicosis by several years, accounting for some cases of euthyroid ophthalmopathy.
Features of Graves’ disease. A. Ophthalmopathy in Graves’ disease; lid retraction, periorbital edema, conjunctival injection, and proptosis are marked. B. Thyroid dermopathy over the lateral aspects of the shins. C. Thyroid acropachy.
Some patients with Graves’ disease have little clinical evidence of ophthalmopathy. However, the enlarged extraocular muscles typical of the disease, and other subtle features, can be detected in almost all patients when investigated by ultrasound or computed tomography (CT) imaging of the orbits. Unilateral signs are found in up to 10% of patients. The earliest manifestations of ophthalmopathy are usually a sensation of grittiness, eye discomfort, and excess tearing. About one-third of patients have proptosis, best detected by visualization of the sclera between the lower border of the iris and the lower eyelid, with the eyes in the primary position. Proptosis can be measured using an exophthalmometer. In severe cases, proptosis may cause corneal exposure and damage, especially if the lids fail to close during sleep. Periorbital edema, scleral injection, and chemosis are also frequent. In 5–10% of patients, the muscle swelling is so severe that diplopia results, typically, but not exclusively, when the patient looks up and laterally. The most serious manifestation is compression of the optic nerve at the apex of the orbit, leading to papilledema; peripheral field defects; and, if left untreated, permanent loss of vision.
The “NO SPECS” scoring system to evaluate ophthalmopathy is an acronym derived from the following changes:
0 = No signs or symptoms
1 = Only signs (lid retraction or lag), no symptoms
2 = Soft tissue involvement (periorbital edema)
3 = Proptosis (>22 mm)
4 = Extraocular muscle involvement (diplopia)
5 = Corneal involvement
6 = Sight loss
Although useful as a mnemonic, the NO SPECS scheme is inadequate to describe the eye disease fully, and patients do not necessarily progress from one class to another; alternative scoring systems that assess disease activity are preferable for monitoring purposes. When Graves’ eye disease is active and severe, referral to an ophthalmologist is indicated and objective measurements are needed, such as lid-fissure width; corneal staining with fluorescein; and evaluation of extraocular muscle function (e.g., Hess chart), intraocular pressure and visual fields, acuity, and color vision.
Thyroid dermopathy occurs in <5% of patients with Graves’ disease (Fig. 405-8B), almost always in the presence of moderate or severe ophthalmopathy. Although most frequent over the anterior and lateral aspects of the lower leg (hence the term pretibial myxedema), skin changes can occur at other sites, particularly after trauma. The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an “orange skin” appearance. Nodular involvement can occur, and the condition can rarely extend over the whole lower leg and foot, mimicking elephantiasis. Thyroid acropachy refers to a form of clubbing found in <1% of patients with Graves’ disease (Fig. 405-8C). It is so strongly associated with thyroid dermopathy that an alternative cause of clubbing should be sought in a Graves’ patient without coincident skin and orbital involvement.
Investigations used to determine the existence and cause of thyrotoxicosis are summarized in Fig. 405-9. In Graves’ disease, the TSH level is suppressed, and total and unbound thyroid hormone levels are increased. In 2–5% of patients (and more in areas of borderline iodine intake), only T3 is increased (T3 toxicosis). The converse state of T4 toxicosis, with elevated total and unbound T4 and normal T3 levels, is occasionally seen when hyperthyroidism is induced by excess iodine, providing surplus substrate for thyroid hormone synthesis. Measurement of TPO antibodies or TRAb may be useful if the diagnosis is unclear clinically but is not needed routinely. Associated abnormalities that may cause diagnostic confusion in thyrotoxicosis include elevation of bilirubin, liver enzymes, and ferritin. Microcytic anemia and thrombocytopenia may occur.
Evaluation of thyrotoxicosis. aDiffuse goiter, positive TPO antibodies or TRAb, ophthalmopathy, dermopathy. bCan be confirmed by radionuclide scan. TSH, thyroid-stimulating hormone.
Diagnosis of Graves’ disease is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, ophthalmopathy, and often a personal or family history of autoimmune disorders. For patients with thyrotoxicosis who lack these features, the diagnosis is generally established by a radionuclide (99mTc, 123I, or 131I) scan and uptake of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis. Scintigraphy is the preferred diagnostic test; however, TRAb measurement can be used to assess autoimmune activity. In secondary hyperthyroidism due to a TSH-secreting pituitary tumor, there is also a diffuse goiter. The presence of a nonsuppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance scan (MRI) scan suggest this diagnosis.
Clinical features of thyrotoxicosis can mimic certain aspects of other disorders, including panic attacks, mania, pheochromocytoma, and weight loss associated with malignancy. The diagnosis of thyrotoxicosis can be easily excluded if the TSH and unbound T4 and T3 levels are normal. A normal TSH also excludes Graves’ disease as a cause of diffuse goiter.
Clinical features generally worsen without treatment; mortality was 10–30% before the introduction of satisfactory therapy. Some patients with mild Graves’ disease experience spontaneous relapses and remissions. Rarely, there may be fluctuation between hypo- and hyperthyroidism due to changes in the functional activity of TSH-R antibodies. About 15% of patients who enter remission after treatment develop hypothyroidism 10–15 years later as a result of the destructive autoimmune process.
The clinical course of ophthalmopathy does not follow that of the thyroid disease. Ophthalmopathy typically worsens over the initial 3–6 months, followed by a plateau phase over the next 12–18 months, with spontaneous improvement, particularly in the soft tissue changes. However, the course is more fulminant in up to 5% of patients, requiring intervention in the acute phase if there is optic nerve compression or corneal ulceration. Diplopia may appear late in the disease due to fibrosis of the extraocular muscles. Radioiodine treatment for hyperthyroidism worsens the eye disease in a small proportion of patients (especially smokers). Antithyroid drugs or surgery have no adverse effects on the clinical course of ophthalmopathy. Thyroid dermopathy, when it occurs, usually appears 1–2 years after the development of Graves’ hyperthyroidism; it may improve spontaneously.
TREATMENT Graves’ Disease
The hyperthyroidism of Graves’ disease is treated by reducing thyroid hormone synthesis, using antithyroid drugs, or reducing the amount of thyroid tissue with radioiodine (131I) treatment or by thyroidectomy. Antithyroid drugs are the predominant therapy in many centers in Europe and Japan, whereas radioiodine is more often the first line of treatment in North America. These differences reflect the fact that no single approach is optimal and that patients may require multiple treatments to achieve remission.
The main antithyroid drugs are the thionamides, such as propylthiouracil, carbimazole (not available in the United States), and the active metabolite of the latter, methimazole. All inhibit the function of TPO, reducing oxidation and organification of iodide. These drugs also reduce thyroid antibody levels by mechanisms that remain unclear, and they appear to enhance rates of remission. Propylthiouracil inhibits deiodination of T4 → T3. However, this effect is of minor benefit, except in the most severe thyrotoxicosis, and is offset by the much shorter half-life of this drug (90 min) compared to methimazole (6 h). Due to the hepatotoxicity of propylthiouracil, the U.S. Food and Drug Administration (FDA) has limited indications for its use to the first trimester of pregnancy, the treatment of thyroid storm, and patients with minor adverse reactions to methimazole. If propylthiouracil is used, monitoring of liver function tests is recommended.
There are many variations of antithyroid drug regimens. The initial dose of carbimazole or methimazole is usually 10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored. Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, and divided doses are usually given throughout the course. Lower doses of each drug may suffice in areas of low iodine intake. The starting dose of antithyroid drugs can be gradually reduced (titration regimen) as thyrotoxicosis improves. Alternatively, high doses may be given combined with levothyroxine supplementation (block-replace regimen) to avoid drug-induced hypothyroidism. The titration regimen is preferred to minimize the dose of antithyroid drug and provide an index of treatment response.
Thyroid function tests and clinical manifestations are reviewed 4–6 weeks after starting treatment, and the dose is titrated based on unbound T4 levels. Most patients do not achieve euthyroidism until 6–8 weeks after treatment is initiated. TSH levels often remain suppressed for several months and therefore do not provide a sensitive index of treatment response. The usual daily maintenance doses of antithyroid drugs in the titration regimen are 2.5–10 mg of carbimazole or methimazole and 50–100 mg of propylthiouracil. In the block-replace regimen, the initial dose of antithyroid drug is held constant, and the dose of levothyroxine is adjusted to maintain normal unbound T4 levels. When TSH suppression is alleviated, TSH levels can also be used to monitor therapy.
Maximum remission rates (up to 30–60% in some populations) are achieved by 12–18 months for the titration regimen and by 6 months for the block-replace regimen. For unclear reasons, remission rates appear to vary in different geographic regions. Younger patients, males, smokers, and patients with severe hyperthyroidism and large goiters are most likely to relapse when treatment stops, but outcomes are difficult to predict. All patients should be followed closely for relapse during the first year after treatment and at least annually thereafter.
The common minor side effects of antithyroid drugs are rash, urticaria, fever, and arthralgia (1–5% of patients). These may resolve spontaneously or after substituting an alternative antithyroid drug. Rare but major side effects include hepatitis (propylthiouracil; avoid use in children) and cholestasis (methimazole and carbimazole); an SLE-like syndrome; and, most important, agranulocytosis (<1%). It is essential that antithyroid drugs are stopped and not restarted if a patient develops major side effects. Written instructions should be provided regarding the symptoms of possible agranulocytosis (e.g., sore throat, fever, mouth ulcers) and the need to stop treatment pending an urgent complete blood count to confirm that agranulocytosis is not present. Management of agranulocytosis is described in Chap. 130. It is not useful to monitor blood counts prospectively, because the onset of agranulocytosis is idiosyncratic and abrupt.
Propranolol (20–40 mg every 6 h) or longer-acting selective β1 receptor blockers such as atenolol may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid drugs take effect. Beta blockers are also useful in patients with thyrotoxic periodic paralysis, pending correction of thyrotoxicosis. In consultation with a cardiologist, anticoagulation with warfarin should be considered in all patients with atrial fibrillation who often spontaneously revert to sinus rhythm with control of hyperthyroidism. Decreased warfarin doses are required when patients are thyrotoxic. If digoxin is used, increased doses are often needed in the thyrotoxic state.
Radioiodine causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs. There is a small risk of thyrotoxic crisis (see below) after radioiodine, which can be minimized by pretreatment with antithyroid drugs for at least a month before treatment. Antecedent treatment with antithyroid drugs should be considered for all elderly patients or for those with cardiac problems to deplete thyroid hormone stores before administration of radioiodine. Carbimazole or methimazole must be stopped 3–5 days before radioiodine administration to achieve optimum iodine uptake. Propylthiouracil appears to have a prolonged radioprotective effect and should be stopped for a longer period before radioiodine is given, or a larger dose of radioiodine will be necessary.
Efforts to calculate an optimal dose of radioiodine that achieves euthyroidism without a high incidence of relapse or progression to hypothyroidism have not been successful. Some patients inevitably relapse after a single dose because the biologic effects of radiation vary between individuals, and hypothyroidism cannot be uniformly avoided even using accurate dosimetry. A practical strategy is to give a fixed dose based on clinical features, such as the severity of thyrotoxicosis, the size of the goiter (increases the dose needed), and the level of radioiodine uptake (decreases the dose needed). 131I dosage generally ranges between 370 MBq (10 mCi) and 555 MBq (15 mCi). Most authorities favor an approach aimed at thyroid ablation (as opposed to euthyroidism), given that levothyroxine replacement is straightforward and most patients ultimately progress to hypothyroidism over 5–10 years, frequently with some delay in the diagnosis of hypothyroidism.
Certain radiation safety precautions are necessary in the first few days after radioiodine treatment, but the exact guidelines vary depending on local protocols. In general, patients need to avoid close, prolonged contact with children and pregnant women for 5–7 days because of possible transmission of residual isotope and exposure to radiation emanating from the gland. Rarely, there may be mild pain due to radiation thyroiditis 1–2 weeks after treatment. Hyperthyroidism can persist for 2–3 months before radioiodine takes full effect. For this reason, β-adrenergic blockers or antithyroid drugs can be used to control symptoms during this interval. Persistent hyperthyroidism can be treated with a second dose of radioiodine, usually 6 months after the first dose. The risk of hypothyroidism after radioiodine depends on the dosage but is at least 10–20% in the first year and 5% per year thereafter. Patients should be informed of this possibility before treatment and require close follow-up during the first year followed by annual thyroid function testing.
Pregnancy and breast-feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely 6 months after treatment. The presence of severe ophthalmopathy requires caution, and some authorities advocate the use of prednisone, 40 mg/d, at the time of radioiodine treatment, tapered over 6–12 weeks to prevent exacerbation of ophthalmopathy. The overall risk of cancer after radioiodine treatment in adults is not increased. Although many physicians avoid radioiodine in children and adolescents because of the theoretical risks of malignancy, emerging evidence suggests that radioiodine can be used safely in older children.
Subtotal or near-total thyroidectomy is an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine. Some experts recommend surgery in young individuals, particularly when the goiter is very large. Careful control of thyrotoxicosis with antithyroid drugs, followed by potassium iodide (3 drops SSKI orally tid), is needed prior to surgery to avoid thyrotoxic crisis and to reduce the vascularity of the gland. The major complications of surgery—bleeding, laryngeal edema, hypoparathyroidism, and damage to the recurrent laryngeal nerves—are unusual when the procedure is performed by highly experienced surgeons. Recurrence rates in the best series are <2%, but the rate of hypothyroidism is only slightly less than that following radioiodine treatment.
The titration regimen of antithyroid drugs should be used to manage Graves’ disease in pregnancy because transplacental passage of these drugs may produce fetal hypothyroidism and goiter if the maternal dose is excessive. If available, propylthiouracil should be used in early gestation because of the association of rare cases of fetal aplasia cutis and other defects, such as choanal atresia with carbimazole and methimazole. As noted above, because of its rare association with hepatotoxicity, propylthiouracil should be limited to the first trimester and then maternal therapy should be converted to methimazole (or carbimazole) at a ratio of 15–20 mg of propylthiouracil to 1 mg of methimazole The lowest effective antithyroid drug dose should be used throughout gestation to maintain the maternal serum free T4 level at the upper limit of the nonpregnant normal reference range. It is often possible to stop treatment in the last trimester because TSIs tend to decline in pregnancy. Nonetheless, the transplacental transfer of these antibodies rarely causes fetal or neonatal thyrotoxicosis. Poor intrauterine growth, a fetal heart rate of >160 beats/min, and high levels of maternal TSI in the last trimester may herald this complication. Antithyroid drugs given to the mother can be used to treat the fetus and may be needed for 1–3 months after delivery, until the maternal antibodies disappear from the baby’s circulation. The postpartum period is a time of major risk for relapse of Graves’ disease. Breast-feeding is safe with low doses of antithyroid drugs. Graves’ disease in children is usually managed with methimazole or carbimazole (avoid propylthiouracil), often given as a prolonged course of the titration regimen. Surgery or radioiodine may be indicated for severe disease.
Thyrotoxic crisis, or thyroid storm, is rare and presents as a life-threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. Management requires intensive monitoring and supportive care, identification and treatment of the precipitating cause, and measures that reduce thyroid hormone synthesis. Large doses of propylthiouracil (500–1000 mg loading dose and 250 mg every 4 h) should be given orally or by nasogastric tube or per rectum; the drug’s inhibitory action on T4 → T3 conversion makes it the antithyroid drug of choice. If not available, methimazole can be used in doses up to 30 mg every 12 h. One hour after the first dose of propylthiouracil, stable iodide is given to block thyroid hormone synthesis via the Wolff-Chaikoff effect (the delay allows the antithyroid drug to prevent the excess iodine from being incorporated into new hormone). A saturated solution of potassium iodide (5 drops SSKI every 6 h) or, where available, ipodate or iopanoic acid (500 mg per 12 h) may be given orally. Sodium iodide, 0.25 g IV every 6 h, is an alternative but is not generally available. Propranolol should also be given to reduce tachycardia and other adrenergic manifestations (60–80 mg PO every 4 h; or 2 mg IV every 4 h). Although other β-adrenergic blockers can be used, high doses of propranolol decrease T4 → T3 conversion, and the doses can be easily adjusted. Caution is needed to avoid acute negative inotropic effects, but controlling the heart rate is important, as some patients develop a form of high-output heart failure. Short-acting IV esmolol can be used to decrease heart rate while monitoring for signs of heart failure. Additional therapeutic measures include glucocorticoids (e.g., hydrocortisone 300 mg IV bolus, then 100 mg every 8 h), antibiotics if infection is present, cooling, oxygen, and IV fluids.
Ophthalmopathy requires no active treatment when it is mild or moderate, because there is usually spontaneous improvement. General measures include meticulous control of thyroid hormone levels, cessation of smoking, and an explanation of the natural history of ophthalmopathy. Discomfort can be relieved with artificial tears (e.g., 1% methylcellulose), eye ointment, and the use of dark glasses with side frames. Periorbital edema may respond to a more upright sleeping position or a diuretic. Corneal exposure during sleep can be avoided by using patches or taping the eyelids shut. Minor degrees of diplopia improve with prisms fitted to spectacles. Severe ophthalmopathy, with optic nerve involvement or chemosis resulting in corneal damage, is an emergency requiring joint management with an ophthalmologist. Pulse therapy with IV methylprednisolone (e.g., 500 mg of methylprednisolone once weekly for 6 weeks, then 250 mg once weekly for 6 weeks) is preferable to oral glucocorticoids, which are used for moderately active disease. When glucocorticoids are ineffective, orbital decompression can be achieved by removing bone from any wall of the orbit, thereby allowing displacement of fat and swollen extraocular muscles. The transantral route is used most often because it requires no external incision. Proptosis recedes an average of 5 mm, but there may be residual or even worsened diplopia. Once the eye disease has stabilized, surgery may be indicated for relief of diplopia and correction of the appearance. External beam radiotherapy of the orbits has been used for many years, but the efficacy of this therapy remains unclear, and it is best reserved for those with moderately active disease who have failed or are not candidates for glucocorticoid therapy. Other immunosuppressive agents such as rituximab have shown some benefit, but their role is yet to be established.
Thyroid dermopathy does not usually require treatment, but it can cause cosmetic problems or interfere with the fit of shoes. Surgical removal is not indicated. If necessary, treatment consists of topical, high-potency glucocorticoid ointment under an occlusive dressing. Octreotide may be beneficial in some cases.
OTHER CAUSES OF THYROTOXICOSIS
Destructive thyroiditis (subacute or silent thyroiditis) typically presents with a short thyrotoxic phase due to the release of preformed thyroid hormones and catabolism of Tg (see “Subacute Thyroiditis,” below). True hyperthyroidism is absent, as demonstrated by a low radionuclide uptake. Circulating Tg levels are usually increased. Other causes of thyrotoxicosis with low or absent thyroid radionuclide uptake include thyrotoxicosis factitia, iodine excess, and, rarely, ectopic thyroid tissue, particularly teratomas of the ovary (struma ovarii) and functional metastatic follicular carcinoma. Whole-body radionuclide studies can demonstrate ectopic thyroid tissue, and thyrotoxicosis factitia can be distinguished from destructive thyroiditis by the clinical features and low levels of Tg. Amiodarone treatment is associated with thyrotoxicosis in up to 10% of patients, particularly in areas of low iodine intake (see below).
TSH-secreting pituitary adenoma is a rare cause of thyrotoxicosis. It is characterized by the presence of an inappropriately normal or increased TSH level in a patient with hyperthyroidism, diffuse goiter, and elevated T4 and T3 levels (Chap. 403). Elevated levels of the α-subunit of TSH, released by the TSH-secreting adenoma, support this diagnosis, which can be confirmed by demonstrating the pituitary tumor on MRI or CT scan. A combination of transsphenoidal surgery, sella irradiation, and octreotide may be required to normalize TSH, because many of these tumors are large and locally invasive at the time of diagnosis. Radioiodine or antithyroid drugs can be used to control thyrotoxicosis.
Thyrotoxicosis caused by toxic MNG and hyperfunctioning solitary nodules is discussed below.