Carbimazole

Although the two terms "thyrotoxicosis" and "hyperthyroidisrn" may reflect subtle differences, they are most often used interchangeably, as will be done in this article. Hyperthyroidism is most often caused by Graves' disease, but it also can be the clinical manifestation of a number of other etiologic processes (Table 1 and Figure 1). Graves' disease is an autoimmune phenomenon in which circulating immunoglobulins attach to thyroid-stimulating hormone (TSH) receptors on the cell membrane of thyroid cells and stimulate the production of thyroid hormones.

Hashimoto's thyroiditis (chronic lymphocytic thyroiditis) is another organ-specific autoimmune disease in which there are high levels of antithyroid autoantibodies. Toxic goiter, either single or multiple nodules, does not have an autoimmune basis and probably results from the development of autonomy in a longstanding goiter. The etiology of most cases of subacute thyroiditis (painful or painless) is unknown, but may be viral. The etiology of the painless, or silent, thyroiditis found in recent epidemics may be due to consumption of thyroid tissue ground into hamburger meat.(1,2) Accurate identification of the underlying disorder is important because treatment differs markedly.

The incidence of hyperthyroidism varies in different populations, but the disease has a distinct affinity for young women (Figure 2). The signs and symptoms of hyperthyroidism are well known: heat intolerance and sweating, fine tremor, palpitations, increased heart rate, diarrhea, anxiety, weight loss despite increased appetite, menstrual dysfunction,muscle weakness and cardiac problems. The thyroid gland may or may not be enlarged, depending on the etiology. Specific signs such as exophthalmos, pretibial myxedema and acropachy (thickening of the fingers and toes) may be found in patients with Graves' disease (Figures 3, 4 and 5). Definitive diagnosis can usually be made when the history, physical examination and laboratory findings are in hand (Table 2). However, the presentation in elderly patients may be subtle.

Diagnosis on the basis of the history and physical examination is usually confirmed by blood tests such as total serum thyroxine (T[.sub.4]), free T[.sub.4], triiodothyronine (T[.sub.3]), sensitive TSH (sTSH) and antithyro-globulin or antimicrosomal antibody levels. Nuclear medicine scans and uptake studies help to identify patients presenting in the toxic phase of thyroiditis. Further investigation, such as fine-needle aspiration of a suspicious gland, is rarely necessary.

Methods of Treatment

There are three major ways to treat hyperthyroidism: antithyroid drugs, radioactive iodine ([.sup.131]I) therapy and surgery (Table 3). In addition, adjunctive therapy can be useful for stabilizing the gland before definitive treatment or for decreasing the clinical manifestations of hyperthyroidism.

ANTITHYROID DRUGS

The most commonly used antithyroid drugs are from the thiourea group: propylthiouracil (PTU), used in the United States, and carbimazole and methimazole (Tapazole), used mainly in Europe. These agents block the synthesis of intrathyroidal hormones(3 ) but do not affect the secretion of preformed stores. PTU has a significant peripheral effect on systemic thyroid hormone concentrations. Thus, weeks to months of therapy may be required to achieve euthyroid status.

Side effects of antithyroid drug therapy occur in less than 10 percent of patients.(4-6) The most common side effects are rash or urticaria and transient leukopenia, which must be differentiated from the mild leukopenia that often accompanies Graves' disease. These side effects are often selflimited and may not necessitate the discontinuation of therapy. Fever, arthralgias and arthritis are less common.

The most serious complication of antithyroid drug therapy is agranulocytosis, which usually occurs early in therapy and is more frequent in older patients than younger patients. Other complications have been reported but are rare. Both PTU and methimazole cross the placenta and are found in breast milk, a consideration when treating pregnant or lactating patients.

The usual initial dosage of PTU is 300 to 600 mg daily (or 30 to 45 mg of methimazole), given in divided doses every eight hours until the patient becomes euthyroid, which usually occurs after six to eight weeks. There are two options for maintenance therapy: a reduced dosage or continued therapy with the initial dosage and supplemental T[.sub.3] or T[.sub.4] to prevent iatrogenic hypothyroidism. At least one study has found significant improvement in remission rates with the higher-dose regimen, but there may be more side effects. Moreover, follow-up thyroid function tests are difficult to interpret because of the use of supplemental thyroid hormone. In any case, patients must be frequently evaluated in the first few months of therapy, during the time of dosage adjustment as indicated by the serum T[.sub.4] levels.

Remission after drug therapy is variable. A six-month course of antithyroid drug therapy is likely to lead to long-lasting remission in approximately 25 percent of patients with Graves' disease, whereas the remission rate increases to about 50 percent when therapy is continued for 18 to 24 months.(8-10) Even at best, however, a significant proportion of patients will not be cured.

True remissions should be differentiated from the transient period of euthyroidism that follows drug withdrawal, and recurrence of hyperthyroidism within a few months of cessation of therapy suggests that the disease was never controlled. Little decrease in goiter size during treatment, a persistently elevated T[.sub.3]/T[.sub.4] ratio or high anti-TSH receptor antibody levels may be predictive of future relapse. The sTSH test may also prove useful. When recurrence develops after an adequate course of antithyroid drugs, treatment with either [.sup.131]I or surgery is indicated.

Antithyroid drugs are particularly useful in the treatment of Graves' disease in children, in some pregnant women and in patients with a small goiter and a short duration of disease. Antithyroid drug therapy is also important in the preoperative preparation of thyrotoxic patients and in the management of thyroid storm due to any underlying etiology.

SUBTOTAL THYROIDECTOMY

The removal of hyperfunctioning tissue by subtotal thyroidectomy can be extremely effective in restoring the euthyroid state. Procedures commonly employed include bilateral subtotal lobectomy or a combination of total lobectomy on one side and subtotal lobectomy on the other side.

The role of surgery is still debated. Some authorities believe that surgery is overly aggressive and involves increased patient risk. However, surgery is particularly appropriate when medical management has failed, when the goiter is large, when rapid control of the toxic process is desirable or when the patient desires surgery."

Children, patients with large goiters, patients with a diffuse goiter with a cold area suspicious of malignancy, and pregnant women are all candidates for surgery. The primary concern is adequate experience in management by the medical-surgical team. The outcome and cost depend on the surgeon's experience, the surgical technique used and the perioperative care.(12)

Combined medical-surgical management is critical if surgery is planned. Many clinicians believe that patients should be euthyroid before thyroidectomy, and all agree that close postoperative follow-up is essential. Failure to achieve a euthyroid state before surgery may result in cardiac irregularities during anesthesia and thyrotoxic crisis postoperatively.(13) The patient can be rendered euthyroid either by administering antithyroid drug therapy for six to 12 weeks before surgery or by administering beta-adrenergic blocking agents before, during and after surgery. Potassium iodide is routinely used preoperatively to reduce the vascularity of the hyperthyroid gland.

The risk of surgical complications is significant, although low. Mortality rates in patients operated on by experienced, careful surgeons are essentially zero. Bleeding, thyrotoxic crisis or thyroid storm, acute respiratory failure, damage to the recurrent laryngeal nerve and hypoparathyroidism may occur,(13) but are now rarely encountered. Such complications are more common in cases of multinodular goiter and in children.

Postoperative hypothyroidism usually occurs within one year after surgery.(13) Surgical patients may be temporarily hypothyroid, but they eventually return to a euthyroid status. Whether the size of the gland remnant is predictive of later hypothyroidism is a matter of controversy." There is general agreement that of all the modalities available for the treatment of hyperthyroidism, surgery offers the best chance of long-term euthyroidism. Unfortunately, this is balanced with the risk of recurrent toxicity, even many years later. (14)

RADIOACTIVE IODINE

[.sup.131]I therapy has become more popular, and surgery less so, because of the ease of [.sup.131]I administration and the efficacy of treatment. Because treatment can only affect the formation of new thyroid hormone, the euthyroid status may not be achieved for several weeks. [.sup.131]I has become the treatment of choice for the majority of patients with Graves' disease, as well as for the older patient with a single toxic adenoma and for the patient with recurrence of Grave's disease after thyroidectomy.

The [.sup.131]I dosage is of concern because radiation damage appears to be roughly dose-dependent. There are two choices: a standard, fixed dosage, which ignores gland size and uptake values, and a variable dosage, which is estimated by this commonly used formula:

Dose (mCi) =Thyroid weight (g) x plannned dose([micro]Ci/g)

___________________________________________________

[.sup.131]I Uptake at 24 hours x 1,000

If the dosage is low, further doses may be needed.

Complications such as radiation-induced thyroiditis are rare. Transient elevation of thyroid hormone levels occurs in about one-third of patients, but overt thyroid storm due to thyroid irradiation is unusual. The major concern is the late development of hypothyroidism. Surprisingly, the risk of later hypothyroidism does not appear to increase with higher doses. About 70 percent of patients treated with [.sup.131]I are hypothyroid ten years after therapy, no matter what the dosage, and the risk of subsequent hypothyroidism persists indefinitely.

The incidence of hypothyroidism after [.sup.131]I therapy has increased over the past 20 years, in part due to the availability of more sensitive laboratory tests, such as the sTSH test. There may be a long period during which the patient remains clinically normal but has elevated TSH levels. The addition of antithyroid drugs to [,sup.131]I therapy does not seem to affect the long-term incidence of hypothyroidism. Hypothyroidism also may be transient, and may even be followed again by hyperthyroidism. There are currently no clear indicators to predict which patients will become hypothyroid.

ADJUNCTIVE TREATMENT

Beta-Adrenergic Blockers. These agents are used to quickly control the symptoms of hyperthyroidism, without affecting thyroid function. These drugs can be used to quell the symptoms while definitive therapy is planned or the patient is stabilized for surgery. Because of the natural remission process in some patients with Graves' disease, beta blockers may even seem to effect a "cure." The dosage is titrated to the individual patient, ranging from 40 to 320 mg per day in three or four divided doses. Use of beta blockers alone, without iodine or antithyroid drugs, is generally considered inadequate for preoperative preparation.

Iodine. The release of thyroid hormone into the blood is blocked by iodine, while hormonal stores in the gland are enriched. (4 ) Thus, iodine is only a short-term therapy by itself, but it is often used with an antithyroid agent in situations such as thyroid storm or preoperative preparation.

Radiocontrast Agents. The peripheral conversion of T[.sub.4] to T[.sub.3] can be blocked by the coadministration of a radiocontrast agent, such as ipodate sodium (Oragrafin), and an antithyroid drug.

Lithium. Because of its chemical similarity to iodine, lithium (Eskalith, Lithane, Lithobid, etc.) is occasionally used to reduce the synthesis and release of new hormone. The dosage is usually 900 to 1,200 mg per day in divided doses, and serum lithium levels must be monitored. Treatment with lithium may be most useful in patients who need preparation for surgery or [.sup.131]I treatment but cannot take thioureas.

Glucocorticoids. Although not commonly used, glucocorticoids act in a variety of ways to decrease serum T[.sub.4] levels in Graves' disease. They may also reduce the inflammation in painful thyroiditis.

Calcium Channel Blockers. These agents may be useful as adjunctive therapy for thyrotoxicosis in the presence of angina, congestive failure and tachyarrhythmias.(15) Treatment of Specific Conditions

Table 4 summarizes the preferred treatment approaches for the different etiologies of hyperthyroidism.

GRAVES' DISEASE

Antithyroid drugs may be used as first-line therapy in Graves' disease, but are often scorned because of the high relapse rate (50 percent). It is well known that Graves' disease fluctuates spontaneously; however, antithyroid drugs seem to have an additional influence on the remission process, perhaps by altering the antithyroid immune response. Characteristics that favor selection of patients for antithyroid drug therapy are a small goiter, a short duration of disease, no previous failure of antithyroid drug treatment and relatively low dosage requirement.(16)

[.sup.131]I is used more commonly in the United States than in Europe, but careful follow-up for years after therapy is vital to ensure that late-onset hypothyroidism is not missed. Surgery may be necessary when an exceptionally large gland causes mechanical compression, when the patient refuses [.sup.131]I therapy or when antithyroid medications do not produce a response.

Long-term clinical remission of Graves' disease can occur in a variety of ways. Normal immunologic control may be restored, part of the disease process (such as ophthalmopathy) may continue, or subclinical malfunction of the gland may be demonstrated by borderline levels of thyroid hormones or sTSH.

Ophthalmopathy, although only occurring in 3 to 5 percent of patients in the severe form, may lead to a vision-threatening optic neuropathy. Control of thyrotoxicosis is associated with regression in about 50 percent of patients. A discussion of the specific treatment of ophthalmopathy is beyond the scope of this article.

HYPERTHYROIDISM IN PREGNANCY

This very special situation imposes significant limitations on the optimal treatment of hyperthyroidism. [.sup.131]I cannot be used because of the possibility of fetal damage (congenital anomalies or ablation of the fetal thyroid gland). Antithyroid drugs may be given, but they cross the placental barrier, increasing the risk of neonatal hypothyroidism and obstructive goiter, especially with high doses. The patient must be carefully monitored, and the dosage should be tapered as quickly as possible after she becomes euthyroid.

Surgery is often the most successful form of therapy during the second trimester,(16) but the patient must be prepared with antithyroid drug therapy. To further complicate the issue, one must always remember that the disease often remits spontaneously during pregnancy, so patients must be carefully monitored. It is also important to assess the infant at birth to rule out hypothyroidism or the rare complication of neonatal thyrotoxicosis.

POSTPARTUM THYROIDITIS

Postpartum thyroiditis may be a more common endocrine result of pregnancy than previously appreciated. The etiology seems to be varied, including Graves' disease and subacute (painless) thyroiditis. Since the thyroiditis frequently resolves spontaneously, management consists of symptomatic treatment and close follow-up to ensure that the patient becomes and remains euthyroid.

HYPERTHYROIDISM IN CHILDHOOD

As in adults, the most common cause of hyperthyroidism in children is Graves' disease. Treatment in children is usually restricted to drug therapy or surgery. [.sup.131]I therapy is generally regarded as unsuitable, because of the juvenile thyroid's susceptibility to radiation and the lack of longterm folloe-up studies.(16) Some authorities, however, prefer high-dose [.sup.131]I as the initial treatment of choice, citing no longterm increased incidence of malignancy.(17)

Medical therapy can be difficult in children, who tend to have a labile response, with increased toxic reactions. The relapse rate is high in children.(18) Surgery offers a rapid cure without the need for long-term medication, but the incidence of postoperative complications is higher in children than in adults.

HYPERTHYROIDISM IN THE ELDERLY

Elderly patients with hyperthyroidism may present with only apathy or with other systemic effects, such as cardiac failure. Hyperthyroidism in this age group is usually treated with [.sup. 131]I after the patient has been made euthyroid by a course of antithyroid drug therapy. Surgery may be required if the patient has an extremely large goiter.

PAINLESS THYROIDITIS

"Silent" thyroiditis is best managed symptomatically during the toxic phase, possibly with short-term use of beta blockers. The possibility of transient or permanent hypothyroidism must also be monitored. [.sup.131]I is useless in this condition, because the uptake by the gland is essentially zero.

PAINFUL THYROIDITIS

Treatment with anti-inflammatory drugs, such as the nonsteroidal agents, is the rule in painful thyroiditis. Occasionally, patients may require a short course of glucocorticoids, and in this circumstance they may be dramatically pain-free within 48 to 72 hours of initiation of treatment. However, patients may subsequently relapse.

ADENOMAS

If mechanical compression is a possibility, the thyroid should be surgically removed, regardless of the patient's age. Surgery is also usually the treatment of choice for toxic adenoma in patients under the age of 40. Treatment with [.sup.131]I may be tried, particularly in an older patient with a single hot nodule, but it is not always successful(12) and may leave behind cold areas, which are difficult to assess later. Antithyroid drugs are ineffective, since they only provide pharmacologic blockade, and are usually only used temporarily as an adjunct to definitive treatment.

HASHIMOTO'S THYROIDITIS

Hashimoto's thyroiditis does not usually present with hyperthyroidism, and some "Hashi-toxic" patients may become euthyroid without treatment. Follow-up is necessary to ensure that the patient does not subsequently become permanently hypothyroid.

Final Comment

Careful diagnosis of the underlying condition that is causing hyperthyroidism, coupled with treatment selected for the individual case and long-term follow-up, ensures good results in almost all cases of hyperthyroidism.

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