Thionamides in the treatment of Graves' disease

INTRODUCTION — The thionamides, methimazole, carbimazole, and propylthiouracil (PTU), are effective treatment of patients with Graves' hyperthyroidism. They are actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines (figure 1) [1]. (See "Thionamides: Side effects and toxicities".)

The clinical use and efficacy of the thionamides in the treatment of Graves' hyperthyroidism will be reviewed here; the pharmacology and toxicity of these drugs, as well as other treatment options for Graves' hyperthyroidism, are reviewed separately. (See "Thionamides: Side effects and toxicities" and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

CLINICAL USE — Thionamides are often started in patients with Graves' hyperthyroidism to attain a euthyroid state rapidly in preparation for radioiodine therapy or thyroidectomy. However, patients who want to avoid or defer ablative therapy with radioiodine or surgery can continue the thionamide for prolonged periods. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

Although hyperthyroidism can almost always be controlled as long as the drug is taken, overall, only approximately 20 to 30 percent of patients achieve a permanent remission after one to two years of treatment. This estimate includes patients with severe disease in whom remissions are unlikely, as well as patients with mild disease in whom remission rates may be as high as 75 percent. Studies using long-term antithyroid drugs for 5 to 10 years or longer have reported remission rates as high as 84 percent [2]. (See 'Rate of prolonged remission' below.)

Patients treated with thionamides take three to eight weeks or longer to become euthyroid because they block new hormone synthesis, and any already formed thyroxine (T4) and triiodothyronine (T3) stored in the colloid must be secreted and metabolized for clinical improvement to occur.

CONTRAINDICATIONS — Thionamide drugs are contraindicated in patients with a previous major adverse reaction to thionamides (eg, agranulocytosis, hepatotoxicity, pancreatitis). (See "Thionamides: Side effects and toxicities", section on 'Rare but serious adverse effects'.)

Because they are teratogenic, their use in women desiring a pregnancy in the next year or two requires a careful discussion of their risks and alternative treatments, such as definitive therapy, prior to conception. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Therapeutic options'.)

INITIATION OF THERAPY — The approach outlined below is largely consistent with Hyperthyroidism Management Guidelines from the American Thyroid Association (ATA) [3].

Choice of drug — Propylthiouracil (PTU) and methimazole are the thionamide drugs available in the United States. Carbimazole is a third option available in many countries, but not in North America. Carbimazole is completely metabolized to methimazole, although the carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher.

Although all of the thionamides are effective for hyperthyroidism, methimazole and carbimazole have a number of advantages over PTU. Methimazole is preferred to PTU for the following reasons (table 1) [4-6]:

●More rapid achievement of euthyroidism

•Methimazole achieves a euthyroid state more rapidly than PTU, especially in patients with more severe hyperthyroidism. In one randomized trial, methimazole 30 mg daily resulted in a higher percentage of patients with free T4 >7 ng/dL having normal free T4 levels at 4, 8, and 12 weeks compared with PTU 300 mg daily [7]. For patients with free T4 less than 7 ng/dL, methimazole 30 or 15 mg and PTU 300 mg daily were equally effective at four and eight weeks, but 30 mg of methimazole was more effective than the other two regimens at 12 weeks.

●Once-daily dosing and better compliance

●Little or no effect on subsequent success of radioiodine therapy

•Methimazole is less likely than PTU to be associated with failure of radioiodine therapy when thionamides are given to normalize thyroid function before radioiodine treatment [5,6]. Seventy-eight percent of patients pretreated with methimazole and only 32 percent of patients pretreated with PTU were cured by a 10 mCi dose of radioiodine [6].

●Less toxicity

•There have been concerns about PTU-associated hepatoxicity. Although hepatotoxicity is still a rare complication, the ATA and the US Food and Drug Administration (FDA) recommend that PTU not be prescribed as a first-line drug in children or adults [8,9]. (See "Thionamides: Side effects and toxicities".)

However, there are three clinical settings in which PTU is preferred:

●In patients during the first trimester of pregnancy (see "Hyperthyroidism during pregnancy: Treatment", section on 'Choice of thionamide')

●For the initial management of patients with life-threatening thyrotoxicosis or thyroid storm (see "Thyroid storm", section on 'Thionamides')

●In patients with minor reactions to methimazole who do not want definitive treatment with radioiodine or surgery (See "Thionamides: Side effects and toxicities", section on 'Common, minor side effects'.)

Rectal [10,11] and intravenous [12,13] preparations of methimazole and PTU can be prepared by hospital or compounding pharmacies for selected patients who are temporarily unable to take oral medication.

Pretreatment evaluation — Prior to initiating thionamides, we obtain baseline blood tests, including a complete blood count (white count with differential) and a liver profile (bilirubin and transaminases) [3]. We do not use thionamides in patients with a baseline absolute neutrophil count <1000 cells/microL or elevated liver transaminases (more than fivefold the upper limit of normal) except in selected patients when the alternatives are less attractive after careful assessment of alternatives and risks.

Dosing — The initial dose of methimazole varies according to the severity of the hyperthyroidism.

●Free T4 1 to 1.5 times the upper limit of normal – In patients with small goiters and mild hyperthyroidism, we usually begin treatment with 5 to 10 mg of methimazole once daily. The dose can be increased if the hyperthyroidism (as assessed clinically and by measurements of serum thyroid-stimulating hormone [TSH], free T4, and T3) is not ameliorated within four to six weeks.

●Free T4 1.5 to 2 times the upper limit of normal – In patients with moderate hyperthyroidism, we usually begin treatment with 10 to 20 mg of methimazole once daily; this low-dose regimen appears to be as effective as higher doses in this subset of patients (figure 2). The dose is tapered to maintenance levels (5 to 10 mg/day) as the patient improves.

●Free T4 2 to 3 times the upper limit of normal – Patients with larger goiters and more severe hyperthyroidism should be started on 20 to 40 mg daily. We administer therapy initially in divided doses (eg, 10 mg two or three times a day or 15 mg twice daily) to normalize thyroid function more quickly and to possibly minimize gastrointestinal side effects and then change to single daily dosing if tolerated and as the dose is reduced. The dose is tapered to maintenance levels (5 to 10 mg/day) as the patient improves. Few patients require more than 40 mg/day of methimazole.

The carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher. For example, a 10 or 20 mg dose of carbimazole yields roughly 6 and 15 mg of methimazole, respectively [14].

Our dose recommendations are influenced by the dose dependence of the major side effects of methimazole. We do not prescribe combined thionamides and L-thyroxine (block and replace therapy), because it requires higher doses of thionamides, resulting in a higher rate of adverse effects. However, block and replace may have utility in those rare patients in whom thyroid function tests fluctuate above and below the normal range despite minimal changes in methimazole dose. It may also be useful in the pediatric population to minimize the need for serial laboratory testing. (See 'Role of combination therapy with T4' below and "Thionamides: Side effects and toxicities".)

The dosing recommendations are supported by randomized trial data [7,15]. In one study of over 300 patients randomly assigned to methimazole 30 mg/day, methimazole 15 mg/day, or PTU 300 mg/day, the following results were seen [7]:

●At 12 weeks, the percentage of patients with normal free T4 levels was 97, 86, and 78 percent in the methimazole 30 mg, methimazole 15 mg, and PTU 300 mg groups, respectively.

●Among patients with severe thyrotoxicosis (initial free T4 concentrations equal to or greater than 7 ng/mL), methimazole 30 mg/day normalized free T4 more rapidly than methimazole 15 mg/day or PTU 300 mg/day. However, in patients with free T4 concentrations less than 7 ng/mL, there was no difference among the regimens.

●Serum T3 levels were normalized more quickly with either methimazole dose compared with PTU, despite PTU's ability to block T4 to T3 conversion, indicating that this effect is more important in the short term rather than over many weeks.

●Side effects were seen in 30, 14, and 52 percent of patients taking methimazole 30 mg, methimazole 15 mg, and PTU, respectively.

These data are supported by older studies. For example, patients given methimazole in doses of 15 mg once daily, 30 mg once daily, or 10 mg three times daily became euthyroid in the same average time (figure 2) [16], while, in a randomized trial in 509 patients, the response to 40 mg/day of methimazole was somewhat more rapid than that to 10 mg/day [15].

PTU, rather than methimazole, is used to treat hyperthyroid women during the first trimester of pregnancy and for the initial management of life-threatening thyrotoxicosis or thyroid storm. Dosing of PTU in these settings is reviewed separately. (See "Thyroid storm", section on 'Thionamides' and "Hyperthyroidism during pregnancy: Treatment", section on 'Initial dosing'.)

An alternative regimen that may be of utility, especially in patients experiencing dose-dependent, minor side effects from methimazole, utilizes both methimazole and inorganic iodine. In a study of patients with untreated Graves' hyperthyroidism (free T4 >5 ng/dL), compared with patients who received 30 mg methimazole daily, patients who were given 15 mg methimazole and 38 mg inorganic iodine daily (one 50 mg potassium iodine [KI] tablet a day) achieved normal free T4 levels more rapidly (74 and 82 percent by 60 and 90 days versus 63 and 75 percent by 60 and 90 days, respectively) and had fewer adverse effects [17].

Complications — Complications of thionamide therapy, including rare but serious adverse effects such as agranulocytosis, hepatotoxicity, and pancreatitis, are discussed in detail elsewhere. It is preferable that information about serious adverse events be given to the patient in writing and discussed at each follow-up visit. (See "Thionamides: Side effects and toxicities", section on 'Agranulocytosis' and "Thionamides: Side effects and toxicities", section on 'Hepatotoxicity'.)

Monitoring — Patients with Graves' disease who are treated with thionamides require monitoring of thyroid function and for the rare but serious adverse effects of thionamides (primarily agranulocytosis, hepatotoxicity, and pancreatitis).

●Thyroid function – Patients with Graves' hyperthyroidism who are treated with a thionamide should have their thyroid function (free T4 and total T3) initially assessed at four- to six-week intervals until stabilized on maintenance thionamide therapy. Once the patient has a normal free T4 and total T3, the dose of methimazole can be decreased by 30 to 50 percent. Subsequent thyroid tests (TSH, free T4) should be repeated four to six weeks after each dose adjustment. A typical maintenance dose of methimazole is 5 to 10 mg daily. When a stable maintenance dose is achieved, thyroid tests (TSH, free T4) can be performed every six months.

It is important to measure both serum free T4 and total T3 initially because serum T3 concentrations may remain high even though serum free T4 concentrations become normal. The serum T3:T4 ratio is particularly high in Graves' hyperthyroidism, and patients with so-called "T3-predominant" Graves' disease may respond less well to thionamide therapy and are less likely to attain prolonged remission [18]. A few patients taking a thionamide have high serum T3 concentrations in association with low serum free T4 concentrations [19]. (See "Laboratory assessment of thyroid function".)

In comparison with the importance of serum T3 and T4 values, serum TSH values may be misleading during the initial period of treatment [20]. Pituitary TSH production is suppressed by hyperthyroidism, an effect that can persist for several months after serum T4 and T3 concentrations become normal. As a result, serum TSH concentrations are often low despite normal or even low serum T4 and T3 concentrations during the first several months of treatment. Often, however, the serum TSH concentration rises into the normal range within a few weeks. When this happens, there is no longer a need to measure serum T3 concentration.

The importance of maintaining a biochemical euthyroid state in patients taking thionamides is suggested by a study that demonstrated increased all-cause mortality during treatment with thionamides (standardized mortality ratio [SMR] 1.30, 95% CI 1.05-1.61) and after radioiodine while still hyperthyroid (SMR 1.24, 95% CI 1.04-1.46) but not after achieving hypothyroidism following radioiodine [21].

●Adverse effects – Controversy exists as to the value of monitoring white blood cell counts. We do not routinely monitor white blood cell count (for the development of agranulocytosis) or liver function tests (for the development of hepatotoxicity) in patients taking thionamides. However, a complete blood count (white count with differential) should be obtained during any febrile illness and at the onset of pharyngitis. We advise patients taking a thionamide to discontinue the drug at the earliest sign of a fever, sore throat, or other infection until the result of the white blood cell count is available. Agranulocytosis is discussed in detail separately. (See "Thionamides: Side effects and toxicities", section on 'Agranulocytosis'.)

Liver function should be assessed in patients with signs or symptoms of hepatitis (eg, jaundice, light-colored stool or dark urine, pruritic rash). Amylase and lipase should be measured in patients with nausea, vomiting, and abdominal pain. Patients should be instructed to discontinue thionamides and contact the clinician when there are such symptoms. (See "Thionamides: Side effects and toxicities", section on 'Hepatotoxicity' and "Thionamides: Side effects and toxicities", section on 'Pancreatitis'.)

APPROACH TO STOPPING THERAPY

Duration of therapy

●Methimazole in preparation for radioiodine – Radioiodine can be administered as initial therapy for hyperthyroidism (without methimazole pretreatment) in most patients with hyperthyroidism, especially if they are receiving adequate therapy with a beta blocker. However, some patients, particularly older patients and others who are more susceptible to the effects of hyperthyroidism, can be treated first with methimazole until euthyroidism is achieved.

For such patients with Graves' hyperthyroidism taking methimazole to attain a euthyroid state rapidly in preparation for radioiodine therapy, we typically pretreat with methimazole for four to six weeks. Radioiodine can then be administered once serum thyroid hormone concentrations are in the normal range. Our practice is to stop methimazole three days before and restart methimazole three days after radioiodine is given to allow better control of thyroid function post-radioiodine administration. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Pretreatment with methimazole'.)

●Methimazole in preparation for thyroidectomy – Patients with hyperthyroidism undergoing thyroidectomy are at risk for developing thyroid storm, a rare condition that usually occurs during surgery or in the first 18 hours after the procedure. Thus, patients with hyperthyroidism who are treated with surgery should receive pretreatment with methimazole until they are euthyroid, typically for four to six weeks. Surgery can be performed once serum thyroid hormone concentrations are in the normal range. Methimazole can be discontinued on the day of surgery. (See "Surgical management of hyperthyroidism", section on 'Thionamide therapy'.)

●Methimazole as primary therapy – For patients taking methimazole as primary therapy, it should initially be continued for 12 to 18 months.

It is best to agree with the patient on a tentative duration of therapy when treatment is begun and then to reexamine the treatment options and goals at the end of this period (table 2). However, methimazole can be stopped at any time to allow patients to proceed with radioiodine or surgery. On the other hand, if remission is not obtained after a 12- to 18-month course of methimazole, long-term treatment with methimazole for 10 years or more has been shown to be effective and safe [2,22,23]. (See 'Rate of prolonged remission' below.)

Remission rates are lower if patients are treated for less than 18 months. In one randomized study of treatment duration, 94 adults were treated with carbimazole for 6 or 18 months, with the respective rates of relapse of hyperthyroidism in the two years after cessation of therapy of 58 and 38 percent [24,25]. These results support the recommendation given above for an initial 12- to 18-month period of treatment.

Evaluation prior to stopping therapy — In patients with normal thyroid function, we typically measure serum thyrotropin receptor antibodies (TRAbs), either using a thyroid-stimulating immunoglobulins (TSI) or a thyrotropin-binding inhibiting immunoglobulin (TBII) assay, initially after 12 to 18 months of thionamide therapy [3]. (See "Laboratory assessment of thyroid function", section on 'Antithyroid antibodies'.)

●Patients with normal levels have a greater chance for remission (up to 80 percent) once thionamides are discontinued. Thus, thionamides can be discontinued if TRAbs and TSH are normal at 12 to 18 months. Patients require monitoring for recurrence. (See 'Monitoring for recurrence' below.)

●Persistently high levels of TRAbs are associated with very high relapse rates. Such patients should either continue methimazole or proceed with definitive therapy (radioiodine or surgery). In some patients with borderline elevated antibody levels who want to be certain that they need definitive treatment, methimazole can be discontinued, and they should be monitored frequently and plan on definitive therapy with radioiodine or preparation for thyroidectomy as soon as recurrent hyperthyroidism is documented. (See 'Treatment of recurrence' below.)

There is an extensive literature regarding various tests, such as serum TRAb measurements [26,27], that can be done during treatment with a thionamide to predict whether a patient has achieved remission of the underlying Graves' disease. As an example, in one study, 97 percent of patients with a TRAb >3.85 international units/L relapsed [27]. In this same study, 80 percent of those patients with TRAb <2 international units/L remained euthyroid for a median follow-up period of 15 months. Another study found high serum TSH-binding inhibitory activity after 18 months of treatment in 60 percent of patients who relapsed and 15 percent who remained in remission [28].

Monitoring for recurrence — The frequency of prolonged remission among patients treated with a thionamide for one to two years is usually under 40 percent [29] (see 'Rate of prolonged remission' below). Thus, after discontinuation of thionamides, patients require monitoring for recurrent hyperthyroidism.

For patients with normal TRAbs and TSH at 12 to 18 months, thionamides are discontinued, and serum TSH, free T4, and total T3 are measured initially at two- to three-month intervals beginning two to three months after stopping treatment or earlier if the patient notes recurrent hyperthyroid symptoms. Using this approach, recurrent biochemical hyperthyroidism is usually detected before the patient develops many symptoms of hyperthyroidism. Not surprisingly, a suppressed TSH level in the face of normal free T4 and T3 is a predictor for relapse [30].

If thyroid tests remain normal for six months, monitoring should occur at four- to six-month intervals for the next six months and then every 6 to 12 months. For patients who remain euthyroid for a year, thyroid testing (TSH) can be performed annually.

Time course of relapse — Recurrent hyperthyroidism is initially manifested by a low serum TSH concentration. The time to relapse is related to the presence or absence of TRAbs. In antibody-positive patients, relapse can occur as soon as 10 days after drug cessation, while in antibody-negative patients, it can take many months or even years for recurrence to develop in that fraction of patients (25 to 30 percent) who eventually recur. Prolonged remission is likely if the patient remains euthyroid for six months, and late relapse occurs in only 8 to 10 percent of patients who remain euthyroid for six months. Recurrences are particularly common in the postpartum period in women who were previously in remission after thionamide treatment [31]. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Postpartum issues'.)

Treatment of recurrence — For patients with recurrent hyperthyroidism after a course of methimazole, radioiodine, surgery, or a longer course of methimazole are all reasonable options. Definitive therapy is preferred by some patients (radioiodine or thyroidectomy), but long-term methimazole is increasingly preferred and is an option for those who want to avoid definitive therapy [23]. Note, however, that antithyroid drugs are teratogenic, and therefore long-term therapy in women desiring pregnancy requires a careful discussion of risks and alternatives. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

If long-term methimazole is chosen, TRAb levels can be monitored every one to two years with discussion of discontinuation of methimazole if TRAb levels become negative with long-term therapy. Such patients require monitoring for recurrence. (See 'Monitoring for recurrence' above.)

REMISSION

Rate of prolonged remission — The frequency of prolonged remission among patients treated with a thionamide for one to two years has been variably reported to be 15 to 80 percent but is usually under 40 percent [29]. After 5 to 10 years of treatment, remission rates have been reported as high as 84 percent [2,23]. The remission rate may be higher in patients whose dietary intake of iodine is low [32].

A question that remains unresolved is whether the remissions that are associated with thionamide therapy are due to the drug or to the natural history of the disease. As an example, the spontaneous remission rate in a group of patients treated with propranolol (which does not alter thyroid secretion) alone was 31 percent, similar to that in patients treated with a thionamide [33]. Although these patients had mild hyperthyroidism, this observation supports the hypothesis that the thionamides primarily buy time for spontaneous remission to occur. On the other hand, the remission rate after 12 to 18 months of thionamide treatment in patients with mild disease may be as high as 50 to 75 percent [1].

Predictors of remission — Because remission rates among patients treated with thionamides are variable, establishing criteria to predict the likelihood of remission when the patient is first seen would be helpful in the discussion of treatment options with patients.

Clinical factors — Several clinical factors have been associated with likelihood of remission, as illustrated by the following observational studies [34].

Remission rates were higher in females and in patients with [35]:

●Mild hyperthyroidism

●Small goiter or a goiter that reduced in size during thionamide therapy compared with large goiter

●Age over 40 years

Cessation of cigarette smoking also increased the chance of remission [36].

Remission rates were lower in:

●Patients with severe ophthalmopathy [37].

●Men compared with women (20 versus 40 percent) [38].

●Patients under age 40 years compared with older patients (33 versus 48 percent) and in children [38].

Thyrotropin receptor antibody — In many studies, the concentration of thyrotropin receptor antibody (TRAb) and the pattern of change during thionamide treatment correlate with the chance of ultimately achieving remission [27,35,39-41]. As an example, in one study, patients who were initially TRAb negative had a higher remission rate than those who are antibody positive (77 versus 36 percent) [39]. In other studies, disappearance of TRAbs during thionamide therapy was associated with a 70 to 80 percent chance of remission [27,40].

Three different patterns showing changes in TRAb levels over time have been described in patients on long-term thionamides:

●Decreasing TRAb levels – In one study of 549 patients on antithyroid drugs for eight years or more, 226 patients had a smooth fall in TRAb levels, and 89 percent of them went into remission [42]. In a retrospective analysis of similar studies, levels of TRAb that fell within two to three years of treatment were associated with a 50 to 60 percent remission rate [43].

●Fluctuating TRAb levels – In the study of 549 patients described above, 207 patients had fluctuating TRAb levels and only 37 percent of them achieved a remission [42]. In the retrospective analysis, fluctuating levels of TRAb that became low after eight years of antithyroid drugs were associated with a 30 to 40 percent remission rate [43].

●Persistently elevated TRAb levels – In the retrospective analysis, persistently elevated TRAb levels were associated with only a 10 percent rate of remission [43].

Role of thionamide dose — Although the initial response is faster with higher than lower doses of thionamides, eventual relapse rates appear similar. Side effects are more common with higher doses. As examples:

●A study from Brazil concluded that higher doses of thionamides resulted in higher remission rates, but the patients receiving high-dose therapy required cotreatment with T3 to prevent hypothyroidism [44]. The remission rate was 75 percent in the group receiving high-dose thionamide and T3 therapy versus 42 percent in the group receiving low-dose thionamide therapy alone, and side effects were more common with the higher doses.

●In a European multicenter trial in which all patients were treated with T4, biochemical euthyroidism was achieved more quickly with a 40 mg compared with a 10 mg dose, but the rates of remission were similar for the two doses [15,45]. Side effects were more common with the higher dose.

●A prospective Japanese study of two doses of methimazole (10 mg three times daily versus 15 mg once daily) found no difference in response between the two doses [46]. In addition, there was no difference in the rate of recurrent hyperthyroidism (61 and 63 percent, respectively) after six years.

●In another study that compared 20 mg with 40 mg per day, after four weeks, serum T4 concentrations were lower in the patients receiving 40 mg [47]. After six weeks and adjustment of the dose to avoid hypothyroidism, the mean concentrations were similar, but more patients receiving 40 mg developed transient hypothyroidism.

Role of duration of therapy — Longer duration of therapy improves remission rates, which have been reported to be as high as 84 percent after 5 to 10 years of treatment [2]. In children, remission rates increased from 25 percent in those treated for two years to 75 percent in those treated for 11 years [48]. Similar conclusions were drawn in subsequent prospective studies in children [49,50].

Role of combination therapy with T4 — We do not prescribe combined thionamides and L-thyroxine (block and replace therapy), because it is of unproven benefit and requires higher doses of thionamides, resulting in a higher rate of adverse effects.

It was initially hypothesized that the lower serum TSH concentrations achieved in patients treated with combined thionamides and T4 resulted in lower TRAb concentrations and, thus, improved remission rates. However, in a meta-analysis of 12 studies, remission rates were similar in patients treated with a thionamide plus T4 compared with a thionamide alone [24].

However, block and replace may have utility in those rare patients in whom thyroid function tests fluctuate above and below the normal range despite minimal changes in methimazole dose.

Mechanism of remission — There are three mechanisms whereby patients with Graves' disease can achieve a spontaneous remission:

●A fall or disappearance of TRAbs (also called thyroid-stimulating immunoglobulins [TSI] or thyrotropin-binding inhibitory immunoglobulins [TBII]).

●Destruction of functioning thyroid tissue by extensive lymphocytic infiltration, similar to chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), may prevent the gland from responding to TRAbs and can eventually result in spontaneous hypothyroidism. Serum antithyroid peroxidase antibody concentrations correlate with the degree of lymphocytic infiltration, and patients with higher concentrations have a higher rate of spontaneous "remission" of Graves' disease [51].

●Rarely, remission can be associated with the appearance of thyrotropin receptor-blocking antibodies (also called thyroid-blocking immunoglobulins), which occupy the thyrotropin receptor and block the stimulatory action of TSH or TRAbs [52]. These patients can spontaneously develop hypothyroidism and occasionally fluctuate between hyperthyroidism and hypothyroidism states depending upon the relative titers of stimulating and blocking antibodies.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

●Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical use – The thionamides, methimazole, carbimazole, and propylthiouracil (PTU), are effective treatment for patients with Graves' hyperthyroidism. They are often started in patients with Graves' hyperthyroidism to attain a euthyroid state rapidly in preparation for definitive therapy with radioiodine therapy or thyroidectomy. In the United States, patients are initially treated for one to two years with the hope of attaining a remission. However, patients who want to avoid or defer ablative therapy with radioiodine or surgery can continue the thionamide for prolonged periods. (See 'Clinical use' above and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

●Choice of thionamide – Although all of the thionamides are effective for hyperthyroidism, methimazole and carbimazole have a number of advantages over PTU. Methimazole is always preferred to PTU (except during the first trimester of pregnancy or during the initial treatment of thyroid storm) because it can reverse the hyperthyroidism more quickly, and it has fewer side effects. There have been increasing concerns about PTU-associated hepatotoxicity. Although hepatotoxicity is still a rare complication, the American Thyroid Association (ATA) and the US Food and Drug Administration (FDA) have issued guidelines on the choice of antithyroid drugs in different clinical settings. (See 'Choice of drug' above.)

●Dosing of methimazole – Patients with small goiters and mild hyperthyroidism (free thyroxine (T4) levels 1 to 1.5 times the upper limit of normal) can be started on 5 to 10 mg of methimazole daily. The dose can be increased if the hyperthyroidism (as assessed clinically and by measurements of serum thyroid-stimulating hormone [TSH], free T4, and total triiodothyronine [T3]) is not improving within four to six weeks. (See 'Dosing' above.)

Patients with moderate or severe hyperthyroidism require larger initial doses (10 to 40 mg daily) of methimazole. For patients taking ≥20 mg daily, we administer therapy initially in divided doses (eg, 10 mg two or three times a day or 15 mg twice daily) to normalize thyroid function more quickly and to possibly minimize gastrointestinal side effects and then change to single daily dosing if tolerated and as the dose is reduced. Few patients require more than 40 mg/day of methimazole.

The carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher.

●Monitoring initial therapy

•Thyroid function – Patients should have their thyroid function (free T4, total T3) initially assessed at four- to six-week intervals. Once the patient has a normal free T4 and total T3, the dose of methimazole can be decreased by 30 to 50 percent. Subsequent thyroid tests (TSH, free T4) should be repeated four to six weeks after each dose adjustment. When a stable maintenance dose is achieved, thyroid tests (TSH, free T4) can be performed every four to six months. (See 'Monitoring' above.)

It is important to measure both serum T4 and T3 initially because serum T3 concentrations may remain high even though serum T4 concentrations become normal. Serum TSH values may be misleading during the initial period of treatment. Often, however, the serum TSH concentration rises into the normal range within a few weeks. When this happens, there is no longer a need to measure serum T3 concentration. (See 'Monitoring' above.)

•CBC – We do not routinely monitor white blood cell count (for the development of agranulocytosis) or liver function tests (for the development of hepatotoxicity) in patients taking thionamides. However, a complete blood count (CBC, white count with differential) should be obtained during any febrile illness and at the onset of pharyngitis. (See 'Monitoring' above.)

•Liver function, amylase, and lipase – Liver function should be assessed in patients with signs or symptoms of hepatitis (eg, jaundice, light-colored stool or dark urine, pruritic rash). Amylase and lipase should be measured in patients with nausea, vomiting, or abdominal pain. (See 'Monitoring' above.)

●Duration of therapy – For patients taking methimazole as primary therapy, it should be continued for 12 to 18 months, then patients should be reassessed. (See 'Duration of therapy' above and 'Evaluation prior to stopping therapy' above.)

●Evaluation prior to stopping therapy – We typically measure serum thyrotropin receptor antibodies (TRAbs) initially after 12 to 18 months of thionamide therapy. Thionamides can be discontinued if TRAbs and TSH are normal at 12 to 18 months. Persistently high levels of TRAbs are associated with very high relapse rates, and patients with elevated antibody levels should either be continued on methimazole or elect definitive therapy with radioiodine or surgery. (See 'Evaluation prior to stopping therapy' above.)

●Monitoring for recurrence – All patients require monitoring for recurrence of hyperthyroidism after discontinuation of thionamides, but it typically occurs months to years after drug cessation in patients whose TRAbs are normal at the time the thionamide is stopped. We measure serum TSH, free T4, and total T3 initially at two- to three-month intervals beginning two to three months after stopping treatment (earlier if the patient has hyperthyroid symptoms). Using this approach, recurrent biochemical hyperthyroidism is usually detected before the patient develops many symptoms of hyperthyroidism. If thyroid tests remain normal for six months, monitoring should occur at four- to six-month intervals for the next six months and then every 6 to 12 months. For patients who remain euthyroid for a year, thyroid testing (TSH) can be performed annually. (See 'Monitoring for recurrence' above.)

●Treatment of recurrence – For patients with recurrent hyperthyroidism after a course of methimazole, radioiodine, surgery, or a longer course of methimazole are all reasonable options. Definitive therapy (radioiodine or thyroidectomy) is preferred by some patients, but long-term methimazole therapy increasingly is the preferred option for those who want to avoid definitive therapy. (See 'Treatment of recurrence' above and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Selection of therapy'.)

●Duration of methimazole treatment and remission – The frequency of prolonged remission among patients treated with a thionamide for one to two years is usually under 40 percent and is more likely in patients with milder disease. Longer duration of therapy improves remission rates, which have been reported to be as high as 84 percent after 5 to 10 years of treatment. (See 'Remission' above.)