Graves' hyperthyroidism in nonpregnant adults: Overview of treatment

INTRODUCTION — Graves' disease is an autoimmune disease that may consist of hyperthyroidism, goiter, thyroid eye disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by thyroid-stimulating hormone (TSH, thyrotropin)-receptor antibodies (TRAb) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter). The presence of TRAb in serum and thyroid eye disease on clinical examination distinguish the disorder from other causes of hyperthyroidism.

This topic will provide an overview of treatment options for Graves' hyperthyroidism in nonpregnant adults. The pathogenesis of Graves' disease, the clinical manifestations and diagnosis of hyperthyroidism, other causes of an overactive thyroid gland, as well as treatment of Graves' disease in pregnant women and in children are reviewed in more detail in separate topic reviews. The treatment of hyperthyroidism due to other etiologies is reviewed in the individual topics.

●(See "Pathogenesis of Graves' disease".)

●(See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●(See "Diagnosis of hyperthyroidism".)

●(See "Disorders that cause hyperthyroidism".)

●(See "Hyperthyroidism during pregnancy: Treatment".)

●(See "Treatment and prognosis of Graves disease in children and adolescents".)

THERAPEUTIC APPROACH — The therapeutic approach to Graves' hyperthyroidism consists of both rapid amelioration of symptoms with a beta blocker and measures aimed at decreasing thyroid hormone synthesis: the administration of a thionamide, radioiodine ablation, or surgery [1].

The approach outlined below is consistent with Hyperthyroidism Management Guidelines from the American Thyroid Association (ATA) [1].

Symptom control: Beta blockers — A beta blocker should be started (assuming there are no contraindications to its use) in most patients as soon as the diagnosis of hyperthyroidism is made, even before confirming that the cause of hyperthyroidism is Graves' disease. We typically start with atenolol 25 to 50 mg daily and increase the dose as needed (up to 200 mg daily) to target a pulse of 60 to 90 beats per minute if blood pressure allows.

Atenolol has the advantages of single daily dosing and beta-1 selectivity; however, all beta-adrenergic blocking drugs effectively diminish hyperthyroid symptoms. Beta blockers ameliorate the symptoms of hyperthyroidism that are caused by increased beta-adrenergic tone [2]. These include palpitations, tachycardia, tremulousness, anxiety, and heat intolerance. Fatigability and shortness of breath were also improved in patients who were treated with a beta blocker and a thionamide versus a thionamide alone [3]. (See "Beta blockers in the treatment of hyperthyroidism".)

Decrease thyroid hormone synthesis

Treatment options — There are three treatment options for Graves' disease: antithyroid drugs (thionamides), radioiodine, or surgery. All three options are effective, but all three options have significant side effects (table 1). Additionally, the treatment options are not mutually exclusive. Antithyroid drugs may be used initially to control hyperthyroidism prior to definitive therapy with radioiodine or surgery, they may be prescribed for one to two years, or longer, to try and attain a remission, or they may be used long term. Radioiodine may be given as initial therapy or after pretreatment with antithyroid drugs, and surgery is usually preceded by antithyroid drugs to attain a euthyroid state preoperatively.

There are few trials comparing the three treatment options [4]:

●In the only randomized trial comparing all three therapies, each was equally effective in normalizing serum thyroid hormone concentrations within six weeks; after treatment, 95 percent or more of the patients were satisfied with their therapy [5,6]. In addition, most patients reported that they would recommend the therapy to a friend without reservation (medical 68 percent, surgical 74 percent, radioiodine 84 percent). The risk of relapse was 37, 21, and 6 percent in the thionamide, radioiodine, and surgery groups, respectively.

Observational studies with three to eight years of follow-up show higher success for radioiodine and surgery compared with thionamides [7-9]. Most of the patients treated with radioiodine or surgery were being treated with levothyroxine for permanent hypothyroidism.

As examples:

●At the Mayo Clinic (720 patients with Graves' hyperthyroidism), the rate of success was reported to be 52, 92, and 100 percent for thionamides, radioiodine, and surgery, respectively, while side effects occurred in 17, 1, and 6 percent of patients, respectively [9].

●A United States administrative data set (4661 patients) reported success rates of 50, 93 and 99 percent for thionamides, radioiodine, and surgery, respectively, with side effects of 12, 6, and 24 percent, respectively [8].

●In a study from Sweden (1186 patients assessed on average eight years later), 65 percent of patients were treated initially with thionamides, whereas 27 percent initially received radioiodine and 4.5 percent surgery [7]. Remission rates after initial therapy with thionamides, radioiodine, or surgery were 45, 82, and 96 percent, respectively. Half of the patients initially treated with thionamides eventually had ablative therapy. Only 39 percent were euthyroid without benefit of medication.

The popularity of antithyroid drugs is increasing in the United States, and the use of radioiodine is decreasing. In a 2011 survey, over half of clinicians in the United States preferred radioiodine while approximately 40 percent initiated a one- to two-year course of antithyroid drugs. Radioiodine was unpopular in Europe and Asia, with over 80 percent of European clinicians choosing antithyroid drugs and only 14 percent choosing radioiodine [10]. In a 2020 analysis of United States insurance claims data, antithyroid drugs were used as initial therapy of Graves' disease in 60 percent of patients, while only 33 percent of patients received radioiodine and 6 percent surgery [8]. At Massachusetts General Hospital, there has been an 85 percent reduction in the use of radioiodine for hyperthyroidism between 2006 and 2019 [11].

It is assumed that antithyroid drugs have become more popular than the other treatment options because of avoidance of hypothyroidism as well as publication of studies demonstrating their long-term safety and higher remission rates after longer periods of treatment. Whereas radioiodine has become less popular because of its association with worsening thyroid eye disease and patient fears regarding radiation exposure. (See "Thionamides in the treatment of Graves' disease", section on 'Remission' and "Thionamides: Side effects and toxicities" and "Radioiodine in the treatment of hyperthyroidism", section on 'Contraindications and precautions' and "Radioiodine in the treatment of hyperthyroidism", section on 'Adverse effects'.)

In the future, immunotherapy may be a therapeutic option. In a phase 1 study utilizing antigen-specific immunotherapy with thyrotropin receptor peptides, hyperthyroidism improved in 70 percent of patients [12].

Selection of therapy — We discuss treatment options with patients and consider their values and preferences when choosing therapy. Considerations in choosing treatment should include success rates, side effects, and the rapidity with which euthyroidism is achieved. This approach is consistent with ATA guidelines [1,13]. (See 'Treatment options' above and 'Thionamides' below and 'Radioiodine ablation' below and 'Surgery' below.)

A study of the determinates of patient and physician choice found that both patients and physicians valued achievement of remission highly (and avoidance of hypothyroidism), and thus a preference for antithyroid drugs [14]. For second choice, patients preferred surgery over radioiodine, while physicians preferred radioiodine over surgery. Individual patient factors (eg, severity of hyperthyroidism, presence of thyroid eye disease, presence of contraindications to selected therapy) influence the choice of initial therapy. Overt hyperthyroidism is best managed by an endocrinologist or other providers trained and experienced with the treatment options and side effects.

The ATA guidelines provided a "rough guide" for the ranges of free thyroxine (T4) seen in patients with mild, moderate, and severe hyperthyroidism, but emphasized that patient symptoms, gland size, and T3 level (when available) were additional important considerations. The following suggests treatment options based upon disease severity:

●Mild hyperthyroidism (eg, free T4 1 to 1.5 times the upper limit of normal with minimal thyroid enlargement) – For patients with mild hyperthyroidism and no thyroid eye disease, a one- to two-year course of thionamides is associated with above average remission rates. For patients who prefer definitive therapy, radioiodine can be used as initial therapy (without thionamide pretreatment) when patients are tolerating hyperthyroid symptoms and are not at risk for complications. Surgery requires pretreatment with a thionamide (in the absence of a contraindication).

●Moderate hyperthyroidism (eg, free T4 1.5 to 2 times the upper limit of normal with moderate thyroid enlargement) – For patients with moderate hyperthyroidism and no thyroid eye disease, a one- to two-year course (or longer) of a thionamide is reasonable. Long-term thionamide therapy may be needed. For patients who prefer definitive therapy, radioiodine can be administered with or without pretreatment with a thionamide depending upon symptoms. Alternatively, patients may prefer surgery after pretreatment with a thionamide.

●Severe hyperthyroidism (eg, free T4 2 to 3 times the upper limit of normal with goiter) and/or high risk of complications – For patients with severe hyperthyroidism, or patients with a significant risk of hyperthyroid complications (eg, older age, cardiovascular disease), we suggest starting a thionamide (in addition to beta blockers) to achieve euthyroidism quickly. This can be followed by ablative therapy with radioiodine (in the absence of thyroid eye disease), by surgery, or by continuation of a thionamide for one to two years or longer with the hope of attaining a remission, or by long-term treatment with a thionamide.

●Thyroid eye disease – For patients with mild hyperthyroidism and minimal thyroid eye disease, radioiodine (with glucocorticoid coverage) or a one- to two-year course of thionamides are good options. For patients with moderate to severe thyroid eye disease, we prefer surgery rather than radioiodine with glucocorticoid coverage for definitive therapy. Radioiodine therapy may be more likely to lead to the development or worsening of orbitopathy than antithyroid drugs or subtotal thyroidectomy since it is associated with an increase in TSH-receptor antibodies (TRAb). (See "Treatment of thyroid eye disease", section on 'Additional treatment according to severity of orbitopathy'.)

●Large goiters, suspicious nodules, or concomitant hyperparathyroidism – Surgery may be the best option for patients with very large goiters and patients with suspicious nodules or hyperparathyroidism but may be a poor option for patients who are older, at high surgical risk, or without access to high-volume thyroid surgeons.

●Pregnancy issues and contraindications – Radioiodine is contraindicated during pregnancy and lactation and should be discouraged or prohibited in patients who cannot follow radiation precautions (eg, sole caregivers for infants or young children, or incontinent older adult patients). Antithyroid drugs are contraindicated in patients with prior adverse reactions (agranulocytosis or hepatitis). Because they are teratogenic, their long-term 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. Long-term use of thionamides may be preferred in patients who want to avoid definitive therapy and in older adult patients with contraindications to surgery and radioiodine. (See "Hyperthyroidism during pregnancy: Treatment" and 'Thionamides' below and 'Radioiodine ablation' below and 'Surgery' below.)

The individual therapies are discussed briefly below and in more detail in the individual topic reviews.

Thionamides — For patients with significant symptoms of hyperthyroidism, we suggest starting a thionamide (in addition to beta blockers) to achieve euthyroidism relatively quickly, prior to potential definitive therapy with radioiodine or surgery. The goal of thionamide therapy in Graves' hyperthyroidism is to attain a euthyroid state within three to eight weeks. This can be followed by ablative therapy with radioiodine or surgery, by continuation of the drug for one to two years or longer with the hope of attaining a remission, or for long-term therapy.

For patients with mild disease and small goiters, who are more likely to achieve remission after one year of treatment, primary antithyroid drug therapy may be preferred. Antithyroid drugs will control hyperthyroidism in most patients as long as the drug is taken, but remission rates (the percentage of patients who remain euthyroid one year after the drug is withdrawn) average under 40 percent after one to two years of treatment [5], but have been reported to exceed 80 percent after 5 to 10 years of treatment [15]. Remission is more likely in patients with mild hyperthyroidism and patients with small goiters or with goiters that shrink during thionamide therapy. Remission is also predicted by the change in TRAb levels over time. (See "Thionamides in the treatment of Graves' disease", section on 'Rate of prolonged remission' and "Thionamides in the treatment of Graves' disease", section on 'Predictors of remission'.)

Administration of thionamides is reviewed briefly below and, in more detail, separately. Contraindications and adverse effects are also reviewed separately. (See "Thionamides in the treatment of Graves' disease" and "Thionamides: Side effects and toxicities".)

●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) [1]. 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 after careful assessment of alternatives and risks. (See "Thionamides in the treatment of Graves' disease", section on 'Initiation of therapy'.)

●Choice of thionamide – The thionamide methimazole is the primary drug used to treat Graves' hyperthyroidism [1]. Methimazole is now almost exclusively used because of its longer duration of action, allowing for once-daily dosing, more rapid efficacy (figure 1), and lower incidence of side effects. Propylthiouracil (PTU) is preferred during the first trimester of pregnancy, because of the more significant teratogenic effects of methimazole, and in patients who have minor drug reactions to methimazole who want to avoid radioiodine or surgery. (See "Thionamides: Side effects and toxicities".)

Carbimazole, rather than methimazole, is available in some countries. It is metabolized to methimazole, and the dose required to yield a similar 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.

●Dosing – The starting dose of methimazole varies according to the severity of the hyperthyroidism. (See "Thionamides in the treatment of Graves' disease", section on 'Dosing'.)

•Patients with small goiters and mild hyperthyroidism (free T4 levels 1 to 1.5 times the upper limit of normal) can be started on 5 to 10 mg once daily.

•Patients with free T4 levels 1.5 to 2 times the upper limit of normal can be started on 10 to 20 mg daily. This regimen is as effective as higher doses in most cases (figure 2), and side effects from methimazole are dose related.

•Patients with larger goiters and more severe hyperthyroidism (free T4 levels approximately 2 to 3 times the upper limit of normal) should be started on 20 to 40 mg daily.

For patients taking ≥20 mg daily, we administer initial therapy in divided doses for a week or two, to normalize thyroid function more quickly and to minimize gastrointestinal (GI) side effects, and then change to single daily dosing (unless GI side effects persist and are minimized by divided dosing).

If long-term medical therapy is chosen, the dose of methimazole is then tapered to a maintenance dose (typical maintenance doses average 5 to 10 mg once daily) with the goal of maintaining a euthyroid state.

Radioiodine ablation — Radioiodine is less expensive and has a lower complication rate than surgery and may be the preferred definitive therapy of hyperthyroidism in nonpregnant patients except in patients with moderate or severe thyroid eye disease. For patients with significant symptoms of hyperthyroidism, who are older, or who have underlying heart disease or other comorbidities, we treat with a thionamide (in addition to beta blockers) to restore euthyroidism prior to radioiodine treatment. For patients with mild, well-tolerated hyperthyroidism, there is no need to pretreat with a thionamide, and radioiodine can be given soon after the diagnosis is made. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Pretreatment with methimazole'.)

If radioiodine is chosen, the patient must be comfortable with the decision to ablate the thyroid and be aware that prolonged thionamide therapy lasting even decades is an acceptable alternative as long as the drug is tolerated and the hyperthyroidism is controlled [16]. Clinicians and patients must also be aware radioiodine therapy can cause the development or worsening of thyroid eye disease more often than antithyroid drug therapy or surgery. The changes are often mild and transient, at least in patients who have mild or no orbitopathy before therapy. The ATA guidelines do not recommend radioiodine for patients with moderate to severe orbitopathy [1], but radioiodine with glucocorticoid coverage is a possible option for such patients who refuse surgery and have contraindications to antithyroid drugs. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Thyroid eye disease' and "Radioiodine in the treatment of hyperthyroidism", section on 'Radioiodine and thyroid eye disease'.)

Radioiodine is administered as a capsule or, less commonly, an oral solution of sodium iodine-131 (I-131), which is rapidly absorbed from the GI tract and concentrated in thyroid tissue. Radioiodine induces extensive tissue damage, resulting in ablation of the thyroid within 6 to 18 weeks [17]. Approximately 10 to 20 percent of patients fail the first radioiodine treatment and require a second or subsequent dose. These patients usually have more severe hyperthyroidism or larger goiters. A discussion on dosing and side effects, including hypothyroidism, can be found elsewhere. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Monitoring' and "Radioiodine in the treatment of hyperthyroidism", section on 'Adverse effects'.)

Surgery — For a patient with severe hyperthyroidism and an obstructive goiter or a very large goiter, we suggest surgery. It is also indicated for patients with moderate to severe, active orbitopathy who desire definitive therapy for their hyperthyroidism; for pregnant women who are allergic to antithyroid drugs; and for patients who have allergies, adverse effects, or poor compliance with antithyroid drugs but are unable to or do not want to receive radioiodine. Surgery would also be indicated if there was a coexisting suspicious or malignant thyroid nodule or primary hyperparathyroidism. However, most thyroid nodules associated with Graves' disease are benign, in which case surgery would not be recommended [18]. (See "Surgical management of hyperthyroidism".)

Surgery is an unpopular therapy for Graves' hyperthyroidism (selected by only 1 percent of thyroid specialists [10]), but it is being used more frequently in patients with active thyroid eye disease [19] and in women desiring definitive therapy prior to a pregnancy, and was the initial treatment used for 6 percent of patients in the United States based on insurance claims data [8].

Preoperative preparation for patients with hyperthyroidism is reviewed in detail separately. (See "Surgical management of hyperthyroidism", section on 'Preoperative preparation'.)

Pregnancy — We advise women desiring to become pregnant in the near future to consider radioiodine or surgery 6 to 12 months in advance of a planned pregnancy, to avoid the need for a thionamide during the pregnancy. However, if radioiodine or surgery is not desired, PTU therapy would be the preferred drug during the first trimester of pregnancy (and may be continued throughout pregnancy). The treatment of hyperthyroidism during pregnancy is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment".)

Adjunctive therapies — Patients who have severe hyperthyroidism or are allergic to thionamides may benefit from alternative medical therapies. We rarely use these adjunctive therapies with the exception of iodine, which we use for preoperative preparation for thyroidectomy in Graves' disease, for the treatment of severe hyperthyroidism or thyroid storm (with thionamides), or less commonly, after administration of radioiodine or with antithyroid drugs. (See "Iodine in the treatment of hyperthyroidism", section on 'Role of iodine'.)

Iodinated contrast agents and iodine — The oral radiocontrast agents sodium ipodate and iopanoic acid are potent inhibitors of the peripheral conversion of T4 to triiodothyronine (T3). They are not used as primary therapy, because of possible induction of resistant hyperthyroidism. However, when given (at doses of 500 to 1000 mg/day) in combination with methimazole, they can rapidly ameliorate severe hyperthyroidism and can also be used to prepare a hyperthyroid patient for early surgery. However, these drugs are not currently available in the United States and most of the world. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

Iodine elixirs, up to 10 drops of saturated solution of potassium iodide (SSKI, 50 mg iodide per drop [0.05 mL]) daily for 7 to 10 days is used perioperatively to reduce gland vascularity. Iodine can also be used beginning one week following radioiodine treatment and continuing for several weeks until the gland is ablated to normalize thyroid function more quickly in patients who would have been pretreated with thionamides if not for intolerance, allergic reactions, or contraindications to thionamides. Iodine may also be used as adjunctive therapy with thionamides to allow the use of lower thionamide doses in patients having dose-related minor reactions to thionamides.

Iodine, in smaller doses (1 to 2 drops per day or less), may also be used as primary therapy to control mild hyperthyroidism for prolonged periods (even decades) and may be quite effective as long-term therapy in patients who remain mildly hyperthyroid after a dose of radioiodine, who prefer not to take another dose. (See "Iodine in the treatment of hyperthyroidism".)

Glucocorticoids — Glucocorticoids inhibit peripheral T4 to T3 conversion and, in patients with Graves' hyperthyroidism, reduce thyroid secretion. They are used for the treatment of thyroid storm and impending thyroid storm. (See "Thyroid storm", section on 'Glucocorticoids'.)

Glucocorticoids are also used to treat moderate-to-severe thyroid eye disease. (See "Treatment of thyroid eye disease", section on 'Initial medical therapy'.)

Cholestyramine — Cholestyramine, given in a dose of 4 g four times daily with methimazole, lowers serum T4 and T3 concentrations more rapidly than methimazole alone and may be useful adjunctive therapy in selected patients who require rapid amelioration of hyperthyroid symptoms. (See "Thyroid storm", section on 'Other therapies'.)

Other medications infrequently used — A number of other medications have been studied in the management of hyperthyroidism, but are rarely used, including the following:

●Lithium blocks thyroid hormone release, but its use has been limited by its toxicity. (See "Lithium and the thyroid".)

●Rituximab, a monoclonal antibody that causes peripheral B cell depletion, may induce a sustained remission in patients with Graves' disease and low TSH-receptor antibodies (TRAb) levels, but its cost and side effects limit its utility [20,21].

●In China and many other countries, Chinese herbal medicines are used alone or in combination with antithyroid drugs to treat hyperthyroidism. These herbs are claimed to weaken the biological effects of T4 and inhibit the transformation of T4 to T3. Some are said to be able to modulate the function of sympathetic nerves or the immune system. In a systematic review and meta-analysis of 13 trials of 1770 participants, the addition of Chinese herbal medicines to antithyroid drugs was beneficial in some patients for reducing relapse rates, improving symptoms, and reducing adverse effects such as agranulocytosis [22]. However, the methodological quality of the trials was poor, and the study authors concluded that there are currently no well-designed trials to provide strong evidence for Chinese traditional herbal medicine in the treatment of hyperthyroidism.

Skeletal health — Overt hyperthyroidism is associated with accelerated bone remodeling, reduced bone density, osteoporosis, and an increase in fracture rate. The bone density changes may or may not be reversible with therapy. These changes in bone metabolism are associated with negative calcium balance, hypercalciuria, and, rarely, hypercalcemia. Since hyperthyroidism results in a negative calcium balance, reduced bone density, and increased fracture risk, patients (with the exception of those with hypercalcemia) should be advised to ingest 1200 to 1500 mg elemental calcium daily through diet or supplements when hyperthyroid. (See "Bone disease with hyperthyroidism and thyroid hormone therapy" and "Calcium and vitamin D supplementation in osteoporosis".)

MONITORING AFTER TREATMENT

Thyroid function tests — Whichever treatment is used, initial monitoring should consist of periodic clinical assessment and measurements of serum free T4 and often total T3 levels. Serum TSH concentrations should be interpreted with caution since they may remain low for several weeks after the patient becomes euthyroid and may even remain low transiently in patients who have become hypothyroid.

●Thionamides – Patients should have their thyroid function assessed at four- to six-week intervals until stabilized on maintenance thionamide therapy, then at three- to six-month intervals. Patients with persistently low serum TSH concentrations after more than six months of therapy with a thionamide are unlikely to have a remission when the drug is stopped. Patients with persistently high levels of TSH-receptor antibodies (TRAb, thyroid-stimulating immunoglobulins [TSI]) after one or more years of treatment are also unlikely to remain euthyroid if thionamides are discontinued [23]. Even patients who are euthyroid and have low levels of TRAb have a 20 percent risk of relapse. Therefore, before trying to discontinue the thionamide, a plan should be established for subsequent treatment of recurrent hyperthyroidism, either definitive therapy (radioiodine or surgery) or another one- to two-year course of a thionamide, or long-term thionamide therapy. (See "Thionamides in the treatment of Graves' disease", section on 'Evaluation prior to stopping therapy'.)

●Radioiodine – For patients treated with radioiodine, we measure free T4, total T3, and TSH four to six weeks after treatment, and then free T4 and TSH (and total T3 if still hyperthyroid) at four- to six-week intervals for up to six months, or until hypothyroid and on stable doses of levothyroxine. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Monitoring'.)

●Surgery – For patients with Graves' disease who undergo near-total or total thyroidectomy, thyroid hormone should be initiated prior to discharge in a euthyroid patient and serum TSH should be measured six to eight weeks later to adjust the dose to maintain the TSH in the normal reference range.

If the patient is still hyperthyroid at the time of surgery, thyroid hormone replacement should be delayed until levels fall into the normal range; the interval can be estimated based on the week-long half-life of T4. (See "Surgical management of hyperthyroidism", section on 'Hypothyroidism'.)

Weight gain — Weight loss is a common feature of hyperthyroidism, and many patients gain considerable weight after treatment of their hyperthyroidism [24-28]. In a study of 1373 hyperthyroid patients, men gained on average 8 kg during the treatment of hyperthyroidism, and women gained 5.5 kg (odds ratio for developing obesity after treatment of hyperthyroidism 1.7 [95% CI 1.3-2.2] for men and 1.3 [95% CI 1.2-1.5] for women) [29]. Patients treated with radioiodine who developed hypothyroidism gained more weight than patients treated with thionamides.

Proposed mechanisms for the excessive weight gain include:

●Subnormal energy expenditure after treatment [25] without concomitant reduction in appetite or food intake [26].

●Inadequate thyroid hormone replacement [28].

Patients should be advised about the likelihood of weight gain, which may in part be prevented by dietary advice [30]. (See "Obesity in adults: Overview of management", section on 'Approach to therapy'.)

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

●General principles – Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by thyroid-stimulating hormone (TSH, thyrotropin)-receptor antibodies (TRAb) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter).

The therapeutic approach to Graves' hyperthyroidism consists of both rapid amelioration of symptoms with a beta blocker and measures aimed at decreasing thyroid hormone synthesis with the administration of a thionamide, radioiodine ablation, or surgery (table 1). (See 'Therapeutic approach' above and 'Selection of therapy' above.)

●Treatment of symptoms – Assuming there are no contraindications to its use, we administer a beta blocker to patients with moderate to severe hyperadrenergic symptoms until euthyroidism is achieved by thionamides, radioiodine, or surgery. (See 'Symptom control: Beta blockers' above and "Beta blockers in the treatment of hyperthyroidism".)

We typically start with atenolol 25 to 50 mg daily and increase the dose as needed (up to 200 mg daily) to target a pulse between 60 and 90 beats per minute if blood pressure allows.

●Treatment to reduce thyroid hormone synthesis – There are three treatment options for Graves' disease: antithyroid drugs (thionamides), radioiodine, or surgery. All three options are effective, but all three options have significant side effects (table 1). The three options are not mutually exclusive.

The choice of therapy should involve active discussion between clinician and patient; it may also be determined by the severity of the patient's hyperthyroidism.

The recommendation to avoid close contact with young children for several days after radioiodine administration may make this treatment temporarily unattractive if alternative childcare is unavailable. Patient desire to avoid hypothyroidism and patient fears regarding radiation exposure or agranulocytosis from thionamides should also be considered. (See 'Selection of therapy' above.)

•Severe hyperthyroidism and/or high risk for complications – For patients with severe hyperthyroidism (eg, free T4 two to three times the upper limit of normal with goiter or with concerning symptoms), or patients with a significant risk of hyperthyroid complications (eg, older age, cardiovascular disease), we suggest a thionamide in addition to beta blockers to achieve euthyroidism quickly (Grade 2C). Methimazole is now used almost exclusively (except during the first trimester of pregnancy and in patients who have minor drug reactions to methimazole who refuse radioiodine or surgery) because of its longer duration of action, allowing for once-daily dosing, more rapid efficacy, and lower incidence of side effects. (See 'Selection of therapy' above and 'Thionamides' above and "Thionamides in the treatment of Graves' disease" and "Thionamides: Side effects and toxicities".)

Once patients with more severe hyperthyroidism are euthyroid on methimazole, definitive therapy with radioiodine or surgery, a one- to two-year course of methimazole or longer if needed, or long-term methimazole are all reasonable alternatives. (See 'Selection of therapy' above.)

In the absence of active thyroid eye disease, we suggest radioiodine therapy if definitive therapy is desired, given its lower cost and lower complication rate than surgery (Grade 2C).

•Mild to moderate hyperthyroidism and not at high risk for complications – For patients with mild to moderate hyperthyroidism (eg, free T4 <2 times the upper limit of normal with minimal to moderate thyroid enlargement) who are tolerating hyperthyroid symptoms and who are not at risk for complications from hyperthyroidism, antithyroid drug therapy may be preferred, as patients with mild hyperthyroidism and small goiters have higher remission rates. For patients who prefer definitive therapy, radioiodine can be used as initial therapy (without antithyroid drug pretreatment). (See 'Selection of therapy' above and "Radioiodine in the treatment of hyperthyroidism", section on 'Pretreatment with methimazole'.)

•Hyperthyroidism with large goiter – For patients with hyperthyroidism due to a very large or obstructive goiter, we suggest surgery (Grade 2C). It is also indicated for patients who are allergic to thionamides and are unable to or do not want to receive radioiodine. Surgery may also be preferred in patients with active thyroid eye disease. (See 'Selection of therapy' above and "Surgical management of hyperthyroidism".)

●Pregnancy planning – We advise women desiring to become pregnant in the near future to consider radioiodine or surgery 6 to 12 months in advance of a planned pregnancy to avoid the need for a thionamide during the pregnancy. However, if radioiodine or surgery is not desired, propylthiouracil (PTU) therapy would be the preferred drug during the first trimester of pregnancy and may be continued throughout pregnancy or transitioned to methimazole at 16 weeks gestation. (See "Hyperthyroidism during pregnancy: Treatment".)

●Monitoring treatment – Whatever treatment is used, initial monitoring following treatment should consist of periodic clinical assessment and measurements of serum free thyroxine (T4) and total triiodothyronine (T3) levels. Measurement of serum TSH can be misleading in the early follow-up period because it can remain low for weeks or even months, even when the patient is biochemically euthyroid or even hypothyroid, with serum free T4 values well within or even below the normal range. (See 'Thyroid function tests' above.)