EXTRA : UP-TO-DATE

Thyrotoxicosis is the term given to any condition that causes exposure of the tissues to high serum concentrations of free thyroxine (T4), free triiodothyronine (T3), or both that results with hypermetabolism and hyperactivity. Hyperthyroidism is the term given to the subgroup of diseases in which the reason of thyrotoxicosis is increased thyroid hormone synthesis and secretion by the thyroid gland.

PRECIPITATING AND PREDISPOSING FACTORS Several factors that predispose to Graves' hyperthyroidism have been proposed (table 3). Genetic susceptibility There is abundant epidemiologic evidence for genetic susceptibility to Graves' hyperthyroidism and chronic autoimmune thyroiditis (table 4) [79-81]. The diseases cluster in families and are more common in women. The concordance rate in monozygotic twins is 20 to 40 percent. The sibling recurrence rate for Graves' disease exceeds 10.0 [82]. There are associations with a number of immune-related genes which have also been found with many other autoimmune diseases and presumably underpin the inherited susceptibility to autoimmunity; for example, with certain alleles of CTLA-4 (cytotoxic T lymphocyte-associated 4) [81,83]. As an example, in one study of 379 patients with Graves' hyperthyroidism in the United Kingdom, 42 percent had a particular allele (G allele) of the CTLA-4 gene, as compared with 32 percent of 363 normal subjects [81,83]. In keeping with an immune-related susceptibility seen in almost all autoimmune diseases, there is a well known association with certain alleles of HLA on chromosome 6 [79]. As an example, a study of Caucasian patients in North America found that HLA-DRB1*08 and DRB3*0202 were associated with the disease and that DRB1*07 was protective [84]. Detailed studies have shown convincingly that the presence of Arg-74 is the important peptide in the HLA DR binding pocket rather than just the HLA subtype [48,85]. As far as thyroid specific gene associations are concerned, there is now evidence of increased risks associated with polymorphisms of intron 1 in the TSH receptor gene [86-89] and the thyroglobulin gene [90]. The data suggest that the influence of HLA and thyroglobulin polymorphisms is more than additive. The associated risks with these gene associations are all relatively low so that their assessment is not clinically useful. Infection Autoimmune thyroiditis can be induced in experimental animals by certain viral infections. If infection were the direct cause of Graves' hyperthyroidism, an identifiable agent should be present in the majority of patients and it should be possible to induce the disease by transferring the agent. Possible infections of the thyroid gland itself (eg, subacute thyroiditis, congenital rubella) have been associated with thyroid autoimmune disease and could initiate class II molecule expression. Hepatitis C infection is a well recognized precipitator of autoimmune thyroid disease when treated with interferon therapy, although most commonly a thyroiditis develops rather than Graves disease [91]. There is, however, no evidence that these or any other infections or exposures lead directly to autoimmune thyroid

disease in the majority of patients [92]. However, a report of retroviral sequences in the thyroid glands of patients with Graves' disease was not confirmed [93,94]. Stress As compared with normal subjects or patients with toxic nodular goiter, patients with Graves' hyperthyroidism more often give a history of some type of psychologic stress, in particular negative life events such as loss of a spouse or a road traffic accident, before the onset of their hyperthyroidism [95-97]. In general, stress appears to induce a state of immune suppression, possibly mediated by the actions of cortisol on immune cells. Stress-induced suppression may be followed by rebound immunologic hyperactivity. Such a response could precipitate autoimmune thyroid disease in genetically susceptible subjects. Gender More women develop Graves' hyperthyroidism than men, with a ratio of approximately 7:1, an effect that is often said to be mediated in some way by more estrogen or less testosterone. There is a large body of evidence that moderate amounts of estrogen enhance immunologic reactivity [98-100]. However, it is just as likely that the X-chromosome is the source of the enhanced susceptibility rather than sex steroids since the susceptibility continues after the menopause. For example, Xchromosome inactivation has been associated with autoimmune thyroid disease [101]. Smoking Smoking is a risk factor for Graves' hyperthyroidism (relative risk approximately 2.0) and an even stronger risk factor for Graves' orbitopathy [102104]. The mechanism is uncertain [105]. Pregnancy Severe Graves' disease is uncommon during pregnancy because hyperthyroidism is associated with reduced fertility and increased pregnancy loss. When it occurs, however, it can endanger both mother and fetus. Luckily, pregnancy is a time of immune suppression so that the disease tends to improve as pregnancy progresses. During pregnancy, both T-cell and B-cell functions are diminished, while Tregs increase dampening the disease [52,106]. The slow rebound from this immunosuppression after delivery results in enhanced immune reactivity and this contributes to the development of postpartum thyroid disease, including the new onset or recurrence of Graves disease [107]. It has also been suggested that fetal microchimerism (the presence of fetal cells in maternal tissue) might play a role in the development of postpartum autoimmune thyroid disease [108]. Up to 30 percent of young women give a history of pregnancy in the 12 months before the onset of Graves' disease [58], indicating that postpartum Graves' disease is a surprisingly common presentation and that pregnancy is a major risk factor in susceptible women. Drugs Iodine and iodine-containing drugs such as amiodarone may precipitate Graves' disease, or a recurrence of Graves' disease, in a susceptible individual [109]. Iodine is most likely to precipitate thyrotoxicosis in an iodine deficient population simply by allowing the TSHR-Abs to be effective in stimulating more thyroid hormone to be formed. Whether there is any other precipitating event is unclear. Iodine and amiodarone may also damage thyroid cells directly and release thyroid antigens to the immune system [110]. Interferon alpha treatment of patients with hepatitis C infection has been widely associated with the development of

autoimmune thyroiditis but Graves' disease may also be precipitated presumably by influencing the immune repertoire [111].

TREATMENT 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]. In the only randomized prospective trial comparing these 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 [2]. 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. Because all three treatment modalities are effective, the choice of therapy should involve active discussion between clinician and patient (table 1) [3]. Individual patient factors may influence choice of therapy. As an example, in a patient with mild hyperthyroidism and minimal thyroid enlargement, thionamides or radioiodine are good options. In a patient with severe hyperthyroidism and a large goiter who requires rapid control of hyperthyroidism, surgery might be the best option. Whatever treatment is used, initial monitoring should consist of periodic clinical assessment and measurements of serum T4 and sometimes T3 levels. Serum TSH concentration may remain low for several weeks after the patient becomes euthyroid. In addition, 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. (See "Laboratory assessment of thyroid function" and "Bone disease with hyperthyroidism and thyroid hormone therapy" and "Calcium and vitamin D supplementation in osteoporosis".) The approach outlined below is consistent with Hyperthyroidism Management Guidelines from the American Thyroid Association and the American Association of Clinical Endocrinologists [4].

Beta blockers Beta blockers ameliorate the symptoms of hyperthyroidism that are caused by increased beta-adrenergic tone [5]. These include palpitations, tachycardia, tremulousness, anxiety, and heat intolerance. Thus, 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 obtaining a 24-hour radioiodine uptake. We usually give atenolol (25 to 50 mg/day), which has the advantages of single daily dosing and beta-1 selectivity; however, all betaadrenergic blocking drugs effectively diminish hyperthyroid symptoms. (See "Beta blockers in the treatment of hyperthyroidism".)

Thionamides The thionamides methimazole and propylthiouracil (PTU) are the primary drugs used to treat Graves' hyperthyroidism [6]. Methimazole is preferred because of its longer duration of action, allowing for once daily dosing, more rapid efficacy, and lower incidence of side effects (figure 1). PTU is preferred during the first trimester of pregnancy because of the potential teratogenic effects of methimazole. (See "Pharmacology and toxicity of thionamides".)

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 or by continuation of the drug for a prolonged period (usually one to two years) with the hope of attaining a permanent remission. (See "Thionamides in the treatment of Graves' disease".)

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) [4]. We do not use thionamides in patients with a baseline absolute neutrophil count <500 mm3 or elevated liver transaminases (more than fivefold the upper limit of normal) except in selected patients after careful assessment of alternatives and risks.

The starting dose of methimazole varies according to the severity of the hyperthyroidism. Patients with small goiters and mild hyperthyroidism can be started on 10 mg once daily; this regimen is as effective as larger doses in most cases (figure 2).

Patients with larger goiters and more severe hyperthyroidism should be started on 20 to 30 mg daily. We administer initial therapy in divided doses in these patients to minimize gastrointestinal side effects, and then change to single daily dosing. If longterm medical therapy is chosen, the dose of methimazole is then tapered to a maintenance dose with the goal of maintaining a euthyroid state.

In countries where methimazole is unavailable, carbimazole can be used. 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.

Patients should have their thyroid function assessed at four to six week intervals until stabilized on maintenance thionamide therapy. 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, and the thionamide should not be discontinued unless a decision has been made to proceed to destructive therapy.

There are several other issues related to thionamide therapy, including management of complications, the prevalence of permanent remission after cessation of therapy (about 20 to 30 percent), the time course of relapse, and their negative effect on subsequent radioactive iodine therapy. (See "Pharmacology and toxicity of thionamides", section on 'Toxicity' and "Thionamides in the treatment of Graves' disease".)

Iodinated contrast agents and iodine Patients who have severe hyperthyroidism or are allergic to thionamides may benefit from alternative medical therapies. The oral radiocontrast agents sodium ipodate and iopanoic acid are potent inhibitors of the peripheral conversion of T4 to T3. They are not used as primary therapy because of possible induction of resistant hyperthyroidism. However, when given in combination with methimazole (at doses of 500 to 1000 mg/day), 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. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".)

Iodine elixirs, such as 10 drops of saturated solution of potassium iodide (SSKI) daily, can be used to ameliorate very mild hyperthyroidism. (See "Iodine in the treatment of hyperthyroidism".)

Other medications A number of other medications have been used in the management of hyperthyroidism, including the following:

Glucocorticoids inhibit peripheral T4 to T3 conversion and, in patients with Graves' hyperthyroidism, reduce thyroid secretion. They have been used in patients with severe hyperthyroidism and thyroid storm, although their efficacy is not well demonstrated. (See "Drug interactions with thyroid hormones".) Lithium blocks thyroid hormone release, but its use has been limited by its toxicity. (See "Lithium and the thyroid".) Cholestyramine, given in a dose of 4 g four times daily with methimazole, lowers serum T4 and T3 concentrations more rapidly than methimazole alone [7], and may be useful adjunctive therapy in selected patients who require rapid amelioration of hyperthyroid symptoms. Carnitine is a naturally occurring peripheral antagonist of thyroid hormone action that has been shown to ameliorate hyperthyroid symptoms and may prove to be useful clinically [8]. Rituximab, a monoclonal antibody that causes peripheral B cell depletion, may induce a sustained remission in patients with Graves' disease and low TRAb levels, but its cost and side effects limit its utility [9]. 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 thyroxine 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 [10]. However, the methodological quality of the trials was poor, and the authors concluded that there are currently no well-designed trials to provide strong evidence for Chinese traditional herbal medicine in the treatment of hyperthyroidism. Radioiodine ablation Radioiodine is widely used for the treatment of Graves' hyperthyroidism. It has been the therapy of choice in the United States, being selected by 60 percent of thyroid specialists who responded to a survey in 2011, but only 13 percent of European thyroid specialists [11]. We usually recommend radioiodine therapy. Although a thionamide provides control of hyperthyroidism as long as the drug is taken, the persistent remission rate when the drug is discontinued one to two years later averages only about 30 percent. However, there are patients in whom it may be reasonable to delay radioiodine (or surgery). Included in this group are patients with mild hyperthyroidism and patients with small goiters or with goiters that shrink during thionamide therapy. 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. Clinicians and patients must also be aware that radioiodine therapy may be associated with an increased risk of the development or worsening of Graves' ophthalmopathy. However, ophthalmopathy did not progress in a study of patients with minimal ophthalmopathy who were carefully monitored to avoid hypothyroidism. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Radioiodine and ophthalmopathy' and "Treatment of Graves' orbitopathy (ophthalmopathy)".) Radioiodine may be given as primary therapy to patients with mild, well-tolerated hyperthyroidism. In comparison, patients who are not tolerating hyperthyroidism well, are elderly, or have underlying heart disease are usually pretreated with a thionamide to ameliorate the hyperthyroidism before radioiodine treatment. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Pretreatment with thionamides'.) Radioiodine is administered as a capsule or, less commonly, an oral solution of sodium 131I, which is rapidly absorbed from the GI tract and concentrated in thyroid tissue. It induces extensive tissue damage, resulting in ablation of the thyroid within 6 to 18 weeks [12]. A discussion on dosing and side effects and particularly late hypothyroidism can be found elsewhere. (See "Radioiodine in the treatment of hyperthyroidism".) The goal of radioiodine therapy is destruction of the gland, with the early development of hypothyroidism. This eliminates the risk of recurrent hyperthyroidism. On the other hand, some clinicians prefer lower doses of radioiodine with the aim of achieving a euthyroid state while lowering the risk of early hypothyroidism [13]. However, many of these patients have persistent subclinical or overt hyperthyroidism. Furthermore, there is a risk both of recurrent overt hyperthyroidism and of the insidious onset of late hypothyroidism. (See "Radioiodine in the treatment of hyperthyroidism".)

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. Surgery Surgery is an unpopular therapy for Graves' hyperthyroidism, being selected by only 1 percent of thyroid specialists [11]. It is primarily indicated in patients who have an obstructive goiter or a very large goiter, in patients with active ophthalmopathy who desire definitive therapy for their hyperthyroidism, in pregnant women who are allergic to antithyroid drugs, and in patients who have allergies or poor compliance on antithyroid drugs but refuse 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 [14]. Patients who want rapid restoration of euthyroidism, fear radioactivity, or have had an adverse effect with thionamide drugs may also prefer surgery. (See "Surgery in the treatment of hyperthyroidism: Indications, preoperative preparation, and postoperative follow-up".) Thyroidectomy during pregnancy may be necessary in women who cannot tolerate thionamides because of allergy or agranulocytosis. The indications for surgery are similar to those in nonpregnant women and men