Antithyroid drugs (ATDs) are the treatment of choice for Graves disease in most countries in the world. The most commonly used in the United States are methimazole at doses from 10 to 40 mg once daily and propylthiouracil (PTU) in doses starting at 100 to 150 mg every 8 hours. PTU is no longer a first-choice drug because of recent reports of severe hepatotoxicity. When treating hyperthyroidism, the lowest dose needed to achieve and maintain clinical euthyroidism should be used because higher doses have not been shown to decrease relapse rates but may increase frequency of adverse effects [35]. Methimazole has the advantage of lower toxicity [36] (particularly when used in lower doses) and longer half-life, allowing single daily dosing, which usually results in increased adherence and more rapid decline in thyroid hormone levels, and is now recommended as the firstline ATD in most patients, whereas PTU is preferred during the first trimester of pregnancy since it is thought to be less likely to cross the placenta and because methimazole has been associated with certain rare congenital anomalies, such as choanal atresia and aplasia cutis [37]. Their major disadvantage is the high incidence of relapse of hyperthyroidism (up to 60%) after discontinuation of therapy. Optimal duration of therapy is between 12 and 18 months [38]. Prolonging treatment beyond 18 months does not seem to provide additional benefits [39, 40]. Longterm treatment appears to be safe [41] and a reasonable option for patients whose hyperthyroidism can be controlled with a low dose of these drugs [42].

A study from Japan reported a significant reduction in relapse (from 35% to 2%) with the addition of LT4 after 6 months of treatment with methimazole (block-replace regimen), and continuing this drug for 3 years after methimazole was stopped [43]. A subsequent study failed to confirm these findings [44]. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was equally effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism [39].

Although controversy exists about the usefulness of ATDs in Graves disease before definitive therapy with¹³¹I, such treatment does not seem to protect against worsening thyrotoxicosis nor to affect time-to-cure or relapse rates [39, 45].

RAI has been used for treatment of hyperthyroidism for over six decades. It is the preferred treatment modality in the United States for patients with Graves hyperthyroidism, though used less commonly worldwide. RAI is appropriate treatment for Graves disease, toxic nodules, and toxic multinodular goiters [46]. It is effective and safe and significantly reduces thyroid volume, although patients with large goiters and severe hyperthyroidism may require several doses [47]. If RAI is used to treat Graves hyperthyroidism, sufficient radiation should be administered in a single dose (typically 10-15 mCi) to render the patient with Graves disease hypothyroid [37]. Most patients treated in this manner will require lifelong replacement with thyroid hormone. Some researchers believe that RAI therapy may transiently worsen Graves ophthalmopathy, a problem that can be prevented by administration of prednisone [48].

Surgery is the treatment of choice for hyperthyroid patients with large goiters who have symptoms of compression, those with a coexistent suspicious thyroid nodule, for patients who have contraindications to or refuse medical therapy and RAI, and in pregnant women, whose symptoms cannot be controlled with, or who experience allergic reactions to, ATDs. It is safe and effective, with an overall success rate of 92% [49].

If surgery is chosen as the primary therapy for Graves disease, near-total or total thyroidectomy (TT) is the procedure of choice [37].

β-Blockers are useful to control the adrenergic symptoms of hyperthyroidism and may be used as initial adjunctive therapy and discontinued after definitive therapy with ATDs, RAI, or surgery that have succeeded in controlling those symptoms. β-Blockers are safe and effective in the preoperative treatment of these patients and result in faster relief of hyperthyroid symptoms when compared with results of conventional preparation with ATDs [50]. They are strongly recommended in elderly patients with symptomatic hyperthyroidism and to other hyperthyroid patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease.

LT4 is the treatment of choice for hypothyroidism. The usual replacement dose is 1.6 to 4.2 μg/kg/d and should be titrated to maintain serum TSH levels within normal range [51]. Serum TSH levels between 0.5 and 2.0 mIU/l are generally considered the optimal target [12]. Whether SCH should be treated remains controversial. Some studies suggest that early treatment may improve cardiac function, reverse mild symptoms of hypothyroidism and lower serum lipids [52, 53], and improve memory [54], whereas others have shown no effect in total or low-density lipoprotein (LDL) cholesterol levels [55] or cognitive function [56].

The use of combination LT4 and T3 in the treatment of hypothyroidism has been proposed as an alternative to LT4-only therapy, as a more physiologic form of thyroid hormone replacement [57]. Initial reports of improved mood and neuropsychological function with this combination [57] have not been confirmed by further controlled studies [58, 59, 60, 61], despite patients’ preference for this combination in some studies [62]. One study showed that combination therapy, when compared to LT4 alone, resulted in favorable changes in lipid profile but also in higher activation of bone resorption [61].

All thyroid nodules confirmed to be malignant and most found suspicious by FNA biopsy should be referred for surgical excision [70, 71]. The extent of the surgical procedure required is a matter of debate, with some authors advocating total or near-TT, and others favoring a more limited approach with lobectomy of the affected side. Benign thyroid nodules do not require surgery, unless they produce symptoms of compression or hyperthyroidism. Surgical excision is a reasonable option for patients with large or hyperfunctioning nodules, particularly if such nodules are associated with pressure symptoms [72].

Controversial evidence exists regarding the effectiveness of thyroid hormone suppressive therapy (THST) in reducing thyroid nodule size. One meta-analysis suggested an apparent therapeutic benefit of LT4 suppressive therapy in a subset
(20%—23%) of patients, with 1.9 to 2.5 times greater probability of achieving at least a 50% reduction in nodule size, when compared with placebo [73, 74]. Another meta-analysis found no statistically significant effect [75]. Predictors of response have not been identified. Suppressive therapy is not indicated for hyperfunctioning nodules. A controlled trial of suppressive therapy in nontoxic multinodular goiters showed a better than 13% decrease in thyroid volume in 58% of patients treated with LT4 compared with only 5% of those given placebo [76]. However, another randomized study comparing LT4 therapy with RAI in patients with nontoxic multinodular failed to show a benefit of LT4 suppressive therapy with regard to goiter size reduction but showed significantly increased bone loss [77]. Routine T4 suppressive therapy for benign nodule is no longer recommended, and potential adverse effects on the cardiovascular and skeletal systems should always be considered [77, 78].

RAI is effective in reducing thyroid volume by up to 60% in patients with nontoxic multinodular goiter and improving compressive symptoms in most [79]. It is successful in the treatment of nearly 90% of single toxic adenomas, although the relatively high doses usually required result in long-term hypothyroidism in 10% to 20% of cases [72]. It is also 80% to 100% effective in the treatment of toxic multinodular goiter, although often several treatments may be necessary [80]. RAI therapy is also effective in patients with sporadic nontoxic goiters, resulting in volume reductions of up to 45% in 1 year [81]. Pretreatment with a single dose of rhTSH has been successfully used in Europe as adjuvant to RAI, improving the efficacy of RAI by enhancing uptake in nontoxic thyroid tissue and allowing the use of lower doses of RAI, while still resulting in greater reduction of goiter size [82]. rhTSH also potentiates the effect of RAI allowing a major reduction of the RAI activity without compromising its efficacy, but it increases fivefold the risk of posttherapy hypothyroidism [83]. Moreover, because the side effects are dose dependent, they are rare following doses of rhTSH of 0.1 mg or less [84].

Percutaneous ethanol injection (PEI) should be reserved for patients who cannot, or will not, undergo standard therapy. Local pain, risk of recurrent laryngeal nerve damage, and the need for repeat treatments make PEI unsuitable for routine treatment of solid thyroid nodules. However, this procedure appears to be safe and effective in the treatment of predominantly cystic nodules, resulting in substantial reduction of nodule volume and amelioration of cosmetic and compressive symptoms in up to 80% of patients [85, 86].

Ultrasound-guided laser thermal ablation (LTA) has emerged as an alternative therapeutic option in the management of patients with benign hypofunctioning thyroid nodules associated with compressive symptoms, who are poor surgical candidates or who refuse such intervention. This procedure has resulted in 45% to 60% reduction in nodule volume 6 months after treatment [87, 88]. The procedure requires considerable skill of the operator and is currently performed only in a few specialized centers.