Approach

The main goal of treatment is to normalise thyroid function parameters. This is achieved with antithyroid medications, by ablation of thyroid tissue with radioactive iodine, or by surgery.[78][79][80][81]​​​ Early and effective control of high thyroid hormone levels is associated with reduced cardiovascular risk and improved survival.[82][83]

No safe and effective therapy is available to correct the basic autoimmune process.[2] Immune modulation and immunosuppressive therapies are reserved for severe forms of orbitopathy and dermopathy, but may have potential for certain patient groups in the future.[18][45]​​[58]​​​​​

Thyroid storm

Thyroid storm is rare but typically develops in untreated or partially treated patients with poor access to the healthcare system.[84] It can occur at any time, depending on precipitating factors. Rarely, thyroid storm may be the initial presentation.

Thyroid storm most commonly occurs postoperatively in a patient who is not medically prepared for surgery (i.e., the patient has not achieved peri-operative euthyroidism), or subsequent to the release of thyroid hormone following radioactive iodine therapy.[85][86] Prevention with antithyroid drugs is important.

Thyroid storm presents with volume depletion, congestive heart failure, confusion, nausea and vomiting, and extreme agitation. Management includes supportive treatment, such as cooling, correction of volume status, respiratory support if indicated, and treatment of underlying sepsis if appropriate. Thyroid storm should be managed in an intensive care environment with input from endocrine consultants. High doses of antithyroid medicines, corticosteroids, beta-blockers, and an iodine solution (e.g., Lugol solution, or saturated solution of potassium iodide [SSKI]) should also be administered.[87][88]​ Lugol solution must be given no earlier than 30 minutes after the first dose of antithyroid medicine in order to avoid exacerbation of thyrotoxicosis due to escape from Wolff-Chaikoff effect. An alternative to Lugol solution and SSKI is sodium iodide, which is given intravenously; however, this is not available in some countries.[89] Colestyramine and lithium may also be given.[87][88]​ Colestyramine reduces enterohepatic circulation of thyroid hormone. Lithium reduces the levels of thyroid hormone.

Subclinical disease

Individualise treatment of subclinical disease. Subclinical hyperthyroidism is associated with increased risk of atrial fibrillation, and an increased risk of bone loss in postmenopausal women who are not receiving oestrogen.[90]

When thyroid-stimulating hormone (TSH) is persistently <0.1 mIU/L, US guidelines recommend treating subclinical hyperthyroidism in the following patient populations:[49]

  • All individuals aged ≥65 years

  • Those with cardiac risk factors, heart disease, or osteoporosis

  • Postmenopausal women who are not on oestrogens or bisphosphonates

  • Individuals with hyperthyroid symptoms

Subclinical hyperthyroidism due to Graves’ disease has an unpredictable course. In one study (median follow-up 32 months), approximately one third of patients remained in a subclinical hyperthyroid state, one third progressed to overt hyperthyroidism, and one third had spontaneous remission (normalised thyroid function); older individuals and those with positive antithyroid peroxidase (TPO) antibodies were at higher risk of progression.​[16]

Symptomatic therapy

Offer a beta-blocker such as propranolol for early symptomatic relief until specific therapy normalises peripheral thyroid hormone levels.

Beta-blockers ameliorate adrenergic symptoms such as tachycardia, tremor, and anxiety.[2] Beta-blockers are not indicated if there is a history of asthma, bradycardia, or heart block.[2]​ They are used early in the course of therapy for symptomatic relief, as well as for preparation for surgery and management of thyroid storm.[2][91]​ Taper dose when specific therapy becomes effective.[2]​ Calcium-channel blockers are an alternative if beta-blockers are not tolerated or are contraindicated.

For management of extrathyroidal manifestations (Graves' orbitopathy and dermopathy), see Complications.

Specific therapy: antithyroid drugs, radioactive iodine, or surgery

Antithyroid drugs, radioactive iodine, and surgery are all effective and relatively safe options for treating Graves' hyperthyroidism.[79] Antithyroid drugs are increasingly the predominant therapy in developed countries.[92][93]​​[94]

Discuss the possible benefits and risks of these treatment options and the likelihood of a good response with patients (and their parents and carers, as appropriate), and take their preferences and values into account in addition to their clinical characteristics.

Guideline recommendations

US guidelines recommend that patients with overt Graves' hyperthyroidism should be treated with any of the three modalities, and that the choice should be individualised.​[49] 

European guidelines recommend treating patients with newly diagnosed Graves’ hyperthyroidism with antithyroid drugs, while radioactive iodine or thyroidectomy may be considered in patients preferring these approaches.[48] 

In the UK, radioactive iodine is first-line therapy for adults with hyperthyroidism secondary to Graves' disease, with the following exceptions: patients for whom antithyroid drugs are likely to achieve remission (e.g., mild and uncomplicated Graves' disease); patients who are unsuitable for radioactive iodine (e.g., concerns about compression; malignancy is suspected; pregnancy or trying to become pregnant, or trying to father a child within the next 4-6 months; or they have active thyroid eye disease).[95]

Comparative efficacy and quality of life

Remission rates of 45.3%, 81.5%, and 96.3% were reported for first-line therapy with antithyroid drugs, 131-I, and surgery, respectively.[96]​ The longitudinal study recruited a cohort of 2430 patients with newly diagnosed Graves' disease who were followed up for 8 ± 0.9 years after diagnosis.[96]

Quality of life was reported to be similar among patients with Graves’ disease who were randomised to antithyroid drugs, radioiodine, or surgery.[97]​ However, a subsequent cohort study of 1186 patients with Graves’ disease reported that patients treated with radioiodine had worse thyroid-related and general quality of life compared with those who received antithyroid drugs or surgery (at 6-10 years follow-up).[98]

Antithyroid drugs

Antithyroid drugs are used in two ways:[99]

  • For a prolonged period of time (typically 12-18 months​, but occasionally longer) to control the hyperthyroidism with the hope that the underlying autoimmune process will go into remission [ Cochrane Clinical Answers logo ]

  • As adjunctive therapy to normalise thyroid function before surgery or radioiodine (when necessary)

These drugs block thyroid hormone synthesis. The group includes carbimazole, thiamazole, and propylthiouracil. Propylthiouracil also inhibits peripheral conversion of T4 to T3. This may be of benefit in the first few weeks of therapy in severe hyperthyroidism ('storm'), but thiamazole is a more potent drug and results in a more rapid return of T3 into the normal range weeks earlier than propylthiouracil.

Unless hyperthyroidism is mild, antithyroid drugs are usually administered initially at higher doses and titrated to lower maintenance doses depending on the biochemical response. Alternatively, high-dose antithyroid drugs can be administered continuously and then levothyroxine given for replacement therapy when the patient becomes euthyroid, which is usually 4-8 weeks after commencing treatment (i.e., the 'block and replace' approach).[100] The 'block and replace' strategy has been used less commonly in the US compared with Europe. The American Thyroid Association states that this approach is not generally recommended because it results in a higher rate of antithyroid drug adverse effects.[49]

Relapse rate after a full course of therapy is reported to vary between 50% and 70% of patients but it may be lower in iodine-deficient areas.[101][102]​​​ If antithyroid drugs must be discontinued because of adverse effects or if relapse occurs after a course of therapy, treatment with radioactive iodine therapy or, in selected cases, surgical thyroidectomy may be considered. Some patients prefer a second course or longer-term treatment with antithyroid drugs; there is some evidence that prolonged treatment may improve remission rates.[45][103]​​[104]​​

Antithyroid drugs: safety

European regulatory agencies have issued drug safety alerts regarding the risk of acute pancreatitis and the increased risk of congenital malformations (when administered during pregnancy) with the use of carbimazole and thiamazole.[105][106][107]​​​​​ Propylthiouracil is associated with hepatic toxicity. Thiamazole should be used initially in all patients except during the first trimester of pregnancy due to its increased association with birth defects.[48][108]​ 

Adverse effects of antithyroid drugs include the following.

  • Skin rash: in 7% to 12% of patients; if mild, may improve with antihistamine treatment.[101][109]

  • Agranulocytosis: a rare adverse effect seen in 0.1% to 0.5% of patients.[110] All patients taking antithyroid drugs should be educated and warned about the early symptoms of agranulocytosis, and advised to stop taking the medication and seek urgent medical attention if these symptoms develop.[111]

  • Antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis: symptoms manifest in approximately 3% of patients treated with antithyroid drugs; the risk is higher with propylthiouracil, younger patients, and increasing duration of treatment.[112] 

Radioactive iodine therapy

Radioactive iodine therapy is used both as first-line treatment for Graves' hyperthyroidism and salvage therapy after failure of antithyroid drugs or surgery.[2]​ 

Treatment with radioactive iodine is associated with a reduced rate of recurrence of hyperthyroidism compared with treatment with antithyroid drugs.[96][113]​​​ The intention of radioactive iodine therapy is to ablate the thyroid. The major sequela is permanent hypothyroidism requiring lifelong thyroxine replacement therapy.[2]​​[91]​​[114]​

Transient hypothyroidism and recurrence of hyperthyroidism can occur in the initial months after therapy.[115][116][117] Most patients will become hypothyroid following 6 months of radioactive iodine therapy if not replaced with levothyroxine. The aim should be to initiate levothyroxine before patients become clinically hypothyroid. Close monitoring is required.[49]​​​[117]​ Hypothyroidism after radioactive iodine should be avoided as it constitutes a risk factor for the development or progression of orbitopathy.[118][119]

Radioactive iodine is contraindicated in pregnancy and during lactation.[49] All women of childbearing age should have a pregnancy test prior to therapy.​

Patients at risk of orbitopathy

Radioactive iodine is considered to be a poor choice for patients with active orbitopathy.[49]​ Studies have found development or aggravation of orbitopathy in 15% to 38% of patients after radioactive iodine therapy.[113][120][121]​​​ This may be prevented by concomitant corticosteroid therapy, especially for patients with pre-existing mild or moderate orbitopathy.[58][121][122]​​ Corticosteroids alongside radioactive iodine therapy can be given in patients with active orbitopathy in the absence of contraindications and when other treatment options for hyperthyroidism are inappropriate or have failed.[58][123]​​ A short course of prednisolone tapered over 2-3 months is reasonable. Risks and benefits should be discussed with the patient.

An alternative approach is to wait until the orbitopathy is inactive before radioiodine treatment (without corticosteroids).

For patients with inactive or no evidence of orbitopathy, observation (without corticosteroids) is reasonable after radioactive iodine therapy without corticosteroids.[124]

Precautions and barriers to radioactive iodine

Radioactive iodine may present logistical barriers to its use due to the need for radiation precautions (e.g., for parents with young children, or older patients with incontinence [who may present unacceptable risk to their carer]).[125]

Pre-treatment with an antithyroid drug may be considered for patients at increased risk of complications (e.g., older adults, very symptomatic patients, and those with comorbidities).[49]​ Taken until the patient is euthyroid (usually several weeks), antithyroid drugs should be stopped before radioactive iodine therapy (generally 3 days before) and then restarted 3-5 days after completion of radioactive iodine therapy. Antithyroid drugs are then tapered and stopped as the patient becomes euthyroid or hypothyroid after radioactive iodine therapy (usually within 1-3 months).[49]

Surgery

Surgery may be preferred in the following scenarios:[49]

  • Women planning a pregnancy in <6 months provided thyroid hormone levels are normal

  • Symptomatic compression or large goitres

  • Relatively low uptake of radioactive iodine

  • Cases when thyroid malignancy is documented or suspected

  • Large thyroid nodules

  • Co-existing hyperparathyroidism requiring surgery

  • Patients with moderate-to-severe active Graves' orbitopathy

Before surgery, patients are treated with antithyroid drugs until euthyroidism is achieved. Some clinics treat patients 7-10 days prior to surgery with pharmacological doses of iodine (e.g., Lugol solution or SSKI) to reduce vascularity of the thyroid gland, leading to less intraoperative blood loss.[126] Iodine is contraindicated in pregnancy at all times as it may inhibit fetal thyroid function to an extent that goitre and even congenital hypothyroidism may ensue.

Surgery may be open or employ a minimally invasive approach. Total or near-total thyroidectomy is preferred over bilateral subtotal thyroidectomy as it prevents recurrent hyperthyroidism; if the patient is euthyroid at the time of surgery, levothyroxine is started immediately postoperatively.[127][128] [ Cochrane Clinical Answers logo ] [Evidence B]

Complications of surgery

The incidence of hypoparathyroidism and vocal cord paralysis (recurrent laryngeal nerve damage) following surgery by experienced surgeons is approximately 2% and 1%, respectively.[129] Whether intraoperative monitoring of the recurrent laryngeal nerve reduces complications is controversial.[130][131]​

Other surgical risks include bleeding, infection, and keloid formation. Endoscopic minimally invasive surgery appears to be associated with reduced rates of blood loss and better cosmetic results compared with open surgery, but with longer operation times.[132]​ Rates of transient recurrent laryngeal nerve palsy, transient hypocalcaemia, postoperative hypothyroidism, and recurrent hyperthyroidism were equivalent between the minimally invasive and open surgery groups.[132] Several factors inform suitability for minimally invasive surgery, including total thyroid volume not exceeding 25 mL as measured by ultrasound.[133] 

Treatment in pregnancy

Antithyroid drugs are used to treat pregnant women; radioactive iodine is contraindicated in pregnancy.

Antithyroid drugs can cross the placenta and affect fetal thyroid function, so the lowest possible dose should be used.[105]​ The goal of treatment is a serum free T4 level at, or moderately above, the normal range for pregnancy.[76] Therefore, many women with mild hyperthyroidism during pregnancy are closely monitored and not treated. However, data from a population-based prospective cohort study indicated a negative impact of mild maternal thyrotoxicosis on the IQ of the offspring.[134]

Surgery during pregnancy is rarely necessary, as low-dose antithyroid drug treatment usually suffices. If antithyroid drugs are discontinued because of adverse effects during pregnancy, second-trimester thyroidectomy is the only other option for symptomatic patients.[108]

Mitigating risk of congenital malformation

Women who are already on treatment with antithyroid drugs for managing Graves’ disease and who are contemplating pregnancy should be switched to propylthiouracil (if on carbimazole therapy). When pregnancy is confirmed and if the disease appears to be in remission (low or negative TSH receptor antibodies) antithyroid drugs can be withdrawn and thyroid functions repeated.[76]

Propylthiouracil is preferred in the first trimester of pregnancy. While all antithyroid drugs have been associated with birth defects, those associated with thiamazole and carbimazole are more common and more severe than those associated with propylthiouracil.[135][136][137]​​ One systematic review and meta-analysis of observational studies reported the following absolute excess risks associated with antithyroid drug exposure (compared with an unexposed general population) for birth defects (any/major): propylthiouracil (10.2/1.3 per 1000 live births); thiamazole/carbimazole (17.8/2.3); untreated hyperthyroidism (9.6/1.2).[137]

US guidelines on the management of thyroid disease in pregnancy state that consideration can be given to discontinuing propylthiouracil after the first trimester and switching to thiamazole in order to decrease the risk of liver failure in the mother. However, due to insufficient evidence, they make no recommendation.[76]​ Treatment can continue for 12-18 months. Relapse rate after a full course of therapy is reported to vary between 50% and 70% of patients.[101]​ It is possible to discontinue treatment with antithyroid drugs in 20% to 30% of women in the last trimester of pregnancy.[76]

Antithyroid drugs at low to moderate doses are thought to be safe for infants of lactating women.[76]

Antithyroid drugs: safety in pregnancy

European regulatory agencies have issued drug safety alerts regarding the risk of acute pancreatitis and the increased risk of congenital malformations (when administered during pregnancy) with the use of carbimazole and thiamazole.[105][106][107]​ Propylthiouracil is associated with hepatic toxicity. Thiamazole should be used initially in all patients except during the first trimester of pregnancy due to its increased association with birth defects.[48][108]

Adverse effects of antithyroid drugs include the following.

  • Skin rash: develops in 7% to 12% of patients; if mild, may improve with antihistamine treatment.[101][109]

  • Agranulocytosis: a rare adverse effect seen in 0.1% to 0.5% of patients.[110]​ All patients taking antithyroid drugs should be educated and warned about the early symptoms of agranulocytosis, and advised to stop taking the medicine​ and seek urgent medical attention if these symptoms develop.[111]

  • ANCA-positive small vessel vasculitis: symptoms manifest in approximately 3% of patients treated with antithyroid drugs; the risk is higher with propylthiouracil, younger patients, and increasing duration of treatment.[112]

Treatment in children

Antithyroid drugs, radioactive iodine, and surgery are all effective and relatively safe options for treating Graves’ hyperthyroidism in children.[48][138]

Consider antithyroid drugs for initial therapy

In children, antithyroid drug treatment is considered first choice, but results in a relapse rate of about 70% after 1-2 years.[49][139][140]​​ However, prolonged treatment (8-10 years) may be associated with up to a 50% remission rate.[141] In these cases, low-dose drug treatment until maturity is appropriate, then surgery (only by experienced paediatric surgeons) or radioiodine should be considered.[142]

Propylthiouracil has an unacceptable risk of life-threatening hepatic injury in children, and should only be used rarely for brief periods (e.g., while waiting for thyroidectomy).[108]

Symptomatic therapy

Offer a beta-blocker such as propranolol for early symptomatic relief until specific therapy normalises peripheral thyroid hormone levels.

Beta-blockers ameliorate adrenergic symptoms such as tachycardia, tremor, and anxiety.[2]​ Beta-blockers are not indicated if there is a history of asthma, bradycardia, or heart block.[2]​ They are used early in the course of therapy for symptomatic relief, as well as for preparation for surgery and management of thyroid storm.[2][91]​ Taper dose when specific therapy becomes effective.[2]​ Calcium-channel blockers are an alternative if beta-blockers are not tolerated or are contraindicated.

Indications for surgery

Surgery is preferred for younger children (e.g., <5 years) and those with Graves’ orbitopathy or a thyroid nodule.[49][138][143]

Surgery is, however, usually a second-line option for children, and can be considered:

  • if a child experiences severe adverse effects with antithyroid therapy;

  • when prolonged therapy has not resulted in remission; or

  • when relapse occurs after a course of antithyroid treatment.

If surgery is considered appropriate, patients are prepared with antithyroid drugs until euthyroidism is achieved. Some clinics treat patients 7-10 days prior to surgery with pharmacological doses of iodine (e.g., Lugol solution or SSKI) to reduce vascularity of the thyroid gland. Beta-blockers are used for symptomatic therapy; calcium-channel blockers are an alternative if beta-blockers are not tolerated or are contraindicated.[2][143]

Surgical complications are more common in children than in adults.[143][144]​​​ Minimally invasive thyroid surgery may be considered in some patients.[133][145]​ Total or near-total thyroidectomy is preferred over bilateral subtotal thyroidectomy as it prevents recurrent hyperthyroidism; levothyroxine therapy is started immediately postoperatively if the patient is euthyroid at the time of surgery.[128][146][147]

Radioactive iodine may be considered in specific children

Radioactive iodine may be an alternative option for children aged over 10 years. It should only be considered for those aged 5-10 years if surgery is not an option. Radioactive iodine should be avoided in children aged under 5 years.

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