Diffuse Toxic Goiter (Graves Disease)

In diffuse toxic goiter, the thyroid gland is usually enlarged to a variable degree and is vascular and diffusely affected. This results in a smooth, rubbery-firm consistency, and often a bruit is heard on auscultation. Microscopically, the thyroid follicular cells are hypertrophic and hyperplastic, and they contain little colloid (stored hormone) and show evidence of hypersecretion. Lymphocytes and plasma cells infiltrate into the thyroid gland and may aggregate into lymphoid follicles.

This condition is an autoimmune disorder whereby the thyroid gland is overstimulated by antibodies directed to the thyroid-stimulating hormone (TSH) receptor on the thyroid follicular cells. This antibody stimulates iodine uptake, thyroid hormonogenesis and release, and thyroid gland growth.[3] Although mainly produced within the thyroid gland, these antibodies reach the circulation and can be measured by various assays in most, but not all, cases.

The association is high with another autoimmune thyroid disease, Hashimoto thyroiditis, and to a lesser degree with other autoimmune diseases in other endocrine glands and other systems in the same person. A strong familial association exists with the same diffuse toxic goiter or the associated disorders, especially Hashimoto thyroiditis. The presence of Hashimoto thyroiditis (which has more of a destructive effect on the thyroid gland) or the presence of another antibody (TSH-receptor blocking antibody) results in a variable natural history of the course of diffuse toxic goiter.

It is believed that 75-80% of the heritability of Graves disease is caused by likely associated genes, variants, and polymorphisms.[4] Environmental and epigenetic factors may play a role in the pathogenesis of this disease (eg, initiation, progression, development), but the interaction among genetic, epigenetic, and immunologic factors remains unclear.[4]

Diffuse toxic goiter and its hyperthyroidism are caused by thyroid-stimulating hormone (TSH)-receptor stimulating antibodies. Although the exact cause is not understood, it has been suggested that there is a genetic lack of suppressor T cells that results in the unregulated production of the antibody, resulting in the autoimmune disease. The antibody may pass the placenta and result in fetal and neonatal hyperthyroidism.

As with most such disorders, usually a combination of genetic and environmental factors is present. The genes involved in Graves’ disease are immune-regulatory genes (HLA region, CD40, CTLA4, PTPN22, and FCRL3) and thyroid autoantigens such as the thyroglobulin and TSH-receptor genes.[2, 5]  Non-genetic risk factors include the following[6] :

• Female sex 
• Pregnancy
• Mental stress
• Smoking and alcohol
• Infectious diseases
• Iodine administration
• Drugs such as lithium and iodine-containing agents, as well as agents, including amiodarone, interferons and interleukins, and antiretroviral agents

Given that the prevalence of Graves disease is 10 times greater in women compared to men,[7]  sex hormones and chromosomal factors, such as the skewed inactivation of the X chromosome, are suspected to be triggers. Other factors are also suspected, such as infection (especially with Yersinia enterocolitica, due to a mechanism of molecular mimicry with the TSH receptor), vitamin D and selenium deficiency, thyroid damage, and immunomodulating drugs. 

Associated ophthalmopathy occurs in approximately 20% of individuals with Graves disease, and it is not well understood. It is thought to be a related but separate autoimmune disorder directed toward the extraocular muscles. The condition may run a course similar to or different from the hyperthyroidism. The presence and degree of clinical ophthalmopathy correlates with the degree of elevation of the anti-TSH receptor antibodies.[6]

Dermopathy (pretibial myxedema) may be brought on or aggravated by local trauma.

United States data

Diffuse toxic goiter is the most common cause of spontaneous hyperthyroidism. A Minnesota study found 0.3 new cases per 1000 per year.

In late childhood, the incidence rate is 3 per 100,000 in girls and 0.5 per 100,000 in boys. Prevalence studies show a rate of 2.7% in women and 0.23% in men.

A marked increase in familial incidence is noted.

International data

Prewar Copenhagen found 0.2 new cases per 1000 per year.

British studies found 0.08-0.2 new cases per 1000 per year.

Race-, sex-, and age-related demographics

No racial predilection exists.

Diffuse toxic goiter is 7-10 times more common in women than in men. It is often associated with or following pregnancy.

Diffuse toxic goiter can occur in persons of all ages, but it is rare in children younger than 10 years and is unusual in elderly persons. The peak incidence is in third and fourth decades of life.

There is an increased incidence in postpartum women, when the first presentation of the disease often occurs.

The natural history of diffuse toxic goiter is usually a benign course and may even spontaneously remit. The intensity of the symptoms and effect on quality of life are variable from person to person and are affected by age and sex.

Mortality is rare, but when it occurs, it is due to cardiovascular problems such as heart failure, arrhythmias, or myocardial infarction.[8, 9] Thyroid storm is rare but may be fatal from dehydration, hyperthermia, and organ failure.

Therapy may be needed for myocardial ischemia, congestive failure, or atrial arrhythmias, which may require anticoagulation. Debility and infection may occur.

Morbidity may result from increased bone turnover and osteoporosis, especially in postmenopausal women, or from atrial fibrillation and its sequelae, such as thromboembolism, especially in older men. Personality changes and psychopathology, muscular weakness, and systemic symptoms all lead to changes in quality of life. Associated oculopathy may be symptomatic, especially with double vision. Rarely, it may progress to affect the integrity of the cornea, and it may even endanger vision.

Associated dermopathy is uncommon and is usually minimally symptomatic, but it may be symptomatic to become debilitating.

Associated hypokalemic periodic paralysis, most commonly seen in Asian males, may be sudden, dramatic, and concerning but usually runs a benign course of recovery after a few hours of skeletal muscle paralysis.

A higher risk of associated immunologic diseases exists, such as adrenal insufficiency; each disease has its own associated morbidity and mortality, especially if it remains undiagnosed.

Generally, when diffuse toxic goiter is suspected, a constellation of information, including the extent and duration of symptoms, past medical history, and social and family history, in addition to the information derived from physical examination, help to guide the clinician to the appropriate diagnosis. Graves disease is an autoimmune disease, and patients often have a family history or past medical history of autoimmune disease (eg, rheumatoid arthritis, vitiligo, pernicious anemia).

Patients with Graves disease often have more marked symptoms than patients with thyrotoxicosis from other causes, because thyroid hormone levels usually are the highest with this form of hyperthyroidism. The diagnosis of Graves disease should also be considered if any evidence of thyroid eye disease exists, including periorbital edema, diplopia, or proptosis.

Many symptoms are adrenergic in origin and may be misdiagnosed as an anxiety disorder. Common symptoms of thyrotoxicosis include the following:

• Nervousness
• Anxiety
• Increased perspiration
• Heat intolerance
• Hyperactivity
• Palpitations

Graves disease is characterized by the stigmata of diffuse toxic goiter, oculopathy, and pretibial myxedema/acropachy. General physical examination findings may include:

• Tachycardia or atrial arrhythmia
• Systolic hypertension with wide pulse pressure
• Warm, moist, smooth skin
• Lid lag
• Stare
• Hand tremor
• Muscle weakness
• Weight loss despite increased appetite (although a few patients may gain weight, if excessive intake outstrips weight loss)
• Reduction in menstrual flow or oligomenorrhea

Thyroid examination

Thyroid size, tenderness, symmetry, and nodularity should also be assessed. Diffuse toxic goiter findings include a mildly enlarged thyroid gland (but may be normal in size, many times normal in size, or difficult to palpate) with a smooth, rubbery firm texture. It is nontender or mildly tender. Sometimes, a thyroid bruit can be heard by using the bell of the stethoscope.

Toxic multinodular goiters generally occur when the thyroid gland is enlarged to at least double to triple the normal size. The gland is often soft, but individual nodules occasionally can be palpated. 

If the thyroid is enlarged and painful, subacute painful or granulomatous thyroiditis is the likely diagnosis. However, degeneration or hemorrhage into a nodule and suppurative thyroiditis should also be considered.

Ophthalmologic and dermatologic examination

Thyroid ophthalmopathy is present in 20-25% of cases and may be manifested only by periorbital edema, but it also can include conjunctival edema (chemosis), injection, poor lid closure, extraocular muscle dysfunction (diplopia), and proptosis. Evidence of thyroid eye disease and high thyroid hormone levels confirms the diagnosis of autoimmune Grave disease.

Thyroid dermopathy occurs rarely. Pretibial myxedema lesions are bilateral, firm, nonpitting, asymmetrical plaques or nodules. Hair follicles are sometimes prominent, giving a peau d'orange texture. Areas of nonpitting edema may develop. Thyroid acropachy may be present (which mimics the appearance of clubbing). Most patients who develop pretibial myxedema and acropachy have associated Graves ophthalmopathy. The onset of dermopathy typically follows the onset of ophthalmopathy by 6-12 months.

Acording to the American Thyroid Association guidelines for diagnosis and management of hyperthyroidism, serum thyroid-stimulating hormone (TSH) should be the initial biochemical evaluation, because it has the highest sensitivity and specificity in the diagnosis of thyroid disorders.[1]  If the diagnosis is not apparent from the clinical presentation and serum TSH measurement, further diagnostic tests should be selected based on available expertise and resources and can include the following:

• Measurement of TSH-receptor antibodies  (TRAb)
• Determination of the radioactive iodine uptake (RAIU)
• Measurement of thyroidal blood flow on ultrasonography
• Thyroid scan (technetium-99m or iodine-123) 

The presence of ophthalmopathy indicates the diagnosis for Graves disease, and no further diagnostic testing is needed regarding the cause of the hyperthyroidism. If confirmation of oculopathy is needed, then orbital computed tomography (CT) scanning or magnetic resonance imaging (MRI) may be performed. 

Diffuse toxic goiter typically demonstrates a suppressed serum TSH level, elevated serum free thyroxine level (or T3 if needed), elevated titers of TRab, or elevated radioiodine uptake.

TSH and thyroid hormone levels

Serum thyroid-stimulating hormone (TSH) (sensitive or third-generation assay) with levels suppressed below normal indicates the need for more tests. Normal serum TSH levels rule out Graves disease.

For serum free thyroxine (T4), if levels are elevated, then hyperthyroidism is diagnosed. Levels will be in the normal range in about 5% of cases. If free thyroxine is normal, then obtain total or free serum triiodothyronine (T3) levels. If the levels are elevated, then hyperthyroidism is diagnosed. If the levels are normal, then subclinical hyperthyroidism is present.

Measurement of serum anti-TSH receptor antibodies can be obtained. These antibodies are present in more than 90% of cases of diffuse toxic goiter, depending on the assay. Concomitant presence of Hashimoto thyroiditis may be detected by serum antithyroid antibodies (anti-TPO or thyroperoxidase).

Drugs that may alter T4 laboratory results include anabolic steroids, androgens, estrogens, heparin, iodine, phenytoin, rifampin, salicylates, and thyroxine/triiodothyronine.

Radioactive iodine uptake (RAIU) test

Thyroid radioactive iodine uptake test results are as follows[2] : 

• Diffuse toxic goiter (Graves disease): Diffuse high radioiodine uptake. 
• Toxic multinodular goiter: Normal or high radioiodine uptake with an asymmetrical pattern 
• Toxic adenoma: Normal or high radioiodine uptake with a localized and focal pattern 
• Thyroiditis: Low radioiodine uptake
• Thyrotoxicosis from extrathyroidal sources of thyroid hormone: Very low uptake 

NOTE: This test is contraindicated in women who are pregnant or breastfeeding.

Ultrasonography

Thyroid ultrasonography and thyroid RAIU have similar sensitivity for the diagnosis of Graves disease. Advantages of ultrasonography are the absence of exposure to ionizing radiation, and a higher accuracy in the detection of thyroid nodules and lower cost than with RAIU.[2]  If Doppler ultrasonography is used to assess vascularity, it accurately distinguishes diffuse toxic goiter (increased blood flow, diffusely enlarged hypoechogenic) from thyroiditis (decreased blood flow), the most common clinical problem in the differential diagnosis of hyperthyroidism.[10, 11]

Testing for comorbidities

Electrocardiography (ECG) should be performed if arrhythmia is suspected; liver function tests may be indicated. If clinical suspicion exists, screen for adrenal insufficiency, type 1 diabetes, gonadal failure, and/or other autoimmune disease (eg, pernicious anemia, rheumatoid arthritis, immune thrombocytopenic purpura). Concomitant Hashimoto thyroiditis may have an effect on spontaneous resolution or progression to a hypothyroid state.

Although the natural history of diffuse toxic goiter is to possibly spontaneously remit (and perhaps later relapse), or even progress into hypothyroidism, observation without intervention, even in minimally symptomatic patients, is not recommended. The risk of bone loss and atrial fibrillation occur, especially in older women and men, even in subclinical cases.

The goals of therapy are to resolve hyperthyroid symptoms and to restore the euthyroid state. The long-term quality of life following treatment is the same in patients randomly allocated to each of the three treatment options (antithyroid drugs [ATDs], radioactive iodine ablation, surgery).[12]  Each therapeutic choice has advantages and disadvantages, therefore treatment should be individualized. Patient input into the treatment choice is important and must be discussed and considered. 

Adjunctive symptomatic therapy, such as the use of beta blockers, may help alleviate adrenergic symptoms. Nonsurgical therapy occurs in the outpatient setting. Surgical therapy requires first normalization of the hyperthyroid state by medication.

Regardless of the therapy used, long-term follow-up is needed to monitor thyroid status, especially with a high risk of becoming hypothyroid in the near and distant future or a relapse into hyperthyroidism.

Ophthalmopathy runs its own course, independent of the thyroid course. Although generally benign, ophthalmopathy may become symptomatic years after the thyroid status has been rendered normal. 

Hospitalization is rarely necessary for diffuse toxic goiter. Severe disease with cardiac or other organ compensation, or thyroid storm may require more intense and controlled therapy. Complications, such as agranulocytosis, may need specialized hospital care.

Diet and activity

Diet must include caloric intake to meet the energy expenditure of the hypermetabolism. High iodine-containing substances, such as kelp, should be avoided.

Physical activity is limited by the presence of symptoms, until recovery occurs. Usually, shortness of breath on exertion, fatigue, and palpitations are the limiting symptoms.

Consultations

Oculopathy usually requires ophthalmologic consultation, and dermopathy may require dermatologic consultation.

Radioactive iodine ablation

The most commonly used therapy for Graves disease is radioactive iodine.[1] Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of thyroid-stimulating immunoglobulin (TSI). 

Oral administration of 131-iodine (I-131) is incorporated into the thyroid follicular cells, and the beta emission results in cell destruction and glandular fibrosis. The effect is seen in 1.5 to 4 months. Off medications, the thyroid hormone levels become normal (requiring continued monitoring), fall below normal (requiring thyroid hormone replacement therapy, likely for life), or remain elevated (requiring another administration of radioiodine). In those becoming euthyroid, there is a 5% chance every year of becoming hypothyroid due to ongoing disease in the gland; occasionally, hyperthyroidism may reoccur. The usual I-131 dose is 6-8 mCi. The dose is adjusted based on the size of the thyroid gland, age of the patient, and severity of the clinical picture. Resistance is increased by age older than 40 years, large goiters, prior therapy with propylthiouracil (PTU), and nodularity (not seen with diffuse toxic goiter). Previous reviews confirmed the safety of the use of radioiodine.[13]

Radioiodine therapy is not used in clinically severe hyperthyroidism or thyroid storm until the hyperthyroid state is medically controlled. Because of transplacental transfer and lactation transfer, it is contraindicated in women who are pregnant or breastfeeding. For the theoretical ovarian exposure, conception in treated women is empirically discouraged for 3-6 months.

Radioiodine may be administered to children, if clinically indicated. Long-term safety data in children are not available.

Worsening of the hyperthyroid state may occur after radioiodine therapy due to the release of prestored hormone. Gland tenderness and swelling is uncommon and may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (not aspirin); they rarely require steroid administration.

Radioiodine administration has been associated with worsening or progression of symptomatic ophthalmopathy. Either radioiodine is avoided in very symptomatic individuals, or corticosteroids (prednisone 0.5 mg/kg) are used beginning the day after the radioiodine administration for 1-3 months, or they are administered if any worsening of the ophthalmopathy occurs after radioiodine administration. Cessation of smoking and avoidance of hypothyroidism also help the course of ophthalmopathy.

The return to the euthyroid state, regardless of therapy, is best monitored by serum free thyroxin, or its equivalent, because the pituitary is suppressed and thyroid-stimulating hormone (TSH) secretion may remain low for some time after a normal or hypothyroid state occurs. Relapse from a euthyroid state to hyperthyroidism is first monitored by new suppression of the serum TSH, and often the serum triiodothyronine (T3) then increases above normal before the serum thyroxine (T4) rises above normal.

Antithyroid drugs (ATDs)

The thionamide drugs PTU and methimazole (MMI) inhibit hormonogenesis within the thyroid gland. PTU has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown added clinical significance. Other than in pregnancy and breastfeeding, MMI has advantages over PTU by a longer half-life with once-a-day dosing, and possibly a more rapid return to the euthyroid state. Although rare, agranulocytosis, lupuslike vasculitis, and hepatitis are more commonly associated with PTU than with MMMI. Agranulocytosis occurs in less than 0.1% of cases but is unpredictable; it may occur at any time. Routine monitoring of the white blood cell (WBC) count is not useful. Should any infection occur, such as a sore throat, the WBC count should then be measured. Discontinuation of the drug results in a rise of WBC within a few days.

Hyperthyroidism itself can result in abnormal liver function tests, thus measure a baseline before initiating medication. A rise to three times above normal dictates discontinuation of the drug.

Minor skin itch or rash may be managed by an antihistamine, without discontinuation of the drug. More marked reactions require discontinuation of that drug.

Granulocyte colony-stimulating factor (GCSF) may need to be administered. Skin rash may perhaps be more common with MMI than PTU; the incidence is about 3%, and it usually occurs within the first few weeks of therapy. MMI is the drug of choice.[14]

Boxed warning for PTU

As noted above, PTU is indicated for hyperthyroidism due to Graves disease. The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the agency, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as MMI, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred; among the pediatric patients, 1 death and 6 liver transplants occurred. These reports suggest an increased risk for liver toxicity with PTU compared with MMI. Serious liver injury was identified with MMI in five cases (three resulting in death).

FDA criteria for PTU prescription

PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of MMI, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with MMI during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert)[15] :

• Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of MMI.

• Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

• For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.

• PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI and no other treatment options are available.

• Counsel patients to promptly contact their healthcare provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Monitor the serum thyroid indices monthly until euthyroid, and then the dose of the drug may be decreased for maintenance. Use the lowest dose needed to maintain the euthyroid state for long-term therapy.

Relapse and remission

Normalization of thyroid function with these drugs must occur for some time, at least 6 months and perhaps for 1-2 years, to maximize the remission rate after drug discontinuation. Despite this, the relapse rate is 50-70%, usually within the first few weeks or months, but occasionally after a few years. Remission is weakly predicted by a short duration of symptoms, age younger than 40 years, minimal enlargement of the thyroid gland, and concomitant presence of Hashimoto thyroiditis.

Relapse after discontinuation of the drug requires a decision regarding radioiodine therapy or surgery for more definitive therapy, or a return to the antithyroid drug. Although general practice is not to use these drugs over the long term, there is no reason why this cannot occur, if that is what the patient chooses.

Pregnancy and breastfeeding

Radioactive iodine is contraindicated during pregnancy and while breastfeeding.[16] Pregnancy often has an effect on improving the immunologic disease state during the pregnancy and then often relapses following delivery. PTU is the treatment of choice because it has less placental transfer than MMI. Rare congenital anomalies reported with MMI (eg, aplasia cutis) are even less associated with PTU. Overall, the congenital abnormality rate with these drugs is similar to background normal rate. MMI may be used if a problem exists with PTU.

The goal is to keep the free thyroxine level in the upper part of normal to minimize fetal drug exposure. Monthly monitoring of serum free thyroxine usually allows the dose of PTU to be decreased and often discontinued in the third trimester. Both PTU and MMI may be used in breastfeeding mothers. A small amount of drug does enter the milk, but neonatal thyroid levels generally remain normal. PTU and MMI are not contraindicated in pregnancy or lactation.

See also the 2017 American Thyroid Association guidelines pertaining to the diagnosis and management of thyroid disease in women during pregnancy and the postpartum period, as well as prior to conception.[16] Selected recommendations regarding thyrotoxicosis in pregnancy are outlined in this article's Guidelines section Thyrotoxicosis in Pregnancy.

Subtotal thyroidectomy may be considered for diffuse toxic goiter if it is the choice of the patient, during the second trimester of pregnancy, after failure (resistance or intolerance) of drug therapy, or in the setting of poor compliance to drug therapy. The procedure risks are low with experienced surgeons but include anesthetic risks, hemorrhage, hypoparathyroidism, and vocal cord paralysis.

Patients should be made euthyroid prior to surgery to minimize anesthetic risks, cardiovascular/hemodynamic complications, and the risk of thyroid storm. If normalizing with antithyroid drugs is not possible, then beta blockers and potassium iodide 4 drops each day for 10 days will decrease the vascularity of the thyroid gland.

Cessation of smoking has a beneficial effect on the course of ophthalmopathy.

The strong familial nature of diffuse toxic goiter dictates that first-degree relatives, especially siblings and children, be aware of the increased risk of developing this or associated disorders. Routine testing is not recommended, but consideration for this risk is needed with new symptom development.

Associated autoimmune disease in other glands is uncommon but is of increased incidence and may clinically occur at presentation or in the near or distant future. New symptoms dictate consideration for these conditions.

2016 American Thyroid Association Guidelines

In 2016, the American Thyroid Association updated the 2011 hyperthyroidism/thyrotoxicosis guidelines it had codeveloped with the American Association of Clinical Endocrinologists. The following is a sampling of the 124 recommendations included in the guideline[1] :

• Beta-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease
• Patients with overt Graves hyperthyroidism should be treated with any of the following modalities: radioactive iodine therapy, antithyroid drugs, or thyroidectomy
• If methimazole is chosen as the primary therapy for Graves disease, the medication should be continued for approximately 12-18 months and then discontinued if the serum thyrotropin and thyrotropin receptor antibody levels are normal at that time
• If surgery is chosen as the primary therapy for Graves disease, near-total or total thyroidectomy is the procedure of choice
• If surgery is chosen as treatment for toxic multinodular goiter, near-total or total thyroidectomy should be performed
• If surgery is chosen as the treatment for toxic adenoma, a thyroid sonogram should be done to evaluate the entire thyroid gland; an ipsilateral thyroid lobectomy (or isthmusectomy, if the adenoma is in the thyroid isthmus), should be performed for isolated toxic adenomas
• Children with Graves disease should be treated with methimazole, radioactive iodine therapy, or thyroidectomy; radioactive iodine therapy should be avoided in very young children (< 5 years); radioactive iodine therapy in children is acceptable if the activity is over 150 μCi/g (5.55 MBq/g) of thyroid tissue and for children between ages 5 and 10 years if the calculated radioactive iodine administered activity is under 10 mCi (< 473 MBq); thyroidectomy should be chosen when definitive therapy is required, the child is too young for radioactive iodine, and surgery can be performed by a high-volume thyroid surgeon
• If methimazole is chosen as the first-line treatment for Graves disease in children, it may be tapered in those children requiring low doses after 1-2 years to determine if a spontaneous remission has occurred, or it may be continued until the child and caretakers are ready to consider definitive therapy, if needed
• If surgery is chosen as therapy for Graves disease in children, total or near-total thyroidectomy should be performed
• In patients with Graves hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, radioactive iodine therapy, antithyroid drugs, and thyroidectomy should be considered equally acceptable therapeutic options

2016 American Thyroid Association Recommendations

The 2016 American Thyroid Association guidelines recommendations on Graves orbitopathy include the following[1] :

• Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with Graves orbitopathy or risk factors for the development of orbitopathy
• In Graves disease patients with mild Graves orbitopathy who are treated with radioactive iodine, steroid coverage is recommended if there are concomitant risk factors for Graves orbitopathy deterioration

2016 European Thyroid Association Recommendations

In 2016, the European Thyroid Association/European Group on Graves' Orbitopathy (EUGOGO) released their updated guidelines for the management of Graves orbitopathy (GO) which included the following key recommendations[6] :

• Activity and severity of GO should be categorized as active or inactive and as mild, moderate to severe or sight threatening
• Euthyroidism should be restored and maintained in all patients 
• All patients should be treated with nonpreserved artificial tears with osmoprotective properties unless corneal exposure requires the higher protection that gels or ointment can offer
• In mild GO, a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms.
• High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO
• Rehabilitative surgery (orbital decompression surgery, squint surgery or eyelid surgery) should be offered when the disease is associated with a significant impact on visual function or quality of life after the disease has been inactive for at least 6 months. 
• Severe corneal exposure should be treated medically or by means of progressively more invasive surgeries as soon as possible to avoid progression to corneal breakdown. The latter should be immediately addressed surgically.

2017 American Thyroid Association Guidelines

In 2017, the American Thyroid Association (ATA) released guidelines pertaining to the diagnosis and management of thyroid disease in women during pregnancy and the postpartum period, as well as prior to conception. Recommendations regarding thyrotoxicosis in pregnancy included the following[16] :

• When a suppressed serum thyroid stimulating hormone (TSH) is detected in the first trimester (TSH less than the reference range), a medical history, physical examination, and measurement of maternal serum free thyroxine (FT4) or total thyroxine (T4) concentrations should be performed; measurement of thyroid-stimulating antibody (TSab) and maternal total triiodothyronine (T3) may prove helpful in clarifying the etiology of thyrotoxicosis
• Radionuclide scintigraphy or radioiodine uptake determination should not be performed in pregnancy
• The appropriate management of abnormal maternal thyroid tests attributable to gestational transient thyrotoxicosis and/or hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed; antithyroid drugs are not recommended, though beta blockers may be considered
• In all women of childbearing age who are thyrotoxic, the possibility of future pregnancy should be discussed; women with Graves disease seeking future pregnancy should be counseled regarding the complexity of disease management during future gestation, including the association of birth defects with antithyroid drug use; preconception counseling should review the risks and benefits of all treatment options and the patient’s desired timeline to conception
• Thyrotoxic women should be rendered stably euthyroid before attempting pregnancy; several treatment options exist, each of which is associated with risks and benefits; these include  ¹³¹I ablation, surgical thyroidectomy, and antithyroid drug therapy
• Women taking methimazole or propylthiouracil should be instructed to confirm potential pregnancy as soon as possible; if the pregnancy test is positive, pregnant women should contact their caregiver immediately
• In pregnant women with a high risk of developing thyrotoxicosis if antithyroid drugs were to be discontinued, continued antithyroid medication may be necessary; factors predicting high clinical risk include being currently hyperthyroid or requirement of >5-10 mg/d methimazole or >100-200 mg/d propylthiouracil to maintain a euthyroid state; in such cases, propylthiouracil is recommended for the treatment of maternal hyperthyroidism through 16 weeks of pregnancy, and when shifting from methimazole to propylthiouracil, a dose ratio of approximately 1:20 should be used (eg, methimazole 5 mg/d = propylthiouracil 50 mg twice daily)
• In women being treated with antithyroid drugs in pregnancy, free thyroxine (FT4)/total thyroxine (T4) and TSH should be monitored approximately every 4 weeks; antithyroid medication during pregnancy should be administered at the lowest effective dose of methimazole or propylthiouracil, targeting maternal serum free thyroxine (FT4)/total thyroxine (T4) at the upper limit of or moderately above the reference range.
• A combination regimen of levothyroxine (LT4) and an antithyroid drug should not be used in pregnancy, except in the rare situation of isolated fetal hyperthyroidism
• Thyroidectomy in pregnancy may be indicated for unique scenarios; if required, the optimal time for thyroidectomy is in the second trimester of pregnancy; if maternal thyroid-stimulating antibody (TSab) concentration is high (>3 times the upper reference for the assay), the fetus should be carefully monitored for development of fetal hyperthyroidism throughout pregnancy, even if the mother is euthyroid postthyroidectomy
• The ATA concurs with the American College of Obstetricians and Gynecologists’ (ACOG) Committee on Obstetric Practice consensus guidelines (written in 2011 and revised in 2015), which state the following: ‘‘1) A pregnant woman should never be denied indicated surgery, regardless of trimester. 2) Elective surgery should be postponed until after delivery. 3) If possible, nonurgent surgery should be performed in the second trimester when preterm contractions and spontaneous abortion are least likely.’’ In the setting of a patient with Graves disease undergoing urgent, nonthyroid surgery, if the patient is well controlled on antithyroid medication, no other preparation is needed; beta blockade should also be utilized if needed
• If the patient has a past history of Graves disease treated with ablation (radioiodine or surgery), a maternal serum determination of thyroid-stimulating antibodies (TSabs) is recommended at initial thyroid function testing during early pregnancy
• If maternal thyroid-stimulating antibody (TSab) concentration is elevated in early pregnancy, repeat testing should occur at weeks 18-22
• If the patient requires treatment with antithyroid drugs for Graves disease through midpregnancy, a repeat determination of thyroid-stimulating antibody (TSab) concentration is again recommended at weeks 18-22
• If elevated thyroid-stimulating antibody (TSab) is detected at weeks 18-22 or the mother is taking antithyroid medication in the third trimester, a TSab measurement should again be performed in late pregnancy (weeks 30-34) to evaluate the need for neonatal and postnatal monitoring
• Fetal surveillance should be performed in women who have uncontrolled hyperthyroidism in the second half of pregnancy and in women with high thyroid-stimulating antibody (TSab) levels detected at any time during pregnancy (>3 times the upper limit of normal); a consultation with an experienced obstetrician or maternal–fetal medicine specialist is recommended; monitoring may include ultrasonography to assess heart rate, growth, amniotic fluid volume, and the presence of fetal goiter
• If antithyroid drug therapy is given for hyperthyroidism caused by autonomous nodules, the fetus should be carefully monitored for goiter and signs of hypothyroidism during the second half of pregnancy; a low dose of antithyroid medication should be administered with the goal of maternal free thyroxine (FT4) or total thyroxine (T4) concentration at the upper limit of or moderately above the reference range

No standard treatment protocols exist for diffuse toxic goiter; individualization of treatment based on clinical experience is protocol. Patient preference after informed consent affects all therapeutic decisions.

A 2020 literature review that evaluated the strategy of long-term antithyroid drugs versus radioactive iodine or surgery for the management of Graves disease found that long-term antithyroid medications are feasible alternatives to ablative treatments, resulting in euthyroidism with minimal complications and low financial cost, as well as offer advantages regarding quality of life and other outcomes.[17]  Individualized decision making remains key.

Beta blockers

Beta blockers should be considered for patients with resting heart rates over 90 bpm or coexistent cardiovascular disease.[1] In symptomatic patients, these drugs decrease the heart rate, systolic blood pressure, muscle weakness, and tremor, as well as improve emotional irritability. Beta blockers may be used during lactation.

Beta blockers are used if symptomatic tremor or palpitations require their use. They may be used even as clinical investigation is ongoing because they have no effect on thyroid gland function, but they block the beta-adrenergic peripheral manifestations of the hyperthyroid state. Propranolol has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown clinical significance with the usual doses. The dose may be decreased and then stopped when the euthyroid state occurs. Beta blockers should not be used in the presence of bronchospasm, even the beta1-selective agents. Calcium channel blockers may be substituted.

Iodine

In severe cases of diffuse toxic goiter, such as thyroid storm, iodine in the form of potassium iodide (SSKI) 10 drops twice a day or iopanoic acid 1-3 g per day may be given. These agents inhibit the release of thyroxine from the gland and inhibit peripheral conversion of T4 to T3. They help render a euthyroid state more rapidly in response to antithyroid drugs, or for preparation for surgery, but will eliminate the use of radioiodine for many months due to expansion of the iodine pool and thereby reducing the delivery of radioiodine to the thyroid gland.

Class Summary

These agents may either inhibit hormonogenesis within the thyroid gland or inhibit release of thyroid hormone from the gland.

Propylthiouracil (PTU)

Actively transported into the thyroid gland and inhibits incorporation of iodine to thyroid hormones, and inhibits peripheral conversion of T4 to T3. Drug recommended in pregnancy and lactation with dose adjustment to minimum needed. Laboratory monitoring of free T4 to adjust dose therapy. The serum TSH may lag behind the changes in free T4. Long-term experience with this drug.

Methimazole (Tapazole)

Actively transported in thyroid gland and inhibits thyroid synthesis by preventing oxidation of trapped iodine. Ten times more potent than PTU, and once-a-day dose is effective. Euthyroid state is achieved in 4-6 wk, and maintenance treatment continued for 12-24 mo. Relapse may be observed 1-6 mo after stopping therapy, occasionally later.

Less desirable than propylthiouracil in pregnancy and lactation but may be used if propylthiouracil cannot be used.

Potassium iodide (Pima, Thyro-Block)

Inhibits thyroid hormone secretion. Contains 8 mg of iodide per gtt. May be mixed with juice or water for intake.

May decrease thyroid gland secretion and vascularity for a short time, such as 2 wk; may be used in severe cases of hyperthyroidism, such as thyroid storm, or to prepare patient for thyroidectomy

Supersaturated potassium iodide (SSKI)

Contains 50 mg of iodide per drop. May be mixed with juice or water for ingestion. Inhibits thyroid hormone release.

Class Summary

These agents have profound and varied metabolic effects.

Dexamethasone (Decadron)

Steroids block peripheral conversion of T4 to T3. Used as adjunct in management of thyroid storm and symptomatic progressive Graves ophthalmopathy.

Class Summary

These agents are used to destroy thyroid cells.

Radioiodine (I-131)

Agent of choice because it is selectively taken up by the thyroid gland. Causes dysfunction or death of thyroid cells over time. Long-term experience suggests good safety profile.

Class Summary

Relief of adrenergic symptoms, especially cardiac and neurologic. Propranolol blocks peripheral conversion of T4 to T3, but this is of unknown clinical significance.

Propanolol (Inderal)

Nonselective beta-adrenergic receptor blocker. Also blocks peripheral conversion of T4 to T3. Used along with antithyroid drugs, before and after radioiodine treatment. Useful in thyroid crisis/storm, or in cardiac complications such as atrial fibrillation. Oral or intravenous use controls cardiac and psychomotor manifestations within minutes. Continue until euthyroid state is achieved.