Appendix A

Appendix A. Hyperthyroidism Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists: Summary of Recommendations

[A]

Background

[B]

How should clinically or incidentally discovered thyrotoxicosis be evaluated and initially managed?

 

Recommendation 1

A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD; a thyroid scan should be added in the presence of thyroid nodularity. 1/+00

 

Recommendation 2

Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease. 1/++0

 

Recommendation 3

Beta-adrenergic blockade should be considered in all patients with symptomatic thyrotoxicosis. 1/+00

[C]

How should overt hyperthyroidism due to GD be managed?

 

Recommendation 4

Patients with overt Graves’ hyperthyroidism should be treated with any of the following modalities: 131I therapy, antithyroid medication, or thyroidectomy. 1/++0

[D]

If 131I therapy is chosen, as treatment for GD, how should it be accomplished?

 

Recommendation 5

Patients with GD who are at increased risk for complications due to worsening of hyperthyroidism (i.e., those who are extremely symptomatic or have free T4 estimates 2–3 times the upper limit of normal) should be treated with beta-adrenergic blockade prior to radioactive iodine therapy. 1/+00

 

Recommendation 6*

Pretreatment with methimazole prior to radioactive iodine therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism (i.e., those who are extremely symptomatic or have free T4 estimate 2–3 times the upper limit of normal). 2/+00

 

Recommendation 7

Medical therapy of any comorbid conditions should be optimized prior to administering radioactive iodine. 1/+00

 

Recommendation 8

Sufficient radiation should be administered in a single dose (typically 10–15 mCi) to render the patient with GD hypothyroid. 1/++0

 

Recommendation 9

A pregnancy test should be obtained within 48 hours prior to treatment in any female with childbearing potential who is to be treated with radioactive iodine. The treating physician should obtain this test and verify a negative result prior to administering radioactive iodine. 1/+00

 

Recommendation 10

The physician administering the radioactive iodine should provide written advice concerning radiation safety precautions following treatment. If the precautions cannot be followed, alternative therapy should be selected. 1/+00

 

Recommendation 11

Follow-up within the first 1–2 months after radioactive iodine therapy for GD should include an assessment of free T4 and total T3. If the patient remains thyrotoxic, biochemical monitoring should be continued at 4–6 week intervals. 1/+00

 

Recommendation 12

When hyperthyroidism due to GD persists after 6 months following 131I therapy, or if there is minimal response 3 months after therapy, retreatment with 131I is suggested. 2/+00

[E]

If antithyroid drugs are chosen as initial management of GD, how should the therapy be managed?

 

Recommendation 13

Methimazole should be used in virtually every patient who chooses antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery. 1/++0

 

Recommendation 14

Patients should be informed of side effects of antithyroid drugs and the necessity of informing the physician promptly if they should develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. Before starting antithyroid drugs and at each subsequent visit, the patient should be alerted to stop the medication immediately and call their physician when there are symptoms suggestive of agranulocytosis or hepatic injury. 1/+00

 

Recommendation 15

Prior to initiating antithyroid drug therapy for GD, we suggest that patients have a baseline complete blood count, including white count with differential, and a liver profile including bilirubin and transaminases. 2/+00

 

Recommendation 16

A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medication. Routine monitoring of white blood counts is not recommended. 1/+00

 

Recommendation 17

Liver function and hepatocellular integrity should be assessed in patients taking propylthiouracil who experience pruritic rash, jaundice, light colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. 1/+00

 

Recommendation 18

Minor cutaneous reactions may be managed with concurrent antihistamine therapy without stopping the antithyroid drug. Persistent minor side effects of antithyroid medication should be managed by cessation of the medication and changing to radioactive iodine or surgery, or switching to the other antithyroid drug when radioactive iodine or surgery are not options. In the case of a serious allergic reaction, prescribing the alternative drug is not recommended. 1/+00

 

Recommendation 19

If methimazole is chosen as the primary therapy for GD, the medication should be continued for approximately 12–18 months, then tapered or discontinued if the TSH is normal at that time. 1/+++

 

Recommendation 20

Measurement of TRAb levels prior to stopping antithyroid drug therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission. 2/+00

 

Recommendation 21

If a patient with GD becomes hyperthyroid after completing a course of methimazole, consideration should be given to treatment with radioactive iodine or thyroidectomy. Low-dose methimazole treatment for longer than 12–18 months may be considered in patients not in remission who prefer this approach. 2/+00

[F]

If thyroidectomy is chosen for treatment of GD, how should it be accomplished?

 

Recommendation 22

Whenever possible, patients with GD undergoing thyroidectomy should be rendered euthyroid with methimazole. Potassium iodide should be given in the immediate preoperative period. 1/+00

 

Recommendation 23

In exceptional circumstances, when it is not possible to render a patient with GD euthyroid prior to thyroidectomy, the need for thyroidectomy is urgent, or when the patient is allergic to antithyroid medication, the patient should be adequately treated with beta-blockade and potassium iodide in the immediate preoperative period. The surgeon and anesthesiologist should have experience in this situation. 1/+00

 

Recommendation 24

If surgery is chosen as the primary therapy for GD, near-total or total thyroidectomy is the procedure of choice. 1/++0

 

Recommendation 25

If surgery is chosen as the primary therapy for GD, the patient should be referred to a high-volume thyroid surgeon. 1/++0

 

Recommendation 26

Following thyroidectomy for GD, we suggest that serum calcium or intact parathyroid hormone levels be measured, and that oral calcium and calcitriol supplementation be administered based on these results. 2/+00

 

Recommendation 27

Antithyroid drugs should be stopped at the time of thyroidectomy for GD, and beta-adrenergic blockers should be weaned following surgery. 1/+00

 

Recommendation 28

Following thyroidectomy for GD, L-thyroxine should be started at a daily dose appropriate for the patient’s weight (0.8 μg/lb or 1.7 μg/kg), and serum TSH measured 6–8 weeks postoperatively. 1/+00

[G]

How should thyroid nodules be managed in patients with GD?

 

Recommendation 29

If a thyroid nodule is discovered in a patient with GD, the nodule should be evaluated and managed according to recently published guidelines regarding thyroid nodules in euthyroid individuals. 1/++0

[H]

How should thyroid storm be managed?

 

Recommendation 30

A multimodality treatment approach to patients with thyroid storm should be used, including beta-adrenergic blockade, antithyroid drug therapy, inorganic iodide, corticosteroid therapy, aggressive cooling with acetaminophen and cooling blankets, volume resuscitation, respiratory support and monitoring in an intensive care unit. 1/+00

[I]

How should overt hyperthyroidism due to TMNG or TA be treated?

 

Recommendation 31

We suggest that patients with overtly TMNG or TA be treated with either 131I therapy or thyroidectomy. On occasion, long term, low-dose treatment with methimazole may be appropriate. 2/++0

[J]

If 131I therapy is chosen as treatment for TMNG or TA, how should it be accomplished?

 

Recommendation 32

Patients with TMNG or TA who are at increased risk for complications due to worsening of hyperthyroidism, including the elderly and those with cardiovascular disease or severe hyperthyroidism, should be treated with beta-blockade prior to radioactive iodine therapy and until euthyroidism has been achieved. 1/+00

 

Recommendation 33†

Pretreatment with methimazole prior to radioactive iodine therapy for TMNG or TA should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism, including the elderly and those with cardiovascular disease or severe hyperthyroidism. 2/+00

 

Recommendation 34

Nonfunctioning nodules on radionuclide scintigraphy or nodules with suspicious ultrasound characteristics should be managed according to recently published guidelines regarding thyroid nodules in euthyroid individuals. 1/++0

 

Recommendation 35

For radioactive iodine treatment of TMNG, sufficient radiation should be administered in a single dose to alleviate hyperthyroidism. 1/++0

 

Recommendation 36

For radioactive iodine treatment of TA, sufficient radiation to alleviate hyperthyroidism should be administered in a single dose. 1/++0

 

Recommendation 37

Follow-up within the first 1–2 months after radioactive iodine therapy for TMNG or TA should include an assessment of free T4, total T3 and TSH. This should be repeated at 1–2 month intervals until stable results are obtained, then at least annually thereafter according to clinical indication. 1/+00

 

Recommendation 38

If hyperthyroidism persists beyond 6 months following 131I therapy for TMNG or TA, retreatment with radioactive iodine is suggested. 2/+00

[K]

If surgery is chosen for treatment of TMNG or TA, how should it be accomplished?

 

Recommendation 39

If surgery is chosen as treatment for TMNG or TA, patients with overt hyperthyroidism should be rendered euthyroid prior to the procedure with methimazole pretreatment (in the absence of allergy to the medication), with or without beta-adrenergic blockade. Preoperative iodine should not be used in this setting. 1/+00

 

Recommendation 40

If surgery is chosen as treatment for TMNG, near-total or total thyroidectomy should be performed. 1/++0

 

Recommendation 41

Surgery for TMNG should be performed by a high-volume thyroid surgeon. 1/++0

 

Recommendation 42

If surgery is chosen as the treatment for TA, an ipsilateral thyroid lobectomy, or isthmusectomy if the adenoma is in the thyroid isthmus, should be performed. 1/++0

 

Recommendation 43

We suggest that surgery for TA be performed by a high-volume surgeon. 2/++0

 

Recommendation 44

Following thyroidectomy for TMNG, we suggest that serum calcium or intact parathyroid hormone levels be measured, and that oral calcium and calcitriol supplementation be administered based on these results. 2/+00

 

Recommendation 45

Methimazole should be stopped at the time of surgery for TMNG or TA. Beta-adrenergic blockade should be slowly discontinued following surgery. 1/+00

 

Recommendation 46

Following surgery for TMNG, thyroid hormone replacement should be started at a dose appropriate for the patient’s weight (0.8 mcg/lb or 1.7 mcg/kg) and age, with elderly patients needing somewhat less. TSH should be measured every 1–2 months until stable, and then annually. 1/+00

 

Recommendation 47

Following surgery for TA, TSH and estimated free T4 levels should be obtained 4–6 weeks after surgery, and thyroid hormone supplementation started if there is a persistent rise in TSH above the normal range. 1/+00

 

Recommendation 48

Radioactive iodine therapy should be used for retreatment of persistent or recurrent hyperthyroidism following inadequate surgery for TMNG or TA. 1/+00

[L]

Is there a role for antithyroid drug therapy in patients with TMNG or TA?

 

Recommendation 49

We suggest that long-term methimazole treatment of TMNG or TA be avoided, except in some elderly or otherwise ill patients with limited longevity who are able to be monitored regularly, and in patients who prefer this option. 2/+00

[M]

Is there a role for radiofrequency, thermal or alcohol ablation in the management of TA or TMNG?

[N]

How should GD be managed in children and adolescents?

 

Recommendation 50

Children with GD should be treated with methimazole, 131I therapy, or thyroidectomy. 131I therapy should be avoided in very young children (<5 years). 131I therapy in patients between 5 and 10 years of age is acceptable if the calculated 131I administered activity is < 10 mCi. 131I therapy in patients older than 10 years of age is acceptable if the activity is > 150 µCi/g of thyroid tissue. Thyroidectomy should be chosen when definitive therapy is required, the child is too young for 131I, and surgery can be performed by a high-volume thyroid surgeon. 1/++0

[O]

If antithyroid drugs are chosen as initial management of GD in children, how should the therapy be managed?

 

Recommendation 51

Methimazole should be used in virtually every child who is treated with antithyroid drug therapy. 1/++0

 

Recommendation 52

Pediatric patients and their caretakers should be informed of side effects of antithyroid drugs and the necessity of stopping the medication immediately and informing their physician if they develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. 1/+00

 

Recommendation 53

Prior to initiating antithyroid drug therapy, we suggest that pediatric patients have, as a baseline, complete blood cell count, including white blood cell count with differential, and a liver profile including bilirubin, transaminases, and alkaline phosphatase. 2/+00

 

Recommendation 54

Beta adrenergic blockade is recommended for children experiencing symptoms of hyperthyroidism, especially those with heart rates in excess of 100 beats per minute. 1/+00

 

Recommendation 55

Antithyroid medication should be stopped immediately, and white blood counts measured in children who develop fever, arthralgias, mouth sores, pharyngitis, or malaise. 1/+00

 

Recommendation 56

When propylthiouracil is used in children, the medication should be stopped immediately and liver function and hepatocellular integrity assessed in children who experience anorexia, pruritis, rash, jaundice, light-colored stool or dark urine, joint pain, right upper quadrant pain or abdominal bloating, nausea or malaise. 1/+00

 

Recommendation 57

Persistent minor cutaneous reactions to methimazole therapy in children should be managed by concurrent antihistamine treatment or cessation of the medication and changing to therapy with radioactive iodine or surgery. In the case of a serious allergic reaction to an antithyroid medication, prescribing the other antithyroid drug is not recommended. 1/+00

 

Recommendation 58

If methimazole is chosen as the first-line treatment for GD in children, it should be administered for 1–2 years and then discontinued, or the dose reduced, to assess whether the patient is in remission. 1/++0

 

Recommendation 59

Pediatric patients with GD who are not in remission following 1–2 years of methimazole therapy should be considered for treatment with radioactive iodine or thyroidectomy. 1/+00

[P]

If radioactive iodine is chosen as treatment for GD in children, how should it be accomplished?

 

Recommendation 60

We suggest that children with GD having total T4 levels of > 20 ug/dL (200 nmol/L) or free T4 estimates > 5 ng/dL (60 pmol/L) who are to receive radioactive iodine therapy be pretreated with methimazole and beta-adrenergic blockade until total T4 and/or free T4 estimates normalize before proceeding with radioactive iodine. 2/+00

 

Recommendation 61

If 131I therapy is chosen as treatment for GD in children, sufficient 131I should be administered in a single dose to render the patient hypothyroid. 1/++0

[Q]

If thyroidectomy is chosen as treatment for GD in children, how should it be accomplished?

 

Recommendation 62

Children with GD undergoing thyroidectomy should be rendered euthyroid with the use of methimazole. Potassium iodide should be given in the immediate preoperative period. 1/+00

 

Recommendation 63

If surgery is chosen as therapy for GD in children, total or near-total thyroidectomy should be performed. 1/++0

 

Recommendation 64

Thyroidectomy in children should be performed by high-volume thyroid surgeons. 1/++0

[R]

How should SH be managed?

 

Recommendation 65

When TSH is persistently < 0.1 mU/L, treatment of SH should be strongly considered in all individuals 65 years of age, and in postmenopausal women who are not on estrogens or bisphosphonates; patients with cardiac risk factors, heart disease or osteoporosis; and individuals with hyperthyroid symptoms. 2/++0

 

Recommendation 66

When TSH is persistently below the lower limit of normal but > 0.1 mU/L, treatment of SH should be considered in individuals 65 years of age and in patients with cardiac disease or symptoms of hyperthyroidism. 2/+00

 

Recommendation 67

If SH is to be treated, the treatment should be based on the etiology of the thyroid dysfunction and follow the same principles as outlined for the treatment of overt hyperthyroidism. 1/+00

[S]

How should hyperthyroidism in pregnancy be managed?

 

Recommendation 68

The diagnosis of hyperthyroidism in pregnancy should be made using serum TSH values, and either total T4 and T3 with total T4 and T3 reference range adjusted at 1.5 times the nonpregnant range or free T4 and free T3 estimations with trimester-specific normal reference ranges. 1/+00

 

Recommendation 69

Transient hCG-mediated thyrotropin suppression in early pregnancy should not be treated with antithyroid drug therapy. 1/+00

 

Recommendation 70

Antithyroid drug therapy should be used for hyperthyroidism due to GD that requires treatment during pregnancy. Propylthiouracil should be used when antithyroid drug therapy is started during the first trimester. Methimazole should be used when antithyroid drug therapy is started after the first trimester. 1/+00

 

Recommendation 71

We suggest that patients taking methimazole who decide to become pregnant obtain pregnancy testing at the earliest suggestion of pregnancy and be switched to propylthiouracil as soon as possible in the first trimester and changed back to methimazole at the beginning of the second trimester. Similarly, we suggest that patients started on propylthiouracil during the first trimester be switched to methimazole at the beginning of the second trimester. 2/+00

 

Recommendation 72

GD during pregnancy should be treated with the lowest possible dose of antithyroid drugs needed to keep the mother’s thyroid hormone levels slightly above the normal range for total T4 and T3 values in pregnancy and the TSH suppressed. Free T4 estimates should be kept at or slightly above the upper limit of the nonpregnant reference range. Thyroid function should be assessed monthly, and the antithyroid drug dose adjusted as required. 1/+00

 

Recommendation 73

When thyroidectomy is necessary for the treatment of hyperthyroidism during pregnancy, the surgery should be performed if possible during the second trimester. 1/+00

 

Recommendation 74

TRAb levels should be measured when the etiology of hyperthyroidism in pregnancy is uncertain. 1/+00

 

Recommendation 75

Patients who were treated with radioactive iodine or thyroidectomy for GD prior to pregnancy should have TRAb levels measured using a sensitive assay either initially at 22–26 weeks of gestation, or initially during the first trimester and, if elevated, again at 22–26 weeks of gestation. 1/+00

 

Recommendation 76

Patients found to have GD during pregnancy should have TRAb levels measured at diagnosis using a sensitive assay and, if elevated, again at 22–26 weeks of gestation. 1/+00

 

Recommendation 77

TRAb levels measured at 22–26 weeks of gestation should be used to guide decisions regarding neonatal monitoring. 1/+00

 

Recommendation 78

In women with thyrotoxicosis after delivery, selective diagnostic studies should be performed to distinguish postpartum thyroiditis from postpartum GD. 1/+00

 

Recommendation 79

In women with symptomatic postpartum thyrotoxicosis, the judicious use of beta-adrenergic blocking agents is recommended. 1/+00

[T]

How should hyperthyroidism be managed in patients with Graves’ ophthalmopathy?

 

Recommendation 80

Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with Graves’ ophthalmopathy or risk factors for the development of ophthalmopathy. 1/++0

 

Recommendation 81

In nonsmoking patients with Graves’ hyperthyroidism who have no clinically apparent ophthalmopathy, 131I therapy without concurrent steroids, methimazole or thyroidectomy should be considered equally acceptable therapeutic options. 1/++0

 

Recommendation 82

Clinicians should advise patients with GD to stop smoking and refer them to a structured smoking cessation program. Patients exposed to secondhand smoke should be identified and advised of its negative impact. 1/++0

 

Recommendation 83

In patients with Graves’ hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, 131I therapy, methimazole, and thyroidectomy should be considered equally acceptable therapeutic options. 1/++0

 

Recommendation 84

Patients with Graves’ hyperthyroidism and mild active ophthalmopathy who have no other risk factors for deterioration of their eye disease and choose radioactive iodine therapy should be considered for concurrent treatment with corticosteroids. 2/++0

 

Recommendation 85

Patients with Graves’ hyperthyroidism and mild active ophthalmopathy who are smokers or have other risk factors for Graves’ ophthalmopathy and choose radioactive iodine therapy should receive concurrent corticosteroids. 1/++0

 

Recommendation 86

Patients with Graves’ hyperthyroidism and active moderate-to-severe or sight-threatening ophthalmopathy should be treated with either methimazole or surgery. 1/+00

 

Recommendation 87

In patients with Graves’ hyperthyroidism and inactive ophthalmopathy, we suggest that 131I therapy without concurrent corticosteroids, methimazole, and thyroidectomy are equally acceptable therapeutic options. 2/++0

[U]

How should overt drug-induced thyrotoxicosis be managed?

 

Recommendation 88

Beta-adrenergic blocking agents alone or in combination with methimazole should be used to treat overt iodine-induced hyperthyroidism. 1/+00

 

Recommendation 89

Patients who develop thyrotoxicosis during therapy with interferon-α or interleukin-2 should be evaluated to determine etiology (thyroiditis vs. GD) and treated accordingly. 1/+00

 

Recommendation 90

We suggest monitoring thyroid function tests before and at 1 and 3 months following the initiation of amiodarone therapy, and at 3–6-month intervals thereafter. 2/+00

 

Recommendation 91

We suggest testing to distinguish type 1 (iodine-induced) from type 2 (thyroiditis) varieties of amiodarone-induced thyrotoxicosis. 1/+00

 

Recommendation 92

The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis in consultation with a cardiologist, based on the presence or absence of effective alternative antiarrhythmic therapy. 1/+00

 

Recommendation 93

Methimazole should be used to treat type 1 amiodarone-induced thyrotoxicosis and corticosteroids should be used to treat type 2 amiodarone-induced thyrotoxicosis. 1/+00

 

Recommendation 94

Combined antithyroid drug and anti-inflammatory therapy should be used to treat patients with overt amiodarone-induced thyrotoxicosis who fail to respond to single modality therapy, and patients in whom the type of disease cannot be unequivocally determined. 1/+00

 

Recommendation 95

Patients with amiodarone-induced thyrotoxicosis who are unresponsive to aggressive medical therapy with methimazole and corticosteroids should undergo thyroidectomy. 1/+00

[V]

How should thyrotoxicosis due to destructive thyroiditis be managed?

 

Recommendation 96

Patients with mild symptomatic subacute thyroiditis should be treated initially with beta-adrenergic-blocking drugs and nonsteroidal anti-inflammatory agents. Those failing to respond or those with moderate-to-severe symptoms should be treated with corticosteroids. 1/+00

[W]

How should thyrotoxicosis due to unusual causes be managed?

 

Recommendation 97

The diagnosis of TSH-secreting pituitary tumor should be based on an inappropriately normal or elevated serum TSH level associated with elevated free T4 estimates and T3 concentrations, usually associated with the presence of a pituitary tumor on MRI and the absence of a family history or genetic testing consistent with thyroid hormone resistance in a thyrotoxic patient. 1/+00

 

Recommendation 98

Patients with TSH-secreting pituitary adenomas should undergo surgery performed by an experienced pituitary surgeon. 1/+00

 

Recommendation 99

Patients with struma ovarii should be treated initially with surgical resection. 1/+00

 

Recommendation 100

Treatment of hyperthyroidism due to choriocarcinoma should include both methimazole and treatment directed against the primary tumor. 1/+00

*Task force opinion was not unanimous; one person held the opinion that pretreatment with methimazole is not necessary in this setting.

†Task force opinion was not unanimous; one member held the opinion that pretreatment with methimazole in patients already treated with beta adrenergic blockade is not indicated in this setting.