Guideline Grading System

Table 1. Causes of Thyrotoxicosis

Thyrotoxicosis associated with a normal or elevated radioactive iodine (RAI) uptake over the necka
GD TA or TMNG Trophoblastic disease Thyroid-stimulating hormone (TSH)-producing pituitary adenomas Resistance to thyroid hormone (T3 receptor β mutation [THRB])b
Thyrotoxicosis associated with a near-absent RAI uptake over the neck
Painless (silent) thyroiditis Amiodarone-induced thyroiditis Subacute (granulomatous, de Quervain's) thyroiditis Palpation thyroiditis Iatrogenic thyrotoxicosis Factitious ingestion of thyroid hormone Struma ovarii Acute thyroiditis Extensive metastases from follicular thyroid cancer

^a In iodine-induced or iodine-exposed hyperthyroidism (including amiodarone type 1), the uptake may be low.
^b Patients are not uniformly clinically hyperthyroid.

Table 2. Beta-Adrenergic Receptor Blockade in the Treatment of Thyrotoxicosis

Drug	Dosage	Frequency	Considerations
Propranolola	10–40 mg	tid – qid	Nonselective β-adrenergic receptor blockade Longest experience May block T4 to T3 conversion at high doses
Atenolol	25–100 mg	qd or bid	Relative β-1 selectivity Increased compliance Avoid during pregnancy
Metoprololb	25–50 mg	bid – tid	Relative β-1 selectivity
Nadolol	40–160 mg	qd	Nonselective β-adrenergic receptor blockade Once daily Least experience to date May block T4 to T3 conversion at high doses
Esmolol	IV pump 50–100 µg/kg/min		In intensive care unit setting of severe thyrotoxicosis or storm

^a Each of these drugs has been approved for treatment of cardiovascular diseases, but to date none has been approved for the treatment of thyrotoxicosis.
^b Also available in once daily preparations.

Table 3. Clinical Situations That Favor a Particular Modality as Treatment for Graves’ Hyperthyroidism

Clinical situations	RAI	ATD	Surgery
Pregnancya	X	P !	A !
Comorbities w/ increased surgical risk and/or limited life expectancy	P	A	X
Inactive Graves’ orbitopathy (GO)	A	A	A
Active GO	b	P	P
Liver disease	P	!	A
Major adverse reactions to ATDs	P	X	A
Patients with previously operated or externally irradiated necks	P	A	!
Lack of access to a high-volume thyroid surgeon	P	A	!
Patients with high likelihood of remission (especially women, with mild disease, small goiters, and negative or low-titer thyrotropin receptor antibodies [TRAb])	A	P	A
Patients with periodic paralysis	P	A	P
Patients with right pulmonary hypertension, or congestive heart failure	P	A	!
Elderly with comorbidities	A	A	!
Thyroid malignancy confirmed or suspected	X	–	P
Large thyroid nodule (s)	–	A	P
Coexisting primary hyperparathyroidism requiring surgery	–	–	P

3. Patients with overt Graves' hyperthyroidism should be treated with any of the following modalities: Radioactive iodine (RAI) therapy, antithyroid drugs (ATDs), or thyroidectomy. (S-M)

RAI

4. Because RAI treatment of GD can cause a transient exacerbation of hyperthyroidism, β-adrenergic blockade should be considered even in asymptomatic patients who are at increased risk for complications due to worsening of hyperthyroidism — i.e., elderly patients and patients with co-morbidities. (W-L)
5. In addition to β-adrenergic blockade (see Recs. 2 & 4), pretreatment with methimazole (MMI) prior to RAI therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism. (W-M)
   • MMI should be discontinued 2–3 days prior to RAI.
6. In patients who are at increased risk for complications due to worsening of hyperthyroidism, resuming MMI 3–7 days after RAI administration should be considered. (W-L)
7. Medical therapy of any comorbid conditions should be optimized prior to RAI therapy. (S-L)
8. Sufficient activity of RAI should be administered in a single application, typically a mean dose of 10–15 mCi (370–555 MBq), to render the patient with GD hypothyroid. (S-M)
9. A pregnancy test should be obtained within 48 hours prior to treatment in any woman with childbearing potential who is to be treated with RAI. (S-L)
   • The treating physician should obtain this test and verify a negative result prior to administering RAI.
10. The physician administering RAI should provide written advice concerning radiation safety precautions following treatment (http://www.thyroid.org/wp-content/uploads/patients/brochures/Radioactive_iodine_brochure.pdf). If the precautions cannot be followed, alternative therapy should be selected. (S-L)
11. Follow-up within the first 1–2 months after RAI therapy for GD should include an assessment of free T₄, total T₃, and TSH. (S-L)
    • Biochemical monitoring should be continued at 4–6 week intervals for 6 months, or until the patient becomes hypothyroid and is stable on thyroid hormone replacement.
12. When hyperthyroidism due to GD persists after 6 months following RAI therapy, retreatment with RAI is suggested. In selected patients with minimal response 3 months after therapy, additional RAI may be considered. (W-L)

ATDs

13. Methimazole (MMI) should be used in virtually every patient who chooses ATD therapy for GD, except during the first trimester of pregnancy when propylthiouracil (PTU) is preferred, in the treatment of thyroid storm, and in patients with minor reactions to MMI who refuse RAI therapy or surgery. (S-M)
14. Patients should be informed of side effects of ATDs 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. (S-L)
    • Preferably, this should be in writing.
    • Before starting ATDs 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.
15. Prior to initiating ATD therapy for GD, the ATA suggests that patients have a baseline complete blood count, including white count with differential, and a liver profile including bilirubin and transaminases. (W-L)
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. (S-L)
17. There is insufficient evidence to recommend for or against routine monitoring of white blood cell counts in patients taking ATDs. (N-In)
18. Liver function and hepatocellular integrity should be assessed in patients taking MMI or PTU who experience pruritic rash, jaundice, light-colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. (S-L)
19. There is insufficient information to recommend for or against routine monitoring of liver function tests in patients taking ATD’s. (N-In)
20. Minor cutaneous reactions may be managed with concurrent antihistamine therapy without stopping the ATD. Persistent symptomatic minor side effects of antithyroid medication should be managed by cessation of the medication and changing to RAI or surgery, or switching to the other ATD when RAI and surgery are not options. In the case of a serious allergic reaction, prescribing the alternative drug is not recommended. (S-L)
21. Measurement of TRAb levels prior to stopping ATD therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission. (S-M)
22. If MMI is chosen as the primary therapy for GD, the medication should be continued for approximately 12–18 months, then discontinued if the TSH and TRAb levels are normal at that time. (S-H)
23. If a patient with GD becomes hyperthyroid after completing a course of MMI, consideration should be given to treatment with RAI or thyroidectomy. (W-L)
    • Continued low-dose MMI treatment for longer than 12–18 months may be considered in patients not in remission who prefer this approach.

Iodine

24. Potassium iodide may be of benefit in select patients with hyperthyroidism due to GD, who have adverse reactions to ATDs, and have a contraindication or aversion to RAI therapy (or aversion to repeat RAI therapy) or surgery. (N-In)
    • Treatment may be more suitable for patients with mild hyperthyroidism, or a prior history of RAI therapy.

Thyroidectomy

25. If surgery is chosen as treatment for GD, patients should be rendered euthyroid prior to the procedure with ATD pretreatment, with or without β-adrenergic blockade. A potassium iodide-containing preparation should be given in the immediate preoperative period. (S-L)
26. Calcium and 25-OH-vitamin D should be assessed preoperatively and repleted if necessary, or given prophylactically. Calcitriol supplementation should be considered preoperatively in patients at increased risk for transient or permanent hypoparathyroidism. (S-L)
27. 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 ATDs, the patient should be adequately treated with β-blockade, potassium iodide, glucocorticoids, and potentially cholestyramine in the immediate preoperative period. (S-L)
    • The surgeon and anesthesiologist should have experience in this situation.
28. If surgery is chosen as the primary therapy for GD, near-total or total thyroidectomy is the procedure of choice. (S-M)
29. If surgery is chosen as the primary therapy for GD, the patient should be referred to a high-volume thyroid surgeon. (S-M)
30. Following thyroidectomy for GD, alternative strategies may be undertaken for management of calcium levels: serum calcium ± intact parathyroid hormone levels can be measured, and oral calcium and calcitriol supplementation administered based on these results, or prophylactic calcium with or without calcitriol prescribed empirically. (W-L)
31. ATD should be stopped at the time of thyroidectomy for GD, and β-adrenergic blockers should be weaned following surgery. (S-L)
32. Following thyroidectomy for GD, L-thyroxine should be started at a daily dose appropriate for the patient’s weight (0.8 µg/lb or 1.6 µg/kg), with elderly patients needing somewhat less, and serum TSH measured 6–8 weeks postoperatively. (S-L)
33. Communication among different members of the multidisciplinary team is essential, particularly during transitions of care in the pre- and postoperative settings. (S-L)

Thyroid Nodules in GD

34. 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. (S-M)

Thyroid Storm

35. The diagnosis of thyroid storm should be made clinically in a severely thyrotoxic patient with evidence of systemic decompensation. Adjunctive use of a sensitive diagnostic system should be considered. (S-M)
    • Patients with a Burch-Wartofsky Point Scale (BWPS) of ≥45 or Japanese Thyroid Association categories of TS1 or TS2 with evidence of systemic decompensation require aggressive therapy.
    • The decision to use aggressive therapy in patients with a BWPS of 25-44 should be based on clinical judgment.
36. A multimodality treatment approach to patients with thyroid storm should be used, including β-adrenergic blockade, antithyroid drug therapy, inorganic iodide, corticosteroid therapy, cooling with acetaminophen and cooling blankets, volume resuscitation, nutritional support, respiratory care and monitoring in an intensive care unit, as appropriate for an individual patient. (S-L)

Table 4. Point Scale for the Diagnosis of Thyroid Storm

Table 5. Thyroid Storm: Drugs and Doses

Drug	Dosage	Comment
Propylthiouracila	500–1000 mg load, then 250 mg every 4 hours	Blocks new hormone synthesis Blocks T4-to-T3 conversion
Methimazole	60–80 mg/day	Blocks new hormone synthesis
Propranolol	60–80 mg every 4 hours	Consider invasive monitoring in congestive heart failure patients Blocks T4-to-T3 conversion in high doses Alternate drug: esmolol infusion
Iodine (saturated solution of potassium iodide)	5 drops (0.25 mL or 250 mg) orally every 6 hours	Do not start until 1 hour after antithyroid drugs Blocks new hormone synthesis Blocks thyroid hormone release Alternative drug: Lugol’s solution
Hydrocortisone	300 mg intravenous load, then 100 mg every 8 hours	May block T4-to-T3 conversion Prophylaxis against relative adrenal insufficiency Alternative drug: dexamethasone

^a May be given intravenously.

Graves' Orbitopathy (GO)

Table 6. Assessment of GO: Clinical Activity Score Elements

Elementsa	Each visit	Comparison with previous visit	Score
Painful feeling behind the globe over last 4 weeks	X		1
Pain with eye movement during last 4 weeks	X		1
Redness of the eyelids	X		1
Redness of the conjunctiva	X		1
Swelling of the eyelids	X		1
Chemosis (edema of the conjunctiva)	X		1
Swollen caruncle (flesh body at medial angle of eye)	X		1
Increase in proptosis ≥2 mm		X	1
Decreased eye movements ≥5° any direction		X	1
Decreased visual acuity ≥1 line on Snellen chart		X	1

^a A 7-point scale (excluding the last three elements) is used when no previous assessment is available. GO is considered active in patients with a CAS ≥3.

Sources: Adapted from Mourits et al. Br J Ophthalmol. 1989;73:639-644. and Mourits et al. Clin Endocrinol. (Oxf)1997;47:9-14.

Table 7. GO Severity Assessment

Graves' Disease with Orbitopathy

37. Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with GO or risk factors for the development of orbitopathy. (S-M)
38. The ATA recommends clinicians advise patients with GD to stop smoking and refer them to a structured smoking cessation program. As both firsthand and secondhand smoking increase GO risk patients exposed to secondhand smoke should be identified and advised of its negative impact. (S-M)
39. In nonsmoking patients with GD without apparent GO, RAI therapy (without concurrent steroids), ATDs or thyroidectomy should be considered equally acceptable therapeutic options in regard to risk of GO. (S-M)
40. In smoking patients with GD without apparent GO, RAI therapy, ATDs, or thyroidectomy should be considered equally acceptable therapeutic options in regard to risk of GO. (W-L)
41. There is insufficient evidence to recommend for or against the use of prophylactic corticosteroids in smokers who receive RAI and have no evidence of GO. (N-In)
42. In patients with Graves’ hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, RAI therapy, ATDs and thyroidectomy should be considered equally acceptable therapeutic options. (S-M)
43. In the absence of any strong contraindication to GC use the ATA suggests considering them for coverage of GD patients with mild active GO who are treated with RAI, even in the absence of risk factors for GO deterioration. (W-L)
44. In GD patients with mild GO who are treated with RAI the ATA recommends steroid coverage if there are concomitant risk factors for GO deterioration. (S-M)
45. In patients with active and moderate to severe or sight-threatening GO the ATA recommends against RAI therapy. Surgery or ATDs are preferred treatment options for GD in these patients. (S-L)
46. In patients with inactive GO the ATA suggests RAI therapy can be administered without steroid coverage. However, in cases of elevated risk for reactivation (high TRAb, Clinical Activity Score [CAS] ≥1 and smokers) that approach might have to be reconsidered. (W-L)

Table 8. Use of Oral Glucocorticoids for Prevention of Graves’ Orbitopathy Development or Progression When Radioactive Iodine is Used to Treat Graves’ Hyperthyroidism^a

	Recommendation	RAI without glucocorticoids	RAI with oral glucocorticoids
No GO (nonsmoker)	39	Recommend	Recommend against
No GO (smoker)	41	Insufficient data to recommend for or against
GO present-active and mild (risk factors absent)	43	Acceptableb	Acceptableb
GO present-active and mild (risk factors present)	44	Recommend against	Recommend
GO present-active and moderate-to-severe or sight-threatening	45	Recommend against	Recommend against
GO present-inactive	46	Recommend	Recommend against

^a ATDs or thyroidectomy are also recommended treatment options in each of these scenarios, and they are the preferred choice of therapy in patients with active and moderate-to-severe or sight-threatening GO.
^b The decision regarding use of concurrent glucocorticoids should be made in light of the risk-benefit ratio relative to the patient's overall health. Risk factors for GO deterioration (high TRAb level, smoking) increase the benefit of glucocorticoids in preventing GO deterioration. Poorly controlled diabetes, osteoporosis, psychiatric illness, high risk for infections increase the likelihood of complications from glucocorticoids.

Table 9. Risk Factors for Graves’ Orbitopathy

Risk factor	Amenable to intervention	Comments
Age	No	Advanced age – risk for more severe GO.
Sex	No	GO is more frequent in women (as GD is); more severe in men.
Genetics/ Ancestry	No	Highest prevalence of GO in Caucasians, lowest in Asians. Immunomodulatory genes likely involved.
Mechanical factors	No	Noted wider lateral wall orbital angle in GO.
TSH receptor antibody	Noa	Predicts GO risk and GO therapy response.
Smoking	Yes	Increases GO progression and decreases therapy efficacy. Smoking-cessation clinics favored for intervention.
Thyroid dysfunction	Yes	Need for expeditious control of hyperthyroidism then prevention of hypothyroidism post GD therapy.
RAI therapy	Yes	Risk is additive to smoking; increased with preexistent and active GO; preventable by glucocorticoids 6–12 weeks post RAI.

^a Decreased TRAb noted with methimazole therapy yet available data is unable to separate that change from the natural history of GO with improving TRAb.

Children and Adolescents

General

47. Children with GD should be treated with MMI, RAI therapy, or thyroidectomy. RAI therapy should be avoided in very young children (<5 years). (S-M)
    • RAI therapy in children is acceptable if the activity is >150 µCi/g (5.55 MBq/g) of thyroid tissue, and for children between 5 and 10 years of age if the calculated RAI administered activity is <10 mCi (<473 MBq).
    • Thyroidectomy should be chosen when definitive therapy is required, the child is too young for RAI, and surgery can be performed by a high-volume thyroid surgeon.
48. Beta adrenergic blockade is recommended for children experiencing symptoms of hyperthyroidism, especially those with heart rates >100 beats per minute. (S-L)

ATD

49. MMI should be used in children who are treated with ATD therapy. (S-M)
50. Pediatric patients and their caretakers should be informed of side effects of ATD preferably in writing, 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. (S-L)
51. Prior to initiating ATD therapy, the ATA suggests 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. (W-L)
52. ATDs should be stopped immediately, and white blood counts measured in children who develop fever, arthralgias, mouth sores, pharyngitis, or malaise. (S-L)
53. In general, PTU should not be used in children. But, if used the medication should be stopped immediately and liver function and hepatocellular integrity assessed in children who experience anorexia, pruritus, rash, jaundice, light-colored stool or dark urine, joint pain, right upper quadrant pain or abdominal bloating, nausea, or malaise. (S-L)
54. Persistent minor cutaneous reactions to MMI therapy in children should be managed by concurrent antihistamine treatment or cessation of the medication and changing to therapy with RAI or surgery. In the case of a serious adverse reaction to an ATD, prescribing the other ATD is not recommended. (S-L)
55. If MMI is chosen as the first-line treatment for GD 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. (S-M)

RAI (For Cancer Risk See Table 15)

56. Pediatric patients with GD who are not in remission following at least 1–2 years of MMI therapy should be considered for treatment with RAI or thyroidectomy. Alternatively, if children are tolerating ATD therapy, ATDs may be used for extended periods. (S-L)
    • This approach may be especially useful for the child not considered to be a candidate for either surgery or RAI. Individuals on prolonged ATD therapy (>2 years) should be reevaluated every 6-12 months and when transitioning to adulthood.
57. The ATA suggests that children with GD having total T4 levels of >20 ug/dL (260 nmol/L) or free T4 >5 ng/dL (60 pmol/L) who are to receive RAI therapy be pretreated with MMI and β-adrenergic blockade until total T4 and/or free T4 normalize before proceeding with RAI treatment. (W-L)
58. If RAI therapy is chosen as treatment for GD in children, sufficient RAI should be administered in a single dose to render the patient hypothyroid. (S-M)

Surgery

59. Children with GD undergoing thyroidectomy should be rendered euthyroid with the use of MMI. A potassium iodide containing preparation should be given in the immediate preoperative period. (S-L)
60. If surgery is chosen as therapy for GD in children, total or near-total thyroidectomy should be performed. (S-M)
61. Thyroidectomy in children should be performed by high-volume thyroid surgeons. (S-M)