- Thyrotoxicosis is a condition having multiple etiologies, manifestations, and potential therapies.
- The term "thyrotoxicosis" refers to a clinical state that results from inappropriately high thyroid hormone action in tissues due to inappropriately high tissue thyroid hormone levels.
- The term "hyperthyroidism," as used in these guidelines, is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid.
- Appropriate treatment of thyrotoxicosis requires an accurate diagnosis.
- For example, thyroidectomy is an appropriate treatment for some forms of thyrotoxicosis and not for others.
- Additionally, β-blockers may be used in almost all forms of thyrotoxicosis, whereas antithyroid drugs (ATDs) are useful in only some.
- In the United States, the prevalence of hyperthyroidism is approximately 1.2% (0.5% overt and 0.7% subclinical).
- The most common causes include Graves' disease (GD), toxic multinodular goiter (TMNG), toxic adenoma (TA) and and painless thyroiditis.
Determination of Etiology
- The etiology of thyrotoxicosis should be determined. If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, diagnostic testing is indicated and can include, depending on available expertise and resources: (S-M)
- measurement of thyrotropin receptor antibodies (TRAb)
- determination of the radioactive iodine uptake (RAIU) or
- measurement of thyroidal blood flow on ultrasonography.
- An 123I or 99mTc pertechnetate scan should be obtained when the clinical presentation suggests a toxic adenoma or toxic multinodular goiter.
Table 1. Causes of Thyrotoxicosis
|Thyrotoxicosis associated with a normal or elevated radioactive iodine (RAI) uptake over the necka|
|Thyrotoxicosis associated with a near-absent RAI uptake over the neck|
b Patients are not uniformly clinically hyperthyroid.
- β-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rates >90 bpm or coexistent cardiovascular disease. (S-M)
Table 2. Beta-Adrenergic Receptor Blockade in the Treatment of Thyrotoxicosis
|10–40 mg||tid – qid|
|Atenolol||25–100 mg||qd or bid|
|Metoprololb||25–50 mg||bid – tid|
|Esmolol||IV pump 50–100 µg/kg/min|
b Also available in once daily preparations.
Table 3. Clinical Situations That Favor a Particular Modality as Treatment for Graves’ Hyperthyroidism
|Pregnancya||X||P !||A !|
|Comorbities w/ increased surgical risk and/or limited life expectancy||P||A||X|
|Inactive Graves’ orbitopathy (GO)||A||A||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|
a For women considering a pregnancy within 6 months, see discussion under Pregnancy.
b Table 14 describes the use of RAI in GO in detail, considering disease activity, severity and other risk factors for GO progression.
- 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)
- 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)
- 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.
- 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)
- Medical therapy of any comorbid conditions should be optimized prior to RAI therapy. (S-L)
- 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)
- 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.
- 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)
- 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.
- 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)
- 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)
- 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.
- 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)
- 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)
- There is insufficient evidence to recommend for or against routine monitoring of white blood cell counts in patients taking ATDs. (N-In)
- 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)
- There is insufficient information to recommend for or against routine monitoring of liver function tests in patients taking ATD’s. (N-In)
- 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)
- 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)
- 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)
- 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.
- 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.
- 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)
- 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)
- 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.
- If surgery is chosen as the primary therapy for GD, near-total or total thyroidectomy is the procedure of choice. (S-M)
- If surgery is chosen as the primary therapy for GD, the patient should be referred to a high-volume thyroid surgeon. (S-M)
- 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)
- ATD should be stopped at the time of thyroidectomy for GD, and β-adrenergic blockers should be weaned following surgery. (S-L)
- 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)
- 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
- 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)
- 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)
- 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 5. Thyroid Storm: Drugs and Doses
|Propylthiouracila||500–1000 mg load, then 250 mg every 4 hours|
|Propranolol||60–80 mg every 4 hours|
|Iodine (saturated solution of potassium iodide)||5 drops (0.25 mL or 250 mg) orally every 6 hours|
|Hydrocortisone||300 mg intravenous load, then 100 mg every 8 hours|
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|
Sources: Adapted from Mourits et al. Br J Ophthalmol. 1989;73:639-644. and Mourits et al. Clin Endocrinol. (Oxf)1997;47:9-14.
Graves' Disease with Orbitopathy
- Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with GO or risk factors for the development of orbitopathy. (S-M)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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’ Hyperthyroidisma
|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|
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.|
Children and Adolescents
- 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.
- Beta adrenergic blockade is recommended for children experiencing symptoms of hyperthyroidism, especially those with heart rates >100 beats per minute. (S-L)
- MMI should be used in children who are treated with ATD therapy. (S-M)
- 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)
- 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)
- ATDs should be stopped immediately, and white blood counts measured in children who develop fever, arthralgias, mouth sores, pharyngitis, or malaise. (S-L)
- 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)
- 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)
- 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)
- 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.
- 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)
- 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)
- 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)
- If surgery is chosen as therapy for GD in children, total or near-total thyroidectomy should be performed. (S-M)
- Thyroidectomy in children should be performed by high-volume thyroid surgeons. (S-M)