A. Background In June 2011, the American Thyroid Association (ATA) and the Association of Clinical Endocrinologists (AACE) jointly published guidelines on the diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis in Thyroid, resulting in a total of 100 recommendations. At the same time, expert reviews from Europe, Japan, Korea, and other countries and regions were published. The previous guidelines of the two organizations were as follows: B. Etiologic Diagnosis and Symptomatic Management n Iodine-131 uptake testing should be performed in patients with non-GD thyrotoxicosis. Additional thyroid imaging should be performed in patients with nodular thyroid disease. Beta-adrenergic blockers should be given to the following patients with thyrotoxicosis: a. Symptomatic elderly patients b. Heart rate greater than 90 beats/min at rest c. Comorbid cardiovascular disease n Beta-adrenergic blockers may be considered for all symptomatic patients with thyrotoxicosis. Effects: slowing down heart rate, lowering systolic blood pressure, relieving muscle weakness, tremor, mental over-excitement, emotional instability, and decreased exercise endurance, etc. C. Treatment of dominant GD The treatment of dominant GD can be any one of iodine-131 therapy, ATD therapy, and thyroidectomy therapy. The choice should be made with due consideration of the indications, contraindications, and relevant influencing factors of the above methods. Iodine-131 therapy is preferred n a. Female patients who plan to have a pregnancy after 4-6 months n b. Presence of comorbidities that increase the risk of surgery n c. History of surgery or external neck irradiation n d. Lack of a high-throughput thyroid surgeon n e. Presence of contraindications to the use of ATDs ATD therapy is preferred n a. Those who have a high likelihood of remission (female , mild disease, mildly enlarged thyroid, negative TRAB or low titer) n b. Elderly, presence of comorbidities that increase surgical risk, or limited survival n c. Caregivers who are unable to comply with radiation safety regulations n d. History of surgical or external neck irradiation n e. Lack of high-throughput thyroid surgeon n f. Moderate to severe active GO Priority for surgical treatment n a. Presence of compressive symptoms or a large goiter (≥ 80 g) n b. Relatively low iodine uptake (<40%) n c. Suspected or diagnosed thyroid malignancy n d. Nonfunctioning nodules n e. Concomitant hyperparathyroidism requiring surgical treatment n f. Pregnancy planned within 4-6 months (especially if TRAB is significantly elevated) n g. Contraindications to moderately or severely active GO n Iodine-131: pregnancy, lactation, concomitant thyroid cancer, inability to comply with radiation safety regulations, pregnancy planned within 4-6 months n ATD: known major side effects n Surgery: severe concomitant disease (cardiac decompensation, advanced cancer, failure); first and third trimesters of pregnancy Influencing factors n Iodine-131: focus on eradication of hyperthyroidism, avoidance of surgery and potential side effects of ATD; downplaying the potential for lifelong thyroxine replacement, immediate relief of hyperthyroidism, and onset and exacerbation of GO n ATD: Focus on potential for remission and avoidance of lifelong thyroxine replacement, surgery, and radiation; downplay potential side effects of ATD, ongoing monitoring, and potential for relapse n Surgery: focus on immediate eradication of hyperthyroidism, avoidance of radiation, and potential side effects of ATD; downplay risks of surgery and lifelong thyroxine replacement D , Iodine-131 treatment for GD Pre-treatment preparation For treatment of GD due to exacerbation of hyperthyroidism (prominent symptoms or free T4 > 2-3 times upper limit of normal) For those at increased risk of complications due to exacerbation of hyperthyroidism (prominent symptoms or free T4 greater than 2-3 times the upper limit of normal), beta-adrenergic blockers should be given prior to iodine-131 therapy. In these patients, pretreatment with MMI should be considered prior to iodine-131 therapy. (One expert in the working group did not think it was necessary) Reasons against: insufficient evidence that iodine-131 therapy exacerbates the clinical manifestations and biochemical indices of hyperthyroidism; delays the duration of iodine-131 therapy; reduces the efficacy of iodine-131 therapy MMI should be temporarily discontinued for 3-5 days prior to iodine-131 therapy, and then reintroduced for 3-7 days after treatment, and thereafter tapering off the dosage every 4-6 weeks until the thyroid function is normal Lithium is not widely enough used, and There is insufficient evidence to recommend Patients with thyrotoxicosis who have other concomitant medical conditions should be optimized for stabilization of the concomitant medical conditions when administering iodine-131 therapy. Dosage In patients with GD hyperthyroidism, a single dose (typically 10-15 mCi) should be sufficient to achieve hypothyroidism in patients with GD. Fixed dose method: 10mCi – 69%; 15mCi – 75% Calculated dose method: Activity (μCi)? =?gland weight (g)? ×?150 μCi/g ×? [1/24 hour uptake on% of dose]) Range: 50-200 μCi/g Precautions A pregnancy test should be performed within 48 hours prior to administering Iodine-131 therapy to women of childbearing age, and the result should be confirmed as negative before administering the therapy. The treating physician should provide the patient with written advice on radiation safety precautions before administering iodine-131 therapy. If the patient is unable to follow this advice, an alternative treatment should be chosen. The irradiated dose to the adult public should be less than 0.5 mSv or the dose rate at 1 m should be less than 7 mrem/h Follow-up Follow-up 1-2 months after iodine-131 treatment should include measurement of fT4 and TT3. If the patient has persistent thyrotoxicosis, biochemical monitoring should be performed every 4-6 weeks. The timing and dose of thyroxine replacement should be determined by thyroid function to avoid overt hypothyroidism (especially in patients with active GO). Lifelong thyroid function testing (yearly) is recommended after thyroid function has reached normalcy TSH is interpreted with caution and is recommended to be measured in conjunction with fT4 and TT3 Repeat therapy Repeat iodine-131 therapy is recommended when hyperthyroidism persists after 6 months of iodine-131 therapy or when the response to therapy is weak after 3 months of therapy. Response to treatment can be assessed by clinical signs and symptoms, thyroid size and function Surgery may be considered in a small number of patients who have not responded to multiple iodine-131 treatments E , ATD treatment Treatment Pre-treatment Preparation n MMI can be used in virtually all patients with GD who choose ATD treatment. Exceptions: the first 3 months of pregnancy; hyperthyroidism crisis; patients with poor response to MMI and refusal of iodine-131 treatment or surgery. n Patients must be informed of the side effects of ATD, such as itchy rash, jaundice, absence of bile stools or dark urine, arthralgia, abdominal pain, nausea, fatigue, fever, pharyngitis should be immediately informed to the doctor. Prior to initiating ATD therapy and at each subsequent follow-up visit, patients should stop the drug immediately and inform their physician when symptoms suggest granulomatous defects or hepatic damage. n It is recommended that patients be given a baseline complete blood count, including a white blood cell count, and liver function tests, including bilirubin and aminotransferases, prior to initiation of ATD therapy. Dosing regimen n Because the blockade-substitution approach raises the ATD dosage and increases the incidence of its side effects, this guideline recommends the titration approach n MMI: 10-20 mg/day once daily (starting), 5-10 mg/day (maintenance) n PTU: 50-150 mg/day three times a day (starting), 50 mg/day (maintenance) Serious side effects n MMI: cholestatic jaundice, neonatal cephalic dysplasia, posterior nares and esophageal atresia n PTU: ANCA-positive small-vessel vasculitis, fulminant hepatic necrosis n MMI and PTU: arthropathy and lupus-like syndrome Follow-up monitoring n A categorical white blood cell count should be performed in the presence of fever and pharyngitis during ATD therapy. Routine monitoring of white blood cell counts is not recommended. n Due to cross-reactivity between the two classes of drugs, drug-to-drug interchanges are contraindicated if serious side effects occur during ATD treatment. n Liver function and hepatocyte integrity should be tested in patients taking PTU if they develop rash, jaundice, light-colored stools or dark-colored urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. n Routine monitoring of liver function can help prevent serious liver toxicity. PTU should be discontinued if aminotransferases exceed 2-3 times the upper limit of normal and do not improve on review within 1 week, and liver function should be monitored weekly thereafter, with referral to Gastroenterology or Hepatology as soon as possible if there is no significant improvement. Management of allergic reactions n Minor skin reactions can be treated with additional antihistamines without discontinuing the ATD. if this skin reaction persists, ATD treatment should be discontinued in favor of iodine-131, surgery, or another ATD. n If the skin reaction persists, ATD treatment should be discontinued. ATD conversion therapy is not recommended for severe allergic reactions. Treatment n MMI therapy for GD needs to be continued for approximately 12-18 months, at which time it may be reduced or discontinued if the TSH is normalized. n It is recommended that TRAb levels be tested before discontinuing an ATD to help predict whether a patient can be weaned off the drug; remission rates are higher in those with normal TRAb levels. n Hyperthyroidism that persists after completion of a course of MMI therapy should be considered as an option for iodine-131 therapy or thyroidectomy. Unremitting patients with a preference for MMI therapy may be considered for a longer course of low-dose MMI therapy. Definition of remission: TSH, FT4, and T3 remain normal for up to 1 year after termination of ATD therapy. US remission rate 20-30%, META analysis found that prolonged treatment failed to improve remission rate. The remission rate is lower in men, smokers, significant goiter (>80 grams), persistently elevated TRAB, and rich blood flow. F .Surgical treatment Preoperative preparation Whenever possible, MMI should be taken before surgery to maintain normal thyroid function. Potassium iodide should be taken before surgery. If thyroid function cannot be normalized before surgery and emergency surgery is needed, or if the patient is allergic to ATD, the patient should be given a sufficient amount of β-blocker and potassium iodide before the upcoming surgery. Surgeons and anesthesiologists should have relevant experience. ATDs can prevent hyperthyroid crises promoted by surgery, anesthesia, and thyroid compression. Potassium iodide facilitates the reduction of bleeding (Lugol’s solution 5-7 drops/dose or SSKI1-2 5-7 drops/dose 3 times/day for 10 days). Glucocorticoid use facilitates rapid preparation for emergency surgery. Surgical options and choice of surgeon First choice is subtotal thyroidectomy or total thyroidectomy. It should be performed by a high-throughput thyroid surgeon. High-throughput thyroid surgeons have low surgical complications: permanent parathyroid decompensation <2%; permanent recurrent laryngeal nerve injury <1%; second surgery for hemorrhage 0.3%-0.7%; mortality rate 1/10,000-5/100,000,000 Post-operative management Measure serum calcium or parathyroid hormone levels and supplement with calcium and calcitriol according to the results. No postoperative discomfort, total serum calcium ≥1.95 mmol/L without decline can be discharged; PTH <10-15 pg/mL need to supplement calcium and osteotriol. ATD should be discontinued at the time of surgery, and β-adrenergic blockers should be discontinued after surgery. Postoperatively, oral levothyroxine (1.7 mcg/kg) should be administered according to the patient's weight, and serum TSH levels should be tested every 6-8 weeks. After TSH is normal and stable, it should be reviewed at least once a year. G. Management of GD with nodules Refer to the recently published guidelines for the diagnosis and management of thyroid nodules in patients with normal thyroid function for evaluation and treatment. H. Hyperthyroidism crisis Patients with hyperthyroidism crisis should be treated with a combination of beta-adrenergic blockers, ATDs, inorganic iodine, corticosteroids, rapid hypothermia (acetaminophen and cooling blankets), volumetric resuscitation, respiratory support, and other modalities, as well as intensive care. I , Toxic nodular goiter (TMNG) and toxic adenoma (TA) Iodine-131 or thyroidectomy is recommended for the treatment of overt TMNG or TA. long-term low-dose MMI therapy is less commonly used. Iodine-131 preferred: elderly, severe concomitant disease, history of neck surgery or scarring, mildly enlarged thyroid, sufficiently high RAIU, lack of high-throughput thyroid surgeon (the latter is particularly important for TMNG); contraindications to iodine-131: pregnancy, lactation, concomitant thyroid cancer, inability to comply with radiation safety regulations, women planning a pregnancy in the 4-6 month period Priority for surgery: women with symptoms or signs of neck pressure, suspicion of thyroid cancer, and pregnancy within 4-6 months Surgery prioritized: women with symptoms of neck pressure or Surgery priority: signs and symptoms of neck compression, suspicion of thyroid cancer, associated with hyperthyroidism requiring surgical treatment, severe enlargement of the thyroid gland (>80 grams), involvement of the posterior sternum, RAIU insufficiency, the need for rapid correction of hyperthyroidism; Contraindications: serious concomitant diseases, early and late pregnancy. J , Iodine-131 treatment Pre-treatment preparation Advanced age, cardiovascular disease, severe hyperthyroidism and other factors increase the risk of iodine-131 treatment, should be used before iodine-131 treatment of β-blocker until the thyroid function is normal. If there are factors such as advanced age, cardiovascular disease, or severe hyperthyroidism, MMI should be given before iodine-131 treatment. (One expert believes that MMI is not necessary with beta-blocker protection.) Nodules that appear “cold” on nuclear scanning or have suspicious characteristics on ultrasound should be managed according to the recently published guidelines for the diagnosis and management of thyroid nodules. In the treatment of TMNG with iodine-131, an adequate dose should be given at one time to relieve hyperthyroidism. Fixed dose method: 30 mCi Calculated dose method: Activity (μCi)? =?goiter weight (g)? ×?150?μCi/g?×? [1/24 hour uptake on % of dose]) Range: 150-200 μCi/g Adequate dose should be given at one time to relieve symptoms of hyperthyroidism during iodine-131 treatment of TA. Fixed dose method: 10-20 mCi Calculated dose method: Activity (μCi)? =?nodule weight (g)? ×?150?μCi/g?×? [1/24 hour uptake on % of dose]) Range: 150-200 μCi/g Follow-up and efficacy Follow-up at 1-2 months after iodine-131 treatment should include measurement of fT4, TT3 and TSH. Follow-up every 1-2 months until results are stable and at least annually thereafter. TMNG: incidence of hypothyroidism at 3 and 6 months is about 55% and 80%, respectively, with a failure rate of 15% and an overall shrinkage rate of about 40% TA: hyperthyroidism resolves in 75% of patients after 3 months and nodule volume shrinks by 45% after 2 years Repeat therapy If hyperthyroidism persists 6 months after iodine-131 therapy, reintroduction of iodine-131 therapy is recommended. Surgery can be considered for patients with severe hyperthyroidism or ineffective iodine-131 treatment. Patients with mild hyperthyroidism after iodine-131 treatment can consider MMI adjuvant therapy until the efficacy of iodine-131 is fully realized. K. Surgery Preoperative Preparation Patients with overt hyperthyroidism should be given MMI (provided that there is no allergy) with or without β-adrenergic blockers prior to surgery, so as to maintain normal thyroid function. Iodine should not be used preoperatively. Surgical options and surgeon selection Patients with TMNG should opt for near-total or total thyroidectomy. TMNG patients should choose a high-throughput thyroid surgeon. Patients with TA should undergo ipsilateral lobectomy or isthmus resection depending on the site of the adenoma. Patients with TA should choose a high-throughput thyroid surgeon. Postoperative management After TMNG, it is recommended that serum calcium or parathyroid hormone levels be tested and calcium and osteotriol supplemented accordingly. MMI should be discontinued at the time of surgery in patients with TMNG or TA. postoperatively, beta-adrenergic blockers should be slowly tapered to discontinuation. Postoperatively, TMNG patients should be treated with the appropriate amount of thyroid hormone according to their body weight (1.7 mcg/kg) and age, with a slight reduction in the dose for older patients. TSH should be tested every 1-2 months until stabilized and then annually. TSH and fT4 levels should be measured every 4-6 weeks after TA, and thyroid hormone supplementation should be initiated if TSH continues to be higher than normal. Management of persistence or recurrence In patients with TMNG or TA, if hyperthyroidism persists or recurs due to inadequate surgical resection, iodine-131 therapy should be administered. L , M Other treatments Prolonged MMI therapy should be avoided in patients with TMNG or TA, except in elderly patients, well-supervised short-lived patients, and those with a preference for MMI therapy. There is limited experience with radiofrequency, thermal ablation, or PEI for the treatment of TMNG and TA, and they are not routinely recommended N , Treatment of patients with juvenile GD For patients with juvenile GD, MMI, iodine-131, or thyroidectomy may be used as an option for treatment. Iodine-131 treatment should be avoided in those <5 years of age. 5-10 years of age can be treated with iodine-131 if the calculated dose is <10 mCi. Iodine-131 treatment at doses >150 uCi/g is acceptable for those >10 years of age. Those who are too young for iodine-131 therapy but require radical treatment should choose a high-throughput thyroid surgeon to perform the surgery. O. ATD therapy MMI is indicated for all children who are suitable for ATD therapy. Patients and their guardians should be informed of the side effects of ATD therapy. Symptoms such as itchy rash, jaundice, bile-less stools and dark-colored urine, arthralgia, abdominal pain, nausea, fatigue, fever, pharyngitis, etc. should be discontinued and the doctor should be informed. Before starting ATD therapy, patients are advised to test baseline complete blood count (including differentiated white blood cell count) and liver function (including bilirubin, transaminases, and alkaline phosphatase). Symptomatic management Beta-adrenergic blockers are recommended for symptomatic patients, especially those with a heart rate >100 beats/min. Follow-up monitoring MMI-treated patients who develop fever, arthralgia, mouth pain, pharyngitis, or other discomforts should be immediately discontinued and have their white blood cell counts tested. PTU-treated persons who experience discomfort such as anorexia, pruritus, rash, jaundice, light-colored stools or dark-colored urine, arthralgia, right upper abdominal pain or bloating, and nausea should be immediately discontinued and tested for liver function and hepatocyte integrity. Disposition of Allergic Reactions Persistent mild skin reactions due to MMI administration should be treated with a combination of antihistamines or suspension of MMI therapy in favor of iodine-131 or surgery. Switching to another ATD drug for treatment is not recommended if there is a severe allergic reaction to the ATD. Treatment If MMI is chosen as first-line treatment, it should be continued for 1-2 years and then discontinued or reduced for maintenance and assessed for remission. If the disease does not resolve after 1-2 years of MMI treatment, switching to iodine-131 therapy or thyroidectomy should be considered. P , Iodine-131 therapy For those with TT4 >260 nmol/L or fT4 >60 pmol/L, MMI and β-adrenergic blocker therapy should be given prior to treatment until TT4 and/or fT4 levels are normalized. A sufficient amount of iodine-131 should be given at one time to allow the patient to develop hypothyroidism. Q. Surgery MMI should be given preoperatively to normalize the patient’s thyroid function, and potassium iodide should be given just prior to surgery. Total or subtotal thyroidectomy should be performed. A high-throughput thyroid surgeon should be chosen to perform the surgery. R , Subclinical hyperthyroidism When TSH is persistently <0.1 mU/L, treatment should be given to all postmenopausal women ≥65 years of age who are not taking estrogen or bisphosphonate therapy, who are at risk for cardiac disease, who have cardiac disease, who have osteoporosis, and who have symptoms of hyperthyroidism. When TSH is persistently below the lower limit of normal but ≥0.1 mU/L, treatment may be considered in patients ≥65 years of age with cardiac disease or symptoms of hyperthyroidism. Treatment of subclinical hyperthyroidism should be based on the etiology of the thyroid abnormality and follow the principles of treatment of overt hyperthyroidism. S , Hyperthyroidism in pregnancy The diagnosis of hyperthyroidism in pregnancy is based on serum TSH values, TT4 and TT3 (reference ranges adjusted to 1.5 times the reference range for non-pregnancy), or fT4 and fT3 (pregnancy-specific normal reference ranges). Transient HCG-induced TSH suppression in early pregnancy does not require treatment with an ATD. GD in pregnancy should be treated with ATD. PTU should be used in the first trimester, after which MMI should be used. Patients previously taking MMI should be tested for pregnancy if there are signs of pregnancy and switched to PTU as early as possible, resuming MMI therapy from mid-pregnancy. Similarly, patients taking PTU in the first trimester should be switched to MMI thereafter. Maternal thyroid hormone levels should be maintained slightly above the normal TT4 and TT3 levels for pregnancy and TSH levels should be slightly suppressed using the lowest dose of ATD. fT4 should be maintained at or slightly above the upper limit of the reference range for non-pregnancy. Test thyroid function monthly and adjust ATD dose as needed. When thyroidectomy is required to treat hyperthyroidism, the procedure should be performed in mid-pregnancy if possible. Value of TRAB testing TRAb levels should be tested when the cause of hyperthyroidism in pregnancy is unknown. The sensitivity and specificity of TRAB for the diagnosis of GD are 95% and 99% respectively Patients with GD who were treated with iodine-131 or thyroidectomy before pregnancy should be tested for TRAb levels at weeks 22-26; those with elevated TRAb in early pregnancy should be retested at weeks 22-26. Patients with GD during pregnancy should be tested for TRAb levels and retested at weeks 22-26 if elevated. TRAb levels at weeks 22-26 of gestation should be used to guide neonatal monitoring. Postpartum thyroiditis Women with thyrotoxicosis should be selected for etiologic diagnosis by appropriate screening after delivery (differentiating between postpartum thyroiditis and postpartum GD). Beta-adrenergic blockers are recommended to be used with caution in symptomatic women with thyrotoxicosis. T , Graves' orbital disease Thyroid function should be corrected and maintained in the normal range as soon as possible in patients with hyperthyroidism with GO or at risk of developing GO. Risk factors: iodine-131 therapy, smoking, elevated T3, elevated TRAB, hypothyroidism after iodine-131 therapy Patients with GD who are nonsmokers and do not have clinical GO may be considered for all three treatment options: iodine-131 therapy (without concomitant steroids), methimazole, or thyroidectomy. Physicians should advise patients with GD to quit smoking, identify passive smokers and inform them of the negative effects. Inactive GO All three treatment options, iodine-131 (without concomitant corticosteroids), MMI, and thyroidectomy, may be considered for patients with GD with inactive GO. Mildly active GO All three treatment options, iodine-131, MMI, and thyroidectomy, may be considered in patients with mildly active GO without risk factors for worsening ocular disease. Mildly active GO without risk factors for worsening ocular disease may be considered with concomitant corticosteroids if iodine-131 treatment is chosen. Those with mildly active GO and risk factors for worsening ocular disease should receive concomitant corticosteroids if iodine-131 treatment is chosen. Dosage: Prednisone: 0.4-0.5mg/kg/d*1M, followed by dose reduction every 2 months. Patients with moderately or severely active GO GD with active moderate or severe or vision-affecting GO should be treated with MMI or surgery. U , Drug-associated thyrotoxicosis Iodine hyperthyroidism can be treated with beta-adrenergic blockers alone or in combination with MMI. Patients who develop thyrotoxicosis during treatment with cytokines such as interferon-alpha or interleukin-2 should have the etiology (thyroiditis or Graves' disease) clarified and treated differently. It is recommended that thyroid function be monitored prior to amiodarone therapy and at 1 and 3 months after initiation of therapy, and at 3-6 month intervals thereafter. Testing is recommended to differentiate between type 1 (iodine hyperthyroidism) and type 2 (thyroiditis) of amiodarone-induced thyrotoxicosis. Discontinuation of amiodarone on the background of thyrotoxicosis should be decided in consultation with a cardiologist, which in turn will lead to the choice or non-choice of another effective antiarrhythmic drug therapy. MMI should be used in the treatment of type 1 thyrotoxicosis, while corticosteroids should be used in the treatment of type 2 thyrotoxicosis. ATDs and anti-inflammatory drugs may be used in combination to treat patients who have failed to respond to a single modality and those who cannot differentiate between disease types. Thyroidectomy should be performed when there is no response to high-dose MMI and corticosteroid medication. V , Thyrotoxicosis due to destructive thyroiditis Initial treatment of patients with mild subacute thyroiditis should be with beta-adrenergic blockers and nonsteroidal anti-inflammatory agents. Those who respond poorly or those with moderate to severe symptoms should be treated with corticosteroids. W , Specific causes of thyrotoxicosis Diagnosis of TSH-secreting pituitary tumor: inappropriately normal or elevated serum TSH levels combined with elevated fT4 and fT3, usually pituitary tumors demonstrable on MRI, no family history of genetic predisposition or negative genetic testing for thyroid hormone resistance. Surgery for TSH-secreting pituitary tumors should be performed by an experienced pituitary surgeon. Patients with ovarian goiter should undergo early surgical removal. Treatment of hyperthyroidism due to choriocarcinoma should include MMI and direct treatment of the primary tumor lesion.