Guideline sources The following summarized guidelines for the evaluation and management of graves' disease (GD) are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the European Thyroid Association (ETA 2022; 2018), and the American Thyroid Association (ATA 2016). 1 2 3 4 5 5 6 6 7 Definition GD is a systemic autoimmune disease that is characterized by production of antibodies to the TSH receptor. 5 Epidemiology GD is caused by autoimmunity rendered by complex interactions between genetic (75-80%)and environmental factors (20-25%). 5 Pathophysiology https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 1/10 7/1/23, 12:05 AM Graves' disease Pathway The annual incidence of GD is estimated at 20-30 cases per 100,000 persons; lifetime risk for women and men is approximately 3% and 0.5%, respectively. 6 Disease course The overproduction of thyroid hormone is caused by thyroid-stimulating immunoglobulins via thyrotropin receptor activation, which results in hypertrophy and hyperplasia of the gland. In addition, the production of cytokines by infiltrating immune cells results in inflammation and altered thyroid cell behavior. The orbital infiltration of immune cells, activation of thyrotropin-insulin-like growth factor 1 receptor complex, signaling of orbital fibroblasts and adipogenesis results in orbital tissue expansion, proptosis, and optic nerve compression. Diffuse goiter, ophthalmopathy, dermopathy, alteration in mental status, and cardiac complications may ensue. 7 Prognosis and risk of recurrence Antithyroid drug therapy is associated with 40-50% remission post 12-18 months treatment; radioactive iodine results in permanent hypothyroidism in >80% cases and a 15-20% risk of inducing/aggravating Graves orbitopathy. 6 Calculator Burch-Wartofsky Point Scale for Guidelines 1. Screening and diagnosis Indications for screening: Consider screening for antithyroid peroxidase and anti-TG antibodies soon after diagnosis in pediatric patients with T1DM. C Measure TSH concentrations at diagnosis when clinically stable or soon after optimizing glycemia. Consider rechecking every 1-2 years or sooner if the initial screening is normal in young patients with positive thyroid antibodies or developing symptoms or signs suggestive of thyroid dysfunction, thyromegaly, an abnormal growth rate, or unexplained glycemic variability. B 2. Diagnostic investigations Thyrotropin receptor antibodies: Obtain TSH receptor autoantibodies for rapid and accurate diagnosis and differential diagnosis of GD. A https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 2/10 7/1/23, 12:05 AM Graves' disease Pathway Consider differentiating TSH receptor autoantibodies functionality, when technically available, as it is helpful and predictive in patients with GD during pregnancy/postpartum and for extrathyroidal manifestations. C Baseline laboratory tests: consider obtaining a baseline CBC, including WBC count with differential, and a liver profile including bilirubin and transaminases before initiating antithyroid drugs. C Diagnostic imaging: Obtain ultrasound, composed of conventional gray-scale analysis and color-flow or power Doppler examination, to support the diagnosis of GD. A Consider obtaining scintigraphy of the thyroid when thyroid nodularity coexists with hyperthyroidism and before radioactive iodine therapy. C 3. Medical management Antithyroid drugs: As per ETA 2018 guidelines, initiatie antithyroid drugs in patients with newly diagnosed GD. A Show 4 more As per ATA 2016 guidelines, initiate methimazole in virtually every patient choosing 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 refusing radioactive iodine therapy or surgery. B Show 3 more Beta-blockers: As per ETA 2018 guidelines, initiate -adrenergic blockers in all suitable patients with GD. A As per ATA 2016 guidelines: Initiate -adrenergic blockers in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with a resting HR > 90 bpm or coexistent CVD. B Consider administering -adrenergic blockers even in asymptomatic patients at increased risk for complications due to worsening of hyperthyroidism (elderly patients and patients with comorbidities), because radioactive iodine therapy can cause a transient exacerbation of hyperthyroidism. C Radioactive iodine: As per ETA 2018 guidelines, consider initiating radioactive iodine therapy in patients with newly diagnosed GD preferring this approach. B Show 6 more As per ATA 2016 guidelines, optimize medical therapy of any comorbid conditions before radioactive iodine therapy. B Show 3 more https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 3/10 7/1/23, 12:05 AM Graves' disease Pathway Antihistamines: administer concurrent antihistamines without stopping the antithyroid drug for the management of minor cutaneous reactions. B Show 2 more Management of thyroid storm: Ensure a multimodality treatment approach in patients with GD with thyroid storm, including: antithyroid drug therapy corticosteroids -adrenergic blockade cooling blankets volume resuscitation nutritional support respiratory care monitoring in an ICU. B Management of subclinical hyperthyroidism: As per ETA 2018 guidelines: Treat subclinical hyperthyroidism in > 65 years old patients with GD with serum TSH levels persistently < 0.1 mIU/L. B Initiate antithyroid drugs as first-line therapy in patients with Graves' subclinical hyperthyroidism. B As per ATA 2016 guidelines, treat subclinical hyperthyroidism if TSH is persistently < 0.1 mU/L in all patients 65 years of age, in patients with cardiac risk factors, heart disease or osteoporosis, in postmenopausal patients not on estrogens or bisphosphonates, and in patients with hyperthyroid symptoms. B Show 3 more 4. Nonpharmacologic interventions Smoking cessation: advise smoking cessation in patients with GD and refer them to a structured smoking cessation program. Identify patients exposed to secondhand smoke and advise of its negative impact, as both firsthand and secondhand smoking increase Graves' orbitopathy risk. B 5. Perioperative care Preoperative care: As per ETA 2018 guidelines, restore euthyroidism by antithyroid drugs before surgery to avoid peri- or postoperative exacerbation of thyrotoxicosis. A Show 2 more As per ATA 2016 guidelines, render patients euthyroid with antithyroid drugs, with or without - adrenergic blockers, before thyroidectomy. B https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 4/10 7/1/23, 12:05 AM Graves' disease Pathway Show 3 more Postoperative care: consider measuring serum calcium with or without intact PTH levels following thyroidectomy, and administer oral calcium and calcitriol supplementation based on these results. Consider administering prophylactic calcium with or without calcitriol prescribed empirically as an alternative strategy. C Show 3 more 6. Surgical interventions Thyroidectomy: As per ETA 2018 guidelines: Consider performing thyroidectomy in patients with newly diagnosed GD preferring this approach. B Perform total thyroidectomy as the procedure of choice by a skilled surgeon with high annual volumes of thyroidectomies, if surgery is selected. A As per ATA 2016 guidelines: Refer the patient to a high-volume thyroid surgeon if surgery is chosen as the primary therapy for GD. B Perform near-total or total thyroidectomy as the procedure of choice if surgery is chosen as the primary therapy for GD. B 7. Specific circumstances Pediatric patients, evaluation: As per ETA 2022 guidelines, obtain WBC count including neutrophil count and LFTs at baseline as both can be affected by the underlying disease process and antithyroid drug therapy. B As per ATA 2016 guidelines, consider obtaining a baseline complete blood cell count, including WBC count with differential, and a liver profile including bilirubin, transaminases, and ALP before initiating antirthyroid drugs. C Pediatric patients, antithyroid drugs: As per ETA 2022 guidelines, initiate prompt treatment in pediatric patients with GD. A Show 7 more As per ATA 2016 guidelines, initiate methimazole as an antirthyroid drug in pediatric patients. B Show 6 more Pediatric patients, beta-blockers: As per ETA 2022 guidelines: Initiatie -adrenergic blockers in patients presenting with marked signs of thyroid hormone excess. Consider discontinuing it once the patient is biochemically euthyroid. B https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 5/10 7/1/23, 12:05 AM Graves' disease Pathway Manage patients with untreated GD on a high dependency or ICU as they can be severely unwell with marked signs of thyroid hormone excess. B As per ATA 2016 guidelines, initiate -adrenergic blockers in pediatric patients experiencing symptoms of hyperthyroidism, especially with a HR > 100 bpm. B Pediatric patients, radioactive iodine: As per ETA 2022 guidelines, consider offering alternative treatment with surgery or radioactive iodine in patients being thyrotoxic despite large doses of carbimazole ( 1.3 mg/kg/day) or methomazole ( 1 mg/kg/day). B Show 6 more As per ATA 2016 guidelines, offer radioactive iodine therapy in pediatric patients if the activity is > 150 mcCi/g (5.55 MBq/g) of thyroid tissue, and in pediatric patients between 5 and 10 years of age if the calculated radioactive iodine administered activity is < 10 mCi (< 370 MBq). B Show 3 more Pediatric patients (immunomodulators): insufficient evidence to recommend immune modulation with new agents such as biologics in the young patients with GD. I Pediatric patients, thyroidectomy: As per ETA 2022 guidelines, consider offering alternative treatment with surgery or radioactive iodine in patients being thyrotoxic despite large doses of carbimazole ( 1.3 mg/kg/day) or methomazole ( 1 mg/kg/day). B Show 5 more As per ATA 2016 guidelines, perform thyroidectomy when definitive therapy is required, the patient is too young for radioactive iodine therapy, and surgery can be performed by a high- volume thyroid surgeon. B Show 2 more Pediatric patients (treatment monitoring): follow-up patients managed with dose titration or block and replace approximately every 4 weeks for the first 3 months and move to 2 and then 3 monthly assessments thereafter depending on the clinical course. B Show 3 more Pediatric patients (management of thyroid nodules): recognize that young patients with GD, like adults, have a slightly higher risk of developing differentiated thyroid cancer. B Show 2 more Pediatric patients (management of orbitopathy): refer pediatric patients with eye symptoms to an orbital specialist, preferably in combined (ophthalmologist/physician) thyroid eye clinics. B Show 3 more Elderly patients: Initiate definitive therapy, usually radioactive iodine, in older patients with AF, HF or cardiac ischemic symptoms precipitated by hyperthyroidism. B Consider initiating long-term methimazole (carbimazole) in older patients with mild GD. C Pregnancy planning: https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 6/10 7/1/23, 12:05 AM Graves' disease Pathway As per ETA 2018 guidelines, provide preconception counseling in female patients with GD of reproductive age, and ensure being stably euthyroid before attempting pregnancy. B Show 3 more As per ATA 2016 guidelines, discuss the possibility and timing of future pregnancy in patients developing hyperthyroidism during their reproductive age range. Consider advising female patients postponing pregnancy until they have become euthyroid with therapy because of the risks of the hyperthyroid state on pregnancy and fetal outcome. B Show 6 more Pregnant patients, evaluation: As per ETA 2018 guidelines: Measure serum TSH receptor antibody levels at the first presentation of pregnancy in all patients with a history of autoimmune thyroid disease, using either a sensitive binding or a functional cell-based bioassay and, if they are elevated, again at 18-22 weeks of gestation. A Monitor the fetus for thyroid dysfunction throughout pregnancy if the maternal TSH receptor antibody concentration remains high (> 3 times the cut-off). A As per ATA 2016 guidelines, diagnose hyperthyroidism in pregnancy based on serum TSH values, and either total T4 and T3 with total T4 and T3 reference ranges increasing to 1.5 times above the nonpregnant range by the second and third trimester or free T4 and total T3 estimations with trimester-specific normal reference ranges. B Show 5 more Pregnant patients, antithyroid drugs: As per ETA 2018 guidelines, administer the lowest possible dose of antithyroid drug during pregnancy and avoid using the block-and-replace antithyroid drug regimen. A Show 4 more As per ATA 2016 guidelines, initiate antithyroid drug therapy in patients with overt hyperthyroidism due to GD during pregnancy. Initiate propylthiouracil when antithyroid drug therapy is given during the first trimester. Initiate methimazole when antithyroid drug therapy is started after the first trimester. B Show 4 more Pregnant patients (thyroidectomy): Recognize that pregnancy is a relative contraindication to thyroidectomy and should only be performed when medical management has been unsuccessful or antithyroid drugs cannot be used. B Perform surgery, when thyroidectomy is necessary for the treatment of hyperthyroidism during pregnancy, during the second trimester if possible. B Breastfeeding: offer lactating patients with GD the same treatments as non-lactating patients. B Show 2 more Patients with immune reconstitution: Do not stop precipitating treatment and do not initiate mandatory definitive therapy for hyperthyroidism in patients with GD precipitated by an immunomodulatory therapy. D https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 7/10 7/1/23, 12:05 AM Graves' disease Pathway Consider obtaining sequential monitoring of serum TSH receptor autoantibodies to guide the duration of antithyroid drug therapy in patients with immune reconstitution GD. C Patients with orbitopathy: As per ETA 2018 guidelines, control hyperthyroidism promptly by antithyroid drugs and maintain stable euthyroidism in patients with Graves' orbitopathy. A Show 4 more As per ATA 2016 guidelines, consider offering radioactive iodine therapy without corticosteroid coverage in patients with inactive Graves' orbitopathy. Reconsider this approach in case of elevated risk for reactivation (high thyroid-stimulation hormone receptor antibody, CAS > 1 and smokers). C Show 5 more 8. Follow-up and surveillance Treatment monitoring: As per ETA 2018 guidelines: Inform patients about the potential side effects of antithyroid drugs and the necessity of informing the physician promptly if they develop jaundice, light-colored stools, dark urine, fever, pharyngitis, or cystitis. B Obtain a differential WBC count in patients taking antithyroid drugs during febrile illness and/or pharyngitis. Assess liver function in patients experiencing jaundice, light-colored stools or dark urine. B As per ATA 2016 guidelines, obtain a differential WBC count during febrile illness and at the onset of pharyngitis in all patients taking antithyroid drugs. B Show 4 more Management of refractory disease: As per ETA 2018 guidelines: Initiate radioactive iodine therapy or perform thyroidectomy as definitive treatment in patients with GD becoming hyperthyroid after completing a first course of antithyroid drugs. B Consider continuing long-term low-dose methimazole in patients not in remission preferring this approach. B As per ATA 2016 guidelines: Consider initiating radioactive iodine therapy or performing thyroidectomy in patients with GD becoming hyperthyroid after completing a course of methimazole. Consider continuing low- dose methimazole treatment for longer than 12-18 months in patients not in remission preferring this approach. C Consider initiating retreatment with radioactive iodine when hyperthyroidism due to GD persists after 6 months following radioactive iodine therapy. Consider offering additional radioactive iodine therapy in selected patients with minimal response 3 months after therapy. C https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 8/10 7/1/23, 12:05 AM Graves' disease Pathway Clinical findings Symptoms Past medical history Amenorrhea Depression Anxiety Neurological exam Change in voice Diarrhea Hyperreflexia Diplopia Tremor Dry eyes Head and neck exam Dysphagia Eye pain Goiter Fatigue Proptosis Globus sensation Thyroid bruit Heat intolerance Increased appetite Lab findings Orthopnea serum free T3 Palpitations serum free T4 Sleeping disorder serum TSH Sweating Watery eyes Weight loss Vital signs Tachycardia Ocular exam Abadie's sign Binocular diplopia Conjunctival injection Exophthalmos Eyelid retraction Griffith's sign Infrequent blinking Joffroy's sign Kocher's sign Lagophthalmos Lid lag on downward gaze Lid lag on upward gaze Von Graefe's sign Widened palpebral fissure https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 9/10 7/1/23, 12:05 AM Graves' disease Pathway Integument exam Acropachy Digital clubbing Onycholysis Palmar erythema Pretibial myxedema Serological findings References 1. Ross DS, Burch HB, Cooper DS et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26 10 1343 1421. Open 2. Christiaan F Mooij, Timothy D Cheetham, Frederik A Verburg et al. 2022 European Thyroid Association Guideline for the management of pediatric Graves disease. Eur Thyroid J. 2022 Jan 1;11 1):e210073. Open 3. Kahaly GJ, Bartalena L, Heged s L et al. 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J. 2018 Aug;7 4 167 186. Open 4. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 5. Wemeau JL, Klein M, Sadoul JL et al. Graves' disease: Introduction, epidemiology, endogenous and environmental pathogenic factors. Ann Endocrinol Paris). 2018 Dec;79 6 599 607. Open 6. Burch HB, Cooper DS. Management of Graves Disease: A Review. JAMA. 2015 Dec 15;314 23 2544 54. Open 7. Smith TJ, Hegedus L. Graves' Disease. N Engl J Med. 2016 Oct 20;375 16 1552 1565. Open 8. Simone De Leo, Sun Y Lee, Lewis E Braverman. Hyperthyroidism. Lancet. 2016 Aug 27;388 10047 906 918. Open https://web.pathway.md/diseases/recjQ6d3sRPWEz3Ca 10/10