Graves Disease Guidelines

Updated: Jan 04, 2023
  • Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Guidelines Summary

American Thyroid Association

In 2016, the American Thyroid Association updated the 2011 hyperthyroidism/thyrotoxicosis guidelines it had codeveloped with the American Association of Clinical Endocrinologists. The following is a sampling of the 124 evidence-based recommendations included in the guideline update [101] :

  • Beta-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease
  • Patients with overt Graves hyperthyroidism should be treated with any of the following modalities: radioactive iodine therapy, antithyroid drugs, or thyroidectomy
  • If methimazole is chosen as the primary therapy for Graves disease, the medication should be continued for approximately 12-18 months and then discontinued if the serum TSH and TSH-receptor antibody levels are normal at that time
  • If surgery is chosen as the primary therapy for Graves disease, near-total or total thyroidectomy is the procedure of choice
  • If surgery is chosen as treatment for toxic multinodular goiter, near-total or total thyroidectomy should be performed
  • If surgery is chosen as the treatment for toxic adenoma, a thyroid sonogram should be done to evaluate the entire thyroid gland; an ipsilateral thyroid lobectomy (or isthmusectomy, if the adenoma is in the thyroid isthmus), should be performed for isolated toxic adenomas
  • Children with Graves disease should be treated with methimazole, radioactive iodine therapy, or thyroidectomy; radioactive iodine therapy should be avoided in very young children (< 5 years); radioactive iodine therapy in children is acceptable if the activity is over 150 μCi/g (5.55 MBq/g) of thyroid tissue and for children between ages 5 and 10 years if the calculated radioactive iodine administered activity is under 10 mCi (< 473 MBq); thyroidectomy should be chosen when definitive therapy is required, the child is too young for radioactive iodine, and surgery can be performed by a high-volume thyroid surgeon
  • If methimazole is chosen as the first-line treatment for Graves disease 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
  • If surgery is chosen as therapy for Graves disease in children, total or near-total thyroidectomy should be performed
  • Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with Graves ophthalmopathy or risk factors for the development of ophthalmopathy
  • In patients with Graves hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, radioactive iodine therapy, antithyroid drugs, and thyroidectomy should be considered equally acceptable therapeutic options
  • In Graves disease patients with mild Graves ophthalmopathy who are treated with radioactive iodine, steroid coverage is recommended if there are concomitant risk factors for Graves ophthalmopathy deterioration

European Group on Graves' Orbitopathy

In 2021, the European Group on Graves' Orbitopathy (EUGOGO) published clinical practice guidelines for the medical management of Graves ophthalmopathy. [73]  Some highlights are as follows:

  • Standardized criteria should be used to assess the clinical activity and severity of Graves ophthalmopathy, with the condition classified as active or inactive, and mild, moderate to severe, or sight threatening; the EUGOGO quality-of-life questionnaire for Graves ophthalmopathy is a recommended tool
  • Smoking cessation should be urged
  • All patients should be rendered euthyroid
  • Oral glucocorticoid prophylaxis should be prescribed to radioactive iodine–treated patients at risk of progression or new ophthalmopathy (smokers, patients with severe/unstable hyperthyroidism, individuals with high TSI); patients with inactive ophthalmopathy can receive radioactive iodine without prophylactic glucocorticoid if the above risk factors are absent; the high-risk regimen is 0.3-0.5 mg/kg, tapered off over 3 months; the low-risk regimen is 0.1-0.2 mg/kg, tapered off over 6 weeks 
  • Moderate to severe and active cases - intermediate dose IV methylprednisolone (0.5 g once weekly x6, then 0.25 g once weekly x6, totaling 4.5 g); more severe cases (eg, diplopia, severe proptosis): high-dose IV methylprednisolone (0.75 g once weekly x6, then 0.5 g once weekly x6, totaling 7.5 g).
  • Local subconjunctival/periocular injections of triamcinolone acetate may be one alternative if systemic glucocorticoids are contraindicated
  • Hyperthyroidism should be treated with anti-thyroid drugs until the ophthalmopathy therapy is finished

First-line treatment for moderate to severe and active ophthalmopathy

First-line treatment for moderate to severe and active ophthalmopathy includes the following:

  • IV methylprednisolone in combination with oral mycophenolate
  • In the more severe forms (such as those characterized by diplopia [constant or not], exophthalmos >25 mm, and severe inflammatory signs), monotherapy with IV methylprednisolone, the cumulative dose being 7.5 g per cycle

Second-line treatment for moderate to severe and active ophthalmopathy

Second-line treatments for moderate to severe and active ophthalmopathy are used If response to primary/first-line treatment is poor. The following second-line treatments should be considered after careful eye examination and measurement of liver enzymes:

  • Monotherapy with a second course of IV methylprednisolone, commencing with high, single doses (0.75 g), the maximal cumulative dose being 8 g per cycle
  • Radiotherapy to the orbit (in combination with glucocorticoids), particularly in patients with diplopia and/or extraocular motion defect
  • Cyclosporine plus oral glucocorticoids
  • Azathioprine plus oral glucocorticoids 
  • Tocilizumab
  • Teprotumumab - Very promising drug with a strong beneficial response; currently used in second-line treatment pending the availability of more clinical data
  • Rituximab - A second-line treatment for patients with moderate to severe and active ophthalmopathy of onset within less than 12 months and refractory to IV glucocorticoids; for use when no optic neuropathy is present

Sight-threatening Graves ophthalmopathy

Guidelines for managing sight-threatening Graves ophthalmopathy include the following:

  • Urgent treatment should be provided for severe corneal exposure, either medically or via increasingly more invasive surgeries, so that there is no progression to corneal breakdown; corneal breakdown should immediately be managed surgically

Thyroid treatment in patients with Graves ophthalmopathy

Thyroid treatment in patients with Graves ophthalmopathy includes the following:

  • Mild and inactive Graves ophthalmopathy - The preferred management is with antithyroid drugs or thyroidectomy; if radioactive iodine is employed, prophylaxis with prednisone/prednisolone should be used
  • Moderate to severe, but long-standing and inactive, ophthalmopathy - Treatment should be the same as for mild and inactive Graves ophthalmopathy, but consider prednisone/prednisolone prophylaxis if choosing radioactive iodine treatment, especially in patients with risk factors for ophthalmopathy (smoking, high TSH-receptor antibodies)