Graves Disease in Adults

Background

• Graves disease is an autoimmune disorder characterized by thyroidal (hyperthyroidism and goiter) and extra-thyroidal (Graves orbitopathy [GO], pretibial myxedema, and Graves acropachy) manifestations.
• Graves disease is the most common cause of hyperthyroidism. It occurs in all age groups and is more common in females than males.
• It is caused by interplay between genetic (for example, polymorphisms in genes encoding thyrotropin receptor and proteins involved in T-cell signaling) and environmental factors (such as excess dietary iodine, exposure to tobacco smoke, infections, and emotional stress) leading to formation of activating thyrotropin-receptor antibodies that induce thyroid hormone overproduction.
• Exacerbation of Graves disease may lead to thyroid storm, a potentially life-threatening endocrine emergency with severe signs and symptoms of thyrotoxicosis and multiorgan decompensation.

Evaluation

• The clinical presentation of patients with Graves disease varies depending on the age of onset, severity and duration of hyperthyroidism, sex and comorbidities. Patients typically present with symptoms and signs of ≥ 1 of:
  • hyperthyroidism, such as palpitations, tremor, weight loss, or sweating
  • goiter, such as diffuse thyroid enlargement (with or without thrill or bruit), and rarely symptoms of upper airway and esophageal obstruction causing globus sensation, dysphagia, or orthopnea
  • extrathyroidal manifestations of underlying autoimmunity including orbitopathy (may present with proptosis and upper eyelid retraction), thyroid dermopathy (also called pretibial myxedema, characterized by nodular or diffuse thickening of skin in pretibial area), and rarely acropachy (characterized by soft tissue swelling and clubbing of fingers and toes)
• Older adults may have an atypical presentation, consisting of depressed mood, fatigue, and weight loss (apathetic hyperthyroidism).
• Diagnosis of Graves disease is based on characteristic clinical features and biochemical abnormalities.
• Initial biochemical testing in patients presenting with signs and symptoms suggestive of hyperthyroidism includes serum thyroid-stimulating hormone (TSH) assay and thyroid hormone levels (free thyroxine [FT4] and total or free tri-iodothyronine [TT3 or FT3]).
  • If the patient has a symmetrically enlarged thyroid, recent development of orbitopathy, and moderate-to-severe hyperthyroidism persisting for 2 months or more, Graves disease is likely and further evaluation for cause of hyperthyroidism is unnecessary.
  • If the patient is thyrotoxic with a non-nodular thyroid and no definite orbitopathy, measure thyrotropin receptor antibody (TRAb) and/or radioactive iodine uptake. A thyroid uptake and scan should be obtained if the thyroid is nodular (with correlation with ultrasound).
  • Graves disease is indicated if there is thyrotoxicosis (low TSH, and elevated or normal FT4 or TT3 or FT3) if:
    • TRAb or (or thyroid-stimulating immunoglobulin [TSI]) is present
    • radionuclide scan shows homogenous increase in uptake
• GO is suggestive by clinical presentation, assessment of activity and severity of orbitopathy using standardized criteria, and orbital imaging.
  • Common clinical features of GO include eyelid retraction, eyelid lag, edema, erythema of the periorbital tissue and conjunctivae, and proptosis (exophthalmos).
  • Various scoring systems can be used to assess GO activity and severity.

Management

• Give beta-blockers for patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rate > 90 beats/minute or concurrent cardiovascular disease, until thyroid hormone levels are normalized (Strong recommendation).
• Treat Graves hyperthyroidism with antithyroid medications, radioactive iodine, or thyroidectomy (Strong recommendation).
  • Antithyroid medication is preferred as first-line treatment to normalize thyroid hormone production for pregnant women, patients with active Graves orbitopathy (GO), and patients with a high likelihood of remission (mild disease, small goiter, negative or low-titer TRAb).
    • If antithyroid medication is chosen as initial treatment, administer methimazole (MMI), except in women during the first trimester of pregnancy (in which case propylthiouracil is preferred), patients with thyroid storm, and patients with minor reactions to MMI who refuse radioactive iodine therapy or surgery (Strong recommendation).
    • Continue MMI for 12-18 months, then taper or discontinue if TSH and TRAb levels are normal (Strong recommendation).
    • If the patient is not in remission, consider continuing low-dose MMI treatment for > 12-18 months (and if this option is preferred by patient) (Weak recommendation).
    • If the patient becomes hyperthyroid after completing MMI treatment, consider treatment with radioactive iodine or thyroidectomy (Weak recommendation).
    • Major adverse effects (reported in about 0.2%-0.3%) include agranulocytosis, hepatotoxicity, and antineutrophil cytoplasmic antibody-associated vasculitis.
  • Radioactive iodine (given orally) may be preferred as first-line treatment in patients with contraindications to antithyroid medications and comorbidities increasing surgical risk.
    • Prior to radioactive iodine administration:
      • in women with childbearing potential
        • obtain pregnancy test within 48 hours prior to radioactive iodine treatment and confirm negative result prior to administering radioactive iodine (Strong recommendation)
        • radioactive iodine is contraindicated in women who are breastfeeding or planning to become pregnant in the next 4-6 months
      • in patients who are at increased risk for complications due to worsening hyperthyroidism (such as older adults and patients with coexisting conditions, such as cardiovascular complications), consider pretreatment with a beta-blocker and MMI (the latter should be discontinued 2-3 days prior to RAI administration and may be resumed 3-7 days afterwards) (Weak recommendation)
    • Administer adequate radiation in a single dose to render patients hypothyroid (Strong recommendation).
    • Perform a follow-up evaluation that includes (Strong recommendation):
      • FT4, TT3, and TSH levels at 1-2 months after radioactive iodine therapy (thyroid function tests)
      • continued biochemical monitoring at 4- to 6-week intervals for 6 months or until patient is hypothyroid and stable on thyroid hormone replacement, or stably euthyroid
    • When patients develop hypothyroidism (FT4 level below normal range), give levothyroxine. The dose should initially be determined based on FT4, as TSH may not rise immediately, taking into consideration residual thyroid function (may require lower dosage than full replacement), but later adjusted and monitored based on TSH levels.
  • Thyroidectomy may be preferred as first-line treatment for symptomatic compression, large goiter, thyroid glands with relatively low uptake of radioactive iodine, documented or suspected thyroid malignancy, coexisting hyperparathyroidism requiring surgery, especially if TRAb levels are particularly high, and patients with moderate-to-severe active GO.
    • If surgery is chosen as the primary therapy for Graves disease, perform a near-total or total thyroidectomy (Strong recommendation). Definitive therapy may be accomplished with near-total thyroidectomy.
    • Preoperative considerations:
      • Render patients euthyroid with antithyroid medication with or without beta-blockers (Strong recommendation).
      • Stop antithyroid drugs at time of thyroidectomy and wean beta-blockers after surgery (Strong recommendation).
      • Administer potassium iodide formulation in immediate preoperative period to help prevent blood loss (Strong recommendation).
      • Assess calcium and 25-hydroxyvitamin D levels preoperatively and replete or administer prophylactically if needed (Strong recommendation).
      • Consider calcitriol supplementation preoperatively in patients at increased risk for transient or permanent hypoparathyroidism (Weak recommendation).
    • Postoperative follow-up:
      • Consider oral calcium and calcitriol supplementation based on results of serum calcium measurement with or without intact parathyroid hormone (iPTH) levels or empiric prophylactic administration of oral calcium with or without calcitriol (Weak recommendation).
      • Start levothyroxine at a daily dose appropriate for the patient's weight (0.8 mcg/lb or 1.6 mcg/kg) (elderly patients may require somewhat less), and measure serum TSH 6-8 weeks postoperatively (Strong recommendation).
• Management of GO
  • Refer patients with overt GO or mild GO at risk for deterioration (including patients with clinically active GO, tobacco use, severe/unstable hyperthyroidism, or high serum TRAB levels) to combined thyroid-eye clinics or specialized centers with endocrinological and ophthalmological expertise (Strong recommendation).
  • For all patients with GO:
    • Urge smoking cessation for all patients with Graves disease, regardless of whether GO is present (Strong recommendation).
    • Promptly restore and maintain euthyroidism (Strong recommendation).
    • Treat all patients with GO extensively with preservative-free artificial tears with osmoprotective properties at all times during the course of the disease unless higher protection (use of gels or ointments) is required due to corneal exposure (Strong recommendation).
  • For patients with mild GO:
    • Provide local treatments (such as artificial tears) and general measures to control risk factors (Strong recommendation).
    • If impact of disease on quality-of-life outweighs risks, consider immunosuppressive therapy for active GO or rehabilitative surgery for inactive GO following extensive counseling and a shared decision-making process with the patient (Weak recommendation).
    • Selenium supplementation for 6 months can be used for patients with mild GO of relatively short duration to improve symptoms and prevent progression of GO.
  • For patients with moderate-to-severe and active GO:
    • Methylprednisolone IV is the preferred first-line treatment in those without significant proptosis or diplopia.
      • For most patients, administer methylprednisolone at starting dose of 0.5 g IV once weekly for 6 weeks, followed by 0.25 g IV once weekly for 6 weeks (cumulative dose 4.5 g) (Strong recommendation).
      • For worst cases within the moderate-to-severe and active GO spectrum, use high dose regimens with starting dose 0.75 g IV once weekly for 6 weeks followed by 0.5 g IV once weekly for 6 weeks (cumulative dose 7.5 g) (Strong recommendation).
    • In those with significant proptosis or diplopia, the preferred first-line therapy is with IV teprotumumab starting at 10 mg/kg IV infusion, then subsequent doses at 20 mg/kg IV infusion every 3 weeks (for total of 8 infusions including initial dosage).
    • Second-line treatment options which should be considered (following careful ophthalmic evaluation and assessment of liver enzymes) in patients with poor response to primary treatment include (Strong recommendation):
      • an additional course of methylprednisolone IV monotherapy, starting with high single doses (0.75 g) and a max cumulative dose of 8 g per cycle
      • prednisone/prednisolone orally combined with either cyclosporine or azathioprine
      • orbital radiation therapy combined with glucocorticoids (oral or IV) (may be particularly useful in patients with diplopia and/or restriction of extraocular motility)
      • other medications, including:
        • tocilizumab
        • rituximab
          • reserve for patients in whom dysthyroid optic neuropathy can be excluded
          • treatment should be applied at experienced centers only due to potentially serious adverse events
  • For patients with sight-threatening GO:
    • Treatment of sight-threatening GO (an emergency) is the highest priority; additionally, hyperthyroidism should be treated with antithyroid drugs until treatment of GO is completed (Strong recommendation).
    • For severe corneal exposure, urgent treatment using medications or progressively more invasive surgeries is indicated to avoid corneal breakdown, which requires immediate surgical repair (Weak recommendation).
    • For patients with optic neuropathy, administer high-dose glucocorticoids (methylprednisolone 0.5-1 g IV daily for 3 consecutive days or alternate days during first week) (Strong recommendation) and consider adding radiation therapy to glucocorticoid therapy. Perform urgent orbital decompression if poor or no response within 1-2 weeks (Strong recommendation).
    • For recent eyeball subluxation, perform orbital decompression as soon as possible (Strong recommendation).
• Additional treatment considerations for hyperthyroidism may be required for patients with or at risk of developing GO, women who are pregnant or lactating, thyroid storm, and subclinical hyperthyroidism.