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Graves Disease
Jasmine S. Beria, DO, MPH
Oksana Davydov, MD
image BASICS
DESCRIPTION
Autoimmune disease in which thyroid-stimulating antibodies cause increased thyroid function; most common cause of hyperthyroidism. Classic findings are goiter, ophthalmopathy (orbitopathy), and occasionally dermopathy (pretibial or localized myxedema).
EPIDEMIOLOGY
Prevalence
  • Overall prevalence of hyperthyroidism in United States: ˜2% for women and 0.2% for men
  • More common in white and Hispanic populations in comparison to the black population
  • Graves disease accounts for 60-80% of all cases of hyperthyroidism.
  • Hyperthyroidism occurs in 0.2% of pregnancies, of which 95% is due to Graves disease.
  • Predominant age: 30 to 40 years
  • Synonym(s): Basedow disease
ETIOLOGY AND PATHOPHYSIOLOGY
  • Excessive production of thyroid-stimulating hormone (TSH) receptor antibodies from B cells primarily within the thyroid, likely due to genetic clonal lack of suppressor T cells
  • Binding of these antibodies to TSH receptors in the thyroid activates the receptor, stimulating thyroid hormone synthesis and secretion as well as thyroid growth (leading to goiter).
  • Binding to similar antigen in retro-orbital connective tissue causes ocular symptoms.
Genetics
Higher risk with personal or family history of any autoimmune disease, especially Hashimoto thyroiditis
RISK FACTORS
  • Female gender
  • Postpartum period
  • Stressful life events
  • Medications: iodine, amiodarone, lithium, highly active antiretroviral (HAART); rarely, immune-modulating medications (e.g., interferon therapy)
  • Smoking (higher risk of developing ophthalmopathy)
GENERAL PREVENTION
Screening TSH in asymptomatic patients is not recommended. No data conclusively show that treatment of subclinical thyroid dysfunction improves quality of life or clinical outcome measures.
COMMONLY ASSOCIATED CONDITIONS
  • Mitral valve prolapse
  • Type 1 diabetes mellitus
  • Addison disease, hypokalemic periodic paralysis
  • Vitiligo, alopecia areata
  • Other autoimmune disorders (myasthenia gravis, celiac disease)
image DIAGNOSIS
Hyperthyroid patients appear hypermetabolic with increased adrenergic tone.
PHYSICAL EXAM
  • Ophthalmologic (present in 50% of cases): Grittiness/discomfort in the eyes, retrobulbar pressure/pain, lid lag/retraction, proptosis, ophthalmoplegia, papilledema, and loss of color vision may signify optic neuropathy.
  • Thyroid: enlarged (goiter), nontender, and without nodules; possible bruit (increased blood flow)
  • Integumentary: fine hair, warm skin, onycholysis, palmar erythema, possible pretibial myxedema (orange peel appearance), possible hyperpigmented plaques (dermopathy)
  • Cardiac: resting tachycardia, hyperdynamic circulation, possible atrial fibrillation
  • Extremities: fine tremor, hyperreflexia, proximal myopathy; rarely, soft tissue edema of extremities and clubbing of digits (acropachy)
DIFFERENTIAL DIAGNOSIS
  • Toxic multinodular goiter (multiple hormone-producing nodules)
  • Toxic adenoma (single hormone-producing nodule)
  • Thyroiditis (hormone leakage)
    • Subacute, usually postviral (thyroid will be tender)
    • Lymphocytic, including postpartum
    • Hashimoto thyroiditis (antithyroperoxidase [TPO] antibodies may stimulate TSH receptors)
  • Iatrogenic (treatment-induced)
    • Iodine-induced (dietary, radiographic contrast, or medications)
    • Amiodarone
    • Thyroid hormone overreplacement (accidental or intentional)
  • Tumor
    • Pituitary adenoma producing TSH
    • Human chorionic gonadotropin (hCG)-producing tumors (stimulate TSH receptors)
    • Extraglandular thyroid hormone production (e.g., struma ovarii or metastatic thyroid cancer)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • TSH is initial test: Suppressed (low or undetectable) TSH confirms hyperthyroidism.
  • Free T4 level will be high in Graves disease.
  • After confirming suppressed TSH and high T4, perform radioactive iodine uptake (RAIU) and scan. Patients with Graves disease will have diffuse, elevated RAIU (vs. localized/nodular elevated uptake in adenoma and multinodular goiter and decreased uptake in thyroiditis or exogenous thyroid hormone).
Pregnancy Considerations
Increase in serum T4-binding globulin concentration and initial stimulation of TSH by hCG results in a total T4 and T3 rise during first half of pregnancy. The TSH level is decreased throughout pregnancy and should be compared to the trimester-specific ranges for pregnancy. Measurement of thyrotropin receptor antibody (TRAb) is positive in 95% of patients with Graves and should be used if diagnosis is unclear in pregnancy (2)[B].
image TREATMENT
MEDICATION
Goal is to correct hypermetabolic state with the fewest side effects and lowest incidence of posttreatment hypothyroidism.
First Line
  • &bgr;-Blockers provide prompt control of adrenergic symptoms; start while workup is in progress. Long-acting propranolol is used most commonly and titrated to symptom control (40 to 320 mg/day). Calcium channel blockers are an alternative in patients who cannot take &bgr;-blockers (3)[C].
  • Radioactive iodine (RAI)
    • Concentrates in the thyroid gland and destroys thyroid tissue
    • Radioiodine plus prednisone therapy might have the least probability of leading to an exacerbation or new appearance of ophthalmopathy, and radioiodine therapy might have the least probability of causing a recurrence (4)[A].
    • Treatment of choice for definitive therapy of hyperthyroidism, in the absence of moderate or severe orbitopathy (4)[A]
    • High cure rate with single treatment, especially with high-dose regimen
    • Risks: side effects (neck soreness, flushing, decreased taste); worsening ophthalmopathy (15% incidence, higher in smokers); posttreatment hypothyroidism (80% incidence, not dosage-dependent); radiation thyroiditis (1% incidence); need to adhere to safety precautions until radiation is eliminated from the body
    • May worsen Graves orbitopathy (GO): Symptoms are usually mild and transient in those patients with no or mild ophthalmopathy; however, treatment for patients with moderate to severe GO is still guided by expert opinion pending further study (5)[C].
    • Pretreatment with antithyroid medication should be considered in patients with severe disease and the elderly, to reduce risk of posttreatment transient hyperthyroidism and posttreatment radiation thyroiditis as well as quicker return to normal thyroid function. Controversy remains regarding whether pretreatment results in treatment failure, and no definitive data support use (6)[C].
    • May be repeated in as soon as 3 months but usually after 6 months if not euthyroid
Pregnancy Considerations
RAI is contraindicated in pregnancy and during breastfeeding.
  • Antithyroid drugs: methimazole (MMI) and propylthiouracil (PTU)
    • Compete with the thyroid for iodine, thereby decreasing the synthesis of thyroid hormone; PTU blocks peripheral conversion of T4 to T3.
    • P.429

    • Treatment of choice for children and for adults who refuse RAI
    • May use as pretreatment for older or cardiac patients before RAI or surgery
    • MMI is now almost exclusively used because of its longer duration of action, allowing for once daily dosing, more rapid efficacy, and lower incidence of side effects (2)[A].
    • No improvement in remission rates were noted with higher dose MMI; lowest effective dose should be used (7)[B].
    • Minor side effects (<5% incidence): controlled by switching from one agent to another: rash, fever, arthralgias, GI side effects
    • Major side effects necessitating change in treatment: polyarthritis (1-2%), agranulocytosis (<0.5%), and cholestasis/jaundice (rare)
    • Discontinue treatment after 1 year if patient is euthyroid.
    • 60% remission rate with 2 years of treatment (standard regimen); newer studies suggest no increased benefit to treatment beyond 18 months (8)[B].
    • Relapse rates up to 50% in patients who respond initially; higher rates if smoker, large goiter, or positive thyroid-stimulating antibodies at end of treatment.
Pregnancy Considerations
PTU is preferred in 1st trimester of pregnancy due to teratogenic effects of MMI. Switch to MMI in 2nd and 3rd trimesters due to risk of PTU-induced hepatotoxicity (9)[A].
ISSUES FOR REFERRAL
  • Endocrinologist for RAI therapy; if patient is pregnant or breastfeeding
  • Graves ophthalmopathy
  • Surgery if failed drug therapy or refusing RAI; obstruction or cosmesis
ADDITIONAL THERAPIES
  • Symptom control may be achieved with iodides, which block conversion of T4 to T3 and inhibit TSH release. Use for pregnant patients who do not tolerate antithyroid medication or in conjunction with antithyroid medications; should not be used long term (may cause paradoxical increase in TSH release) or in combination with radioactive iodine.
  • For corneal protection: tinted glasses when outdoors, artificial tears, patching/taping the lids at night
  • For orbitopathy: Mild cases can be treated with lubricants, nocturnal ointments, botulinum toxin injection for upper lid retraction, and smoking cessation (10)[C]. Moderate to severe cases should be treated with pulse-dose IV glucocorticoid if no contraindications (11)[C]. Alternative is PO steroid (prednisone 60 to 80 mg/day for 2 to 4 weeks, then taper off).
  • For dermopathy, medium- to high-potency topical corticosteroid
SURGERY/OTHER PROCEDURES
With regard to ophthalmopathy progression, postoperative bleeding, permanent hypoparathyroidism, temporary and permanent recurrent laryngeal nerve palsy—total thyroidectomy (TT) is consistent with subtotal thyroidectomy (ST) in patients with Graves disease. However, TT is associated with a reduced incidence of recurrent hyperthyroidism and results in an increase in temporary hypoparathyroidism (12)[A].
COMPLEMENTARY & ALTERNATIVE MEDICINE
Nutritional supplementation with L-carnitine may act as an antagonist of thyroid hormone and reduce hyperthyroid symptoms as well as decrease bone demineralization.
INPATIENT CONSIDERATIONS
Indications for hospital admission:
  • Thyroid storm (rare but a life-threatening complication): Admit to ICU.
  • Ophthalmopathy with visual impairment: severe cardiac symptoms (heart failure, rapid atrial fibrillation, angina)
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monitoring is for the resolution of hyperthyroidism and for the development of hypothyroidism.
  • Check TSH and T4 levels every 1 to 2 months for the first 6 months after treatment, then every 3 months for a year, then every 6 to 12 months thereafter. For patients on treatment with PTU and MMI, check CBC yearly. Also, check anti-TSH receptor antibodies at 12 months of treatment to determine possibility of discontinuing medication.
Pregnancy Considerations
Postpartum exacerbation of hyperthyroidism is common for women not currently under treatment, so TSH and symptoms should be monitored.
PATIENT EDUCATION
Adherence to both follow-up surveillance and medication regimens is the most important way to achieve a good outcome and promote lifelong health.
PROGNOSIS
  • Generally good with treatment
  • May have irreversible ocular, cardiac, and psychiatric consequences
  • Increased morbidity and mortality due to osteoporosis, atherosclerotic disease, insulin resistance and obesity, and endothelial cell dysfunction (thromboembolic risk)
REFERENCES
1. Bartalena L. The dilemma of how to manage Graves' hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab. 2011;96(3):592-599.
2. Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21(6):593-646.
3. Reid JR, Wheeler SF. Hyperthyroidism: diagnosis and treatment. Am Fam Physician. 2005;72(4):623-630.
4. Ren Z, Qin L, Wang JQ, et al, Comparative efficacy of four treatments in patients with Graves' disease: a network meta-analysis. Exp Clin Endocrinol Diabetes. 2015;123(5):317-322.
5. Boelaert K, Torlinska B, Holder RL, et al. Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study. J Clin Endocrinol Metab. 2010;95(6):2715-2726.
6. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab. 2009;94(6):1881-1882.
7. Helfand M. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004;140(2):128-141.
8. Maugendre D, Gatel A, Campion L, et al. Antithyroid drugs and Graves' disease—prospective randomized assessment of long-term treatment. Clin Endocrinol. 1999;50(1):127-132.
9. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125.
10. Melcescu E, Horton WB, Kim D, et al. Graves orbitopathy: update on diagnosis and therapy. South Med J. 2014;107(1):34-43.
11. Zang S, Ponto KA, Kahaly GJ. Clinical review: intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011;96(2):320-332.
12. Guo Z, Yu P, Liu Z, et al. Total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves' diseases: a meta-analysis of randomized clinical trials. Clin Endocrinol. 2013;79(5):739-746.
See Also
&NA;
Algorithms: Anxiety; Cardiac Arrhythmias; Weight Loss, Unintentional
Codes
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ICD10
  • E05.00 Thyrotoxicosis w diffuse goiter w/o thyrotoxic crisis
  • E05.01 Thyrotoxicosis w diffuse goiter w thyrotoxic crisis or storm
  • E05.20 Thyrotxcosis w toxic multinod goiter w/o thyrotoxic crisis
Clinical Pearls
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Thyroid hormone controls metabolic rate and affects many organ systems. Hyperthyroid patients appear hypermetabolic, with symptoms and signs of increased adrenergic tone.