Topic Editor: Robert Giles, MBBS, BPharm

Review Date: 12/08/2012

Definition

Graves' disease is an autoimmune disease in which thyroid-stimulating autoantibodies bind to thyroid cells and activate the thyrotropin receptor (thyroid stimulating hormone receptor). Activation leads to thyroid gland enlargement, increased thyroid hormone production and thyrotoxicosis. Extrathyroidal manifestations of Graves' disease are common and include opthalmopathy, dermopathy and acropachy (digital clubbing, digital swelling, periosteal reaction of bones in the extremities)

Description

• Graves' disease is the most common cause of hyperthyroidism in the developed world
• Patients present with clinical manifestations of thyrotoxicosis plus diffuse goiter, opthalmopathy, dermopathy and acropachy (digital clubbing, digital swelling and periosteal reaction of bones in the extremities)
• Antibodies directed against thyrotropin receptors target the endothelial surface of thyroid cells, causing follicular hypertrophy and hyperplasia plus excess thyroid hormone secretion
• Immunologic features include high serum concentration of antibodies against thyroglobulin, thyroid peroxidase, and the sodium iodide co-transporter in thyroid tissue
• Graves' disease is primarily treated with radioactive iodine therapy, antithyroid drugs or surgery. Adjunctive therapy may be needed to control symptoms in thyrotoxic patients

Epidemiology

Incidence/Prevalence

• Graves' disease is the most common autoimmune disorder in the United States
• Prevalence of hyperthyroidism is estimated to be 2% in women and 0.2% in men. 60- 80% of all hyperthyroidism in the United States is due to Graves' disease

• Peak incidence is between 40 to 60 years

Gender

• Graves disease is 5-10 times more common in females compared with males

Genetics

• PTPN22 and CTLA-4 genes increase susceptibility to autoimmune thyroid diseases which include Graves' disease
• Concordance rate is 20% among monozygotic twins but lower among dizygotic twins and HLA-identical siblings

Risk factors

• Environmental toxins
• Excessive iodine intake
• Female gender due to the modulation of autoimmune responses by estrogens
• Family history
• Infection
• Medications such as amiodarone, lithium, radioactive iodine, highly active antiretroviral therapy (HAART), and interferon
• Postpartum period
• Smoking
• Stressful life events
• Trauma to the thyroid gland (e.g., thyroid manipulation/surgery)

Etiology

• Autoimmune antibodies are produced against the TSH receptor antigen. Binding of these antibodies to the receptor mimics the effects of TSH and stimulates thyroid follicles to produce excessive thyroid hormone
• Unlike a normally regulated system there is no negative/suppressant feedback response
• An interplay between genetics and the environment is implicated in causing the autoreactivity of T and B cells in Graves' disease.

History

• Cardiovascular
• Chest Pain
• Dyspnea
• Edema
• Palpitations
• Dermatologic
• Goiter
• Heat intolerance and sweating
• Hyperpigmented skin
• Rapid hair shedding causing diffuse hair loss and thinning
• Pruritis/hives
• Soft and loosened fingernails
• Unusually soft skin
• Warm and clammy skin
• Gastrointestinal/renal
• Diarrhea / Hyperdefecation
• Dysphagia (secondary to goiter)
• Polyuria/ polydipsia
• Vomiting
• Metabolic
• Poor diabetic control
• Weight loss: Despite an increased appetite and increased caloric intake, loss of both fat and lean body mass is commonly found in patients with Graves' disease. Weight loss is especially prevalent in older patients
• Neuromuscular symptoms
• Fatigue
• Hyperactivity
• Muscle weakness
• Tremor
• Ophthalmologic
• Eyelid lag
• Diplopia
• Proptosis
• Stare
• Psychiatric
• Anxiety
• Agitation
• Dysphoria/depression
• Insomnia
• Irritability
• Nervousness
• Psychosis
• Reproductive
• Gynecomastia
• Loss of libido
• Oligomenorrhea

Physical findings on examination

• Graves' disease can usually be diagnosed clinically with hyperthyroidism confirmed on laboratory studies
• Physical examination reveals thyroid enlargement (goiter) in most patients
• Signs of thyrotoxicosis include sinus tachycardia, atrial fibrillation, systolic hypertension, high cardiac output, profuse perspiration, erythema, sweaty palms, tremor, hyperkinesis, large-muscle weakness, hyperreflexia and soft, smooth skin
• Ophthalmopathy:
• Hyperthyroidism is found in 90% of the patients with ophthalmopathy
• Older male smokers have the highest risk of ophthalmopathy
• Frequent signs of ophthalmopathy include:
• Eyelid lag or retraction
• Exophthalmos (proptosis)
• Extraocular-muscle dysfunction
• Exposure keratitis
• Feeling of grittiness and discomfort in the eye
• Optic neuropathy
• Periorbital edema, chemosis, scleral injection
• Retrobulbar pressure or pain
• Localized dermopathy (pretibial myxedema) and thyroid acropachy (digital clubbing, digital swelling, periosteal reaction of bones in the extremities) are rare signs observed in less than 1% of patients. Dermopathy may occur at any site (especially after trauma) but is commonly found on the anterolateral aspect of the shin
• Atypical presentations of hyperthyroidism:
• Anemia
• Angioedema
• Erythema annulare centrifugum
• Heart block
• Jaundice
• Leukopenia/thrombocytopenia
• Myocardial infarction (MI)
• Pancytopenia
• Pulmonary hypertension
• Right heart failure

Blood test findings

• A complete thyroid panel evaluates serum levels of TSH, Free T4, Free T3, Total T4 and Total T3
• TSH level is the first test which should be ordered upon suspicion of thyroid dysfunction (hyper/hypothyroidism). A normal result effectively rules out primary thyroid dysfunction (including Graves' disease). An abnormal result should be followed by further investigations to identify the cause of dysfunction and to directly measure thyroid hormone levels
• A low/undetectable TSH level is diagnostic of thyrotoxicosis (rarely due to primary pituitary failure)
• Total T3 and total T4 are measures of both protein-bound and unbound hormone concentrations. Most circulating hormone is bound to thyroxine-binding globulin (TBG). Thus factors that alter concentration/binding of TBG may affect the utility of total T3/T4 assays
• Free T3 and Free T4 estimate the biologically active unbound (free) fraction of hormone and as such are not affected by fluctuations in TBG level or binding . Some laboratories are unable to directly measure free hormone levels and instead calculate values indirectly
• Patients with T3 toxicosis have an elevated T3 with a normal T4 and low TSH. T3 toxicosis is commonly found in Graves' disease and toxic multinodular goiter
• Thyroxine /triiodothyronine (T4/T3) ratio may be used when radioactive iodine uptake testing is contraindicated or unavailable. T3/T4 ratio >20 is consistent with diagnosis of Graves' disease or toxic nodular goiter
• Antibody testing:
• TSH-binding inhibitor immunoglobulin assay (TBII) which detects circulating TSH-receptor antibodies is generally not needed to diagnose Graves' disease but may be useful if the diagnosis is in doubt and radionuclide imaging is unavailable or contraindicated (e.g. pregnancy/breast feeding). It is also useful to predict the risk of thyrotoxicosis to the fetus or neonate when the mother is thyrotoxic . Persistent elevation is related to disease activity. Decreased activity may be observed in remission
• Thyroid peroxidase (TPO) antibodies test: Measures antibodies to the enzyme thyroid peroxidase. Levels are most often increased in patients with Hashimoto's thyroiditis but the test is nonspecific and levels may also be elevated in patients with Graves' disease
• Nonspecific laboratory findings include anemia, and elevation of blood glucose, calcium, transaminases (ALT and AST), and alkaline phosphatase

Radiological findings

• Radioactive imaging:
• Radionuclide scans are used to identify the cause of thyrotoxicosis
• Technetium-99m (Tc-99m) pertechnetate scintigraphy may be preferred over radioactive iodine uptake because of a rapid turnover and lower radioactivity exposure
• Radionuclide scans should be considered in a thyrotoxic patient without clinical features to definitively diagnose Graves' disease
• The total uptake and pattern of uptake of radionuclide isotopes helps characterize each disease
• Scans in Graves' disease usually reveal a diffuse increased uptake throughout the thyroid
• Thyroid ultrasonography
• Not generally required for the routine workup of thyrotoxic patients but may be useful when the diagnosis is uncertain and radioactive studies are contraindicated or not available
• Helps detect thyroid nodules and goiters that are not easily evident on examination
• May help differentiate Graves' disease from thyroiditis by quantitatively measuring blood flow
• Neck computed tomography (CT) or magnetic resonance imaging (MRI): Indicated only if a goiter is suspected of causing upper airway or thoracic inlet obstruction
• Orbital CT or MRI: Useful in cases where the cause of ophthalmopathy is uncertain

• Anxiety disorders
• Carcinoid syndrome
• Cocaine toxicity
• Delirium tremens
• Depression
• Diabetes Mellitus
• Drug induced thyrotoxicosis
• Euthyroid hyperthyroxinemia
• Factitious thyrotoxicosis
• Heat Stroke
• Hyperemesis Gravidarum
• Hypothalamic Stroke
• Malignancy
• Malignant hyperthermia
• Menopause
• Metastatic thyroid cancer
• Neuroleptic malignant syndrome
• Pheochromocytoma
• Pituitary macroadenomas
• Pituitary microadenomas
• Sepsis
• Struma ovarii
• Sympathomimetic ingestion
• Thyroid, papillary carcinoma
• Thyroiditis [lymphocytic (Hashimoto's), subacute granulomatous/viral, drug induced, postpartum)
• Thyrotropin-producing pituitary adenomas
• Toxic adenoma
• Toxic multinodular goiter

General treatment items

The treatment of Graves' disease involves symptom management followed by definitive therapy with either antithyroid medications, radioactive iodine or surgical thyroidectomy. All treatments are equally effective, with therapy individualized to the patient.

• Antithyroid medications:
• The thionamide antithyroid medications propylthiouracil (PTU) and methimazole are used to treat Graves' disease
• Thionamides major action is prevention of thyroid hormone synthesis by inhibiting thyroid peroxidase catalyzed reactions and interfering with the organification of iodine
• 90% of patients taking antithyroid therapy are euthyroid within several weeks of therapy
• 40% to 60% of patients achieve remission with prolonged therapy (12 to 18 months). The risk of relapse is >50%. There is little evidence to support the effectiveness of thionamides beyond 1to 2 years of treatment
• Due to easier dosing and a better safety profile methimazole is the preferred antithyroid agent in all patients except those with:
• Thyroid storm (PTU has an added effect of blocking deiodination of T4 to T3 which rapidly reduces serum T3 concentrations)
• Previous allergy to methimazole
• First trimester pregnancy (PTU has a lower risk of congenital abnormalities as compared with methimazole)
• Initiate antithyroid drug therapy at the lowest possible dose
• Thionamides have been associated with agranulocytosis and liver failure. Patients taking thionamides should undergo baseline blood testing and be aware of warning symptoms of hepatic and bone marrow failure
• Radioactive iodine:
• Radioactive iodine (¹³¹I) is taken up by the thyroid gland in a manner similar to natural iodine and is concentrated in thyroid tissue. Beta particle emission from ¹³¹I ablates the follicular cells leading to tissue destruction
• ¹³¹I is the preferred treatment for Graves' disease and may be used after failure of antithyroid therapy
• The goal of ¹³¹I therapy is to render the patient euthyroid or hypothyroid. Approximately 80% to 90% of patients are rendered euthyroid within 8 weeks of the initial ¹³¹I dose
• Antithyroid medication before ¹³¹I therapy may be considered in patients with severe thyrotoxicosis
• The American Thyroid Association advocates radioactive iodine as a safe and highly effective intervention, assuming appropriate post-treatment care is taken
• ¹³¹I therapy is contraindicated in pregnant women and lactating mothers due to the risk of damage to the fetus, and to a breastfeeding infant's thyroid gland
• ¹³¹I therapy may worsen ophthalmopathy in patients with Graves' disease if moderate-severe ophthalmopathy is pre-existing
• Thyroidectomy
• Thyroidectomy is less popular with most patients, but is indicated in:
• Active moderate-severe ophthalmopathy
• Allergy to or non-compliance with medications
• Large or obstructing goiters
• Pregnancy or those desiring pregnancy in the immediate future
• Refusal of radioactive iodine therapy
• Severe hyperthyroidism in a child
• Patients are usually rendered euthyroid using methimazole prior to the surgery
• Beta blockers and potassium iodide are also commonly used prior to surgery
• Subtotal thyroidectomy is the most commonly performed procedure however there is a recurrence rate of 8% at 5 years
• Total thyroidectomy has almost no risk of recurrence and is indicated when the possibility of recurrence is otherwise high, e.g., severe disease or large-sized goiters
• Levothyroxine (weight-based dose) should be initiated in patients following thyroidectomy
• Post-surgical complications may include recurrent laryngeal nerve injury, permanent hypoparathyroidism, transient hypocalcemia, hemorrhage, and infection
• Adjunctive therapy
• Beta blockers: Beta blockers such as atenolol, metoprolol, and propranolol can provide immediate symptomatic relief to thyrotoxic patients by inhibiting adrenergic effects. They are often used in conjunction with surgery, radioactive iodine, and thionamide therapy to relieve tachycardia, tremor, sweating and anxiety in thyrotoxic patients
• Levothyroxine: Interventions aimed at treating hyperthyroidism may cause hypothyroidism and if so, thyroid hormone will need to be replaced
• Potassium iodide: Owing to its rapid reduction of thyroid hormone levels, it may be used in patients with thyroid storm, or to reduce thyroid vascularity prior to thyroidectomy
• Treating ophthalmopathy
• Mild to moderate cases usually improve spontaneously with the following measures:
• Avoidance of bright light and dust
• Diuretic therapy
• Maintaining euthyroidism
• Sleeping with head raised
• Smoking cessation
• Use of artificial tears
• Use of simple eye ointments at night
• Non steroidal anti-inflammatory drugs (NSAIDS) may be useful in treating mild eye irritation Severe cases show improvement in two-thirds of patients if treated with high doses of glucocorticoids, orbital irradiation, or both. Orbital decompression may improve optic neuropathy and exophthalmos if used initially or following glucocorticoid therapy failure
• Higher doses of prednisone/prednisolone 100mg per day and lower dose regimes 30-40mg per day are considered by some to be equally effective
• High dose intravenous methylprednisolone 500mg initially, then 250mg weekly for 6 weeks showed improvement over oral prednisone in one trial other trials using similar dosing regimens appear to support benefit of high dose IV as compared to oral steroids

Medications indicated with specific doses

Antithyroid drugs

• Methimazole
• Adult Dosing
• Pediatric Dosing
• Propylthiouracil
• Adult Dosing
• Pediatric Dosing

• Sodium iodide I-131
• Adult Dosing

• Levothyroxine [Oral]
• Adult Dosing
• Pediatric Dosing

• Atenolol
• Adult Dosing
• Pediatric Dosing
• Metoprolol [Oral]
• Adult Dosing
• Pediatric Dosing
• Propranolol [Oral]
• Adult Dosing
• Pediatric Dosing

• Potassium iodide
• Adult Dosing
• Pediatric Dosing

• Prednisolone [Oral]
• Adult Dosing
• Prednisone
• Adult Dosing
• Pediatric Dosing
• Methylprednisolone [Injectable]
• Adult Dosing
• Pediatric Dosing

Dietary or Activity restrictions

• A small study found that nutritional supplementation with L-carnitine may be useful in treating symptoms of hyperthyroidism and have a beneficial effect on bone mineralization. Its therapeutic use is unknown at present

Disposition

Admission Criteria

• Impaired vision secondary to ophthalmopathy
• Intravenous drugs required to maintain heart rate
• Serious cardiovascular manifestations such as congestive heart failure (CHF), atrial fibrillation, or angina
• Severely symptomatic
• Thyroid storm

• Patients with good symptom control and response to oral medications may be discharged

Monitoring

• TSH measurement in patients being treated for hyperthyroidism should be repeated after a minimum of 3 months as there may be prolonged suppression of pituitary TSH. Free thyroxine levels should be measured to assess thyroid status during this time
• Patients receiving antithyroid medications should have thyroid function tests every 4-8 weeks until euthyroid levels are achieved with a focus on utilization of minimal doses of thionamides
• White blood cell count should be checked in all patients taking thionamides who develop fever and pharyngitis to aid the early detection of agranulocytosis. Thionamides may cause transient elevations of serum transaminases; LFTs should be monitored
• Therapeutic response to radioiodine treatment can be measured by observing the patients clinical features, gland size and thyroid function tests. Following therapy, patients should be monitored for relapse or hypothyroidism. Thyroid function tests should be carried out at 6 weeks, 12 weeks, 6 months, and annually thereafter once the patient is euthyroid

Complications

• Complications of Graves disease
• Atrial fibrillation
• Bone mineral loss
• CHF
• Dermopathy
• Endothelial dysfunction
• Obesity and insulin resistance following treatment
• Pulmonary hypertension
• Recurrent hyperthyroidism
• Visual impairment due to ophthalmopathy
• Complications of thyroidectomy
• Hypoparathyroidism
• Hypothyroidism
• Laryngeal nerve damage
• Permanent vocal cord palsy
• Complications of radioactive iodine therapy
• Postablation hypothyroidism
• Complications of antithyroid therapy
• Acute inflammatory hepatitis (rare)
• Agranulocytosis
• Aplastic anemia (rare)
• Leukopenia
• Lupus-like syndrome (rare)
• Polyarthritis syndrome
• Reversible cholestasis due to methimazole
• Thrombocytopenia (rare)
• Vasculitis (rare)

Prognosis

• Patients with hyperthyroidism have a good prognosis if treated appropriately
• Patients may develop irreversible ocular, cardiac, and psychological consequences even when treated aggressively
• There is an increased risk of all-cause mortality from cardiovascular/cerebrovascular diseases, and hip fractures due to bone mineral density loss
• Treatment of hyperthyroidism may make patients more susceptible to obesity and insulin resistance

Associated conditions

• Addison's disease
• Alopecia areata
• Celiac disease
• Hypokalemic periodic paralysis
• Mitral valve prolapse
• Myasthenia gravis
• Other autoimmune disorders associated with the HLA-DR haplotype
• Pernicious anemia
• Type 1 diabetes mellitus
• Vitiligo

Pregnancy/pediatric effects on the condition

• Untreated hyperthyroidism during pregnancy may result in serious adverse maternal, fetal, and neonatal outcomes
• Adverse maternal outcomes include spontaneous abortion, pregnancy-induced hypertension, heart failure, premature labor, placental abruption and thyroid storm
• Adverse fetal and neonatal outcomes include fetal growth impairment, preterm birth, stillbirth, low birth weight, hyper/hypothyroidism and goiter
• Graves' hyperthyroidism has a higher likelihood of relapse both during pregnancy and during the year following delivery
• PTU is the preferred drug during the first trimester of pregnancy following which patients should be switched to methimazole. Treatment with the lowest effective dose is recommended
• Treatment with radioiodine is absolutely contraindicated during pregnancy and lactation. Thyroidectomy is preferable if intolerance to PTU occurs
• Continued monitoring of thyroid function following parturition is recommended until the patient becomes euthyroid

Synonyms/Abbrevations

Synonyms

• Thyrotoxicosis

ICD-9-CM

• 242.00 Toxic diffuse goiter without mention of thyrotoxic crisis or storm
• 242.01 Toxic diffuse goiter with mention of thyrotoxic crisis or storm

ICD-10-CM

• E05 Thyrotoxicosis [hyperthyroidism]

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