Graves’ Disease – Causes, Symptoms, Treatment

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Graves’ disease is an¬†autoimmune disorder¬†that causes¬†hyperthyroidism¬†or overactive thyroid. With this disease, your¬†immune system¬†attacks the thyroid and causes it to make more thyroid¬†hormone¬†than your body needs. The thyroid is a small, butterfly-shaped gland in the front of your neck. Thyroid hormones control how your body uses energy, so they affect nearly every organ in your body‚ÄĒeven the way your heartbeats.

Graves’ disease is the most common cause of hyperthyroidism. It is a disorder with systemic manifestations that primarily affect the heart, skeletal muscle, eyes, skin, bone, and liver. Failure to diagnose Graves’ disease in a timely manner can predispose to thyroid storm which carries high morbidity and mortality. Clinicians ought to be aware of systemic manifestations of Graves’ disease and the different modalities available for treatment. Early diagnosis and management of Graves’ disease can also prevent severe cardiac complications such as atrial flutter, atrial fibrillation, and high output cardiac failure. This activity reviews the evaluation and treatment of Graves’ disease and highlights the role of the interprofessional team in reducing morbidity and improving care for affected patients.

Graves’ disease is an autoimmune disease that primarily affects the thyroid gland. It may also affect multiple other organs including eyes and skin. It is the most common cause of hyperthyroidism. In this chapter, we attempt to review different aspects of Graves‚Äô disease.

Causes of Graves’ Disease

Like all autoimmune diseases, it occurs more commonly in patients with a positive family history. It is more common in monozygotic twins than in dizygotic twins. It is precipitated by environmental factors like stress, smoking, infection, iodine exposure, and postpartum, as well as after highly active antiretroviral therapy (HAART) due to immune reconstitution.

Genetics

A¬†genetic¬†predisposition for Graves’ disease is seen, with some people more prone to develop¬†TSH receptor¬†activating antibodies due to a genetic cause.¬†Human leukocyte antigen¬†DR (especially DR3) appears to play a role.[10]¬†To date, no clear genetic defect has been found to point to a¬†single-gene¬†cause.

Genes believed to be involved include those for¬†thyroglobulin,¬†thyrotropin receptor,¬†protein tyrosine phosphatase nonreceptor type 22, and¬†cytotoxic T-lymphocyte‚Äďassociated antigen 4, among others.[rx]

Infectious trigger

Since Graves’ disease is an autoimmune disease that appears suddenly, often later in life, a viral¬†or¬†bacterial infection may trigger antibodies that cross-react with the human TSH receptor, a phenomenon known as¬†antigenic mimicry.[rx]

The bacterium¬†Yersinia enterocolitica¬†bears structural similarity with the human thyrotropin receptor[rx]¬†and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.¬†In the 1990s, it was suggested that¬†Y. enterocolitis¬†may be¬†associated¬†with Graves’ disease.[rx]¬†More recently, the role for¬†Y. enterocolitis¬†has been disputed.[rx]

Epstein‚ÄďBarr virus¬†(EBV) is another potential trigger.[rx]

Pathophysiology

Graves’ disease is caused by thyroid-stimulating immunoglobulin (TSI), also known as a thyroid-stimulating antibody (TSAb). B lymphocytes primarily synthesize Thyroid stimulating immunoglobulin within the thyroid cells, but it can also be synthesized in lymph nodes and bone marrow. B lymphocytes are stimulated by T lymphocytes which get sensitized by antigen in the thyroid gland. Thyroid-stimulating immunoglobulin binds with thyroid-stimulating hormone (TSH) receptor on the thyroid cell membrane and stimulates the action of the thyroid-stimulating hormone. It stimulates both, thyroid hormone synthesis and thyroid gland growth, causing hyperthyroidism and thyromegaly.

Several environmental factors including pregnancy (mainly postpartum), iodine excess, infections, emotional stress, smoking, and interferon alfa trigger immune responses on susceptible genes to eventually cause Graves’ disease.

Graves’ orbitopathy (ophthalmopathy) is caused by inflammation, cellular proliferation, and increased growth of extraocular muscles and retro-orbital connective and adipose tissues due to the actions of thyroid-stimulating antibodies and cytokines released by cytotoxic T lymphocytes (killer cells). These cytokines and thyroid-stimulating antibodies activate periorbital fibroblasts and preadipocytes, causing the synthesis of excess hydrophilic glycosaminoglycans (GAG) and retro-orbital fat growth. Glycosaminoglycans cause muscle swelling by trapping water. These changes give rise to proptosis, diplopia, congestion, and periorbital edema. If left untreated, it eventually leads to irreversible fibrosis of the muscles.

Pathogenesis of other rare manifestations of Graves disease like pretibial myxedema and thyroid acropachy are poorly understood and are believed to be due to cytokines-mediated stimulation of fibroblasts. Many symptoms of hyperthyroidism like tachycardia, sweating, tremors, lid lag, and stare are thought to be related to increased sensitivity to catecholamine.

Symptoms

Common signs and symptoms of Graves’ disease include:

  • Anxiety and irritability
  • A fine tremor of the hands or fingers
  • Heat sensitivity and an increase in perspiration or warm, moist skin
  • Weight loss, despite normal eating habits
  • Enlargement of the thyroid gland (goiter)
  • Change in menstrual cycles
  • Erectile dysfunction or reduced libido
  • Frequent bowel movements
  • Bulging eyes (Graves’ ophthalmopathy)
  • Fatigue
  • Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
  • Rapid or irregular heartbeat (palpitations)
  • Sleep disturbance

Additional Symptoms

  • Goitre¬†(enlarged thyroid). If the thyroid grows large enough, it may compress the¬†recurrent laryngeal nerve, producing¬†vocal cord paralysis,¬†dysphonia, and even respiratory¬†stridor. Compression of the¬†sympathetic chain¬†may result in¬†Horner’s syndrome.
  • Graves’ ophthalmopathy¬†(protrusion of one or both eyes)
  • Pretibial myxedema
  • Cardiovascular features may include¬†hypertension, and heart rate that may be¬†rapid¬†or¬†irregular in character; these may be perceived as¬†palpitations. Less common findings include¬†left ventricular hypertrophy, premature atrial and ventricular contractions,¬†atrial fibrillation,¬†congestive heart failure,¬†angina,¬†myocardial infarction, systemic embolization, death from¬†cardiovascular collapse¬†and resistance to some drug effects (digoxin,¬†coumadin).
  • Hyperreflexia, with a rapid relaxation phase.
  • A distinctly excessive reaction to all sorts of stimuli.
  • A marked increase in¬†fatigability, or¬†asthenia, is often prominent. This increased weariness may be combined with¬†hyperactivity; patients remark that they are impelled to incessant activity, which, however, causes great fatigue.
  • Insomnia
  • Tremor (usually fine shaking; tremor of the outstretched fingers). In a small study of newly diagnosed hyperthyroid patients, tremor was observed in 76% of them. Some studies lay the cause for hyperthyroid tremor with a heightened beta-adrenergic state, others suggest an increased metabolism of¬†dopamine.
  • Weight loss¬†despite normal or increased appetite. Some patients (especially younger ones)¬†gain¬†weight due to excessive appetite stimulation that exceeds the weigh loss effect.
  • Increased appetite.
  • Weakness¬†or¬†muscle weakness¬†(especially in the large muscles of the arms and legs). This latter occurs in 60 to 80 percent of patients with untreated hyperthyroidism. Muscle weakness is rarely the chief complaint. The likelihood and degree of muscle weakness is correlated with the duration and severity of the hyperthyroid state, and become more likely after the age of 40. Muscle strength returns gradually over several months after the hyperthyroidism has been treated.
  • Muscle degeneration
  • Shortness of breath
  • Increased sweating
  • Heat intolerance
  • Warm and moist skin
  • Thin and fine hair
  • Redness of the elbows is frequently present. It is probably the result of the combination of increased activity, an exposed part, and a hyperirritable¬†vasomotor system.
  • Chronic¬†sinus infections
  • Brittle nails
  • Plummer’s nail
  • Abnormal breast enlargement in men
  • Gastrointestinal symptoms. This includes¬†increased bowel movements, but malabsorption is unusual.
  • Augmented calcium levels in the blood (by as much as 25% ‚Äď known as¬†hypercalcemia). This can cause stomach upset, excessive urination, and impaired kidney function.
  • Diabetes may be activated or intensified, and its control worsened. The diabetes is ameliorated or may disappear when the thyrotoxicosis is treated
  • Evidence of mild or severe liver disease may be found.
  • Reproductive symptoms in men may include reduced free¬†testosterone¬†(due to the elevation of testosterone-estrogen binding globulin level), diminished¬†libido,¬†erectile dysfunction¬†and (reversible) impaired sperm production with lower mean sperm density, a high incidence of sperm abnormalities, and reduced mobility of the sperm cells. Women may experience¬†infrequent menstruation¬†or¬†irregular and scant menstrual flow¬†along with difficulty conceiving,¬†infertility,¬†and recurrent¬†miscarriage.
  • Neurological seizures,¬†neuropathy¬†from nerve entrapment by lesions of pretibial myxedema, and¬†hypokalemic periodic paralysis¬†may occur.¬†Athetoid,¬†choreia, and¬†corticospinal tract damage¬†are rare. An acute thyrotoxic¬†encephalopathy¬†is very rare.
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Diagnosis of Graves’ Disease

Most patients with Graves disease present with classic signs and symptoms of hyperthyroidism. Initial presentation of Graves disease with only Graves orbitopathy or pretibial myxedema is rare. Presentation depends on the age of onset, severity, and duration of hyperthyroidism. In the elderly population, symptoms may be subtle or masked, and they may present with non-specific signs and symptoms like fatigue, weight loss, and new-onset atrial fibrillation. Atypical presentation of hyperthyroidism in elderly is also referred as apathetic thyrotoxicosis.

In younger patients, common presentations include heat intolerance, sweating, fatigue, weight loss, palpitation, hyper defecation, and tremors. Other features include insomnia, anxiety, nervousness, hyperkinesia, dyspnea, muscle weakness, pruritus, polyuria, oligomenorrhea or amenorrhea in the female, loss of libido, and neck fullness. Eye symptoms include lids swelling, ocular pain, conjunctival redness, double vision. Palpable goiter is more common in the younger population, age younger than 60 years.  Up to 10 % of patients may have weight gain.

Physical signs of hyperthyroidism include tachycardia, systolic hypertension with increased pulse pressure, signs of heart failure (like edema, rales, jugular venous distension, tachypnea), atrial fibrillation, fine tremors, hyperkinesia, hyperreflexia, warm and moist skin, palmar erythema and onycholysis, hair loss, diffuse palpable goiter with thyroid bruit and altered mental status.

Signs of extrathyroidal manifestations of Graves’ disease include ophthalmopathy like eyelid retraction, proptosis, periorbital edema, chemosis, scleral injection, exposure keratitis. Thyroid dermopathy causes marked thickening of the skin, mainly over tibia which is rare, seen in 2% to 3% of cases. The thickened skin has peau d’orange appearance and is difficult to pinch. Bone involvement includes subperiosteal bone formation and swelling in the metacarpal bones which is called osteopathy or thyroid acropachy. Onycholysis (Plummer nails) and clubbing are very rare.

Evaluation

Diagnosis of Graves disease starts with a thorough history and physical examination. History should include a family history of Graves’ disease. 

  • Blood tests.¬†Blood tests can help your doctor determine your levels of thyroid-stimulating hormone (TSH) ‚ÄĒ the pituitary hormone that normally stimulates the thyroid gland ‚ÄĒ and your levels of thyroid hormones. People with Graves’ disease usually have lower than normal levels of¬†TSH¬†and higher levels of thyroid hormones.Your doctor may order another lab test to measure the levels of the antibody known to cause Graves’ disease. It’s usually not needed to diagnose the disease, but results that don’t show antibodies might suggest another cause of hyperthyroidism.
  • Radioactive iodine uptake.¬†Your body needs iodine to make thyroid hormones. By giving you a small amount of radioactive iodine and later measuring the amount of it in your thyroid gland with a specialized scanning camera, your doctor can determine the rate at which your thyroid gland takes up iodine. The amount of radioactive iodine taken up by the thyroid gland helps determine if Graves’ disease or another condition is the cause of the hyperthyroidism. This test may be combined with a radioactive iodine scan to show a visual image of the uptake pattern.
  • Ultrasound.¬†Ultrasound uses high-frequency sound waves to produce images of structures inside the body. It can show if the thyroid gland is enlarged. It’s most useful in people who can’t undergo radioactive iodine uptake, such as pregnant women.
  • Imaging tests. If the diagnosis of Graves’ disease isn’t clear from a clinical assessment, your doctor may order special imaging tests, such as a CT scan or MRI.
  • Thyroid function tests to diagnose hyperthyroidism – The initial test for diagnosis of hyperthyroidism is the thyroid-stimulating hormone (TSH) test. If TSH is suppressed, one needs to order Free T4 (FT4) and Free T3 (FT3). If free hormone assays are not available, total T4 (Thyroxine) and total T3 (Triiodothyronine) can be ordered. Suppressed TSH with high FT4 or FT3 or both will confirm the diagnosis of hyperthyroidism. In subclinical hyperthyroidism, only TSH is suppressed, but FT4 and FT3 are normal.
  • Tests to differentiate Graves from other causes of hyperthyroidism – Graves’s diagnosis can be obvious with a careful history and physical examination. Features suggestive of Graves disease include a positive family history of Graves disease, the presence of orbitopathy, diffusely enlarged thyroid with or without bruit, and pretibial myxedema.
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Measurement of TSH receptor antibody (TRAb) –¬† There are two available assays, the thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibiting (TBI) immunoglobulin or thyrotropin-binding inhibitory immunoglobulin (TBII). Measurement of TRAb with third-generation assay has sensitivity and specificity of 97% and 99% for the diagnosis of Graves disease. TRAb measurement is indicated in the following conditions:

  • Hyperthyroidism during pregnancy when thyroid uptake scan is contraindicated
  • Pregnant women with h/o Graves disease to determine possible fetal and neonatal hyperthyroidism as these antibodies cross the placenta
  • Patients with possible Graves‚Äô orbitopathy without biochemical hyperthyroidism
  • Patients with recent h/o large iodine load where thyroid uptake scan cannot be reliable, e.g., recent amiodarone use, recent imaging studies with iodinated contrast
  • To determine the prognosis of hyperthyroidism who are being treated.

 Radioactive iodine uptake scan with I-123 or I-131:  In Graves disease, the uptake will be high and diffuse whereas, in a toxic nodule, the uptake will be focal known as a hot nodule. Toxic multinodular goiter will have heterogeneous uptake. The radioactive iodine uptake in subacute or silent thyroiditis, factitious hyperthyroidism, and recent iodine load will be low.

Thyroid Ultrasonogram with Doppler: The thyroid gland in Graves disease is usually hypervascular. T3/T4 ratio greater than20 (ng/mcg) or FT3/FT4 ratio greater than 0.3 (SI unit) suggests Graves disease and can be used to differentiate Graves’ disease from thyroiditis induced thyrotoxicosis.

Other Tests – CT or MRI of orbits can be performed to diagnose Graves orbitopathy in patients who present with orbitopathy without hyperthyroidism. Patients with hyperthyroidism can have microcytic anemia, thrombocytopenia, bilirubinemia, high transaminases, hypercalcemia, high alkaline phosphatase, low LDL and HDL cholesterol.

Treatment of Graves’ Disease

Treatment for Graves’ disease depends on its presentation. Treatment consists of rapid symptoms control and reduction of thyroid hormone secretion.

A beta-adrenergic blocker should be started for symptomatic patients, specifically for patients with a heart rate of more than 90 beats/min, patients with a history of cardiovascular disease, and elderly patients. Atenolol 25 mg to 50 mg orally once daily may be considered the preferred beta-blocker due to its convenience of daily dosing, and it is cardioselective (beta-1 selective). Some prescribers recommend Propranolol 10 mg to 40 mg orally every six to eight hours, due to its potential effect to block peripheral conversion of T4 to T3. If a beta-blocker after that, calcium channel blockers like diltiazem and verapamil can be used to control heart rate.

There are three options to reduce thyroid hormone synthesis. These options are:

  • Antithyroid drugs block thyroid hormone synthesis and release
  • Radioactive iodine (RAI) treatment of the thyroid gland
  • Total or subtotal thyroidectomy.

All three options have pros and cons, and there is no consensus on which one is the best option. It is very important to discuss all three options in detail with the patients and make an individualized decision.

Anti-thyroid Drugs (Thionamides)

Methimazole (MMI) and propylthiouracil (PTU) are two anti-thyroid drugs available in the USA. Outside USA, carbimazole, a derivative of methimazole that is rapidly metabolized to methimazole, is also available. These thioamides inhibit Thyroid Peroxidase (TPO) mediated iodination of thyroglobulin in the thyroid gland, blocking the synthesis of T4 and T3. To some extent, Propylthiouracil also blocks the peripheral conversion of T4 to T3.

In nonpregnant patients, methimazole is the drug of choice due to its less frequent side effects (especially hepatotoxicity), once-daily dosing, and more rapid achievement of normal thyroid function. During the first trimester of pregnancy, propylthiouracil must be used due to its less teratogenic side effects. We can start methimazole from the second trimester of pregnancy. American Thyroid Association (ATA) recommends propylthiouracil for patients with thyroid storm and for patients with minor reactions to methimazole therapy who refuses surgery or RAIA.

Before starting ethionamide treatment, patients should be informed about possible side effects including allergic reactions, neutropenia, and hepatotoxicity. A complete blood count with differentials and liver function tests should be obtained. Ethionamide should not be started if the baseline transaminase level is more than five times the upper limit of normal or if absolute neutrophil count (ANC) is less than 1000/ml.

Dosage: Initiate methimazole 5 mg to 10 mg oral daily if FT4 is 1 to 1.5 times the upper limit of normal (ULN), 10 mg to 20 mg oral daily if FT4 is 1.5 to 2 times ULN, 30 mg to 40 mg oral daily if FT4 is more than two to three times ULN.  Start PTU 50 mg t0 150 mg orally three times daily based on the severity of hyperthyroidism. Once thyroid function improves, the thioamide dose can be tapered and continued at maintenance doses once TFTs become euthyroid. Methimazole is usually maintained at 5 mg to 10 mg daily, and propylthiouracil is maintained at 50 mg two to three times a day.

Adverse effects: Minor side-effects include pruritus and rash (3% to 6%), and major side effects include hepatocellular injury (2.7% propylthiouracil, 0.4% Methimazole), agranulocytosis (0.7%, ANC  less than 500/ml), and vasculitis (rarely lupus and pANCA-positive small vessel vasculitis; more with propylthiouracil than methimazole). Rarely hypoglycemia has been reported with methimazole therapy.

Follow-up and monitoring: Monitor thyroid function tests (TFTs) every four to six weeks for the ethionamide dose adjustment. Once TFTs improve, we can reduce the ethionamide dose by 30% to 50% until a maintenance dose is achieved. Once on a maintenance dose, TFTs can be checked every three months for up to 18 months, thereafter every six months is acceptable. Monitor for adverse effects and perform blood tests as needed based on clinical information. Stop the thioamide if the transaminase level is more than three times of ULN.  Routine monitoring of liver function tests and complete blood count is not necessary. Thionamides can be continued for minor cutaneous reactions with or without concurrent use of antihistamines, but if the problem persists, alternative treatment options including surgery or RAI therapy should be considered.

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Duration of treatment: For patients on long-term, thionamide therapy who are on maintenance doses, we can consider stopping the therapy after 12 to 8 months, if TSH and TRAb levels normalize during follow-up. If patients remain clinically and biochemically euthyroid, we can repeat TFTs every two to three months during the first six months after stopping the treatment, then every four to six months for another six months, then every six to 12 months. If TSH remains normal for one year without treatment, annual monitoring with TSH is enough.

RAI Therapy

It is preferred for non-pregnant adult patients older than 21 years, patients not planning to get pregnant within the next six to 12 months after treatment, patients with risky comorbid conditions for surgery, and patients with contraindications for thioamides. It is contraindicated during pregnancy, lactation, coexisting thyroid cancer, in patients with moderate to severe Graves orbitopathy, and for individuals who cannot follow radiation safety guidelines.

Preparation: Beta-adrenergic blockade and pretreatment with methimazole (propylthiouracil pretreatment has a high failure rate for RAI treatment) should be considered for patients with an increased risk of complications from hyperthyroidism and patients with very high thyroid hormone levels. If methimazole is started, it should be stopped three to five days before RAI treatment. It can be restarted for high-risk patients three to seven days after treatment. A pregnancy test is required before RAI treatment.

Dosage: I-131 is administered as a capsule or liquid. The I-131 dose can be calculated or one may use a fixed-dose. The calculated dose is based on thyroid volume, uptake of RAI, and local factors. A fixed-dose can be 10 to 25 mCi of I-131. The patient should be provided with a written radiation safety precautions after RAI treatment to avoid exposure to household members or community members, especially children, and pregnant women.

Follow-up and monitoring: TFTs should be monitored every four to six weeks for six months or until the patient becomes hypothyroid. Once the patient is on a stable levothyroxine dose, TFTs can be repeated every six to 12 months. If hyperthyroidism persists after six months of RAI therapy, it can be considered a treatment failure, and repeat treatment with RAI may be needed.

Thyroidectomy

Thyroidectomy is preferred for patients with very large goiter (more than 80 grams), anterior neck compressive symptoms, co-existing suspicious thyroid cancer, large thyroid nodules (greater than 4 cm), cold nodules, co-existing parathyroid adenoma, very high TRAb, and moderate to severe Graves orbitopathy.

Preparation: 

  • Use thioamides to achieve a near or complete euthyroid state before surgery
  • Use Beta-blockers as needed
  • Use potassium iodide, five to seven drops of Lugol‚Äôs solution, or one to two drops of SSKI, mixed in water or juices three times a day, starting seven to ten days before surgery to reduce vascularity
  • Assess calcium and Vitamin D levels and replace if needed

Post-op follow-up:

Thionamides should be stopped after surgery and beta-blockers should be weaned off. Levothyroxine is started at 1.6 micrograms per kg body weight, and the dose is adjusted based on TSH level every six to eight weeks.

Other Adjunct Treatment for Graves Hyperthyroidism

Iodinated contrast agents, sodium iodate, and iopanoic acid inhibit the peripheral conversion of T4 to T3. They are used with methimazole but not as a solo agent as they can cause resistant hyperthyroidism. They are not available in the United States. Iodide (SSKI drops) can be used for mild hyperthyroidism especially after RAI treatment. Glucocorticoid, cholestyramine, lithium, carnitine are other agents that have also been tried. Rituximab may induce remission in patients with Graves disease, but it is costly. 

Treatment of Graves Orbitopathy (GO)

Rapid achievement of euthyroid level should be sought in patients with Graves orbitopathy. Patients should be advised to quit smoking if they do.  Treatment depends on the severity of orbitopathy. For patients with mild orbitopathy who undergo RAI treatment, prednisone 0.4 mg/kg/day to 0.5 mg/kg/day should be started one to three days after treatment and continued for one month. It should be tapered slowly over two months. Mild active Graves orbitopathy should be treated with artificial tears, and glucocorticoid therapy can be considered. Elevation of the head during sleep reduces orbital congestion. Selenium treatment has doubtful benefits. Prompt ophthalmology referral should be considered for all cases of Graves orbitopathy.

Treatment of moderate to severe active Graves orbitopathy requires up to 100 mg of oral prednisone daily for one to two weeks, then tapered over six to 12 weeks or intravenous (IV) methylprednisolone 500 mg/wk for six weeks followed by 250 mg/wk for six weeks. Other options include orbital irradiation, rituximab, and emergency orbital decompression.

Treatment of inactive Graves orbitopathy involves interval close clinical monitoring, elective orbital decompression, strabismus repair and eyelid repair depending upon severity.

Treatment of Dermopathy and Acropachy

Graves dermopathy usually does not need treatment. If treatment is considered, topical high potency glucocorticoid with occlusive dressing can be considered. Rituximab treatment to reduce B-cell may be beneficial, but it remains experimental. There is no treatment available for acropachy.

References

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