Graves’ disease is caused by the production of autoantibodies to the thyroid-stimulating hormone receptor (TSHR) causing symptoms of hyperthyroidism. Stimulatory autoantibodies in Graves’ disease activate the TSHR on thyroid follicular cells, leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion.⁵ In some patients, antibodies can antagonize TSHR by either blocking thyroid-stimulating hormone binding or interacting with TSHR epitopes that inhibit cAMP production, causing symptoms related to Hypothyroidism.⁶

thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms).

Signs and symptoms of Graves’ disease

Scientists have yet to elucidate what makes the immune system breakdown allowing the body to form autoimmune disorders such as Graves’ disease.

There is a genetic predisposition to the development of Graves’ disease and there is about an eight to one, female to male ratio in patients diagnosed with Graves’ disease. 

Prevention
Having a family member with Graves’ disease or any autoimmune disease (Lupus, Rheumatoid Arthritis or Type 1 Diabetes, etc.) increases the risk of developing the disease. Knowing that someone has this risk factor, some recommendations to help prevent Graves’ disease include:

• Living a healthy lifestyle
• Reducing stress
• Not smoking

Eating whole foods, exercising, meditating and enjoying life are tips to keep a body healthy. Smoking increases risk and is associated with more serious eye manifestations.

The diagnosis of Graves’ disease starts with a healthcare worker recognizing the signs and symptoms and considering the possibility of hyperthyroidism. The classic presentation of Graves’ disease includes symptoms of an overactive thyroid gland. There is a range of symptoms. Mild symptoms include:

• Palpitations
• Racing heart
• Weight loss
• Muscle weakness
• Tremors

Frank thyrotoxicosis, or thyroid storm, is associated with severe and life-threatening consequences of hyperthyroidism.

Patients may also present with signs and symptoms of eye disease such as “bug eyes” called proptosis (exophthalmos). Some patients present with classic thyroid eye disease but are euthyroid at the time of presentation. A significant number of patients present with atypical or non-classic symptoms such as isolated tremors, atrial fibrillation or anxiety. In these cases, the diagnosis of Graves’ disease is not considered for many months and definitive diagnosis is unfortunately delayed.^8,9

Diagnostic dilemma ^{1, 10, 11}

There are classic symptoms that are usually definitive and associated with hyperthyroidism and hypothyroidism. But as is true of many autoimmune disorders, there are many earlier symptoms are not mutually exclusive to one diagnosis.

Measurement of thyroid-stimulating hormone (TSH), which if below normal (suppressed), raises suspicion of a hyperthyroid state and requires further evaluation with FT4 and potentially FT3 levels to confirm the diagnosis and assess severity. Elevation of thyroid hormone levels then would confirm the presence of clinical hyperthyroidism. The differential diagnosis of hyperthyroidism includes Graves’ disease as well, in over 70% of suspected hyperthyroid patients.^8,10

Two types of tests are available for clinical laboratories to measure anti-TSHR autoantibodies. One type is a competitive binding test. This test is called a thyrotropin receptor antibody test and measures the ability of the antibodies to bind to the TSHR regardless of the biological activity of the antibodies. Another type of test, referred to as bioassays, measures the ability of the anti-TSHR to stimulate thyroid cells. These tests measure what are called thyroid-stimulating immunoglobulin (TSI) or thyroid-stimulating antibody. TSI is specific for Graves’ disease because it is the stimulating antibodies that lead to hyperthyroidism. Data show that TSI levels correlate with the severity of thyroid eye disease.

Thyroid-specific antibodies – over 70% of hyperthyroid patients are TSI positive^{,8, 10}

Why generic TRAb assays fall short

• Specificity, Sensitivity and Functionality
• Stimulating (TSI) causes hyperthyroidism
• Blocking (TBI) causes hypothyroidism
• Neutral (binding) suspected in apoptosis of the thyrocyte
• TRAb assays cannot differentiate between TSI or TBI

Why different TSH-R antibody assay platforms matter^1,9[JH1]

TRAb or TBII Binding Assays

• Competitive-binding immunoassays (TRAb or TBII)
• Receptor bound to plastic well or bead
• Measure total antibody TSHr binding activity (anything that hits the receptor)
• Can not distinguish functional types

Cell-based bioassays^1,9

• Transfected cell lines: TSHr-reporter gene
• Show the functionality of the antibodies to the receptor
• Bioassays can distinguish the TSHr types
• Stimulating antibody-specific (TSI/TSAb) HYPERthyroidism
• Blocking antibody-specific (TBI/TBAb) HYPOthyroidism

Traditionally, the next step would be radioactive iodine uptake and scanning to define and characterize the overactivity of the gland often in anticipation of radioactive iodine ablation of the gland as definitive therapy (primarily in the U.S.). More commonly the diagnostic evaluation involves anatomical characterization of the thyroid gland with ultrasonography, which defines the size of the gland and determines the degree of vascularity (blood flow). A diffuse increase in both size and vascularity is consistent with the diagnosis of Graves’ disease.

This evaluation, when combined with the clinical symptoms and the hormone levels may be sufficient to make the diagnosis and initiate therapy. Many cases of Graves’ disease are not easily diagnosed, and measurement of thyroid receptor-stimulating autoantibodies is often helpful to confirm the diagnosis. New ATA and ETA guidelines now recommend the use of TRAb (specifically TSI) antibody as a primary option in the diagnosis and management of Graves’ disease.

Additional diagnostic evaluation

Traditionally, the next step would be radioactive iodine uptake and scanning to define and characterize the overactivity of the gland often in anticipation of radioactive iodine ablation of the gland as definitive therapy (primarily in the U.S.). More commonly the diagnostic evaluation involves anatomical characterization of the thyroid gland with ultrasonography, which defines the size of the gland and determines the degree of vascularity (blood flow). A diffuse increase in both size and vascularity is consistent with the diagnosis of Graves’ disease.

This evaluation, when combined with the clinical symptoms and the hormone levels may be sufficient to make the diagnosis and initiate therapy. Many cases of Graves’ disease are not easily diagnosed, and measurement of thyroid receptor-stimulating autoantibodies is often helpful to confirm the diagnosis. New ATA and ETA guidelines now recommend the use of TRAb (specifically TSI) antibody as a primary option in the diagnosis and management of Graves’ disease.

ATA Hyperthyroid Guidelines (updated 2016)

*Recommendation 1

The etiology of thyrotoxicosis should be determined. If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, diagnostic testing is indicated and can include, depending on available expertise and resources, (1) measurement of TRAb, (2) determination of the radioactive iodine uptake (RAIU) or (3) measurement of thyroidal blood flow on ultrasonography. An iodine-123 or technetium-99m pertechnetate scan should be obtained when the clinical presentation suggests a toxic adenoma or toxic multinodular goiter. Strong recommendation, moderate-quality evidence[JH1] .¹²

The recommendation to test for thyroid receptor antibodies is here mentioned for the first time in the guidelines.

• Hyperthyroidism is typically characterized by signs like low or suppressed thyroid-stimulating hormone (TSH) levels and elevated T4 and/or T3 values.
• Over 70% of these hyperthyroid patients have an autoimmune disease called Graves’ disease.
• The causative agent of Graves’ disease is thyroid-stimulating immunoglobulin (TSI).
• Elevated levels of TSI in a patient’s bloodstream can be detected using the Thyretain TSI Reporter BioAssay. Positive results can provide healthcare providers with an important specific aid in the diagnosis of Graves’ disease.

Generic and specific descriptions of thyroid-stimulating hormone receptor (TSHr) antibodies just the target antibodies.^9,13

TSI Function^,5,9

In normal thyroid metabolism, thyroid hormone production is tightly regulated by the hypothalamic-pituitary-thyroid axis.

Normal thyroid function¹⁴

Negative feedback loop

Graves’ disease is an autoimmune disorder that primarily affects the thyroid. The Thyroid is responding to the stimulation of TSI and is not “malfunctioning” per se. Thyroid stimulating immunoglobulin (TSI) mimics the action of TSH on the TSH receptor, in that it causes T4 to be over produced. TSI is not regulated by the same negative feedback system.

Effects of TSI – patients with Graves’ disease^1,9,12,14

Graves’ disease treatment^1,9,12,15

Treatment is a personal choice and QuidelOrtho does not advocate one therapy over another.

There are three possible forms of treatment for the hyperthyroidism of Graves’ disease. Radioactive iodine therapy involves administering an appropriate radioiodine dose, which concentrates in the thyroid and destroys thyroid cells. Following this form of therapy, the patient loses thyroid function and becomes hypothyroid and thus dependent on thyroid hormone replacement for life. There are two antithyroid drugs (ATD) available for treatment of Graves’ disease, propylthiouracil and methimazole. Beta-blockers may also be prescribed to help with symptom relief. Total thyroidectomy can be performed if radioiodine is contraindicated and ATDs are not effective or not tolerated.

Medical management therapy

Antithyroid drugs (ATD) are suppressive drugs meant to inhibit the production of thyroid hormones T4 and/or T3 in an effort to treat the symptoms of Graves’ disease. These medications include Methimazole (MMI) and propylthiouracil (PTU). MMI and PTU act by inhibiting the synthesis (the production) of thyroid hormone. PTU use has been stopped especially in children, due to effects on liver function. MMI is widely used and does not carry this restriction. Medical management has a success rate of ~45-50% using current medical management guidelines. Patients retain their thyroid and may have remission of the autoimmune response. Those patients who do not respond to the ATD therapy can either continue the ATD or choose the definitive cure options listed below.

There are some side effects when using ATDs that can occur. Most are mild (rash occurs in 3-4% of patients), but one in particular is severe (agranulocytosis occurs in ~0.3% of patients). This is extremely rare and corrected by stopping the ATD therapy. Additionally, there are new monoclonal therapies for Graves’ eye disease or TED that can reduce inflammation. 

Definitive therapies^9,12

Radioiodine ablation therapy

Iodine-131 (Radioiodine) is given orally to destroy the function of a hyperactive gland. Usually, one dose is sufficient, but some patients might require more than one treatment. The radioactive iodine is picked up by the active cells in the thyroid, which use iodine to produce T4, and destroys these cells.

Radioiodine is an ablative approach and is considered the definitive cure for hyperthyroidism brought about by eliminating most if not all of the target organ; however, >80% of patients develop permanent hypothyroidism soon after treatment and require lifelong synthetic hormone replacement. Hypothyroidism is believed to be an easier disease to manage than hyperthyroidism.

Theoretically, the radioiodine could be dosed to only destroy part of the thyroid gland, but the dosage is extremely difficult to determine, and if thyroid tissue remains, the body can still produce TSI against any remnant tissue. These antibodies can still cause Graves’ eye disease even after ablative therapy.

However, for incompletely ablated women in their childbearing years, these antibodies could be passed across the placenta during pregnancy, leading to the child developing Graves’ disease. This has been addressed in the ATA, ETA and AACE guidelines for treating pregnant women and those considering pregnancy who have undergone this treatment (see Graves’ disease and pregnancy).

Surgery

This option is also considered a definitive cure for Graves’ disease. For patients who cannot tolerate medicines or who are allergic to or decline iodine-131, a surgical treatment option is available. Full or partial thyroidectomy is used uncommonly in the US and is not considered a primary option for Graves’ disease treatment, due to risks from surgery and anesthesia. If this option is chosen, it is important to select a surgeon with sufficient skill in thyroid surgery specifically.

Treatment can vary by region

TSI antibodies can pass through the placenta and affect the fetus. As a result, the ATA/AACE issued the following guidance^3,8:

• Recommendation 74: TSH receptor (TSH-R) antibody levels should be measured to differentiate the etiology of hyperthyroidism in pregnancy.
• Recommendation 75: Patients who were treated for Graves’ disease prior to pregnancy should have TSH-R antibody levels measured initially during the first trimester and, if elevated, again at 22-26 weeks of gestation.
• Recommendation 76: Patients diagnosed with Graves’ disease during pregnancy should have TSH-R antibody levels measured at diagnosis and again at 22-26 weeks of gestation.
• Recommendation 77: TSH-R antibody levels measured at 22-26 weeks of gestation should be used to guide decisions regarding neonatal monitoring.

The American Thyroid Association recommends that the following high-risk women be screened for thyroid disease either prior to becoming pregnant or as soon as feasible once a woman becomes pregnant:

• Women with a history of thyroid disease or thyroid surgery
• Women with a family history of thyroid disease
• Women with a goiter
• Women with known thyroid antibodies
• Women with symptoms or clinical signs of hyperthyroidism or hypothyroidism
• Women with Type I diabetes mellitus
• Women with other autoimmune disorders
• Women with infertility
• Women with previous therapeutic head or neck irradiation
• Women with a history of miscarriage or preterm delivery

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15. Laurberg P, Wallin G, Tallstedt L, Abraham-Nordling M, Lundell G, Tørring O. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol. 2008;158(1):69-75. doi:10.1530/EJE-07-0450