At a Glance

Graves disease or diffuse toxic thyroid hyperplasia is an autoimmune disease caused by autoantibody binding to the thyroid stimulating hormone receptor (TSHR), resulting in increased thyroid hormone synthesis and secretion. Thyroid growth may occur, resulting in goiter formation. Extrathyroid effects of the anti-TSHR antibody may include opthalmopathy and pretibial myxedema (or thyroid localized dermopathy). The classic clinical presentation of Graves disease is driven by overactivity of the thyroid gland or hyperthyroidism, although patients with longstanding disease can be hypothyroid or euthyroid.

Graves disease patients may present with heat intolerance, increased sweating, insomnia, frequent loose stools, fatigue, dysmenorrhea, arrhythmia, tremor, weight loss, and neuropsychological symptoms, such as anxiety. Hyperthyroidism is rare in pediatric populations and, when it occurs, the majority of cases are caused by Graves disease. Graves disease is most common in women 20 year of age or older, although both genders can be affected. The trigger for TSHR-antibody production is unknown, although there is a strong hereditary component.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Laboratory tests for the assessment of a patient with suspected Graves disease include thyroid stimulating hormone (TSH), total triiodothyronine (T3), and free thyroxine (fT4). TSH is a glycoprotein hormone with an alpha and beta subunit. TSH is secreted by the anterior pituitary gland as a result of a negative feedback loop involving T3 and fT4.

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TSH is suppressed in Graves disease, as it is in all hyperthyroid patients, except those with a TSH-secreting pituitary tumor. This fact is utilized by the thyroid releasing hormone (TRH) stimulation test when TRH is given and TSH remains suppressed in Graves disease patients. A diagnosis of hyperthyroidism can be made with a pattern of low TSH and elevated T3/fT4 is seen.

Antimicrosomal antibodies are directed against thyroid cell microsomes and can be found in 85% of all patients with Graves disease. Low titers can be seen in healthy individuals. Thyroid peroxidase is the primary autoantigen of microsomes, and testing for antithyroid peroxidase (anti-TPO) antibodies may provide greater sensitivity and specificity over assays for microsomal antibodies in detecting autoimmune thyroiditis.

Like antimicrosomal antibodies, anti-TPO antibodies are found in all of Hashimoto’s thyroiditis patients and the majority of individuals with Graves disease, although these entities are easily distinguished by hypothyroidism in the former and hyperthyroidism in the latter. Low levels may still be detected in healthy individuals and are seen increasingly in elderly patients.

Anti-thyrotropin-receptor antibodies (TRAbs) bind thyroid cell membranes near the TSH receptor site. Like anti-TPO antibodies, the presence of these immunoglobulins is indicative of one of a number of thyroid autoimmune disorders, including Graves disease. A direct radioreceptor assay for anti-TRAbs measures the ability of thyrotropin-binding inhibitor immunoglobulins (TBII) to inhibit TSH binding to thyroid membrane preparations. This assay is used to assess the risk of fetal or neonatal hyperthyroidism in infants of women with present or past Graves disease.(Table 1)

Table 1
TSH free T4 total T3
<0.1 mcIUnits/mL >1.8 ng/dL >181 ng/dL

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Hospitalized patients may have transiently low or high TSH. Most frequently, TSH levels are suppressed during the acute phase of illness or during treatment on glucocorticoid or dopamine therapy. Other drugs like amiodarone can increase TSH levels. Critically ill euthyroid patients may be differentiated from hyperthyroid ill patients, because the latter show profoundly low TSH values, less than 0.01 mU/L. Increases in T3 and T4 may occur with ingestion of large quantities of exogenous thyroid hormone.

What Lab Results Are Absolutely Confirmatory?

Although no lab test is absolutely confirmatory for Graves disease, the pattern of low TSH and elevated T3/T4 suggests hyperthyroidism and the presence of anti-microsome or anti-TPO antibodies confirms an autoimmune etiology.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnosis of Graves disease is often straight forward when both the clinical symptoms, as well as the expected pattern of low TSH and elevated T3/T4, are present. However, in some cases that are less clear cut, a TRH administration test should show the absence of an increase in TSH in Graves disease. This same absence of response with the TRH administration test is usual in euthyroid Graves as well.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Generally, a diagnosis of hyperthyroidism is made when a pattern of low TSH and elevated T4 is seen. Occasionally, a patient will present with clinical symptoms of hyperthyroidism and the TSH will be low but the T4 will be normal. In these patients, it is important to check T3 concentration, as this may be elevated to a greater degree than T4 in some patients with early Graves disease or in Plummers disease (T3 thyrotoxicosis). Suppression of TSH with normal concentrations of T3 and T4 may occur in asymptomatic patients with subclinical hyperthyroidism.