Laboratory evaluation of thyroid function
Myxedema is caused by the deposition of hyaluronic acid in patients with thyroid disease.
At a glance
- The serum thyroid-stimulating hormone is the best initial test of thyroid function.
- Abnormal protein levels can have significant effect on the total thyroxine (T4) results.
- Subclinical hyperthyroidism and subclinical hypothyroidism are exclusively laboratory diagnoses.
- Re-evaluate patients with subclinical hypothyroidism within three months of detection and then every six months.
Blood tests to measure thyroid function are readily available and widely used. To understand a test's scientific basis and what it can tell us, a quick review of the thyroid gland's pathophysiology is in order. The major hormone secreted by the thyroid is thyroxine, also called T4 because it contains four iodine atoms.1 To exert its effects, T4 is converted to triiodothyronine (T3) by the removal of an iodine atom. This occurs mainly in the liver and in certain tissues where T3 acts, such as the brain. The amount of T4 produced by the thyroid is controlled by thyroid-stimulating hormone (TSH), which is produced and released by the pituitary gland. As is the case with many endocrine glands, regulation of the thyroid occurs through a negative feedback loop. If the pituitary detects very little T4 in the blood, it produces more TSH, which then signals the thyroid to produce more T4. Once the T4 in the bloodstream rises above a certain level, the pituitary's production of TSH is shut off, thereby signaling the thyroid to produce less T4. Conditions that interfere with this normal process are categorized as influencing the thyroid either directly or indirectly. Whichever the case, simple blood tests are useful in identifying the most common causes of thyroid dysfunction.
Evaluating thyroid function
The serum TSH is the best initial test of thyroid function. The latest generation of this assay has high sensitivity and is an excellent screening tool for those patients with a low pretest probability of thyroid disease.2,3 A TSH of 0.5-4.0 mU/L is highly diagnostic for normal thyroid function. A high TSH (>5.0 mU/L is an indication for further testing, such as a free T4 (FT4) determination or a free thyroxine index (FTI). When there is a high pretest probability for thyroid disease, e.g., in the presence of risk factors or clinical signs and symptoms, initial testing should include a serum TSH as well as an FT4 or an FTI.2,3 A patient who has a TSH in the gray zone (4.1–5.0 mU/L) is very likely to develop hypothyroidism and should be screened regularly. Treatment for subclinical hypothyroidism in asymptomatic individuals with TSH <10 mU/L is controversial.2
A high TSH indicates that the thyroid is failing because of a problem directly affecting the gland.1 This direct relationship is known as primary hypothyroidism. Occasionally, a low TSH may result from an abnormality in the pituitary that prevents it from making enough TSH to stimulate the thyroid. This indirectly caused state is known as secondary hypothyroidism. The opposite situation, in which the TSH level is low, usually indicates that the person has an overactive thyroid that is producing too much thyroid hormone (hyperthyroidism).1 In most healthy individuals, a normal TSH value means that the thyroid is functioning well and the patient's condition is considered to be euthyroid. The newest version of the TSH assay is sensitive enough to distinguish hyperthyroidism from the below-normal TSH values observed in transient circumstances (such as euthyroid sick syndrome).2-4 The TSH is likewise useful for following patients on thyroid medication.2-4
Generally, the serum T4 represents about 90% of circulating thyroid hormone.4 T4 circulates in the blood in two forms: T4 bound to proteins which prevent the hormone from entering the various tissues that need it and FT4 (not bound to protein), which enters the various target tissues and exerts its effects. The FT4 fraction represents only about 5% of total T4 but is the most important for determining how the thyroid is functioning since it is the metabolically active form of the hormone.4 Abnormal protein levels can have significant effect on the total T4 results.4 For example, an increase in thyroxine-binding globulins (TBGs) will raise the level of total T4, while a decrease in TBG will lower total T4.4 Note that while changes in TBGs, which transport T4 and T3, can affect the levels of circulating T4, such alterations may not affect the patient's metabolic state.
Variations among laboratory test methods and variance in patients' globulin status make the FTI a better indicator of true thyroid function than FT4.4 Because the FTI corrects for changes in TBGs, it can be used to diagnose thyroid disorders in patients with protein abnormalities and to monitor their therapy. For example, women who are pregnant have increased globulin levels, while persons on certain globulin-binding drugs, e.g., phenytoin (Dilantin), may have decreased levels of available globulin.
An elevated FT4 or FTI indicates hyperthyroidism, while a low FT4 or FTI indicates hypothyroidism.1,4 Combining the TSH test with the FT4 or FTI accurately determines how the thyroid is functioning. The finding of an elevated TSH and low FT4 or FTI indicates primary hypothyroidism due to disease in the thyroid itself.1,4 A low TSH and low FT4 or FTI indicates secondary hypothyroidism, i.e., a problem outside the thyroid, likely involving the pituitary.1,4 A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.1,4 (Table 1 summarizes the interpretation of various test results.)
T3 tests are often useful to diagnose hyperthyroidism or to determine its severity. Patients who are hyperthyroid will have an elevated T3 level. In some patients with a low TSH, only the T3 is elevated and the FT4 or FTI is normal.1,4 T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to become abnormal.1,4 Clinically, this raises the possibility for patients to be severely hypothyroid with a high TSH, low FT4 or FTI, and a normal T3.
Some persons produce antibodies against their thyroid that either stimulate or damage the gland. The two major antibodies that interfere with thyroid function are antithyroid peroxidase (anti-TPO) and antithyroglobulin.1,4 Both antibodies are readily detected in the serum. The presence of anti-TPO and/or antithyroglobulin antibodies in a patient with clinical hypothyroidism is diagnostic for Hashimoto's thyroiditis.1,4 When these same antibodies are detected in a patient with clinical hyperthyroidism, suspect autoimmune thyroid disease.1,4
A summary of the tests used to evaluate thyroid function appears in Table 2.