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Thyroid Function Tests

Thyrotropin releasing hormone (TRH), a hypothalamic peptide, stimulates the anterior pituitary to synthesize and secrete thyroid stimulating hormone (TSH). TSH stimulates the release of triiodothyronine (T₃) and (thyroxine) T₄ from thyroglobulin and their secretion by the thyroid. T₄ and T₃ are secreted in a ratio of 10:1. Most circulating T₃ and T₄ are protein bound. Only the free fraction is metabolically active. In peripheral tissue, T₄ is converted to T₃, which is the active hormone that migrates into the target cell nuclei and binds to DNA.

Primary hypothyroidism is the most common thyroid disorder. In this condition, the thyroid fails to respond to TSH. The pituitary secretes more TSH in response to decreasing circulating T₄ concentrations. The failing thyroid gland partially compensates by increasing the ratio of secreted T₃ to T₄. If this last attempt to restore homeostasis fails, the patient’s metabolic rate falls. At this stage of hypothyroidism, TSH is elevated and T₄ and free T₄ are decreased.

The opposite condition, hyperthyroidism or thyrotoxicosis, is caused by too much circulating T₄. Graves’s disease, an autoimmune disorder caused by antibody to TSH receptors, leads to uncontrolled release of T₄ and T₃, which suppress circulating TSH. Serum T₄, FT₄, T₃, and FT₃ concentrations are elevated two to three times above the upper limit of normal and TSH is undetectable.

Thyroid function tests are among the most common laboratory tests. They account for 4% of all outpatient laboratory tests and 8% of laboratory charges. Traditionally, at least two thyroid function tests, thyroxine (T₄) and T₃ uptake (T₃U), were ordered on each patient. The product of these tests was reported as the free thyroxine index (FTI) or T₇. New methods for direct measurement of free T₄ has eliminated the need to estimate free hormone levels with T₃U and FTI.

The introduction of sensitive TSH (thyroid stimulating hormone) assays has transformed thyroid function testing from a thyroxine to a TSH based strategy. The American Thyroid Association recommends the combined use of TSH and free T₄ as the most efficient combination of blood tests for diagnosis and follow-up of both ambulatory and hospitalized patients.

Testing begins with TSH, because it is the most sensitive indicator of thyroid metabolism in patients with normal pituitary gland function. TSH usually shifts out of the normal range sooner than thyroxine or FT₄. Linear changes in FT₄ concentration result in logarithmic changes in TSH secretion. About 85% of patients have normal TSH values and do not require further testing.

Decreased TSH values suggest primary hyperthyroidism, exogenous hyperthyroxinemia, or the effect of glucocorticoids. Subsequent measurement of FT₄ serves as an index of the severity of hyperthyroidism, because TSH levels can be suppressed even by small increases in FT₄. If FT₄ is normal, total or free T₃ should be measured to detect T₃ toxicosis.

Increased TSH levels suggest primary hypothyroidism. However, the rare conditions of a TSH secreting pituitary adenoma or thyroid hormone resistance may be present. If FT₄ levels are low, the patient is hypothyroid. Normal FT₄ levels are consistent with either a euthyroid state or subclinical hypothyroidism. These two possibilities may be distinguished by testing for thyroid peroxidase antibodies.

Patients with pituitary disease or neuropsychiatric disorders may require more extensive testing. Pituitary tumors may produce TSH, which can cause secondary hyperthyroidism. Patients with previous thyroid ablation may have decreased TSH related to secondary hypothyroidism.

The following medications may increase TSH levels: dopamine antagonists,chlorpromazine, haloperidol, and iodine containing drugs. TSH may be decreased by exogenous thyroxine, glucocorticoids, dopamine, levodopa, dopamine agonists,apomorphine, and pyridoxine.

Nonthyroid illness and poor nutrition can cause many aberrations in pituitary and thyroid function. Seventeen percent of hospitalized adults have abnormal elevations or depression of TSH. In general, the more severe the illness, the more abnormal the tests. In critically ill patients, especially those receiving dopamine, TSH production is often reduced. As the illness progresses, T₄ production is also reduced. A smaller group of patients with nonthyroid illness have increased serum T₄ levels.

The median TSH level increases with age, starting at about age 50, in a disease free population.

The median TSH level in the total population is 1.49 uIU/mL, which is considerably below the 5.5 uIU/mL upper limit of normal reported by most laboratories. A growing number of endocrinologists believe that a TSH result above 3.0 uIU/mL is abnormal, regardless of the fT4 result.

Reference range for TSH is 0.35 - 5.5 uIU/mL.

Reference range for free T4 is 0.8 - 1.6 ng/dL.

During the past 20 years, the upper reference limit for TSH has steadily declined from ~10 to 5.5 mIU/mL because of improvements in TSH assays and the enhanced sensitivity of thyroid antibody tests used to pre-screen subjects for reference range determinations. More than 95% of rigorously screened euthyroid volunteers have TSH values between 0.4 and 2.5. Individuals with a TSH >2.0 have an increased odds ratio of developing hypothyroidism. In the future, it is likely that the upper limit of the normal range will be reduced to 2.5.

Serum TSH levels exhibit considerable diurnal variation, with a maximum level occurring around midnight. TSH levels decrease as much as 50% by 08:00 to 09:30 a.m. The concentration then remains relatively constant until evening, with a smaller nadir in the late afternoon. Because of this significant diurnal variation, sequential specimens should be drawn at the same time of day.

Specimen requirement for both tests is one SST tube of blood.