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Overview of Thyroid Function

by Jerome M. Hershman, MD

The thyroid gland, located in the anterior neck just below the cricoid cartilage, consists of 2 lobes connected by an isthmus. Follicular cells in the gland produce the 2 main thyroid hormones, tetraiodothyronine (thyroxine, T 4 ) and triiodothyronine (T 3 ). These hormones act on cells in virtually every body tissue by combining with nuclear receptors and altering expression of a wide range of gene products. Thyroid hormone is required for normal brain and somatic tissue development in the fetus and neonate, and, in people of all ages, regulates protein, carbohydrate, and fat metabolism.

T 3 is the most active form in binding to the nuclear receptor; T 4 has only minimal hormonal activity. However, T 4 is much longer lasting and can be converted to T 3 (in most tissues) and thus serves as a reservoir for T 3 . A 3rd form of thyroid hormone, reverse T 3 (rT 3 ), has no metabolic activity; levels of rT 3 increase in certain diseases.

Additionally, parafollicular cells (C cells) secrete the hormone calcitonin , which is released in response to hypercalcemia and lowers serum Ca levels (see Overview of Disorders of Calcium Concentration : Regulation of Calcium Metabolism).

Synthesis and Release of Thyroid Hormones

Synthesis of thyroid hormones requires iodine (see Figure: Synthesis of thyroid hormones.). Iodine, ingested in food and water as iodide, is actively concentrated by the thyroid and converted to organic iodine (organification) within follicular cells by thyroid peroxidase. The follicular cells surround a space filled with colloid, which consists of thyroglobulin, a glycoprotein containing tyrosine within its matrix. Tyrosine in contact with the membrane of the follicular cells is iodinated at 1 (monoiodotyrosine) or 2 (diiodotyrosine) sites and then coupled to produce the 2 forms of thyroid hormone (diiodotyrosine + diiodotyrosine T 4 ; diiodotyrosine + monoiodotyrosine T 3 ).

Synthesis of thyroid hormones.

T 3 and T 4 remain incorporated in thyroglobulin within the follicle until the follicular cells take up thyroglobulin as colloid droplets. Once inside the thyroid follicular cells, T 3 and T 4 are cleaved from thyroglobulin. Free T 3 and T 4 are then released into the bloodstream, where they are bound to serum proteins for transport, the major one being thyroxine-binding globulin (TBG), which has high affinity but low capacity for T 3 and T 4 . TBG normally carries about 75% of bound thyroid hormones. The other binding proteins are thyroxine-binding prealbumin (transthyretin), which has high affinity but low capacity for T 4 , and albumin, which has low affinity but high capacity for T 3 and T 4 . About 0.3% of total serum T 3 and 0.03% of total serum T 4 are free and in equilibrium with bound hormones. Only free T 3 and free T 4 are available to act on the peripheral tissues.

All reactions necessary for the formation and release of T 3 and T 4 are controlled by thyroid-stimulating hormone (TSH), which is secreted by pituitary thyrotropic cells. TSH secretion is controlled by a negative feedback mechanism in the pituitary: Increased levels of free T 4 and T 3 inhibit TSH synthesis and secretion, whereas decreased levels increase TSH secretion. TSH secretion is also influenced by thyrotropin -releasing hormone (TRH), which is synthesized in the hypothalamus. The precise mechanisms regulating TRH synthesis and release are unclear, although negative feedback from thyroid hormones inhibits TRH synthesis.

Most circulating T 3 is produced outside the thyroid by monodeiodination of T 4 . Only one fifth of circulating T 3 is secreted directly by the thyroid.

Laboratory Testing of Thyroid Function

TSH measurement is the best means of determining thyroid dysfunction (see Table: Results of Thyroid Function Tests in Various Clinical Situations). Normal results essentially rule out hyperthyroidism or hypothyroidism, except in patients with central hypothyroidism due to disease in the hypothalamus or pituitary gland or in rare patients with pituitary resistance to thyroid hormone. Serum TSH can be falsely low in very sick people. The serum TSH level also defines the syndromes of subclinical hyperthyroidism (low serum TSH) and subclinical hypothyroidism (elevated serum TSH), both of which are characterized by normal serum T 4 , free T 4 , serum T 3 , and free T 3 levels.

Results of Thyroid Function Tests in Various Clinical Situations

Physiologic State

Serum TSH

Serum Free T 4

Serum T 3

24-h Radioiodine Uptake

Hyperthyroidism

Untreated

Low

High

High

High

T 3 toxicosis

Low

Normal

High

Normal or high

Hypothyroidism

Primary, untreated

High

Low

Low or normal

Low or normal

Secondary to pituitary disease

Low or normal

Low

Low or normal

Low or normal

Euthyroidism

Patient taking iodine

Normal

Normal

Normal

Low

Patient taking exogenous thyroid hormone

Normal

Normal in patient taking T 4 , low in patient taking T 3

High in patient taking T 3 , normal in patient taking T 4

Low

Patient taking estrogen

Normal

Normal

High

Normal

Euthyroid sick syndrome

Normal, low, or high

Normal or low

Low

Normal

T 3 = triiodothyronine; T 4 = thyroxine; TSH = thyroid-stimulating hormone.

Total serum T 4 is a measure of bound and free hormone. Changes in levels of thyroid hormone–binding serum proteins produce corresponding changes in total T 4 , even though levels of physiologically active free T 4 are unchanged. Thus, a patient may be physiologically normal but have an abnormal total serum T 4 level. Free T 4 in the serum can be measured directly, avoiding the pitfalls of interpreting total T 4 levels.

Free T 4 index is a calculated value that corrects total T 4 for the effects of varying amounts of thyroid hormone–binding serum proteins and thus gives an estimate of free T 4 when total T 4 is measured. The thyroid hormone–binding ratio or T 3 resin uptake is used to estimate protein binding. Free T 4 index is readily available and compares well with direct measurement of free T 4 .

Total serum T 3 and free T 3 can also be measured. Because T 3 is tightly bound to TBG (although 10 times less so than T 4 ), total serum T 3 levels are influenced by alterations in serum TBG level and by drugs that affect binding to TBG. Free T 3 levels in the serum are measured by the same direct and indirect methods (free T 3 index) described for T 4 and are used mainly for evaluating thyrotoxicosis.

TBG can be measured. It is increased in pregnancy, by estrogen therapy or oral contraceptive use, and in the acute phase of infectious hepatitis. TBG may also be increased by an X-linked abnormality. It is most commonly decreased by illnesses that reduce hepatic protein synthesis, use of anabolic steroids, and excessive corticosteroid use. Large doses of certain drugs, such as phenytoin and aspirin and their derivatives, displace T 4 from its binding sites on TBG, which spuriously lowers total serum T 4 levels.

Autoantibodies to thyroid peroxidase are present in almost all patients with Hashimoto thyroiditis (some of whom also have autoantibodies to thyroglobulin) and in most patients with Graves disease. These autoantibodies are markers of autoimmune disease but probably do not cause disease. However, an autoantibody directed against the TSH receptor on the thyroid follicular cell is responsible for the hyperthyroidism in Graves disease. Antibodies against T 4 and T 3 may be found in patients with autoimmune thyroid disease and may affect T 4 and T 3 measurements but are rarely clinically significant.

The thyroid is the only source of thyroglobulin, which is readily detectable in the serum of healthy people and is usually elevated in patients with nontoxic or toxic goiter. The principal use of serum thyroglobulin measurement is in evaluating patients after near-total or total thyroidectomy (with or without 131 I ablation) for differentiated thyroid cancer. Normal or elevated serum thyroglobulin values indicate the presence of residual normal or cancerous thyroid tissue in patients receiving TSH-suppressive doses of l -thyroxine or after withdrawal of l -thyroxine. However, thyroglobulin antibodies interfere with thyroglobulin measurement.

Radioactive iodine uptake can be measured. A trace amount of radioiodine is given orally or IV; a scanner then detects the amount of radioiodine taken up by the thyroid. The preferred radioiodine isotope is 123 I, which exposes the patient to minimal radiation (much less than 131 I). Thyroid 123 I uptake varies widely with iodine ingestion and is low in patients exposed to excess iodine.

The test is valuable in the differential diagnosis of hyperthyroidism (high uptake in Graves disease, low uptake in thyroiditis—see Hyperthyroidism : Diagnosis). It may also help in the calculation of the dose of 131 I needed for treatment of hyperthyroidism.

Imaging using a scintillation camera can be done after radioisotope administration (radioiodine or technetium 99m pertechnetate) to produce a graphic representation of isotope uptake. Focal areas of increased (hot) or decreased (cold) uptake help distinguish areas of possible cancer (thyroid cancers exist in < 1% of hot nodules compared with 10 to 20% of cold nodules).

Screening

Screening every 5 yr by measuring serum TSH is recommended for all men 65, for all women 35, and for pregnant women. For those with risk factors for thyroid disease, the serum TSH should be checked more often. Screening for hypothyroidism is as cost effective as screening for hypertension, hypercholesterolemia, and breast cancer. This single test is highly sensitive and specific in diagnosing or excluding two prevalent and serious disorders (hypothyroidism and hyperthyroidism), both of which can be treated effectively. Because of the high incidence of hypothyroidism in the elderly, screening on an annual basis is reasonable for those > age 70.

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