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Merck Manual > Health Care Professionals > Endocrine and Metabolic Disorders > Thyroid Disorders

Overview of Thyroid Function


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, T4) and
triiodothyronine (T3). 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.
T3 is the most active form in binding to the nuclear receptor; T4 has only minimal hormonal activity. However, T4 is much
longer lasting and can be converted to T3 (in most tissues) and thus serves as a reservoir for T3. A 3rd form of thyroid
hormone, reverse T3 (rT3), has no metabolic activity; levels of rT3 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 Electrolyte Disorders: Regulation of Calcium Metabolism).

Synthesis and Release of Thyroid Hormones


Synthesis of thyroid hormones requires iodine (see Fig. 1: Thyroid Disorders: 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 T4; diiodotyrosine + monoiodotyrosine T3).

Fig. 1
Synthesis of thyroid hormones.

T3 and T4 remain incorporated in thyroglobulin within the follicle until the follicular cells take up thyroglobulin as colloid
droplets. Once inside the thyroid follicular cells, T3 and T4 are cleaved from thyroglobulin. Free T3 and T4 are then
released into the bloodstream, where they are bound to serum proteins for transport, the major one being thyroxinebinding globulin (TBG), which has high affinity but low capacity for T3 and T4. 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 T4, and albumin, which has low affinity but high capacity for T3 and T4. About 0.3% of total serum T3 and
0.03% of total serum T4 are free and in equilibrium with bound hormones. Only free T3 and free T4 are available to act
on the peripheral tissues.

All reactions necessary for the formation and release of T3 and T4 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 T4 and T3 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 T3 is produced outside the thyroid by monodeiodination of T4. Only one fifth of circulating T3 is secreted
directly by the thyroid.

Laboratory Testing of Thyroid Function


TSH measurement is the best means of determining thyroid dysfunction (see Table 1: Thyroid Disorders: 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 T4, free T4, serum T3, and free T3 levels.
Table 1

Results of Thyroid Function Tests in Various Clinical


Situations
Physiologic
State

Serum
TSH

Serum Free
T4

Serum T3

24-h
Radioiodine
Uptake

Low

High

High

High

Hyperthyroidism

Untreated

T3 toxicosis

Low

Normal

High

Normal or
high

Primary,
untreated

High

Low

Low or
normal

Low or
normal

Secondary
to pituitary
disease

Low or
normal

Low

Low or
normal

Low or
normal

Patient
taking
iodine

Normal

Normal

Normal

Low

Patient
taking
exogenous
thyroid
hormone

Normal

Normal in
patient
taking T4,

High in
patient
taking T3,

Low

low in
patient
taking T3

normal in
patient
taking T4

Patient
taking
estrogen

Normal

Normal

High

Normal

Euthyroid
sick

Normal,
low, or

Normal or
low

Low

Normal

Hypothyroidism

Euthyroidism

syndrome

high

T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Total serum T is a measure of bound and free hormone. Changes in levels of thyroid hormonebinding serum proteins

produce corresponding changes in total T4, even though levels of physiologically active free T4 are unchanged. Thus, a
patient may be physiologically normal but have an abnormal total serum T4 level. Free T4 in the serum can be measured
directly, avoiding the pitfalls of interpreting total T4 levels.
Free T4 index is a calculated value that corrects total T4 for the effects of varying amounts of thyroid hormonebinding
serum proteins and thus gives an estimate of free T4 when total T4 is measured. The thyroid hormonebinding ratio or
T3 resin uptake is used to estimate protein binding. Free T4 index is readily available and compares well with direct
measurement of free T4.
Total serum T3 and free T3 can also be measured. Because T3 is tightly bound to TBG (although 10 times less so than
T4), total serum T3 levels are influenced by alterations in serum TBG level and by drugs that affect binding to TBG. Free
T3 levels in the serum are measured by the same direct and indirect methods (free T3 index) described for T4 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 T4 from its binding sites on TBG, which
spuriously lowers total serum T4 levels.
Autoantibodies to thyroid peroxidase are present in almost all patients with Hashimoto's 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 T4 and T3 may
be found in patients with autoimmune thyroid disease and may affect T4 and T3 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 131I 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 123I, which exposes the patient to
minimal radiation (much less than 131I). Thyroid 123I 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
thyroiditissee Thyroid Disorders: Diagnosis). It may also help in the calculation of the dose of 131I needed for treatment of
hyperthyroidism.
Imaging by 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.
Last full review/revision May 2012 by Jerome M. Hershman, MD
Content last modified May 2012

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