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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.
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
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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