Download Thyroid and Parathyroid Testing - American Proficiency Institute

EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING
Educational commentary is provided through our affiliation with the American Society for Clinical
Pathology (ASCP). To obtain FREE CME/CMLE credits click on Continuing Education on the left side of
the screen.
Learning Outcomes
Upon completion of this exercise, the participant will be able to:
•
Discuss the symptoms of Hashimoto’s thyroiditis and Graves disease.
•
List laboratory tests used to investigate thyroid and parathyroid dysfunction.
•
Interpret thyroid and parathyroid test results.
An estimated 13 million Americans have thyroid-related disease, making it the second (to diabetes) most
common endocrine disorder. The incidence of thyroid disease increases with age and is more prevalent
in women than men. As many as 8 million cases of thyroid disease in the United States are undiagnosed.
Once diagnosed, both hypo- and hyperthyroidism are easily treatable. Laboratory tests are crucial in the
diagnosis and treatment monitoring of thyroid disease.
Thyroid Function
The thyroid gland, a large bilobed gland located in the neck anterior to the trachea, is often described as
butterfly-shaped. It synthesizes and releases iodine-containing thyroid hormones, including thyroxine
(tetraiodothyronine) (T4) and two forms of triiodothyronine (T3 and reverse T3). Although T4 is present in
the highest concentration in plasma, T3 is the biologically most active form. Most circulating T4 and T3 is
bound to the plasma proteins thyroxine-binding globulin (TBG), transthyretin (thyroxine-binding
prealbumin), and albumin with only approximately 0.03 % of T4 and 0.3 % of T3 circulating as the free or
unbound form. Only free hormone is available to tissues to induce the metabolic effects regulated by
these hormones. Equilibrium between bound and free hormone and changes in levels of the binding
proteins must be considered when interpreting hormone concentrations.
Thyroid hormones are involved in the regulation of multiple metabolic processes. Large quantities of
these hormones are stored in the gland and the rate of secretion to maintain normal metabolic activity is
controlled by feedback mechanisms via the hypothalamic, pituitary, and thyroid axis. The hypothalamus
releases thyroxine-releasing hormone (TRH) that stimulates the pituitary to produce and release thyroidstimulating hormone (TSH) that then regulates formation and release of thyroid hormones by the thyroid
gland. Increased levels of T3 and T4 inhibit secretion of TRH and TSH.
Thyroid Disorders
The signs and symptoms of thyroid disease are nonspecific and fairly frequently encountered, and are
often undiagnosed or attributed to the aging process or some other condition. These clinical features
include weight loss, irritability, tachycardia, heat intolerance, and dyspnea for hyperthyroidism; and weight
rd
American Proficiency Institute – 2005 3 Test Event
EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.)
gain, dry skin, cold intolerance, and bradycardia for hypothyroidism. An enlarged thyroid (goiter) may
occur in both hypo- and hyperthyroidism. There is not a consensus among professional medical societies
concerning general population screening for the detection of thyroid disease, but the American Thyroid
Association recommends screening adults beginning at age 35 years and every 5 years thereafter. Other
organizations recommend screening women over the age of 50, asymptomatic adults over the age of 60,
or those at high risk, such as pregnant and postpartum women. Newborn screening programs in the US
test for T4, frequently using dried blood on filter paper. Available thyroid function tests include TSH, total
and free T4, and T3 as well as tests for the binding proteins and thyroid autoantibodies.
Thyroid Function Testing
The preferred initial test for thyroid dysfunction in an ambulatory population is TSH. Although free
hormone levels mediate the metabolic processes, TSH is the preferred test because the inverse log/linear
relationship between free T4 and TSH is such that a two-fold change in free T4 causes a 100-fold change
in TSH levels. Current TSH immunoassays, with functional sensitivity of at least 0.02 mIU/L, are able to
distinguish between hypo-, hyper-, and euthyroidism and are referred to as third-generation or ultrasensitive TSH assays. Reference ranges for TSH are being refined as more studies using the current
immunoassays are published. The upper limit has declined from 10 to 4.0 or 4.5 mIU/L and there is
support to lower it to 2.5 mIU/L or lower. The lower limit is typically 0.2-0.4 mIU/L, and some studies in
the elderly indicate that these levels may represent thyroid hormone excess. Total T4 levels may be
determined to confirm a diagnosis, but free T4 assays reflect true thyroid status. Free hormone levels can
be approximated using an index method in which the fraction of free hormone is estimated using the total
hormone concentration and an assessment of thyroid-binding protein concentration using either an
immunoassay for TBG or more commonly a T4 or T3 “uptake” test called Thyroid Hormone Binding Ratio
(THBR).
In a hospitalized population, severe nonthyroidal illness (NTI) and medication can affect thyroid test
results so testing should be limited to patients with symptoms or a history of thyroid dysfunction. In such
cases both TSH and free T4 followed by total T4 may be necessary. If T4 and TSH results in these patients
are concordant, there is probably a true thyroid dysfunction.
Hypothyroidism
Hypothyroidism accounts for approximately 80% of all thyroid disease and the most frequent form is the
autoimmune condition known as Hashimoto’s thyroiditis. An elevated TSH is diagnostic for
hypothyroidism, but additional testing may help to confirm or to refine the diagnosis. A low free T4
concentration confirms the diagnosis. The presence of autoantibodies may be determined using the
thyroid peroxidase antibody (TPOAb) test. Occasionally, hypothyroidism may be caused by pituitary
(secondary) or hypothalamic (tertiary) dysfunction and TSH results will be decreased. In these cases,
rd
American Proficiency Institute – 2005 3 Test Event
EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.)
TRH stimulation testing in which TSH levels are measured following TRH administration helps to
elucidate the cause.
Hyperthyroidism
Graves’ disease, the most common cause of hyperthyroidism, is caused by an autoantibody, thyroidstimulating immunoglobulin (TSI), that mimics the action of TSH and causes overproduction of the thyroid
hormones. These elevated T4 and T3 levels suppress production and release of TSH resulting in the
decreased TSH levels diagnostic for hyperthyroidism. The diagnosis can be confirmed by demonstration
of elevated free T4 levels. One type of hyperthyroidism, known as T3 thyrotoxicosis, is characterized by
decreased TSH, normal free T4, and elevated free and/or total T3.
Laboratory Concerns
The National Academy of Clinical Biochemistry (NACB) practice guidelines, entitled Laboratory Support
for the Diagnosis and Monitoring of Thyroid Disease (available at www.nacb.org), includes
recommendations and items of particular interest to the laboratory. In addition to appropriate use of
thyroid function tests, the guidelines address analytical issues. One question often asked by physicians
is whether successive test values are clinically significant. Although Table 1 lists the estimated clinically
significant differences when monitoring patient response to therapy, these values, which include
analytical and biological variability, could be used in other situations involving successive thyroid function
test values. When investigating discordant thyroid test results, laboratorians should be aware of possible
interference due to heterophile antibodies or occurrence of the hook effect with the immunoassays that
they use. Results of discordant results should be retested using an immunoassay from a different
manufacturer in order to eliminate assay-related interferences.
Table 1.
Clinically significant differences in thyroid test values when monitoring a patient’s response to therapy
Test
Difference
Total T4
2.2 µg/dL
Free T4
0.5 ng/dL
Total T3
35 ng/dL
Free T3
0.1 ng/dL
TSH
0.75 mIU/L
Reproduced with permission of the National Academy of Clinical Biochemistry, Washington, DC.
Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid
Disease, 2003. (available for download at www.nacb.org)
Parathyroid Function Testing
Parathyroid hormone (PTH), synthesized and secreted by the 4 parathyroid glands located beside the
thyroid gland, helps to maintain blood calcium levels. PTH is released in response to low calcium levels
rd
American Proficiency Institute – 2005 3 Test Event
EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.)
and helps raise the calcium by mobilizing it from bone, stimulating renal activation of vitamin D, and
increasing renal retention of calcium. PTH is typically ordered to investigate hyper-or hypocalcemia, but it
is also helpful when monitoring treatment for diseases affecting calcium regulation, or in chronic
conditions such as renal disease. Interpretation of PTH levels is made in conjunction with calcium
results. Elevated calcium and PTH levels are diagnostic for primary hyperparathyroidism. Low or normal
PTH levels in the presence of low calcium levels indicates hypoparathyroidism.
The short half-life of PTH (3-4 minutes) allows the use of point-of-care methods for monitoring PTH levels
during parathyroid surgery for hyperparathyroidism. Samples are collected and analyzed before and at 5and 10-minute intervals after removal of abnormal parathyroid tissue. A decline of more than 50% in PTH
from 0 to 5 minutes postexcision indicates successful surgery. This intraoperative PTH monitoring
provides rapid feedback to the surgeon to ensure that sufficient tissue has been removed.
Conclusion
In summary, laboratory testing is invaluable in the diagnosis and monitoring of therapy for disorders of
both thyroid and parathyroid function. Laboratorians should be aware of the characteristics of the assays
that they use for this testing in order to be able to troubleshoot potential problems.
© ASCP 2005
rd
American Proficiency Institute – 2005 3 Test Event