Download Laboratory evaluation of thyroid function

FEATURE: LAURA M. GUNDER, DHSC, MHE, PA-C, AND SARA HADDOW, MSA, PA-C
Laboratory evaluation
of thyroid function
Blood tests can detect thyroid dysfunction, which can result in cardiac, GI, and
menstrual disturbances as well as abnormalities in fetal neural development.
Myxedema is a skin
condition caused
by the deposition
of hyaluronic acid in
patients with
thyroid disease.
lood tests to measure thyroid function are
readily available and widely used.To understand a test’s scientific basis and what it
can tell us, a quick review of the thyroid gland’s
pathophysiology is in order.The major hormone
secreted by the thyroid is thyroxine,also called T4
because it contains four iodine atoms.1 To exert
its effects, T4 is converted to triiodothyronine
(T3) by the removal of an iodine atom.This occurs mainly in the liver and in certain tissues
where T3 acts,such as the brain.The amount of T4
produced by the thyroid is controlled by thyroidstimulating hormone (TSH), which is produced
and released by the pituitary gland.As is the case
with many endocrine glands, regulation of the
thyroid occurs through a negative feedback loop.
If the pituitary detects very little T4 in the blood,
it produces more TSH, which then signals the
thyroid to produce more T4. Once the T4 in the
bloodstream rises above a certain level, the pituitary’s production of TSH is shut off,thereby signaling the thyroid to produce less T4.Conditions
that interfere with this normal process are categorized as influencing the thyroid either directly
or indirectly. Whichever the case, simple blood
tests are useful in identifying the most common
causes of thyroid dysfunction.
B
Evaluating thyroid function
© ISM / PHOTOTAKE
The serum TSH is the best initial test of thyroid
function.The latest generation of this assay has
high sensitivity and is an excellent screening tool
for those patients with a low pretest probability
of thyroid disease.2,3 A TSH of 0.5-4.0 mU/L is
26 THE CLINICAL ADVISOR • DECEMBER 2009 • www.clinicaladvisor.com
THYROID FUNCTION
A high TSH indicates that the thyroid is failing
because of a problem directly affecting the gland.
This is known as primary hypothyroidism.
highly diagnostic for normal thyroid function. A high TSH
(>5.0 mU/L is an indication for further testing,such as a free
T4 (FT4 ) determination or a free thyroxine index (FTI).
When there is a high pretest probability for thyroid disease,
e.g.,in the presence of risk factors or clinical signs and symptoms, initial testing should include a serum TSH as well as an
FT4 or an FTI.2,3 A patient who has a TSH in the gray zone
(4.1–5.0 mU/L) is very likely to develop hypothyroidism and
should be screened regularly.Treatment for subclinical hypothyroidism in asymptomatic individuals with TSH <10 mU/L
is controversial.2
A high TSH indicates that the thyroid is failing because of a
problem directly affecting the gland.1 This direct relationship
is known as primary hypothyroidism. Occasionally, a low
TSH may result from an abnormality in the pituitary that
prevents it from making enough TSH to stimulate the thyroid.This indirectly caused state is known as secondary hypothyroidism. The opposite situation, in which the TSH
level is low,usually indicates that the person has an overactive
thyroid that is producing too much thyroid hormone (hyperthyroidism).1 In most healthy individuals, a normal TSH
value means that the thyroid is functioning well and the patient’s condition is considered to be euthyroid.The newest
version of the TSH assay is sensitive enough to distinguish
hyperthyroidism from the below-normal TSH values observed in transient circumstances (such as euthyroid sick
syndrome).2-4 The TSH is likewise useful for following patients on thyroid medication.2-4
Generally, the serum T4 represents about 90% of circulating
thyroid hormone.4 T4 circulates in the blood in two forms:T4
bound to proteins which prevent the hormone from entering
the various tissues that need it and FT4 (not bound to protein),
which enters the various target tissues and exerts its effects.
The FT4 fraction represents only about 5% of total T4 but is
the most important for determining how the thyroid is functioning since it is the metabolically active form of the hormone.4 Abnormal protein levels can have significant effect on
the total T4 results.4 For example, an increase in thyroxinebinding globulins (TBGs) will raise the level of total T4, while
a decrease in TBG will lower total T4.4 Note that while
changes in TBGs,which transport T4 and T3,can affect the levels of circulating T4, such alterations may not affect the patient’s metabolic state.
Variations among laboratory test methods and variance in
patients’globulin status make the FTI a better indicator of true
thyroid function than FT4.4 Because the FTI corrects for
changes in TBGs, it can be used to diagnose thyroid disorders
in patients with protein abnormalities and to monitor their
therapy. For example, women who are pregnant have increased globulin levels, while persons on certain globulinbinding drugs, e.g., phenytoin (Dilantin), may have decreased
levels of available globulin.
An elevated FT4 or FTI indicates hyperthyroidism, while a
low FT4 or FTI indicates hypothyroidism.1,4 Combining the
TSH test with the FT4 or FTI accurately determines how the
thyroid is functioning.The finding of an elevated TSH and low
FT4 or FTI indicates primary hypothyroidism due to disease in
the thyroid itself.1,4 A low TSH and low FT4 or FTI indicates
secondary hypothyroidism, i.e., a problem outside the thyroid,
likely involving the pituitary.1,4 A lowTSH with an elevated FT4
or FTI is found in individuals who have hyperthyroidism.1,4
(Table 1 summarizes the interpretation of various test results.)
Continues on page 30
TABLE 1. Thyroid function test interpretation
TSH result
Subsequent
FT4 result*
Possible diagnoses
Elevated TSH
(>5 mU/L)
Low FT4
Primary hypothyroidism
Normal FT4
Subclinical hypothyroidism
High FT4
TSH-mediated hyperthyroidism
(secondary or tertiary hyperthyroidism)
Low FT4
Central hypothyroidism (rare)
Normal FT4
Subclinical hyperthyroidism
Check T4; may recheck FT4 and T4
every two to three months
High FT4
Hyperthyroidism or thyrotoxicosis
Check RAIU to identify cause
Low TSH
(<0.1 mU/L)
*In some patients, an freethyroxine index (FTI) may provide more information. See text
for discussion of FTI.
FT4=free thyroxine, RAIU=radioactive iodine uptake;TSH=thyroid-stimulating hormone
Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Demers LM, Spencer CA. Laboratory
Support for the Diagnosis and Monitoring of Thyroid Disease.American Association for
Clinical Chemistry; 2002.Available at www.aacc.org/members/nacb/Archive/LMPG
/ThyroidDisease/Pages/ThyroidDiseasePDF.aspx.Accessed October 26, 2009; Supit EJ,
Peiris AN. Interpretation of laboratory thyroid function tests for the primary care physician. South Med J. 2002;95:481-485.
www.clinicaladvisor.com • THE CLINICAL ADVISOR • DECEMBER 2009 29
THYROID FUNCTION
Consideration of subclinical thyroid disorders
is crucial in the presence of abnormal test results
regardless of clinical presentation.
T3 tests are often useful to diagnosis hyperthyroidism or to
determine its severity.Patients who are hyperthyroid will have
an elevated T3 level.In some patients with a low TSH,only the
T3 is elevated and the FT4 or FTI is normal.1,4 T3 testing rarely
is helpful in the hypothyroid patient, since it is the last test to
become abnormal.1,4 Clinically, this raises the possibility for
patients to be severely hypothyroid with a high TSH,low FT4
or FTI,and a normal T3.
Some persons produce antibodies against their thyroid that
either stimulate or damage the gland.The two major antibodies that interfere with thyroid function are antithyroid
peroxidase (anti-TPO) and antithyroglobulin.1,4 Both antibodies are readily detected in the serum. The presence of
anti-TPO and/or antithyroglobulin antibodies in a patient
with clinical hypothyroidism is diagnostic for Hashimoto’s
thyroiditis.1,4 When these same antibodies are detected in a
patient with clinical hyperthyroidism, suspect autoimmune
thyroid disease.1,4
A summary of the tests used to evaluate thyroid function
appears in Table 2.
Which tests to order and when
In clinical practice, three basic scenarios indicate a need for
laboratory evaluation of thyroid function: (1) suspicion of
thyroid disease based on clinical signs and symptoms,1-4
(2) screening for thyroid disease,1-6 and (3) evaluation of treatment for thyroid disease.1,4,7,8
Working up symptomatic patientsWhen clinical signs
and symptoms of hypothyroidism or hyperthyroidism (Table
3) are present, evaluation of a serum TSH and FTI or FT4 is
indicated.1,4 Because thyroid dysfunction may develop insidiously over a long period, consideration of subclinical thyroid
TABLE 2. Summary of blood tests to evaluate thyroid function and their clinical utility
Entity
tested
Description
Clinical utility
TSH
Thyroid-stimulating hormone or thyrotropin
•
•
•
•
T4
Serum total thyroxine
• Used to make diagnosis of underactive or overactive thyroid when TSH is
abnormal
• Used with TSH for monitoring patients with Graves’ disease
• Newborn screening test for hypothyroidism
• Fairly accurate in patients with no protein abnormalities and not pregnant
FT4
Free thyroxine is the metabolically active thyroid
hormone – not bound to protein
• Should be ordered when TSH is abnormal to determine thyroid hyperfunction
or hypofunction.
FTI
• Used for making the diagnosis of thyroid disease in patients with protein
Free thyroxine index – measure of free T4 determined
abnormalities and in pregnant patients
by measuring thyroxine level and either thyroid• Used for monitoring therapy in above patient groups with hyperthyroidism
binding globulin or hormone-binding ratio
T3
Serum total triiodothyronine
• Used to diagnose hyperthyroidism when TSH is low and T4 is still normal
Thyroid
antibodies
• Antithyroid peroxidase (antimicrosomal)
antibodies
• Antithyroglobulin antibodies
• Used to diagnose suspected Hashimoto’s thyroiditis in hypothyroidism
• Used to diagnose autoimmune thyroiditis or Graves’ disease in hyperthyroidism
Best thyroid function screening test
Initial test for suspected thyroid disease
Used to follow patients on thyroid hormone therapy
Used in conjunction with T4 to manage patients with Graves’ disease
Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Demers LM, Spencer CA. Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease.American Association for Clinical
Chemistry; 2002.Available at www.aacc.org/members/nacb/Archive/LMPG/ThyroidDisease/Pages/ThyroidDiseasePDF.aspx.Accessed October 26, 2009; Supit EJ, Peiris AN. Interpretation
of laboratory thyroid function tests for the primary care physician. South Med J. 2002;95:481-485.
30 THE CLINICAL ADVISOR • DECEMBER 2009 • www.clinicaladvisor.com
disorders is crucial in the presence of abnormal test results regardless of clinical presentation. Subclinical hyperthyroidism
and subclinical hypothyroidism are exclusively laboratory diagnoses.7,8 Subclinical hypothyroidism should be suspected
when the serum TSH is increased above the upper limit of the
reference range (>5.0 mU/L) in combination with a normal
T4.1,5,7,8 Conversely,subclinical hyperthyroidism is likely when
TSH is decreased below the lower limit of the reference range
(<0.10 mU/L) in the presence of a normal T4 (Table 1).1,5,7,8
Screening Patients not previously diagnosed or treated for
thyroid disease should be screened if they are older than 60 years
or if they have a personal history of surgery or irradiation of the
thyroid or neck, any family history of autoimmune disease, or
an existing thyroid nodule or goiter.3,6 Screening is also indicated for those patients who are currently using or who have
a history of long-term use of amiodarone or lithium.3,6 Newborns are screened to detect hypothyroidism in infancy by performing a serum T4 level on the blood spot collected shortly
after birth; hypothyroidism that is detected early can be treated
and mental retardation or cretinism prevented.2-4
Subclinical hyperthyroidism is estimated to occur in 2% of
the adult population.1,5,7,8 The condition may be due to TSH
suppression from an exogenous source or to endogenous production of thyroid hormone that suppresses pituitary TSH
production and keeps FT4 and T3 levels normal.1,2,7,8 Such circumstances may represent the early stages of clinical hyperthyroidism and should be considered a risk factor for the
development of osteoporosis and adverse cardiac manifestations, such as atrial fibrillation.1,2 Once the suppressed TSH is
detected, repeat evaluation is needed to document that the
low level is persistent.The American Academy of Clinical Endocrinologists (AACE) recommends that TSH, FT4, and T3
determinations be repeated two to four months after the initial discovery of low TSH.1,2 While treatment guidelines for
subclinical hyperthyroidism have not been established, patients who have persistently low TSH levels should be reevaluated at six-month intervals thereafter.1
Subclinical hypothyroidism occurs in about 5% of the adult
population, but prevalence may be as high as 20% in women
older than 60 years.1,5,7,8 Approximately 5% of patients with
subclinical hypothyroidism will progress to clinical hypothyroidism each year.5,8 Subclinical hypothyroidism increases the
risks for hyperlipidemia, atherosclerosis, and possibly neurobehavioral disorders.2,5,7,8 Patients with subclinical hypothyroidism (TSH >5.0 mU/L) should be re-evaluated within
three months and then every six months.8
Treatment monitoring The same tests that are used for
diagnosis of thyroid disease can be used to follow treatment.
TABLE 3. Signs and symptoms of thyroid disease
Hypothyroidism
Hyperthyroidism
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Cold intolerance
Fatigue
Depression
Memory impairment/
decreased concentration
Weight gain
Dry skin and dry hair
Hair loss with increasing
coarseness
Constipation
Myalgias
Menstrual irregularities
Hoarseness
Goiter
Bradycardia
Myxedema
Hyperlipidemia
Delayed return of deep
tendon reflexes
•
•
•
•
•
•
•
•
•
•
Heat intolerance
Muscle weakness
Fine resting tremor
Tachycardia
Palpitations/
irregular heart rate
Fatigue
Weight change
Increased frequency of stool
Irritability
Anxiety
Sleep disturbance
Ophthalmopathy
Menstrual irregularities
Myxedema
Hyperreflexia
Sources: Baskin HJ et al2;Wilson GR and Curry RW8; Fitzgerald PA. Endocrine
disorders. In: McPhee SJ, Papdakis MA, eds. Current Medical Diagnosis and Treatment.
48th ed. New York, NY: McGraw-Hill; 2009:976-1003.
Hypothyroid patients who are started on levothyroxine
should have their TSH measured every six to eight weeks to
guide dose adjustments.2,4 Dosing is considered therapeutic
once TSH levels reach normal ranges and the patient is no
longer symptomatic.1-4
Female patients who become pregnant while taking
levothyroxine should have a TSH level assessed immediately
after pregnancy is diagnosed, since the replacement dose of
levothyroxine will typically increase during pregnancy.1-4
These patients will also need TSH assessment at regular interAT A GLANCE
●
The serum thyroid-stimulating hormone is the best initial test
of thyroid function.
●
Abnormal protein levels can have significant effect on the
total thyroxine (T4) results.
●
Subclinical hyperthyroidism and subclinical hypothyroidism
are exclusively laboratory diagnoses.
●
Re-evaluate patients with subclinical hypothyroidism within
three months of detection and then every six months.
www.clinicaladvisor.com • THE CLINICAL ADVISOR • DECEMBER 2009 31
THYROID FUNCTION
vals throughout the pregnancy and postpartum period even if
they had stable TSH levels prior to pregnancy.1-4 Left untreated,maternal hypothyroidism can cause defects of the fetal
neural development.
Patients with low TSH who are treated for Graves’ disease,
thyroid nodules, and thyroiditis may also be monitored using
TSH and T4 levels at four-week intervals during treatment.1-4
Monitoring of such patients should continue until thyroid
levels normalize and symptoms resolve. ■
Dr.Gunder and Ms.Haddow are assistant professors in the School of
Allied Health Sciences at the Medical College of Georgia in Augusta.
References
1. Ladenson P, Kim M.The thyroid. In: Goldman L,Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa.: Saunders; 2007: chap 244.
“I wasn’t texting.I was building
this ship in a bottle.”
2. Baskin HJ, Cobin RH, Duick DS, et al;American Association of Clinical
Endocrinologists Thyroid Task Force.American Association of Clinical
Endocrinologists medical guidelines for clinical practice for the evaluation
and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;
8:457-469.
3. American Academy of Family Physicians (AAFP). Summary of recommendations for clinical preventive services. Revision 6.8. Leawood, Kan.:American Academy of Family Physicians (AAFP); October 2009.Available at
www.aafp.org/online/etc/medialib/aafp_org/documents/clinical/CPS
/rcps08-2005.Par.0001.File.tmp/Oct2009RCPSwithedits.pdf.
4. Wu A, ed. Teitz Clinical Guide to Laboratory Tests. 4th ed. Philadelphia, Pa.:
Saunders; 2006.
5. U.S. Preventive Services Task Force. Screening for thyroid disease: recommendation statement. Ann Intern Med. 2004;140:125-127.Available at
“You smell like a chimney.”
www.annals.org/cgi/reprint/140/2/125.pdf.
6. Vanderpump MP,Tunbridge WM, French JM, et al.The incidence of thyroid
vey. Clin Endocrinol (Oxf). 1995;43:55-68.
7. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific
review and guidelines for diagnosis and management. JAMA. 2004;291:228238.Available at jama.ama-assn.org/cgi/content/full/291/2/228.
8. Wilson GR, Curry RW. Subclinical thyroid disease. Am Fam Physician. 2005;
72:1517-1524.Available at www.aafp.org/afp/20051015/1517.html.
All electronic documents accessed November 10, 2009.
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