At 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.

Blood 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 thyroid-stimulating 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.

Evaluating thyroid function

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 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

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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 thyroxine-binding 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 globulin-binding 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 low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.1,4 (Table 1 summarizes the interpretation of various test results.)

T3 tests are often useful to diagnose 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 patients: When 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 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 re-evaluated 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. 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 intervals 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.


1. Ladenson P, Kim M. The thyroid. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa.: Saunders; 2007: chap 244.
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.
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.
6. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow up of the Wickham Survey. 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;291:228-238.
8. Wilson GR, Curry RW. Subclinical thyroid disease. Am Fam Physician. 2005;72:1517-1524.

All electronic documents accessed November 19, 2009.