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Test code(s) 899

Question 1. What is TSH and how is it measured?

Thyroid stimulating hormone (TSH) is one of the most important hormones currently used to diagnose thyroid abnormalities. This glycoprotein is secreted by the pituitary and stimulates release of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. TSH release from the pituitary is controlled by thyrotropin releasing hormone (TRH) stimulation and negative feedback from free T3 and free T4.

We currently test TSH using an ultrasensitive 3rd generation chemiluminescent assay (sensitivity = 0.01 mIU/L). A high TSH concentration typically suggests hypothyroidism, whereas a low concentration suggests a hyperthyroid state.

Question 2. Does the time of day matter when sampling for TSH testing?

Yes. TSH concentration follows a diurnal rhythm. Typically, the peak occurs around midnight and the nadir (~50% of the peak value) around mid-day. Population-based reference intervals are generally obtained from subjects tested in the daytime, closer to the trough than to the peak. So, when evaluating a patient’s serial TSH concentrations, differences in sample collection time should be considered.

Question 3. How variable is TSH?

TSH has moderate intraindividual variability and even more marked interindividual variability. The interindividual coefficient of variation is about 32%; consequently there is a wide population-based reference interval for TSH. Since the intraindividual variation is considerably less, comparing a specific patient’s current TSH level with any past level may be more illuminating than comparing the patient’s current TSH level to the reference interval. A difference of 0.7 mIU/L or greater is considered significant when evaluating a patient’s serial TSH values.1

Question 4. My patient’s free T4 and TSH results do not seem to correlate. Which should I believe?

That depends on the clinical situation. There are multiple things that can give the appearance of discrepant results even though they are not truly discrepant. For example, an elevation or drop in TSH with a normal free T4 may be one of the first signs of subclinical disease. In subclinical hypothyroidism, the elevated TSH is allowing the body to “compensate,” keeping the free T4 concentration normal. Many, but not all, of these patients will progress to frank disease if left untreated, so such concentrations may need to be monitored.

In general, TSH appears to be the more sensitive indicator of thyroid hormone status. However, it may take days to weeks for TSH concentrations to reestablish a steady state following changes in thyroid dosing (or when a noncompliant patient takes “extra” medication just before being seen by the doctor). In these circumstances the free T4 may be the more reliable indicator of the current thyroid hormone status.

In another example, a patient with successfully treated Graves hyperthyroidism may appear euthyroid by all indications other than a suppressed TSH level. In most cases, allowing up to 6-8 weeks for TSH to stabilize after a significant change in thyroid hormone status will be sufficient, although some patients with Graves disease may have suppressed TSH for months even after treatment has restored euthyroidism.

Question 5. My patient’s TSH is much higher than I expected. Could there be some interference causing this?

Antibody interference may be the cause. Some patients develop heterophilic antibodies such as human anti-mouse antibodies (HAMA). HAMA can interfere with many standard immunoassays, causing either an artificially high (or low) result. If you suspect your patient has a heterophilic antibody, the test can be repeated using either a different method or specific blocking agents. Such agents are used in the TSH with HAMA Treatment test (test code 19537).

Other factors can also cause a higher than expected TSH result. Hypothyroidism and patient compliance withmedication are common causes.

Question 6. I’ve heard different recommendations for TSH reference intervals. What should I use as a “normal” value?

The TSH reference interval is still controversial. One reason is that TSH measurement is dependent on the method used. Different concentrations can be obtained from different assays. Therefore, when monitoring a patient, we recommend using the same assay from the same laboratory.

Another reason for varying reference intervals is the variation in study results and expert opinion. A review of data from NHANES III suggests that the upper limit of the reference interval is close to 4 mIU/L.2 The National Academy of Clinical Biochemists has suggested a much lower cutoff of 2.5 mIU/L.3 In 2012, the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA) suggested using the reference interval established by any given laboratory that is using a third generation TSH assay. If this is not available, the next option would be to use the NHANES III range of 0.45-4.12 mIU/L.4

Most clinical laboratories have not lowered the upper cutoff for TSH based on observations that “22 to 28 million more Americans would be diagnosed with hypothyroidism without any clinical or therapeutic benefit from this diagnosis.”5 Surveys of academic clinical endocrinologists have shown that many physicians may monitor patients more frequently once the TSH rises above the 2.5 to 3.0 mIU/L cutoff, but few will treat until the TSH is significantly higher (eg, 10 mIU/L or more) or unless other significant cofactors (eg, antithyroid antibodies, low free T4) are present.

Different TSH clinical cutoffs are used for pregnant women. These cutoffs are based on clinical studies showing adverse health effects of maternal hypothyroidism for both mother and infant. The ATA released guidelines in 2011 that specify lower cutoffs for TSH during pregnancy.6 If a lab does not have its own trimester-specific TSH reference intervals, then the ATA suggests using a TSH reference interval of 0.1–2.5 mIU/L during the first trimester, 0.2–3.0 mIU/L during the second trimester, and 0.3–3.0 mIU/L during the third trimester. Not all those who have a TSH above the trimester-specific cutoff need treatment, but they should all be evaluated further (eg, TPO antibody testing) and monitored more closely.

Low TSH values (below the laboratory’s reference interval) do not always indicate hyperthyroidism and a need to treat. Low values might indicate a need for further evaluation, especially when symptoms of hyperthyroidism are present.


  1. Browning MC, Ford RP, Callaghan SJ, et al. Intra- and interindividual biological variation of five analytes used in assessing thyroid function: implications for necessary standards of performance and the interpretation of results. Clin Chem. 1986;32:962-966.
  2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499.
  3. Wartofsky L, Dickey RA. The evidence for a nar­rower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90:5483-5488.
  4. Garber J, Cobin R, Gharib H, et al.Clinical Practice Guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endo Pract. 2012;18:989-1028.
  5. Fatourechi V.Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84:65-71.
  6. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21:1081-1125.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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