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Secretion of the thyroid hormone T4 (thyroxine) by the thyroid is regulated by TSH which is, in turn, secreted by the pituitary. TSH secretion by the pituitary is controlled through negative feedback by thyroid hormones coming from the thyroid. Very small changes in T4 levels induce very large reciprocal changes in the TSH concentration. It has been my experience that the level of TSH has been a poor predictor of the degree of hypothyroidism or hyperthyroidism in individual patients. Assessment of thyroid function often requires measurement of both TSH & thyroid hormone.


  •  Serum TSH concentration
  •  Serum total T4 concentration
  •  Serum total T3 concentration
  •  Estimation of the serum free T4 (or T3) concentration

Serum TSH Assays

First generation TSH assays have detection limits of about 5 to 10 mU/L. Since the normal range for TSH is about 0.5 to 5.0 mU/L, these assays often miss mild hypothyroidism (where the TSH is usually just above 5) and are totally inadequate for assessment of hyperthyroidism (where the TSH is usually below 0.5). As a result, most laboratories have stopped using the first generation TSH assay.

Second generation TSH assays have a lower detection limit of about 0.1 mU/L. These assays distinguish normal from hypothyroid patients with a high degree of accuracy. Since the detection limit is just below the normal range for TSH of about 0.5 to 5.0 mU/L, these assays can also be used as screening tests to distinguish hyperthyroidism from normal thyroid function. Second generation assays are currently in wide use.

Third generation TSH assays have become available with detection limits of about 0.01 mU/L. Because of the considerably lower detection limit, these assays can reliably distinguish between normal and hyperthyroid patients. Because the distinction between normal and hyperthyroid patients is usually not a problem, these assays have limited value and are not widely utilized.

A few exceptions need to be kept in mind when interpreting TSH values. In situations where patient's thyroid function is changing rapidly, the TSH may lag behind. Patients who are recovering from hyperthyroidism may continue to have suppressed TSH for a variable amount of time after recovery. There are rare patients who have TSH secreting pituitary tumors and will have a minimally elevated TSH in the face of hyperthyroidism.

Serum Total T4 and Total T3 Assays

The thyroid secretes mainly T4. Most of the serum T3 comes from conversion of T4 to T3 in the peripheral tissues although some is secreted by the thyroid. Virtually all of serum T4 (99.97%) is bound to thyroxine binding globulin (TBG). A smaller but still very high percentage of the T3 in the serum is also bound.

The total T4 is frequently called T4.  Total T4 values measure both bound and unbound ("free") T4. Normal ranges vary among laboratories; a typical range is 4.6 to 11.2 µg/dL.

The total serum T3 concentration is also called T3 by RIA by some laboratories. The normal range is even more variable among laboratories than that for total T4; a typical range is approximately 75 to 195 ng/dL and tends to decrease with age.

The unbound or free T4 & T3 concentrations are the active forms that are available for uptake into cells. The bound hormone, on the other hand, represents a circulating storage pool that is not immediately available for uptake into cells.

Since drugs and illness can alter concentrations of TBG or change the binding of T4 & T3 to TBG, the free and total hormone levels may not be concordant. As an example, estrogen caused the production of more TBG resulting in higher levels of total T4 but the physiologically important free T4 levels remain normal. This is also why total T4 levels tend to be higher in women. It is therefore necessary to estimate free hormone levels in some situations. Since free hormone levels are present in only minute quantities, they are generally estimated rather than measured directly.

Estimation of Free Thyroid Hormone Levels

Free T4 assay - The free T4 measurements are becoming increasingly popular. The name of the test is misleading as this test does not measure unbound T4 directly. The Free T4 assay estimates the acual free T4. The perceived advantage is that one number is provided. The disadvantage is that no currently available test provides correct free T4 values for all the binding abnormalities that have been described. Another disadvantage of this test is that many physicians think that the test actually measures the unbound T4 and they do not understand the limitations of the test. Free T3 measurements are also available, but have limited utility.

Free T4 index (FTI) - Calculation of the free T4 index has the advantage that the clinician is given both a total T4 and a thyroid hormone binding ratio or index, making it clear when the patient has a potential binding protein abnormality. The disadvantages are: (1) the calculation is poorly understood by many physicians; and (2) the free T4 index, as with direct free T4 measurements, fails to give correct values for many described binding protein abnormalities.

The T3 resin uptake (T3U) is the traditional test utilized along with the Total T4 assay to calculate the free hormone indices (FTI). This test does not measure any of the thyroid hormones, it simply provides an indication of the amount of thyroid binding globulin (TBG) present. It is called "T3" resin uptake because T3 is used in the test procedure. The normal range varies considerable among laboratories but is generally between 25 & 35%. The test is designed so that the higher the value, the lower the amount of binding globulin (TBG) which is present.


Screening for thyroid dysfunction

"Screening" refers to the measurement of thyroid function tests in patients suspected of having thyroid disease who are presently not known to have thyroid disease. I generally recommend that both a total T4 & a second generation TSH assay be used for screening in most patients. In those patients who are ill or taking medications known to interfere with TBG, screening should be done using both the second generation TSH and one of the estimates of  free T4.

Monitoring thyroid hormone therapy

One of the more common reasons for assessing thyroid function is to monitor therapy. Patients with primary hypothyroidism (failure of the thyroid) who are taking thyroid hormone therapy can be monitored with just the serum TSH. If TSH is high, the dose of thyroid hormone needs to be increased; if TSH is low, the dose needs to be reduced. In patients with secondary hyopthyroidism (failure of the pituitary), the TSH can not be used because these patients have impaired TSH release. One of the estimates of Free T4 should be used in these patients.

The goal and requirement for monitoring are different in patients taking thyroid hormone to suppress TSH to prevent growth thyroid nodules or thyroid cancer. These patients should have subnormal serum TSH levels. As a result, it is necessary to estimate free T4 and measure TSH to assess the appropriateness of therapy. In this setting, the TSH should be subnormal but the serum free T4 estimate should not be excessively elevated. It has been suggested that a third generation TSH assay alone may be adequate here but this has not been my practice.

Monitoring treatment of hyperthyroidism

The serum concentration of T3 is often elevated more than that of the T4 in many types of hyperthyroidism. As a result, serum T3 measurements may be useful for evaluating and following many patients with this disorder. Serum TSH measurements are useful for the diagnosis of hyperthyroidism, but they are unable to distinguish the degree of hyperthyroidism. Furthermore, during the early treatment of hyperthyroidism, serum TSH may remain subnormal for several weeks and rarely for several months. One must therefore rely upon serum free T4 and T3 estimates when assessing the efficacy of antithyroid drugs, radioiodine, or surgery.