The THBR is a variant of what is commonly known as the T3 uptake, or T3U. T3U does not measure T3, as its name might imply, but instead estimates the amount of non occupier (unsaturated) thyroid hormone-binding sites on serum protein. Therefore, the American Thyroid Association has recommended that the name thyroid hormone-binding ratio replace the name T3 uptake. The T3U was originally used as a substitute for direct T4 measurement. Radioactive T3 placed into patient serum competes for binding sites both with patient serum proteins and with a special hormone-binding resin (or other added binding material). The number of T3 binding sites available on serum proteins depends primarily on the amount of T4 occupying the protein binding sites, since T4 molecules greatly outnumber T3 molecules. Radioactive T3 not able to bind to protein is forced onto the resin. Therefore, the greater the amount of T4 bound to protein, the fewer protein binding sites are available for radioactive T3, and the greater is the radioactive T3 uptake by the resin.

Several modifications of the basic resin uptake procedure are sold by commercial companies. Although the various kits in general give similar results, in my experience there have been definite and significant differences between some of the kits. In particular, some may produce occasional and inexplicable mildly decreased results. There also is some confusion in the way that resin uptake results are reported. Most T3 uptake kits use a reference range expressed in percent of resin uptake. A few count radioactivity in the serum proteins, which produces opposite values to those derived from resin uptake. Some kits (including the THBR) report results as a ratio between resin uptake and a “normal” control.

Results in thyroid disease. As a thyroid function test, THBR becomes an indirect estimate of T4 when the quantity of thyroxine-binding protein is normal, since the number of T3 binding sites is determined primarily by the amount of T4 and the amount of binding protein. There are rather widely variant opinions on diagnostic accuracy of THBR in thyroid disease. Some reports were highly favorable, although recent ones tend to be less so. There is reasonably good sensitivity for hyperthyroidism (approximately 80%, with a literature range of 46%-96%). The test is not affected by iodine. However, there is relatively poor separation of normal from hypothyroid conditions (sensitivity for hypothyroidism is approximately 50%-60%, with a literature range of 27%-92%).

Drawbacks. Problems in diagnosis of hypothyroidism were mentioned previously. Also, since the test depends on the number of binding sites, changes in the amount of thyroxine-binding protein will affect results. Increased TBG decreases the THBR, and decreased TBG or medications (such as Dilantin) that bind to TBG increase THBR. TBG alterations may be congenital, drug induced, or produced by non thyroid illness (see the box). There is interference by a considerable number of medications, the majority of which also affect serum T4 assay (see Table 37-14). In addition, atrial fibrillation, severe acidosis, or hypoalbuminemia have been reported to sometimes falsely increase the THBR. Current use of the THBR is mainly as an adjunct to a T4 assay to provide a warning of alterations in T4-binding protein. The THBR can also be of some help in ruling out laboratory error as a cause for T4 elevation; if both the T4 and resin uptake levels are increased, the T4 elevation is probably genuine.

Causes for Increased or Decreased Thyroxine-Binding Globulin

I. Increased TBG
A. Increased estrogens
1. Pregnancy
2. Oral contraceptives
3. Estrogen therapy
B. Other medications
1. Perphenazine (Trilafon) occasionally
2. Heroin and methadone (variable degree)
C. Severe liver disease
1. Severe acute hepatitis
2. Severe cirrhosis (occasionally)
D. Congenital
E. Acute intermittent porphyria
F. Human immunodeficiency virus (HIV) infection
II. Decreased TBG
A. Certain medications
1. Androgens
2. Drugs that compete with T4and T3 for binding sites on TBG or albumin (e.g., phenytoin, valproic acid, Ponstel, salicylate)
B. Severe non thyroidal illness
C. Congenital decrease
D. Nephrotic syndrome or conditions leading to severe hypoalbuminemia