The American Thyroid Association has recommended that the entity most commonly known as the free thyroxine index (TI, or T-7, T-12, Clark and Horn index) be renamed the free T4 index (FT4I). The FT4I was developed to correct the T4 assay for effects of thyroxine-binding protein alterations. It consists basically of the serum T4 result multiplied by the THBR result. This manipulation takes advantage of the fact that THBR (T3U) and T4 values travel in opposite directions when TBG alterations are present, but they proceed in the same direction when the TBG value is normal and the only variable is the amount of T4. For example, in hyperthyroidism both the T4 and THBR values are increased, and the two high values, when multiplied together, produce an elevated TI. On the other hand, estrogen in birth control medication or pregnancy elevates TBG levels. Normally, TBG is about one third saturated with T4. If the TBG level is increased, the additional TBG also becomes one third saturated.

Causes for Increased Thyroxine or Free Thyroxine Values

Lab error
Primary hyperthyroidism (T4/T3) type)
Severe TBG elevation; some patients with some FT4 kits
Excess therapy of hypothyroidism
Synthroid in adequate dose; some patients
Active thyroiditis (subacute, painless, early active Hashimoto’s disease); some patients
Familial dysalbuminemic hyperthyroxinemia (some FT4 kits, esp. analog types)
Peripheral resistance to T4 syndrome
Amiodarone or propranolol; some patients
Post partum transient toixcosis
Factitious hyperthyroidism
Jod-Basedow (iodine-induced) hyperthyroidism
Severe non thyroid illness, occasional patients
Acute psychosis (esp. paranoid schizophrenia); some patients
T4 sample drawn 2-4 hours after Synthroid dose
Struma ovarii
Pituitary TSH-secreting tumor; some patients
Certain x-ray contrast media (Telepaque and Oragrafin)
Acute porphyria; some patients
Heparin effect (some T4 and FT4 kits)
Amphetamine, heroin, methadone, and PCP abuse; some patients
Perphenazine or 5-fluorouracil; some patients
Antithyroid or anti-IgG heterophil (HAMA*) autoantibodies (some sandwich-method monoclonal antibody kits); occasional patients
“T4” hyperthyroidism
Hyperemesis gravidarum; about 50% of patients
High altitudes, some patients
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*Human antimouse antibodies.

Thus, the total T4 value is increased due to the normal amount of T4 plus the extra T4 on the extra TBG. Thyroxine-binding globulin binding sites are similarly increased by the additional TBG, leading to a decreased THBR, because additional radioactive T3 is bound to the additional TBG, with less T3 attracted to the resin. Therefore, if estrogens increase the TBG value, the T4 level is increased and the THBR is decreased; the high number multiplied by the low number produces a middle-range normal index number. Actually, if one knows the reference values for the T4 assay and the THBR, one simply decides whether assay values for the two tests have similar positions in their separate reference ranges (i.e., both increased or both near the middle of the reference range) or whether the values are divergent (i.e., one near the upper limit and the other near the lower limit). If the values are considerably divergent, there is a question of possible thyroxine-binding protein abnormality. Therefore, it is more helpful to have the T4 and THBR values than the index number alone, because these values are sometimes necessary to interpret the index or provide a clue to technical error.

Results in thyroid disease. In general, the FT4I does an adequate job in canceling the effects of thyroxine-binding protein alterations without affecting results in thyroid dysfunction. Reported sensitivity in hyperthyroidism is approximately 95% (literature range 90%-100%). Reported sensitivity in hypothyroidism is approximately 90%-95% (literature range, 78%-100%). Therefore, as with T4, there seems to be more overlap in the hypothyroid than the hyperthyroid area.

Drawbacks. Although there is general agreement in the literature that the FT4I is more reliable than T4 in the diagnosis of hypothyroidism when the T4 value is decreased, and also more accurate in the diagnosis of thyroid dysfunction when TBG alteration is present, the FT4I itself gives misleading results in a significant minority of cases. In TBG alteration due to estrogen in oral contraceptives or in pregnancy, the reported incidence of T4 elevation is approximately 40% of cases, whereas the reported incidence of FT4I elevation is approximately 10%-15% (literature range, 0%-29%). The FT4I is usually normal in mild non thyroid illness, but in severe illness it may be decreased in approximately 20%-25% of cases (literature range, 4%-63%). There is some correlation with the severity of illness.

“Corrected” thyroxine assays

Several manufacturers have devised techniques for internally “correcting” T4 results for effects of TBG alterations. Depending on the manufacturers these have been called ETR, Normalized T4, and other brand names. The ETR is the only test from this group for which there are evaluations from a substantial number of laboratories. In general, results were not as favorable as those obtained with the FT4I.