Articles on Medical Diseases and Conditions

Tag: THBR

  • Thyroid Function Tests: Free thyroxine index

    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
    _______________________________________________________________
    *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.

  • Thyroid Function Tests: Thyroid hormone-binding ratio (THBR; T3 uptake)

    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