Articles on Medical Diseases and Conditions

Tag: thyroxine

  • Thyroid Tests in Hypothyroidism

    Serum thyroxine. Thyroxine is frequently used as the major screening test for hypothyroidism, since the T4 level is low in most cases. There is some overlap between hypothyroid patients and normal persons in the lower part of the T4 reference range, since persons with mild, early, or subclinical disease may be inadvertently included in groups of clinically normal persons used to establish the reference range. There is some evidence that nearly all hypothyroid patients within euthyroid population reference limits have T4 values in the lower 50% of the reference range, so that T4 values in the upper half of the reference range are generally reliable in excluding hypothyroidism. Laboratory error, of course, must be considered if the laboratory result does not conform to the clinical picture. If the patient specimens are kept at room temperature for more than 48-72 hours, as might happen when they are sent by mail, increase in fatty acids during transit may falsely increase T4values when competitive binding (displacement) T4 methods rather than radioimmunoassay methods are used. Conditions that alter T4 results, such as TBG changes, non thyroidal illness, and certain medications must be remembered. Some endocrinologists are using TSH assay as a screening test instead of T4.

    Triiodothyronine-radioimmunoassay. T3-RIA has not proved very useful in the diagnosis of hypothyroidism. The majority of reports indicate that one fourth to one third of hypothyroid patients have T3-RIA values within normal range. In some cases, typically in Hashimoto’s thyroiditis or after treatment of hyperthyroidism with radioactive iodine, it is thought that normal-range T3-RIA values are due to preferential secretion of T3 in what has been called the “failing gland syndrome.” Test alterations due to non thyroidal illness, age-related decrease, and TBG alterations further complicate interpretation.

    Thyroid hormone-binding ratio. The THBR (T3U) test is another test that has not been very helpful in screening for myxedema because of substantial overlap with the euthyroid reference range. The major benefit from its use in possible hypothyroidism is for detection of TBG abnormality.

    Serum thyrotropin (TSH) assay. Serum TSH levels are increased in the great majority of patients with primary hypothyroidism, and serum TSH assay is currently the most useful first-line confirmatory test. Since secondary hypothyroidism (pituitary failure) is uncommon and dysfunction due to hypothalamic etiology is rare, TSH assay has also been advocated as a screening test. Until recently TSH assay had not found wider use in screening for thyroid disease in general because of considerable overlap in the low range between hyperthyroid and euthyroid persons. This occurred because in most TSH assay kits the lower limit of the euthyroid reference range is relatively close to zero. In addition, these kits had relatively poor sensitivity in the low range, so that it was difficult to separate hyperthyroid values, which typically are subnormal, from zero on one hand and lower limit of normal on the other. Some euthyroid lowerormal specimens demonstrated the same problem. Therefore, TSH assay was restricted mostly to diagnosis of hypothyroidism. As mentioned earlier, several ultra sensitive TSH kits have recently become available that have adequate sensitivity in the low range to reliably separate decreased TSH values from low normal values. The ultra sensitive TSH is now being advocated by some investigators as the best single screening test for thyroid disease in general. But as I mentioned earlier, in my experience, at present all ultra sensitive TSH kits are not equally reliable. The TSH levels may be increased, usually (but not always) to mild degree, in some clinically euthyroid patients with a variety of conditions (see the box). When the TSH level is elevated in conditions other than primary hypothyroidism, TSH values are usually less than twice the upper reference range limit. However, sometimes they may be as high as 3 times the upper limit and occasionally even higher.

    Primary hypothyroidism constitutes 95% or more of hypothyroid cases. The TSH assay in conjunction with the serum T4 assay is sufficient for diagnosis in the great majority of these patients (decreased T4 level with TSH level elevated more than twice and preferably more than 3 times the upper reference limit). In equivocal cases, a TRH test may be useful either to confirm primary hypothyroidism or to differentiate primary from secondary or tertiary etiology. As noted in the section on the TRH test, usefulness of the TRH test may be limited in severe non thyroidal illness. In those circumstances, a TSH stimulation test might be useful.

    It has been reported that there are several subgroups of patients with primary hypothyroidism, ranging from those with classic symptoms and markedly elevated TSH values to those with milder symptoms and only mildly elevated TSH values to those with equivocal or single symptoms and T4 and TSH values remaining within population reference range and only the TRH test result abnormal.

    About 5%-10% of patients referred to psychiatrists with symptoms of mood depression (“melancholia”) have been reported to have laboratory evidence of hypothyroidism. This evidence ranges from decreased T4and elevated TSH levels to an exaggerated TRH test response as the only abnormality.

    In secondary hypothyroidism, the thyroid is normal but malfunction occurs in either the hypothalamus or the pituitary. Typically, both T4 (or FT4) and TSH values are decreased. In a few cases, the TSH value is within normal range; the TSH however is structurally defective and cannot stimulate the thyroid normally.

    Thyrotropin-releasing hormone (TRH) test. A more complete discussion of the TRH test is located in the early part of this chapter. The TRH test has been mentioned as a confirmatory test for hypothyroidism. The TRH test has also been used to differentiate secondary from tertiary hypothyroidism. A significant increase in TSH after administration of TRH should theoretically suggest a hypothalamic rather than pituitary etiology for nonprimary hypothyroidism. Unfortunately, 40% of TSH hyposecretors of pituitary origin demonstrate adequate response to TRH stimulation. Therefore, only proof of pituitary hyposecretion by a poor response is considered sufficiently reliable for definite diagnosis. Even a poor response may not be reliable in the presence of severe non thyroidal illness.

  • Thyroid Function Tests: Free thyroxine assay

    Another approach to the problem of thyroxine-binding protein alteration is to measure free T4 rather than total T4. The amount of protein-bound inactive T4 by itself has no direct influence on the serum level of metabolically active free hormone. The original Sterling technique involved separation of free from protein-bound T4 by a dialysis membrane after adding radioactive T4. The amount of free T4 was estimated indirectly by measuring total T4, obtaining the percentage of radioactivity in the dialysis fluid compared to total radioactivity added to the patient specimen measured before dialysis, and then calculating FT4 by multiplying the percentage of the dialysate radioactivity by total T4 quantity. This method generally gave normal results in patients with TBG abnormalities but frequently produced elevated results in patients with severe non thyroid illness. Several years later, Nelson and Tomei developed a modification of the dialysis method using a different dialysis solution buffer and measuring FT4 directly in the dialysis fluid using a more sensitive T4 immunoassay than was available to Sterling. Nelson’s results showed that most specimens were within reference range in both TBG abnormality and in severe non thyroid illness. Some investigators consider the Nelson equilibrium dialysis direct method to be the current FT4 gold standard. However, dialysis is time consuming, relatively expensive, and cannot be automated. Therefore, most laboratories use non dialysis immunoassay methods, which are commercially available based on several different principles but that are simple enough to be within the technical ability of most ordinary laboratories. The “two-step” FT4 is one such method; this involves tubes with anti-T4 antibody coating the tube walls. This antibody captures FT4 in patient serum but not T4 bound to serum proteins. The patient serum is then removed; the tube washed; and a solution containing T4 labeled with an isotope or an enzyme is added. The labeled T4 solution is removed after incubation. The amount of labeled T4 captured by the antibody on the tube surface is proportional to the amount of FT 4 in the patient sample (that is, how many antibody binding sites are occupied by patient FT4 and therefore not available to labeled T4). At present, most kit manufacturers use the “T4 analogue” method, because it is the easiest and least expensive. A synthetic molecule similar to T4 (T4 analogue) is created that will not bind to TBG but will compete with nonbound (free) T4 for anti-T4 antibody. This analogue is labeled with an isotope or enzyme system, so that the amount of analogue bound to the antibody is proportional to the amount of FT4 available. The analogue kits appear to function as well or slightly better than the FT4I in differentiating euthyroid persons from hyperthyroid and hypothyroid patients.

    Drawbacks. Unfortunately, in patients with severe non thyroid illness most of the first-generation analogue kits were falsely decreased as often as the ordinary T4 methods and more often than the FT4I. Although the reasons for this have been disputed, the consensus indicates that the analogues bind to albumin to some degree and also are affected by nonesterified fatty acids. Albumin is often decreased in severe non thyroid illness. The manufacturers now attempt to “correct”their analogue kits in various ways, most often by adding a blocking agent that is supposed to prevent analogue binding to albumin. At present, most analogue kits are less affected by non thyroid illness than previously, but they still are affected, with a rate of false decrease about the same as the FT4I. However, not all FT4 kits perform equally well. In several multikit evaluations, one-step analog kits gave decreased values in severe non thyroid illness in about 40% of patients (range, 2%-75%) and increased values in about 1% (range 0%-9%). In several different dialysis and several two-step method kits, there were decreased values in about 20% of patients (range, 0%-81%) and increased values in about 12% (range, 0%-42%). There was considerable variation in results between different kits. Heparin increases free fatty acid concentration, which falsely decreases some of the FT4 kit results, particularly some analog methods; ordinary total T4 is not affected. Some two-step FT4 kits can be affected, producing mildly elevated results in some cases.

  • 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
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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.