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  • Thyroid Function Tests: Serum thyrotropin assay (TSH)

    Thyrotropin previously was known as thyroid stimulating hormone (TSH), and the abbreviation TSH is still used. Direct assay of TSH is now possible with commercially available kits that are as easy to use as those for T4 assay. Thyrotropin has a diurnal variation of 2 to 3 times baseline (literature range, 33%-600%), with highest levels occurring at about 10-11 P.M. (range, 6 P.M.-2 A.M.) and lowest levels at about 10A.M. (range, 8 A.M.-4 P.M.).

    Results in thyroid disease. Serum TSH levels are elevated in about 95% of patients with myxedema due to primary thyroid disease, which comprises 95%-96% of hypothyroid patients. Serum TSH levels are low in most cases of secondary (pituitary or hypothalamic) myxedema (about 4% of hypothyroid patients). Some patients with secondary hypothyroidism have normal TSH values when one would expect low TSH levels. The pituitary of these patients is able to secrete a small amount of TSH, not enough to maintain normal T4 levels but enough to leave TSH values within reference range. The T3-RIA values in these patients may be decreased; but in some instances may be low normal, either because of preferential secretion of T3 rather than T4 by subnormal TSH stimulation or because of problems with kit sensitivity in low ranges. In primary hyperthyroidism, serum TSH is decreased; the percentage of patients with decreased values depends on the sensitivity of the particular kit used. Before 1985, most commercially available kits were poorly sensitive in the lower part of their range, and could not easily differentiate low values from zero or from lowormal values. Theoretically, in typical cases of hyperthyroidism the excess thyroid hormone produced causes the pituitary to completely stop production of TSH, reducing serum TSH to zero. The closer a TSH assay can approach zero in detecting TSH, the better it can differentiate between hyperthyroidism and certain other causes for decreased serum TSH (which usually produces a serum TSH value somewhere between lower reference limit and zero). Some nonhyperthyroid etiologies include partial pituitary insufficiency, early or mild hyperthyroidism in some patients, severe non thyroid illness in some patients (depending on the particular TSH assay kit), monitoring thyroid suppressive therapy, and dopamine or high-dose glucocorticoid therapy in some patients.

    Therefore, about 1985, many manufacturers had begun modifying their TSH kits so as to increase sensitivity at the lower end of the TSH assay range in order to differentiate lesser decreases of TSH (less likely due to hyperthyroidism) from marked decreases (more likely due to hyperthyroidism). Manufacturers called the new TSH kits “high-sensitivity,” “ultra sensitive,” or “first, second, and third generation.” Unfortunately, these terms were used in different ways, the two most common being the theoretical lower limit the assay might achieve under the best experimental conditions and the “functional” lower limit the assay usually did achieve with a between-assay coefficient of variation less than 20%. Based on the most common usage in the literature, the theoretical lower limit of detection for first-generation assays could detect TSH as low as 0.3-0.1 mU/L (µU/ml); but their functional lower limit usually was no better than 0.3, frequently was no better than 0.5, and sometimes was 0.6-1.0. Second-generation assays theoretically can detect between 0.1-0.01 mU/L. Most have a functional lower limit between 0.07-0.04 mU/L. Generally, a functional ability to detect less than 0.1 mU/L qualifies the assay for second-generation or high-sensitivity (ultra sensitive) status. In the 1990s, a few third generation kits have been reported; these have a theoretical lower limit of detection between 0.01-0.005 mU/L and functional detection at least below 0.01 mU/L.

    Drawbacks. Evaluations in the literature and my own experience have shown that not all TSH kits (either “standard” or ultra sensitive) perform equally well. Moreover, laboratory error may produce false normal or abnormal results. In addition, there are conditions other than hypothyroidism or hyperthyroidism that can increase TSH values or decrease TSH values (see box 1 and box 2).

    Conditions That Increase Serum Thyroid-Stimulating Hormone Values

    Lab error
    Primary hypothyroidism
    Synthroid therapy with insufficient dose; some patients
    Lithium or amiodarone; some patients
    Hashimoto’s thyroiditis in later stage; some patients
    Large doses of inorganic iodide (e.g., SSKI)
    Severe non thyroid illness in recovery phase; some patients
    Iodine deficiency (moderate or severe)
    Addison’s disease
    TSH specimen drawn in evening (peak of diurnal variation)
    Pituitary TSH-secreting tumor
    Therapy of hypothyroidism (3-6 weeks after beginning therapy [range, 1-8 weeks]; sometimes longer when pretherapy TSH is over 100 µU/ml); some patients
    Acute psychiatric illness; few patients
    Peripheral resistance to T4 syndrome; some patients
    Antibodies (e.g., HAMA) interfering with monoclonal sandwich method of TSH assay
    Telepaque (Iopanic acid) and Oragrafin (Ipodate) x-ray contrast media; some patients
    Amphetamines; some patients
    High altitudes; some patients

    Conditions That Decrease Serum Thyroid-Stimulating Hormone Values*

    Lab error
    T4/T3 toxicosis (diffuse or nodular etiology)
    Excessive therapy for hypothyroidism
    Active thyroiditis (subacute, painless, or early active Hashimoto’s disease); some patients
    Multinodular goiter containing areas of autonomy; some patients
    Severe non thyroid illness (esp. acute trauma, dopamine or glucocorticoid); some patients
    T3 toxicosis
    Pituitary insufficiency
    Cushing’s syndrome (and some patients on high-dose glucocorticoid)
    Jod-Basedow (iodine-induced) hyperthyroidism
    TSH drawn 2-4 hours after Synthroid dose; few patients
    Postpartem transient toxicosis
    Factitious hyerthyroidism
    Struma ovarii
    Radioimmunoassay, surgery, or antithyroid drug therapy for hyperthyroidism; some patients, 4-6 weeks (range, 2 weeks-2 years) after the treatment
    Interleukin-2 drugs (3%-6% of cases) or alpha-interferon therapy (1% of cases)
    Hyperemesis gravidarum
    Amiodarone therapy; some patients
    __________________________________________________
    *High sensitivity TSH method is assumed.

    Some cases of elevated free T4 levels accompanied by TSH values that were inappropriately elevated (above the lower third of the TSH reference range) rather than depressed have been reported. These cases have been due to TSH-producing pituitary tumors, defective pituitary response to thyroid hormone levels, or peripheral tissue resistance to the effects of thyroid hormone (laboratory error in T4 or TSH assay also must be excluded). Some (a minority) of the current TSH kits (predominantly the solid-phase double-antibody technique) may cross-react with hCG if hCG is present in very large amounts. These TSH kits will indicate varying degrees of (false) TSH increase during pregnancy and in the rare syndrome of hyperthyroidism due to massive hCG production by a hydatidiform mole or choriocarcinoma. Likewise, some of the double-antibody kits using the “sandwich” technique with one or both of the antibodies being the monoclonal type may become falsely elevated due to interference by a heterophil-type antibody in the patient serum that reacts with mouse-derived antibodies. This occurs because monoclonal antibodies are usually produced by a fused (hybrid) cell containing a mouse spleen cell that produces the antibody combined with a myeloma tumor cell that reproduces the hybrid for long periods of time. These human antimouse antibodies (HAMAs) usually occur without known cause and in one study were found in 9% of blood donors. Some manufacturers have attempted to counteract or neutralize the effect of these antibodies, with a variable degree of success. Another antibody problem of a different type concerns artifactual interference in TSH assay procedure by anti-TSH antibodies in patients who had previous TSH injections and who developed antibodies against the injected material.

    In severe non thyroid illness, it was soon noticed that a considerable number of the “ultra sensitive” TSH kits produced some abnormal results in clinically euthyroid patients. Previous “standard” TSH kits, although less sensitive in the lower range, generally produced normal TSH values in severe non thyroid illness. The percentage of abnormal results in the ultra sensitive kits varies between different kits. Most abnormality is reported in severe non thyroid illness, and is manifested by decreased TSH in about 15% of cases (range, 0%-72%) and elevated TSH in about 7% of cases (range, 0%-17%). When decreased in true hyperthyroidism, TSH usually is zero; whereas in non thyroid illness it is usually not that low (first generation TSH assays cannot make this distinction). Of those elevated, most (but not all) were less than twice the upper limit of the reference range. The decreased values return toward normal as the patient recovers; in some reports, most of the elevated values occurred in the recovery phase. This has been interpreted as pituitary inhibition during the acute phase of the illness and release of inhibition in the recovery phase

    There is some controversy whether or not elevated TSH levels in some of these conditions (except adrenal insufficiency and heterophil or anti-TSH antibodies) represent a mild hypothyroid state with the pituitary forced to secrete more TSH to maintain clinical euthyroidism. The serum TSH level in primary hypothyroidism is usually elevated to values more than twice normal and frequently to more than 3 times normal, whereas TSH levels in the other conditions frequently are less than twice normal and in most cases are less than 3 times normal.

  • Thyroid Function Tests: Total serum triiodothyronine (T3-RIA)

    Serum T3 may be assayed by the same technique as T4-RIA. Total serum T3 (T3-RIA) is a specific, direct measurement of T3 using anti-T3antibody and should not be confused with the test formerly called the T3U. As previously mentioned, the T3U (THBR) is primarily an estimate of serum protein unsaturated binding sites, which secondarily provides an indirect estimate of T4 but not of T3. It is unfortunate that many used to speak of the T3U as “the T3 test,” making it difficult to be certain whether T3U or T3-RIA was meant. Analogous to T4 assay, serum T3 consists mostly of protein-bound T3. Therefore, serum T3 measurement is affected by alterations in thyroxine-binding proteins in the same direction as serum T4, although to a slightly lesser degree than serum T4. One may obtain a free T3 index using T3-RIA and THBR (T3U) values, The T3-RIA may be elevated for 1-2 hours after T3 (liothyronine) administration. It may also be temporarily increased for several hours after desiccated thyroid intake

    Results in thyroid disease. Under usual circumstances, T3-RIA has at least as good sensitivity as T4 in detecting thyrotoxicosis. In fact, some investigators have stated that T3-RIA is the most sensitive test for standard hyperthyroidism associated with increase of both T4 and T3, occasionally demonstrating elevation at an early stage before T4 values have risen above reference range upper limits. In addition, T3-RIA helps to detect that form of hyperthyroidism known as “T3 toxicosis” in which the T3 level is elevated but not the T4 level. Triiodothyronine toxicosis has been estimated to comprise about 3%-4% of hyperthyroid patients.

    Drawbacks. Unfortunately, T3-RIA has several substantial drawbacks. First, although T3-RIA test kits are as easy to use as T4-RIA kits, there seems to be more variation in results among T3 kits from different manufacturers than among T4 kits. Second, as noted previously, T3-RIA is affected by thyroxine-binding protein alterations similarly to T4. Third, perhaps the most serious drawback is the strong tendency of many severe acute or chronic non thyroid illnesses to decrease T3-RIA values even though the patient remains clinically euthyroid. In many of these cases T4 conversion to T3 in peripheral tissues is temporarily decreased and instead is shunted toward reverse T3 production. The decrease associated with severe non thyroid illness varies but often is very substantial and is the most common cause for artifactual T3-RIA decrease. Therefore, this severely decreases the usefulness of the T3-RIA in hospitalized patients. Fourth, T3-RIA is not reliable in hypothyroidism, because there is considerable overlap between values from hypothyroid patients and the lowormal reference range. A few reports suggest that occasionally persons have mildly hypothyroid T4 levels but enough T3 secretion by the thyroid to maintain a clinically euthyroid state. Fifth, T3-RIA is increased in iodine deficiency.

    A sixth problem affecting T3-RIA is difficulty in defining the reference range. Persons over age 60 may have reference limits that are significantly lower than those for persons under age 60. Most studies have found a10%-30% decrease in mean values after age 60, although reports have varied from 0%-52%, possibly because the degree of age effect differs between individual manufacturer’s kits or there may have been some differences in the populations tested. Unfortunately, very few laboratories determine age-related values for the particular T3-RIA kit that they use. If the kit used by any individual laboratory is affected, this implies that since a result in an elderly person within the reference range but near the upper limit of the range could be artifactually decreased, that apparent normal value might in fact be elevated for that patient if the reference range was not age-corrected. A few studies report a lifelong decrease of 5-10 ng/ml/ 10 years. This implies that T3-RIA values in childhood are higher than those for adults. Finally, certain medications (e.g., propranolol, dexamethasone) have been reported to decrease T3-RIA levels, although not severely.

  • 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
    _______________________________________________________________
    *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: Total serum thyroxine

    T4 can be measured directly by radioassay (or, more recently, by enzyme-linked assay). Radioassay involves competition of patient hormone and radioactive hormone for a hormone binder. In T4by radioimmunoassay (T4-RIA) the binder is anti-T4antibody; in T4 competitive binding (T4-CPB) or T4 displacement methods (T4-D) the binder is T4-binding serum protein. After patient T4 and radioactive T4 have reacted with the T4 binder, the bound complex is separated from the free (unbound) hormone and the radioactivity in either the bound or free fraction is counted. The amount of patient T4 determines the amount of radioactive T4 allowed to attach to the binder. There is general (but not unanimous) agreement that T4 values are not greatly changed in old age.

    Results in thyroid disease. The sensitivity of T4 assay is approximately 95% (literature range, 90%-100%) for hyperthyroidism, and approximately 92% (literature range, 54%-100%) for hypothyroidism. There is some difficulty in evaluating T4 data for hypothyroidism from the literature since patients with a temporary T4 decrease from thyroiditis or severe non thyroid illness may be included with patients having true primary hypothyroidism in some reports.

    Drawbacks. As noted previously, more than 99% of total serum T4 is protein bound, so that the contribution of free T4 to the test results is negligible. Therefore, serum T4 by any current method essentially measures protein-bound T4 and will be affected by alterations in T4-binding proteins. These alterations may be congenital, drug induced, or secondary to severe non thyroid illness. As a rule of thumb, estrogens from pregnancy or birth control medication increase T4 levels by increasing TBG levels, and amphetamine abuse is reported to increase T4 levels in some patients by increasing pituitary secretion of TSH. Most other drugs that affect T4 produce decreased T4 levels by decreasing TBG levels or T4 binding to TBG (or albumin). Medications that may affect T4 assay are listed in Table 37-14. The most commonly encountered medication problems, in my experience, are associated with administration of levothyroxine (Synthroid), estrogens, or phenytoin (Dilantin). Like phenytoin, valproic acid, furosemide, and some of the nonsteroidal anti inflammatory drugs can decrease T4 levels by displacing T4 from its binding proteins. However, these medications, especially furosemide, are often administered to patients who already have severe non thyroid illness, so that it may be difficult to separate the effect of the drug from the effect of the illness.

    Another condition producing false T4 increase is familial dysalbuminemic hyperthyroxinemia (FDH), which is uncommon but not rare. This is a congenital condition transmitted as an autosomal dominant trait, which results in production of an albumin variant that has an increased degree of T4 binding (albumin normally has only a weak affinity for T4). Therefore, in FDH more T4 binds to albumin, which raises serum total T4 values. Thyroid function is not affected and there apparently is no association with disease. Yet another cause for false T4 elevation is the very uncommon syndrome of peripheral resistance to T4. Peripheral tissue utilization of T4 is decreased to variable degree; whether symptoms develop depends to some extent on the degree of “resistance.” The pituitary response to T4 feedback may be decreased in some patients. Total T4, free T4, and total T3 are elevated; serum THBR (T3U), TSH, and TSH response in the TRH test are normal or elevated.

    With the possible exception of TBG alterations, the most frequent false abnormalities in T4 are produced by severe non thyroidal illness (see the box). Severe non thyroid illnesses or malnutrition of various etiologies may decrease T4 below the lower limits of the T4 reference range.

    Some Nonthyroid Illnesses that Can Affect Thyroid Tests

    Cirrhosis or severe hepatitis
    Renal failure
    Cancer
    Chemotherapy for cancer
    Severe infection or inflammation
    Trauma
    Postsurgical condition
    Extensive burns
    Starvation or malnutrition
    Acute psychiatric illness

    The incidence of decreased T4 is roughly proportional to the severity of illness. Therefore, the overall incidence of decreased T4 in non thyroid illness is low but in severe illness reports indicate decreased T4 levels in approximately 20%-30% of cases (literature range, 9%-59%). In fewer cases the free T4 index (TI) or even free T4 assay (especially analog methods) is reduced below reference limits. On the other hand, in the majority of patients, and in patients without alterations in albumin or TBG, the T4 remains within reference range (although possibly decreased from baseline values). In occasional patients (for poorly understood reasons) the T4 value may be mildly elevated. This has been called “sick euthyroid syndrome” by some investigators. The TSH value may decrease in severe non thyroid illness somewhat parallel to T4 but to a lesser extent, usually (but not always) remaining within reference range. In the recovery phase, TSH levels increase before or with T4 and could temporarily even become elevated. The THBR value in severe non thyroid illness is most often normal but may be mildly increased, reflecting decreased TBG levels. Occasionally the THBR is decreased, mainly in acute hepatitis virus hepatitis

    Cushing’s syndrome produces a mild or moderate T4 decrease below lower limit of reference range in two thirds or more of patients. Free T4 (FT4) levels are usually normal.

    Conditions producing a decrease in T4 are listed in the box and conditions producing an increase in T4 are listed in the box.

    One group of conditions involves certain iodine-containing substances. For many years it was thought that neither organic iodine nor inorganic iodide would interfere with T4 by immunoassay methods. However, it was subsequently found that a few x-ray contrast media such as ipodate (Oragrafin) and iopanoic acid (Telepaque) can elevate

    Causes for Decreased Thyroxine or Free Thyroxine Values

    Lab error
    Primary hypothyroidism
    Severe non thyroid illness;* many patients
    Lithium therapy; some patients
    Severe TBG decrease (congenital, disease, or drug-induced) or severe albumin decrease*
    Dilantin, Depakene, or high-dose salicylate drugs*
    Pituitary insufficiency
    Large doses of inorganic iodide (e.g., SSKI)
    Moderate or severe iodine deficiency
    Cushing’s syndrome
    High-dose glucocorticoid drugs; some patients
    Pregnancy, third trimester (low-normal or small decrease)
    Addison’s disease; some patients (30%)
    Heparin effect (a few FT4 kits)
    Desipramine or amiodarone drugs; some patients
    Acute psychiatric illness; a few patients
    ___________________________________________________________________
    *FT4 less affected than T4; two-step FT4 method affected less than analog FT4 method.

    T4values above reference range in some patients and that the iodinated antiarrhythmic drug amiodarone can produce temporary hyperthyroidism in some patients and hypothyroidism in others. These compounds do not affect the T4 assay directly but can increase T4 values by certain metabolic actions (e.g., blocking of T4 deiodination) that are still being investigated. Effects of iodine on the thyroid will be discussed in detail later

  • 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

  • Thyroid Function Tests: Radioactive iodine uptake

    Radioactive iodine uptake is an indirect estimate of thyroid hormone production based on the need of the thyroid for iodine to make thyroid hormone, which, in turn, depends on the rate of thyroid hormone synthesis. A small dose of radioactive iodine is given, and a radiation detector measures the amount present in the gland at some standard time (usually 24 hours after the dose). The radioactive iodine uptake (RAIU) measurement is one of the oldest currently used thyroid function tests, but it has several drawbacks:

    Thyroid Function Tests*

    I. Thyroid uptake of iodine
    A. RAIU
    II. Thyroxine tests
    A. “Direct” measurement
    1. T4 by RIA or EIA
    2. Free T4assay
    B. “Indirect” measurement
    1. THBR (T3 uptake, or T3U)
    2. Free T4 index
    III. Triiodothyronine tests
    A. T3-RIA
    IV. Pituitary and hypothalamic function tests
    A. TSH assay
    B. TRH assay
    V. Other
    A. Stimulation and suppression tests
    B. Thyroid scan
    C. Thyroid autoantibody assay

    *RAIU = radioactive iodine uptake; = radioimmunoassay; EIA = enzyme immunoassay; THBR = thyroid hormone–binding ratio; TRH = thyrotropin-releasing hormone.

    1. The RAIU result is falsely normal in 50%-70% (literature range, 20%-80%) of patients with hyperthyroidism due to toxic nodules.
    2. The RAIU results are affected by a considerable number of medications (see Table 36-24) and may be elevated during the last trimester of pregnancy.
    3. Any condition that alters thyroid requirements for iodine will affect the RAIU response. Iodine deficiency goiter elevates RAIU results, and some reports indicate that elevation for similar reasons occurs in 25%-50% of patients with cirrhosis. Excess iodine in the blood contained in certain medicines (inorganic iodide) or in x-ray contrast media (organic iodine) competes with radioactive iodine for thyroid uptake, thereby preventing uptake of some radioactive iodine and falsely decreasing test results.
    4. The standard 24-hour uptake requires two patient visits and 2 days.
    5. Normal values are uncertain due to increasing environmental and foodstuff iodine content. Before 1960 the average 24-hour RAIU reference range was 15%-40%. Reports from 1960-1970 suggest a decrease of the range to 8%-30%. There have been little recent data on this subject, and most nuclear medicine departments are unable to obtain reference values for their own locality.
    6. Occasionally patients with hyperthyroidism have unusually fast synthesis and release (turnover) of T4 and T3. The RAIU measurement depends not only on uptake of radioactive iodine but also on retention of the radioactive iodine (incorporated into hormone) within the gland until the amount of radioactivity within the gland is measured. By 24 hours a significant amount of newly formed hormone may already be released, providing falsely lower thyroid radioactivity values compared with earlier (2-6 hours) uptake measurements.
    7. The RAIU provides relatively poor separation of normal from hypothyroid persons. Before 1960, approximate sensitivity of the RAIU was 90% for hyperthyroidism and 85% for hypothyroidism. Current RAIU sensitivity in thyroid disease is difficult to determine because of reference range problems. However, sensitivity is probably about 80% for hyperthyroidism and about 50%-60% for hypothyroidism. One study found that patients over age 65 may have a higher incidence of normal 24-hour RAIU than younger persons. The 24-hour RAIU was normal in 15% of hyperthyroid patients under age 65 and 41% of those over age 65. Various factors can decrease the RAIU besides severe destruction of thyroid tissue (see the box).
    8. The patient receives a certain small amount of radiation (especially if a scan is done), whereas thyroid hormone assays, even those using radioisotopes, are performed outside the patient’s body and therefore do not deliver any radiation to the patient.

    Etiologies of Decreased Radioactive Iodine Uptake Values

    Hypothyroidism, primary or secondary
    Technical error
    Excess organic iodine or inorganic iodide with euthyroidism
    Subacute thyroiditis
    Painless (silent) thyroiditis
    Postpartum transient toxicosis
    Chronic (Hashimoto’s) thyroiditis (some patients)
    Amiodarone-induced hyerthyroidism
    Self-administered (factitious) thyroid hormone intake
    Iodide-induced (Jod-Basedow) hyperthyroidism
    Struma ovarii

    These difficulties have precluded use of the RAIU measurement for screening purposes. However, RAIU in conjunction with the thyroid scan has definite value in patients when there is laboratory evidence of hyperthyroidism. As will be discussed later, the RAIU can help differentiate between primary hyperthyroidism and hyperthyroidism secondary to thyroiditis or self-administration of thyroid hormone; and the thyroid scan can differentiate Graves’ disease from Plummer’s disease.

  • Thyroid Function Tests

    The classic picture of hyperthyroidism or hypothyroidism is frequently not complete and may be totally absent. There may be only one noticeable symptom or sign, and even that may be vague or misleading or suggestive of some other disease. The physician must turn to the laboratory to confirm or exclude the diagnosis.

    There is a comparatively large group of laboratory procedures that measure one or more aspects of thyroid function (see the box). The multiplicity of these tests implies that none is infallible or invariably helpful. To get best results, one must have a thorough knowledge of each procedure, including what aspect of thyroid function is measured, sensitivity of the test in the detection of thyroid conditions, and the rate of false results caused by non thyroid conditions. In certain cases, a brief outline of the technique involved when the test is actually performed helps clarify some of these points.

  • Signs and Symptoms of Thyroid Disease

    Many persons have at least one sign or symptom that could suggest thyroid disease. Unfortunately, most of these signs and symptoms are not specific for thyroid dysfunction. Enumeration of the classic signs and symptoms of thyroid disease is the best way to emphasize these facts.

    Hyperthyroidism

    Thyrotoxicosis from excess secretion of thyroid hormone is usually caused by a diffusely hyperactive thyroid (Graves’ disease, about 75% of hyperthyroid cases) or by a hyperfunctioning thyroid nodule (Plummer’s disease, about 15% of hyperthyroid cases). A much less common cause is iodine-induced hyperthyroidism (Jod-Basedow disease), and rare causes include pituitary overproduction of TSH, ectopic production of thyroid hormone by the ovary (struma ovarii), high levels of chorionic gonadotropin (with some thyroid-stimulating activity) from trophoblastic tumors, and functioning metastic thyroid carcinoma. Thyroiditis (discussed later) may produce symptoms of thyrotoxicosis (comprising about 10% of hyperthyroid cases), but the symptoms are caused by leakage of thyroid hormones from damaged thyroid tissue rather than over secretion from intact tissue. Many hyperthyroid patients have eye signs such as exophthalmos, lid lag, or stare. Other symptoms include tachycardia; warm, moist skin; heat intolerance; nervous hyperactive appearance; loss of weight; and tremor of fingers. Less frequent symptoms are diarrhea, atrial fibrillation, and congestive heart failure. The hemoglobin level is usually normal; the white blood cell (WBC) count is normal or slightly decreased. There is sometimes an increase in the lymphocyte level. The serum alkaline phosphatase level is elevated in 42%-89% of patients. In elderly patients the clinical picture is said to be more frequently atypical, with a higher incidence of gastrointestinal symptoms, atrial fibrillation, and apathetic appearance.

    Hypothyroidism

    Myxedema develops from thyroid hormone deficiency. Most common signs and symptoms include nonpitting edema of eyelids, face, and extremities; loss of hair in the outer third of the eyebrows; large tongue; cold, dry skin; cold intolerance; mood depression; lethargic appearance; and slow mental activity. Cardiac shadow enlargement on chest x-ray film is common, with normal or slow heart rate. Anorexia and constipation are frequent. Laboratory tests show anemia in 50% or more of myxedema patients, with a macrocytic but non- megaloblastic type in approximately 25%. The WBC count is usually normal. The cerebrospinal fluid (CSF) usually has an elevated protein level with normal cell counts, for unknown reasons. Serum creatine kinase (CK) is elevated in about 80% (range, 20%-100%) of patients; aspartate aminotransferase (AST; formerly SGOT) is elevated in about 40%-50%; and serum cholesterol is frequently over 250 mg/dl in overt cases.

    Hypothyroidism in the infant is known as “cretinism.” Conditions that superficially resemble or simulate cretinism include mongolism and Hurler’s disease (because of mental defect, facial appearance, and short stature); various types of dwarfism, including achondroplasia (because of short stature and retarded bone age); and nephrosis (because of edema, high cholesterol levels, and low T4 levels). Myxedema in older children and adults may be simulated by the nephrotic syndrome, mental deficiency (because of mental slowness), simple obesity, and psychiatric depression.

  • Thyroid Hormone Production

    Thyroid hormone production and utilization involve several steps (Fig. 29-1). Thyroid gland activity is under the control of thyroid-stimulating hormone (TSH, space or thyrotropin), produced by the anterior pituitary. Pituitary TSH secretion is regulated by space thyrotropin-releasing hormone (TRH, thyroliberin, protirelin) from the hypothalamus. The main space raw material of thyroid hormone is inorganic iodide provided by food. Thyroid hormone synthesis space begins when inorganic iodide is extracted from the blood by the thyroid. Within the thyroid, space in organic iodide is converted to organic iodine, and one iodine atom is incorporated into a space tyrosine nucleus to form monoiodotyrosine. An additional iodine atom is then attached to form space diiodotyrosine. Two diiodotyrosine molecules are combined to form tetraiodothyronine (thyroxine, T4), or one monoiodotyrosine molecule can be combined with one diiodotyrosine molecule to form triiodothyronine (T3). Thyroid hormone is stored in the thyroid acini as thyroglobulin, to be reconstituted and released when needed. Under normal conditions the greater part of thyroid hormone secretion is T4, with only about 7% being T3. In the blood, more than 99% of both T4and T3 is bound to serum proteins. About 80%-85% of T4attaches to T4-binding globulin (TBG), an alpha-1 globulin; about 10%-15% to pre albumin; and about 5% to albumin. Parenthetically, although only a small percentage binds to albumin, there is a large quantity of albumin, so that large changes in serum albumin (usually a decrease) may significantly affect the amount of T4 bound to protein. About 70% of T3 is bound to TBG and most of the remainder to albumin. Protein-bound hormone is metabolically inactive, as though it were in a warehouse for storage. The unbound (“free”) T4and T3 are metabolically active in body cells. Within body cells, particularly the liver, about 80% of daily T3 production takes place by conversion of free T4 to T3. Thyroxine is also converted into a compound known as “reverse T3,” which is not biologically active. Finally, there is a feedback system of control over thyroid hormone production and release. Decreased serum levels of free T4 and T3 stimulate TRH production, whereas increased levels of free T4 and T3 directly inhibit pituitary secretion of TSH as well as inhibit TRH production.

    29-1

    Fig. 29-1 Iodine and thyroid hormone metabolism.

    Certain drugs affect aspects of thyroid hormone production. Perchlorate and cyanate inhibit iodide trapping by the thyroid. The thionalide compounds propylthiouracil (PTU) and methimazole (Tapazole) inhibit thyroid hormone synthesis within the gland from iodine and tyrosine. In addition, PTU inhibits liver conversion of T4 to T3. Iodine in large amounts tends to decrease thyroid vascularity and acinar hyperplasia and to have some inhibitory effect on thyroid hormone release in Graves’ disease. Cortisol has some inhibitory effect on pituitary TSH secretion.