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  • 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.

  • Laboratory Test Patterns in Hypothyroidism

    The physiology of thyroid hormone production in hypothyroidism is similar to that described in hyperthyroidism. Hypothyroidism may be divided into three types, depending on functional defect. Each of these categories may have various etiologies: (1) primary (primary thyroid T4/T3 secretion defect), (2) secondary (pituitary TSH secretion defect), and (3) tertiary (hypothalamus TRH secretion defect).

    From the laboratory standpoint there are three basic laboratory test patterns:

    1. Decreased T4 value and markedly elevated TSH value (usually more than 3 times reference range upper limit). This pattern is diagnostic of primary hypothyroidism (with the possible exception of very severe iodine deficiency) and is found in the great majority of primary hypothyroid patients.
    2. Thyroxine level in the lower half of the reference range with markedly elevated TSH level. This pattern may be seen in patients with early or mild primary hypothyroidism.
    3. Decreased T4 level with decreased TSH values. This pattern suggests secondary or tertiary hypothyroidism.

  • Confirmatory Tests for Hyperthyroidism

    The existence of deceptive laboratory hyperthyroidism with the various forms of pseudo toxicosis accentuates the need for reliable confirmatory tests. This is especially true when the patient has severe non thyroidal illness and symptoms such as atrial fibrillation that may be due to thyrotoxicosis. At present, the two most useful confirmatory procedures for hyperthyroidism are the T3 suppression test and the TRH test. Of these, the main advantage of T3 suppression over TRH is lower cost. Major disadvantages include potential danger in persons with cardiac disease and the prolonged time period necessary for the test. The TRH test has emerged as the gold standard for diagnosis of hyperthyroidism. The procedure appears to be safe, with relatively minor side effects. It can be completed in less than 1 day and can be used in most (but not all) patients with non thyroidal illness. The major disadvantage is that a small minority of persons without clinical or biochemical evidence of thyrotoxicosis are reported to demonstrate TRH test results compatible with hyperthyroidism. A relative disadvantage is the high cost of the test, although the cost is not prohibitive and is comparable to the cost of nuclear medicine scans or radiologic procedures such as laminograms or skeletal surveys.
    From the preceding discussion, several conclusions seem warranted:

    1. The basic screening test for hyperthyroidism is serum T4 or FT4. Some are using the newer ultra sensitive TSH assay instead.
    2. The THBR when ordered with the T4 may be useful for two reasons: (1) the assurance it provides for hyperthyroidism when the THBR value is elevated in association with an elevated T4 value and (2) as an indicator of TBG alterations when the results are compared with those of T4 assay.
    3. Free thyroxine index or FT4 assay provide T4 values corrected for effects of TBG alterations; but if the TBG value is elevated and thereby produces falsely elevated T3-RIA values, a normal FT4I or FT4 assay result may lead to misdiagnosis of T3 toxicosis.
    4. Decreased or mildly elevated T4 results (or even decreased TI or FT4 results, depending on the individual commercial kit) must be interpreted with caution when a patient has severe non thyroid illness.
    5. The T3-RIA results are not reliable when a patient has moderate or severe non thyroid illness. A normal or reduced T3-RIA result must be interpreted with caution if the patient is over age 60 or has any significant degree of non thyroid illness.
    6. An RAIU test is not recommended as a screening test but is helpful as a follow-up procedure to detect factitious hyperthyroidism and thyroiditis.
    7. Thyroid scan is useful to differentiate between Graves’ disease and Plummer’s disease and to help reveal thyroiditis.
    8. The TRH test may be necessary to confirm or exclude the diagnosis of hyperthyroidism when the patient has non thyroidal illness (not severe enough to decrease T4 below reference range), when thyroid function tests disagree, when test results are equivocal, and when test results do not fit the clinical picture. A normal test result is reasonably conclusive in ruling out hyperthyroidism, whereas an abnormal test result (abnormally low TSH response) is suggestive evidence of hyperthyroidism but is not completely reliable in confirming the diagnosis.

  • Deceptive (Misleading) Test Patterns of Laboratory Hyperthyroidism

    Each of the three categories of true laboratory thyrotoxicosis has a counterpart in which the apparent pattern does not reflect true thyroid hormone status. I would like to call the resulting test patterns “deceptive laboratory hyperthyroidism.” These patterns are misleading because of non thyroidal alteration of one or both thyroid hormone levels. Deceptive laboratory hyperthyroidism represents a significant (although relatively small) percentage of hyperthyroid patients. Therefore it is important to recognize these patients and to anticipate a potential problem when situations associated with deceptive test results arise. The categories of deceptive test results are the following:

    1. Pseudo–T4/T3 hyperthyroidism (both T4 and T3-RIA test results are elevated, not due to Graves’ disease or Plummer’s disease)
    2. Pseudo–T3 hyperthyroidism (T3-RIA value elevated; T4 test result not elevated)
    3. Pseudo–T4 hyperthyroidism (T4 test result elevated; T3-RIA value not elevated)

    Laboratory error may produce apparent abnormality in a euthyroid person or may reduce one or both of the hormone levels in true thyrotoxicosis. Therefore, unexpected test patterns or results may require repetition of one or more of the tests before a definitive diagnosis is made. Abnormality of the same type on two tests (i.e., both test results elevated) is more helpful for diagnosis than abnormality of only one.

    Pseudo–T4/T3 hyperthyroidism (T4 and T3-RIA both elevated)

    Causes of pseudo–T4/T3 Graves’ disease or Plummer’s disease are listed in the box. Pseudohyperthyroidism is most commonly produced by increase of thyroid binding proteins, principally TBG. The most common etiology is increased estrogens, either in pregnancy or through use of birth control pills. Both T4 and T3-RIA values are elevated in many of these patients. However, in some, the T3-RIA value may remain in upper reference range while only the T4 value is elevated.

    Effects of TBG alterations on T4 levels can be counteracted in most instances by using the FT4I or by measuring FT4 rather than total T4 values.

    Pseudo–T4/T3 Hyperthyroidism

    Increased TBG values
    Thyroiditis
    Subacute
    Painless (silent) thyroiditis
    Some patients with Hashimoto’s thyroiditis
    Peripheral resistance to thyroid hormones
    Factitious (self-medication with thyroid hormone)

    The FT4I or FT4 value will usually be normal in TBG abnormalities. If the FT4I or FT4 and the T3-RIA values are measured in a patient with increased TBG, the T3-RIA will appear to be elevated since TBG alterations affect T3-RIA as well as T4, and the combination of elevated T3-RIA plus normal. FT4I values or FT4 value would suggest T3 toxicosis. Therefore, “correction” of TBG effect on T4 may prevent pseudo-T4/T3 toxicosis but produce pseudo-T3 toxicosis. This hazard can be prevented by either applying the same basic FT4I formula to T3-RIA (thus generating an FT3I) or simply inspecting the two separate components of the FT4I, the T4 and THBR (T3U). If T4 and TBHR are at the opposite ends of their respective reference ranges, this suggests artifact due to TBG alteration. Unfortunately, many laboratories that generate FT4I report only the single FT4I result without separate T4 and THBR values. The FT4I value alone has no feature that could lead anyone to suspect TBG abnormality.

    Occasionally patients have been discovered with the syndrome of peripheral tissue resistance to thyroid hormone. These patients are usually euthyroid but have elevated T4 and T3-RIA values. TSH is normal or elevated.

    Factitious (self-administered) ingestion of T4 compounds by a patient may be deliberate, may be due to prior therapy that is not mentioned by the patient, or may represent T4 included in diet-control pills unknown to the patient. In both factitious T4 ingestion and subacute thyroiditis the RAIU value is typically low. Spurious causes for a low RAIU value must be excluded, such as iodine ingestion (e.g., SSKI or amiodarone) or x-ray contrast medium administration within the past 3-4 weeks (see the box).

    Thyrotoxicosis in thyroiditis is usually temporary and is produced by release of thyroid hormone from damaged thyroid tissue rather than by hypersecretion. Subacute thyroiditis typically has pain in the thyroid area and is accompanied by a low RAIU value. The erythrocyte sedimentation rate (ESR) is usually elevated (>50 mm/hour, Westergren method). Occasional cases of thyroiditis (“painless thyroiditis”) may present with the clinical picture of subacute thyroiditis, including hyperthyroidism, but without a painful thyroid gland and with a normal ESR. Chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) typically is associated with normal thyroid hormone blood levels, normal or decreased 24-hour RAIU value, normal ESR, and increased thyroid autoantibody levels. However, in occasional patients, chronic lymphocytic thyroiditis presents with hyperthyroidism that is clinically similar to nonpainful thyroiditis. The 24-hour RAIU value is typically decreased (although a few patients are reported to have normal values, and one study included a few patients with elevated values). Thyroid hormone levels are elevated, and the ESR is normal. Therefore, an elevated ESR favors subacute thyroiditis rather than factitious hyperthyroidism, painless thyroiditis, or thyrotoxic chronic lymphocytic thyroiditis.

    Other entities with elevated T4 or elevated T3-RIA values associated with low RAIU values include T4/T3 toxicosis with artifactual RAIU suppression by exogenous iodine, iodine-induced hyperthyroidism (Jod-Basedow disease), radiation-induced active thyroid disease (caused by RAI therapy or external radiotherapy), and ectopic T4 production (struma ovarii). In severe (not mild or moderate) iodine deficiency, T3-RIA values may be increased, T4 values may be decreased, and TSH and RAIU values may be increased.

    Pseudo–T3 hyperthyroidism (T3-RIA elevated; T4 not elevated)

    Pseudo–T3 toxicosis may be of two types: (1) true hyperthyroid type, T4/T3 hyperthyroidism with normal-range T4 test result; and (2) false hyperthyroid type, elevated T3-RIA test result without hyperthyroidism (see the box).

    True hyperthyroid type. Such cases are uncommon. It is said that T3 values may rise before T4 values in early thyrotoxicosis, and T3-RIA values are usually elevated to a greater degree than T4 values. Examples of isolated T3 elevation that eventually was joined by T4 elevation have been reported. An early or mild T4 abnormality may be masked in the upper area of population reference range (if a person’s normal T4 value were in the lower part of population reference range, the T4 value could double and still remain within reference range).

    False hyperthyroid type. This type of pseudo–T3 toxicosis may be produced by measurement of T3-RIA plus either the FT4I or the FT4 in

    Pseudo–T3 Hyperthyroidism

    True hyperthyroidism
    Rise of T3 level before T4 level in early T4/T3 hyperthyroidism
    False Hyperthyroidism
    Increased TBG with TI (or FT4) and T3-RIA results
    1-2 hr after dose of T3 (liothyronine [Cytomel])
    For several hours after dose of desiccated thyroid Severe iodine deficiency

    patients with increased TBG values. Since FT4I and FT4 values usually remain normal when TBG values are altered, an increased TBG value would be associated with normal FT4I or FT4 values plus artifactual increase in T3-RIA value. The T3-RIA value may be increased alone for 1-2 hours after T3 (liothyronine) administration. It may also be temporarily increased for several hours after desiccated thyroid intake. Iodine deficiency of moderate degree usually is associated with normal T3-RIA and T4 levels, although mean T3-RIA values are higher than in normal persons. In severe iodine deficiency, T3-RIA values are sometimes increased, T4 values may be decreased, and TSH values may be increased. The RAIU value is increased in iodine deficiency, providing additional potential for misdiagnosis. As noted previously, one report indicates that occasional free T3 index elevations can be found in amphetamine abusers.

    Pseudo–T4 hyperthyroidism (T4 elevated; T3-RIA not elevated)

    Pseudo–T4 toxicosis may be of two types: (1) true hyperthyroidism, T4/T3 toxicosis with (temporarily) reduced T3-RIA test result; and (2) false hyperthyroidism, elevated T4 test result in euthyroid patient (see the box).

    True hyperthyroidism. Ordinarily, both T4 and T3-RIA values are elevated in T4/T3 toxicosis or

    Pseudo–T4 Hyperthyroidism

    True hyperthyroidism (patient is hyperthyroid)
    Factitious ingestion of levothyroxine
    T4/T3 hyperthyroidism plus decrease in T3-RIA result due to:
    Severe non thyroid illness
    Advanced age
    Certain medications (e.g., dexamethasone, propranolol)
    False hyperthyroidism (patient is euthyroid)
    Increased TBG value plus decrease in T3-RIA result
    Severe non thyroid illness occasionally producing falsely elevated T4 levels
    Increased TBG value with disproportionate T4 increase relative to T3-RIA
    Acute psychiatric illness (some patients)
    Amphetamine abuse
    Certain x-ray contrast media
    Certain medications (e.g., propranolol, amiodarone)
    Specimen obtained 1-4 hr after levothyroxine dose rather than just before the dose
    Patient taking therapeutic levothyroxine

    when the TBG value is increased. Pseudo–T4 toxicosis may be produced in patients who have T4/T3 toxicosis if the T3-RIA level becomes decreased for some reason while the T4 level remains elevated. The most common causes for T3-RIA decrease in T4/T3 toxicosis are severe non thyroid illness and effect on T3-RIA of old age. Many severe non thyroid illnesses, particularly when chronic (see Table 28-3), depress T3-RIA levels, often to very low levels. The free T3 index also decreases but to a lesser extent. The effect of severe illness persists for variable periods of time and usually involves a shift from production of T3 toward reverse T3. Another factor that depresses T3-RIA levels but not T4 levels is the effect of advanced age. For patients over age 60 years, most T3-RIA kits have demonstrated a progressive decrease with time of approximately 10%-30% (literature range, 0%-52%). The degree of effect differs with individual manufacturers’ kits. Unfortunately, very few laboratories determine age-related values for the particular kit that they use. There is general but not unanimous agreement that T4 values are not greatly changed in old age. Certain medications (propranolol, dexamethasone) have been reported to decrease T3-RIA levels, although not severely.

    False hyperthyroidism. Artifactual T4 elevation may result when TBG levels are increased, artifactually elevating both T4 and T3-RIA results, but some condition is superimposed that decreases T3-RIA results, leaving only the T4 value elevated. As noted previously, the most common reason for artifactual T3-RIA decrease is severe non thyroid illness. Another possibility is the effect of advanced age. In patients with normal TBG levels, severe non thyroidal illness may be associated with T4 values that are increased, decreased, or that remain within normal population range. Thyroxine levels most commonly display slight or mild decreases but still remain within normal limits. In a significant minority of patients (depending on the severity of illness), the T4 level is decreased below its reference range to varying degrees, producing pseudo hypothyroidism (clinical euthyroidism with laboratory test results falsely suggesting hypothyroidism). A small minority of patients exhibit an increase in T4 results for poorly understood reasons. In these patients, Pseudo–T4 toxicosis would be produced without clinical hyperthyroidism or increased TBG levels (designated “T4 euthyroidism” by some investigators). The TSH value in severe non thyroidal illness is most often normal but may be mildly increased. The THBR level may be normal but is sometimes mildly increased, reflecting decreased TBG levels. Occasionally the THBR level is decreased, mainly in acute hepatitis.

    Certain conditions produce artifactual elevation of T4 values but not T3-RIA values. In some patients with increased TBG values without severe non thyroid illness, T3-RIA values remain within upper reference range while the T4 levels are elevated. One explanation is that increase in binding proteins affects T4 levels somewhat more than T3-RIA values. However, an increased TBG level frequently produces an elevated T3-RIA value as well as a T4 value. Elevated T4 values with normal T3-RIA values have been reported in some patients with acute psychiatric illness who were clinically euthyroid and where T4 values returned to the reference range after treatment of the psychiatric problem. However, the possibility of true thyrotoxicosis should not be ignored.

    Amphetamine abuse has been reported to increase serum T4 values without affecting T3-RIA values. Both the TI and FT3I are elevated in some of these patients. Some of these patients had mildly elevated serum TSH values and some did not. Increased FT3I was also found in some cases without increase of FT4 index.

    Certain x-ray contrast media such as ipodate and iopanoic acid gallbladder visualization agents decrease T3-RIA values and may increase T4 values somewhat. Dexamethasone and propranolol are reported to decrease T3-RIA values, as noted previously. Propranolol has been reported to increase T4 values, but there is some disagreement as to whether this occurs.

    If a patient is taking therapeutic levothyroxine (Synthroid, Levothroid), and a blood specimen happens to be drawn 1-4 hours after a dose has been administered, a result above steady-state level will often be obtained that might be above the reference range. Peak values after an oral dose are reached in 2-4 hours and average 1-3 µg above steady-state level. Even at steady-state levels and drawn just before the scheduled dose, patients who are clinically normal and whose TSH and T3-RIA values are within reference range may have a steady state T4 level as much as 2 µg above the upper limit of the T4 reference range (discussed later). This is a problem because the dose is not always given at the scheduled time, the laboratory usually does not know what medications the patient is receiving to schedule the time of venipuncture, and sometimes the physician is unaware that a new patient is taking levothyroxine.

    It has been reported that some hyperthyroid patients with elevated T4 levels but normal-range T3-RIA values have an elevated FT3I.

    Hyperthyroidism with false laboratory euthyroidism. One final category of deceptive hyperthyroidism may be added, clinical hyperthyroidism with falsely normal T4 and T3-RIA values (see the box). Patients with decreased TBG

    Hyperthyroidism With False Laboratory Euthyroidism
    Hyperthyroidism plus decreased TBG value (see the box)
    Hyperthyroidism plus severe non thyroid illness

    levels may have falsely decreased T4 and T3-RIA levels that could convert elevated values to normal-range assay results. Severe non thyroidal illness decreases T3-RIA values and may decrease T4 values. This could mask expected T3-RIA elevation in T3 toxicosis and T3-RIA plus some patients with T4 elevation in some cases of T4/T3 or T4 toxicosis.

    Isolated Graves’ ophthalmopathy

    Besides the two classic types of clinical hyperthyroidism, there is one additional form known as isolated Graves’ ophthalmopathy, or “euthyroid Graves’ disease.” This consists of eye signs associated with hyperthyroidism but without other clinical evidence of thyrotoxicosis and with normal RAIU, T4, and T3-RIA values. Evidence of true hyperthyroidism consists of reports that about 50%-70% of these patients fail to demonstrate thyroid suppression on the T3 suppression test (literature range, 50%-100% in several small series of patients). About two thirds have a flat or blunted TSH response on the TRH test, suggestive of thyroid autonomy. A considerable number of these patients have detectable thyroid-stimulating immunoglobulins (TSI test;). However, published reports of the latest versions of this test show considerable differences in sensitivity between laboratories. Similar differences were reported in detection rates for Graves’ disease.

  • Laboratory Test Patterns in Hyperthyroidism

    The diagnosis of thyroid disease now depends as much on laboratory results as it does on clinical findings. One might therefore use the term “laboratory hyperthyroidism” when considering the spectrum of test results in thyrotoxicosis in the same manner that one employs the term “clinical hyperthyroidism” when evaluating patient signs and symptoms. Laboratory diagnosis is usually based on elevated values of serum T4 and T3, the two active thyroid hormones. Laboratory hyperthyroidism can be subdivided into three categories, depending on T4 and T3-RIA results:

    1. Standard T4/T3 toxicosis (both T4 and T3-RIA elevated).
    2. T3 toxicosis (T3-RIA elevated, T4 not elevated).
    3. T4 toxicosis (T4 elevated, T3-RIA not elevated).

    Standard T4/T3 toxicosis includes nearly 95% of cases of hyperthyroidism.

    T3 toxicosis is estimated to occur in 3%-5% of hyperthyroidism patients (literature range, 2.4%-30%). Although T3-RIA values are increased in T3 toxicosis, the T4, THBR, and RAIU values are usually all normal. There is some evidence that T3 toxicosis is more common in patients with atrial fibrillation, and it may be associated more often with Plummer’s disease than with Graves’ disease (although not all investigators agree). One report indicates that T3 toxicosis is more common in iodine-deficiency areas (although some of these cases might have been pseudo-T3 toxicosis with T4 levels decreased because of the iodine deficiency). TSH is decreased in T3 toxicosis.

    T4 toxicosis has not received much attention, and it was assumed to be less frequent than T3 toxicosis. In the more recent articles on this subject in the literature, incidence ranged from 0%-21% of hyperthyroid patients, although the true incidence is probably less than that of T3 toxicosis. Several investigators report that T4 toxicosis is more commonly found with iodine-induced hyperthyroidism (Jod-Basedow disease). T4 toxicosis is also found more commonly in elderly persons, but in some reports it is difficult to be certain that some cases were not actually T4/T3 toxicosis with depressed T3-RIA values due to concurrent severe illness.

  • Thyroid Tests in Phenytoin Therapy

    There are conflicting statements in the literature on the effect of phenytoin (diphenylhydantoin; Dilantin) on certain thyroid tests. Dilantin is known to compete for binding sites on TBG, but it may also affect thyroid tests due to activation (“induction”) of liver microsomal enzymes, resulting in accelerated metabolic alteration of T4. The majority of reports indicate that T4, free T4, and T3-RIA values are somewhat decreased from pretreatment levels. The T4 level is said to decrease about 25%-33% from pretreatment level, whereas the T3-RIA value decreases about 15%. In one study, the T4 level decreased below reference range in 40% of patients, whereas the T3-RIA value remained within reference range in all patients. The THBR, TSH and TRH tests are not significantly affected.

  • Effects of Iodine on Thyroid Tests

    Iodine deficiency

    Iodine deficiency goiter is rare in the United States but still might be encountered by a physician. Iodine deficiency leads to an increase in RAIU. In mild or moderate iodine deficiency there is said to be a decrease in T4 and THBR values, but values usually remain within their reference range. Often T3-RIA is increased. Assay levels of TSH are usually normal. In severe iodine deficiency, T4 and THBR values often decrease and T3-RIA increases. The TSH level may be elevated but only to a mild or moderate degree. Thus, iodine deficiency may simulate thyrotoxicosis (goiter and RAIU increases), T3 toxicosis (goiter with normal or decreased T4 levels and elevated T3-RIA) or even hypothyroidism (decreased T4 level).

    Iodine excess

    As noted previously, excess iodine usually results from inorganic iodide, most commonly found in respiratory tract medications such as SSKI, or from organic iodine present in x-ray contrast media and in certain medications such as the antiarrhythmic drug amiodarone. With long-term SSKI therapy, when the medication is initially administered, there is a decrease in T4 values of varying degree accompanied by an increase in TSH values, followed by a return of the T4 and TSH values toward baseline levels in days or weeks. However, some of those whose T4 level stabilizes within reference range have persisting mildly elevated TSH level. A minority of patients have persistently decreased T4 and increased TSH values, which tend to be more frequent in patients with preexisting thyroid diseases such as Hashimoto’s thyroiditis, therapy with lithium carbonate, previous iodine deficiency, and patients with treated Graves’ disease or toxic nodules. On the other hand, inorganic iodide can occasionally induce thyrotoxicosis (Jod-Basedow disease), most commonly when administered to persons who are iodine deficient. As noted previously, certain x-ray contrast media (ipodate and iopanoic acid) may temporarily increase T4 levels (due to inhibition of T4 to T3 conversion) but usually only to a mild degree (20%-40% over baseline). This may or may not be accompanied by a mild increase in TSH values. Marked T4 elevation suggests Jod-Basedow disease. If this occurs, it is usually associated with a decreased RAIU value. Amiodarone is an antiarrythmia drug that contains a considerable amount of inorganic iodide. It produces more frequent and substantial thyroid test abnormalities than does x-ray contrast media. In some patients it may cause iodine-induced thyrotoxicosis (Jod-Basedow disease; more common in patients with preexisting iodine deficiency). In others, it may lead to iodine suppression of the thyroid (similar to SSKI therapy), producing decreased T4 and elevated TSH values. A third effect is inhibition of peripheral tissue conversion of T4 to T3; the patients remain euthyroid, but there is elevation of T4 and TSH in some patients, while T3-RIA is relatively normal. Overall, in patients on amiodarone therapy the T4 level is elevated over reference range upper limit in 20%-30% (range, 10%-40%) of patients; there are no clinical signs of hyperthyroidism, and the elevated T4 level is accompanied by increased reverse T3 and normal T3-RIA, THBR, and TSH values. The RAIU value can be decreased or normal. In those patients who develop iodine-induced clinically evident thyrotoxicosis, the T4, FT4, FT4 I, THBR, and T3-RIA values are elevated, whereas the TSH value is low. On the other hand, decreased T4 and elevated TSH values with clinical hypothyroidism occurs in 15%-20% of patients. In almost all patients with thyroid test abnormalities, the test results usually return to normal in 3-7 months after the end of amiodarone therapy.

  • Thyroid Function Tests: Thyroid scan

    Thyroid uptake of radioactive isotopes of iodine or technetium may be counted by a special radiation detector that produces a visual overall pattern of gland radioactivity. This permits visual localization of areas that may be hyperactive or hypoactive. Thyroid scan has two major applications:

    1. In patients with hyperthyroidism, the scan can differentiate between diffuse hyperplasia and a hyperfunctioning nodule (“toxic nodule”), entities that require different treatment. In addition, occasionally patients with symptoms of hyperthyroidism have chronic lymphocytic thyroiditis. Serum T4 and T3 levels are frequently elevated. Both elevated and low 24-hour RAIU values have been reported. Early (2-6 hours) RAIU values may be elevated more frequently than the 24-hour uptake. Thyroid scan frequently has a rather characteristic nonuniform appearance that can be helpful in suggesting the diagnosis. Factitious (self-medication) hyperthyroidism and subacute thyroiditis usually are associated with a low RAIU value in conjunction with an elevated T4 level (falsely low RAIU due to excess iodine or previous antithyroid therapy must be excluded).

    2. In patients with a palpable thyroid nodule, the scan may demonstrate lack of radioactivity in that area (“cold” nodule), suggesting a lack of functional activity that would increase suspicion of carcinoma. Most reports agree that a hyperfunctioning nodule is rarely malignant. Single nonfunctioning nodules have a 10%-20% incidence of malignancy. Truly nonfunctioning nodules are much more likely to be malignant than nodules that retain some function. At times, however, normal thyroid tissue above or below a nodule may contribute some degree of apparent function to a nonfunctioning area. However, there is some controversy over the usefulness of thyroid scanning in the evaluation of thyroid nodules for possible malignancy (see Chapter 33).

    Thyroid-stimulating immunoglobulin (TSI) assay

    A group of immunoglobulins (antibodies) of the IgG class that could prevent binding of TSH to TSH receptors on the thyroid cell membrane were discovered. The antibody also has the ability to stimulate adenylate cyclase to produce cyclic AMP production, which causes release of T4 and T3. The antibody can exert effect over a relatively prolonged period of time. The antibody was originally named “long-acting thyroid stimulator” (LATS) and was measured with a bioassay system (McKenzie) using mouse thyroid. The LATS was considered to be fairly specific for Graves’ disease, although it was also found in a few patients with Hashimoto’s disease and occasionally in low titer in some other conditions. It could be detected in only 40%-45% (range, 9%-55%) of patients with Graves’ disease. It was present more frequently when the patients had pretibial edema or hyperthyroidism with eye signs (but it was found in only about 15% of patients with so-called isolated Graves’ ophthalmopathy). The titer tended to decrease after 6-12 months of clinically active disease, after treatment was given, or when the disease became inactive. There was not a close relationship between titer and severity of illness.

    It was subsequently found that LATS would bind to human thyroid tissue but could not stimulate it, so that the antibody was renamed “mouse thyroid stimulator.” In addition, once serum containing LATS was incubated with human thyroid tissue, that serum no longer showed any LATS activity in the McKenzie mouse bioassay (i.e., the LATS activity was destroyed or neutralized).

    More recently, other related IgG antibodies were found that prevented adsorption of LATS onto human thyroid tissue and (as a group) was therefore called “LATS protector.” This abnormal IgG antibody (or antibodies) can be demonstrated by three different assay techniques. One technique used high-titer LATS antibody as the indicator system whose endpoint was to show that antibody in patient serum blocked uptake of the LATS antibody by human thyroid tissue; since the LATS antibody activity in the McKenzie bioassay would be neutralized by human thyroid tissue and the patient antibody prevented such neutralization, the patient antibody was called LATS protector antibody. A second technique measured the ability of patient antibody to inhibit or block the binding of radioactive TSH to human or animal thyroid acinar cell membranes. This has been called the “TSH-binding inhibiting immunoglobulin” (TBII) assay. The third technique measured the ability of the antibody to stimulate human or animal thyroid acinar cell membrane-bound adenylate cyclase, producing increased cyclic adenosine monophosphate (AMP) activity. The original assay method used human thyroid tissue, so the antibody was originally called “human thyroid-stimulating immunoglobulin.” Since animal thyroid tissue can be used, the assay now is simply called “thyroid-stimulating immunoglobulin” (TSI). For example, one modification of the TSI uses special TSH-dependent FRTL-5 rat tissue culture thyroid cells.

    The LATS-protector assay is reported to detect about 75%-80% (range, 60%-90%) of patients with Graves’ disease. The LATS-protector assay was very complicated; few laboratories performed the assay and few if any do now. The TBII technique is reported to detect about 70%-80% (range, 39%-100%) of Graves’ disease, and the TBI detects about 75%-80% (range, 18%-100%). Neither the TBII nor the TBI are simple or easy. Most laboratories using either technique use “homemade” reagents, which accounts for much of the great variation in sensitivity reported in the literature. Since many nonresearch laboratories base their test performance claims on data from one or more research laboratories using the same technique but their own reagents, performance claims based on someone else’s results may not be valid. Therefore, it is desirable to send specimens to laboratories that can verify better sensitivity based on adequate numbers of well-diagnosed patients with Graves’ disease that they assayed themselves. Besides sensitivity, it is necessary to question specificity, since different laboratories may find different numbers of false positive results when patients with hyperfunctioning thyroid nodules, nonfunctioning nodules or goiter, thyroiditis, autoimmune disorders, and clinically normal status are tested.

    At present, TSI assay is used mainly for patients with borderline or conflicting evidence of Graves’ disease, patients who have some condition that affects the results of other tests, or patients who have “isolated Graves’ ophthalmopathy” (a condition in which all standard thyroid tests are normal). However, a negative test result in most laboratories does not completely exclude the diagnosis, and there is a possibility of false positive results.

  • Thyroid Function Tests: Thyrotropin-releasing hormone (TRH) test

    Synthetic TRH (Thypinone) is now available. Intravenous bolus administration of TRH normally results in a marked rise in serum TSH levels by 30 minutes after the dose. Serum prolactin levels also increase. There is some disagreement as to how much TRH to administer, with doses reported in the literature ranging from 100-500 µg. Early studies reported that at least 400 µg was needed to obtain full TRH effect. Interpretation depends on whether the patient has evidence of hyperthyroidism or hypothyroidism. One problem, however, is disagreement in the literature concerning how much TSH increase over baseline is considered “exaggerated.” The normal limit of increase over baseline varies in the literature from 20-40 µU/ml, so that 25 µU/ml seems to be a reasonable compromise. Reactions to the TRH injection are uncommon, but can occur, and the patients should be closely monitored during the procedure. In general, the smaller the dose, the lower the incidence of reactions. Therefore, many laboratories and investigators use a 200-µg dose; and a few, even a 100-µg dose. However, I have not seen any reports that compared sensitivity of these doses to the gold standard of the 400- or 500-µg dose. Even if such a report appears, it would take several studies including a very substantial number of patients with hypothyroidism and hyperthyroidism to verify satisfactory performance.

    Drawbacks. (1) There is conflicting evidence in the literature regarding the effects of severe non thyroid illness on TRH test results. At least one report indicates that a blunted response may occur in some apparently euthyroid patients with depressed T4 levels associated with severe non thyroid illness and also in some patients with hypothyroidism who also had severe non thyroid illness. This would complicate the diagnosis of hypothyroidism in some cases as well as the differential diagnosis of primary versus secondary etiology. (2) Several reports suggest that TSH response to TRH may be less in elderly persons. (3) In addition, certain conditions such as psychiatric unipolar depression, fasting more than 48 hours duration, and therapy with aspirin, levodopa, or adrenocorticosteroids depress TSH response to TRH. (4) Patients should discontinue desiccated thyroid or T4 therapy for 3-4 weeks (literature range, 2-5 weeks) before a TRH test. (5) Another (although not major) drawback is the $30-$40 cost for TRH and the need for two or three TSH assay specimens.

    Thyrotropin-releasing hormone results in hyperthyroidism. In hyperthyroidism, pituitary TSH production is suppressed by direct effect of excess circulating T4/T3 on the pituitary, and TSH assay after TRH fails to demonstrate a significant degree of TSH increase from pretest baseline values (positive test result). Unfortunately, about 5% false positive results (failure to elevate serum TSH levels after TRH) have been reported in persons without demonstrable hyperthyroidism. A flat or blunted TSH response to TRH has also been reported in patients with autonomous thyroid nodules but no clinical evidence of hyperthyroidism, in a considerable number of patients after adequate treatment of Graves’ disease, and in some patients with multinodular goiter. Certain other conditions (discussed later) may also affect results. A flat TRH test result is therefore considered very suggestive but not conclusive evidence of thyrotoxicosis. A normal result (normal degree of TSH elevation after TRH) is considered very reliable in excluding thyrotoxicosis. For this reason the TRH test is currently considered the most reliable confirmatory procedure for hyperthyroidism and is the standard against which all other tests are compared for accuracy.

    Thyrotropin-releasing hormone results in hypothyroidism. In primary hypothyroidism the TRH test usually demonstrates an exaggerated TSH response. This may render the test useful in the occasional patient with both equivocal symptoms and equivocal serum TSH values. Theoretically, the TRH test should be able to differentiate between hypothyroidism from inability of the pituitary to secrete TSH due to pituitary disease (secondary hypothyroidism) and inability of the hypothalamus to secrete TRH (tertiary hypothyroidism). In pituitary disease, the serum TSH level should not rise significantly after TRH administration, whereas in hypothalamic disease there characteristically is a TSH response that is normal in degree but that is delayed for approximately 30 minutes. Unfortunately, a substantial number of patients with pituitary lesions demonstrate relatively normal or delayed TRH test response. Therefore, absent or markedly blunted response is strongly suggestive of primary pituitary disease, but response to TRH is not diagnostic of hypothalamic disease.

    Thyrotropin-releasing hormone results in psychiatric patients. There have been reports that the TRH test is useful in differentiating unipolar (primary depression only) from bipolar (manic-depressive) psychiatric illness and from secondary types of depression. In unipolar depression, TRH-induced TSH response is said to be blunted in up to two thirds of patients, whereas most patients with other categories of depression have normal TSH response. Occasional patients with symptoms of depression may actually have thyrotoxicosis (“apathetic hyperthyroidism”) and some may have hypothyroidism.

  • Thyroid Function Tests: Thyroid stimulation and suppression tests

    Thyrotropin stimulation test. In some patients with myxedema, the question arises as to whether the etiology is primary thyroid disease or a malfunction secondary to pituitary deficiency. Normally, administration of TSH more than doubles a baseline RAIU or T4 value. Failure of the thyroid to respond to TSH stimulation strongly suggests primary thyroid failure, whereas normal gland response implies either a pituitary or hypothalamic problem or else some artifactual abnormality in the original screening tests. The same procedure can be used to confirm the diagnosis of primary hypothyroidism, since the thyroid should not be able to respond to TSH. The test may be helpful in patients who have been on long-term thyroid hormone treatment and who must be reevaluated as to whether the original diagnosis of hypothyroidism was correct. The TSH stimulation test can be done while thyroid hormone is still being administered, whereas it would take several weeks after cessation of long-term therapy for the pituitary-thyroid relationship to reach pretherapy equilibrium. An occasional use for TSH stimulation is to see whether parts of the thyroid that are not functioning on a thyroid scan are capable of function (versus being not capable of function or being suppressed by hypersecretion from other thyroid areas).

    Drawbacks. The TSH stimulation test is performed using bovine TSH. Some persons form antibodies against this material that may interfere with future TSH assay or produce allergic reaction if TSH is used again. Therefore, the test is infrequently used today. To avoid this potential problem, some investigators use a T3 withdrawal test rather than TSH stimulation. A potential problem using RAIU in TSH stimulation tests is some correlation of patient iodine status to degree of RAIU response to TSH. In general, as iodine deprivation increases, RAIU response also increases; iodine overload decreases the RAIU response.

    Triiodothyronine withdrawal test. The patient is placed on T3 therapy for 1 month (instead of other therapy). The T3 is then discontinued for 10 days, after which a serum TSH assay is performed. With medication containing T4 it is necessary to wait at least 4 weeks after withdrawal before routine thyroid function tests (T4, T3, TSH), are performed to allow the thyroid-pituitary-hypothalamic feedback system to regain normal equilibrium. After T3 withdrawal, it takes only 10 days to achieve the same effect. If the patient has primary hypothyroidism, the serum TSH level will be elevated after 10 days without T3. In euthyroid persons or those with secondary and tertiary hypothyroidism, the TSH level will be normal or decreased. The major drawbacks to this procedure are the long time intervals necessary and the fact that not enough experience with this test has been reported to ascertain how many exceptions or false results may be expected. This test also is rarely used today.

    Thyroid suppression test. This is frequently called “T3 suppression,” although T4 could be used instead of T3, and the pituitary rather than the thyroid is the actual organ directly suppressed by T3 administration (the thyroid is affected secondarily). A standard dose of T3 is given daily for 1 week. In normal persons, exogenous T3 (added to the patient’s own T4) suppresses pituitary secretion of TSH, leading to a decrease in patient thyroid hormone manufacture. Values of RAIU or T4 after T3 administration drop to less than 50% of baseline. In hyperthyroidism, the thyroid is autonomous and continues to manufacture hormone (with little change in RAIU or T4 level), although the pituitary is no longer stimulating the thyroid. The suppression test is thought to be very reliable in confirming borderline hyperthyroidism, although there are reports that 25% or more of patients with nontoxic nodular goiter may fail to show suppression. The same basic technique may be used in conjunction with the thyroid scan to demonstrate that a nodule seen on original scan is autonomous. This may be helpful, since reports indicate that 50%-80% of toxic nodular goiter patients have normal RAIU values and many have normal T4 test results. The procedure must be used with caution in elderly persons or patients with cardiac disease. The T3 suppression test has been largely replaced by the TRH test.