Articles on Medical Diseases and Conditions

Month: December 2009

  • Thyroiditis

    The usual classification of thyroiditis includes acute thyroiditis, subacute thyroiditis, chronic thyroiditis, and Riedel’s struma.

    Acute thyroiditis is generally defined as acute bacterial infection of the thyroid. Signs, symptoms, and laboratory data are those of acute localized infection.

    Riedel’s struma consists of thyroid parenchymal replacement by dense connective tissue. In some cases at least this presumably represents scar tissue from previous thyroiditis. Thyroid function tests are either normal (if sufficient normal thyroid remains) or indicate primary hypothyroidism.

    Subacute thyroiditis (granulomatous thyroiditis or de Quervain’s disease) features destruction of thyroid acini with a granulomatous reaction consisting of multinucleated giant cells of the foreign body reaction type and large histiocytes. The etiology is unknown but possibly is viral or autoimmune. The classic syndrome of subacute thyroiditis includes thyroid enlargement (usually less than twice normal size) with pain and tenderness, symptoms of thyrotoxicosis, substantially increased ESR, increased T4, T3-RIA, and THBR (T3U) values, and decreased RAIU values. Thyroid scans demonstrate patchy isotope concentration throughout the thyroid gland (occasionally, only in focal areas) or else very little uptake. Classic cases have been reported to progress through four sequential stages: hyperthyroidism, followed by transient euthyroidism, then hypothyroidism, and then full recovery. Recovery in most cases takes place in 3-5 months. The classic syndrome is estimated to occur in approximately 50%-60% of patients with subacute thyroiditis. Milder or nonclassic cases lack the symptoms and laboratory findings of thyrotoxicosis. However, the ESR is usually elevated, and the RAIU value is usually decreased.

    Painless thyroiditis (also called “silent thyroiditis”) describes a group of patients with a syndrome combining some elements of subacute thyroiditis with some aspects of chronic thyroiditis (Hashimoto’s disease). These patients have nonpainful thyroid swelling with or without clinical symptoms of thyrotoxicosis. Laboratory data include increased T4, T3-RIA, and THBR values, decreased RAIU value, patchy thyroid scan, and normal or minimally elevated ESR. Painless thyroiditis thus differs from subacute thyroiditis by lack of pain in the thyroid area and by normal ESR. Although some consider this syndrome to be a painless variant of subacute thyroiditis, biopsies of most cases have disclosed histologic findings of chronic lymphocytic thyroiditis rather than subacute thyroiditis. The reported incidence of this condition has varied from 5%-30% of all cases of hyperthyroidism. However, one report suggests that the incidence varies with geographic location, with the highest rates being in the Great Lakes region of the United States and in Japan.

    Postpartum transient toxicosis is a syndrome that is said to occur in as many as 5%-6% (literature range, 5%-11%) of previously euthyroid postpartum women. There is transient symptomatic or asymptomatic thyrotoxicosis with elevated T4 and low RAIU values, similar to the findings in thyrotoxic silent thyroiditis. This episode in some cases is followed by transient hypothyroidism. Thyroid autoantibody titers are elevated, suggesting lymphocytic thyroiditis.

    Chronic thyroiditis is characterized histologically by dense lymphocytic infiltration of the thyroid with destruction of varying amounts of thyroid parenchyma. Chronic thyroiditis is frequently divided into two subdivisions: lymphocytic thyroiditis, most frequent in children and young adults, and Hashimoto’s disease, found most often in adults aged 30-50 years. In both cases females are affected much more often than males. In approximately one half of chronic thyroiditis patients, serum T4 levels are normal and the patients are clinically euthyroid. In 20%-40% the T4level is decreased, and there may be variable degrees of hypothyroidism. In some patients with decreased T4 levels the T3-RIA may be normal and presumably is responsible for maintaining clinical euthyroidism. The RAIU value is normal in 30%-50% of cases. In 10%-30% the RAIU value is increased, especially in the early stages of the disease. In fact, an elevated RAIU value with a normal T4 value definitely raises the possibility of active (early) chronic thyroiditis. The ESR is usually normal. Thyroid scan discloses generalized patchy isotope distribution in approximately 50% of cases and focal patchy or reduced uptake in 5%-10% more. In approximately one third of cases various precursors of T4 or abnormal thyroglobulin derivatives are released from damaged thyroid acini. In about 5% of patients with chronic thyroiditis, release of thyroid hormone derivatives produces hyperthyroidism with increased serum T4 levels. The RAIU value may be elevated or decreased. If the RAIU value is decreased, these patients might be considered part of the “thyrotoxic silent thyroiditis” group. On the other hand, some patients with chronic thyroiditis eventually develop sufficient damage to the thyroid to produce permanent hypothyroidism.

    Lymphocytic thyroiditis and Hashimoto’s disease are very similar, and some do not differentiate between them. However, in lymphocytic thyroiditis the goiter tends to enlarge more slowly, abnormal iodoproteins tend to appear more often, and the RAIU value tends to be elevated more frequently. Hashimoto’s disease tends to have more histologic evidence of a peculiar eosinophilic change of thyroid acinar epithelial cells called “Askenazi cell transformation.” Exact diagnosis of chronic thyroiditis is important for several reasons: to differentiate the condition from thyroid carcinoma, because a diffusely enlarged thyroid raises the question of possible thyrotoxicosis, and because treatment with thyroid hormone gives excellent results, especially in childhood lymphocytic thyroiditis.

    Thyroid autoantibodies. Both subgroups of chronic thyroiditis are now considered to be either due to or associated with an autoimmune disorder directed against thyroid tissue. Autoantibodies against one or another element of thyroid tissue have been detected in most cases. In addition, there is an increased incidence of serologically detectable thyroid autoantibodies in rheumatoid-collagen disease patients, conditions themselves associated with disturbances in the body autoimmune mechanisms. There are two major subgroups of thyroid autoantibodies, those active against thyroglobulin and those directed against the microsome component of thyroid cells. There are several different techniques available to detect these antibodies, including, in order of increasing sensitivity: latex agglutination (antithyroglobulin antibodies only), immunofluorescence, hemagglutination (also known as the tanned [tannic acid-treated] red blood cell [or TRC] test), and radioassay. At present radioimmunoassay and immunofluorescence are not widely available, and most reference laboratories use some modification of the hemagglutination test.

    In general, antimicrosomal antibodies are found more often in chronic thyroiditis than antithyroglobulin antibodies. Antithyroglobulin antibodies are found less often in diseases other than chronic thyroiditis, but this increase in specificity is only moderate, and neither test has adequate selectivity for chronic thyroiditis (Table 29-1). High titers are much more likely to be associated with chronic thyroiditis than with nontoxic nodular goiter or thyroid carcinoma. High titers of antimicrosomal antibodies (or both antimicrosomal and antithyroglobulin antibodies) are not specific for chronic thyroiditis, because patients with Graves’ disease or primary hypothyroidism may have either high or low titers. Normal or only slightly elevated titers, however, constitute some evidence against the diagnosis of chronic thyroiditis.

    29-1

    Table 29-1 Thyroid autoantibody test results in thyroid diseases (hemagglutination method)*

  • Monitoring of Replacement Therapy

    Desiccated thyroid and presumably other T4 and T3 combinations result in T3-RIA values that may become elevated for several hours after administration and then decrease into the reference range. T4 values remain within the reference range if replacement is adequate. In the few instances when clinical evidence and T4 results disagree, TSH assay is helpful. Elevated TSH values suggest insufficient therapy. Unfortunately, low TSH values using standard TSH kits is not a reliable indicator of over treatment since most of these kits produce considerable overlap between normal persons and those with decreased values in the low reference range area. Ultra sensitive TSH kits should solve this problem if the kit is reliable.

    L-Thyroxine (Synthroid, Levothroid) results in T3-RIA values that, in athyrotic persons, are approximately two thirds of those expected at a comparable T4 level when thyroid function is normal. This is due to peripheral tissue conversion of T4 to T3. The T3-RIA values are more labile than T4 values and are more affected by residual thyroid function. The standard test to monitor L-thyroxine therapy is the T4 assay. There is disagreement whether T4 values must be in the upper half of the T4 reference range or whether they can be mildly elevated. In general, when the TSH value returns to its reference range, the T4 level stabilizes somewhere between 2 µg above and below the upper limit of the T4 range. T4 elevation more than 2 µg above reference range probably suggests too much dosage. A minority believe that T4 values should not be above the reference range at all. On the other hand, T4 values in the lower half of the reference range are usually associated with elevated TSH levels and probably represent insufficient replacement dose. Some investigators favor T3-RIA to monitor therapy rather than T4 or TSH. The THBR value is most often within reference range with adequate replacement dose but has not been advocated for monitoring therapeutic effect.

    One report indicates that dosage requirement decreases after age 65 years.

  • Comments Regarding Use of Thyroid Tests

    As previously noted, some thyroidologists and laboratorians advocate screening for thyroid disease with a single test, often citing need for cost containment. The ultra sensitive TSH appears to be advantageous for this purpose. The T4 test result is more frequently normal in mild disease and more frequently abnormal in the absence of thyroid disease than is the ultra sensitive TSH. The FT4 test has many of the same problems as the T4 test, although the FT4 is less frequently affected by non thyroid conditions. The major problem with the one-test approach is that the clinician becomes very dependent on the laboratory to select a reliable method or commercial kit. I can verify that not all commercially available kits are equally reliable and that it takes search for published evaluations of the exact manufacturer’s kit under consideration in addition to extensive evaluation of the kit in the potential user’s own laboratory to establish proof of reliability. In addition, each laboratory should establish its own reference range using a statistically satisfactory number (at least 20) of blood donors or other clinically normal persons.

    Finally, one has to consider the possibility of laboratory error, even though it may not be frequent on a statistical basis. For these and other reasons, some order two tests rather than one for screening purposes, such as the FT4 plus the ultra sensitive TSH. If both test results are normal, this is very reassuring. If one or both are abnormal, either or both can be repeated to verify abnormality. The diagnosis sometimes can be made with this evidence plus clinical findings, or additional tests may be needed.

    Since the T4 (or its variants) and the ultra sensitive TSH are being used extensively to screen for and diagnose thyroid disease, it might be useful to catalog the patterns encountered using these two tests and some of the conditions that produce these patterns (see the box).

  • Summary of Laboratory Tests in Hypothyroidism

    From the preceding discussion, several conclusions seem warranted:

    1. Serum T4 is the most widely used screening test for hypothyroidism, but some physicians use FT4 or serum TSH assay instead. Values in the upper half of the T4 and FT4 reference range are strong evidence against hypothyroidism unless the TBG level is increased (congenital, pregnancy, or estrogen induced).
    2. The THBR test is useful to detect TBG-induced alterations in T4.
    3. The new FT4 methods circumvent the majority of TBG-induced problems and significantly reduce the number of pseudo hypothyroid cases due to severe non thyroidal illness. However, even the FT4 may give falsely decreased results in seriously ill patients.
    4. The TSH assay is the most useful single test to confirm primary hypothyroidism. In occasional patients a TRH test may be necessary.
    5. Certain conditions may produce decreased T4 levels, increased TSH levels, or both in occasional patients without primary hypothyroidism.

  • False Laboratory Euthyroidism in Hypothyroid Patients

    Normal T4 values in a hypothyroid patient may occur in the following conditions:

    1. In early or very mild hypothyroidism. Serum TSH values are usually elevated. Some investigators have reported patients in whom the T4 and TSH values were both within reference range, but the TRH test result exhibited an exaggerated response suggestive of hypothyroidism.
    2. When the T4 level in a hypothyroid person is artifactually increased into the normal population reference range. This may be due to elevated TBG levels or because the reference range overlaps with values for some patients with mild hypothyroidism. The TSH level should be elevated in most cases, unless the reason for the patient’s hypothyroidism is pituitary insufficiency.

  • Pseudohypothyroidism

    Pseudo hypothyroidism may be defined as a deceased T4 level in a euthyroid person. This may occur with (1) decreased TBG or TBG binding (congenital or drug induced), (2) certain medications (e.g., phenytoin, lithium, dopamine, corticosteroid), (3) some patients with severe non thyroidal illness, (4) some clinically euthyroid patients with Hashimoto’s thyroiditis, (5) after recent therapy of hyperthyroidism or thyroid cancer with radioactive iodine (some patients eventually develop true hypothyroidism), (5) Cushing’s syndrome, (7) in some patients with SSKI therapy, and (8) severe iodine deficiency.

    Most of these conditions have been discussed previously (see the box). The TSH levels are normal when the TBG level is decreased and in most of the drug-induced causes of nonhypothyroid T4 decrease. Cushing’s syndrome is associated with decreased T4, T3-RIA, TSH, and TBG levels in most patients. The TRH test results usually show a blunted TSH response. The TSH level becomes elevated in some (usually a minority) of patients with the remainder of the conditions listed above (also see the box); TSH values are usually (but not always) less than 3 times the upper limit of the reference range and most frequently are less than twice that limit. Decreased T4 levels with elevated TSH levels in thyroiditis and following radioiodine therapy might be considered true hypothyroidism, even if it is only temporary, especially since some of these patients go on to develop clinical as well as laboratory hypothyroidism. Lithium carbonate therapy might be included in pseudo hypothyroidism since the abnormalities it produces are reversible. On the other hand, in some cases of long-term therapy the laboratory abnormalities persist after medication is stopped. About 8%-10% of patients have decreased T4 levels, and about 15% (range, 2.3%-30%) of patients develop some degree of elevated serum TSH levels. This may develop in less than a month or may take several months. In about 5% of patients the clinical as well as laboratory indices are compatible with true myxedema.

  • 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.