Articles on Medical Diseases and Conditions

Category: Thyroid Function Tests

  • Neonatal Hypothyroid Screening

    Congenital hypothyroidism occurs in approximately 1 in 6,000 infants (literature range, 1-3/10,000), which makes it about 3 times as common as phenylketonuria (PKU). Approximately 85% of cases are due to thyroid agenesis and 10% are defects of enzymes in thyroid hormone synthesis, so that about 95% of all cases are primary hypothyroidism and 3%-5% are secondary to pituitary or hypothalamic malfunction. Screening tests that have received the most attention include T4, TSH, and reverse T3.

    There is minimal T4 and T3 placental transfer from mother to fetus in utero. At birth, cord blood T4 values range from the upper half of normal to mildly elevated, compared with nonpregnant adult reference values (e.g., cord blood average levels of 11-12 µg/100 ml [142-154 nmol/L] compared with nonpregnant adult average values of about 9 µg/100 ml [116 nmol/L]). The T3-RIA level is about one third to one half of adult levels, the reverse T3level is about 5 times the adult levels, and the TSH has a mean value about twice that of adults but ranges from near zero to nearly 3 times adult upper limits. There is a strong correlation between birth weight and neonatal T4 and TSH values. At birth, premature infants have T4 values averaging one third lower than those of normal birth weight infants (although individual measurements are variable), with the subsequent changes in T4levels between premature and full-term infants remaining roughly parallel for several days. The TSH value at birth is also about one third lower in premature than in full-term infants but becomes fairly close to full-term infant levels at 24 hours of age.

    After birth, the TSH value surge about 5-7 times birth values to a peak at 30 minutes, then falls swiftly to levels about double birth values at 24 hours. The fall continues much more slowly to values about equal to those at birth by 48 hours and values about one half of birth levels at 4-5 days. After birth, the T4 level increases about 30%-40%, with a plateau at 24-48 hours, and returns to birth levels by about 5 days. The TBG value does not change appreciably.

    There is some disagreement in the literature regarding the best specimen to use for neonatal screening (heel puncture blood spot on filter paper vs. cord blood) and the best test to use (T4 vs. TSH assay). Most screening programs use filter paper methods because cord blood is more difficult to obtain and transport. Most programs use T4 assay as the primary screening test because T4 assay in general is less expensive than TSH assay, because TSH is more likely to become falsely negative when the specimen is subjected to adverse conditions during storage and transport, and because TSH assay values will not be elevated in the 10% of cases that are due to pituitary or hypothalamic dysfunction. Disadvantages of T4 assay include occasional mildly hypothyroid infants with T4 levels in the lower portion of the reference range but with clearly elevated TSH values. In one series this pattern occurred in 2 of 15 hypothyroid infants (13%). Some institutions therefore retest all infants whose T4 values fall in the lower 10% of the reference range. Another problem concerns approximately 20% of neonatal T4 results in the hypothyroid range that prove to be false positive (not hypothyroid), most of which are due to prematurity or decreased TBG.

    In conclusion, the box lists conditions that can produce various T4 (TI or FT4) and TSH patterns.

    Interpretation of T4 and TSH Patterns*

    T4 Low, TSH Low
    Lab error (T4 or TSH)
    Some patients with severe non thyroid illness (esp. acute trauma, dopamine, or glucocorticoid drugs)†
    Pituitary insufficiency
    Cushing’s syndrome (and some patients on high-dose glucocorticoid therapy)
    T3 toxicosis plus dilantin therapy or severe TBG deficiency
    T4 Low, TSH Normal
    Lab error (T4 or TSH)
    Severe nonthyroid illness*
    Severe TBG or albumin deficiency
    Dilantin, valproic acid (Depakene) or high-dose salicylate therapy)
    Moderate iodine deficiency
    Furosemide combined with decreased albumin or TBG
    Few patients with secondary hypothyroidism (mild TSH decrease in patient with previous TSH in upper-normal range)
    Pregnancy in third trimester (many, not all, FT4 kits)
    Some female distance runners in training
    Some patients with mild hypothyroidism plus prolonged fasting or severe non thyroid illness
    Heparin effect (some FT4 kits)
    T4 Low, TSH Elevated
    Lab error (T4 or TSH)
    Primary hypothyroidism
    Some patients with severe non thyroid illness in recovery phase†
    Large doses of inorganic iodide (e.g., SSKI)
    Some patients on lithium or amiodarone therapy
    Some patients on Synthroid therapy with slightly insufficient dose or patient noncompliance
    Some patients on dilantin or high-dose salicylate therapy or with severe TBG deficiency plus some non-hypothyroid cause for elevated TSH
    “T4 low-TSH normal” conditions plus presence of antibodies interfering with TSH assay§
    Severe iodine deficiency
    Some patients (30%) with Addison’s
    Disease interleukin-2 therapy (15%-26% of cases)
    Alpha-interferon therapy (1.2% of cases)
    T4 Normal, TSH Low
    Lab error (T4 or TSH)
    T3 toxicosis
    Mild hyperthyroidism plus decreased TBG, Dilantin therapy, and/or severe non thyroid illness
    Early hyperthyroidism (TSH mildly decreased, T4 upper normal [Free T3 may be elevated])
    Pituitary insufficiency plus increased TBG
    Some patients with Synthroid therapy in slightly excess dose
    Few patients with severe non thyroid illness†
    Some patients 4-6 weeks (2 weeks-2 yrs) after RAI, surgery, or antithyroid drug therapy for hyperthyroidism
    Some patients with multinodular goiter containing areas of autonomy
    “T4 low-TSH low” plus heparin therapy
    T4 Normal, TSH Normal
    Normal thyroid function
    Lab error (T4 or TSH)
    Few patients with early hypothyroidism (only the TRH test abnormal)
    “T4 low-TSH normal” plus heparin therapy†
    T4 Normal, TSH Elevated
    Lab error (T4 or TSH)
    Mild hypothyroidism
    Hypothyroidism plus increased TBG
    Hypothyroidism with slightly inadequate dose of replacement therapy
    Addison’s disease (majority of cases)
    TSH specimen drawn in the evening (peak of diurnal variation)
    Few patients with iodine deficiency (T4 is usually decreased)
    Few patients with severe non thyroid illness in recovery phase†
    Some patients with mild Hashimoto’s disease
    Insufficient time after start of therapy for hypothyroidism; usually need 3-6 weeks (range, 1-8 weeks, sometimes longer when pre-therapy TSH is over 100)
    “T4 normal-TSH normal” status plus antibodies interfering with TSH assay§
    Some patient on lithium therapy (T4 usually but not always decreased)
    Few patients with acute psychiatric illness
    Hypothyroidism with familial dysalbuminemic hyperthyroxinemia
    “T4 low-TSH elevated” plus heparin therapy†
    T4 Elevated, TSH Low
    Lab error (T4 or TSH)
    Primary hyperthyroidism
    Excess therapy of hypothyroidism
    Some patients with active thyroiditis (subacute, painless, early active Hashimoto’s disease)
    Jod-Basedow hyperthyroidism
    TSH drawn 2-4 hours after Synthroid dose (few patients)
    Postpartum transient toxicosis
    Factitious hyperthyroidism
    Struma ovarii
    Hyperemesis gravidarum
    Alpha-interferon therapy (1.2% of cases)
    Interleukin-2 therapy (3%-6% of cases)
    T4 Elevated, TSH Normal
    Lab error (T4 or TSH)
    TBG increased
    Some patients with Synthroid therapy in adequate dose
    Occasional patient with severe nonthyroid illness†
    Some acute psychiatric patients (esp. paranoid schizophrenics)
    T4 sample drawn 2-4 hours after T4 dose
    Peripheral resistance to T4 syndrome (some patients)
    Some patients with pituitary TSH-secreting tumor (when pretumor TSH was low normal)
    Some patients on amiodarone therapy
    Occasional patients on propranolol therapy
    Certain x-ray contrast media‡
    Acute porphyria
    Heroin abuse or acute hepatitis B (causing increased TBG)
    Heparin effect (some FT4 kits)
    Familial dysalbuminemic hyperthyroxinemia (analog FT4 methods)
    Amphetamine or PCP abuse (some patients)
    Desipramine drugs (some patients)
    T4 Elevated, TSH Elevated
    Lab error (T4 or TSH)
    Pituitary TSH-secreting tumor
    Some patients with certain x-ray contrast media‡
    Peripheral resistance to T4 syndrome (some patients)
    Some patients on amiodarone therapy or amphetamines
    “TSH elevated-T4 normal” status plus some independent reason for T4 to become elevated
    Few patients with acute psychiatric illness
    ________________________________________________________________
    *High-sensitivity TSH method is assumed; FT4 or TI can be substituted for T4, but in general are not altered as frequently as T4 in nonthyroid conditions.
    †Depends on individual TSH and/or FT4 kit.
    ‡Telepaque (iopanoic acid) and Oragrafin (ipodate).
    §Some (not all) sandwich-method double-antibody kits, using mouse-derived monoclonal antibody.

  • 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.