Pitfalls to avoid while interpreting thyroid function tests: five illustrative cases. (Featured CME Topic: Thyroid Dysfunction/Disease).

THYROID DISORDERS occur in 5% to 10% of the population. As a result, laboratory tests of thyroid function are among the more common tests ordered in clinical practice. Treating physicians have at their disposal a large number of tests from which to choose in evaluating patients with suspected thyroid dysfunction (Table 1). In this era of cost consciousness, it is important not only to select tests that will provide the most information regarding thyroid function, but also to interpret the results accurately.

Several important points regarding laboratory assessments of thyroid function are worth mentioning. Test results must be interpreted in conjunction with a clear understanding of the pathophysiology and natural history of the suspected disorders. While clear patterns of test abnormalities are associated with certain disease states, many disorders are not static (eg, postpartum thyroiditis). One must keep in mind that laboratory tests only represent a snapshot of thyroid function at the time that the blood sample was obtained. Thyroid function test abnormalities do not always reflect thyroid dysfunction. A number of drugs and disorders affect thyroid hormone transport, metabolism, and the radioimmunossays used to determine hormone concentrations. In many of these situations, patients are demonstrably euthyroid, despite obvious test abnormalities. Conversely, some test results may be normal in the setting of real thyroid dysfunction (eg, subclinical hyperthyroidism and hypothyroidism). Additional tests are often necessary to ascertain the economy of thyroid function and to determine if normal results reflect any deviation from the patient's true set-point of thyroid function. It is important to recognize that, in most cases, normal ranges of thyroid function tests are established by assessing a reference population and setting the reference range limits at + or -] 2 standard deviations from the mean. Reference ranges vary depending on age, laboratory, and methodology. (1)

A comprehensive review of all aspects of thyroid function tests and their interpretation is beyond the scope of this manuscript. Therefore, we will use exemplary cases referred to us in the endocrinology clinics for evaluation. In each case, errors in interpretation of thyroid function tests were made, and these will serve to initiate relevant discussion.

CASE 1

A 72-year-old Woman presented with chronic fatigue, malaise, and weight loss. Physical examination was said to have been unrevealing. The serum thyroid-stimulating hormone (TSH) concentration was 2.4 [mu]U/mL (normal, 0.32 to 5.0 [mu]U/mL and the free thyroxine ([T.sub.4]) level was 0.7 ng/dL) normal, 0.9 to 1.9 ng/dL). (2) Her symptoms persisted, and she had nausea and vomiting. A repeat evalualion 2 years later revealed a woman appearing chronically ill, with pallor, absence of secondary sexual hair, and delayed relaxation of the deep tendon reflexes. Laboratory studies revealed the following values: serum TSH, 4.5 [mu]U/mL; total [T.sub.4], 4.7 [mu]g/dL (normal, 5 to 11 [mu]/DL); tri-iodothyronine ([T.sub.3]) uptake, 29% (normal, 25% to 35%); and calculated free [T.sub.4] index, 1.4 (normal, 1.5 to 4.0). She was found to have hyponatremia, which prompted the discovery of adrenal dysfunction and led to an ultimate diagnosis of panhypopituitarism due to a 3 cm pituitary adenoma.

DISCUSSION

This case illustrates the typical thyroid function test abnormalities seen in patients with central hypothyroidism, which accounts for approximately 5% of all cases of hypothyroidism. (3) As in this patient, central hypothyroidism may herald significant pituitary disease, and it is often overlooked for several years. Most patients have clinical or biochemical evidence of additional pituitary dysfunction. Some, however, have isolated deficiencies of TSH due to limited pituitary disease, abnormalities of the thyrotropin-releasing hormone (TRH) receptor, or deficiencies in the TSH [beta]-subunit gene. (3)

Thyroid stimulating hormone is a peptide hormone, composed of a distinct [beta]-subunit and a common [beta]-subunit that is secreted by the thyrotroph cells of the anterior pituitary gland. It is secreted in a pulsatile fashion and in a diurnal variation, with most of the mass of TSH secreted during sleep. The regulation of TSH secretion by the pituitary is via several mechanisms, including negative feedback by [T.sub.4] and [T.sub.3]; stimulation by TRH; and inhibition by somatostatin, glucocorticoids, and dopamine. (4) Thyroid stimulating hormone binds to its receptor on the follicular cells of the thyroid gland to stimulate numerous processes essential for the production and release of [T.sub.4] and [T.sub.3]. These cellular processes include follicular cell differentiation and proliferation, iodine uptake and organification, and thyroid peroxidase activity.

Central hypothyroidism may result from any hypothalamic or pituitary disorder that impairs the synthesis and/or secretion of TSH and leads to impaired thyroid hormone synthesis. Hypothalamic diseases lead to impaired secretion of TRH and consequent impaired TSH gene transcription, translation, and impaired posttranslational processing and release of pituitary TSH. Pituitary disorders may reduce the actual number of thyrotroph cells and lead to a decrease mass or quantity of TSH secreted. Evidence suggests that some cases of central hypothyroidism may be attributed to impaired biologic activity of TSH due to defects in glycosylation and alterations in the diurnal variation of TSH secretion. (5-7) In the latter circumstance, TSH levels may be in the normal range, but the lack of a nocturnal rise in TSH results in impaired thyroid hormonogenesis, possibly due to a decrease in the daily mass of TSH secreted by the pituitary gland.

The cardinal laboratory finding in central hypothyroidism is a low or low-normal free [T.sub.4] level or free thyroxine index. Serum TSH levels are inappropriately low, normal, or even slightly elevated. Triiodothyronine levels are often normal or low-normal as 5'-deiodinase activity is increased and [T.sub.4] is more readily converted to [T.sub.3]. Thyroid stimulating hormone responses to TRH injections are usually absent or blunted. Some patients have responses characterized by a delay in the time to a peak TSH level and a prolongation of TSH secretion in response to TRH. (3) We do not advocate routine use of the TRH stimulation test by primary physicians, due to its expense, relatively low yield, and the numerous caveats that must be kept in mind when evaluating the TSH response. Assessment of the nocturnal TSH surge may be a sensitive and reliable test for central hypothyroidism in children and adults. (8)

Several clinical scenarios may mimic the biochemical findings of central hypothyroidism. Hospitalized patients with severe illness may have low [T.sub.4] and [T.sub.3] states and low or suppressed TSH levels. There is considerable controversy over whether to administer [T.sub.4] or [T.sub.3] to these patients. Phenytoin has complex effects on the clearance of [T.sub.4] and [T.sub.3] and on TSH secretion. (9) It is not unusual to find low [T.sub.4] levels and normal TSH levels in treated patients. Patients taking supraphysiologic doses of [T.sub.3], either inappropriately as a supplement or as therapy for chronic fatigue, or as thyroid hormone replacement therapy, often have suppressed TSH levels. The fall in TSH secretion leads to a corresponding fall in endogenous thyroid hormone production and [T.sub.4] levels; [T.sub.3] levels are often elevated. Resolution of longstanding hyperthyroidism after I-131 therapy, antithyroid drug therapy, or the natural history of the underlying disease, is often marked by lo w [T.sub.4] and [T.sub.3] levels, and a low TSH level until the pituitary thyrotrophs recover from chronic suppression.

CASE 2

A 21-year-old woman was referred for evaluation of "hyperthyroidism." She had felt well at the time of a gynecologic examination to renew her oral contraceptive pill prescription. Physical examination was normal. Routine thyroid function tests revealed a serum TSH level of 2.5 [micro]U/mL, a total [T.sub.4] level of 17 [micro]g/dL, and a [T.sub.3] uptake of 20%. A diagnosis of hyperthyroidism was made. She was treated with methimazole. Ten weeks later, she complained of weakness and fatigue, a lump in her neck, and hoarseness. Physical examination revealed diastolic hypertension, a nontender thyroid that was twice normal size, delayed relaxation of the deep tendon reflexes, and periorbital puffiness. Thyroid function tests revealed a serum TSH level of 88 [micro]U/mL, a total [T.sub.4], level of 8.5 [micro]g/dL, and a [T.sub.3] uptake of 15%. Magnetic resonance imaging of the sella, done because of a suspected TSH-secreting pituitary adenoma, was normal. These findings prompted endocrine consultation.

DISCUSSION

This case presentation illustrates the consequences of misinterpretation of thyroid function tests in women taking oral contraceptives. Only a small fraction of [T.sub.4] circulates in the "free" or unbound state. Approximately 99.9% of [T.sub.4] in the circulation is bound to serum proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin, albumin, and lipoproteins. (9, 10) About 99.7% of [T.sub.3] is bound to its carrier protein, transthyretin. Alterations in serum levels of these binding proteins will alter the total levels of the thyroid hormones in serum. As an example, oral estrogen administration affects the glycosylation of TBG and delays its clearance, leading to an increased serum concentration of TBG and, intuitively, an increased number of available sites to bind [T.sub.4]. (11) Since the bound and free fractions of [T.sub.4] are in equilibrium, an increase in the number of [T.sub.4] binding sites will be accompanied by a fall in the free [T.sub.4] level. The normal hypot halamic-pituitary-thyroid axis will respond to the fall in [T.sub.4] levels, and thyroid hormone synthesis will increase. Once TBG levels are stable and the new sites are occupied such that the basal equilibrium between free and bound [T.sub.4] is restored and the free [T.sub.4] remains normal, thyroid hormone synthesis will return to baseline to maintain normal free [T.sub.4] levels. Total [T.sub.4] levels are, however, increased as a consequence of the increased concentration of TBG and the increased number of [T.sub.4] molecules in the serum as a result of the increased number of available binding sites. Factors that result in decreased TBG levels lead to opposite, adaptive responses and lower total [T.sub.4] levels, while free [T.sub.4] levels are maintained in the normal range.

The [T.sub.3] uptake test, or [T.sub.3] resin uptake test, as it is also known, was developed to permit one to identify and account for alterations in TBG. The details of the test are beyond the scope of this manuscript. Suffice it to say that, when the total [T.sub.4] level is determined, the free [T.sub.4] economy can be estimated by calculation of the free [T.sub.3] index. This figure is derived by multiplying the free [T.sub.3] by the [T.sub.3] uptake result, and expressed as a decimal. In the case presented, the basal free [T.sub.3] index is calculated as follows:

17 x 0.2 = 3.4

Normal results vary depending on the laboratory but, in general, results between 1.5 and 4.5 are normal. Thus, this result confirms that the patient presented was euthyroid, as evidenced by her clinical history, examination, and measurement of her serum TSH level. After the initiation of antithyroid drugs, she had clinical manifestations of hypothyroidism, her free thyroxine index fell to 1.28 (a low result reflective of a low T4 state), her TSH level rose appropriately in response to [T.sub.4] and [T.sub.3] deficiency, and she had a goiter as a result of excessive TSH stimulation.

While calculation of the free [T.sub.4] index is a useful exercise, measurement of the free [T.sub.4] level by radioimmunoassay or equilibrium dialysis can eliminate judgment errors in the interpretation of total [T.sub.4] and [T.sub.3] levels. The only drawback of relying on the measurement of free [T.sub.4] is that clinically important causes of alterations of TBG will not be recognized by the assessment of thyroid function (Table 2). Another useful way to interpret total [T.sub.4] and [T.sub.3] uptake results is to evaluate the pattern of results deviations from their respective normal ranges. As a general rule, alterations in TBG levels lead to discordant changes in total [T.sub.4] levels and the [T.sub.3] uptake, while alterations in thyroid function lead to concordant changes in total [T.sub.4] levels and the [T.sub.3] uptake (Table 3).

Familial dysalbuminemic hyperthyroxinemia is a clinically important yet underrecognized autosomal dominant disorder that is characterized by an elevated total [T.sub.4] level, a normal [T.sub.3] uptake, and, thus, an elevated free [T.sub.4] index, in a euthyroid patient with a normal serum TSH concentration. (12) In affected patients, serum concentrations of TBG are normal. They do, however, have circulating albumin that has a high affinity for [T.sub.4], and increases binding in much the same was as an excess TBG level would. The [T.sub.3] uptake result is usually normal, since total [T.sub.3] levels are normal, and the abnormal albumin does not bind [T.sub.3]. A [T.sub.4] uptake test can be performed by a reference laboratory when this disorder is suspected. As expected, the [T.sub.4] uptake is typically low, and the free [T.sub.4] index, calculated as the product of the total [T.sub.4] and the [T.sub.4] uptake, is usually normal.

Euthyroid hyperthyroxinemia, the situation when the total [T.sub.4] level is elevated in the setting of euthyroidism, is relatively common and due to a number of different disorders (Table 4). (13) Treating physicians should be aware of these clinical scenarios to avoid errors in the interpretation of seemingly abnormal thyroid function tests.

CASE 3

A 36-year-old man presented for evaluation of abnormal thyroid functions. He was first diagnosed with Hashimoto's thyroiditis 3 years before consultation, at which time he exhibited symptoms and signs of profound hypothyroidism. Since that time, he had been treated with increasing doses of levothyroxine, due to persistent symptoms of hypothyroidism and elevated TSH levels. His serum TSH level 8 months before consultation was 79 [mu]U/mL (normal, 0.3 to 5.0 [mu]U/mL). Physical examination revealed a man with no apparent thyroid eye disease, a firm thyroid with a palpable pyramidal lobe and isthmus, no cervical adenopathy, delayed deep tendon reflexes, and no tremor. His mental status was normal. Laboratory values were TSH 96.6 [mu]U/mL, free [T.sub.4] >8 ng/dL (normal, 0.60 to 5.00 ng/dL), and total [T.sub.3] 95 ng/dL (normal, 30 to 160 ng/dL).

Based on these clinical and laboratory findings, the free thyroxine level was measured by equilibrium dialysis and found to be low. The patient responded well to therapy with increased thyroxine and supplementation with triiodothyronine.

DISCUSSION

This case illustrates one of the many caveats of serologic thyroid testing in patients with autoimmune thyroiditis. Autoimmune thyroid disease is common in western populations, and represents the most common cause of thyroid dysfunction in the United States. (14,15) Graves' disease and Hashimoto's thyroiditis are 2 forms of autoimmune thyroid disease that have different manifestations. While the autoimmune destruction characteristic of Hashimoto's thyroiditis generally leads to eventual hypothyroidism, hyperthyroidism characterizes Graves' disease. Although the genesis of autoimmunity remains incompletely understood, the advent of serum antibody assays has dramatically improved our ability to diagnose these disorders, and has also offered insight into other laboratory testing abnormalities.

A number of antibody studies are utilized to diagnose and classify autoimmune thyroid diseases and may help predict the long-term course of the disorders. (16,17) Antithyroglobulin antibodies and antithyroperoxidase antibodies have both been utilized to diagnose the presence of autoimmune thyroid disease or the likelihood of progression to autoimmune thyroiditis. (18) Antithyroglobulin antibodies are specifically directed against the thyroglobulin stored in thyroid follicles, which is endocytosed and lysed within the follicular cells of the thyroid to liberate thyroxine. Antithyroperoxidase (antimicrosomal) antibodies, however, likely target the thyroperoxidase enzyme present on the cell membrane of thyroid follicular cells. (19) These antibodies are present in 90% of patients with Hashimoto's disease and two thirds of patients with Graves' disease. Since the antimicrosomal antibodies fix complement and are directly cytotoxic, they may be responsible for the majority of autoimmune destruction in most autoimmu ne thyroid disease.

Thyroid-stimulating immunoglobulin (TSI) is the autoantibody believed to be responsible for Graves' disease. This immunoglobin binds to the TSH receptor of the thyroid follicular cell, and in doing so stimulates the TSH receptor, increases intracellular cyclic adenosine monophosphate (AMP) production, and leads to thyroid glandular hyperactivity. (16) Since the assay for TSI is readily available, detection of this antibody may help differentiate Graves disease from other causes of hyperthyroidism.

Anti-thyroid-hormone antibodies may be present in any patient with autoimmune thyroiditis. In fact, as many as 40% of patients with Hashimoto's disease may have detectable levels of anti-thyroid-hormone antibodies. (20) Although the clinical implications probably vary based upon the affinity of a particular patient's antibodies for [T.sub.4], the existence of these antibodies creates a potential pitfall in thyroid laboratory testing and treatment. (21) As shown by this case, anti-thyroid-hormone antibodies may interfere with measurements and thyroid hormone supplementation. When measured by radioimmunoassay, anti-thyroid-hormone antibodies may generate an artificially elevated free thyroxine measurement, as well as lead to increased rate of metabolic clearance of thyroid hormone itself. Patients often require doses of thyroxine far above the amount predicted for their weight. Free thryroxine, measured by equilibrium dialysis, avoids this laboratory testing inaccuracy. Administration of higher doses of [T.sub .4] and/or [T.sub.3] increases the effective hormone concentrations in the bloodstream and therefore should return the patient to a euthyroid state.

CASE 4

A 24-year-old woman was referred for evaluation of a discrepancy in thyroid function tests. She complained of fatigue, weight gain, heavy frequent menses, and cold intolerance. Physical examination had been remarkable for diastolic hypertension, a goiter, dry skin, and delayed relaxation of the deep tendon reflexes. Laboratory values were serum TSH 150 [micro]U/mL, a free [T.sub.4] of 0.5 ng/mL, and a total [T.sub.3] of 65 ng/dL (normal, 80 to 160 ng/dL). Thyroid antibodies were positive. An 1-123 scan showed a heterogeneous pattern of radiotracer distribution throughout the thyroid, and the 6-hour uptake was elevated at 58% (normal, 10% to 25%), which was thought to be consistent with Graves' disease. Based on the scan findings, the treating physician suspected a diagnosis of TSH-mediated hyperthyroidism.

DISCUSSION

This case illustrates the confusion that can result when thyroid function tests and thyroid scans are not interpreted in conjunction with one another. Clearly, based on the levels of TSH, free [T.sub.4], and total [T.sub.3], and the thyroid antibody test results, this patient has hypothyroidism due to autoimmune thyroid disease.

Hyperthyroid states caused by TSH (eg, TSH-secreting pituitary adenomas and central or pituitary thyroid-hormone resistance) are associated with clinical findings of hyperthyroidism and elevated [T.sub.4] and [T.sub.3] levels. (22) Levels of TSH are either inappropriately normal or elevated in these disorders, since hypersecretion of TSH is the result of abnormalities in thyrotroph function. In the patient presented, TSH levels are elevated due to thyrotroph secretion of TSH in response to thyroid failure, as evidenced by low [T.sub.4] and [T.sub.3] levels.

Provided that the thyroid mechanisms of uptake of iodide and other similarly sized molecules (eg, pertechnetate) are conserved in a disease state, any cause of hypersecretion of TSH will be associated with increased uptake of radiotracer during a thyroid scan. (23,24) In this patient, despite the autoimmune thyroid disease, iodide uptake and trapping were obviously preserved. These events are regulated by TSH and other stimulators of thyroid function (thyroid stimulating immunoglobulins in Graves' disease and human chorionic gonadotropin in pregnancy and choriocarcinoma). (25) It stands to reason that increases in these thyroid stimulators will lead to increases in radioiodine (or pertechnetate) uptake when the mechanisms of iodide incorporation have been preserved. Disorders characterized by areas of thyroid autonomy and excessive secretion of [T.sub.4] and [T.sub.3] (eg, toxic multinodular goiter, toxic adenoma), where iodide uptake is increased independent of TSH, which is usually suppressed, may also be associated with elevated radioiodine uptake. Subacute, postpartum, and chronic lymphocytic thyroiditis are associated with sufficient thyroidal inflammation and destruction and, when these patients are hyperthyroid, low TSH levels. (26) As a result, these disorders are typically associated with low radioiodine uptake.

CASE 5

A 56-year-old man was evaluated in the surgical intensive care unit for abnormal thyroid function tests. He was admitted 3 weeks previously for an elective 3-vessel coronary artery bypass grafting, but developed severe postoperative pneumonia for which he required intravenous antibiotic therapy and reintubation a week after the surgery. After extubation, the patient remained extremely somnolent 2 days after all sedatives were withdrawn. As part of an altered mental status evaluation, thyroid function tests were ordered. The serum TSH level was 0.7 [micro]U/mL, free [T.sub.4] level was 0.5 ng/mL, and total [T.sub.3] level was 60 ng/dL. Endocrine consultation was sought to evaluate the possibility of central hypothyroidism. Physical examination revealed a middle-aged man who was arousable but somnolent. His thyroid was normal in consistency and size, and there were no palpable nodules. He could not cooperate with visual-field testing, but his skin was normal in texture and his reflexes were normal in amplitude and rate. The remainder of his physical examination was remarkable only for wounds consistent with his surgical procedure.

A decision was made to withhold treatment with levothyroxine, since the thyroid function test abnormalities were thought to be due to nonthyroidal illness (NTI). His mental status improved over the next 4 days, and he was subsequently discharged from the intensive care unit. Thyroid function tests at the conclusion of his hospitalization demonstrated a TSH level of 7.1 [micro]U/mL and a free [T.sub.4] level of 1.5 ng/mL. Six weeks later, the laboratory values were normal in the outpatient setting.

DISCUSSION

This case illustrates a classic example of the NTI syndrome. This syndrome may constitute an adaptive response of the neuroendocrine system to illness or trauma and is seen in as many as 70% of hospitalized patients. It has been described in patients with myocardial infarction, (26) surgery, (27) bone marrow transplantation, (28) and starvation. (29) There are 2 major subtypes of NTI: a low [T.sub.3] state and a low [T.sub.4] state. Although they are described separately, they are likely a continuum of the same pathophysiologic or adaptive process but correspond to differing severities of NTI.

The low [T.sub.3] state is the most common type of NTI seen in clinical practice, and is accompanied by a high reverse [T.sub.3] level. It may occur in virtually any illness, and the thyroid hormonal abnormalities may be striking. Serum total [T.sub.3] concentrations may drop to as low as 60% of the normal value, while free [T.sub.4] concentrations may fall to 40% of baseline. (30) These changes are believed to be due to inhibition of the type 1 iodothyronine deiodinase that converts [T.sub.4] to [T.sub.3]. As a result, [T.sub.3] levels fall and [T.sub.4] levels may remain normal. Because the same enzyme also deiodinates reverse [T.sub.3], reverse [T.sub.3] levels rise. (30) As illness severity increases, reverse [T.sub.3] levels remain stably elevated, while serum concentrations of [T.sub.3] progressively decline. The low [T.sub.3] state itself is not believed to be associated with any particular increased mortality, except in patients with end-stage human immunodeficiency virus disease.

The low [T.sub.4] state, almost always in association with a low level of [T.sub.3], represents the other major form of NTI. Down-regulation of TSH secretion by the anterior pituitary and/or a decrease in the sensitivity of the thyrotrophs to TRH may account for these changes. (31) Reverse [T.sub.3] levels remain normal or elevated in this disorder, and [T.sub.3] and [T.sub.4] levels may decline even further. Detectable levels of TSH usually distinguish those with NIL from those with true hyperthyroidism, whose TSH levels are usually suppressed. (32) In addition to corresponding with worsening illness, low [T.sub.4] and [T.sub.3] levels correlate with increased mortality. (33)

Recovery from NTI has been well documented. Levels of [T.sub.4] tend to normalize over a period of approximately 4 days, although some patients may recover more slowly. During the recovery phase, TSH concentrations may rise between twofold and 13-fold. Since the rise in TSH level typically occurs before elevations in [T.sub.4] level, recovery from NIL is likely TSH-mediated. (34) This patient was clearly in the recovery phase of NTI at the conclusion of his hospitalization.

Treatment of low [T.sub.4] and [T.sub.3] levels during NIL does not appear to be necessary, but controversy over replacement therapy does exist among experts. Administration of [T.sub.4] to severely ill patients further decreases TSH values, and yet neither increases [T.sub.3] levels nor decreases mortality. (35) Administration of [T.sub.3] to critically ill burn victims also did not affect mortality. (36-38) Close monitoring while treating the underlying disorders and reevaluation of thyroid functions 6 weeks after hospital discharge is recommended, since this approach usually permits one to differentiate those with NTI from those who have thyroid disease.

TABLE 1

Common Laboratory Tests of Thyroid Function


Thyroid stimulating hormone
Total thyroxine
Free [T.sub.4]
Free [T.sub.4] by equilibrium dialysis
Total triiodothyronine
Free [T.sub.3]
[T.sub.3] Uptake
Reverse [T.sub.3]
Thyroxine-binding globulin
Thyroglobulin
Thyroid-stimulating immunoglobulins
Antithyroglobulin antibodies
Antithyroid peroxidase antibodies
TABLE 2

Factors and Conditions That Alter Thyroxine Binding Globulin (TBG)
Levels

Increase TBG Level             Decrease TBG Level

Congenital                     Congenital
Pregnancy                      Androgens
Oral estrogens                 Nephrotic syndrome
Estrogen-secreting tumors      Cirrhosis
Acute hepatitis                L-asparaginase
Primary biliary cirrhosis      Glucocorticoids
Narcotics (heroin, methadone,
hydrocodone)
Clofibrate
5-fluorouracil
Acute intermittent porphyria
TABLE 3.

Evaluation of Thyroid Function Using the Total [T.sub.4] Level and the
[T.sub.3] Uptake

Disorder                                Total       [T.sub.3]
                                      [T.sub.4]       Uptake

Hypothyroidism                       [down arrow]  [down arrow]
Hyperthyroidism                       [up arrow]    [up arrow]
Thyroid-binding globulin excess       [up arrow]   [down arrow]
Thyroid-binding globulin deficiency  [down arrow]   [up arrow]

Disorder                                 Free          TSH
                                      [T.sub.4]

Hypothyroidism                       [down arrow]   [up arrow]
Hyperthyroidism                       [up arrow]   [down arrow]
Thyroid-binding globulin excess           N             N
Thyroid-binding globulin deficiency       N             N

Arrows indicate deviation from normal.

N = Normal.
TABLE 4.

Causes of Euthyroid Hyperthyroxinemia.


Increased thyroid-binding globulin
Familial dysalbuminemic hyperthyroxinemia
Peripheral resistance to thyroid hormone
Acute psychiatric illness
Amiodarone
Ipodate
Propranolol

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From the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

Reprint requests to Michael J. Fowler, MD, Vanderbilt University Medical Center, 715 PRB, Nashville, TN 37232-6303.