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Clinical and Laboratory Assessment of Thyroid Abnormalities
Symposium on Thyroid Disease
Clinical and Clinical and Laboratory laboratory Assessment Assessment of of Thyroid Thyroid Abnormalities Abnormalities Michael M. Kaplan, M.D.*
Severe hyperthyroidism and hypothyroidism often present with such characteristic clinical manifestations that their presence is virtually unmistakable. At other times, for both conditions, the features of mild to moderate disease can be quite subtle and nonspecific. Conversely, most patients who have mild complaints suggestive of hyper- or hypothyroidism prove to have their symptoms on another basis. Also, palpable thyroid abnormalities often have several possible etiologies, even after the initial clinical assessment. This review will detail methods currently available for the diagnosis of thyroid abnormalities, with attention to their optimal uses, their limitations, and the clinical implications of variations in methods. The goal is to provide an aid in establishing accurate diagnoses, while avoiding unnecessary procedures.
CLINICAL EVALUATION The medical history should have special emphasis on the manifestations of thyroid hormone excess or deficiency, as summarized elsewhere in this volume. The patient should also be asked about local symptoms in the neck. Pain of thyroid origin can radiate upward to the ear, and the radiated pain can occasionally be more severe than pain in the lower anterior neck. Pain in the thyroid gland can be caused by hemorrhage into a thyroid cyst or tumor, or subacute thyroiditis, in which the patient may have exquisite tenderness over the gland, to the slightest touch. Other local symptoms rego iter or isolated mass, sult from mass effects: increasing neck size, a visible goiter hoarseness, dysphagia, and upper airway obstruction. The latter symptoms, when due to enlargement of all or part of the thyroid gland, require a con-
*Associate Professor of Medicine, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Massachusetts
America-Vo!' 69, No. 5, September 1985 Medical Clinics of North America-Vol.
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MICHAEL M. M. KAPLAN
siderable degree of enlargement, and are virtually always accompanied by a palpable goiter or by chest roentgenographic evidence of a substernal goiter. Several physical findings are of particular usefulness in the setting of possible thyroid disease. Skillful palpation of the thyroid gland takes practice, but cannot be replaced by multiple imaging procedures. Because the thyroid is fixed to the trachea, it moves up and down during deglutition. Its edges, therefore, are usually easiest to define when the patient swallows small sips of water (repeated swallowing without liquid is quite difficult for most people). Occasionally the thyroid gland is easier to see than to feel, if the patient swallows water with the neck slightly extended and with a light source coming from the side to accentuate shadows. According to the examiner's preference and training, palpation can be carried out from the front or from behind. The normal thyroid gland is usually palpable, but is easier felt in women than in men. It is often asymmetric, and when this is so, the right lobe is almost invariably the larger one. When a diffuse process, such as Hashimoto's thyroiditis or Graves' disease, affects the gland, the underlying asymmetry persists, but may be more readily detected since the whole gland becomes easier to feel. For an initial anatomic orientation, it is useful to remember that the isthmus of the thyroid gland is about 1 cm below the cricoid cartilage. Tracheal deviation can be a clue to the presence of a substernal goiter. I find it most useful to record the size of the thyroid gland according to the vertical dimensions of each lobe, also estimating the width and thickness if the shape of the lobe seems abnormal. Abnormalities of the isthmus and the presence of a pyramidal lobe should also be noted. The consistency of the thyroid gland (soft, firm, or hard), the surface texture (smooth, irregular, lobulated, or nodular), and the presence of tenderness should be recorded. The presence of any discrete nodules should, of course, be noted along with their size, consistency, and mobility. In hyperthyroidism, the blood flow to the thyroid gland may be greatly increased, and there may be a palpable thrill, a systolic or to-and-fro bruit, or a ve. nous hum. The value of thyroid palpation cannot be overstated. It is risk-free and costs nothing. When performed properly, palpation can disclose nodules that do not appear on scintiscans because of small size, peripheral or posterior location, or tracer uptake equal to that of surrounding tissue. In a hyperthyroid patient, the palpatory finding of diffuse thyroid enlargement often makes scintiscanning unnecessary. Conversely, it is by palpation that nodules in need of further work-up are usually discovered. I cannot reliably distinguish solid from cystic thyroid nodules by palpation, but a very hard nodule or the concomitant presence of cervical lymphadenopathy should increase one's concern about a malignant lesion. Another area of particular significance is the eye examination. There can be soft, periorbital swelling in hypothyroidism and firm, rubbery, periorbital swelling in Graves' disease. The function of the extraocular muscles should be assessed carefully in suspected or definite Graves' disease, along with the extent of protrusion of the globe beyond the orbital notch. The latter measurement can be made with reasonable accuracy and reproduc-
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ibility with the inexpensive Luedde exophthalmometer, though the Hertel exophthalmometer is more precise. Exophthalmometer readings are expressed in millimeters, and normal ranges differ among caucasian, black, and asiatic racial groups. The timing of the Achilles tendon reflex is useful, being less subject to effects of gravity and muscle strength than other deep tendon reflexes. In states of thyroid hormone excess or deficiency, the relaxation phase changes more than the contraction phase, but both phases tend to be abnormally brisk in thyrotoxicosis and prolonged ("hung up") in hypothyroidism. If this reflex cannot be elicited when the patient is sitting, it can often be brought out by having the patient kneel on a chair and put his weight on the chair back, with the ankles separated by a few inches. When the Achilles tendon is struck, the backward and forward movement of the foot is observed. The Achilles reflex is absent even with this maneuver in a number of older patients and in some with any of several medical illnesses, notably diabetes mellitus.
QUANTITATIVE ASSESSMENT OF THYROID HORMONE EFFECTS ON TARGET ORGANS Although thyroid hormone excess and deficiency cause alterations in quantifiable functions of numerous organs, the measurements needed for such assessment are cumbersome, nonspecific, or both-with the exception of evaluation of the pituitary-thyroid axis. Only in a research setting, where the precise tinling timing or magnitude of target organ responses is important, or in the rare case in which resistance to thyroid hormone is under consideration, are such measurements helpful. The most time-honored test of target organ response is the basal metabolic rate (BMR)-that is, the oxygen consumption rate in a standard, resting, fasting state. 33 Unless a laboratory performs this test routinely, and with meticulous attention to technique and possible confounding factors, the result can show considerable variation from day to day, and considerable overlap between normals and patients with thyroid disease. Quantitative timing of the Achilles reflex, so-called kinemometry, also suffers from a great deal of overlap between normals and patients with abnormal thyroid function. 33, 8 In hyperthyroidism, the hypercontractile state of the heart can be documented by noninvasive tests, such as systolic time intervals, 88 but the variation between a particular patient's results in the hyperthyroid and euthyroid states may be of the same order of magnitude as the day-to-day variation in results expected for any individual. Some of the many serum and urinary measurements which can be abnormal in thyrotoxicosis or hypothyroidism and which usually return to normal upon restoration of the euthyroid state, are listed in Table 1. None are specific and none can supplant the measurement of serum thyroid hormones and thyroid-stimulating hormone (TSH).
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\!rCHAEL \1. \\. KAPLAN KAPL.-\:\f \IICHAEL
Table 1.
Diagnostic Tests That May Be Abnormal Due to Thyrotoxicosis or Hypothyroidism
THYROTOXICOSIS
a. Serum or Plasma t alkaline phosphatase t calcium !~ parathyroid hormone !t 1.25-dihydroxyvitamin D t angiotensin-converting enzyme t coagulation factor VIII t gastrin t free fatty acids t glutamic-oxaloacetic transaminase b. Urine t calcium t creatine t hydroxyproline
HYPOTHYROIDISM
a. Serum, Plasma, or Whole Blood t cholesterol t low-density lipoproteins tt creatine phosphokinase (skeletal muscle isozyme) t lactic dehydrogenase t glutamic-oxaloacetic transaminase t myoglobin ! sodium t norepinephrine t carcinoembryonic antigen !~ coagulation factor VIII !~ hemoglobin and hematocrit t erythrocyte mean corpuscular volume t erythrocyte sedimentation rate b. Urine tt norepinephrine c. Cerebrospinal Fluid t protein
t
SERUM HORMONE MEASUREMENTS SERUM THYROXINE
Serum thyroxine (T4) is the major secretory product of the thyrOid thyroid gland and the major form of thyroid hormone in the circulation. Moreover, the thyroid gland is the sole endogenous source of T4. Serum T4 is measured by radioimmunoassay, or variants such as competitive protein binding or enzyme-linked immunoassay. Older methods based on iodine measurements, like the protein-bound iodine (PBI), butanol extractable iodine (BEl), and "T4 by column," are outmoded, being subject to cross-reaction by numerous iodine-containing substances. The T4 radioimmunoassay is remarkably free from artifactual results. 17
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flg per dl (60 to 140 The normal serum T4 range is approximately 4.7 to 11 f.Lg nanomoles per L). Falsely high or falsely low results can be found in the rare situation of an endogenous anti-T4 antibody, usually seen in the setting of Hashimoto's thyroiditis. The nonsteroidal drug, fenclofenac, not available in the United States at the time of this writing, competes strongly for T4 binding sites on thyroxine-binding globulin (TBG), and gives a falsely high serum T4 value in competitive protein-binding assays but not in radioimmunoassays. Binding of T T44 to Serum Proteins
T4 circulates in plasma strongly bound to plasma proteins, principally TBG, an alpha globulin. Smaller amounts are bound to prealbumin and albumin. Because the unbound, or free, T4 concentration appears to determine the tissue levels of T4, it is advisable to obtain an assessment of T4 binding to serum proteins together with the total serum T4 concentration if thyroid hormone excess or deficiency is being seriously considered. The two direct methods for assessing serum protein binding are equilibrium dialysis and ultrafiltration, both technically demanding and costly. Therefore, 17 Most are based on indirect measurements are more commonly employed. 17 the principle of competition for tracer triiodothyronine (T3) or T4 between serum-binding proteins and an added adsorbant, such as charcoal, ion exchange resins, talc, or immobilized antibodies. T3 is most' commonly used as the tracer, but even then, it is the binding of T4 as well as T3 that is being assessed; the T3 uptake test has nothing to do with the serum T3 concentration. The per cent of tracer bound to the adsorbant varies directly with the per cent free T4 in the serum. It is therefore a protein-binding index which, when multiplied by the total serum T4 concentration, yields an index of the serum free T4 concentration (free T4 index). An algebraic manipulation of the T3 or T4 uptake value has been recommended to de13, 29 rive a free T4 index more linearly related to the free T4 concentration. 4, 13,29 Another technique for estimating the free T4 concentration is to measure the serum TBG concentration and calculate the ratio of the T4 to the TBG concentration. This ratio is proportional to the free T4 concentration except in conditions of marked TBG deficiency. Yet another methodologic variant is the "unbound analog" method, using a labeled T4 analog that binds to a T4 antibody but not to the usual serum-binding proteins. These indirect methods of assessing serum protein binding are adequate in most clinical situations, but most of them show discrepancies with free T4 measurements by dialysis in unusual situations of abnormal binding 27 and in the fairly common situation of T4 to serum albumin or prealbumin 27 nonthyroidal of altered thyroid function due to severe non thyroidal illness. 20, 20, 25 25 None of these indirect methods is clearly superior or inferior to any of the others, but their limitations vary, and the clinician must learn the properties of the one used by the local laboratory. In addition, some manufacturers of kits for these indirect methods call them "direct free T4" measurements, even though they are not direct. This issue of terminology does not alter the usefulness of these tests, but the clinician should be aware of precisely what type of result is being reported in order to interpret it accurately.
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M. KAPLAN MICHAEL M. SERUM TRIIODOTHYRONINE
Serum triiodothyronine (T3) circulates in the blood in approximately the molar concentration of T4. The normal range for serum T3 is about 70 to 220 ng per dl (1.1 to 3.0 nanomoles per L). Like T4, it is tightly hound bound to serum-binding proteins, but unlike T4, 75 to 80 per cent of the circulating T3 is made from T4 outside of the thyroid gland, by a process termed "5' -deiodination." The total serum T3 concentration can be readily measured by radioimmunoassay,17 and the only artifact of note in this assay is, again, the presence of endogenous anti-T3 antibodies in rare patients with autoimmune thyroid disease. Since T3 is strongly bound to the same serum proteins that bind T4, a "free T3 index," or estimate of the free T3 concentration, can" can be calculated using the total serum T3 concentration and the same estimate of protein binding used for T4. The free T3 index is so well correlated with direct measurement of free T3 by equilibrium dialysis that the latter, available commercially at considerable expense, is superfluous. The serum T3 concentration is elevated in hyperthyroidism, usually to 19 Rarely, the serum T3 can be elevated a greater degree than the serum T4. 19 when the T4 and free T4 are clearly normal. This condition, termed "T3toxicosis," often represents mild or early hyperthyroidism and can occur with any cause of hyperthyroidism, or in the course of drug treatment of hyperthyroidism. In hypothyroidism, by contrast, the serum T3 often remains within the normal range, though usually in the lower half, until the disease becomes severe. In several conditions-namely, fasting, IPalnutritpalnutrition, fetal life, drug therapy, and severe nonthyroidal illness of any typedecreased T4 5'-deiodination causes the serum total and free T3 concentrations to fall to low-normal or subnormal levels in the absence of thyroid disease. A serum T3 measurement is helpful "in in these situations: (1) to clarify the meaning of a top-normal or equivocally high serum free T4, (2) when a patient has symptoms suggestive of hyperthyroidism even if the estimated serum free T4 is normal, (3) when overlooking the diagnosis of hyperthyroidism, even if it is unlikely, is highly undesirable, as in an older patient with unexplained atrial fibrillation, and (4) in monitoring the course of therapy of hyperthyroidism. '140 Y40
SERUM REVERSE T3 T3
Serum reverse T3 (rT3) is a hormonally inactive T3 isomer, also largely produced from T4 outside of the thyroid gland. It can be measured by radio17 Serum rT3 concentrations are usually elevated in hyperthyimmunoassay. 17 roidism and often low in hypothyroidism, though there is considerable overlap between the hypothyroid and normal ranges. Serum rT3 is usually non thyroidal diseases, and its measupranormal in euthyroid patients with nonthyroidal surement has been suggested as a possibly useful discriminant between euthyroid patients who have low estimated free T4 levels due to nonthyroidal illness only, and patients who are truly hypothyroid. 77 However,
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other studies have found overlap between these two groups of patients, hence a serum TSH measurement is probably a more reliable discriminant in this situation. 12, 12. 18 18 SERUM THYROID-STIMULATING HORMONE
Serum thyroid-stimulating hormone (Thyrotropin, TSH) is secreted by the thyrotropic cells of the anterior pituitary gland. Its secretion is regulated by a classic negative feedback 100p.22 loop.22 Serum free T4 and free T3 are inversely correlated with TSH secretion and serum TSH concentrations. Within the thyrotropic cells, serum T4 is converted to T3, and it is the intracellular T3 concentration that actually regulates TSH synthesis and re-deiodination within pituitary thyrolease. Because of this active T4 5' 5'-deiodination tropes, intrapituitary T3 concentrations are governed both by plasma free T4 and free T3. 22 ., 23 23 Another crucial regulator of TSH secretion is thyrotropin-releasing hormone (TRH), the tripeptide made in the brain and released from the hypothalamus into the pituitary portal blood,16 blood. 16 TRH stimulates TSH release, but the effect of TRH can be inhibited by even mild thyroid hormone excess and potentiated by even minimal thyroid hormone deficiency. TRH given exogenously, in pharmacologic doses, also stimulates prolactin release into the circulation, but TRH is probably not an important physiologic regulator of prolactin secretion. Somatostatin, dopamine, and glucocorticoids all inhibit TSH secretion and the TSH response to exogenous TRH. The serum TSH concentration is routinely measured by radioimmuVnits noassay. Concentrations are expressed in bioassayable International Units (V) (U) compared to a reference standard. In most assays, the upper limit of j.LV per m!' ml. Some assays normal for the serum TSH concentration is 5 to 6 f.1U j.L V per ml, m!, probably due to nonspecific reacgive normal ranges up to 10 f.1U tion of some serum components in the assay. The clinician needs to know not only the normal range for the local TSH assay but also the reproducibility of the assay within the normal range, in order to be able to interpret a TRH stimulation test accurately. Except with the most highly sensitive TSH assays, capable of measuring 0.5 f.1U j.LV of TSH per ml with precision, many normal individuals will have basal serum TSH concentrations below the sensitivity limit of the assay. The serum TSH concentration rises when thyroid gland function becomes impaired or when iodine is in insufficient supply. This helps to 23 maintain normal serum T4 and T3 concentrations for as long as possible. 23 Thus, an elevated serum TSH almost always means an abnormal thyroid gland, and usually means hypothyroidism as well. This measurement can therefore be used to help decide if a borderline-low estimated free T4 repT4 is unequivocally low, a resents primary hypothyroidism. When the free 1'4 serum TSH is also very useful in distinguishing between primary thyroid damage, in which the TSH will be elevated, and hypopituitarism, in which the TSH will not rise. In hyperthyroidism, serum TSH measurements are not usually indicated, because almost all TS H assays fail to distinguish the TSH
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low values in hyperthyroidism from normal values, and because hyperthyroidism due to TSH hypersecretion is exceedingly rare. 99 THYROTROPIN-RELEASING STIMULATION TEST THYROTROPIN -RELEASING HORMONE HORMONE STIMULATION TEST (TRHTEST) (TRHTEST)
Administration of synthetic TRH, known generically as protirelin and available for clinical use, can be used to magnify abnormalities in the dynamics ofTSH of TSH secretion. 14, 16 TRH is injected intravenously in a dose of 400 to 500 f.1g, /-Lg, and serum TSH is measured just before and 30 minutes after the injection. If pituitary or hypothalamic disease is suspected, 60- and 120minute samples may be useful as well. Patients should be warned that they may experience a feeling of facial flushing, an urge to urinate, or nausea for up to 5 minutes after the injection, but that these sensations are harmless, self-limited, and not indicative of any problem or abnormality. Normally /-LU per ml30 minutes after the TRII TRH injection, the serum TSH rises 5 to 25 f.1U except in normal men over age 40, in whom the rise may be smaller, but /-LU per ml. In hypothyroidism due to thyroid gland usually still at least 3 f.1U damage, the TSH rise becomes exaggerated, whereas in hypothyroidism due to pituitary or hypothalamic disease the TSH rise may be absent, blunted, delayed, or prolonged. In hyperthyroidism, the TSH rise is abolished. Given the normal range ofTSH rise, it can be seen why the accuracy of the TSH assay within the normal range, mentioned above, is important in the interpretation of the TRH test. The most common situations in which the TRH test is useful are (1) suspected hyperthyroidism when the estimated free T4 and the T3 are only equivocally high, (2) when the estimated free T4 is borderline-low and the serum TSH is not clearly elevated, and (3) known or suspected hypopituitarism, in which case it is often helpful to assess both the prolactin and 30 TRH.30 TSH response to TRH. SERUM SERUM THYROGLOBULIN THYROGLOBULIN
Thyroglobulin, the colloid protein of the thyroid gland and the protein matrix on which T4 and T3 are synthesized (to be distinguished from thyroxine-binding globulin, the serum carrier protein), is a normal secretory product of the thyroid gland and can be measured in serum by radioimmunoassay. The serum thyroglobulin concentration is elevated in a variety of conditions, including hypersecretory states, subacute thyroiditis, both benign and malignant neoplasms, and goiter of any cause. Because of the nonspecific nature of an elevated serum thyroglobulin level, it cannot be used to separate benign from malignant thyroid tumors of follicular cell origin. However, if a patient is known to have a thyroid carcinoma that has caused an elevated thyroglobulin level, this measurement can subsequently 28 , 33 be used as a marker for residual, recurrent, or metastic disease. 28, 33 In such a case, the sensitivity is greatly increased if the patient is withdrawn from thyroid hormone suppression long enough for the serum TSH to rise, and
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the specificity is greatly increased if there is no remaining remnant of normal thyroid tissue. Serum for thyroglobulin should be drawn before, and not after a thyroid needle aspiration biopsy, because that procedure can cause release of substantial quantities of thyroglobulin and elevate the serum level considerably, possibly for as long as 22 to 3 weeks. In the case of elevated serum thyroid hormone levels in a patient with a very low radioiodine uptake, a serum thyroglobulin measurement can be of use in distinguishing thyrotoxicosis factitia (in which the serum thyroglobulin is low) from painless subacute thyroiditis (in which the serum thyroglobulin is usually elevated). NORMAL RANGES
Table 2 summarizes the normal ranges for serum thyroid hormone and related measurements, based on what I consider the most accurate meth15,• 17 17 For per cent free T4, free T4, free T3, and rT3 concentrations, ods. OdS. 15 published normal values obtained using different assays vary as much as two-fold, owing to technical differences. EFFECTS OF DRUGS ON SERUM HORMONE MEASUREMENTS
Many drugs can alter serum thyroid hormone or TSH concentrations,6. 34 as summarized in Table 3. In most cases, the patient is clinically tions,6, euthyroid and treatment is not necessary. The exception is when thyroid hormone synthesis or secretion is inhibited (Table 3). The physician's task, therefore, is to recognize when abnormal hormone measurements reflect drug effects rather than thyroid disease. A few drugs deserve special discussion. The effects of salicylate, furoA semide, and phenytoin on inhibition of T4 and T3 binding to serum proTable 2.
Normal Ranges for Serum Thyroid Hormone Concentrations and Related Serum Measurements
T4 Per cent Free T4 Free T4 concentration T3 Per cent Free T3 Free T3 concentration T4 orT3 uptake Free T4 or free T3 index Thyroxine-binding globulin rT3 Thyroid-stimulating hormone Increment in serum TSH 30 min. after 400 to 500 fLg of TRH fJ-g ofTRH intravenously Thyroglobulin Anti-thyroglobulin and antimicrosomal thyroid antibodies by hemagglutination
fLg'dl 4.7-11 fJ-g/dl 0.015--0.030% 0.~2.5 0.S-2.5 ng/dl ng'dl 70-220 ng/dl ng'dl 0.20-0.40% pg'dl 300-550 pg/cll Varies with method Varies with method mg'L 15--30 mgL 10-30 ng/dl ng'dl 0.5--6.0 fLUldl fJ- V/dl 5--25 fJ-V fLU TSWml ng'ml or less 28 ng/ml 1: 100 titer or less 1:100
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Table 3.
Abnormalities of Thyroid Function Tests That Can Be Caused by Drugs
ABNORMALITY
!t it
TSH TSH Serum TS H or TS H response to TRH Serum TSH
!t
Serum T4 and free T4 with it serum TSH, due to decreased thyroid hormone biosynthesis or secretion (usually in the setting of underlying glandular damage)
!
Serum T4 and t per cent free T4 with normal serum free T4 and TSH concentrations
it
DRUGS RESPONSIBLE
Dopamine, L-dopa, glucocorticoids, thyroid hormones
Metoclopramide and dOluperidone domperidone (mild transient Metocloprmuide effects), amphetamine abuse (may cause increased serum thyroid hormones) Sulfonylureas, sulfonamides, ethionamide, phenylbutazone, 6-mercaptopurine, resorcinol, aminoglutethimide, sodium nitroprusside, lithium carbonate, inorganic iodide
(a) Due to ! serum TBG concentration
Glucocorticoids, androgens, danazol, L-asparaginase
(b) Due to inhibition of binding of T4 (and T3) to TBG
Salicylates, phenylbutazone, fenclofenac, phenytoin (diphenylhydantoin), halofenate, mitotane (o,p'-DDD), 5-fluorouracil, furosemide nlitotane
Serum T4 and T3, with normal serum free T3, free T4, and TSH, due to it serum TBG concentration
methadone, heroin, perphenazine, Estrogens, nlethadone, clofibrate
Normal serum T4, it serum free T4 but normal tissue T4, due to decreased tissue uptake of T4
Heparin
!
Serum T4 and T3, ! serum free T4, it tissue T4 uptake
Phenytoin, phenobarbital (seen in hypothyroid patients taking T4 and phenobarbital)
!t
Serum T3 with normal or it serum T4, due to ! extrathyroidal conversion of T4 to T3
Glucocorticoids, propranolol, iopanoic acid (Telepaque), sodium ipodate (Oragrafin), amiodarone, propylthiouracil
21 ,31 When serum is diluted in teins are highly concentration-dependent. 21,31 the test tube for per cent free hormone measurements, even by dialysis, the drug is also diluted, and the inhibition of binding (that is, the increased per cent free T4 or free T3 that exists in vivo) is no longer detectable in vitro. For this reason, the estimated per cent free T4, and therefore the estimated free T4 concentrations, are artifactually low. The effect of salicylate on T4 and T3 binding to serum proteins requires high doses, in the range of 2.4 gm daily. 21 The effect of furosemide also requires very high daily.21 serum levels, such as those in patients with renal failure, to whom high doses are given and in whom renal clearance of the drug is simultaneously 31 reduced. 31
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Phenytoin has another effect, shared with phenobarbital, of accelerating uptake and metabolism of T4 in tissues, thereby decreasing the serum free T4 concentration to a mild degree, perhaps 20 to 30 per cent. Patients remain clinically euthyroid. Recent evidence suggests that one reason for the normal metabolic status of patients taking phenytoin is that the drug has weak thyroid hormone agonist activity. These actions of phenytoin occur at usual therapeutic doses and serum phenytoin levels. EFFECTS OF NONTHYROIDAL MEDICAL CONDITIONS ON SERUM HORMONE MEASUREMENTS
The many alterations in thyroid hormone economy and thyroid hornon thyroidal illnesses (Table mone serum measurements caused by serious nonthyroidal 32 4) are discussed in detail elsewhere in this volume. 32 In addition, several nonpathologic conditions, such as pregnancy, can alter serum protein binding of thyroid hormones (Table 5). The clinical significance of abnormal binding ofT4 to serum albumin or prealbumin, both rare conditions, is that the effects are selective for T4, so that if T3 is used as tracer in the assessment of protein binding, as in the T3 resin uptake test, the decreased per cent free T4 will be missed, and the free T4 will falsely appear to be very high. This raises the danger of inappropriate treatment for hyperthyroidism. These conditions should be suspected when the serum T3 concentration is normal in the face of an apparently high free T4 concentration. The T4 binding should then be reassessed by a more specific method, such as dialysis. Table 6 gives examples of how alterations in serum T4 thyroid hormone measurements caused by binding protein abnormalities and alterations caused by true thyroid disorders combine algebraically when they coexist. SERUM TESTS OF THYROID AUTOIMMUNITY
Thyroid Antibodies Antibodies to thyroglobulin and to a thyroid microsomal antigen can be readily measured. The most common technique for both is hemagglutination of red cells coated with the antigen of interest. 15 By this method, 5 to 10 per cent of normal individuals have a weakly positive titer in each test. In patients with thyroid disease, many have only elevated antimicrosoTable 4.
Patterns of Abnormal Serum Thyroid Function Tests Seen in Nonthyroidal Illness Nonthyroidal Isolated low serum T3 and free T3 Low serum T4 with low free T4 (and lowT3) Low serum T4 with normal free T4 Normal serum T4 with high free T4 (and low-normal or low T3) High serum T4 and free T4 (and low-normal or low T3)
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MrCHAEL M. KAPLAN MICHAEL
Table 5.
Causes of Abnormal Binding of Thyroid Hormones to Serum Proteins
it Serum TBG, causing it serum T4 and T3 concentrations, ~ per cent free T4 and T3, and normal serum free T4 and free T3 concentrations. Newborn period Chronic active hepatitis Familial
Pregnancy Acute hepatitis Acute intermittent porphyria Drugs (see Table 3)
it
Binding to proteins other than TBG (a) Relatively selective for T4, causing it serum T4, ~ per cent free T4 (but normal T3 uptake measurements), and normal free T4. it serum albumin subfractions with high affinity for T4 ("familial dysalbuminemic hyperthyroxinemia") it Serum prealbumin Endogenous anti-T4 antibody (b) Selective for T3 Endogenous anti-T3 antibody
~ Serum TBG causing ~ serum T4 and T3, and free T T33 concentrations.
it
Severe systemic illness Nephrotic syndrome Cushing's syndrome Familial
per cent free T4 and T3, and normal free T4 Protein-calorie malnutrition Severe hepatic failure Acromegaly Drugs (see Table 3)
mal antibody titers, some have elevated titers of both, and a few have only elevated anti thyroglobulin titers. Other methods of measuring antithyrogloantithyroglobulin bulin antibodies, such as serum binding of radiolabeled thyroglobulin, increase the sensitivity of this determination to a level comparable to that of the microsomal antibody. Virtually all patients with Hashimoto's thyroiditis Table 6.
Interactions of Thyroid Diseases and TBG Abnormalities in the Assessment of Serum Free Thyroid Hormones
TOTAL SERUM T4 AND T3 CONCENTRATIONS
Hyperthyroidism Hypothyroidism Pregnancy Hyperthyroidism in pregnancy Hypothyroidism in pregnancy TBG deficiency Hyperthyroidism with TBG deficiency Hypothyroidism with TBG deficiency NL=normal, NL = normal,
x X
PER CENT FREE HORMONE OR PROTEINBINDING INDEX
FREE T4 AND FREE T3 CONCENTRATIONS OR FREE HORMONE INDICES
t
it
it
~
it
~ ~
~ NL
it it
NL or ~
it
NL ~
~ ~
it
~ NL
NL
t it
it
t
NL
~
= increased, it =
~ ~
= decreased =
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have elevated antithyroid antibodies, as do 60 to 70 per cent of patients with Graves' disease and a smaller fraction of patients with subacute thyroiditis. Elevated antibody titers are no more frequent in patients with nodular goiters, whether euthyroid or hyperthyroid, or in patients with benign or malignant thyroid tumors, than in the normal population. Thyroid antibody measurements can help identify the cause of a goiter. Elevated titers in a euthyroid or hypothyroid patient suggest Hashimoto's thyroiditis as the most likely diagnosis. In a patient with a single palpable nodule, elevated antibody titers may make the physician more willing to try thyroid hormone suppression therapy, because in Hashimoto's thyroiditis the most easily palpable abnormality in a diffusely affected gland may feel like a nodule. Elevated antibody titers in a hyperthyroid patient strongly suggest Graves' disease or, less often, subacute thyroiditis, as the cause, rather than toxic multinodular goiter or solitary adenoma. Thyroid-Stimulating Immunoglobulins Hyperthyroidism in Graves' disease is considered to be caused by stimulation of the thyroid gland by autoantibodies to the TSH receptor on 35 Measurement techniques for this type of antithe thyroid follicular cells. 35 body have been developed, are in use in some research laboratories, and are now beginning to be available in commercial clinical laboratories. The two general types of assay measure either stimulation of thyroidal adenylate 24 cyclase or inhibition of binding of radiolabeled TSH to TSH receptors. 24 Both types of measurements are difficult technically, and both exhibit some overlap in results between normals and patients with Graves' disease. Measurement of thyroid-stimulating immunoglobulins may be of some use when it is crucial to distinguish Graves' disease from toxic multinodular goiter and physical findings are not diagnostic. However, this distinction is not usually of such great importance, and conventional antithyroid antibody tests may accomplish the same goal. The test may also have some utility in evaluating euthyroid patients with exophthalmos. One situation in which thyroid-stimulating antibody measurements will probably prove valuable is in predicting the risk of congenital hyperthyroidism in the infant of a pregnant patient with Graves' disease. This condition appears usually to result from transplacental passage of maternal thyroid-stimulating immunoglobulins and can occur even if the mother has been rendered euthyroid by therapy. In reports of assay methods for thyroid-stimulating immunoglobulins, maternal titers have generally been high in cases in which the baby was affected, although the majority of women with high titers still had unafll ,26 Thus, a low titer (the exact level needs to be estabfected children. 11,26 lished for each assay) is useful in predicting a low risk for congenital Graves' disease, while a high titer should increase the vigilance of the woman's physicians for this possibility. It is possible that other uses for this measurement will become evident as experience with it grows.
Long-Acting Thyroid Stimulator Both TSH and thyroid-stimulating immunoglobulins from patients with Graves' disease cause release of iodine from the thyroid glands of mice pretreated with radioiodine. This forms the basis of the standard TSH bio-
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assay. The effect of thyroid-stimulating immunoglobulins is prolonged relative to TSH, and, in the initial studies of this phenomenon, the term "long24. 35 There is acting thyroid stimulator" (LATS) was therefore formulated. 24, variable species specificity among Graves' patients' immunoglobulins, and though most show positive results when their serum is tested for LATS activity, many do not. A variant of the assay, termed "LATS-protector"35 increases the percentage of Graves' patients exhibiting abnormal results. The LATS and LATS-protector assay are available commercially at great expense, carried out by the bioassay protocol, and require many mice for each determination. Even before the availability of in vitro thyroidimmunoglobulin assays, I believed that there was little or no stimulating iInmunoglobulin place in routine clinical practice for the LATS assay, and the current availability of antithyroid antibodies and of the in vitro thyroid-stimulating antibody assays further reinforces this opinion. THYROID IMAGING AND RADIOIODINE UPTAKE TESTS
Thyroid Scintiscanning Thyroid scintiscanning is carried out using either radioactive sodium iodide or sodium pertechnetate. Iodide is both concentrated and organified by thyroid follicular cells, whereas pertechnetate is concentrated, by the same active transport system as iodide, but not organified. The advantages of pertechnetate scanning are that it takes the least amount of time, does not require two trips to the nuclear medicine department, delivers the least amount of radiation to the thyroid and the rest of the body, and produces a high-quality image with good resolution. When iodide is used as 1231\ the scanning agent, the isotope should be 123 11, unless the patient is known to have thyroid carcinoma, or the possibility of a substernal goiter is being evaluated. 1231 delivers much less radiation than the alternative, 131 1, and produces a good-quality image with the gamma camera. When 131 1 is used, . a rectilinear scanner must be used to produce a detailed image. Resolution 1311 than with the other agents, although the image is is much lower with 131 life-sized, an occasionally useful property. Bone attenuates the photons 1311 much less than those of either 1231 or 99mtechnetium, hence the from 131 preference for 1311 in imaging a substernal goiter. In searching for residual 131 1, combined with or m.etastatic metastatic thyroid carcinoma, the longer half-life of 131 its retention in functioning thyroid cells-a property not shared by pertechnetate-gives an 1311 scan the highest sensitivity. When either 1231 or pertechnetate is used as the scanning agent, oblique views added to the standard anterior view will increase the number of abnormalities detected. It is also helpful to obtain an image that incorporates a size marker, such as a 2-cm lead square placed over the thyroid, because the size of the image from the gamma camera is greatly dependent on the position of the detector. If a thyroid nodule is being investigated by scan, it is very important for the nodule to be marked on one or more images, because hypofunctioning nodules can lie entirely outside the silhouette of functioning tissue, because defects at the margin of the thyroid sil-
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houette can be very difficult to distinguish from normal variations in the shape of thyroid lobes, and because precise localization of a nodule can be impossible from a diffusely inhomogeneous image alone. Thyroid scintiscanning should not be used as a screening test but rather to answer specific questions: Is there functioning thyroid tissue in the neck? Is there functioning thyroid tissue elsewhere, such as in an ovarian teratoma (struma ovarii) or in metastatic thyroid carcinoma? What is the functional status of a thyroid nodule or nodules compared with surrounding non-nodular tissue? Are there abnormal areas in the thyroid gland of a patient exposed to head or neck X-ray therapy whose neck is difficult to palpate? Has ablative therapy for thyroid cancer been successful in eliminating both normally and abnormally functioning thyroid tissue? When a thyroid gland is diffusely abnormal by palpation, there are no specific findings on scintiscan alone which can distinguish between Hashimoreover, moto's thyroiditis and multinodular goiter in a euthyroid patient; n10reover, a toxic multinodular goiter can sometimes have a uniform uptake and therefore cannot always be separated from Graves' disease by scan. Iodide and pertechnetate almost always give concordant information about the function of thyroid tissue, but there are occasional nodules that have an active concentrating mechanism, but little or no capacity for organlO ification. lO In that case, the nodule will appear more active on a pertechnetate scan than on an iodide scan, sometimes to the point that the former will show an area of increased uptake relative to surrounding tissue, whereas the latter will show the same area to have decreased activity. This discordance has no particular prognostic significance, being seen in adenomas as well as carcinomas. However, while increased activity in an isolated nodule on an iodide scintiscan decreases the likelihood of carcinoma, 2 increased activity on a pertechnetate scan should probably be verified by iodide scanning before being used to estimate the chances of cancer in a thyroid nodule. In the continuing search for reliable means of separating benign from malignant thyroid nodules, several other scanning techniques have been studied, but none has yet been proven to have any clinical utility.2 In fluorescence scanning, the stable endogenous iodine in the thyroid gland is excited through the skin by emissions from 23lamericium. The atoms then fluoresce as they return to the ground energy state. 20IThallium scintiscanning and thyroid thermography have also been attempted. In subacute thyroiditis, a 67 gallium scan may be abnormal, but neither the sensitivity nor the specificity of this finding is established.
Thyroid Echography Thyroid echography,5 echography, 5 or ultrasound imaging, is most useful for answering the specific question of whether a single thyroid nodule is a simple cyst-with a smooth wall, round contour, and no internal echoes at all. Such a purely cystic lesion, if less than 4 cm in diameter, has a low likelihood of harboring carcinoma. No other echographic finding significantly reduces the likelihood of malignancy in a nodule. Many authorities recommend aspiration of cystic lesions, to eliminate the mass and to obtain cytologic confirmation of the benign nature of the lesion. If aspiration is
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planned, whether a nodule is solid or cystic, and if the nodule is easy to localize by palpation, then echography will"not will not alter managment plans and becomes a redundant test and a needless expense. The finding of punctate calcific densities in a nodule suggests psammoma bodies, and therefore is suspicious for papillary carcinoma, but the specificity of this finding is unclear. In occasional patients thyroid echography may have other potential uses-for example, in performing a needle biopsy under real-time ultrasound guidance, or in obtaining objective and precise measurements of the size of a nodule during suppression therapybut such cases are very rare in my experience. Thyroidal Radioiodine Uptake This test quantitates the fraction of a dose of radioiodide which is present in the thyroid gland 24 hours after administration. The normal range in the United States at this time is 5 to 30 per cent, in the setting of an average daily dietary iodine intake of 500 to 1000 J.Lg. This test cannot by itself establish hyperthyroidism or hypothyroidism, -because because the results can be high, normal, or low in the setting of either metabolic disturbance. However, the thyroidal radioiodine uptake is usually elevated in hyperthyroidism due to Graves' disease, toxic multinodular goiter, or toxic adenoma. Therefore, this test is useful for distinguishing from the other causes two causes of hyperthyroidism in which the uptake is very low: subacute thyroiditis and exogenous thyroid hormone ingestion. The test is also used to determine how much 131 I should be given to treat a hyperthyroid patient. The thyroidal radioiodine uptake can be reduced, sometimes to near zero, by an iodine load. This occurs for up to 2 weeks after intravenous pyelography, angiography, or computerized tomographic scanning procedures with contrast injection, for up to 2 to 3 months after oral cholecystography, and for years after lymphangiography or myelography with lipophilic agents. The perchlorate ion is a competitive inhibitor of iodide transport by thyroid cells but does not affect organification. Therefore, sodium perchlo- , radio iodine to ascertain if there rate can be administered a few hours after radioiodine is an abnormally large intrathyroidal pool of unorganified iodide due to defective organification. If so, the tracer diffuses back to the blood pool rapidly, or is "discharged"-hence the term "perchlorate discharge test"-and the radioiodine uptake decreases after the perchlorate is given. Defective organification occurs in some cases of congenital goitrous cretinism, and as an acquired abnormality in Hashimoto's thyroiditis, but the availability of other tests for these conditions make the perchlorate test seldom indicated. CONCLUSION
With this battery of current diagnostic tests, thyroid abnormalities can be defined with reasonable precision. Some diagnostic problems may never become easily solvable: there may really be thyroid hormone deficiency at the cellular level in some "euthyroid-sick" patients, and some follicular thyroid carcinomas are so well differentiated that only examination of the en-
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tire lesion by the pathologist may ever be definitive. Forthcoming developments, such as rapid and accurate free T4 measurements and Graves' immunoglobulin assays will likely prove to be helpful, as refinements but not revolutionary advances, in our clinical practice.
REFERENCES 123 J. E., and Pinsky, S.: Comparison of ofOOmTc J. Nucl. Nuc!. 1. Arnold, J. 99mTc and !23I 1 for thyroid imaging. J. Med., 17:261-267, 1976. J.: Management of thyroid nodules. 11: II: Scanning 2. Ashcraft, M. W., and Van Herle, A. J.: techniques, thyroid suppressive therapy and fine needle aspiration. Head Neck Surg., 3;297-322.
880 24.
25. 26. 27. 28.
29. 30. 31. 32. 33. 34. 35.
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Endocr. Rev., intracellular thyroid hormones: Physiological and clinical implications. E'ndocr. 2:87-102, 1981. Loeffier, M., Zakarija, M., and McKensie, J. M.: Comparisons of different assays for the thyroid-stimulating antibody of Graves' disease. J. Clin. Endocrinol. Metab., 57:603608, 1983. Melmed, S., Geola, F. L., Reed, A. W., et al.: A comparison of methods for assessing thyroid function in nonthyroidal illness. J. Clin. Endocrinol. Metab., 54:300-306, 1982. Rapoport, B., Greenspan, F. S., Filetti, S., et al.: Clinical experience with a human thyroid cell bioassay for thyroid-stimulting immunoglobulin. J. Clin. Endocrinol. Metab., 58:332-338, 1984. Ruiz, M., Rajatanavin, R., Young, R. A., Taylor, C., et al.: Familial dysalbuminemic hyperthyroxinemia. N. Engl. J. Med., 306:635-640, 1982. Schneider, A. B., Line, B. R., Goldman, J. J. M., et al.: Sequential serum thyroglobulin 131 1 scans, and 131 1311 uptakes after triiodothyronine withdrawal in patients determinations, 131 with thyroid cancer. J. Clin. Endocrinol. Metab., 53:1199-1206, 1981. Schaffuer, F., and Korn, F.: Increased serum thyroid hormone binding Schussler, G. C., Schaffner, and decreased free hormone in chronic active liver disease. N. Engl. J. J. Med., 299:510516, 1978. J., Jacobs, L. S., Rabello, M. M., et al.: Diagnostic value of thyrotrophinSnyder, P. J., releasing hormone in pituitary and hypothalamic diseases. Ann. Intern. Med., 81:75181 :751757, 1974. J. R., Lim, C., Barlow, J. W., et al.: High concentrations offurosemide Stockigt, J. of furosemide inhibit serum binding of thyroxine. J. Clin. Endocrinol. Metab., 59:62-66, 1984. non thyroidal illness on thyroid function. Med. Tibaldi, J. M., and Surks, M. 1.: I.: Effects of nonthyroidal Clin. North Am. 69:899-912, 1985. Herle, A. J., J., and VIler, R. P.: Elevated serum thyroglobulin: A marker of metastases Van HerIe, J. Clin. Invest., 56:272-277, 1975. in differentiated thyroid carcinoma. J. Wenzel, K. W.: Pharmacological interference with in vitro tests of thyroid function. Metabolism, 30:717-732, 1981. significance of assay of thyroidZakarija, M., McKenzie, J. J. M., and Banovac, K.: Clinical Significance 93:21h32, 1980. stimulating antibody in Graves' disease. Ann. Intern. Med., 93:28-32,
Endocrinology Division New England Medical Center 171 Harrison Avenue Boston, Massachusetts 02111
Clinical and Clinical and Laboratory laboratory Assessment Assessment of of Thyroid Thyroid Abnormalities Abnormalities Michael M. Kaplan, M.D.*
Severe hyperthyroidism and hypothyroidism often present with such characteristic clinical manifestations that their presence is virtually unmistakable. At other times, for both conditions, the features of mild to moderate disease can be quite subtle and nonspecific. Conversely, most patients who have mild complaints suggestive of hyper- or hypothyroidism prove to have their symptoms on another basis. Also, palpable thyroid abnormalities often have several possible etiologies, even after the initial clinical assessment. This review will detail methods currently available for the diagnosis of thyroid abnormalities, with attention to their optimal uses, their limitations, and the clinical implications of variations in methods. The goal is to provide an aid in establishing accurate diagnoses, while avoiding unnecessary procedures.
CLINICAL EVALUATION The medical history should have special emphasis on the manifestations of thyroid hormone excess or deficiency, as summarized elsewhere in this volume. The patient should also be asked about local symptoms in the neck. Pain of thyroid origin can radiate upward to the ear, and the radiated pain can occasionally be more severe than pain in the lower anterior neck. Pain in the thyroid gland can be caused by hemorrhage into a thyroid cyst or tumor, or subacute thyroiditis, in which the patient may have exquisite tenderness over the gland, to the slightest touch. Other local symptoms rego iter or isolated mass, sult from mass effects: increasing neck size, a visible goiter hoarseness, dysphagia, and upper airway obstruction. The latter symptoms, when due to enlargement of all or part of the thyroid gland, require a con-
*Associate Professor of Medicine, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Massachusetts
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siderable degree of enlargement, and are virtually always accompanied by a palpable goiter or by chest roentgenographic evidence of a substernal goiter. Several physical findings are of particular usefulness in the setting of possible thyroid disease. Skillful palpation of the thyroid gland takes practice, but cannot be replaced by multiple imaging procedures. Because the thyroid is fixed to the trachea, it moves up and down during deglutition. Its edges, therefore, are usually easiest to define when the patient swallows small sips of water (repeated swallowing without liquid is quite difficult for most people). Occasionally the thyroid gland is easier to see than to feel, if the patient swallows water with the neck slightly extended and with a light source coming from the side to accentuate shadows. According to the examiner's preference and training, palpation can be carried out from the front or from behind. The normal thyroid gland is usually palpable, but is easier felt in women than in men. It is often asymmetric, and when this is so, the right lobe is almost invariably the larger one. When a diffuse process, such as Hashimoto's thyroiditis or Graves' disease, affects the gland, the underlying asymmetry persists, but may be more readily detected since the whole gland becomes easier to feel. For an initial anatomic orientation, it is useful to remember that the isthmus of the thyroid gland is about 1 cm below the cricoid cartilage. Tracheal deviation can be a clue to the presence of a substernal goiter. I find it most useful to record the size of the thyroid gland according to the vertical dimensions of each lobe, also estimating the width and thickness if the shape of the lobe seems abnormal. Abnormalities of the isthmus and the presence of a pyramidal lobe should also be noted. The consistency of the thyroid gland (soft, firm, or hard), the surface texture (smooth, irregular, lobulated, or nodular), and the presence of tenderness should be recorded. The presence of any discrete nodules should, of course, be noted along with their size, consistency, and mobility. In hyperthyroidism, the blood flow to the thyroid gland may be greatly increased, and there may be a palpable thrill, a systolic or to-and-fro bruit, or a ve. nous hum. The value of thyroid palpation cannot be overstated. It is risk-free and costs nothing. When performed properly, palpation can disclose nodules that do not appear on scintiscans because of small size, peripheral or posterior location, or tracer uptake equal to that of surrounding tissue. In a hyperthyroid patient, the palpatory finding of diffuse thyroid enlargement often makes scintiscanning unnecessary. Conversely, it is by palpation that nodules in need of further work-up are usually discovered. I cannot reliably distinguish solid from cystic thyroid nodules by palpation, but a very hard nodule or the concomitant presence of cervical lymphadenopathy should increase one's concern about a malignant lesion. Another area of particular significance is the eye examination. There can be soft, periorbital swelling in hypothyroidism and firm, rubbery, periorbital swelling in Graves' disease. The function of the extraocular muscles should be assessed carefully in suspected or definite Graves' disease, along with the extent of protrusion of the globe beyond the orbital notch. The latter measurement can be made with reasonable accuracy and reproduc-
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ibility with the inexpensive Luedde exophthalmometer, though the Hertel exophthalmometer is more precise. Exophthalmometer readings are expressed in millimeters, and normal ranges differ among caucasian, black, and asiatic racial groups. The timing of the Achilles tendon reflex is useful, being less subject to effects of gravity and muscle strength than other deep tendon reflexes. In states of thyroid hormone excess or deficiency, the relaxation phase changes more than the contraction phase, but both phases tend to be abnormally brisk in thyrotoxicosis and prolonged ("hung up") in hypothyroidism. If this reflex cannot be elicited when the patient is sitting, it can often be brought out by having the patient kneel on a chair and put his weight on the chair back, with the ankles separated by a few inches. When the Achilles tendon is struck, the backward and forward movement of the foot is observed. The Achilles reflex is absent even with this maneuver in a number of older patients and in some with any of several medical illnesses, notably diabetes mellitus.
QUANTITATIVE ASSESSMENT OF THYROID HORMONE EFFECTS ON TARGET ORGANS Although thyroid hormone excess and deficiency cause alterations in quantifiable functions of numerous organs, the measurements needed for such assessment are cumbersome, nonspecific, or both-with the exception of evaluation of the pituitary-thyroid axis. Only in a research setting, where the precise tinling timing or magnitude of target organ responses is important, or in the rare case in which resistance to thyroid hormone is under consideration, are such measurements helpful. The most time-honored test of target organ response is the basal metabolic rate (BMR)-that is, the oxygen consumption rate in a standard, resting, fasting state. 33 Unless a laboratory performs this test routinely, and with meticulous attention to technique and possible confounding factors, the result can show considerable variation from day to day, and considerable overlap between normals and patients with thyroid disease. Quantitative timing of the Achilles reflex, so-called kinemometry, also suffers from a great deal of overlap between normals and patients with abnormal thyroid function. 33, 8 In hyperthyroidism, the hypercontractile state of the heart can be documented by noninvasive tests, such as systolic time intervals, 88 but the variation between a particular patient's results in the hyperthyroid and euthyroid states may be of the same order of magnitude as the day-to-day variation in results expected for any individual. Some of the many serum and urinary measurements which can be abnormal in thyrotoxicosis or hypothyroidism and which usually return to normal upon restoration of the euthyroid state, are listed in Table 1. None are specific and none can supplant the measurement of serum thyroid hormones and thyroid-stimulating hormone (TSH).
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\!rCHAEL \1. \\. KAPLAN KAPL.-\:\f \IICHAEL
Table 1.
Diagnostic Tests That May Be Abnormal Due to Thyrotoxicosis or Hypothyroidism
THYROTOXICOSIS
a. Serum or Plasma t alkaline phosphatase t calcium !~ parathyroid hormone !t 1.25-dihydroxyvitamin D t angiotensin-converting enzyme t coagulation factor VIII t gastrin t free fatty acids t glutamic-oxaloacetic transaminase b. Urine t calcium t creatine t hydroxyproline
HYPOTHYROIDISM
a. Serum, Plasma, or Whole Blood t cholesterol t low-density lipoproteins tt creatine phosphokinase (skeletal muscle isozyme) t lactic dehydrogenase t glutamic-oxaloacetic transaminase t myoglobin ! sodium t norepinephrine t carcinoembryonic antigen !~ coagulation factor VIII !~ hemoglobin and hematocrit t erythrocyte mean corpuscular volume t erythrocyte sedimentation rate b. Urine tt norepinephrine c. Cerebrospinal Fluid t protein
t
SERUM HORMONE MEASUREMENTS SERUM THYROXINE
Serum thyroxine (T4) is the major secretory product of the thyrOid thyroid gland and the major form of thyroid hormone in the circulation. Moreover, the thyroid gland is the sole endogenous source of T4. Serum T4 is measured by radioimmunoassay, or variants such as competitive protein binding or enzyme-linked immunoassay. Older methods based on iodine measurements, like the protein-bound iodine (PBI), butanol extractable iodine (BEl), and "T4 by column," are outmoded, being subject to cross-reaction by numerous iodine-containing substances. The T4 radioimmunoassay is remarkably free from artifactual results. 17
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flg per dl (60 to 140 The normal serum T4 range is approximately 4.7 to 11 f.Lg nanomoles per L). Falsely high or falsely low results can be found in the rare situation of an endogenous anti-T4 antibody, usually seen in the setting of Hashimoto's thyroiditis. The nonsteroidal drug, fenclofenac, not available in the United States at the time of this writing, competes strongly for T4 binding sites on thyroxine-binding globulin (TBG), and gives a falsely high serum T4 value in competitive protein-binding assays but not in radioimmunoassays. Binding of T T44 to Serum Proteins
T4 circulates in plasma strongly bound to plasma proteins, principally TBG, an alpha globulin. Smaller amounts are bound to prealbumin and albumin. Because the unbound, or free, T4 concentration appears to determine the tissue levels of T4, it is advisable to obtain an assessment of T4 binding to serum proteins together with the total serum T4 concentration if thyroid hormone excess or deficiency is being seriously considered. The two direct methods for assessing serum protein binding are equilibrium dialysis and ultrafiltration, both technically demanding and costly. Therefore, 17 Most are based on indirect measurements are more commonly employed. 17 the principle of competition for tracer triiodothyronine (T3) or T4 between serum-binding proteins and an added adsorbant, such as charcoal, ion exchange resins, talc, or immobilized antibodies. T3 is most' commonly used as the tracer, but even then, it is the binding of T4 as well as T3 that is being assessed; the T3 uptake test has nothing to do with the serum T3 concentration. The per cent of tracer bound to the adsorbant varies directly with the per cent free T4 in the serum. It is therefore a protein-binding index which, when multiplied by the total serum T4 concentration, yields an index of the serum free T4 concentration (free T4 index). An algebraic manipulation of the T3 or T4 uptake value has been recommended to de13, 29 rive a free T4 index more linearly related to the free T4 concentration. 4, 13,29 Another technique for estimating the free T4 concentration is to measure the serum TBG concentration and calculate the ratio of the T4 to the TBG concentration. This ratio is proportional to the free T4 concentration except in conditions of marked TBG deficiency. Yet another methodologic variant is the "unbound analog" method, using a labeled T4 analog that binds to a T4 antibody but not to the usual serum-binding proteins. These indirect methods of assessing serum protein binding are adequate in most clinical situations, but most of them show discrepancies with free T4 measurements by dialysis in unusual situations of abnormal binding 27 and in the fairly common situation of T4 to serum albumin or prealbumin 27 nonthyroidal of altered thyroid function due to severe non thyroidal illness. 20, 20, 25 25 None of these indirect methods is clearly superior or inferior to any of the others, but their limitations vary, and the clinician must learn the properties of the one used by the local laboratory. In addition, some manufacturers of kits for these indirect methods call them "direct free T4" measurements, even though they are not direct. This issue of terminology does not alter the usefulness of these tests, but the clinician should be aware of precisely what type of result is being reported in order to interpret it accurately.
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M. KAPLAN MICHAEL M. SERUM TRIIODOTHYRONINE
Serum triiodothyronine (T3) circulates in the blood in approximately the molar concentration of T4. The normal range for serum T3 is about 70 to 220 ng per dl (1.1 to 3.0 nanomoles per L). Like T4, it is tightly hound bound to serum-binding proteins, but unlike T4, 75 to 80 per cent of the circulating T3 is made from T4 outside of the thyroid gland, by a process termed "5' -deiodination." The total serum T3 concentration can be readily measured by radioimmunoassay,17 and the only artifact of note in this assay is, again, the presence of endogenous anti-T3 antibodies in rare patients with autoimmune thyroid disease. Since T3 is strongly bound to the same serum proteins that bind T4, a "free T3 index," or estimate of the free T3 concentration, can" can be calculated using the total serum T3 concentration and the same estimate of protein binding used for T4. The free T3 index is so well correlated with direct measurement of free T3 by equilibrium dialysis that the latter, available commercially at considerable expense, is superfluous. The serum T3 concentration is elevated in hyperthyroidism, usually to 19 Rarely, the serum T3 can be elevated a greater degree than the serum T4. 19 when the T4 and free T4 are clearly normal. This condition, termed "T3toxicosis," often represents mild or early hyperthyroidism and can occur with any cause of hyperthyroidism, or in the course of drug treatment of hyperthyroidism. In hypothyroidism, by contrast, the serum T3 often remains within the normal range, though usually in the lower half, until the disease becomes severe. In several conditions-namely, fasting, IPalnutritpalnutrition, fetal life, drug therapy, and severe nonthyroidal illness of any typedecreased T4 5'-deiodination causes the serum total and free T3 concentrations to fall to low-normal or subnormal levels in the absence of thyroid disease. A serum T3 measurement is helpful "in in these situations: (1) to clarify the meaning of a top-normal or equivocally high serum free T4, (2) when a patient has symptoms suggestive of hyperthyroidism even if the estimated serum free T4 is normal, (3) when overlooking the diagnosis of hyperthyroidism, even if it is unlikely, is highly undesirable, as in an older patient with unexplained atrial fibrillation, and (4) in monitoring the course of therapy of hyperthyroidism. '140 Y40
SERUM REVERSE T3 T3
Serum reverse T3 (rT3) is a hormonally inactive T3 isomer, also largely produced from T4 outside of the thyroid gland. It can be measured by radio17 Serum rT3 concentrations are usually elevated in hyperthyimmunoassay. 17 roidism and often low in hypothyroidism, though there is considerable overlap between the hypothyroid and normal ranges. Serum rT3 is usually non thyroidal diseases, and its measupranormal in euthyroid patients with nonthyroidal surement has been suggested as a possibly useful discriminant between euthyroid patients who have low estimated free T4 levels due to nonthyroidal illness only, and patients who are truly hypothyroid. 77 However,
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other studies have found overlap between these two groups of patients, hence a serum TSH measurement is probably a more reliable discriminant in this situation. 12, 12. 18 18 SERUM THYROID-STIMULATING HORMONE
Serum thyroid-stimulating hormone (Thyrotropin, TSH) is secreted by the thyrotropic cells of the anterior pituitary gland. Its secretion is regulated by a classic negative feedback 100p.22 loop.22 Serum free T4 and free T3 are inversely correlated with TSH secretion and serum TSH concentrations. Within the thyrotropic cells, serum T4 is converted to T3, and it is the intracellular T3 concentration that actually regulates TSH synthesis and re-deiodination within pituitary thyrolease. Because of this active T4 5' 5'-deiodination tropes, intrapituitary T3 concentrations are governed both by plasma free T4 and free T3. 22 ., 23 23 Another crucial regulator of TSH secretion is thyrotropin-releasing hormone (TRH), the tripeptide made in the brain and released from the hypothalamus into the pituitary portal blood,16 blood. 16 TRH stimulates TSH release, but the effect of TRH can be inhibited by even mild thyroid hormone excess and potentiated by even minimal thyroid hormone deficiency. TRH given exogenously, in pharmacologic doses, also stimulates prolactin release into the circulation, but TRH is probably not an important physiologic regulator of prolactin secretion. Somatostatin, dopamine, and glucocorticoids all inhibit TSH secretion and the TSH response to exogenous TRH. The serum TSH concentration is routinely measured by radioimmuVnits noassay. Concentrations are expressed in bioassayable International Units (V) (U) compared to a reference standard. In most assays, the upper limit of j.LV per m!' ml. Some assays normal for the serum TSH concentration is 5 to 6 f.1U j.L V per ml, m!, probably due to nonspecific reacgive normal ranges up to 10 f.1U tion of some serum components in the assay. The clinician needs to know not only the normal range for the local TSH assay but also the reproducibility of the assay within the normal range, in order to be able to interpret a TRH stimulation test accurately. Except with the most highly sensitive TSH assays, capable of measuring 0.5 f.1U j.LV of TSH per ml with precision, many normal individuals will have basal serum TSH concentrations below the sensitivity limit of the assay. The serum TSH concentration rises when thyroid gland function becomes impaired or when iodine is in insufficient supply. This helps to 23 maintain normal serum T4 and T3 concentrations for as long as possible. 23 Thus, an elevated serum TSH almost always means an abnormal thyroid gland, and usually means hypothyroidism as well. This measurement can therefore be used to help decide if a borderline-low estimated free T4 repT4 is unequivocally low, a resents primary hypothyroidism. When the free 1'4 serum TSH is also very useful in distinguishing between primary thyroid damage, in which the TSH will be elevated, and hypopituitarism, in which the TSH will not rise. In hyperthyroidism, serum TSH measurements are not usually indicated, because almost all TS H assays fail to distinguish the TSH
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low values in hyperthyroidism from normal values, and because hyperthyroidism due to TSH hypersecretion is exceedingly rare. 99 THYROTROPIN-RELEASING STIMULATION TEST THYROTROPIN -RELEASING HORMONE HORMONE STIMULATION TEST (TRHTEST) (TRHTEST)
Administration of synthetic TRH, known generically as protirelin and available for clinical use, can be used to magnify abnormalities in the dynamics ofTSH of TSH secretion. 14, 16 TRH is injected intravenously in a dose of 400 to 500 f.1g, /-Lg, and serum TSH is measured just before and 30 minutes after the injection. If pituitary or hypothalamic disease is suspected, 60- and 120minute samples may be useful as well. Patients should be warned that they may experience a feeling of facial flushing, an urge to urinate, or nausea for up to 5 minutes after the injection, but that these sensations are harmless, self-limited, and not indicative of any problem or abnormality. Normally /-LU per ml30 minutes after the TRII TRH injection, the serum TSH rises 5 to 25 f.1U except in normal men over age 40, in whom the rise may be smaller, but /-LU per ml. In hypothyroidism due to thyroid gland usually still at least 3 f.1U damage, the TSH rise becomes exaggerated, whereas in hypothyroidism due to pituitary or hypothalamic disease the TSH rise may be absent, blunted, delayed, or prolonged. In hyperthyroidism, the TSH rise is abolished. Given the normal range ofTSH rise, it can be seen why the accuracy of the TSH assay within the normal range, mentioned above, is important in the interpretation of the TRH test. The most common situations in which the TRH test is useful are (1) suspected hyperthyroidism when the estimated free T4 and the T3 are only equivocally high, (2) when the estimated free T4 is borderline-low and the serum TSH is not clearly elevated, and (3) known or suspected hypopituitarism, in which case it is often helpful to assess both the prolactin and 30 TRH.30 TSH response to TRH. SERUM SERUM THYROGLOBULIN THYROGLOBULIN
Thyroglobulin, the colloid protein of the thyroid gland and the protein matrix on which T4 and T3 are synthesized (to be distinguished from thyroxine-binding globulin, the serum carrier protein), is a normal secretory product of the thyroid gland and can be measured in serum by radioimmunoassay. The serum thyroglobulin concentration is elevated in a variety of conditions, including hypersecretory states, subacute thyroiditis, both benign and malignant neoplasms, and goiter of any cause. Because of the nonspecific nature of an elevated serum thyroglobulin level, it cannot be used to separate benign from malignant thyroid tumors of follicular cell origin. However, if a patient is known to have a thyroid carcinoma that has caused an elevated thyroglobulin level, this measurement can subsequently 28 , 33 be used as a marker for residual, recurrent, or metastic disease. 28, 33 In such a case, the sensitivity is greatly increased if the patient is withdrawn from thyroid hormone suppression long enough for the serum TSH to rise, and
CLINICAL AND LABORATORY ASSESSMENT OF THYROID ABNORMALITIES
871
the specificity is greatly increased if there is no remaining remnant of normal thyroid tissue. Serum for thyroglobulin should be drawn before, and not after a thyroid needle aspiration biopsy, because that procedure can cause release of substantial quantities of thyroglobulin and elevate the serum level considerably, possibly for as long as 22 to 3 weeks. In the case of elevated serum thyroid hormone levels in a patient with a very low radioiodine uptake, a serum thyroglobulin measurement can be of use in distinguishing thyrotoxicosis factitia (in which the serum thyroglobulin is low) from painless subacute thyroiditis (in which the serum thyroglobulin is usually elevated). NORMAL RANGES
Table 2 summarizes the normal ranges for serum thyroid hormone and related measurements, based on what I consider the most accurate meth15,• 17 17 For per cent free T4, free T4, free T3, and rT3 concentrations, ods. OdS. 15 published normal values obtained using different assays vary as much as two-fold, owing to technical differences. EFFECTS OF DRUGS ON SERUM HORMONE MEASUREMENTS
Many drugs can alter serum thyroid hormone or TSH concentrations,6. 34 as summarized in Table 3. In most cases, the patient is clinically tions,6, euthyroid and treatment is not necessary. The exception is when thyroid hormone synthesis or secretion is inhibited (Table 3). The physician's task, therefore, is to recognize when abnormal hormone measurements reflect drug effects rather than thyroid disease. A few drugs deserve special discussion. The effects of salicylate, furoA semide, and phenytoin on inhibition of T4 and T3 binding to serum proTable 2.
Normal Ranges for Serum Thyroid Hormone Concentrations and Related Serum Measurements
T4 Per cent Free T4 Free T4 concentration T3 Per cent Free T3 Free T3 concentration T4 orT3 uptake Free T4 or free T3 index Thyroxine-binding globulin rT3 Thyroid-stimulating hormone Increment in serum TSH 30 min. after 400 to 500 fLg of TRH fJ-g ofTRH intravenously Thyroglobulin Anti-thyroglobulin and antimicrosomal thyroid antibodies by hemagglutination
fLg'dl 4.7-11 fJ-g/dl 0.015--0.030% 0.~2.5 0.S-2.5 ng/dl ng'dl 70-220 ng/dl ng'dl 0.20-0.40% pg'dl 300-550 pg/cll Varies with method Varies with method mg'L 15--30 mgL 10-30 ng/dl ng'dl 0.5--6.0 fLUldl fJ- V/dl 5--25 fJ-V fLU TSWml ng'ml or less 28 ng/ml 1: 100 titer or less 1:100
872 872
MICHAEL M. KAPLAN
Table 3.
Abnormalities of Thyroid Function Tests That Can Be Caused by Drugs
ABNORMALITY
!t it
TSH TSH Serum TS H or TS H response to TRH Serum TSH
!t
Serum T4 and free T4 with it serum TSH, due to decreased thyroid hormone biosynthesis or secretion (usually in the setting of underlying glandular damage)
!
Serum T4 and t per cent free T4 with normal serum free T4 and TSH concentrations
it
DRUGS RESPONSIBLE
Dopamine, L-dopa, glucocorticoids, thyroid hormones
Metoclopramide and dOluperidone domperidone (mild transient Metocloprmuide effects), amphetamine abuse (may cause increased serum thyroid hormones) Sulfonylureas, sulfonamides, ethionamide, phenylbutazone, 6-mercaptopurine, resorcinol, aminoglutethimide, sodium nitroprusside, lithium carbonate, inorganic iodide
(a) Due to ! serum TBG concentration
Glucocorticoids, androgens, danazol, L-asparaginase
(b) Due to inhibition of binding of T4 (and T3) to TBG
Salicylates, phenylbutazone, fenclofenac, phenytoin (diphenylhydantoin), halofenate, mitotane (o,p'-DDD), 5-fluorouracil, furosemide nlitotane
Serum T4 and T3, with normal serum free T3, free T4, and TSH, due to it serum TBG concentration
methadone, heroin, perphenazine, Estrogens, nlethadone, clofibrate
Normal serum T4, it serum free T4 but normal tissue T4, due to decreased tissue uptake of T4
Heparin
!
Serum T4 and T3, ! serum free T4, it tissue T4 uptake
Phenytoin, phenobarbital (seen in hypothyroid patients taking T4 and phenobarbital)
!t
Serum T3 with normal or it serum T4, due to ! extrathyroidal conversion of T4 to T3
Glucocorticoids, propranolol, iopanoic acid (Telepaque), sodium ipodate (Oragrafin), amiodarone, propylthiouracil
21 ,31 When serum is diluted in teins are highly concentration-dependent. 21,31 the test tube for per cent free hormone measurements, even by dialysis, the drug is also diluted, and the inhibition of binding (that is, the increased per cent free T4 or free T3 that exists in vivo) is no longer detectable in vitro. For this reason, the estimated per cent free T4, and therefore the estimated free T4 concentrations, are artifactually low. The effect of salicylate on T4 and T3 binding to serum proteins requires high doses, in the range of 2.4 gm daily. 21 The effect of furosemide also requires very high daily.21 serum levels, such as those in patients with renal failure, to whom high doses are given and in whom renal clearance of the drug is simultaneously 31 reduced. 31
CLINICAL AND LABORATORY ASSESSMENT OF THYROID ABNORMALITIES
873 873
Phenytoin has another effect, shared with phenobarbital, of accelerating uptake and metabolism of T4 in tissues, thereby decreasing the serum free T4 concentration to a mild degree, perhaps 20 to 30 per cent. Patients remain clinically euthyroid. Recent evidence suggests that one reason for the normal metabolic status of patients taking phenytoin is that the drug has weak thyroid hormone agonist activity. These actions of phenytoin occur at usual therapeutic doses and serum phenytoin levels. EFFECTS OF NONTHYROIDAL MEDICAL CONDITIONS ON SERUM HORMONE MEASUREMENTS
The many alterations in thyroid hormone economy and thyroid hornon thyroidal illnesses (Table mone serum measurements caused by serious nonthyroidal 32 4) are discussed in detail elsewhere in this volume. 32 In addition, several nonpathologic conditions, such as pregnancy, can alter serum protein binding of thyroid hormones (Table 5). The clinical significance of abnormal binding ofT4 to serum albumin or prealbumin, both rare conditions, is that the effects are selective for T4, so that if T3 is used as tracer in the assessment of protein binding, as in the T3 resin uptake test, the decreased per cent free T4 will be missed, and the free T4 will falsely appear to be very high. This raises the danger of inappropriate treatment for hyperthyroidism. These conditions should be suspected when the serum T3 concentration is normal in the face of an apparently high free T4 concentration. The T4 binding should then be reassessed by a more specific method, such as dialysis. Table 6 gives examples of how alterations in serum T4 thyroid hormone measurements caused by binding protein abnormalities and alterations caused by true thyroid disorders combine algebraically when they coexist. SERUM TESTS OF THYROID AUTOIMMUNITY
Thyroid Antibodies Antibodies to thyroglobulin and to a thyroid microsomal antigen can be readily measured. The most common technique for both is hemagglutination of red cells coated with the antigen of interest. 15 By this method, 5 to 10 per cent of normal individuals have a weakly positive titer in each test. In patients with thyroid disease, many have only elevated antimicrosoTable 4.
Patterns of Abnormal Serum Thyroid Function Tests Seen in Nonthyroidal Illness Nonthyroidal Isolated low serum T3 and free T3 Low serum T4 with low free T4 (and lowT3) Low serum T4 with normal free T4 Normal serum T4 with high free T4 (and low-normal or low T3) High serum T4 and free T4 (and low-normal or low T3)
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MrCHAEL M. KAPLAN MICHAEL
Table 5.
Causes of Abnormal Binding of Thyroid Hormones to Serum Proteins
it Serum TBG, causing it serum T4 and T3 concentrations, ~ per cent free T4 and T3, and normal serum free T4 and free T3 concentrations. Newborn period Chronic active hepatitis Familial
Pregnancy Acute hepatitis Acute intermittent porphyria Drugs (see Table 3)
it
Binding to proteins other than TBG (a) Relatively selective for T4, causing it serum T4, ~ per cent free T4 (but normal T3 uptake measurements), and normal free T4. it serum albumin subfractions with high affinity for T4 ("familial dysalbuminemic hyperthyroxinemia") it Serum prealbumin Endogenous anti-T4 antibody (b) Selective for T3 Endogenous anti-T3 antibody
~ Serum TBG causing ~ serum T4 and T3, and free T T33 concentrations.
it
Severe systemic illness Nephrotic syndrome Cushing's syndrome Familial
per cent free T4 and T3, and normal free T4 Protein-calorie malnutrition Severe hepatic failure Acromegaly Drugs (see Table 3)
mal antibody titers, some have elevated titers of both, and a few have only elevated anti thyroglobulin titers. Other methods of measuring antithyrogloantithyroglobulin bulin antibodies, such as serum binding of radiolabeled thyroglobulin, increase the sensitivity of this determination to a level comparable to that of the microsomal antibody. Virtually all patients with Hashimoto's thyroiditis Table 6.
Interactions of Thyroid Diseases and TBG Abnormalities in the Assessment of Serum Free Thyroid Hormones
TOTAL SERUM T4 AND T3 CONCENTRATIONS
Hyperthyroidism Hypothyroidism Pregnancy Hyperthyroidism in pregnancy Hypothyroidism in pregnancy TBG deficiency Hyperthyroidism with TBG deficiency Hypothyroidism with TBG deficiency NL=normal, NL = normal,
x X
PER CENT FREE HORMONE OR PROTEINBINDING INDEX
FREE T4 AND FREE T3 CONCENTRATIONS OR FREE HORMONE INDICES
t
it
it
~
it
~ ~
~ NL
it it
NL or ~
it
NL ~
~ ~
it
~ NL
NL
t it
it
t
NL
~
= increased, it =
~ ~
= decreased =
CLINICAL AND LABORATORY ASSESSMENT OF THYROID ABNORMALITIES
875
have elevated antithyroid antibodies, as do 60 to 70 per cent of patients with Graves' disease and a smaller fraction of patients with subacute thyroiditis. Elevated antibody titers are no more frequent in patients with nodular goiters, whether euthyroid or hyperthyroid, or in patients with benign or malignant thyroid tumors, than in the normal population. Thyroid antibody measurements can help identify the cause of a goiter. Elevated titers in a euthyroid or hypothyroid patient suggest Hashimoto's thyroiditis as the most likely diagnosis. In a patient with a single palpable nodule, elevated antibody titers may make the physician more willing to try thyroid hormone suppression therapy, because in Hashimoto's thyroiditis the most easily palpable abnormality in a diffusely affected gland may feel like a nodule. Elevated antibody titers in a hyperthyroid patient strongly suggest Graves' disease or, less often, subacute thyroiditis, as the cause, rather than toxic multinodular goiter or solitary adenoma. Thyroid-Stimulating Immunoglobulins Hyperthyroidism in Graves' disease is considered to be caused by stimulation of the thyroid gland by autoantibodies to the TSH receptor on 35 Measurement techniques for this type of antithe thyroid follicular cells. 35 body have been developed, are in use in some research laboratories, and are now beginning to be available in commercial clinical laboratories. The two general types of assay measure either stimulation of thyroidal adenylate 24 cyclase or inhibition of binding of radiolabeled TSH to TSH receptors. 24 Both types of measurements are difficult technically, and both exhibit some overlap in results between normals and patients with Graves' disease. Measurement of thyroid-stimulating immunoglobulins may be of some use when it is crucial to distinguish Graves' disease from toxic multinodular goiter and physical findings are not diagnostic. However, this distinction is not usually of such great importance, and conventional antithyroid antibody tests may accomplish the same goal. The test may also have some utility in evaluating euthyroid patients with exophthalmos. One situation in which thyroid-stimulating antibody measurements will probably prove valuable is in predicting the risk of congenital hyperthyroidism in the infant of a pregnant patient with Graves' disease. This condition appears usually to result from transplacental passage of maternal thyroid-stimulating immunoglobulins and can occur even if the mother has been rendered euthyroid by therapy. In reports of assay methods for thyroid-stimulating immunoglobulins, maternal titers have generally been high in cases in which the baby was affected, although the majority of women with high titers still had unafll ,26 Thus, a low titer (the exact level needs to be estabfected children. 11,26 lished for each assay) is useful in predicting a low risk for congenital Graves' disease, while a high titer should increase the vigilance of the woman's physicians for this possibility. It is possible that other uses for this measurement will become evident as experience with it grows.
Long-Acting Thyroid Stimulator Both TSH and thyroid-stimulating immunoglobulins from patients with Graves' disease cause release of iodine from the thyroid glands of mice pretreated with radioiodine. This forms the basis of the standard TSH bio-
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MrCHAEL M. KAPLAN MICHAEL
assay. The effect of thyroid-stimulating immunoglobulins is prolonged relative to TSH, and, in the initial studies of this phenomenon, the term "long24. 35 There is acting thyroid stimulator" (LATS) was therefore formulated. 24, variable species specificity among Graves' patients' immunoglobulins, and though most show positive results when their serum is tested for LATS activity, many do not. A variant of the assay, termed "LATS-protector"35 increases the percentage of Graves' patients exhibiting abnormal results. The LATS and LATS-protector assay are available commercially at great expense, carried out by the bioassay protocol, and require many mice for each determination. Even before the availability of in vitro thyroidimmunoglobulin assays, I believed that there was little or no stimulating iInmunoglobulin place in routine clinical practice for the LATS assay, and the current availability of antithyroid antibodies and of the in vitro thyroid-stimulating antibody assays further reinforces this opinion. THYROID IMAGING AND RADIOIODINE UPTAKE TESTS
Thyroid Scintiscanning Thyroid scintiscanning is carried out using either radioactive sodium iodide or sodium pertechnetate. Iodide is both concentrated and organified by thyroid follicular cells, whereas pertechnetate is concentrated, by the same active transport system as iodide, but not organified. The advantages of pertechnetate scanning are that it takes the least amount of time, does not require two trips to the nuclear medicine department, delivers the least amount of radiation to the thyroid and the rest of the body, and produces a high-quality image with good resolution. When iodide is used as 1231\ the scanning agent, the isotope should be 123 11, unless the patient is known to have thyroid carcinoma, or the possibility of a substernal goiter is being evaluated. 1231 delivers much less radiation than the alternative, 131 1, and produces a good-quality image with the gamma camera. When 131 1 is used, . a rectilinear scanner must be used to produce a detailed image. Resolution 1311 than with the other agents, although the image is is much lower with 131 life-sized, an occasionally useful property. Bone attenuates the photons 1311 much less than those of either 1231 or 99mtechnetium, hence the from 131 preference for 1311 in imaging a substernal goiter. In searching for residual 131 1, combined with or m.etastatic metastatic thyroid carcinoma, the longer half-life of 131 its retention in functioning thyroid cells-a property not shared by pertechnetate-gives an 1311 scan the highest sensitivity. When either 1231 or pertechnetate is used as the scanning agent, oblique views added to the standard anterior view will increase the number of abnormalities detected. It is also helpful to obtain an image that incorporates a size marker, such as a 2-cm lead square placed over the thyroid, because the size of the image from the gamma camera is greatly dependent on the position of the detector. If a thyroid nodule is being investigated by scan, it is very important for the nodule to be marked on one or more images, because hypofunctioning nodules can lie entirely outside the silhouette of functioning tissue, because defects at the margin of the thyroid sil-
CLINICAL AND LABORATORY ASSESSMENT OF THYROID ABNORMALITIES
877
houette can be very difficult to distinguish from normal variations in the shape of thyroid lobes, and because precise localization of a nodule can be impossible from a diffusely inhomogeneous image alone. Thyroid scintiscanning should not be used as a screening test but rather to answer specific questions: Is there functioning thyroid tissue in the neck? Is there functioning thyroid tissue elsewhere, such as in an ovarian teratoma (struma ovarii) or in metastatic thyroid carcinoma? What is the functional status of a thyroid nodule or nodules compared with surrounding non-nodular tissue? Are there abnormal areas in the thyroid gland of a patient exposed to head or neck X-ray therapy whose neck is difficult to palpate? Has ablative therapy for thyroid cancer been successful in eliminating both normally and abnormally functioning thyroid tissue? When a thyroid gland is diffusely abnormal by palpation, there are no specific findings on scintiscan alone which can distinguish between Hashimoreover, moto's thyroiditis and multinodular goiter in a euthyroid patient; n10reover, a toxic multinodular goiter can sometimes have a uniform uptake and therefore cannot always be separated from Graves' disease by scan. Iodide and pertechnetate almost always give concordant information about the function of thyroid tissue, but there are occasional nodules that have an active concentrating mechanism, but little or no capacity for organlO ification. lO In that case, the nodule will appear more active on a pertechnetate scan than on an iodide scan, sometimes to the point that the former will show an area of increased uptake relative to surrounding tissue, whereas the latter will show the same area to have decreased activity. This discordance has no particular prognostic significance, being seen in adenomas as well as carcinomas. However, while increased activity in an isolated nodule on an iodide scintiscan decreases the likelihood of carcinoma, 2 increased activity on a pertechnetate scan should probably be verified by iodide scanning before being used to estimate the chances of cancer in a thyroid nodule. In the continuing search for reliable means of separating benign from malignant thyroid nodules, several other scanning techniques have been studied, but none has yet been proven to have any clinical utility.2 In fluorescence scanning, the stable endogenous iodine in the thyroid gland is excited through the skin by emissions from 23lamericium. The atoms then fluoresce as they return to the ground energy state. 20IThallium scintiscanning and thyroid thermography have also been attempted. In subacute thyroiditis, a 67 gallium scan may be abnormal, but neither the sensitivity nor the specificity of this finding is established.
Thyroid Echography Thyroid echography,5 echography, 5 or ultrasound imaging, is most useful for answering the specific question of whether a single thyroid nodule is a simple cyst-with a smooth wall, round contour, and no internal echoes at all. Such a purely cystic lesion, if less than 4 cm in diameter, has a low likelihood of harboring carcinoma. No other echographic finding significantly reduces the likelihood of malignancy in a nodule. Many authorities recommend aspiration of cystic lesions, to eliminate the mass and to obtain cytologic confirmation of the benign nature of the lesion. If aspiration is
878
MICHAEL M. KAPLAN
planned, whether a nodule is solid or cystic, and if the nodule is easy to localize by palpation, then echography will"not will not alter managment plans and becomes a redundant test and a needless expense. The finding of punctate calcific densities in a nodule suggests psammoma bodies, and therefore is suspicious for papillary carcinoma, but the specificity of this finding is unclear. In occasional patients thyroid echography may have other potential uses-for example, in performing a needle biopsy under real-time ultrasound guidance, or in obtaining objective and precise measurements of the size of a nodule during suppression therapybut such cases are very rare in my experience. Thyroidal Radioiodine Uptake This test quantitates the fraction of a dose of radioiodide which is present in the thyroid gland 24 hours after administration. The normal range in the United States at this time is 5 to 30 per cent, in the setting of an average daily dietary iodine intake of 500 to 1000 J.Lg. This test cannot by itself establish hyperthyroidism or hypothyroidism, -because because the results can be high, normal, or low in the setting of either metabolic disturbance. However, the thyroidal radioiodine uptake is usually elevated in hyperthyroidism due to Graves' disease, toxic multinodular goiter, or toxic adenoma. Therefore, this test is useful for distinguishing from the other causes two causes of hyperthyroidism in which the uptake is very low: subacute thyroiditis and exogenous thyroid hormone ingestion. The test is also used to determine how much 131 I should be given to treat a hyperthyroid patient. The thyroidal radioiodine uptake can be reduced, sometimes to near zero, by an iodine load. This occurs for up to 2 weeks after intravenous pyelography, angiography, or computerized tomographic scanning procedures with contrast injection, for up to 2 to 3 months after oral cholecystography, and for years after lymphangiography or myelography with lipophilic agents. The perchlorate ion is a competitive inhibitor of iodide transport by thyroid cells but does not affect organification. Therefore, sodium perchlo- , radio iodine to ascertain if there rate can be administered a few hours after radioiodine is an abnormally large intrathyroidal pool of unorganified iodide due to defective organification. If so, the tracer diffuses back to the blood pool rapidly, or is "discharged"-hence the term "perchlorate discharge test"-and the radioiodine uptake decreases after the perchlorate is given. Defective organification occurs in some cases of congenital goitrous cretinism, and as an acquired abnormality in Hashimoto's thyroiditis, but the availability of other tests for these conditions make the perchlorate test seldom indicated. CONCLUSION
With this battery of current diagnostic tests, thyroid abnormalities can be defined with reasonable precision. Some diagnostic problems may never become easily solvable: there may really be thyroid hormone deficiency at the cellular level in some "euthyroid-sick" patients, and some follicular thyroid carcinomas are so well differentiated that only examination of the en-
CLINICAL AND LABORATORY ASSESSMENT OF THYROID ABNORMALITIES
879
tire lesion by the pathologist may ever be definitive. Forthcoming developments, such as rapid and accurate free T4 measurements and Graves' immunoglobulin assays will likely prove to be helpful, as refinements but not revolutionary advances, in our clinical practice.
REFERENCES 123 J. E., and Pinsky, S.: Comparison of ofOOmTc J. Nucl. Nuc!. 1. Arnold, J. 99mTc and !23I 1 for thyroid imaging. J. Med., 17:261-267, 1976. J.: Management of thyroid nodules. 11: II: Scanning 2. Ashcraft, M. W., and Van Herle, A. J.: techniques, thyroid suppressive therapy and fine needle aspiration. Head Neck Surg., 3;297-322.
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25. 26. 27. 28.
29. 30. 31. 32. 33. 34. 35.
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Endocr. Rev., intracellular thyroid hormones: Physiological and clinical implications. E'ndocr. 2:87-102, 1981. Loeffier, M., Zakarija, M., and McKensie, J. M.: Comparisons of different assays for the thyroid-stimulating antibody of Graves' disease. J. Clin. Endocrinol. Metab., 57:603608, 1983. Melmed, S., Geola, F. L., Reed, A. W., et al.: A comparison of methods for assessing thyroid function in nonthyroidal illness. J. Clin. Endocrinol. Metab., 54:300-306, 1982. Rapoport, B., Greenspan, F. S., Filetti, S., et al.: Clinical experience with a human thyroid cell bioassay for thyroid-stimulting immunoglobulin. J. Clin. Endocrinol. Metab., 58:332-338, 1984. Ruiz, M., Rajatanavin, R., Young, R. A., Taylor, C., et al.: Familial dysalbuminemic hyperthyroxinemia. N. Engl. J. Med., 306:635-640, 1982. Schneider, A. B., Line, B. R., Goldman, J. J. M., et al.: Sequential serum thyroglobulin 131 1 scans, and 131 1311 uptakes after triiodothyronine withdrawal in patients determinations, 131 with thyroid cancer. J. Clin. Endocrinol. Metab., 53:1199-1206, 1981. Schaffuer, F., and Korn, F.: Increased serum thyroid hormone binding Schussler, G. C., Schaffner, and decreased free hormone in chronic active liver disease. N. Engl. J. J. Med., 299:510516, 1978. J., Jacobs, L. S., Rabello, M. M., et al.: Diagnostic value of thyrotrophinSnyder, P. J., releasing hormone in pituitary and hypothalamic diseases. Ann. Intern. Med., 81:75181 :751757, 1974. J. R., Lim, C., Barlow, J. W., et al.: High concentrations offurosemide Stockigt, J. of furosemide inhibit serum binding of thyroxine. J. Clin. Endocrinol. Metab., 59:62-66, 1984. non thyroidal illness on thyroid function. Med. Tibaldi, J. M., and Surks, M. 1.: I.: Effects of nonthyroidal Clin. North Am. 69:899-912, 1985. Herle, A. J., J., and VIler, R. P.: Elevated serum thyroglobulin: A marker of metastases Van HerIe, J. Clin. Invest., 56:272-277, 1975. in differentiated thyroid carcinoma. J. Wenzel, K. W.: Pharmacological interference with in vitro tests of thyroid function. Metabolism, 30:717-732, 1981. significance of assay of thyroidZakarija, M., McKenzie, J. J. M., and Banovac, K.: Clinical Significance 93:21h32, 1980. stimulating antibody in Graves' disease. Ann. Intern. Med., 93:28-32,
Endocrinology Division New England Medical Center 171 Harrison Avenue Boston, Massachusetts 02111