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JOURNAL OF NUCLEAR MEDICINE 6:853-901, 1965
Principles of, and Pitfalls in, Thyroid Function Tests
James C. Sisson, M.D.'
Ann Arbor, Michigan
INTRODUCTION
Thyroid function tests are now readily available to, and widely used by, practitioners of the medical arts. However, proper interpretation of the results of such tests requires an understanding of the physiological processes being evaluated, and how this evaluation is accomplished. It is the purpose of this communication to describe the principles of, and some pitfalls in, the uses of certain well established clinical tests with an em phasis on the vagaries encountered. Not all thyroid function procedures will be reviewed, but only those which are in common usage, and which, by apparent inconsistencies, may puzzle the practitioner. Thyroid diseases will not be discussed in any detail. The various clinical entities of thyroid dysfunction will be discussed only as they affect the function tests, and hyper- and hypothyroidism will be included only as points of reference for the laboratory procedures. Hyperthyroidism may be defined as the state of response of the body tissues to too much thyroid hormone, and, conversely, hypothyroidism occurs when the body tissues function in the presence of too little thyroid hormone. No laboratory procedure now available specifically indicates the existence of hyper- or hypo thyroidism. Of the clinical tests in current usage, the basal metabolic rate (BMR) best reflects the action of thyroid hormones on the body cells. However, many factors other than thyroid hormones are involved in the rate of body metabolism, and the BMR is perforce a nonspecific and frequently an imprecise diagnostic aid in thyroid dysfunction.
‘From the Department of Internal Medicine (Nuclear Medicine Unit), The University of Michigan, Ann Arbor, Michigan.
854 JAMESC. SISSON
Fortunately, laboratory tests which measure thyroid hormone production, secretion, and serum concentration have a high degree of correlation with the clinical status of the patient as related to thyroid hormones. These tests, because they do not directly reflect thyroid hormone effect on tissues, are occasionally altered by factors other than hyper- and hypothyroidism. I. Serum Protein Bound Iodine (PB!).
A. General Considerations. Nearly all of the circulating thyroid hormones, thyroxine (T4) and triiodo thyronine (T3), are bound to serum proteins. The precipitation of serum pro teins followed by careful washes, and the determination of the iodine content of the precipitate constitutes the basic procedure for the determination of the protein bound iodine (1, 2). Normal values for the PB! determination are usually in the range of 3.5-8. 1zg/100 ml serum (3, 4), with all but 0.5-1.0 ,Lg/100 ml representing hormonal iodine. At the University of Michigan Medical Center (UMMC), the normal range [by the method of Acland (5)1, is 3.5-7.5 ,Lg/100 ml serum. The iodine concentration in the supernatant after the serum protein precipi tation indicates the level of circulating inorganic iodine (iodide). The serum inorganic iodine may also be determined by subtracting the PB! from the total serum iodine concentration. The normal range for the serum inorganic iodine' by the former method (UMMC) is up to 5.0 @g/100ml serum, but usually less than 3.0 ,@g/100 ml, and by the latter procedure (Bio-Science Laboratories, Los Angeles, California) is usually less than 10 per cent, but occasionally as much as 25 per cent of the total iodine (6). The PB! determination should be accurate enough so that the difference in values of duplicate samples is less than 0.6 @g/100ml and in different sera from the same individual less than 1.0 @zg/100ml (8). There is no difference in PB! values between normal men and women (9), and no change with age in males beyond adolescence (10), but a slight and significant decrease in PB! was noted in a group of patients of both sexes over age 50 (lOa). There is a mild diphasic seasonal variation with PB! values being lower in midsummer and midwinter in populations living in a temperature climate (9).
B. Factors Affecting the PB! Determination.
- Thyroid Diseases. a. Hyper- and hypothyroidism will not be discussed here except to say that the PB! may be more accurate in the diagnosis of hypothyroidism than of hyperthyroidism (lOa).
‘These normal values of inorganic iodine are erroneously high (7) because of the tech nique of determination, but they serve as a helpful reference point in estimating increased quantities of iodide in a patient.
856 JAMES^ C.^ SISSON
therapy will be a manifestation of only exogenous hormone at any dosage level. The alterations of the PB! from administered thyroid hor mone in a subject where the thyroid-hypothalamus-pituitary axis is no longer functioning because of hyperthyroidism will be discussed under the section on Suppression Tests. In myxedematous and normal subjects, the maximum re sponses in the PB! may be expected after about four weeks of thyroid hormone administration in suppressive or nearly sup pressive amounts (see Table I). After withdrawal of the hor mone treatment, the effect on the PB! disappears in about the same period of time (24). b. Iodine.
- lodides (or inorganic iodine), when administered to a pa tient, may interfere with a valid PB! determination by either or both of the following mechanisms: a) Simple contamination of the PB! determination may occur from the overwhelming presence of iodine in the patient's serum. If the washes of serum protein precipi tate remove 97 per cent of the serum supernatant
TABLE I
EFFECT OF THYROID HORMONES ON THE PBI
Euthyroid or Myxedematous Subjects Receiving Maintenance Dosage Daily Hormone Dosage (mg)PBI (@g/1OOml) References Desiccated Thyroid (Armour) 120—180 Normal (4.0—7.2) or Low Normal (2.9—6.2) Desiccated Thyroid (Warner Chilcott Special Prep.) Purified Thyroglobulin (Proloid of Warner-Chilcott)
Thyroxine (Synthyroid of Flint)
Triiodothyronine (Cytomel of Smith, Kline and French) 0.05—0.1 Low (0.4—1.4)
120—180 Low (3.3—3.7)
120—180 Low to Low Normal (1.6—4.8) 0.2—0.3 High Normal to High (5.6—11.2)
1Lists of substances, including those used in external applications, may be obtained from laboratories performing PBI determinations and from companies supplying radioactive iodine.
PRINCIPLES OF, AND PITFALLS IN, THYROID FUNCTION TESTS 857
(containing the circulating iodide), the remaining three per cent of the supernatant with a normal inorganic io dine, 3.0 1.tg/100 ml, adds little, 0.03 @g/100 ml, to the precipitate iodine (PB!). However, if the serum inorganic iodine level should be 100 @Lg/100 ml or more, than the contamination of the precipitate and PB! by supernatant iodide is appreciable. This type of interference with a valid PB! determination should be easily recognized by an elevated serum inorganic iodine value. b) The production of a nonhormonal iodinated protein, or protein-like substance, by some body tissue( s) (25) in the presence of high levels of iodide may lead to artifactual rises in the PB!. This is probably a more troublesome type of alteration in the PB! concentra tion by administered iodides. The mechanism is poorly understood, and the PB! changes are “capricious, of variable magnitude, and sometimes large― (4). Al though an elevated serum inorganic iodine concen tration (especially greater than 10 /Lg/100 ml) is usu ally suggestive of iodide contamination, it is not always well correlated with the magnitude of PB! aberration. It is said that the ingestion of up to 125 mg of iodide per day will not appreciably alter the PB! levels of an individual (26). However, this may be true for only relatively brief periods of administration (10 days in the study of Friend (26) and four to seven weeks in the work of Danowski, et al (27)), and lesser amounts of daily iodide intake over weeks or months may have more definite effects on the PB! test. The elevation of the PB! concentration by iodides may persist for one half to two and one half months after moderate dosage, 200-600 mg/d, and as long as four months after massive amounts, 3-6 g/d, of iodides (27, 28).
- Iodine compounds (organic iodine) are, when in the serum, bound by proteins, and thereby distort the protein bound iodine determination. Iodine compounds are re moved from the body by metabolic degradation with the release of iodide, and/or by excretion of the intact, or par tially degraded, compound. Arbitrarily, these iodinated substances may be divided into three types by the time required for biological removal from the human body:
PRINCIPLES OF, AND PITFALLS IN, THYROID FUNCTION TESTS 859
e. Miscellaneous drugs.
- Adrenal corticosteroids (in doses equivalent to 100 mg of cortisone or more) have been shown to produce a mild to moderate depression in PB! values (40, 41), but incon sistently (41, 42). The mechanism of this action has not been fully elucidated (43).
- Although in the chloric acid method of Zak (2) the PB! values are falsely low for a few days following the admin istration of a mercurial diuretic to a patient, this is not true when the alkaline dry ash method of Barker is used
(44). Other clinical diuretics do not affect the PB! concen
tration (44).
- Extra-thyroidal diseases. a. Choriocarcinoma and embryonal testicular carcinoma may ele vate the PB! values as well as other thyroid function parame ters, probably from secretion of a thyrotropin-like substance from the tumors (45-47). b. Acute intermittent porphyria may increase the PB! concentra tion, possibly by increasing the total extra-thyroidal thyroxine
pool (48, 49).
c. Collagen diseases may be associated with an elevation in PB! values of unknown etiology (50). d. Disturbances in PB! concentrations by liver disease, nephrosis will be considered under the Triiodothyronine Red Cell Up take Test.
Addendum: Recently, therapy with Au salts has been found to result in low PB! levels for an unknown length of time due to artifactual changes in the labora tory technique induced by the gold (206).
I!. Serum Butanol-Extractable Iodine (BE!) and Thyroxine-by-Column Chro matography (T4 by Column) and Other Tests of Serum Hormonal Iodine. A. General Considerations. Serum extracted with acidified n-butyl alcohol and subsequently treated with alkali will result in a solvent residue of thyroxine and triiodothy ronine. This hormonal extraction is expressed in terms of iodine concen tration: Butanol-Extractable Iodine. A similar result is achieved by col umn chromatography using Dowex-1, x-2 resin and the iodine concen tration is termed: Thyroxine-by-Column (52). The values obtained by both methods are similar with a normal range of 3.2-6.4 1@g/100 ml of serum (52, 53). The BE! concentrations generally average 0.6 /Lg/ ml below the PB! values, but differences of 2.0 @g/100 ml may not be unusual (17, 51). Both the BE! and T4-by-Column are difficult to per form and are likely to be less precise than the PB! determination.
Additions to serumSerum
ml.)PB! level (@sg.iodine/tOO
methodBE! (^) methodColumn
(fraction)1method 2 I 3 3.5 I 0.6 0. :1.3 0. 0.1None 3.1 I
MIT+DITt KI@4.
7.1—9.93,
860 JAMESC. SISSON
TABLE hA
EFFECT OF IODOTYROSINES AND IODIDE OX RELIABILITY OF PB!, BE! AND COLUMN METHODS*
- PB! and BE! values are averages of 4 determinations; column values are averages of duplicate analyses.
@ t MonoiodotyrosineanddiiodotyrosinePresentat a (‘oneentration of 3.3 per.
ml. (as iodine) each. @ K! present at a concentration of 1000 @g.per 100 ml. (as iodine); precipitate washed four times with distilled water. Table HA. These data are reproduced from the article by Pileggi et al in J. Clin. Endocr. 21:1272, 1961 by permission of the authors and publishers. The column method results are expressed as a sum of fractions 1 and 2.
The BE!, and presumably T4-by-Column, measurements under physi ologic circumstances will fluctuate in the same direction as the PB! values (see above). The BE! concentration may be in the low normal range in adolescent males (54). B. Factors affecting the BIE and T4-by-Column Determination. The prin cipal value of these techniques is to circumvent the artifactual changes which invalidate the PB! as a thyroid function test.
- The major indication for use is the presence of iodine contamination of sera. a. The administration of iodides does not alter the values of BE! and T4-by-Column (Table !!A). b. In general, most iodine compounds distort the results of both of these specialized methods of estimating thyroid hormone levels in serum. However, there are exceptions such as iodipamide methyl glucamine (Cholografin) and iodoalphionic acid (Priodax) which elevate the PB! and BE! but not the T4-by-Column values. Table IIB lists a number of iodine compounds in common medical use and their effects on these tests.
- The release of noncalorigenic iodinated proteins by the thyroid gland has been mentioned under the section on the PB!. In general, these unusual substances are insoluable in the butanol extraction, and pos sibly do not show up in the T4-by-Column. A variety of thyroid dis eases appear to produce the syndrome of an unusually large differ ence between the PB! and BE! values: goitrous cretins, goitrous euthyroid adults, colloid goiter, subacute thyroiditis (14), chronic thyroiditis, Hashimoto's disease, (14, 17), follicular adenoma (14),
862 JAMES C. SISSON
cent of total 131! given to the subject that is accumulated in the thyroid gland will also represent the percentage of the iodide pool (in /Lg) that has entered the gland. Normal values of RAIU (in per cent of dose) may be established at any time after the administration of the tracer 131!, but useful and conve nient times have been 2, 4, 6 and 24 hours. Because of variation in early iodide absorption, uptakes should not be performed until at least two hours after ingestion of 131!. The normal limits vary from laboratory to laboratory depending upon the details of technique, and upon the geographical area which determines, to a considerable degree, the average iodide intake and subsequent iodide pool in a member of the residing population (58). Problems in technique
TABLE IIC Summary of PB! and Associated BEL Changes' BEI Values with Reference to FBI Concordant Normal and discordant Normal and discordant
Concordant Concordant
Normal and discordant Usually concordant, but may be normal
Concordant Concordant Concordant Concordant
Concordant Concordant Concordant Concordant
Concordant
Concordant Concordant
Elevated FBI Hyperthyroidism Chronic thyroiditis Subacute thyroiditis Increased hormone binding by serum proteins (T3 Test) Thyroxine administration Iodine administration lodides hodine compounds
Extrathyroidal disease Choriocarcinonia Pheochromocytoma Acute intermittent porphyria Acute liver disease (binding protein change)
Depressed FBI Hypothyroidism Chronic thyroiditis Subacute thyroiditis Decreased hormone binding by serum proteins (see T3-Test) Triiodothyronine secretion or adni inistration Extrathyroidal disease Nephrosis (binding protein change) Cirrhosis (binding protein change) ‘Normallythe BE! varies concordantly with the PB!, but averages 0.6 @g/1®ml less (51).
PRINCIPLES OF, AN)) PIT1'ALLS I?@t,THYROID FUNCTION its'rs 863
have recently been analyzed in an international meeting (59), and the procedure used at the UMMC Nuclear Medicine Unit follows the sugges tions of this conference. The reproducibility of the RAIU, for unknown reasons, is less precise than one would expectfrom the experimentaltechnique(60).The vari ability of the 24 hour RAIU in the same individual has been recorded as ± 7 per cent, of the uptake value, but on occasion is as high as 10 per cent (61). Earlier times of uptake estimation after the tracer administra tion probably have similar reproducibiities. There is a slight decrease in percentage of radioiodine accumulated by the thyroid of males at two and six hours with increasing age (62), but no statistically significant decline was seen in the 24 hour RAIU values with aging (62, 63). No definite influence of sex or season on the RA!U measurements was found in one study (63). More recently it has been suggested that the warmer summer months may be associated with a decrease in RA!U values, perhaps because of a smaller distribution space for 131! (64). Normal valuesaresummarized inTable !I!A.
B. FactorsAffectingtheThyroidalRadioactiveIodineUptake.
- Thyroid Diseases. a. Hyper- and hypothyroidism. Uptakes determined a few hours after the administration of the tracer 131! have been found to be more accurate than the 24 hour interval in the diagnosis of hyper thyroidism. The change from the 8 to the 48 hour values was
TABLE lilA
Normal Values of Thyroidal Radioactive Iodine
Normal Value Hours After (% of dose as a range Dose or mean ± SD) Oral Administrationof ‘@‘I
AtUM1\IC 2 1.4— 13.
6 2.0— 25. 24 10.5—38. In New England (65) 24 20 — 50
IntravenousAdministrationof 131! 131 Males Aged 41—94(62) 2 12.2 ± 3. 6 20.3± 6. 24 35.9± 9.
PRINCIPLES OF, AND PITFALLS IN, THYROID FUNCTION TESTS 865
roid to normal subjects for varying periods of up to several years resulted in RA!U suppression that persisted in most cases for about two weeks after withdrawal of the drug, but occasionally low uptakes were present for 6-12 weeks (69 ). In some patients, withdrawal of desiccated thyroid medication is also followed by a
brief high rebound phase (69, 69a). A crude thyroxine preparation
reduced RA!U values to low levels which gradually returned to normal over one to two months following the therapy (70). I). !odine.
- !odides(inorganiciodine) lodides,inthe vastmajorityof cases,affectthe RA!U testsby alteringthebody iodidepoolfrom which thethyroidglandextracts itsneedsforhormonogenesis. A chronic deficiency in daily iodide ingestion will result in a low iodide pool,and the percentageof thispool required for normal thyroid hormonogenesis is higher than normal (Table !I!B). Individuals with low iodide pools may not be rare in the United States, (71) although such instances are generally con sidered characteristic of endemic goiter areas. Normally, man ingests 100-300 @tgof iodide with food and water each day, but iodides of unusual quantity may enter the body through the skin,vagina,respiratorymucosa, and by paren teralinjectionas wellas viathe gastrointestinaltract.The normal @ human iodidepool may be picturedas containing 280 of io dide' from which the thyroid gland accumulates 70 @g(25%) in 24 hours (7). The relationships of different iodide pools to the RA!U are demonstrated in Table !!!B. Since in normal individuals hormonogenesis continues in the presence of excessive iodide pools, the thyroidal requirement for iodide, 70 @g/d,does not change.
‘Thisvalue is too high if the iodide pool is calculated from the clearance of serum iodide (7). However, this pool must turn over rapidly, and the use of 280 @gis convenient for purposes of illustration. 2Actually the thyroid gland is slow to recognize increased serum levels of iodides. Thus, with iodide ingestion of up to 1000 @&g/d,the thyroid gland for a few days takes up more iodide so that the RAIU (the percentage of the enlarged iodide pool) changes very little (7,72,82). Gradually, the thyroid gland adapts to the high iodide environment, and the RAIU falls as the total iodide uptake by the gland returns toward normal. It should be em phasized that the failure of changing pool size to alter the RAIU occurs only over a brief period of time and a relatively narrow range of iodide ingestion. The vast majority of cases of excessive iodide intake are beyond this range and affect the RAIU by dilution of the pool. This sluggish adaptation in the accumulation of iodide by the thyroid gland in response to varying serum iodide concentrations is fortunate for the clinician, since moderate fluctua tions in daily iodide ingestion are not reflected in the RAIU. A diet of measured iodide content as a preparation for a RAIU is obviated by this thyroid phenomenon.
866 JAMES C.SISSON
TABLE IIIB Variable Iodide Pools and the RAIU Iodide Fool Thyroid Uptake at 24 Hours
@ (Mg) (Mg) % (RAIU)
Normal 280 70 25
Iodide Deficiency 100 70 70
IodideExcess 2800 70 2. IodideExcess 28000 70 0. TSH in IodideExcess 28000 105 0.
Iodidepools exceeding28,000 @zgare not unusual sinceLu gol's iodine and saturated solution of potassium iodide contain respectively,8,300and 50,000 @gper drop. !n a singleadministration 2000 @tgof iodidewilllower the RAIU to a modest extentin euthyroidindividualsalthoughallof this reduction may not be due to dilution of the iodide pool in such an acute experiment (72). Chronic excessiveiodideadministra tion will resultin an expanded iodide pool and a low RA!U roughlyproportionalto the levelof iodideintake. The lengthof the depressiveeffectof prolongedand excessive iodideson the RA!U afterwithdrawalof the medicationisusually 3 to 14 days (73).Occasionallya prolongedsuppressionup to one year may occur (73), presumably from a chronicallyexpanded iodidepool which,forunknown reasons,isnot reduced to normal by renaliodideexcretion.Also,a rebound of RAIU issometimes seen withinfivedays of withdrawal of iodidetherapy when the uptake of 131! rises to supernormal levels and persists in this range foraslongas49 days (73). Knowledge of the concentrationof serum inorganiciodineis frequently helpful, but this is only a rough and insensitive index of body iodidepoolsize. Although the administrationof thyroidstimulatinghormone (TSH) will increasethe functionof the normal thyroid gland during the RAIU depressionby excessiveiodides,thisincreased functioncannotbe detectedin the presenceof a largeiodidepool because of the technicalinabilityto measure the change in the verysmallRA!U values(Table !!!B). There appearsto be no significantlossor retentionof iodide throughdefectsinexcretion(74). Another possiblebut much lessfrequentinfluenceof excessive iodideson the thyroidaluptake of 131!isthrough pharmacologic effectson the gland.Such effectsare not well understood but appear to involvean inhibitionof thyroidhormone releaseand a block of organificationof iodine(75,76). This latteractionof
868 JAMESC. SISSON
since the trapping of iodide is unaffected, iodide accumulation and the early RA!U values may be increased following an augmenta tion of thyrotropin secretion due to decreased thyroid hormono genesis. A rebound of the RA!U to high levels may occur follow ing the cessation of these drugs (88). Perchlorate and thiocyanate treatments inhibit the trapping of iodide by the thyroid gland, and the resulting RAIU values are low at all intervals following a tracer dose. d. Miscellaneous drugs. Adrenal corticosteroids in relatively large doses (greater than 100 mg/d of cortisone) lower RAIU values (40, 41) simultaneously with reduction of the PB! concentrations. The mechanism is not entirely understood (43), Phenylbutazone therapy also depresses RAIU values by an undetermined action (89).
- Extrathyroidal diseases. a. As was noted above,allthyroidfunctionparameters,includingthe RAIU, may be increasedin cases of choriocarcinomaand em bryonalcellcarcinomaof the testisprobablybecause of secretion ofthyrotropin-likesubstancesfrom thetumors (45-47). b. Gastrointestinalmalabsorptionstatesordinarilydo not influence theRA!U significantly(74). c. Impaired liverfunctionmay be associatedwith increasedRAIU valueswith normal PB! measurements (90,91). Itispossiblethat poor dietaryhabitshave led to diminishediodidepoolsin these individuals. d. Renal diseasesusuallyhave littleor no effecton the RAIU values (74,92),but occasionallythe urinaryhormonal lossin nephrosis may lead to elevated levels of thyroid uptake (93). e. Congestiveheartfailure,forunknown reasons,isoccasionallyas sociated with low RAIU measurements (94). A summary of the factors affecting the RAIU and the corresponding PB! changes is seen in Table IIIC.
IV. StimulationTests.
A. General Considerations.
When the diagnosis of hypothyroidism is established, the important ques
tion of pathogenesis requires attention. Differentiation of primary thyroid failure from the hypothyroidismassociatedwith pituitaryhyposecretionof thyrotropin may be accomplished by the clinical history and physical examination, but occa sionally this problem requires special laboratory aids for solution. The diagnosis of the type of myxedema, primary or pituitary, that is present in an individualisnot readilyverifiedby the usuallaboratorytestsof endocrine function.Thyroid functiontestsgive low valueswhich are usuallycompatible with eitherdisorder.Evaluationof otherendocrineorgans may be misleading. A selective loss of thyrotropin in pituitary disease may produce little in the way
PRINCIPLES OF, AND PITFALLS IN, THYROID FUNCTION TESTS 869
of changes in other endocrine organs that might provide clues as to the principal disease process (95, 96). Also, thyroid gland failure itself frequently leads to depression of adrenal and gonadal function tests (97, 98), although insufficiency of clinical significance may not exist in these latter endocrine organs. Serum levels of thyrotropin are ordinarily high in early primary thyroid failure, but prolonged myxedema may be associated with low or absent serum thyrotropin values (99- 101). Estimation of the thyroid functional integrity through stimulation tests offers a laboratory method of resolving the dilemma.
TABLE IIIC Summary of Thyroidal Radioactive Iodine Uptake Changes Type of RA I U Disturbance ELEVATED VALUES Hyperthyroidism Hyperthyroidism Adequately Treated Low Iodide Po@I Thyroid Diseases Hashimoto's (Early) Subacute Thyroiditis (Recovery) Intrathyroidal Biochemical Disturbances Rebound from Inhibition of Hornionogenesis After Iodide Therapy After Antithyroid Drug Therapy Extrathyroidal Diseases Cirrhosis Nephrosis Choriocarcinoma
DEPRESSED VALUES
Hypothyroidism Large Iodide Pool Iodide Administration Organic Iodine Administration Thyroid Diseases Hashimoto's (Late) Subacute Thyroiditis (Early) Intrathyroidal Biochemical Disturbances Thyroid Hormones Antithyroid Drugs Adrenal Corticosteroids Extrathyroidal Diseases Congestive Heart Failure
Concomitant FBI
High Normal Normal
Normal or High Low or Normal Low or Normal
Normal Low or Normal
Low or Normal Low High
Low
Normal or High High
Low Normal or High Low or Normal Depends on Type Low or Normal Low
Normal
PRINCIPLES OF, AND PITFALLS IN, THYROID FUNCTION TESTS 871
normal PB! increases ( 104, 105 ). Three daily injections of thyrotropin produce a cumulative rise in the RAIU ( 113). Because of the high frequency of untoward symptoms following receipt of TSH in large quantities,' individual doses of any practical test must be limited to about 0.1 U/kg (5-10 U in most subjects), although multiple injections of 5U do not seem to induce added symptoms (113). b. Time of Testing The maximal increase in the RA!U values of normal subjects appeared between 18 and 24 hours following a TSH injection (102, 103). The augmentationof the PB! concentrationin normal individuals appeared to be greatest between 24 and 48 hours subsequent to the administrationof thyrotropin(108,109).Although a peak PB! level may be achievedas earlyas 15 hours post-ThH, (114),PB ‘s'!data also point to the 24-28 hour period for the maximal PB! response to thyrotropin (102). The administration of thyroid hormone to subjects, who then presumably have subnormal endogenous thyrotropinse cretion, may result in a peak PB! response that is delayed to 72 hours following a TSH injection (109). c. Type of RAIU test. Jefferies notes that 10 per cent of individuals will have a natural variation between two 3-hour RAIU tests of a magnitude to obscure any TSH effect (115). This variability may be no less between two 24-hour RAIU tests, (60), although this longer period for uptake tests is more commonly used.
- Recommendations for a Thyroid Stimulation Test. Using the knowledge gained from the literature as noted above, it is possible to recommend a thyroid stimulation test protocol for the average clinical laboratory. a. A baseline 24 hour RAIU and PB! are determined. b. Thyrotropin, 5 units, is given intramuscularly (the remaining hormone in a commercial vial may be stored for a few days in a refrigerator). c. Twenty-four hours after the thyrotropin injection, and following a count of residual activity in the thyroid gland, a second tracer of ‘@‘Iis administered,and a 24 hour RAIU is completed the followingday (48hourspost-TSH). d. A secondPB! isobtained48 hoursaftertheTSH injection. e. Normal values may be estimated from the data of Taunton, et at, Tables IV A and IV B, but are best determinedfor each labora tory.
1Symptoms (principally hyperthyroidism, nausea and vomiting, fever, and precordial pain) occurred in 7% of males and 15% of females following 0.1 U/kg of TSH (102); and 8% and 17% of all subjects tested after 5U on 3 days and lOU on 1 day, respectively (104).
872 JAMES C. SISSON
f. If there is a subnormal response in the results of either the RA!U or the PB!, the stimulation test should be repeated using thyrotropin 5U injections on each of three days instead of one. Again, normal values may be seen in Tables IV A-B.
- Pitfalls in Stimulations Tests. a. It should be recognized that the thyroid stimulation test as de scribed above is an indirect assessment of pituitary hyposecretion of thyrotropin as a cause of hypothyroidism.' Since some normal subjects will have RAIU and PB! values that, through natural biological variation, fall outside an accepted range of normal, a true state of hypothyroidism should be proven to exist before ac cepting adequate thyroid gland responses to TSH as indicative of pituitarydysfunction. b. Neutralizing antibodies to commercial thyrotropin have been dem onstrated in human subjects after multiple injections of this hor mone (116). Although such antibodies usually do not result in a refractoriness to TSH until after many doses have been given, some patients will be encountered who have had multiple tests of thyropituitary function using commercial thyrotropin. Caution should be exercisedin the interpretationof poor thyroidalre sponses to TSH in these individuals. c. Occasionally pituitary failure will be associated with irreversible thyroid atrophy (105, 114, 117, 118), and possibly quite frequently in Sheehan's syndrome (104). Thus, stimulation tests, as with all laboratory data, should comprise only a part of a complete clinical evaluation.Prolongedthyroidhormone therapymay alsoresultin thyroidgland suppressionthatisunresponsiveto the usual stim ulation test (105, 118). In a few instances of the latter category, the thyroid may resume normal function after cessation of hor mone treatment, and the gland may later be responsive to TSH (118). d. Untoward reactions, and possibly death (104), may result from stimulation tests, especially with the larger thyrotropin doses. The testshouldbe used with clearindications.Athough probablyrare, adrenalcrisismay be precipitatedby the increasedmetabolism from the thyroid hormone released by TSH in a patient with pituitary insufficiency (119). This would be more likely to follow multiple injections than a single dose of thyrotropin. Again, a complete clinical evaluation will alert the physician to the possi bility of hypoadrenocorticism which may be worsened by thyroid stimulation. The latter catastrophe can be obviated by prior ad renocortical hormone therapy.
‘Atest which assesses endogenous thyrotropin secretion by evaluating its effect on the thyroid gland has been described (95).
