Misleadingly Low Free Thyroxine Index and Usefulness of Reverse Triiodothyronine Measurement in Nonthyroidal Illnesses

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1 Misleadingly Low Free Thyroxine Index and Usefulness of Reverse Triiodothyronine Measurement in Nonthyroidal Illnesses INDER J. CHOPRA, M.D.; DAVID H. SOLOMON, M.D.; GERSHON W. HEPNER, M.D.; and ALAN A. MORGENSTEIN, M.D.; Los Angeles and Torrance, California Nonthyroidal illness is frequently associated with subnormal serum thyroxine (T 4 ) and free T 4 index. To unravel the resultant diagnostic problems, we have studied several variables of thyroid function in the sera of 47 patients hospitalized with nonthyroidal illnesses and seven hypothyroid patients encountered during the same period. Of the 47 euthyroid sick patients, 18 had low T 4. Among these 18, free T 4 index was normal in only five, whereas free T 4 concentration measured by equilibrium dialysis was normal or high in 15 and 3,3,5- triiodothyronine (reverse T 3 ) normal or high in all 18. Reverse T 3f free T 4 concentration, and free T 4 index were subnormal in all seven hypothyroid patients. Thus, measurement of free T 4 index may be misleading in evaluation of thyroid function in patients with nonthyroidal illnesses, whereas measurement of serum concentration of reverse T 3 and free T 4 is quite discriminating. DETERMINATION OF free thyroxine (T 4 ) index is a popular test for evaluation of thyroid function status. Several methods have been devised to calculate this determinant (1-11); it is commonly ascertained by multiplying serum total T 4 concentration by 3,5,3'-triiodothyronine (T 3 ) uptake ratio, which in turn is derived by dividing the patient's percentage of resin (or red cell, charcoal, or talc) T 3 uptake value by that in pooled sera of normal subjects. Free T 4 index has been of value in correct interpretation or "adjustment" of serum total T 4 values when serum concentration of thyroxine-binding globulin is abnormal, as during administration of estrogen and in pregnancy and genetic abnormalities of thyroxine-binding globulin synthesis (1-8). With few exceptions, the information on thyroid functional status derived from free T 4 index has related quite favorably with that derived from direct measurement of free T 4 concentration by equilibrium dialysis (2, 5, 7, 8). More recently, the use of the free hormone index has also been encouraged for accurate interpretation of serum total T 3 (10, 11). Free T 3 index in pregnant women and in patients with hypothyroidism and hyperthyroidism correlates well with free T 3 concentration (10, 11). Experience with free T 4 index in evaluation of thyroid function in patients with nonthyroidal illnesses is much less extensive than that in states of altered serum thyroxine-binding globulin and thyroid disease. The limited available data suggest that free T 4 index is usually normal in nonthyroidal illnesses (3, 4, 7, 12). We have been intrigued recently by the finding of low free T 4 index and From the Departments of Medicine, UCLA Center for the Health Sciences, Los Angeles, and Harbor General Hospital, Torrance; California. low total T 4 in several patients hospitalized for nonthyroidal illnesses in whom the additional diagnosis of hypothyroidism could be considered. This consideration heightened the diagnostic problem and prompted us to undertake study of the relative usefulness of free T 4 index and other thyroid function test variables in evaluation of hypothyroidism in hospitalized patients. Besides conventional thyroid function tests, we have studied the serum concentration of 3,3',5'-T 3 (reverse T 3 ). Reverse T 3 is a calorigenically inactive iodothyronine produced, like T 3, predominantly from extrathyroidal metabolism of T 4 (13-15). Reverse T 3 was studied because its concentration in sera of euthyroid "sick" patients is generally elevated or normal when serum T 3 is low and serum T 4 is normal or low (15-18). Materials and Methods Blood samples (one each) for measurement of serum concentrations of total and free T 4, total and free T 3, T 3 resin uptake, reverse T 3, and thyrotropin (TSH) were obtained from 47 euthyroid patients, 20 to 62 years of age, hospitalized for various nonthyroidal illnesses at the UCLA Center for the Health Sciences, Los Angeles, or Harbor General Hospital, Torrance, California. Because previous experience had suggested that low T 4 values are more commonly seen in critically than in mildly "sick" patients, we did not exclude very ill patients from this study. When the blood sample was obtained, no patient was taking any drug known to influence thyroid function tests. Patients who had, in the previous 4 weeks, undergone diagnostic procedures with iodinated radiocontrast agents, which may alter circulating thyroid hormone levels, were also excluded from the study (19, 20). The main clinical problem was liver disease (alcoholic cirrhosis, viral hepatitis, chronic active hepatitis) in 27 patients; metastatic neoplastic disease in 11 patients (site for the primary lesion was lung in four, pancreas in two, prostate in two, breast in one, and unknown in two); cardiovascular disease in four patients (myocardial infarction with congestive heart failure in three and bacterial endocarditis in one); renal disease (azotemia) in three patients; diabetic ketoacidosis in one patient; and pulmonary disease (pneumonia) with hypoxia in one patient. The data on hospitalized patients from our previous reports on nonthyroidal illnesses (17, 21) have not been included here. Blood samples were also obtained from seven hypothyroid patients, 35 to 65 years of age, judged to be sufficiently (but moderately) ill so as to require hospitalization in the UCLA Hospital during this study. The results of thyroid function tests in various groups were compared with those in healthy euthyroid subjects, 18 to 56 years of age, by Student's two-tailed t test for unpaired data. For statistical computations, one half of the lowest value for sensitivity of the assay was used when a hormonal measurement was below the sensitivity of the assay. HORMONAL MEASUREMENTS Serum concentrations of T 4, T 3, reverse T 3, and TSH were measured by appropriate radioimmunoassays (14, 22-24). Free T 4 and free T 3 fractions were measured by equilibrium dialysis Annals of Internal Medicine 90: , American College of Physicians 905

2 Figure 1. Comparison of thyroid function test data in patients with nonthyroidal illnesses with normal thyroxine (T 4) or low T 4 and in hypothyroid patients. T 3 = 3,5,3'-triiodothyronine; reverse T 3= 3,3'5'-triiodothyronine; TSH = thyrotropin. and concentrations of free T 4 and free T 3 determined by multiplying total T 4 or T 3 values by the corresponding dialyzable fraction (25-28). Resin uptake of T 3 was measured by Res-O- Mat kits (available commercially from Mallinckrodt Inc., St. Louis, Missouri). Triiodothyronine uptake ratio and free T 4 index were calculated by the commonly used method, which has been ratified by a committee of the American Thyroid Association (29). It was also calculated by a new method proposed by Bermudez and colleagues (7). Since free T 4 index is simply an "index,*' no units of concentration have been assigned to express its level. Serum concentration of thyroxine-binding globulin was measured by radioimmunoassay (through the courtesy of Dr. Albert Nichols of Nichols Institute of Endocrinology, San Pedro, California). Results Individual values of various thyroid function tests are shown in Figure 1 (and in Appendix Table 1) and mean values in Table 1. Among the 47 patients with various nonthyroid illnesses, 18 had low T 4. The data from these 18 cases are listed separately, since these patients were the ones who presented a diagnostic problem. Serum T 4 concentration ranged from 1.0 to 4.5 jwg/dl (normal range, 4.8 to 13 jutg/dl) in patients with systemic (nonthyroidal) illnesses with low T 4 ; from 4.8 to 13 jutg/dl in patients with normal T 4 ; and from < 0.5 to 1.9 jutg/dl in hypothyroid patients. Resin uptake of T 3 was supranormal (range, 37.3% to 43.5%; normal range, 25% to 35%) in 13 of 18 patients with systemic illnesses with low T 4. Among 29 patients with systemic illnesses with normal T 4, 11 had supranormal (range, 35.4% to 41.5%) T 3 resin uptake. The mean T 3 resin uptake of 38% in patients with systemic illnesses with low T 4 and 34% in patients with normal T 4 were significantly higher than the normal mean value, 30% (P < 0.02). Resin uptake of T 3 was subnormal in one and normal in six of the hypothyroid patients. The mean T 3 resin uptake in hypothyroid patients (28%) did not differ significantly from the mean value in normal subjects. The increase in T 3 resin uptake was not of sufficient magnitude to yield a normal value for free T 4 index in most of the patients with systemic illnesses with low T 4. As calculated by the traditional method (29), free T 4 index was within the normal range (4.8 to 13) in only five of 18 such patients; like total T 4, free T 4 index was subnormal in the other 13 patients. Free T 4 index was in the normal range, 906 June 1979 Annals of Internal Medicine Volume 90 Number 6

3 however, in all 29 patients with systemic illnesses with normal T 4. Free T 4 index was subnormal in all hypothyroid patients. The mean free T 4 index of 3.4 in patients with systemic illnesses with low T 4 and 0.71 in hypothyroid patients was significantly (P < 0.01) lower than that of 7.6 in patients with systemic illnesses with normal T 4 and 8.2 in normal subjects. Because the traditional method of calculating free T 4 index may have been inadequate in the presence of a systemic illness, we recalculated the free T 4 index data by the method of Bermudez and associates (7). Free T 4 index was in the normal range in a few more patients with systemic illnesses with low T 4, but still only in eight of 18; it was clearly subnormal in the remaining 10 patients. The mean (± SEM) free T 4 index, calculated by the method of Bermudez and co-workers (7), of 4.2 ± 0.4 in patients with systemic illnesses with low T 4 was significantly (P < 0.01) lower than the 7.6 ± 0.4 in patients with systemic illnesses with normal T 4 and the 8.2 ± 0.3 in normal subjects. The dialyzable fraction of T 4 was clearly supranormal in all 18 patients with systemic illnesses with low T 4 and in 24 of 29 patients with normal T 4. The mean dialyzable fraction of T 4 in patients with systemic illnesses with low T 4 and normal T 4 of 0.13% and 0.10%, respectively, did not differ significantly. These values were threefold to fourfold higher than the mean values in normal subjects (0.033%) or in hypothyroid patients (0.037%). The highest values of dialyzable fraction of T 4 in patients with systemic illnesses with low T 4 and normal T 4 were 0.20% and 0.27%, respectively. Free T 4 concentration was in the normal range or was high in 15 of 18 patients with systemic illnesses with low T 4 ; it was low in the remaining three patients in this group (1.0, 1.1, and 1.6 ng/dl; normal range, 1.8 to 4.2 ng/dl). Free T 4 concentration of 3.9 ng/dl in patients with systemic illnesses with low T 4 was significantly (P < 0.01) higher than that of 2.8 ng/dl in normal subjects but significantly (P < 0.01) lower than the corresponding value of 6.6 ng/dl in patients with systemic illnesses with normal T 4. The mean free T 4 concentration of 0.31 ng/dl in hypothyroid patients was markedly subnormal (P < 0.001). Serum total T 3 concentration was subnormal in 16 of 18 patients with systemic illnesses with low T 4, in 20 of 29 patients with normal T 4, and in four of six hypothyroid patients. The mean serum T 3 concentrations ranged from 27 to 40 ng/dl in these groups. These values were not statistically different from one another but were all significantly (P < 0.001) less than those in normal subjects. The mean dialyzable fraction of T 3 of 0.84% in patients with systemic illnesses with low T 4 was modestly but significantly (P < 0.01) higher than that of 0.63% in patients with systemic illnesses with normal T 4. Both values were twofold to threefold higher than those in normal (0.34%) and hypothyroid subjects (0.33%). Free T 3 concentration was below the normal range (237 to 619 pg/dl) in 12 of 18 patients with systemic illnesses with low T 4 ; it was normal in the remaining six patients. Among 29 patients with systemic illnesses with normal T 4, free T 3 concentration was subnormal in 11, normal in 17, and borderline supranormal (660 pg/dl) in one. Free T 3 concentration was subnormal in all but one of six hypothyroid patients; it was normal in the remaining patient. The mean free T 3 concentration in the two groups of patients with systemic illnesses and in hypothyroid patients did not differ statistically from one another, but each value was significantly (P < 0.001) less than that in normal subjects (Table 1). Table 1. Thyroid Function Test Findings in Patients Hespital lized for Nc >nth yroidal Illnesses, Hypol thyroid Pati< jnts, and Normal Subjects Thyroid Function Normal Subjects Patients with Systemic Hypothyroid Test* (Nonthyroidal) Illnesses Patier itsf With Normal T 4 J With Low T 4 T 4, ng/dl 8.4 =fc 0.2(108) 6.9 d= 0.4** 3.0 =fc o.3tm 0.70 =fc 0.2** T 3 resin uptake, % 30 =fc 0.6 (21) 34 db =fc 1.2tt 28 ± 1.1 Free T 4 index 8.0 =fc 0.3 (21) 7.6 =b ± 0.4tt 0.71 db 0.2** Dialyzable T 4, % ± (25) 0.10 db 0.01** 0.13 ± 0.01ft ± Free T 4 concentration, ng/dl 2.8 ± 0.1 (25) 6.6 =fc 0.6** 3.9 ± 0.5ft 0.31 =fc 0.08** T 3, ng/dl 126 =fc 3.2 (108) 40 ± 3.9** 27 =fc =fc 14** Dialyzable T 3, % 0.34 =fc 0.01 (16) 0.63 =fc 0.04** 0.84 =fc 0.07ft 0.33 db 0.02 Free T 3 concentration, pg/dl 401 ± 27 (16) 233 =b29** 211 db ±48** TBG, mg/dl 3.6 =fc 0.08 (95) 3.6 ± 0.4 (5) 2.1 =fc 0.11 (8)tt Reverse T 3, ng/dl 41 =h 2.0 (27) 87 db 13** 142 ± 31 (16)tt 10 db 2.5** TSH,/xC//wL 2.4 =b 0.4 (14) 3.4 =fc 0.8 (26) 4.5 =fc 0.9 (17) 75 =1=22** *T 4 = thyroxine; Ti = 3,5,3'-triiodothyronine; TBG = thyroxine-binding globulin; Reverse Ti = S.S'.S'-triiodothyronine; TSH» thyrotropin. t^v =7. j N = 29 (unless indicated in parentheses). N = 18 (unless indicated in parentheses). Mean +SEM (number of subjects). ** Comparison with normal subjects, P < ft Comparison with patients with normal T 4, P < It All values in patients with systemic illness with low T 4 were significantly (P < 0.01) different from those in normal subjects except serum TSH concentration. P < Chopra eta/. Thyroid Function Tests in Systemic Illness 907

4 Reverse T 3 was measured in 16 patients with systemic illnesses with low T 4. It was clearly high (64 to 470 ng/ dl) in 11 patients and normal (34 to 60 ng/dl) in the remaining five patients (normal range, 27 to 62 ng/dl). Serum reverse T 3 ranged from 250 to 470 ng/dl in the three patients with systemic illnesses with low free and total T 4 concentrations (see above). Serum TSH value of < 2.5 jiiu/ml in all three of these cases was consistent with the clinical impression of euthyroidism. Reverse T 3 was measured in 26 patients with systemic illnesses with normal T 4 : It was clearly high (70 to 310 ng/dl) in 14 and normal (27 to 56 ng/dl) in 12 of these patients. Reverse T 3 was clearly subnormal ( < 10 to 20 ng/dl) in all seven hypothyroid patients. To gain some insight into the basis for low T 4 and high dialyzable fractions of T 4 and T 3 in nonthyroidal illnesses, serum concentration of thyroxine-binding globulin was measured in some cases. Of eight patients with systemic illnesses with low T 4, five had serum thyroxinebinding globulin in the normal range (2.0 to 5.2 mg/dl) while three had borderline low values (1.6, 1.7, and 1.9 mg/dl); the mean serum thyroxine-binding globulin concentration of 2.1 mg/dl in this group was significantly (P < 0.001) less, however, than that of 3.6 mg/dl in normal subjects. Serum thyroxine-binding globulin values ranged from 2.8 to 4.6 mg/dl in five patients with systemic illnesses with normal T 4 ; the mean serum thyroxine-binding globulin concentration of 3.6 mg/dl in this group was similar to that in normal subjects. Dialyzable fraction of T 4 (0.078% to 0.18%) and T 3 (0.59% to 1.18%), however, was clearly supranormal in all five patients with systemic illnesses with normal T 4 in whom serum concentration of immunoassayable thyroxinebinding globulin was measured and found to be normal. Serum TSH was measured in 17 patients with systemic illnesses with low T 4 and in 26 patients with normal T 4. Slightly high values were found in five patients with low T 4 (8.5 to 13.5 jutu/ml; normal range, < 2.5 to 7.5 JHU/ ml) and two patients with normal T 4 (14.0 and 18.0 JULU/ ml). The mean serum TSH in the two groups with systemic illnesses did not differ from each other or from that (2.4 jxu/ml) in normal subjects. Serum TSH was clearly supranormal, however, in all seven hypothyroid patients. Discussion Our findings of normal or low total T 4, normal or high free T 4, normal or low total T 3 and free T 3, normal or high reverse T 3, and normal or borderline high TSH concentrations in the sera of patients with nonthyroidal illnesses are similar to those observed in previous studies from many laboratories (7, 14-18, 21, 30-34). These changes have been attributed to complex abnormalities in hypothalamo-pituitary-thyroid relationships and to an alteration in extrathyroidal metabolism of T 4 whereby its conversion to T 3 is reduced while that to reverse T 3 is maintained at normal or is increased. It has been suggested (17, 21, 30) that high serum concentration of free T 4 in hepatic cirrhosis (and perhaps in other nonthyroidal illnesses) may represent a compensatory response to reduction in extrathyroid conversion of T 4 to T 3. Since serum TSH was high in only a few cases and free T 3 concentration was normal in several cases, it seems that compensatory mechanisms can become quite effective. The combination of normal free T 4 index and high free T 4 concentration in nonthyroidal illnesses has been observed in several previous studies (3, 12). The combination of clearly subnormal free T 4 index and high-normal or high free T 4 concentration in nonthyroidal illnesses has not, however, been highlighted previously. If we had relied entirely on free T 4 index, the combination of low free T 4 index and normal or undetectable TSH would have strongly suggested the diagnosis of secondary hypothyroidism in many of our patients who appeared clinically quite euthyroid. The high-normal to high free T 4 concentration was far more compatible with the clinical impression of euthyroidism. On the other hand, hyperthyroidism could not be diagnosed in the face of low normal or low concentration of free T 3. Previous studies have documented supranormal serum concentration of total and free T 4 in apparently euthyroid patients with systemic illnesses (31). These abnormalities are typically transient and subside with recovery from the systemic illness. High total or free T 4 of systemic illness, so-called "T 4 toxicosis" (32), may at times present problems of differential diagnosis with hyperthyroidism (Graves' disease). Absence of goiter and hypermetabolism, low normal or low serum concentration of total and free T 3, normal serum TSH response to thyrotropin-releasing hormone, and normal T 3 suppression test are some features that would favor a nonthyroidal systemic illness (over Graves' disease) as the cause of hyperthyroxinemia. Changes in T 3 resin uptake and dialyzable fraction of T 4 correlate well in various circumstances other than a systemic illness (2, 5, 7, 8). In nonthyroidal illnesses, however, the dialyzable fraction of T 4 is abnormal to a much greater degree than is T 3 resin uptake. The reasons for this marked and clinically very important discrepancy are not clear. Since thyroxine-binding prealbumin binds T 4 much more avidly than it binds T 3 (35, 36), one may attribute part of the discrepancy to a reduction in serum concentration of thyroxine-binding prealbumin in nonthyroidal illnesses (37, 38). Additionally, T 3 resin uptake is measured in the presence of barbital ions or at a ph that may inhibit the binding of iodothyronines to thyroxine-binding prealbumin (6, 12). Under these circumstances the effect of reduction of thyroxine-binding prealbumin on binding of T 3 (or T 4 ) to serum proteins will not be reflected well in measurements of T 3 resin uptake. However, since even complete inhibition of binding of T 4 to thyroxine-binding prealbumin and to albumin has been calculated to cause an increase in dialyzable fraction of T 4 of only about 30% (36), and since dialyzable T 4 was increased by 200% to 800% in many of our patients, it seems likely that factors other than reduction in thyroxine-binding prealbumin (or albumin) are critical to the observed discrepancy between dialyzable fraction of T 4 and T 3 resin uptake. One possibility is the existence in sera of "sick" patients of material(s) that inhibits the binding of thyroid hormones to serum proteins under the 908 June 1979 Annals of Internal Medicine Volume 90 Number 6

5 conditions of equilibrium dialysis to a much greater extent than under those of T 3 resin uptake. The finding in this and previous studies (17, 39) of markedly high dialyzable T 4 in several patients with systemic illnesses with clearly normal serum thyroxine-binding globulin concentration favors this possibility. Further, preliminary studies in our laboratories have indeed suggested the presence of a nondialyzable, heat-labile substance in the sera of several "sick" patients that inhibits the binding of thyroid hormones to serum proteins at physiologic ph (7.4). The inhibiting activity diminished markedly after diluted sera were brought to acid ph (4.5), centrifuged to remove insoluble matter, and dialyzed against buffers at physiologic ph before retesting. Results of these and other studies to characterize the nature of the inhibitor are detailed in a separate publication (40). It is interesting to recall that the ph of the resin used in the traditional T 3 resin uptake tests ranges between 4.3 and 5.2, and it is likely that the inhibitor is rendered inactive at this ph. In addition, correlation between T 3 resin uptake and dialyzable fractions of T 4 was unusually good in one recent study (7) in which physiologic ph (7.4) and activated charcoal were used to measure T 3 uptake instead of the ion exchange resin commonly used. We measured serum reverse T 3 concentration in this study to assess its value in the diagnosis of thyroid functional state in patients with low T 4 and nonthyroid illnesses. This seemed hopeful because reverse T 3 is high in the sera of many sick patients due to reduced clearance of reverse T 3 from the circulation and an apparent diversion of T 4 from outer-ring to inner-ring monodeiodination (15). Our studies indicate that serum reverse T 3 is at least normal and frequently clearly high in patients with nonthyroid illnesses with low T 4. On the other hand, serum reverse T 3 was uniformly subnormal in hypothyroid patients studied simultaneously. Although previous studies have shown some overlap between serum reverse T 3 values in hypothyroid patients and normal subjects (14, 41), the finding of high normal or high serum reverse T 3 concentrations seems to weigh heavily against the diagnosis of hypothyroidism in patients with nonthyroid illnesses. Actually, reverse T 3 measurement in our study seemed to be even more reliable in confirming the clinical impression of euthyroidism than did free T 4 concentration. We had three sick patients with low free T 4 concentrations in whom serum reverse T 3 was high and clinical impression and serum TSH values suggested euthyroidism. In the absence of reverse T 3 measurements in such cases, one may have been tempted to consider the diagnosis of secondary hypothyroidism and subject the patient, probably erroneously, to treatment with thyroid hormones. Why some sick patients have low free T 4 but do not manifest clinical or full biochemical evidence of hypothyroidism is not known. Possibly, the measurement of free T 4 concentration by equilibrium dialysis has some limitations, or perhaps some severely ill patients are truly hypothyroid. This may be the case in the few patients with nonthyroid illnesses who have low serum reverse T 3 as well as low T 4 and T 3 (42). However, since extrathyroid metabolism of T 4 is the main source of reverse T 3 in humans (15), the usual finding of high reverse T 3 in patients with nonthyroid illnesses argues that substantial quantities of precursor (that is, T 4 ) are available to tissues for metabolism to reverse T 3 and that treatment with thyroid hormones is not clearly indicated. This inference may have to be modified if subsequent studies are to show that serum reverse T 3 can be supranormal in sick patients with hypopituitarism. This however, seems unlikely. ACKNOWLEDGMENTS: The authors thank Ms. Guadalupe N. Chua Teco and Ms. Aimee Nguyen for able technical assistance and Ms. Kate Kavanagh for excellent secretarial assistance. This study was supported in part by U.S. Public Health Service grants AM-16155and AM Requests for reprints should be addressed to Inder J. Chopra, M.D.; Department of Medicine, UCLA Center for the Health Sciences; Los Angeles, CA Received 12 October 1978; revision accepted 15 February References 1. OSORIO C, JACKSON DJ, GARTSIDE JM, GOOLDEN AWG: The assessment of free thyroxine in plasma. Clin Sci 23: , CLARK F, HORN DB: Assessment of thyroid function by the combined use of the serum protein-bound iodine and resin uptake of '^-triiodothyronine. J Clin Endocrinol Metab 25:39-45, ANDERSON BG: Free thyroxine in serum in relation to thyroid function. JAMA 203: , HAMADA S, NAKAGAWA T, MORI T, TORIZUKA K: Re-evaluation of thyroxine binding and free thyroxine in human serum by paper electrophoresis and equilibrium dialysis, and a new free thyroxine index. / Clin Endocrinol Metab 31: , STEIN RB, PRICE L: Evaluation of adjusted total thyroxine (free thyroxine index) as a measure of thyroid function. / Clin Endocrinol Metab 34: , ROSENFELD L: "Free thyroxine index." A reliable substitute for "free" thyroxine concentration. Am J Clin Pathol 61: , BERMUDEZ F, SURKS MI, OPPENHEIMER JH: High incidence of decreased serum triiodothyronine concentration in patients with nonthyroidal disease. / Clin Endocrinol Metab 41:27-40, UCHIMURA H, NAGATAKI S, TABUCHI T, MIZUNO M, INGBAR SH: Measurements of free thyroxine: comparison of per cent of free thyroxine in diluted and undiluted sera. / Clin Endocrinol Metab 42: , SOUMA JA, NIEJADLIK DC, COTTRELL S, RANKEL S: Comparison of thyroid function in each trimester of pregnancy with the use of triiodothyronine uptake, thyroxine iodine, free thyroxine, and free thyroxine index. Am J Obstet Gynecol 116: , PARSLOW ME, ODDIE TH, FISHER DA: Evaluation of serum triiodothyronine and adjusted triiodothyronine (free triiodothyronine index) in pregnancy. Clin Chem 23: , SAWIN CT, CHOPRA D, ALBANO J, AZIZI F: The free triiodothyronine (T,) index. Ann Intern Med 88: , HOWORTH PJN, WARD RL: The (T 4 ) free thyroxine index as a test of thyroid function of first choice. / Clin Pathol 25: , BRAVERMAN LE, INGBAR SH, STERLING K: Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin Invest 49: , CHOPRA IJ: A radioimmunoassay for measurement of 3,3',5'-triiodothyronine (reverse T,). J Clin Invest 54: , CHOPRA IJ: An assessment of daily production and significance of thyroidal secretion of 3,3',5'-triiodothyronine (reverse T,) in man. / Clin Invest 58:32-40, REICHLIN S, BOLLINGER J, NEJAD I, SULLIVAN P: Tissue thyroid hormone concentration of rat and man determined by radioimmunoassay: biologic significance. Mt Sinai J Med 40: , CHOPRA IJ, CHOPRA U, SMITH SR, REZA M, SOLOMON DH: Reciprocal changes in serum concentrations of 3,3',5'-triiodothyronine (reverse T,) and 3,3',5-triiodothyronine (T,) in systemic illnesses. J Clin Endocrinol Metab 41: , NICOD P, BURGER A, STAEHELI V, VALLOTTON MB: A radioimmunoassay for 3,3',5'-triiodo-L-thyronine in unextracted serum: method and clinical results. / Clin Endocrinol Metab 42: , BtJRGI H, WlMPFHEIMER C, BURGER A, ZAUNBAUER W, ROSLER H, LEMARCHAND-BERAUD T: Changes of circulating thyroxine, triiodothyronine and reverse triiodothyronine after radiographic contrast agents. / Clin Endocrinol Metab 43: , 1976 Chopra et al. Thyroid Function Tests in Systemic Illness 909

6 Appendix Table 1. Tl lyroid Function Test 1 Data in Patients wi1 th Nonthyroidal Illi lesses and in Hy pothyroid Patients Group Patient Total T 4 * T 3 f Resin Free T 4 Dialyzable Free T 4 Uptake Index Fraction of T 4 Concentration ng/dl % % ng/dl Patients with systemic illnesses with normal T Mean ± SEM 6.9 ± ± ± ± ± 0.58 Patients with systemic illnesses with low T Mean ± SEM 3.0 ± ± ± ± ± 0.49 Hypothyroid patients < < < < Mean ± SEM 0.70 ± ± ± ± ±0.08 Normal Mean ± SEM (no.) 8.4 ± 0.2 (108) 30.4 ±0.6 (21) 8.0 ± 0.3 (21) ± (25) 2.8 ±0.1 (25) Range * Ti = thyroxine. t Ti = 3,^'-triiodothyronine. j Reverse Ti = 3,3',5'-triiodothyronine. TSH = thyrotropin. For undetectable values, one half of the value for sensitivity of the assay was used for statistical computations. 910 June 1979 Annals of Internal Medicine Volume 90 Number 6

7 Appendix Table 1. (Continued) Total T 3 Free T 3 Index Dialyzable Fraction of T 3 Free T 3 Concentration Reverse T 3 J Thyroxine-binding Globulin TSH ng/dl C/ pg/dl ng/dl mg/dl nu/ml < <10 ^ < <3.7 <10 <\ < <3.7 <10 < < ^4 < < ^8 <2J ^ < < < < < < < < < < ± ± ± ± ± ± ± < < <15 < <r <^2.5 <15 < < <15 < < ' <10 < < <2.5 <10 < < <2.5 <10 < <93 52 < < < < ± ± ± ± ± ± ± < < <10 38 <10 < < <10 < <43.4 < ± ± ± ± ± ± ±3.2(108) 122 ±6.1 (21) 0.34 ±0.01 (16) 401 ± 27 (16) 41 ± 2.0 (27) 3.6 ± 0.08 (95) 2.4 ± 0.4 (14) < Chopra eta/. Thyroid Function Tests in Systemic Illness 911

8 20. Wu SY, CHOPRA IJ, SOLOMON DH, BENNETT LR: Changes in circulating iodothyronines in euthyroid and hyperthyroid subjects given ipodate (Oragrafin), an agent for oral cholecystography. / Clin Endocrinol Metab 46: , CHOPRA IJ, SOLOMON DH, CHOPRA U, YOUNG RT, CHUA TECO GN: Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine. / Clin Endocrinol Metab 39: , CHOPRA IJ: A radioimmunoassay for measurement of thyroxine in unextracted serum. J Clin Endocrinol Metab 34: , CHOPRA IJ, Ho RS, LAM R: An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies. / Lab Clin Med 80: , (^DELL WD, WILBER JF, UTIGER RD: Studies of thyrotropin physiology by means of radioimmunoassay. Recent Prog Horrn Res 23:47-85, STERLING K, BRENNER MA: Free thyroxine in human serum; simplified measurement with the aid of magnesium precipitation. J Clin Invest 45: , SCHUSSLER GC, PLAGER JE: Effect of preliminary purification of UI I- thyroxine on the determination of free thyroxine in serum. / Clin Endocrinol Metab 27: , SOLOMON DH, BEALL GN: Effect of thyroxine on thyroid-stimulating activity in the serum of rabbits immunized with thyroid tissue. Endocrinology 86: , CHOPRA IJ, SOLOMON DH, CHUA TECO GN: Thyroxine: just a prohormone or a hormone too? / Clin Endocrinol Metab 36: , SOLOMON DH, BENOTTI J, DEGROOT LJ, GREER MA, OPPENHEIMER JH, PlLEGGI VJ, ROBBINS J, SELENKOW HA, STERLING K, VOLPE R: Revised nomenclature for tests of thyroid hormones in serum (letter). / Clin Endocrinol Metab 42: , GREEN JRB, SNITCHER EJ, MOW AT NAG, EKINS RP, REES LH, DAWSON AM: Thyroid function and thyroid regulation in euthyroid men with chronic liver disease: evidence of multiple abnormalities. Clin Endocrinol (Oxf) 7: , BIRKHAUSER M, BURER T, BUSSET R, BURGER A: Diagnosis of hyperthyroidism when serum-thyroxine alone is raised. Lancet 2:53-56, MCLELLAN GH, RILEY WJ, DAVIES CP: T4 toxicosis (letter). Lancet 2:660, CARTER JN, EASTMAN CJ, CORCORAN JM, LAZARUS L: Effect of severe, chronic illness on thyroid function. Lancet 2: , NOMURA S, PITTMAN CS, CHAMBERS JB JR, BUCK MW, SHIMIZU T: Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J Clin Invest 56: , INGBAR SH: Observations concerning the binding of thyroid hormones by human serum prealbumin. / Clin Invest 42: , LARSEN PR: Salicylate-induced increases in free triiodothyronine in human serum. Evidence of inhibition of triiodothyronine binding to thyroxine-binding globulin and thyroxine-binding prealbumin. / Clin Invest 51: , OPPENHEIMER JH, SQUEF R, SURKS MI, HAUER H: Binding of thyroxine by serum proteins evaluated by equilibrium dialysis and electrophoretic techniques. Alterations in non-thyroidal illness. / Clin Invest 42: , BERNSTEIN G, OPPENHEIMER JH: Factors influencing the concentration of free and total thyroxine in patients with nonthyroidal disease. / Clin Endocrinol Metab 26: , BURROWS AW, COOPER E, SHAKESPEAR RA, AICKIN CM, FRASER S, HESCH RD, BURKE CW: LOW serum L-T3 levels in the elderly sick: protein binding, thyroid and pituitary responsiveness, and reverse T3 concentrations. Clin Endocrinol (Oxf) 7: , CHOPRA I J, CHUA TECO GN, NGUYEN A, SOLOMON DH: In search of an inhibitor of thyroid hormone binding to serum proteins in nonthyroid illnesses. / Clin Endocrinol Metab, in press. 41. KAPLAN MM, SCHIMMEL M, UTIGER RD: Changes in serum 3,3',5'-triiodothyronine (reverse T 3 ) concentrations with altered thyroid hormone secretion and metabolism. / Clin Endocrinol Metab 45: , GAVIN L, RAPOPORT B, HAMMOND M, CAVALIERI RR: Variable serum reverse-t, (rt 3 ) and decreased T 3 concentrations in non-thyroidal systemic illness (SI) (abstract). Clin Res 24:272A, June 1979 Annals of Internal Medicine Volume 90 Number 6