IN MANY patients with thyrotoxicosis due to painless

0021-972X/87/6502-0359$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1987 by The Endocrine Society Vol. 65, No. 2 Printed in U...
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0021-972X/87/6502-0359$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1987 by The Endocrine Society

Vol. 65, No. 2 Printed in U.S.A.

Lower Serum Free Thyroxine (T4) Levels in Painless Thyroiditis Compared with Graves' Disease Despite Similar Serum Total T4 Levels CHIAKI SHIGEMASA, KYOJU ABE, SHIN-ICHI TANIGUCHI, YASUO MITANI, YOSHIHIKO UEDA, TOSHIAKI ADACHI, KEITA URABE, TAKASHI TANAKA, AKIO YOSHIDA, AND HIROTO MASHIBA First Department of Internal Medicine, Tottori University School of Medicine, and the Department of Nursing, Tottori University College of Medical Care Technology (K.A.), Yonago 683, Japan

ABSTRACT. Serum total T4 (T4), total T 3 (T3), free T4 (FT4), free T3 (FT3), and T4-binding globulin concentrations and T 3 resin uptake values were measured in 17 women with thyrotoxicosis due to painless thyroiditis (PT) and compared with the same parameters in 17 women with thyrotoxicosis due to Graves' disease (GD) with similar serum T4 levels. The mean serum T3 resin uptake value and T3, FT4, and FT3 concentrations in the PT patients were significantly lower than those in the GD patients. The mean serum T4-binding globulin concentration [20.2 ± 4.2 (±SD) Mg/mL] in patients with PT did not differ significantly from those in patients with GD (18.0 ± 2.6 ng/ mL)and normal euthyroid women (21.9 ± 4.0 fig/mL). The serum

I

N MANY patients with thyrotoxicosis due to painless thyroiditis (PT) (1-3), the serum T 3 resin uptake (T3-RU) values are in the normal range or only slightly increased despite markedly elevated total serum T4 (T4) levels. On the other hand, Christiansen et al. (4) reported that serum T3-RU values and percent free T4 (%FT4) measured by equilibrium dialysis in patients with subacute thyroiditis were significantly lower than those in patients with thyrotoxic Graves' disease (GD), although serum T4 levels were similar in the two groups. These differences have been explained by a difference between the T4-binding protein (TBP)-binding capacity in the two diseases. However, there have been no detailed studies of the relationship between serum T4, FT4, and T4binding globulin (TBG) in patients with PT. Moreover, whether the decrease in TBG binding contributes to the elevation of %FT4 in thyrotoxicosis is uncertain. This paper describes lower serum T3-RU values and FT4 concentrations in patients with thyrotoxicosis due to PT than in patients with thyrotoxicosis due to GD Received December 29,1986. Address requests for reprints to: Chiaki Shigemasa, M.D., First Department of Internal Medicine, Tottori University School of Medicine, 36-1 Nishimachi, Yonago, 683 Japan.

T3 to T4 (nanogram per ng) ratio was higher than 20 in 14 GD patients, but lower than 20 in all patients with PT, whereas the individual serum FT3 to FT4 ratio values considerably overlapped in the 2 groups. In patients with PT, FT4 correlated well with T4 at various times during the clinical course. These findings indicate that the elevation in serum FT4 in patients with PT is mostly due to the increase in circulating T4 levels, whereas GD patients also have some diminution in T4 binding. The serum T3 to T4 ratio, but not the FT3 to FT4 ratio, may be helpful for differentiation between the two diseases. (J Clin Endocrinol Metab 65: 359,1987)

despite similarly elevated serum T4 levels. We also sought possible reasons for these discrepant values between the two diseases by measuring total T 3 (T3), free T 3 (FT3), and TBG concentrations during their clinical courses. Subjects and Methods Eleven women with thyrotoxicosis due to spontaneous PT, aged 18-59 yr, and 6 women with postpartum PT, aged 22-28 yr, were studied. The diagnosis of PT was based on clinical and laboratory findings, including a high FT4 index and marked depression of thyroid radioactive iodine uptake (RAIU). Patients receiving drugs were excluded. The duration of symptoms before the initial examination varied between 2 and 10 weeks. Liver function tests were all normal. Seventeen women, aged 18-59 yr, with untreated thyrotoxicosis due to GD whose serum T4 concentrations were similar also were studied. Their duration of symptoms varied between 5 and 24 months. All patients with PT were followed at 2- to 4-week intervals, but no drugs were given. All patients with GD were treated with methimazole until they became euthyroid, as judged by normal serum FT4 and FT 3 levels. For determination of the normal ranges of the thyroid function tests, 42 normal women, aged 20-59 yr, were studied. The 24-h thyroid uptake of [123I]iodine (RAIU; normal range, 15-40%) was determined by standard procedures. The serum

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360

T4 concentrations and T3-RU values were measured using commercial kits (Thyrotest RIA-4 and Thyrotest-3, respectively, Nuclear Medical Laboratories, Irving, TX); normal ranges, 4.5-12.3 Mg/dL and 33.0-45.0%, respectively. Serum T 3 and TBG concentrations were measured by RIA (T3-RIA Bead and Riagnost-TBG, Dainabot Radioisotope Laboratories, Tokyo, Japan and Hoechst, Behring, West Germany, respectively; normal ranges, 80-190 ng/dL and 14.0-29.8 Mg/mL, respectively). The serum FT4 and FT 3 concentrations were determined by RIAs using Amerlex kits (Radiochemical Centre, Amersham, United Kingdom), using 125I-labeled T4 and T3 derivatives which cross-react with T4 and T3-specific antisera, but not with TBP. The normal range was 0.8-2.0 ng/dL for FT4 and 2.2-5.2. pg/mL for FT3. Serum FT4 and FT3 levels were also measured using Immophase kits (Corning Medical Laboratories, Medfield, MA) in which FT4 and FT 3 are quantified by solid phase RIA on the basis of the kinetics of T4 and T 3 binding to an immobilized T4 and T 3 antibody. The normal range using these latter assays was 1.0-2.2 ng/dL for FT4 and 3.2-6.9 pg/mL for FT3. All assays were carried out in duplicate. Statistical analysis was performed by means of Student's t test, but if variances were unequal, the Mann-Whitney U test was employed. Correlations were demonstrated by linear regression analysis. The normal ranges of the various thyroid function tests are given as the mean ± 2 SD.

Results Table 1 shows the results in each patient with PT, and Table 2 shows comparisons between the mean (±SD) levels of the same parameters, as well as the ratios of T 3 to T4 and FT 3 to FT4, in patients with PT and those

JCE & M • 1987 Vol 65 • No 2

with GD at the time of the initial examination and when they were euthyroid. The mean serum T4 level in the PT patients was almost identical to that in the GD patients (Table 2). The serum T3-RU values were within the normal range in four PT patients despite high serum T4 levels (Table 1). Thus, the mean T3-RU value (48.4 ± 5.6%) in the PT patients was significantly lower than that (56.6 ± 4.6%) in the GD patients (P < 0.01; Table 2). The mean serum FT 4 (3.82 ± 1.31 ng/dL (Amerlex) and 3.25 ± 0.97 ng/dL (Immophase)) levels in the PT patients also were significantly lower than those (5.85 ± 2.01 and 4.62 ± 1.27 ng/dL, respectively) in the GD patients (P < 0.01 and P < 0.01, respectively; Table 2). The mean serum T 3 and FT 3 concentrations in the PT patients were elevated, but were significantly lower than those in the GD patients (P < 0.005, P < 0.001, and P < 0.001, respectively; Table 2). The mean serum T 3 to T4, and Amerlex and Immophase FT 3 to FT4 ratios in the PT patients were significantly lower than those in the GD patients (P < 0.001, P < 0.01, and P < 0.05, respectively; Table 2). Individual serum T 3 to T 4 and Amerlex FT 3 to FT 4 ratios in the two types of thyrotoxicosis are shown in Fig. 1. The serum T 3 to T4 (nanogram per ng) ratios were higher than 20 in 14 of 17 GD patients, but lower than 20 in all PT patients. On the other hand, individual FT 3 to FT 4 ratios considerably overlapped between the 2 groups. Individual Immophase FT 3 to FT 4 ratios also overlapped (data not shown). The mean serum TBG level (20.2 ± 4.2 jug/mL) in the PT patients was similar to that (21.9 ± 4.0 ixg/mL) in the normal women

TABLE 1. Thyroid function tests at the initial examination in patients with thyrotoxicosis due to PT

Patient no. Spontaneous PT 1 2 3 4 5 6 7 8 9 10 11 Postpartum PT 12 13 14 15 16 17 Normal range

FT4 (ng/dL)

FT3 (pg/mL)

T4 (Mg/dL)

T3 uptake (%)

T3 (ng/dL)

Amerlex

Immophase

Amerlex

Immophase

TBG (Mg/mL)

Albumin (g/dL)

18.0 22.8 21.9 24.0 14.5 16.7 26.9 28.0 15.1 15.1 17.5

46.5 46.5 45.2 39.2 59.4 58.7 55.3 53.8 47.4 53.0 48.6

214 210 179 253 260 230 321 540 215 250 310

4.50 3.75 3.52 4.20 4.17 3.81 6.05 7.48 2.90 3.85 3.95

3.62 3.05 2.75 3.62 3.71 3.02 5.13 6.02 2.51 2.92 3.11

7.0 7.2 7.0 8.0 12.6 7.1 12.0 22.0 6.8 8.0 10.0

9.0 9.5 9.8 10.2 14.2 8.5 13.5 15.7 8.9 9.7 13.0

17.7 25.5 18.5 29.0 15.5 14.8 22.0 22.0 21.0 13.4 19.0

3.7 4.3 4.1 4.0 3.2 4.6 4.2 4.0 3.8 3.8 —

16.3 13.0 12.7 14.2 18.2 13.5

45.9 44.2 45.2 43.8 43.0 47.8

290 180 180 235 267 217

3.46 2.12 2.40 2.81 3.10 2.93

2.86 2.20 2.52 3.00 2.72 2.66

9.6 6.0 6.8 5.4 6.8 6.5

11.0 9.3 8.9 7.8 8.0 7.9

18.4 18.2 27.0 23.0 18.0 21.0

4.1 4.5 4.2 — 3.8 —

4.5-12.3

33-45

80-190

0.8-2.0

1.0-2.2

2.2-5.2

3.2-6.9

14.0-29.8

3.5-5.0

—, Not determined.

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361

TABLE 2. The thyroid function test results in patients with thyrotoxicosis due to PT or Graves' disease

At initial examination PT GD When euthyroid PT GD Values are the mean " P < 0.01 vs. GD. * P < 0.005 vs. GD. C P< 0.001 vs. GD. d P•

FT3 (pg/mL)

Immophase Amerlex Immophase

PT GD

FIG. 1. Individual serum T 3 to T4 and FT 3 to FT4 (Amerlex) ratios in patients with thyrotoxicosis due to PT or GD.

and that (18.0 ± 2.6 Mg/mL) in the GD patients. The difference between the mean serum TBG level in the GD patients and that in the normal women was significant (P < 0.05). In the PT patients, serum FT 4 declined to the normal range 5-16 weeks after the onset of illness. Eleven patients had transient hypothyroidism, which lasted for 614 weeks. The mean serum TBG levels in the euthyroid (n = 16), hypothyroid (n = 11), and recovery phase (n = 11) were 20.9 ± 3.4, 22.9 ± 2.9, and 22.1 ± 2.9 Mg/mL, respectively. The GD patients were all euthyroid within 7 weeks after the initiation of methimazole treatment. There were no significant differences between the mean values of the various thyroid function tests in the two groups when they were euthyroid (Table 2). As shown in Fig. 2, serum FT 4 and serum T4 levels correlated with one another during the clinical course in the PT patients (r = 0.8192 at the initial examination; r = 0.8903 in the other three phases). There was no significant difference between the slopes of the regression lines.

The mean serum T 3 -RU value in patients with thyrotoxicosis due to P T was significantly lower than that in patients with thyrotoxicosis due to GD despite similar serum T 4 levels. The finding of normal or slightly elevated serum T 3 -RU values in many P T patients despite markedly elevated serum T 4 levels is in agreement with the initial reports of P T (1-3). In addition, we found that the mean serum FT 4 concentration, measured by RIA, in the P T patients was significantly lower than that in the GD patients. On the other hand, our findings are similar to previous observations (5-7) that serum FT 4 concentrations, measured by RIA, in GD patients are increased more than serum T 4 levels. The elevation of %FT 4 measured by equilibrium dialysis in GD has been ascribed to both an increase in circulating T 4 and a net decrease in the binding capacity of T 4 to T B P (8-10). The latter may be due not only to diminution of the binding capacity of TBG (8, 11), but also to a fall in T 4 binding prealbumin (TBPA) (9,12). Therefore, our findings indicate that the T 4 -binding capacity of T B P in P T patients is not as low as that in GD patients. The difference in serum TBG in these two diseases may reflect the longer duration of thyrotoxicosis in GD (13, 14). Indeed, as reported previously (7, 15, 16), the mean serum TBG level in our GD patients was slightly but significantly decreased compared with that in normal subjects. On the other hand, the mean serum TBG level in the P T patients was slightly but not significantly higher than that in the GD patients. Amino et al. (15) also did not find a significant difference in serum TBG levels in P T patients and GD patients. Therefore, the decreased serum T 3 -RU values and FT 4 concentrations in the P T patients cannot be explained only by the difference in TBG concentrations in the two diseases. Recently, familial euthyroid hyperthyroxinemia resulting from increased T 4 binding to TBPA (17) or albumin (18) was reported. On the other hand, the relationships between the serum T 4 and T 3 concentrations and T 3 -RU values in our P T patients were similar to

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JCE & M • 1987 Vol 65 • No 2

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362

3 0-

thyrotoxic phase r = 0-1192 y = 3.32l3X+5.5893

25

T3 FIG. 2. The relationship between serum T4 and FT4 (Amerlex) levels during the thyrotoxic phase (O) and during the euthyroid, hypothyroid, and recovery phases (•) in patients with PT.

20



15

E

10

V GO

other three phases

5

r=O.I9O3 y=4.0633X+2.5270

0

1

2

3

4

5

6

7

8

Serum FT4 ( n g / d l ) those in untreated GD patients with elevated TBG levels (19). However, there were no significant differences between the mean serum T4, T3, FT4, and TBG concentrations and T3-RU values in the two groups when the patients became euthyroid. Accordingly, it is unlikely that the PT patients had idiopathic TBG elevation or familial euthyroid hyperthyroxinemia due to increased T4 binding to TBPA (17) or albumin (18). Yoshida et al. (20) speculated that the diminished capacity of TBPA as well as increased circulating T4 levels might contribute to the elevation of %FT4 in thyrotoxic patients with subacute thyroiditis. However, the elevation of %FT4 in our PT patients may be mostly due to the increased serum T4 levels, because there was no significant difference in the slope of the regression line relating FT 4 to T4 during the thyrotoxic and other phases in the PT patients. The mean serum FT 4 level in the GD patients was significantly higher than that in the PT patients despite their similar serum T 4 and TBG levels, indicating that the elevation of %FT4 in GD might be due to decreased T 4 binding to TBG (21, 22) and/or TBPA (9,10). Our findings of serum T 3 to T4 ratios greater than 20 in 14 of 17 GD patients and lower than 20 in all PT patients are in agreement with those of Amino et al. (15, 23). Similarly, the mean serum FT 3 to FT 4 ratio was

significantly higher in GD than in PT, but individual values overlapped considerably. Thus, the measurements of T4, T3, and T3-RU are more helpful for differentiating between thyrotoxicosis due to PT and GD than are measurements of FT4 and FT3. In contrast, Walfish (24) and Nikolai et al. (25) found that the serum T 3 to T 4 ratio did not reliably differentiate between the two causes of thyrotoxicosis. These conflicting results mean that RAIU or technetium uptake is still the best test to differentiate between the two causes of thyrotoxicosis, if the cause is not obvious from ocular examination, etc. Spontaneous resolution of the thyrotoxicosis to overt or subclinical hypothyroidism is confirmatory of PT. Serum FT 4 and FT 3 levels, measured using the Amerlex kits, may be influenced by changes in other binding proteins than TBG (26, 27), such as may occur with the longer duration of thyrotoxicosis in GD. On the other hand, Braverman et al. (5) reported normal FT 4 levels using the Immophase kit in systemically ill euthyroid patients and a highly significant correlation between Immophase FT 4 and equilibrium dialysis FT 4 levels in various clinical states and diseases, including hyperthyroidism. Our results using the two kits were almost identical. Accordingly, it is unlikely that our results are peculiar to the Amerlex kit method. A more definite conclusion about the reasons for the

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COMMENTS difference between the T4-binding capacity of TBP in the two types of thyrotoxicosis will require further studies. They should include a search for binding inhibitors (28, 29) and measurement of serum TBPA concentrations and TBG- and TBPA-binding affinities for T4 and T3.

Acknowledgments The authors thank Miss Keiko Iwata for technical assistance, and Miss Yuri Nakamura for secretarial assistance.

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13. Glinoer D, McGuire RA, Dubois A, Cogan JP, Robbins J, Berman M 1979 TBG metabolism in rhesus monkey: effects of hyper- and hypothyroidism. Endocrinology 104:175 14. Gershengorn MC, Glinoer D, Robbins J 1980 Transport and metabolism of thyroid hormones. In DeVisscher M (ed) The Thyroid Gland. Raven Press, New York, p 81 15. Amino N, Yabu Y, Miki K, Morimoto S, Kumahara Y, Mori H, Iwatani Y, Nishi K, Nakatani K, Miyai K 1981 Serum ratio of triiodothyronine to thyroxione and thyroxine-binding globulin and calcitonine concentrations in Graves' disease and destructioninduced thyrotoxicosis. J Clin Endocrinol Metab 53:113 16. Levy PR, Marshall JS, Velayo NL 1971 Radioimmunoassay of human thyroxine binding globulin (TBG). J Clin Endocrinol Metab 32:372 17. Moses AC, Lamber J, Haddow J, Jockson IMD 1982 Familial euthyroid hyperthyroxinemia resulting from increased thyroxin binding to thyroxine binding prealbumin. N Engl J Med 306:966 18. Ruiz M, Rajatanavin R, Young RA, Taylar C, Brown R, Braverman LE, Ingbar SH 1982 Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med 306:635 19. Yabu Y, Amino N, Nakatani K, Ichihara K, Azukizawa M, Niyai K 1980 Graves' disease associated with elevated serum thyroxinebinding globulin concentrations. J Clin Endocrinol Metab 51:325 20. Yoshida K, Sakurada T, Raise N, Kaise K, Kitaoka H, Fukazawa H, Yamamoto M, Saito S, Yoshinaga K 1982 Serum free thyroxine and triiodothyromine concentrations in subacute thyroiditis. J Clin Endocrinol Metab 55:185 21. Prince HP, Ramsden DB 1977 A new theoretical description of the binding of thyroid hormones by serum proteins. Clin Endocrinol (Oxf) 7:307 22. Yoshida K, Sakurada T, Kaise N, Kaise K, Kitaoka H, Fukazawa H, Suzuki M, Yamamoto M, Saito S 1981 The association constant of thyroxine binding for thyroxine in patients with hyperthyroidism. Folia Endocrinol Jpn 57:157 23. Amino N, Yabu Y, Miyai K, Fujie T, Azukizawa M, Ohnishi T, Kumahara Y 1978 Differentiation of thyrotoxicosis induced by thyroid destruction from Graves' disease. Lancet 2:344 24. Walfish PG 1978 T 3 /T 4 ratio in thyroid disease. Lancet 2:1056 25. Nikolai TF, Brosseau J, Kettrick MA, Roberts R, Beltaos E 1980 Lymphocytic thyroiditis with spontaneously resolving hyperthyroidism (silent thyroiditis). Arch Intern Med 140:478 26. Stockigt JR, De Graris M, Csicsmann J, Barlow JW, White EL, Hurley DM 1981 Limitation of a new free thyroxine assay (Amerlex Free T4). Clin Endocrinol (Oxf) 15:313 27. Amino N, Nishi K, Nakatani K, Mizuta H, Ichihara K, Tanizawa O, Miyai K 1983 Effect of albumin concentration on the assay of serum free thyroxine by equilibrium radioimmunoassay with labeled thyroxine analog (Amerlex Free T4) Clin Chem 29:321 28. Chopra IJ, Chuo Teco GN, Nguyen AH, Solomon DH 1979 In search of inhibitor of thyroid hormone binding to serum proteins and rat hepatocytes. J Clin Endocrinol Metab 54:757 29. Woeber K, Maddux BA 1981 Thyroid hormone binding in non thyroidal illness. Metabolism 30:412

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