Hyperthyroidism with Normal Concentrations of Total Serum Thyroxine and Triiodothyronine JAMES B. GERSTNER,* AND ROBERT H. CAPLAN Department of Medicine, Gundersen Clinic, Ltd., and La Crosse Lutheran Hospital, 1836 South Avenue, La Crosse, Wisconsin ABSTRACT. Normal concentrations of total serum thyroxine (T4) and triiodothyronine (T3) were found in a patient who was hyperthyroid because of a hyperfunctioning thyroid adenoma. After surgical removal of the adenoma, the patient became clinically euthyroid; the abnormally high free thyroxine (FT4), triiodothyronine resin uptake (T3R), and rapid achilles reflex time (ART) returned to normal. A low-normal concentration of thyroxinebinding globulin (TBG) determined by polyacrylamide gel electrophoresis and a low level of TBG determined by radioimmunoassay were found in the patient. The TBG remained low-normal after the restitution of euthyroidism. Low TBG levels were found in the patients 5
brothers and maternal uncle, and a low-normal concentration was found in her mother. It is postulated that the patient was a heterozygous carrier for a genetically determined partial (non-zero) TBG deficiency and that a low-normal TBG concentration decreased total T3 as well as T4 when the patient was hyperthyroid. To the authors' knowledge, this is the first case of hyperthyroidism associated with both normal total T4 and T3 concentrations. The diagnosis of hyperthyroidism in the presence of low TBG is difficult, and determination of FT4 and free triiodothyronine (FT3) may be necessary to establish the diagnosis. (J Clin Endocrinol Metab 42: 64, 1976)
S
ENSITIVE and specific measurements of circulating thyroxine (T4) (1) and triiodothyronine (T3) (2-9) have clarified the relative roles of these hormones in the production of hyperthyroidism. Although both hormones are usually elevated (5), in the syndrome called "T3-toxicosis" there is an excess concentration of T 3 but normal concentrations of T4 and free thyroxine (FT4) (10-14). When hyperthyroidism is associated with a deficiency of thyroxinebinding globulin (TBG), T4 is normal, as in "T3-toxicosis", but FT 4 is elevated (15-16). In the only case of hyperthyroidism with TBG deficiency in which T 3 was measured, this hormone was elevated (17). However, we report a patient with an autonomous hyperfunctioning thyroid ade-
noma and a probable partial TBG deficiency in whom repeated determinations of both T4 and T 3 were normal. Case Report A 25-year-old woman was found to have a thyroid nodule during a routine physical examination (January, 1973) 7 months prior to her examination at the Gundersen Clinic. She was initially asymptomatic but gradually developed fatigue, generalized weakness, heat intolerance, excessive diaphoresis, nervousness, insomnia, and tremulousness. Although she lost 10 kg the previous year with purposeful dieting, her weight recently was stable. She denied taking any medications. Serum T4 in January, 1973 was 9.5 fig per 100 ml (normal, 5-13.7 fig per 100 ml). Repeat T4 determinations in March and July, 1973 were 5.7 fig per 100 ml and 4.3 fig per 100 ml (normal, 2.6-7.2 fig per 100 ml). The 24-hr uptake of 131I (U24) in January, 1973 was 37% (normal, 0-24%) and a thyroid scintigram (Fig. 1) revealed all radioiodine was concentrated in a nodule in the left lobe. Three weeks after treatment with 25 fig of triiodothyronine (Cytomel®) four times daily (March, 1973),
Received August 25, 1975. * Present address: United States Army Hospital, Fort Campbell, Kentucky. Supported by a grant from the Adolf Gundersen Medical Foundation. Reprints: Robert H. Caplan, M.D., Gundersen Clinic, Ltd., 1836 South Avenue, La Crosse, Wisconsin 54601. Non proprietary and trade names of drugs: Triiodothyronine—Cytomel®; Sodium Iodide I131—Iodotope I13', Iodotope Therapeutic, Oriodide-131, Radiocaps-131, Theriodide-131, Tracervial-131.
64
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HYPERTHYROIDISM WITH NORMAL T4 AND T3 the U24 was 44% and the left lobe continued to function (Fig. 1). Because of the persistently normal T4 despite clinical evidence of hyperthyroidism, the patient was referred to the Gundersen Clinic. On physical examination (July 26, 1973), the patient weighed 66 kg. Her pulse rate was 120 beats per min. She appeared tense and hyperkinetic and a fine tremor was present on extension of the hands. The skin was warm and moist. Lid lag and lid retraction were present, but there were no eye changes of infiltrative ophthalmopathy or pretibial myxedema. A firm, symmetrical nodule, estimated to weigh 30 g was palpated in the left lobe of the thyroid gland. The right lobe was barely palpable. There was no clinical or laboratory evidence of any chronic illness other than hyperthyroidism. The serum albumin was 5 g per 100 ml (normal, 3.5-5 g per 100 ml). The results of the thyroid function tests are summarized in Table 1. Although the T4 and T3 were repeatedly normal, the typical clinical picture, elevated FT 4 and rapid achilles reflex time (ART) strongly suggested that the patient was hyperthyroid. After euthyroidism was achieved with propylthiouracil and saturated solution of potassium iodide, a left hemithyroidectomy was performed (November 7,1973). An encapsulated thyroid nodule measuring 4.8 x 3.2 x 2.5 cm and weighing 25 g was removed. Histologically, the lesion was a benign follicular adenoma. Four weeks after surgery, the patient was improved and appeared clinically euthyroid. Her pulse was 72 beats per min. Thyroid function studies (Table 1) were normal and a scintigram of the thyroid (Fig. 1) revealed function in the previously suppressed right lobe. Eighteen and 28 weeks after surgery, the patient was well, and her test results (Table 1) remained normal. Materials and Methods The total serum T4 was measured by an adaptation of the competitive protein binding
65
FlGS. la-c. Scintigrams of the thyroid 24 hours after the oral administration of radioactive iodide 13II. (top) Pretrearment (January, 1973). Essentially all radioactive iodine is in the left sided nodule. U24 is 37% (normal 0-24%). (center) Three weeks after treatment with triiodothyronine (Cytomel®) 25 ug four times daily (March 21, 1973). The left lobe continues to function. U24 is 44%. (bottom) Postoperative (December 17, 1973). Scintigram of the thyroid 30 min after IV administration of technetium (i)9mTc) pertechnetate. The left lobe shows little function since only a small remnant remains. The previously suppressed right lobe now functions normally.
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66
JCK & M • 1976 V»l 42 • No I
GERSTNER AND CAPLAN
TABLE 1. Results of laboratory tests* before and after removal of a hyperfunctioning thyroid adenoma (/ig/100ml)
(/xg/100ml)
T3R (%)
FT4f (ng/100ml)
(ng/tOOml)
T3t (ng/lOOml)
TBCt WlOOml)
TBG} (mg/lOOml)
TBPA (ng/lOOml)
ART (msec)
Normal
3.3-9.3
4-11
25-35
0.6-2.6
120-312
80-220
16-24
2.5-4.8
10-40
280-400
Date
7/26/73
7.4
10.6
38.1
3.0
247
-
17.6
-
9/13/73§
7.4
10.9
37.6
3.1
223
216
16.4
2.0
23.5
220
12/17/73 (4 weeks postop)
3.7
4.3
31.5
0.9
157
85
16.6
2.5
25.0
320
4/4/74H (18 weeks postop)
5.2
5.9
29
1.1
166
17.8
—
—
320
6/22/74 (28 weeks postop)
4.7
* T 4 = thyr jxine; T,R = triiodothyronine
—
17.8
31.2
resin
uptake;
FT4 = free
thyroxine; T, = triiodothyr
-
-
27.5
ine; TBG = thryoxine-bindinK globulin;
TBPA = thyrox ne-binding prealbumin; ART = achilles reflex time; TSH = thyrotropin. f Determii ied by the Mayo Clinic Laboratories, Rochester, Minnesota, 55901. ) Determii ed by the Nichols Institute for Endocrinology, San Pedro, California, 90731. § Treat mer t with antithyroid dnigs started. HTSH5.6 mU/ml (normal, 0-15 niU/ml).
technique (18) and the resin uptake of radioactive triiodothyronine (T3R) (19) by commercial kits (Tetrasorb®-125 and Trisorb®-125 available from Abbott Laboratories, North Chicago, 111.). The Mayo Clinic Laboratories determined the T4 by the method of Murphy (3), FT 4 by a slight modification of the method of Sterling and Brenner (20), T 3 by radioimmunoassay (6), thyrotropin (TSH) by radioimmunoassay (21), and TBG by polyacrylamide gel electrophoresis (22). Serum obtained prior to treatment (Sept. 12, 1973) and after the restitution of euthyroidism (Dec. 17, 1973) was also analyzed by the Nichols Institute for Endocrinology for T3 by radioimmunoassay (23) and TBG by radioimmunoassay (24). Thyroxine-binding prealbumin (TBPA) was determined by radial gel diffusion (25) with the use of commercial kit (available from Behring Diagnostics, Dept. of Hoechst Pharmaceuticals, Inc., Somerville, NJ.) the half-relaxation time of the achilles reflex (ART) was determined with a Burdick photomotograph (26).
Comment Despite persistently normal T4 and T3, this patient had a typical clinical picture of hyperthyroidism. The failure to suppress a large nodule of the left lobe of the thyroid gland by the exogenous administration of triiodothyronine (Cytomel®) and the return to normal function of the sup-
pressed nonadenomatous side of the thyroid gland after removal of the adenoma prove autonomous function of the adenoma. In a euthyroid subject, a high-normal T4 is associated with a reciprocal decrease in the T3R. However, the high-normal T4 in our patient was associated with an elevated T3R, which is typical of hyperthyroidism with TBG deficiency (15-17). Although the FT4 may be elevated in chronic illness, the T3 in this circumstance is low (27-28). There was no clinical or laboratory evidence of chronic illness in our patient, other than hyperthyroidism, and the elevated FT4 was associated with normal rather than depressed T3. Thus, the typical clinical picture, elevated FT4, high U24, and rapid ART suggest the diagnosis of hyperthyroidism. Furthermore, the unequivocal clinical improvement to antithyroid drug treatment and subsequent removal of the autonomous nodule, normalization of the FT4 and rapid ART, and lowering of the T4, T3R, and T3 strongly support the diagnosis of hyperthyroidism. The elevated T3R and FT4 with a highnormal T4 suggested a deficiency of TBG in a hyperthyroid patient. Low-normal values of TBG were found by polyacrylamide gel electrophoresis and a low concentra-
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67
HYPERTHYROIDISM WITH NORMAL T4 AND T3 tion was detected by radioimmunoassay. In 23 cases of active hyperthyroidism, Inada and Sterling found decreased levels of TBG in 17 (29). Braverman and his colleagues also noted decreased thyroxine-binding proteins in 12 hyperthyroid patients. The concentration of these binding proteins returned to normal after euthyroidism was achieved (30). Little increase in the TBG concentration was noted after the restitution of euthyroidism in our patient. When the low-normal TBG concentration failed to increase after achieving euthyroidism, we studied the patient's family. Low TBG levels in her 5 brothers and maternal uncle indicate a genetic form of partial (non-zero) TBG deficiency (31). The inheritance of partial TBG deficiency in all published pedigrees (31) and in our family is compatible with sex-linked genetic transmission. Males, who are hemizygotes, are always more affected than females. Heterozygous females, identified by analysis of progeny, may have TBG values in
a range between the clearly low values of hemizygous males and normal subjects (31). Thus, females with partial familial TBG deficiency may have TBG concentrations in the low-normal range. The patient's mother (when euthyroid and not taking estrogens) had a low-normal TBG concentration similar in value to that of the patient and is probably a heterozygous carrier. Thus, although the data are not conclusive, it seems likely that the patient was also heterozygous for the gene that caused the partial TBG deficiency in her family. Alterations in the concentration of thyroxine-binding proteins affect the concentration of T4. Thyroxine is strongly bound to plasma proteins; approximately 60% is associated with TBG, 30% with TBPA, and the remainder with serum albumin (32). The free, metabolically active form of the hormone varies from 0.016 to 0.024%.f When TBG is decreased in concentration, the total f Mayberry, W. E., unpublished observations.
TABLE 2. Results of laboratory tests* in the patients family.
Normal Subject
Relationship
E. L.f
Mother
t «
T
T (Aig/lOOml)
T3R (%)
FT4 (ng/lOOml)
(ng/lOOml)
TBG Oig/100ml)
TBPA (ng/lOOml)
3.3-9.3
25-35
0.6-2.6
120-312
15-25
10-40
7.4 2.4 4.7
26.0 27.0 32.2
0.4
78
28.8 21.3 17.6
33.5 30.5 22.5
1.3
148
19
34.5
L. L., Sr.
Father
5.1
32.0
H. B.
Maternal Aunt
5.2
31
—
—
19.9
30.5
A. H.
Maternal Uncle
4.0
36
0.7
155
—
T. L.
Brother
3.6
36.2
1.4
157
11.3 11.7
32.5
M. L.
Brother
3.1
36.8
0.7
148
11.8
—
L. L.
Brother
3.7
30.0
0.9
152
14.6
30.0
H. L.
Brother
3.9
40.5
1.4
165
11.2
28.5
G. L.
Brother
5.3
35.7
1.3
160
14.2
37.0
S. L.
Sister
5.0
29.2
1.2
180
18.9
—
* T4 = thyroxine; T3R = triiodothyronine resin uptake; FT 4 = free thyroxine; T3 = triiodothyronine; TBG = thyroxine-binding globulin; TBPA = thryoxine-binding prealbumin; TSH = thyrotropin. f Taking 180 mg of desiccated thyroid and oral contraceptives daily. | Three months after discontinuing desiccated thyroid and oral contraceptives; clinically hypothyroid; TSH = 43.9 mU/ml (normal, 0-15 mU/ml). § Two months after reinstituting desiccated thyroid, 180 mg daily; clinically euthyroid.
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68
M • 1976 Vol 42 • No 1
GERSTNER AND CAPLAN
T4 is decreased, and the T3R, an indirect measure of unoccupied thyroid hormone binding sites, is elevated. Normal concentrations of FT4 maintain euthyroidism. The rare association of hyperthyroidism with diminished TBG frequently results in a normal, albeit high-normal T4; the T3R and FT4, however, are elevated (15-17). There is controversy concerning the degree of in vivo binding of T3 to plasma proteins (33-36). Triiodothyronine is primarily bound to TBG, but its affinity is two-to sixfold less than that of T4 (37). Binding to TBPA and albumin is also weak. Alterations of TBG concentrations do not affect the binding of T3 when studied indirectly by the disappearance of 131I-labeled T3 (33-34). In the one case of hyperthyroidism associated with TBG deficiency, in which T3 was measured, it was markedly elevated (17). The authors did not find low serum concentration of T3 in a euthyroid subject with complete absence of TBG. The method used (5), however, is subject to artifactual elevation and has largely been supplanted by radioimmunoassay methods. Triiodothyronine concentrations determined by radioimmunoassay in seven euthyroid subjects with familial TBG deficiency were 55 ng per 100 ml compared to 105 ng per 100 ml in normal subjects (36). Larsen also found low T3 in 3 euthyroid subjects with familial TBG deficiency (35). The T3 concentrations in our patient when she was euthyroid and in her brothers and maternal uncle were within the normal range. Although the number of determinations is small, the mean T3 of 156 ng per 100 ml in affected males is statistically lower (P < .01) than the mean value of 218 ng per 100 ml reported for the T3 method used. Thus, alterations in the TBG concentration may reduce T3 in a manner similar to T4. Triiodothyronine concentration is increased in virtually all patients with hyperthyroidism reported to date (10-14,35). The cause for the normal T3 concentration in our patient is not completely clear. Serum albumin and TBPA concentrations were nor-
mal. Decreased T3 secretion, alterations in the peripheral conversion of T4 to T3, or abnormalities in cellular binding and/or metabolism of T3 were not directly measured. The most likely explanation, however, is that the patient is a heterozygous carrier for a genetically determined partial TBG deficiency and that low-normal TBG concentrations decreased the bound forms of both T4 and T3. The hyperthyroidism was produced by increased levels of FT4 and presumably free triiodothyronine (FT3). No single test of thyroid function can now exclude the diagnosis of hyperthyroidism, and measurements of FT4 and FT3 may be necessary in some patients. Acknowledgments This study was supported by a grant from the Adolf Gundersen Medical Foundation. The authors thank Dr. Horace J. Anderson, Winona Clinic, Winona, Minnesota for referring the patient; Dr. Thomas F. Nikolai, Marshfield Clinic, Marshfield, Wisconsin for performing the TBG analysis in the patient's family; Dr. W. E. Mayberry, Mayo Clinic, Rochester, Minnesota for statistical analysis and helpful suggestions. We also wish to express our appreciation to Jean Bottcher, Kathy Ekberg, and Joan Egland for secretarial assistance and Ronna Cline for help in preparation of the manuscript.
References 1. Murphy, B. P., The determination of thyroxine by competitive protein-binding analysis employing an anion-exchange resin and radiothyroxine, J Lab Clin Med 66: 161, 1965. 2. Hollander, C. S., On the nature of the circulating thyroid hormone: clinical studies of triiodothyronine and thyroxine in serum using gas chromatographic methods, Trans Assoc Am Physicians 82: 76, 1968. 3. Nihei, N. D., M. C. Gershengorn, T. Mitsuma, et al., Measurements of triiodothyronine and thyroxine in human serum by gas-liquid chromatography, Anal Biochem 43: 433, 1971. 4. Nauman, J. A., A. Nauman, and S. C. Werner, Total and free triiodothyronine in human serum, J Clin Invest 46: 1346, 1967. 5. Sterling, K., D. Bellabarba, E. S. Newman, et al., Determination of triiodothyronine concentration in human serum,; Clin Invest 48: 1150, 1969. 6. Gharib, H., E. J. Ryan, W. E. Mayberry, et al., Radioimmunoassay for triiodothyronine (T3): I. Affinity and specificity of the antibody for T3, J Clin Endocrinol Metab 33: 509, 1971.
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HYPERTHYROIDISM WITH NORMAL T 4 AND T 3 7. Mitsuma, T., N. Nihei, M. C. Gershengom, et al., Serum triiodothyronine: measurements in human serum by radioimmunoassay with corroboration by gas-liquid chromatography, J Clin Invest 50: 2679, 1971. 8. Chopra, I. J., D. H. Solomon, and B. N. Beall, Radioimmunoassay for measurement of triiodothyronine in human serum, J Clin Invest 50: 2033, 1971. 9. Lieblich, J. M., and R. D. Utiger, Triiodothyronine radioimmunoassay, J Clin Invest 51: 157, 1972. 10. Sterling, K., S. Refetoff, and H. A. Selenkow, T3 thyrotoxicosis. Thyrotoxicosis due to elevated serum triiodothyronine levels, JAMA 213: 571, 1970. 11. Ivy, H. K., H. W. Wahner, and C. A. Gorman, "Triiodothyronine (T3) toxicosis." Its role in Grave's disease, Arch Intern Med 128: 529, 1971. 12. Hollander, C. S., T. Mitsuma, N. Nihei, et al., Clinical and laboratory observations in cases of triiodothyronine toxicosis confirmed by radioimmunoassay, Lancet 1: 609, 1972. 13. Bellabarba, D., Further observations on T3 thyrotoxicosis, Clin Res 19: 716, 1971. 14. Hollander, C. S., and L. Shenlman, The physiological role of triiodothyronine, Am J Med Sci 264: 5, 1972. 15. Lemarchand-Beraud, B., M. R. Assayah, and A. Vannatti, Alterations of thyroxine-binding protein in clinically hypo- and hyperthyroid patients with normal PBI level, Ada Endocrinol (Kbh) 45: 99, 1964. 16. Cavalieri, R. R., Hyperthyroidism and decreased thyroxine-binding by serum proteins, J Clin Endocrinol Metab 21: 1455, 1961. 17. Wahner, H. W., R. F. Emslander, and C. A. Gorman, Thyroid overactivity and TBG deficiency simulating "T3-hyperthyroidism," J Clin Endocrinol Metab 33: 93, 1971. 18. Braverman, L. E., A. G. Vagenakis, A. E. Foster, et al., Evaluation of a simplified technique for a specific measurement of serum thyroxine concentration, J Clin Endocrinol Metab 32: 497, 1971. 19. Leonards, J. R., Correlation between results of a new T-3 test and the percentage of free thyroxine in serum, Clin Chem 16: 922, 1970. 20. Arango, G., W. E. Mayberry, T. G. Hocket, et al, Total and free human serum thyroxine in normal and abnormal thyroid states, Mayo Clinic Proc 43: 503, 1968. 21. Mayberry, W. E., H. Gharib, J. M. Bolstad, et al., Radioimmunoassay for human thyrotropin: clinical value in patients with normal and abnormal thyroid function, Ann Intern Med 74: 471, 1971. 22. Nikolai, T. F., and U. S. Seal, X-chromosome linked familial decrease in thyroid-binding globulin activity, J Clin Endocrinol Metab 26: 835, 1966.
69
23. Chopra, I. J., R. S. Ho, and R. Lam, An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies,; Lab Clin Med 80: 729, 1972. 24. Levy, R. P., J. S. Marshall, and N. L. Velayo, Radioimmunoassay of human thyroxine-binding globulin (TBG), J Clin Endocrinol Metab 32: 372, 1971. 25. Becker, W., Determination of antisera titres in the single radial immunodiffusion method, Immunochem 6, 539, 1969. 26. Reinfrank, R. F., R. P. Kaufman, H. J. Wetstone, et al., Observations of the achilles reflex test, JAMA 199: 1, 1967. 27. Sullivan, P. R. C , J. A. Ballinger, and S. Reichlin, Selective deficiency of tissue: triiodothyronine: A proposed mechanism of elevated free thyroxine in the euthyroid sick, J Clin Invest 52: 83a, 1973, (Abstract #306). 28. Chopra, I. J., D. H. Soloman, U. Chopra, et al., Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyroninej Clin Endocrinol Metab 39: 501, 1974. 29. Inada, M., and K. Sterling, Thyroxine transport in thyrotoxicosis and hypothyroidism,/ Clin Invest 46: 1442, 1967. 30. Braverman, L. E., A. E. Foster, and S. H. Ingbar, Thyroid hormone transport in the serum of patients with thyrotoxic Graves' disease before and after treatment,; Clin Invest 47: 1349, 1968. 31. Refetoff, S., N. I. Robin, and C. A. Alper, Study of four new kindreds with inherited thyroxinebinding globulin abnormalities. Possible mutations of a single gene locus, J Clin Invest 51: 848, 1972. 32. Oppenheimer, J. H., Role of plasma proteins in the binding distribution and metabolism of the thyroid hormones, N EnglJ Med 278: 1153, 1968. 33. Zaninovich, A. A., R. Volpe, and C. Ezrin, Effects of variations of thyroxine-binding globulin capacity on the disappearance of triiodothyronine from plasma, J Clin Endocrinol Metab 29: 1601, 1969. 34. , H. Farach, C. Ezrin, et al., Lack of significant binding of L-triiodothyronine by thyroxine-binding globulin vivo as demonstrated by acute disappearance of 131I-labeled triiodothyronine, 7 Clin Invest 45: 1290, 1966. 35. Larsen, P. R., Triiodothyronine. Review of recent studies of its physiology and pathophysiology in man, Metabolism 21: 1073, 1972. 36. Dussault, J. H., D. A. Fisher, J. T. Nicoloff, et al., The effect of alteration of thyroxinebinding capacity on the dialyzable and absolute fractions of triiodothyronine in circulation, Ada Endocrinol (Kbh) (Kobenhavn) 72: 265, 1973. 37. Rail, J. E., J Robbins, and C. G. Lewellen, In Pincus, G., K. Themion, and E. Astwood, (eds.), The Hormones, Academic Press, New York, 1964, p 159.
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brothers and maternal uncle, and a low-normal concentration was found in her mother. It is postulated that the patient was a heterozygous carrier for a genetically determined partial (non-zero) TBG deficiency and that a low-normal TBG concentration decreased total T3 as well as T4 when the patient was hyperthyroid. To the authors' knowledge, this is the first case of hyperthyroidism associated with both normal total T4 and T3 concentrations. The diagnosis of hyperthyroidism in the presence of low TBG is difficult, and determination of FT4 and free triiodothyronine (FT3) may be necessary to establish the diagnosis. (J Clin Endocrinol Metab 42: 64, 1976)
S
ENSITIVE and specific measurements of circulating thyroxine (T4) (1) and triiodothyronine (T3) (2-9) have clarified the relative roles of these hormones in the production of hyperthyroidism. Although both hormones are usually elevated (5), in the syndrome called "T3-toxicosis" there is an excess concentration of T 3 but normal concentrations of T4 and free thyroxine (FT4) (10-14). When hyperthyroidism is associated with a deficiency of thyroxinebinding globulin (TBG), T4 is normal, as in "T3-toxicosis", but FT 4 is elevated (15-16). In the only case of hyperthyroidism with TBG deficiency in which T 3 was measured, this hormone was elevated (17). However, we report a patient with an autonomous hyperfunctioning thyroid ade-
noma and a probable partial TBG deficiency in whom repeated determinations of both T4 and T 3 were normal. Case Report A 25-year-old woman was found to have a thyroid nodule during a routine physical examination (January, 1973) 7 months prior to her examination at the Gundersen Clinic. She was initially asymptomatic but gradually developed fatigue, generalized weakness, heat intolerance, excessive diaphoresis, nervousness, insomnia, and tremulousness. Although she lost 10 kg the previous year with purposeful dieting, her weight recently was stable. She denied taking any medications. Serum T4 in January, 1973 was 9.5 fig per 100 ml (normal, 5-13.7 fig per 100 ml). Repeat T4 determinations in March and July, 1973 were 5.7 fig per 100 ml and 4.3 fig per 100 ml (normal, 2.6-7.2 fig per 100 ml). The 24-hr uptake of 131I (U24) in January, 1973 was 37% (normal, 0-24%) and a thyroid scintigram (Fig. 1) revealed all radioiodine was concentrated in a nodule in the left lobe. Three weeks after treatment with 25 fig of triiodothyronine (Cytomel®) four times daily (March, 1973),
Received August 25, 1975. * Present address: United States Army Hospital, Fort Campbell, Kentucky. Supported by a grant from the Adolf Gundersen Medical Foundation. Reprints: Robert H. Caplan, M.D., Gundersen Clinic, Ltd., 1836 South Avenue, La Crosse, Wisconsin 54601. Non proprietary and trade names of drugs: Triiodothyronine—Cytomel®; Sodium Iodide I131—Iodotope I13', Iodotope Therapeutic, Oriodide-131, Radiocaps-131, Theriodide-131, Tracervial-131.
64
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HYPERTHYROIDISM WITH NORMAL T4 AND T3 the U24 was 44% and the left lobe continued to function (Fig. 1). Because of the persistently normal T4 despite clinical evidence of hyperthyroidism, the patient was referred to the Gundersen Clinic. On physical examination (July 26, 1973), the patient weighed 66 kg. Her pulse rate was 120 beats per min. She appeared tense and hyperkinetic and a fine tremor was present on extension of the hands. The skin was warm and moist. Lid lag and lid retraction were present, but there were no eye changes of infiltrative ophthalmopathy or pretibial myxedema. A firm, symmetrical nodule, estimated to weigh 30 g was palpated in the left lobe of the thyroid gland. The right lobe was barely palpable. There was no clinical or laboratory evidence of any chronic illness other than hyperthyroidism. The serum albumin was 5 g per 100 ml (normal, 3.5-5 g per 100 ml). The results of the thyroid function tests are summarized in Table 1. Although the T4 and T3 were repeatedly normal, the typical clinical picture, elevated FT 4 and rapid achilles reflex time (ART) strongly suggested that the patient was hyperthyroid. After euthyroidism was achieved with propylthiouracil and saturated solution of potassium iodide, a left hemithyroidectomy was performed (November 7,1973). An encapsulated thyroid nodule measuring 4.8 x 3.2 x 2.5 cm and weighing 25 g was removed. Histologically, the lesion was a benign follicular adenoma. Four weeks after surgery, the patient was improved and appeared clinically euthyroid. Her pulse was 72 beats per min. Thyroid function studies (Table 1) were normal and a scintigram of the thyroid (Fig. 1) revealed function in the previously suppressed right lobe. Eighteen and 28 weeks after surgery, the patient was well, and her test results (Table 1) remained normal. Materials and Methods The total serum T4 was measured by an adaptation of the competitive protein binding
65
FlGS. la-c. Scintigrams of the thyroid 24 hours after the oral administration of radioactive iodide 13II. (top) Pretrearment (January, 1973). Essentially all radioactive iodine is in the left sided nodule. U24 is 37% (normal 0-24%). (center) Three weeks after treatment with triiodothyronine (Cytomel®) 25 ug four times daily (March 21, 1973). The left lobe continues to function. U24 is 44%. (bottom) Postoperative (December 17, 1973). Scintigram of the thyroid 30 min after IV administration of technetium (i)9mTc) pertechnetate. The left lobe shows little function since only a small remnant remains. The previously suppressed right lobe now functions normally.
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66
JCK & M • 1976 V»l 42 • No I
GERSTNER AND CAPLAN
TABLE 1. Results of laboratory tests* before and after removal of a hyperfunctioning thyroid adenoma (/ig/100ml)
(/xg/100ml)
T3R (%)
FT4f (ng/100ml)
(ng/tOOml)
T3t (ng/lOOml)
TBCt WlOOml)
TBG} (mg/lOOml)
TBPA (ng/lOOml)
ART (msec)
Normal
3.3-9.3
4-11
25-35
0.6-2.6
120-312
80-220
16-24
2.5-4.8
10-40
280-400
Date
7/26/73
7.4
10.6
38.1
3.0
247
-
17.6
-
9/13/73§
7.4
10.9
37.6
3.1
223
216
16.4
2.0
23.5
220
12/17/73 (4 weeks postop)
3.7
4.3
31.5
0.9
157
85
16.6
2.5
25.0
320
4/4/74H (18 weeks postop)
5.2
5.9
29
1.1
166
17.8
—
—
320
6/22/74 (28 weeks postop)
4.7
* T 4 = thyr jxine; T,R = triiodothyronine
—
17.8
31.2
resin
uptake;
FT4 = free
thyroxine; T, = triiodothyr
-
-
27.5
ine; TBG = thryoxine-bindinK globulin;
TBPA = thyrox ne-binding prealbumin; ART = achilles reflex time; TSH = thyrotropin. f Determii ied by the Mayo Clinic Laboratories, Rochester, Minnesota, 55901. ) Determii ed by the Nichols Institute for Endocrinology, San Pedro, California, 90731. § Treat mer t with antithyroid dnigs started. HTSH5.6 mU/ml (normal, 0-15 niU/ml).
technique (18) and the resin uptake of radioactive triiodothyronine (T3R) (19) by commercial kits (Tetrasorb®-125 and Trisorb®-125 available from Abbott Laboratories, North Chicago, 111.). The Mayo Clinic Laboratories determined the T4 by the method of Murphy (3), FT 4 by a slight modification of the method of Sterling and Brenner (20), T 3 by radioimmunoassay (6), thyrotropin (TSH) by radioimmunoassay (21), and TBG by polyacrylamide gel electrophoresis (22). Serum obtained prior to treatment (Sept. 12, 1973) and after the restitution of euthyroidism (Dec. 17, 1973) was also analyzed by the Nichols Institute for Endocrinology for T3 by radioimmunoassay (23) and TBG by radioimmunoassay (24). Thyroxine-binding prealbumin (TBPA) was determined by radial gel diffusion (25) with the use of commercial kit (available from Behring Diagnostics, Dept. of Hoechst Pharmaceuticals, Inc., Somerville, NJ.) the half-relaxation time of the achilles reflex (ART) was determined with a Burdick photomotograph (26).
Comment Despite persistently normal T4 and T3, this patient had a typical clinical picture of hyperthyroidism. The failure to suppress a large nodule of the left lobe of the thyroid gland by the exogenous administration of triiodothyronine (Cytomel®) and the return to normal function of the sup-
pressed nonadenomatous side of the thyroid gland after removal of the adenoma prove autonomous function of the adenoma. In a euthyroid subject, a high-normal T4 is associated with a reciprocal decrease in the T3R. However, the high-normal T4 in our patient was associated with an elevated T3R, which is typical of hyperthyroidism with TBG deficiency (15-17). Although the FT4 may be elevated in chronic illness, the T3 in this circumstance is low (27-28). There was no clinical or laboratory evidence of chronic illness in our patient, other than hyperthyroidism, and the elevated FT4 was associated with normal rather than depressed T3. Thus, the typical clinical picture, elevated FT4, high U24, and rapid ART suggest the diagnosis of hyperthyroidism. Furthermore, the unequivocal clinical improvement to antithyroid drug treatment and subsequent removal of the autonomous nodule, normalization of the FT4 and rapid ART, and lowering of the T4, T3R, and T3 strongly support the diagnosis of hyperthyroidism. The elevated T3R and FT4 with a highnormal T4 suggested a deficiency of TBG in a hyperthyroid patient. Low-normal values of TBG were found by polyacrylamide gel electrophoresis and a low concentra-
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67
HYPERTHYROIDISM WITH NORMAL T4 AND T3 tion was detected by radioimmunoassay. In 23 cases of active hyperthyroidism, Inada and Sterling found decreased levels of TBG in 17 (29). Braverman and his colleagues also noted decreased thyroxine-binding proteins in 12 hyperthyroid patients. The concentration of these binding proteins returned to normal after euthyroidism was achieved (30). Little increase in the TBG concentration was noted after the restitution of euthyroidism in our patient. When the low-normal TBG concentration failed to increase after achieving euthyroidism, we studied the patient's family. Low TBG levels in her 5 brothers and maternal uncle indicate a genetic form of partial (non-zero) TBG deficiency (31). The inheritance of partial TBG deficiency in all published pedigrees (31) and in our family is compatible with sex-linked genetic transmission. Males, who are hemizygotes, are always more affected than females. Heterozygous females, identified by analysis of progeny, may have TBG values in
a range between the clearly low values of hemizygous males and normal subjects (31). Thus, females with partial familial TBG deficiency may have TBG concentrations in the low-normal range. The patient's mother (when euthyroid and not taking estrogens) had a low-normal TBG concentration similar in value to that of the patient and is probably a heterozygous carrier. Thus, although the data are not conclusive, it seems likely that the patient was also heterozygous for the gene that caused the partial TBG deficiency in her family. Alterations in the concentration of thyroxine-binding proteins affect the concentration of T4. Thyroxine is strongly bound to plasma proteins; approximately 60% is associated with TBG, 30% with TBPA, and the remainder with serum albumin (32). The free, metabolically active form of the hormone varies from 0.016 to 0.024%.f When TBG is decreased in concentration, the total f Mayberry, W. E., unpublished observations.
TABLE 2. Results of laboratory tests* in the patients family.
Normal Subject
Relationship
E. L.f
Mother
t «
T
T (Aig/lOOml)
T3R (%)
FT4 (ng/lOOml)
(ng/lOOml)
TBG Oig/100ml)
TBPA (ng/lOOml)
3.3-9.3
25-35
0.6-2.6
120-312
15-25
10-40
7.4 2.4 4.7
26.0 27.0 32.2
0.4
78
28.8 21.3 17.6
33.5 30.5 22.5
1.3
148
19
34.5
L. L., Sr.
Father
5.1
32.0
H. B.
Maternal Aunt
5.2
31
—
—
19.9
30.5
A. H.
Maternal Uncle
4.0
36
0.7
155
—
T. L.
Brother
3.6
36.2
1.4
157
11.3 11.7
32.5
M. L.
Brother
3.1
36.8
0.7
148
11.8
—
L. L.
Brother
3.7
30.0
0.9
152
14.6
30.0
H. L.
Brother
3.9
40.5
1.4
165
11.2
28.5
G. L.
Brother
5.3
35.7
1.3
160
14.2
37.0
S. L.
Sister
5.0
29.2
1.2
180
18.9
—
* T4 = thyroxine; T3R = triiodothyronine resin uptake; FT 4 = free thyroxine; T3 = triiodothyronine; TBG = thyroxine-binding globulin; TBPA = thryoxine-binding prealbumin; TSH = thyrotropin. f Taking 180 mg of desiccated thyroid and oral contraceptives daily. | Three months after discontinuing desiccated thyroid and oral contraceptives; clinically hypothyroid; TSH = 43.9 mU/ml (normal, 0-15 mU/ml). § Two months after reinstituting desiccated thyroid, 180 mg daily; clinically euthyroid.
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68
M • 1976 Vol 42 • No 1
GERSTNER AND CAPLAN
T4 is decreased, and the T3R, an indirect measure of unoccupied thyroid hormone binding sites, is elevated. Normal concentrations of FT4 maintain euthyroidism. The rare association of hyperthyroidism with diminished TBG frequently results in a normal, albeit high-normal T4; the T3R and FT4, however, are elevated (15-17). There is controversy concerning the degree of in vivo binding of T3 to plasma proteins (33-36). Triiodothyronine is primarily bound to TBG, but its affinity is two-to sixfold less than that of T4 (37). Binding to TBPA and albumin is also weak. Alterations of TBG concentrations do not affect the binding of T3 when studied indirectly by the disappearance of 131I-labeled T3 (33-34). In the one case of hyperthyroidism associated with TBG deficiency, in which T3 was measured, it was markedly elevated (17). The authors did not find low serum concentration of T3 in a euthyroid subject with complete absence of TBG. The method used (5), however, is subject to artifactual elevation and has largely been supplanted by radioimmunoassay methods. Triiodothyronine concentrations determined by radioimmunoassay in seven euthyroid subjects with familial TBG deficiency were 55 ng per 100 ml compared to 105 ng per 100 ml in normal subjects (36). Larsen also found low T3 in 3 euthyroid subjects with familial TBG deficiency (35). The T3 concentrations in our patient when she was euthyroid and in her brothers and maternal uncle were within the normal range. Although the number of determinations is small, the mean T3 of 156 ng per 100 ml in affected males is statistically lower (P < .01) than the mean value of 218 ng per 100 ml reported for the T3 method used. Thus, alterations in the TBG concentration may reduce T3 in a manner similar to T4. Triiodothyronine concentration is increased in virtually all patients with hyperthyroidism reported to date (10-14,35). The cause for the normal T3 concentration in our patient is not completely clear. Serum albumin and TBPA concentrations were nor-
mal. Decreased T3 secretion, alterations in the peripheral conversion of T4 to T3, or abnormalities in cellular binding and/or metabolism of T3 were not directly measured. The most likely explanation, however, is that the patient is a heterozygous carrier for a genetically determined partial TBG deficiency and that low-normal TBG concentrations decreased the bound forms of both T4 and T3. The hyperthyroidism was produced by increased levels of FT4 and presumably free triiodothyronine (FT3). No single test of thyroid function can now exclude the diagnosis of hyperthyroidism, and measurements of FT4 and FT3 may be necessary in some patients. Acknowledgments This study was supported by a grant from the Adolf Gundersen Medical Foundation. The authors thank Dr. Horace J. Anderson, Winona Clinic, Winona, Minnesota for referring the patient; Dr. Thomas F. Nikolai, Marshfield Clinic, Marshfield, Wisconsin for performing the TBG analysis in the patient's family; Dr. W. E. Mayberry, Mayo Clinic, Rochester, Minnesota for statistical analysis and helpful suggestions. We also wish to express our appreciation to Jean Bottcher, Kathy Ekberg, and Joan Egland for secretarial assistance and Ronna Cline for help in preparation of the manuscript.
References 1. Murphy, B. P., The determination of thyroxine by competitive protein-binding analysis employing an anion-exchange resin and radiothyroxine, J Lab Clin Med 66: 161, 1965. 2. Hollander, C. S., On the nature of the circulating thyroid hormone: clinical studies of triiodothyronine and thyroxine in serum using gas chromatographic methods, Trans Assoc Am Physicians 82: 76, 1968. 3. Nihei, N. D., M. C. Gershengorn, T. Mitsuma, et al., Measurements of triiodothyronine and thyroxine in human serum by gas-liquid chromatography, Anal Biochem 43: 433, 1971. 4. Nauman, J. A., A. Nauman, and S. C. Werner, Total and free triiodothyronine in human serum, J Clin Invest 46: 1346, 1967. 5. Sterling, K., D. Bellabarba, E. S. Newman, et al., Determination of triiodothyronine concentration in human serum,; Clin Invest 48: 1150, 1969. 6. Gharib, H., E. J. Ryan, W. E. Mayberry, et al., Radioimmunoassay for triiodothyronine (T3): I. Affinity and specificity of the antibody for T3, J Clin Endocrinol Metab 33: 509, 1971.
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HYPERTHYROIDISM WITH NORMAL T 4 AND T 3 7. Mitsuma, T., N. Nihei, M. C. Gershengom, et al., Serum triiodothyronine: measurements in human serum by radioimmunoassay with corroboration by gas-liquid chromatography, J Clin Invest 50: 2679, 1971. 8. Chopra, I. J., D. H. Solomon, and B. N. Beall, Radioimmunoassay for measurement of triiodothyronine in human serum, J Clin Invest 50: 2033, 1971. 9. Lieblich, J. M., and R. D. Utiger, Triiodothyronine radioimmunoassay, J Clin Invest 51: 157, 1972. 10. Sterling, K., S. Refetoff, and H. A. Selenkow, T3 thyrotoxicosis. Thyrotoxicosis due to elevated serum triiodothyronine levels, JAMA 213: 571, 1970. 11. Ivy, H. K., H. W. Wahner, and C. A. Gorman, "Triiodothyronine (T3) toxicosis." Its role in Grave's disease, Arch Intern Med 128: 529, 1971. 12. Hollander, C. S., T. Mitsuma, N. Nihei, et al., Clinical and laboratory observations in cases of triiodothyronine toxicosis confirmed by radioimmunoassay, Lancet 1: 609, 1972. 13. Bellabarba, D., Further observations on T3 thyrotoxicosis, Clin Res 19: 716, 1971. 14. Hollander, C. S., and L. Shenlman, The physiological role of triiodothyronine, Am J Med Sci 264: 5, 1972. 15. Lemarchand-Beraud, B., M. R. Assayah, and A. Vannatti, Alterations of thyroxine-binding protein in clinically hypo- and hyperthyroid patients with normal PBI level, Ada Endocrinol (Kbh) 45: 99, 1964. 16. Cavalieri, R. R., Hyperthyroidism and decreased thyroxine-binding by serum proteins, J Clin Endocrinol Metab 21: 1455, 1961. 17. Wahner, H. W., R. F. Emslander, and C. A. Gorman, Thyroid overactivity and TBG deficiency simulating "T3-hyperthyroidism," J Clin Endocrinol Metab 33: 93, 1971. 18. Braverman, L. E., A. G. Vagenakis, A. E. Foster, et al., Evaluation of a simplified technique for a specific measurement of serum thyroxine concentration, J Clin Endocrinol Metab 32: 497, 1971. 19. Leonards, J. R., Correlation between results of a new T-3 test and the percentage of free thyroxine in serum, Clin Chem 16: 922, 1970. 20. Arango, G., W. E. Mayberry, T. G. Hocket, et al, Total and free human serum thyroxine in normal and abnormal thyroid states, Mayo Clinic Proc 43: 503, 1968. 21. Mayberry, W. E., H. Gharib, J. M. Bolstad, et al., Radioimmunoassay for human thyrotropin: clinical value in patients with normal and abnormal thyroid function, Ann Intern Med 74: 471, 1971. 22. Nikolai, T. F., and U. S. Seal, X-chromosome linked familial decrease in thyroid-binding globulin activity, J Clin Endocrinol Metab 26: 835, 1966.
69
23. Chopra, I. J., R. S. Ho, and R. Lam, An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies,; Lab Clin Med 80: 729, 1972. 24. Levy, R. P., J. S. Marshall, and N. L. Velayo, Radioimmunoassay of human thyroxine-binding globulin (TBG), J Clin Endocrinol Metab 32: 372, 1971. 25. Becker, W., Determination of antisera titres in the single radial immunodiffusion method, Immunochem 6, 539, 1969. 26. Reinfrank, R. F., R. P. Kaufman, H. J. Wetstone, et al., Observations of the achilles reflex test, JAMA 199: 1, 1967. 27. Sullivan, P. R. C , J. A. Ballinger, and S. Reichlin, Selective deficiency of tissue: triiodothyronine: A proposed mechanism of elevated free thyroxine in the euthyroid sick, J Clin Invest 52: 83a, 1973, (Abstract #306). 28. Chopra, I. J., D. H. Soloman, U. Chopra, et al., Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyroninej Clin Endocrinol Metab 39: 501, 1974. 29. Inada, M., and K. Sterling, Thyroxine transport in thyrotoxicosis and hypothyroidism,/ Clin Invest 46: 1442, 1967. 30. Braverman, L. E., A. E. Foster, and S. H. Ingbar, Thyroid hormone transport in the serum of patients with thyrotoxic Graves' disease before and after treatment,; Clin Invest 47: 1349, 1968. 31. Refetoff, S., N. I. Robin, and C. A. Alper, Study of four new kindreds with inherited thyroxinebinding globulin abnormalities. Possible mutations of a single gene locus, J Clin Invest 51: 848, 1972. 32. Oppenheimer, J. H., Role of plasma proteins in the binding distribution and metabolism of the thyroid hormones, N EnglJ Med 278: 1153, 1968. 33. Zaninovich, A. A., R. Volpe, and C. Ezrin, Effects of variations of thyroxine-binding globulin capacity on the disappearance of triiodothyronine from plasma, J Clin Endocrinol Metab 29: 1601, 1969. 34. , H. Farach, C. Ezrin, et al., Lack of significant binding of L-triiodothyronine by thyroxine-binding globulin vivo as demonstrated by acute disappearance of 131I-labeled triiodothyronine, 7 Clin Invest 45: 1290, 1966. 35. Larsen, P. R., Triiodothyronine. Review of recent studies of its physiology and pathophysiology in man, Metabolism 21: 1073, 1972. 36. Dussault, J. H., D. A. Fisher, J. T. Nicoloff, et al., The effect of alteration of thyroxinebinding capacity on the dialyzable and absolute fractions of triiodothyronine in circulation, Ada Endocrinol (Kbh) (Kobenhavn) 72: 265, 1973. 37. Rail, J. E., J Robbins, and C. G. Lewellen, In Pincus, G., K. Themion, and E. Astwood, (eds.), The Hormones, Academic Press, New York, 1964, p 159.
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