Serum Thyroxine and Triiodothyronine Concentrations During Iodide Treatment of Hyperthyroidism CHARLES H. EMERSON, ARLENE J. ANDERSON, WILLIAM J. HOWARD, AND ROBERT D. UTIGER Endocrine Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19174 ABSTRACT. Serum thyroxine (T4) and triiodothyronine (T3) concentrations were measured at frequent intervals in 9 hyperthyroid patients treated with iodide alone. Serum T4 and T3 levels fell initially in all patients. In 6 patients, after a mean fall in serum T4 of 46% and in serum T3 of 47% after 4 to 11 days of therapy, thyroid hormone levels began to rise. In the 3 remaining patients a
rise in thyroid hormone levels was not seen following the initial fall. However, in one of this group T4 and T3 levels did not reach the normal range despite 60 days of therapy. These data support the concept that iodide alone is not an ideal agent for the treatment of hyperthyroidism. (J Clin Endocrinol Metab 40: 33, 1975)
F
OLLOWING Plummer's description in 1923 of the use of stable iodide to prepare patients with exophthalmic goiter for surgery (1), a number of papers have documented clinical improvement in hyperthyroid patients during iodide therapy (2,3). It was soon recognized, however, that iodide was not an ideal agent for the treatment of such patients. Not all patients responded to its use and, amongst those who did, there were many in whom reappearance of hyperthyroidism occurred despite continued therapy (4). Extensive laboratory studies beginning in 1944 have complemented these observations and established the concept of an acute antithyroid effect of iodide with subsequent escape (5,6). With the introduction of thiourea drugs, the use of iodide alone was largely abandoned. As a result there have been few measurements of serum thyroid hormone concentrations in hyperthyroid patients treated with iodide alone and the information available is confined to reports of protein bound iodide (PBI) determinations (7-11). This test provides no information about serum triiodothyronine levels, and,
as an indicator of serum thyroxine, is subject to distortion by numerous factors (12). Because iodide alone is still occasionally used for therapy in selected patients with hyperthyroidism, it was deemed worthwhile to determine serum T4 and T3 concentrations in a group of iodide-treated patients. This report describes the results of such measurements in a group of nine hyperthyroid patients. Of interest was the degree of improvement achieved and the timing of "escape" from the antithyroid effects of this agent. Materials and Methods Patients. Nine patients with hyperthyroidism were studied. Five were women and four were men. Their ages ranged from 23 to 42 yr. All subjects were newly diagnosed except for 1 who had received methimazole for several weeks 2 months earlier. The diagnosis was established by the presence of typical clinical features of hyperthyroidism and elevated serum T4 and T3 concentrations. All patients had diffuse thyroid enlargement and were free of complicating illness. Clinical and baseline laboratory information are shown in Table 1. Treatment program. The patients received 150 mg (three drops) of saturated solution of potassium iodide once daily. Five were followed as outpatients and 4 were followed in the Clinical Research Center of the Philadelphia General
Received June 14, 1974. Supported by USPHS Grants 5 TO 1 AM 05649, 5 RO 1 AM 14039 and RR-00107.
33
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JCE & M • 1975 Vol 40 • No 1
EMERSON, ANDERSON, HOWARD AND UTIGER
34
TABLE 1. Clinical data in hyperthyroid patients treated with iodide Patient
Age
Sex
Initial T4 Mg/100 ml
1 2 3 4
32 26 32 23 23 24 42 36 35
M M F F F M M F F
24.3 24.5 25.0 17.5 26.4 18.4 23.8 16.5 22.4
5 6
7 8 9
Initial T3 ng/100 ml 575 585 570 535 575
1,200 640 323 740
Hospital. On each visit the patients were clinically evaluated as to the degree of hyperthyroidism and blood was obtained for thyroxine (T4) and triiodothyronine (T3) measurements. Patient reliability was checked by measurement of serum total iodine concentrations (Bioscience Laboratories (15)); all but three values were >20 /ug/100 ml in both outand inpatients. Evaluation of the signs and symptoms of hyperthyroidism as described by Gurney et al. (13) and Crooks et al. (14) was utilized as an aid in determining clinical response. All patients improved initially. Treatment was continued for 2 months in those patients in whom clinical improvement was sustained. In those patients in whom an initial favorable response was followed by an exacerbation of hyperthyroid signs and symptoms iodide treatment was terminated at the first clinical evidence of this occurrence and therapy with organic antithyroid drugs instituted. Hormone determinations. Serum T4 was measured by competitive protein binding analysis (16) and serum T3 by radioimmunoassay (17). All samples from an individual patient were assayed at the same time in each assay. Normal ranges for these hormones are, T4—5 to 11 Aig/100 ml and T3—70 to 150 ng/100 ml.
Results
Treatment with iodide resulted in a fall in serum T4 and T3 levels during the first few days of therapy in all patients studied. However, in 6 of the patients this response was not sustained and serum levels of thyroid hormones again began to rise. Figure 1 shows the serum T4 and T3 levels in
these 6 patients up to the time when iodide was discontinued and organic antithyroid drug therapy initiated. Although thyroid hormone levels clearly fell following the onset of iodide treatment, in only 2 patients did serum T4 levels reach the normal range before escape, and then only barely. No patient achieved a normal T3 level. Table 2 shows the maximal percentage fall in serum T4 and T3 concentrations, calculated from the difference between the pretreatment value and the lowest level of hormone reached. The mean percentage fall in T4 was 46 ± 11 so 25 20 15 10
I2OO IIOO 1000 g 900 O 800 » 700
f 600 500 2 g 400 K
to 300 200 100 10
20
30
40
50
60
DAYS OF TREATMENT FIG. 1. Serum thyroxine and triiodothyronine levels in patients who had an unsustained response to iodide therapy. The horizontal dashed lines indicate the limits of the normal range.
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SERUM T4 AND T3 DURING IODIDE THERAPY TABLE 2. Maximal fall and day of lowest thyroid hormone level in hyperthyroid patients treated with iodide whose response was not sustained Day of lowest T4
Maximal fall T3 (percent)
Day of lowest T3
7 8 9 11 11 7
50 34 49 36 59 56
7 8 9 4 11 7
Maximal fall T 4
Patient
(percent)
1 o
51 33 55 48 60
3 4 5 6
Menu
29 46 ± 11 (SD)
47 ± 9 (SD)
(SD) and the mean percentage fall in T3 was 47 ± 9 (SD). In these six patients in whom the effect of iodide was not sustained, the lowest level of T 3 and T4 was found on the same day in all but 1 patient and this nadir occurred after 4 to 11 days of therapy. Since daily sampling was not done, the day on which the maximal antithyroid effect was found can only be approximated. Figure 2 shows serum T4 and T3 levels in 2 patients in whom there was a sustained response to iodide. In patient 7, both serum T4 and T3 levels remained above the euthyroid range for the 60 days of the study. Patient 8 was the only one to achieve and maintain normal T4 and T3 levels for the duration of the study. Data from patient 9 is included in Fig. 2. In this patient a striking fall in thyroid hormone levels occurred following the onset of iodide treatment. Unfortunately, on the 9th day of therapy iodide was discontinued because of the development of fever thought to be due to iodide sensitivity.
35
the PBI reach euthyroid levels. Volpe et al. reported results similar to that of Winkler in hyperthyroid subjects receiving 4 mg iodide daily (9). In this study, serum T4 levels at some time during the study reached the euthyroid range in 4 patients, approached normality in 2 and remained clearly elevated in 3 patients. In contrast, serum T3 levels remained clearly outside the normal range in all but 2 patients in the present study. The T3 data suggest that control of hyperthyroidism in iodide-treated patients may not be as great as previously thought. 30 r
Discussion Results of earlier studies of iodide treatment of hyperthyroidism have been variable. Nagataki et al. reported a decline to euthyroid levels in the PBI in all of 12 hyperthyroid patients treated with 30 mg iodide daily (11). Winkler et al. found that the PBI usually declined during therapy with 750 mg iodide daily (7,8). However, in only about 25% of patients so treated did
20 30 40 50 DAYS OF TREATMENT
FIG. 2. Serum thyroxine and triiodothyronine levels in 2 patients who had a sustained response to iodide and in the one patient who received therapy for 9 days. The horizontal dashed lines indicate the limits of the normal range.
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36
EMERSON, ANDERSON, HOWARD AND UTIGER
Nagataki et al. (11) noted a recurrence of hyperthyroidism in half of the patients in their series following 6 to 14 weeks of iodide therapy. Other than this report, little information is available concerning the duration of the antithyroid effect which iodide exerts in hyperthyroid patients. In the current study "escape" was generally noted between the first and second week of therapy if it occurred. Whether thyroid hormone levels would have returned to or exceeded pretreatment values in these patients is unclear since the study was discontinued when exacerbation of hyperthyroidism first became clinically apparent. The possibility that iodide would have continued to exert some definite, but reduced, antithyroid effect in these patients cannot be excluded. In contrast to the rather incomplete antithyroid effects of iodide in untreated hyperthyroid patients noted in this and other studies are the findings of Cevallos et al. (18) that all patients in their series who had previously received radioactive iodide therapy became euthyroid during the administration of stable iodide when hyperthyroidism recurred. Braverman et al. (19) have proposed that the susceptibility of certain patients to the antithyroid actions of iodide is related to abnormal organic iodine binding by the thyroid as revealed by a positive iodide-perchlorate discharge test. The observations of Suzuki and Moshimo (20) that the iodide-perchlorate discharge test was more abnormal in 131Itreated hyperthyroid patients who were euthyroid 3 to 34 months after therapy than in untreated hyperthyroid patients may offer an explanation for the seemingly greater antithyroid effect of iodide in patients treated with 131I. It is clear that inhibition of organic iodine formation in the thyroid is but one of the mechanisms of the antithyroid action of iodide. Iodide has also been shown to inhibit thyroid hormone secretion (21-24), and it is primarily this action which accounts for the rapid initial fall in serum T4
JCE & M • 1975 Vol 40 • No 1
and T3 levels after initiation of iodide therapy. The data presented here show that in most hyperthyroid patients treated only with iodide there is a definite, but usually incomplete and unsustained, amelioration of this condition. These results support and extend the current view that iodide alone is not adequate therapy for the control of hyperthyroidism. References 1. Plummer, H. S., J Am Med Assoc 80: 1955, 1923 (Abstract). 2. Starr, P., H. P. Walcott, H. N. Segall, and J. H. Means, Arch Intern Med 34: 355, 1924. 3. Thompson, W. O., E. G. Thorp, P. K. Thompson, and A. C. Cohen, Arch Intern Med 45: 481, 1930. 4. , P. K. Thompson, A. G. Brailey, and A. C. Cohen, Arch Intern Med 45: 481, 1930. 5. Morton, M. E., I. L. Chaikoff, and S. RosenfeldJ Biol Chem 154: 381, 1944. 6. Ingbar, S. H., Mayo Clin Proc 47: 814, 1972. 7. Winkler, A. W., D. S. Riggs, K. W. Thompson, and E. B. Man, / Clin Invest 25: 404, 1946. 8. , E. B. Man, and T. S. Danowski, J Clin Invest 26: 446, 1947. 9. Volpe, R., and M. W. Johnston, Ann Intern Med 56: 577, 1962. 10. Harden, R. McC, D. A. Koutras, W. D. Alexander, and E. J. Wayne, Clin Sci 27: 399, 1964. 11. Nagataki, S., K.'Shizume, and K. Nakao, J Clin Endocrinol Metab 30: 469, 1970. 12. Davis, P. J., A m / Med 40: 918, 1966. 13. Gurney, C , S. G. Owen, R. Hall, M. Roth, M. Harper, and G. A. Smart, Lancet 2: 1275, 1970. 14. Crooks, J., I. P. C. Murray, and E. J. Wayne, Quart J Med 28: 211, 1959. 15. Barker, S. B., M. J. Humphrey, and M. H. SoleyJ Clin Invest 30: 55, 1951. 16. Murphy, B. E. P., and C. J. Pattee, J Clin Endocrinol Metab 24: 187, 1964. 17. Lieblich, J. M., and R. D. UtigerJ Clin Invest 51: 157, 1972. 18. Cevallos, J. L., G. A. Hagen, F. Maloof, and E. M. Chapman, N EnglJ Med 290: 141, 1974. 19. Braverman, L. E., A. G. Vagenakis, C. Wang, F. Maloof, and S. H. Ingbar, Trans Assoc Am Phy 84: 130, 1971. 20. Suzuki, H., and K. Moshimo, / Clin Endocrinol Metab 34: 332, 1972. 21. Goldsmith, R. E., and M. L. Eisele, / Clin Endocrinol Metab 16: 130, 1956. 22. Greer, M. A., and L. J. DeGroot, Metabolism 5: 682, 1956. 23. Solomon, D. H., Metabolism 5: 667, 1956. 24. Wartofsky, L., B. J. Ransil, and S. H. IngbarJ Clin Invest 49: 78, 1970.
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rise in thyroid hormone levels was not seen following the initial fall. However, in one of this group T4 and T3 levels did not reach the normal range despite 60 days of therapy. These data support the concept that iodide alone is not an ideal agent for the treatment of hyperthyroidism. (J Clin Endocrinol Metab 40: 33, 1975)
F
OLLOWING Plummer's description in 1923 of the use of stable iodide to prepare patients with exophthalmic goiter for surgery (1), a number of papers have documented clinical improvement in hyperthyroid patients during iodide therapy (2,3). It was soon recognized, however, that iodide was not an ideal agent for the treatment of such patients. Not all patients responded to its use and, amongst those who did, there were many in whom reappearance of hyperthyroidism occurred despite continued therapy (4). Extensive laboratory studies beginning in 1944 have complemented these observations and established the concept of an acute antithyroid effect of iodide with subsequent escape (5,6). With the introduction of thiourea drugs, the use of iodide alone was largely abandoned. As a result there have been few measurements of serum thyroid hormone concentrations in hyperthyroid patients treated with iodide alone and the information available is confined to reports of protein bound iodide (PBI) determinations (7-11). This test provides no information about serum triiodothyronine levels, and,
as an indicator of serum thyroxine, is subject to distortion by numerous factors (12). Because iodide alone is still occasionally used for therapy in selected patients with hyperthyroidism, it was deemed worthwhile to determine serum T4 and T3 concentrations in a group of iodide-treated patients. This report describes the results of such measurements in a group of nine hyperthyroid patients. Of interest was the degree of improvement achieved and the timing of "escape" from the antithyroid effects of this agent. Materials and Methods Patients. Nine patients with hyperthyroidism were studied. Five were women and four were men. Their ages ranged from 23 to 42 yr. All subjects were newly diagnosed except for 1 who had received methimazole for several weeks 2 months earlier. The diagnosis was established by the presence of typical clinical features of hyperthyroidism and elevated serum T4 and T3 concentrations. All patients had diffuse thyroid enlargement and were free of complicating illness. Clinical and baseline laboratory information are shown in Table 1. Treatment program. The patients received 150 mg (three drops) of saturated solution of potassium iodide once daily. Five were followed as outpatients and 4 were followed in the Clinical Research Center of the Philadelphia General
Received June 14, 1974. Supported by USPHS Grants 5 TO 1 AM 05649, 5 RO 1 AM 14039 and RR-00107.
33
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JCE & M • 1975 Vol 40 • No 1
EMERSON, ANDERSON, HOWARD AND UTIGER
34
TABLE 1. Clinical data in hyperthyroid patients treated with iodide Patient
Age
Sex
Initial T4 Mg/100 ml
1 2 3 4
32 26 32 23 23 24 42 36 35
M M F F F M M F F
24.3 24.5 25.0 17.5 26.4 18.4 23.8 16.5 22.4
5 6
7 8 9
Initial T3 ng/100 ml 575 585 570 535 575
1,200 640 323 740
Hospital. On each visit the patients were clinically evaluated as to the degree of hyperthyroidism and blood was obtained for thyroxine (T4) and triiodothyronine (T3) measurements. Patient reliability was checked by measurement of serum total iodine concentrations (Bioscience Laboratories (15)); all but three values were >20 /ug/100 ml in both outand inpatients. Evaluation of the signs and symptoms of hyperthyroidism as described by Gurney et al. (13) and Crooks et al. (14) was utilized as an aid in determining clinical response. All patients improved initially. Treatment was continued for 2 months in those patients in whom clinical improvement was sustained. In those patients in whom an initial favorable response was followed by an exacerbation of hyperthyroid signs and symptoms iodide treatment was terminated at the first clinical evidence of this occurrence and therapy with organic antithyroid drugs instituted. Hormone determinations. Serum T4 was measured by competitive protein binding analysis (16) and serum T3 by radioimmunoassay (17). All samples from an individual patient were assayed at the same time in each assay. Normal ranges for these hormones are, T4—5 to 11 Aig/100 ml and T3—70 to 150 ng/100 ml.
Results
Treatment with iodide resulted in a fall in serum T4 and T3 levels during the first few days of therapy in all patients studied. However, in 6 of the patients this response was not sustained and serum levels of thyroid hormones again began to rise. Figure 1 shows the serum T4 and T3 levels in
these 6 patients up to the time when iodide was discontinued and organic antithyroid drug therapy initiated. Although thyroid hormone levels clearly fell following the onset of iodide treatment, in only 2 patients did serum T4 levels reach the normal range before escape, and then only barely. No patient achieved a normal T3 level. Table 2 shows the maximal percentage fall in serum T4 and T3 concentrations, calculated from the difference between the pretreatment value and the lowest level of hormone reached. The mean percentage fall in T4 was 46 ± 11 so 25 20 15 10
I2OO IIOO 1000 g 900 O 800 » 700
f 600 500 2 g 400 K
to 300 200 100 10
20
30
40
50
60
DAYS OF TREATMENT FIG. 1. Serum thyroxine and triiodothyronine levels in patients who had an unsustained response to iodide therapy. The horizontal dashed lines indicate the limits of the normal range.
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SERUM T4 AND T3 DURING IODIDE THERAPY TABLE 2. Maximal fall and day of lowest thyroid hormone level in hyperthyroid patients treated with iodide whose response was not sustained Day of lowest T4
Maximal fall T3 (percent)
Day of lowest T3
7 8 9 11 11 7
50 34 49 36 59 56
7 8 9 4 11 7
Maximal fall T 4
Patient
(percent)
1 o
51 33 55 48 60
3 4 5 6
Menu
29 46 ± 11 (SD)
47 ± 9 (SD)
(SD) and the mean percentage fall in T3 was 47 ± 9 (SD). In these six patients in whom the effect of iodide was not sustained, the lowest level of T 3 and T4 was found on the same day in all but 1 patient and this nadir occurred after 4 to 11 days of therapy. Since daily sampling was not done, the day on which the maximal antithyroid effect was found can only be approximated. Figure 2 shows serum T4 and T3 levels in 2 patients in whom there was a sustained response to iodide. In patient 7, both serum T4 and T3 levels remained above the euthyroid range for the 60 days of the study. Patient 8 was the only one to achieve and maintain normal T4 and T3 levels for the duration of the study. Data from patient 9 is included in Fig. 2. In this patient a striking fall in thyroid hormone levels occurred following the onset of iodide treatment. Unfortunately, on the 9th day of therapy iodide was discontinued because of the development of fever thought to be due to iodide sensitivity.
35
the PBI reach euthyroid levels. Volpe et al. reported results similar to that of Winkler in hyperthyroid subjects receiving 4 mg iodide daily (9). In this study, serum T4 levels at some time during the study reached the euthyroid range in 4 patients, approached normality in 2 and remained clearly elevated in 3 patients. In contrast, serum T3 levels remained clearly outside the normal range in all but 2 patients in the present study. The T3 data suggest that control of hyperthyroidism in iodide-treated patients may not be as great as previously thought. 30 r
Discussion Results of earlier studies of iodide treatment of hyperthyroidism have been variable. Nagataki et al. reported a decline to euthyroid levels in the PBI in all of 12 hyperthyroid patients treated with 30 mg iodide daily (11). Winkler et al. found that the PBI usually declined during therapy with 750 mg iodide daily (7,8). However, in only about 25% of patients so treated did
20 30 40 50 DAYS OF TREATMENT
FIG. 2. Serum thyroxine and triiodothyronine levels in 2 patients who had a sustained response to iodide and in the one patient who received therapy for 9 days. The horizontal dashed lines indicate the limits of the normal range.
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36
EMERSON, ANDERSON, HOWARD AND UTIGER
Nagataki et al. (11) noted a recurrence of hyperthyroidism in half of the patients in their series following 6 to 14 weeks of iodide therapy. Other than this report, little information is available concerning the duration of the antithyroid effect which iodide exerts in hyperthyroid patients. In the current study "escape" was generally noted between the first and second week of therapy if it occurred. Whether thyroid hormone levels would have returned to or exceeded pretreatment values in these patients is unclear since the study was discontinued when exacerbation of hyperthyroidism first became clinically apparent. The possibility that iodide would have continued to exert some definite, but reduced, antithyroid effect in these patients cannot be excluded. In contrast to the rather incomplete antithyroid effects of iodide in untreated hyperthyroid patients noted in this and other studies are the findings of Cevallos et al. (18) that all patients in their series who had previously received radioactive iodide therapy became euthyroid during the administration of stable iodide when hyperthyroidism recurred. Braverman et al. (19) have proposed that the susceptibility of certain patients to the antithyroid actions of iodide is related to abnormal organic iodine binding by the thyroid as revealed by a positive iodide-perchlorate discharge test. The observations of Suzuki and Moshimo (20) that the iodide-perchlorate discharge test was more abnormal in 131Itreated hyperthyroid patients who were euthyroid 3 to 34 months after therapy than in untreated hyperthyroid patients may offer an explanation for the seemingly greater antithyroid effect of iodide in patients treated with 131I. It is clear that inhibition of organic iodine formation in the thyroid is but one of the mechanisms of the antithyroid action of iodide. Iodide has also been shown to inhibit thyroid hormone secretion (21-24), and it is primarily this action which accounts for the rapid initial fall in serum T4
JCE & M • 1975 Vol 40 • No 1
and T3 levels after initiation of iodide therapy. The data presented here show that in most hyperthyroid patients treated only with iodide there is a definite, but usually incomplete and unsustained, amelioration of this condition. These results support and extend the current view that iodide alone is not adequate therapy for the control of hyperthyroidism. References 1. Plummer, H. S., J Am Med Assoc 80: 1955, 1923 (Abstract). 2. Starr, P., H. P. Walcott, H. N. Segall, and J. H. Means, Arch Intern Med 34: 355, 1924. 3. Thompson, W. O., E. G. Thorp, P. K. Thompson, and A. C. Cohen, Arch Intern Med 45: 481, 1930. 4. , P. K. Thompson, A. G. Brailey, and A. C. Cohen, Arch Intern Med 45: 481, 1930. 5. Morton, M. E., I. L. Chaikoff, and S. RosenfeldJ Biol Chem 154: 381, 1944. 6. Ingbar, S. H., Mayo Clin Proc 47: 814, 1972. 7. Winkler, A. W., D. S. Riggs, K. W. Thompson, and E. B. Man, / Clin Invest 25: 404, 1946. 8. , E. B. Man, and T. S. Danowski, J Clin Invest 26: 446, 1947. 9. Volpe, R., and M. W. Johnston, Ann Intern Med 56: 577, 1962. 10. Harden, R. McC, D. A. Koutras, W. D. Alexander, and E. J. Wayne, Clin Sci 27: 399, 1964. 11. Nagataki, S., K.'Shizume, and K. Nakao, J Clin Endocrinol Metab 30: 469, 1970. 12. Davis, P. J., A m / Med 40: 918, 1966. 13. Gurney, C , S. G. Owen, R. Hall, M. Roth, M. Harper, and G. A. Smart, Lancet 2: 1275, 1970. 14. Crooks, J., I. P. C. Murray, and E. J. Wayne, Quart J Med 28: 211, 1959. 15. Barker, S. B., M. J. Humphrey, and M. H. SoleyJ Clin Invest 30: 55, 1951. 16. Murphy, B. E. P., and C. J. Pattee, J Clin Endocrinol Metab 24: 187, 1964. 17. Lieblich, J. M., and R. D. UtigerJ Clin Invest 51: 157, 1972. 18. Cevallos, J. L., G. A. Hagen, F. Maloof, and E. M. Chapman, N EnglJ Med 290: 141, 1974. 19. Braverman, L. E., A. G. Vagenakis, C. Wang, F. Maloof, and S. H. Ingbar, Trans Assoc Am Phy 84: 130, 1971. 20. Suzuki, H., and K. Moshimo, / Clin Endocrinol Metab 34: 332, 1972. 21. Goldsmith, R. E., and M. L. Eisele, / Clin Endocrinol Metab 16: 130, 1956. 22. Greer, M. A., and L. J. DeGroot, Metabolism 5: 682, 1956. 23. Solomon, D. H., Metabolism 5: 667, 1956. 24. Wartofsky, L., B. J. Ransil, and S. H. IngbarJ Clin Invest 49: 78, 1970.
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