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The 24-hour thyroidal uptake test
The 24-Hour Thyroidai Uptake Test Sidney C. W e r n e r
1948, when the basal metabolic rate I N(BMR) and cholesterol were still the main clinical tools employed to assess thyroid function, and serum protein-bound iodine was being introduced, the likelihood was indicated that measurement of the uptake of 131I directly over the human thyroid 24 hr after its ingestion would be valuable for this purpose. 1 This usefulness was then extensively documentedfl ~ It would be nice to attribute the beginnings of the test to a burst of scientific insight; however, like most developments, the process was evolutionary and had begun a number of years earlier. The basis was set by the researches of three outstanding nonthyroidal thyroidologists. Hevesy 5 was the first, in 1923. He introduced the concept of the "tracer" into biology when he used natural lead and radioactive thorium B as markers in the study of plant physiology. Fermi 6 was the next in 1934, when he produced radioactive iodine, an artificial isotope, by bombarding iodine with neutrons. The last was Schoenheimer. 7 In 1935, he administered deuterium to man and animals and declared: "[the] body does not discriminate between isotopes of the same element, radioactive or stable." Three years later, Livingood and Seaborg prepared several radioactive isotopes of iodine in quantity, including 1311.8 A year later, Hamilton and Soley9 determined the curve of accumulation of 131I within the thyroid in man, and the urinary and fecal excretion of the isotope. They also observed that these functions were altered in hyper- and hypothyroidism. Shortly thereafter, measurement of urinary excretion was suggested as a diagnostic procedure. 1~
From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, and the Presbyterian Hospital in the City of New York, and presently the Department of Internal Medicine, University of Arizona Health Sciences Center, Tucson, Arizona. Aided by Grant A8, Division of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Md. Address reprint requests to Sidney C. Werner, M.D., University of Arizona Health Sciences Center, Tucson, Arizona 85724. Receivedfor publication July 16, 1975. 9 1979 by Grune & Stratton, Inc. 0001-2998/79/0901~007502.00/0 156
By the summer of 1946, the Atomic Pile at Oak Ridge made 131I available for general use; several months thereafter, our research group began its own diagnostic and therapeutic investigations with this nuclide. Edith Quimby was the physicist and I, the clinician. Diagnostically, our goal was to establish a simple noninvasive clinical test of thyroid function for routine purposes, which would be convenient for both patient and laboratory and involve the least possible risk to the patient. As a starter, Dr. Quimby calculated that 100#Ci of 131I would provide a test dose that could be measured feasibly with available equipment over the thyroid and other tissues, as well as in the urine, and without providing an undue radiation dose to the patient. Measurements were made at frequent intervals after oral administration, and the corresponding urinary concentrations of 13JI were determined also. There was no Human Use Committee, Radiation Safety Committee, or book of rules about ethical behavior. Yet, the patients were well informed, and knew that an experiment was being conducted and knew of its nature; their questions were answered. No one had to be reminded of the validity of Means's dictumll: "The patient places a colossal trust in the doctor. The doctor must see to it that he takes no undue advantage of it." Several data soon became apparent. Extrathyroidal tissue concentrations of the isotope became negligible 24 hr after ingestion due to urinary excretion. Thus, measurements of the thigh simultaneous with those of the neck could be avoided; i.v. administration of 131I w a s unnecessary; the patient did not have to come to the laboratory in the fasting state; and (as a final bonus) almost all patients preferred returning the next day for the 24-hr measurement to waiting around the hospital the same day for a 4or 6-hr measurement. With an evidently useful procedure and good correlation with the clinical problem in the early trials, 2'3 we proposed to the Department of Medicine that the test be introduced routinely. This was greeted with something less than ethusiasm, and we were forced to develop a large series (n = 1000). 4 With Dr. Edgar Leifer, then on the Seminars in Nuclear Medicine, Vol. IX, No. 3 (July), 1979
24-HOUR THYROIDAL UPTAKE TEST
157
resident staff, to enlist the in-patients, in addition to the thyroid clinic patients a l r e a d y under investigation, the study was finally completed. 4 During this study, it was observed that u p t a k e by the thyroid of the patient with acute (or s u b a c u t e ) nonsuppurative thyroiditis was negligible, 3 and also t h a t the h y p e r t h y r o i d patient, unlike the euthyroid subject, showed no suppression of u p t a k e after triiodothyronine a d m i n i s t r a tion. ~2 This then led to the d e v e l o p m e n t of the T3 suppression test, ~3 and the subsequent observation that normal thyroid suppressibility returned earlier and in a g r e a t e r p e r c e n t a g e of h y p e r t h y roid patients postsurgery than after 13JI therapy.~4 This finding has been recently related by others to d i s a p p e a r a n c e from the blood of the so-called " t h y r o i d - s t i m u l a t i n g i m m u n o g l o b u l i n s ( T S I ) , ''~5 p r e s u m a b l y reflecting subsidence of one or more pathogenetic mechanisms. T h e T3 suppression test also enabled us to investigate a group of patients who had the eye changes of G r a v e s ' disease but had never been hyperthyroid, and to establish that they did indeed have G r a v e s ' disease. ~6 This variant is presently t e r m e d euthyroid G r a v e s ' disease, and it is distinct from the onset of eye changes after t r e a t m e n t of h y p e r t h y r o i d i s m . By 1951, the idea dawned t h a t instead of
suppression of the thyroid as a test for hyperthyroidism, stimulation of the gland might detect hypothyroidism. W e had just c o m p l e t e d our observations using thyrotropin as the s t i m u l a t o r 4 when Dr. A n d r e a s Q u e r i d o of Leyden, then working at the M a s s a c h u s e t t s G e n e r a l Hospital with Dr. John S t a n b u r y , visited our d e p a r t m e n t of medicine. H e said that he and S t a n b u r y had been working on a test to s t i m u l a t e the thyroid with t h y r o i d - s t i m u l a t i n g hormone ( T S H ) . So had we and with the s a m e n u m b e r and kind of patients, T S H dosage and timing, and good results.3'~ 7 C o n c u r r e n t l y kinetic studies of thyroidal function were first described in 1947, and included: thyroid c l e a r a n c e and disposal rate measurements~8; the conversion rate ~9 and other proteinbound 131I tests of thyroidal release. Also, a m a c h i n e was devised to scan the thyroid. W i t h respect to this last development, " a h a p p e n i n g " is of interest. W i t h persuasion, Dr. Mones Berman, then at the M e m o r i a l Hospital and S l o a n - K e t t e r i n g Institute, agreed to build a scanner for our laboratory. H e constructed a fine instrument with a minor p r o b l e m - - t h e printouts were inverted and transposed to the opposite side. Perhaps hard to understand, the field of nuclear medicine nevertheless survived.
REFERENCES
1. Werner SC, Quimby EH, Schmidt C: Clinical experience in diagnosis and treatment of thyroid disorders with radioactive iodine (eight-day half-life). Radiology 51:564, 1948. 2. Werner SC, Quimby EH, Schmidt C: The use of tracer doses of radioactive iodine 1 TM, in the study of normal and disordered thyroid function in man. J Clin Endocrinol Metab 9:342, 1949 3. Werner SC, Goodwin LD, Quimby EH, et al: Some results from the use of radioactive iodine, I TM,in the diagnosis and treatment of toxic goiter. Am J Roentgenol Radium Ther 63:889, 1950 4. Werner SC, Hamilton HB, Leifer E, et al: An appraisal of the radioiodine tracer technic as a clinical procedure in the diagnosis of thyroid disorders: uptake measurement directly over the gland and a note on the use of thyrotropin. J Clin Endocrinol Metab 10:1054, 1950 5. Heresy G: 111.The absorption and translocation of lead by plants. Biochem J 17:439, 1923 6. Fermi E: Radioactivity induced by neutron bombardment. Nature 133:757, 1934 7. Schoenheimer R, Rittenberg D: Isotopes in Biology: Dynamic State of Body Constituents. Cambridge, Harvard Univ Press, ! 946
8. Livingood J J, Seaborg GT: Radioactive isotopes of iodine. Physiol Rev 53:1015, 1938 9. Hamilton JG, Soley MH: Studies in iodine metabolism by the use of a new radioactive isotope of iodine. Am J Physiol 127:557, 1939 10. Keating FR Jr, Power MN, Berkson J, et al: The urinary excretion of radioiodine in various thyroid states. J Clin Invest 26:1138, 1947 11. Means JH: The Thyroid and Its Diseases (ed 1). Philadelphia, Lippincott, 1937, preface 12. Werner SC, Hamilton H: Pituitary thyroid relations. Lancet 1:796, 1953 13. Werner SC, Spooner M: A new and simple test for hyperthyroidism employing l-triiodothyronine and the 24 hour 1-131 uptake methods. Bull NY Acad Med 31:137, 1955 14. Werner SC: Response to triiodothyronine as index of persistence of disease in the thyroid remnant of patients in remission from hyperthyroidism. J Clin Invest 35:57, 1956 15. Mukhtar ED, Smith BR, Pyle G, et al: Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine and antithyroid drugs. Lancet 1:713, 1975 16. Werner SC: Euthyroid patients with early eye signs of Graves'disease. Am J Med 18:608, 1955
158
17. Querido A, Stanbury JB: The response of the thyroid gland to thyroid hormone as an aid in the differential diagnosis of primary and secondary hypothyroidism. J Clin Endocrinol Metab 10:1192, 1950 18. Keating FR Jr, Albert A: Metabolism of iodine in
SIDNEY C. WERNER
man as disclosed by use of radioiodine. Prog Horm Res 4:429, 1949 19. Clark DE, Moe RH, Adams EE: The rate of conversion of administered inorganic radioactive iodine into protein bound iodine of plasma as an aid in the evaluation of thyroid function. Surgery 26:331, 1949.
1948, when the basal metabolic rate I N(BMR) and cholesterol were still the main clinical tools employed to assess thyroid function, and serum protein-bound iodine was being introduced, the likelihood was indicated that measurement of the uptake of 131I directly over the human thyroid 24 hr after its ingestion would be valuable for this purpose. 1 This usefulness was then extensively documentedfl ~ It would be nice to attribute the beginnings of the test to a burst of scientific insight; however, like most developments, the process was evolutionary and had begun a number of years earlier. The basis was set by the researches of three outstanding nonthyroidal thyroidologists. Hevesy 5 was the first, in 1923. He introduced the concept of the "tracer" into biology when he used natural lead and radioactive thorium B as markers in the study of plant physiology. Fermi 6 was the next in 1934, when he produced radioactive iodine, an artificial isotope, by bombarding iodine with neutrons. The last was Schoenheimer. 7 In 1935, he administered deuterium to man and animals and declared: "[the] body does not discriminate between isotopes of the same element, radioactive or stable." Three years later, Livingood and Seaborg prepared several radioactive isotopes of iodine in quantity, including 1311.8 A year later, Hamilton and Soley9 determined the curve of accumulation of 131I within the thyroid in man, and the urinary and fecal excretion of the isotope. They also observed that these functions were altered in hyper- and hypothyroidism. Shortly thereafter, measurement of urinary excretion was suggested as a diagnostic procedure. 1~
From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, and the Presbyterian Hospital in the City of New York, and presently the Department of Internal Medicine, University of Arizona Health Sciences Center, Tucson, Arizona. Aided by Grant A8, Division of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Md. Address reprint requests to Sidney C. Werner, M.D., University of Arizona Health Sciences Center, Tucson, Arizona 85724. Receivedfor publication July 16, 1975. 9 1979 by Grune & Stratton, Inc. 0001-2998/79/0901~007502.00/0 156
By the summer of 1946, the Atomic Pile at Oak Ridge made 131I available for general use; several months thereafter, our research group began its own diagnostic and therapeutic investigations with this nuclide. Edith Quimby was the physicist and I, the clinician. Diagnostically, our goal was to establish a simple noninvasive clinical test of thyroid function for routine purposes, which would be convenient for both patient and laboratory and involve the least possible risk to the patient. As a starter, Dr. Quimby calculated that 100#Ci of 131I would provide a test dose that could be measured feasibly with available equipment over the thyroid and other tissues, as well as in the urine, and without providing an undue radiation dose to the patient. Measurements were made at frequent intervals after oral administration, and the corresponding urinary concentrations of 13JI were determined also. There was no Human Use Committee, Radiation Safety Committee, or book of rules about ethical behavior. Yet, the patients were well informed, and knew that an experiment was being conducted and knew of its nature; their questions were answered. No one had to be reminded of the validity of Means's dictumll: "The patient places a colossal trust in the doctor. The doctor must see to it that he takes no undue advantage of it." Several data soon became apparent. Extrathyroidal tissue concentrations of the isotope became negligible 24 hr after ingestion due to urinary excretion. Thus, measurements of the thigh simultaneous with those of the neck could be avoided; i.v. administration of 131I w a s unnecessary; the patient did not have to come to the laboratory in the fasting state; and (as a final bonus) almost all patients preferred returning the next day for the 24-hr measurement to waiting around the hospital the same day for a 4or 6-hr measurement. With an evidently useful procedure and good correlation with the clinical problem in the early trials, 2'3 we proposed to the Department of Medicine that the test be introduced routinely. This was greeted with something less than ethusiasm, and we were forced to develop a large series (n = 1000). 4 With Dr. Edgar Leifer, then on the Seminars in Nuclear Medicine, Vol. IX, No. 3 (July), 1979
24-HOUR THYROIDAL UPTAKE TEST
157
resident staff, to enlist the in-patients, in addition to the thyroid clinic patients a l r e a d y under investigation, the study was finally completed. 4 During this study, it was observed that u p t a k e by the thyroid of the patient with acute (or s u b a c u t e ) nonsuppurative thyroiditis was negligible, 3 and also t h a t the h y p e r t h y r o i d patient, unlike the euthyroid subject, showed no suppression of u p t a k e after triiodothyronine a d m i n i s t r a tion. ~2 This then led to the d e v e l o p m e n t of the T3 suppression test, ~3 and the subsequent observation that normal thyroid suppressibility returned earlier and in a g r e a t e r p e r c e n t a g e of h y p e r t h y roid patients postsurgery than after 13JI therapy.~4 This finding has been recently related by others to d i s a p p e a r a n c e from the blood of the so-called " t h y r o i d - s t i m u l a t i n g i m m u n o g l o b u l i n s ( T S I ) , ''~5 p r e s u m a b l y reflecting subsidence of one or more pathogenetic mechanisms. T h e T3 suppression test also enabled us to investigate a group of patients who had the eye changes of G r a v e s ' disease but had never been hyperthyroid, and to establish that they did indeed have G r a v e s ' disease. ~6 This variant is presently t e r m e d euthyroid G r a v e s ' disease, and it is distinct from the onset of eye changes after t r e a t m e n t of h y p e r t h y r o i d i s m . By 1951, the idea dawned t h a t instead of
suppression of the thyroid as a test for hyperthyroidism, stimulation of the gland might detect hypothyroidism. W e had just c o m p l e t e d our observations using thyrotropin as the s t i m u l a t o r 4 when Dr. A n d r e a s Q u e r i d o of Leyden, then working at the M a s s a c h u s e t t s G e n e r a l Hospital with Dr. John S t a n b u r y , visited our d e p a r t m e n t of medicine. H e said that he and S t a n b u r y had been working on a test to s t i m u l a t e the thyroid with t h y r o i d - s t i m u l a t i n g hormone ( T S H ) . So had we and with the s a m e n u m b e r and kind of patients, T S H dosage and timing, and good results.3'~ 7 C o n c u r r e n t l y kinetic studies of thyroidal function were first described in 1947, and included: thyroid c l e a r a n c e and disposal rate measurements~8; the conversion rate ~9 and other proteinbound 131I tests of thyroidal release. Also, a m a c h i n e was devised to scan the thyroid. W i t h respect to this last development, " a h a p p e n i n g " is of interest. W i t h persuasion, Dr. Mones Berman, then at the M e m o r i a l Hospital and S l o a n - K e t t e r i n g Institute, agreed to build a scanner for our laboratory. H e constructed a fine instrument with a minor p r o b l e m - - t h e printouts were inverted and transposed to the opposite side. Perhaps hard to understand, the field of nuclear medicine nevertheless survived.
REFERENCES
1. Werner SC, Quimby EH, Schmidt C: Clinical experience in diagnosis and treatment of thyroid disorders with radioactive iodine (eight-day half-life). Radiology 51:564, 1948. 2. Werner SC, Quimby EH, Schmidt C: The use of tracer doses of radioactive iodine 1 TM, in the study of normal and disordered thyroid function in man. J Clin Endocrinol Metab 9:342, 1949 3. Werner SC, Goodwin LD, Quimby EH, et al: Some results from the use of radioactive iodine, I TM,in the diagnosis and treatment of toxic goiter. Am J Roentgenol Radium Ther 63:889, 1950 4. Werner SC, Hamilton HB, Leifer E, et al: An appraisal of the radioiodine tracer technic as a clinical procedure in the diagnosis of thyroid disorders: uptake measurement directly over the gland and a note on the use of thyrotropin. J Clin Endocrinol Metab 10:1054, 1950 5. Heresy G: 111.The absorption and translocation of lead by plants. Biochem J 17:439, 1923 6. Fermi E: Radioactivity induced by neutron bombardment. Nature 133:757, 1934 7. Schoenheimer R, Rittenberg D: Isotopes in Biology: Dynamic State of Body Constituents. Cambridge, Harvard Univ Press, ! 946
8. Livingood J J, Seaborg GT: Radioactive isotopes of iodine. Physiol Rev 53:1015, 1938 9. Hamilton JG, Soley MH: Studies in iodine metabolism by the use of a new radioactive isotope of iodine. Am J Physiol 127:557, 1939 10. Keating FR Jr, Power MN, Berkson J, et al: The urinary excretion of radioiodine in various thyroid states. J Clin Invest 26:1138, 1947 11. Means JH: The Thyroid and Its Diseases (ed 1). Philadelphia, Lippincott, 1937, preface 12. Werner SC, Hamilton H: Pituitary thyroid relations. Lancet 1:796, 1953 13. Werner SC, Spooner M: A new and simple test for hyperthyroidism employing l-triiodothyronine and the 24 hour 1-131 uptake methods. Bull NY Acad Med 31:137, 1955 14. Werner SC: Response to triiodothyronine as index of persistence of disease in the thyroid remnant of patients in remission from hyperthyroidism. J Clin Invest 35:57, 1956 15. Mukhtar ED, Smith BR, Pyle G, et al: Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine and antithyroid drugs. Lancet 1:713, 1975 16. Werner SC: Euthyroid patients with early eye signs of Graves'disease. Am J Med 18:608, 1955
158
17. Querido A, Stanbury JB: The response of the thyroid gland to thyroid hormone as an aid in the differential diagnosis of primary and secondary hypothyroidism. J Clin Endocrinol Metab 10:1192, 1950 18. Keating FR Jr, Albert A: Metabolism of iodine in
SIDNEY C. WERNER
man as disclosed by use of radioiodine. Prog Horm Res 4:429, 1949 19. Clark DE, Moe RH, Adams EE: The rate of conversion of administered inorganic radioactive iodine into protein bound iodine of plasma as an aid in the evaluation of thyroid function. Surgery 26:331, 1949.