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. 1976 Feb;57(2):485–495. doi: 10.1172/JCI108301

Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

S Refetoff, V S Fang, J S Marshall, N I Robin
PMCID: PMC436674  PMID: 56342

Abstract

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.

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Selected References

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  1. AvRuskin T. W., Braverman L. E., Crigler J. F., Jr Thyroxine-binding globulin deficiency and associated neurological deficit. Pediatrics. 1972 Oct;50(4):638–645. [PubMed] [Google Scholar]
  2. Bode H. H., Rothman K. J., Danon M. Linkage of thyroxine-binding globulin deficiency to other X-chromosome loci. J Clin Endocrinol Metab. 1973 Jul;37(1):25–29. doi: 10.1210/jcem-37-1-25. [DOI] [PubMed] [Google Scholar]
  3. Braverman L. E., AvRuskin T., Cullen M. J., Vagenakis A. G., Ingbar S. H. Effects of norethandrolone on the transport and peripheral metabolism of thyroxine in patients lacking thyroxine-binding globulin. Observations on the physiological role of thyroxine-binding prealbumin. J Clin Invest. 1971 Aug;50(8):1644–1649. doi: 10.1172/JCI106653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Braverman L. E., Ingbar S. H. Effects of norethandrolone on the transport in serum and peripheral turnover of thyroxine. J Clin Endocrinol Metab. 1967 Mar;27(3):389–396. doi: 10.1210/jcem-27-3-389. [DOI] [PubMed] [Google Scholar]
  5. Braverman L. E., Socolow E. L., Woeber K. A., Ingbar S. H. Effect of norethandrolone on the metabolism of 125-I-labeled thyroxine-binding prealbumin. J Clin Endocrinol Metab. 1968 Jun;28(6):831–835. doi: 10.1210/jcem-28-6-831. [DOI] [PubMed] [Google Scholar]
  6. Cavalieri R. R., McMahon F. A., Castle J. N. Preparation of 125-I-labeled human thyroxine-binding alpha globulin and its turnover in normal and hypothyroid subjects. J Clin Invest. 1975 Jul;56(1):79–87. doi: 10.1172/JCI108082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Costre P., Buhler U., DeGroot L. J., Refetoff S. Diurnal rhythm in total serum thyroxine levels. Metabolism. 1971 Aug;20(8):782–791. doi: 10.1016/s0026-0495(71)80008-2. [DOI] [PubMed] [Google Scholar]
  8. Fang V. S., Refetoff S. Radioimmunoassay for serum triiodothyronine: evaluation of simple techniques to control interference from binding proteins. Clin Chem. 1974 Sep;20(9):1150–1154. [PubMed] [Google Scholar]
  9. Heinonen O. P., Lamberg B. A., Virtamo J. Inherited decrease of the binding capacity of thyroxine-binding globulin (TBG). Acta Endocrinol (Copenh) 1970 May;64(1):171–180. doi: 10.1530/acta.0.0640171. [DOI] [PubMed] [Google Scholar]
  10. Hennemann G., Docter R., Dolman A. Relationship between total thyroxine and absolute free thyroxine and the influence of absolute free thyroxine on thyroxine disposal in humans. J Clin Endocrinol Metab. 1971 Jul;33(1):63–67. doi: 10.1210/jcem-33-1-63. [DOI] [PubMed] [Google Scholar]
  11. Inada M., Sterling K. Thyroxine transport in thyrotoxicosis and hypothyroidism. J Clin Invest. 1967 Sep;46(9):1442–1450. doi: 10.1172/JCI105636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Leiba S., Landau B., Ber A., Adam A., Sterling K. Thyroxine-binding-globulin (T.B.G.) deficiency and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in the same family. J Clin Endocrinol Metab. 1974 Apr;38(4):569–573. doi: 10.1210/jcem-38-4-569. [DOI] [PubMed] [Google Scholar]
  13. Levy R. P., Marshall J. S., Velayo N. L. Radioimmunoassay of human thyroxine-binding globulin (TBG). J Clin Endocrinol Metab. 1971 Mar;32(3):372–381. doi: 10.1210/jcem-32-3-372. [DOI] [PubMed] [Google Scholar]
  14. Malvaux P., De Nayer P. X-chromosome linked inheritance of decreased thyroxine-binding globulin. Arch Dis Child. 1972 Aug;47(254):635–638. doi: 10.1136/adc.47.254.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marshall J. S., Levy R. P., Steinberg A. G. Human thyroxine-binding globulin deficiency. A genetic study. N Engl J Med. 1966 Jun 30;274(26):1469–1473. doi: 10.1056/NEJM196606302742604. [DOI] [PubMed] [Google Scholar]
  16. Marshall J. S., Pensky J., Green A. M. Studies on human thyroxine-binding globulin. VI. The nature of slow thyroxine-binding globulin. J Clin Invest. 1972 Dec;51(12):3173–3181. doi: 10.1172/JCI107144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nusynowitz M. L., Clark R. F., Strader W. J., 3rd, Estrin H. M., Seal U. S. Thyroxine-binding globulin deficiency in three families, and total deficiency in a normal woman. Am J Med. 1971 Apr;50(4):458–464. doi: 10.1016/0002-9343(71)90335-4. [DOI] [PubMed] [Google Scholar]
  18. OPPEHNEIMER J. H., SURKS M. I., BERNSTEIN G., SMITY J. C. METABOLISM OF IODINE-131--LABELED THYROXINE-BINDING PREALBUMIN IN MAN. Science. 1965 Aug 13;149(3685):748–750. doi: 10.1126/science.149.3685.748. [DOI] [PubMed] [Google Scholar]
  19. Odell W. D., Wilber J. F., Utiger R. D. Studies of thyrotropin physiology by means of radioimmunoassay. Recent Prog Horm Res. 1967;23:47–85. doi: 10.1016/b978-1-4831-9826-2.50005-2. [DOI] [PubMed] [Google Scholar]
  20. Oppenheimer J. H. Role of plasma proteins in the binding, distribution and metabolism of the thyroid hormones. N Engl J Med. 1968 May 23;278(21):1153–1162. doi: 10.1056/NEJM196805232782107. [DOI] [PubMed] [Google Scholar]
  21. Pensky J., Marshall J. S. Studies on thyroxine-binding globulin (TBG). II. Separation from human serum by affinity chromatography. Arch Biochem Biophys. 1969 Dec;135(1):304–310. doi: 10.1016/0003-9861(69)90544-x. [DOI] [PubMed] [Google Scholar]
  22. Refetoff S., Fang V. S., Marshall J. S. Studies on human thyroxine-binding globulin (TBG). IX. Some physical, chemical, and biological properties of radioiodinated TBG and partially desialylated TBG. J Clin Invest. 1975 Jul;56(1):177–187. doi: 10.1172/JCI108066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Refetoff S., Hagen S. R., Selenkow H. A. Estimation of the T 4 binding capacity of serum TBG and TBPA by a single T 4 load ion exchange resin method. J Nucl Med. 1972 Jan;13(1):2–12. [PubMed] [Google Scholar]
  24. Refetoff S., Robin N. I., Alper C. A. Study of four new kindreds with inherited thyroxine-binding globulin abnormalities. Possible mutations of a single gene locus. J Clin Invest. 1972 Apr;51(4):848–867. doi: 10.1172/JCI106880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Refetoff S., Selenkow H. A. Familial thyroxine-binding globulin deficiency in a patient with Turner's syndrome (XO). Genetic study of a kindred. N Engl J Med. 1968 May 16;278(20):1081–1087. doi: 10.1056/NEJM196805162782002. [DOI] [PubMed] [Google Scholar]
  26. Robbins J. Inherited variations in thyroxine transport. Mt Sinai J Med. 1973 May-Jun;40(3):511–519. [PubMed] [Google Scholar]
  27. Robin N. I., Hagen S. R., Collaço F., Refetoff S., Selenkow H. A. Serum tests for measurement of thyroid function. Hormones. 1971;2(5):266–279. doi: 10.1159/000178240. [DOI] [PubMed] [Google Scholar]
  28. STERLING K. The turnover rate of serum albumin in man as measured by I131-tagged albumin. J Clin Invest. 1951 Nov;30(11):1228–1237. doi: 10.1172/JCI102542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Socolow E. L., Woeber K. A., Purdy R. H., Holloway M. T., Ingbar S. H. Preparation of I-131-labeled human serum prealbumin and its metabolism in normal and sick patients. J Clin Invest. 1965 Oct;44(10):1600–1609. doi: 10.1172/JCI105266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Thomson J. A., Meredith E. M., Baird S. G., McAinsh W. R., Hutchison J. H. Raised free thyroxine values in patients with familial elevation of thyroxine binding globulin. Q J Med. 1972 Jan;41(161):49–56. [PubMed] [Google Scholar]
  31. Zaninovich A. A., Degrossi O., Gotta H. Effects of oestrogens on serum thyroxine-binding globulin capacity and on the peripheral metabolism of thyroxine in patients with hepatic cirrhosis. Acta Endocrinol (Copenh) 1971 May;67(1):73–84. doi: 10.1530/acta.0.0670073. [DOI] [PubMed] [Google Scholar]
  32. de Nayer P., Oei L. S., Broeckx J., de Visscher M. Familial partial thyroxine-binding globulin deficiency. Ann Endocrinol (Paris) 1971 Jul-Aug;52(4):617–620. [PubMed] [Google Scholar]

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