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THYROXINE IN BLOOD AND TISSUES
1095 Professor Greitz’s arguments may be valid in the syndrome of communicating hydrocephalus with dementia, but the same arguments cannot necessarily be applied to other conditions associated with ventricular dilatation. Regional Neurological Centre, M. D. O’BRIEN. Newcastle General Hospital.
THYROXINE IN BLOOD AND TISSUES SIR,-Your leading article (May 10, p. 974) presents a clear statement of the " classical " view on thyroxine binding, emphasising the fundamental position held in this view by " free thyroxine ". It provides a list of situations in which a correlation is observed between free thyroxine and the level of thyroid function, such a correlation providing the clinical value of the concept of free thyroxine. However, a list of similar length consisting of situations in which free thyroxine does not correlate with thyroid function has recently been compiled by Oppenheimer,! who concludes that " the turnover of thyroid hormones cannot always be explained exclusively in terms of alterations in the binding proteins or free thyroxine concentration." He proposes an alternative hypotheses of a correlation between thyroid function and tissue-exchangeable thyroxine, thus implying that a significant proportion of tissue thyroxine is not exchangeable. In view of such deficiencies in the concept of free thyroxine it is worth examining the basis on which it entirely rests. This basis is the hypothesis that thyroxine freely and rapidly exchanges throughout its distribution space, thus allowing the maintenance of a reversible equilibrium. The evidence in favour of this hypothesis is circumstantial. Direct evidence against it is to be found in the observed lack of exchange of radiothyroxine bound in vivo to plasma-proteins in rabbits and the observed diverging curves of plasma and whole-body radiothyroxine in rats2 and guineapigs.3 A divergence could not occur if all the thyroxine were capable of exchanging freely. Your leading article is misleading when it states that a divergence of disappearance curves is not found in man. We have looked for and found such a divergence in both normal and diseased subjects (to be published). The quoted referencefails to report plasma activities in the subjects in whom whole-body disappearance-rates were measured. In view of the above observations we conclude that " free thyroxine ", as at present defined and estimated, is an invalid concept. Pathology Department, University of Glasgow, Western Infirmary, Glasgow, and W. A. HARLAND Department of Clinical Physics and Bioengineering, Glasgow. J. S. ORR.
SIR,-Your leading article concludes by discussing evidence against the " classical " view of thyroxine metabolism and transport, citing the difference between blood and whole-body thyroxine curves found by other workers after injection of radioactive iodine-labelled hormone.56 In the paper by Ray and Premachandra8 whole-body counting was not performed and analysis was confined to differences between thyroxine and triiodothyronine metabolism. Divergence of whole-body and plasma radioactivity curves after injection of labelled thyroxine is not reported in man and is not true of rabbits (see below); one wonders whether Harland and Orr’s findingsin the rat cannot be explained in other ways, as, for example, below. (1) Free iodide jn the body-water was not taken into account. In small animals, after injection of iodine-labelled thyroxine, depending on the rate of excretion of iodide, up 1. 2. 3. 4.
5. 6.
Oppenheimer, J. H. New Engl. J. Med. 1968, 278, 1153. Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297. Brown-Grant, K. ibid. 1967, 191, 167. Oddie, T. H., Fisher, D. A., Rodgers, C. J. clin. Endocr. Metab. 1964, 24, 628. Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297. Ray, A. K., Premachandra, B. N. Endocrinology, 1964, 74, 800.
Residual body and plasma radioactivity in rabbit after injection
1261-I-thyroxine. x=Residual body radioactivity derived from serial subtraction of excreted counts and corrected for measured total-body iodide. 0= plasma protein-bound radioactivity per ml.
10% or 20% of total plasma radioactivity may be contributed by non-protein-bound counts. Since the total iodidedistribution space exceeds the thyroxine space, a considerable proportion of the whole-body activity may be accounted for by released iodide, and correction of both curves for free iodide may reduce the degree of divergence. (2) No allowance was made for fascal thyroxine. In the rat up to 60% of administered labelled thyroxine may be excreted in the faeces within 3 days 7; that portion of the dose which is non-exchangeable within the gut should be deducted from the whole-body activity curve to avoid spurious prolongation of its half-life. (3) In small animals it is unlikely that the final exponential term of the plasma-thyroxine-activity curve will have been reached by 72 hours (when the rat experiments of Harland and Orr ended), for the loss of thyroxine from plasma by excretion and degradation is rapid in comparison with the loss by equilibration with extravascular binding sites. This process of equilibration may materially contribute to the plasma curve in the first few days of a turnover study. As an example, a recent study in a rabbit provided a plasmathyroxine-radioactivity curve of the form to
At 60 hours the second term, presumably reflecting continued equilibration, contributes about 17% to the overall equation; even at 90 hours its contribution is over 7%-i.e., the final exponential term has not yet been reached. What is misleading is that the slope of plasma-radioactivity often appears to be linear (exponential) between 30 and 60 hours after intravenous administration of labelled thyroxine, due possibly to the balance between the contributions of the second and third terms over this period. The accompanying figure clearly shows this point. Had the experiment been stopped at 72 hours, whole-body and plasma radioactivity curves would have been seen to diverge; continuation for a further few days exposes the true curvilinear nature of the plasma slope, and parallelism between the two is approximated. It is always refreshing to find old concepts challenged, but further work is needed to clarify the relationship between plasma and tissue thyroxine. Division of Biophysics, National Institute for Medical Research, Mill Hill, London N.W.7. 7.
R. HOFFENBERG E. G. BLACK.
Albert, A., Keating, F. R. ibid. 1952, 51, 427.
THYROXINE IN BLOOD AND TISSUES SIR,-Your leading article (May 10, p. 974) presents a clear statement of the " classical " view on thyroxine binding, emphasising the fundamental position held in this view by " free thyroxine ". It provides a list of situations in which a correlation is observed between free thyroxine and the level of thyroid function, such a correlation providing the clinical value of the concept of free thyroxine. However, a list of similar length consisting of situations in which free thyroxine does not correlate with thyroid function has recently been compiled by Oppenheimer,! who concludes that " the turnover of thyroid hormones cannot always be explained exclusively in terms of alterations in the binding proteins or free thyroxine concentration." He proposes an alternative hypotheses of a correlation between thyroid function and tissue-exchangeable thyroxine, thus implying that a significant proportion of tissue thyroxine is not exchangeable. In view of such deficiencies in the concept of free thyroxine it is worth examining the basis on which it entirely rests. This basis is the hypothesis that thyroxine freely and rapidly exchanges throughout its distribution space, thus allowing the maintenance of a reversible equilibrium. The evidence in favour of this hypothesis is circumstantial. Direct evidence against it is to be found in the observed lack of exchange of radiothyroxine bound in vivo to plasma-proteins in rabbits and the observed diverging curves of plasma and whole-body radiothyroxine in rats2 and guineapigs.3 A divergence could not occur if all the thyroxine were capable of exchanging freely. Your leading article is misleading when it states that a divergence of disappearance curves is not found in man. We have looked for and found such a divergence in both normal and diseased subjects (to be published). The quoted referencefails to report plasma activities in the subjects in whom whole-body disappearance-rates were measured. In view of the above observations we conclude that " free thyroxine ", as at present defined and estimated, is an invalid concept. Pathology Department, University of Glasgow, Western Infirmary, Glasgow, and W. A. HARLAND Department of Clinical Physics and Bioengineering, Glasgow. J. S. ORR.
SIR,-Your leading article concludes by discussing evidence against the " classical " view of thyroxine metabolism and transport, citing the difference between blood and whole-body thyroxine curves found by other workers after injection of radioactive iodine-labelled hormone.56 In the paper by Ray and Premachandra8 whole-body counting was not performed and analysis was confined to differences between thyroxine and triiodothyronine metabolism. Divergence of whole-body and plasma radioactivity curves after injection of labelled thyroxine is not reported in man and is not true of rabbits (see below); one wonders whether Harland and Orr’s findingsin the rat cannot be explained in other ways, as, for example, below. (1) Free iodide jn the body-water was not taken into account. In small animals, after injection of iodine-labelled thyroxine, depending on the rate of excretion of iodide, up 1. 2. 3. 4.
5. 6.
Oppenheimer, J. H. New Engl. J. Med. 1968, 278, 1153. Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297. Brown-Grant, K. ibid. 1967, 191, 167. Oddie, T. H., Fisher, D. A., Rodgers, C. J. clin. Endocr. Metab. 1964, 24, 628. Harland, W. A., Orr, J. S. J. Physiol., Lond. 1969, 200, 297. Ray, A. K., Premachandra, B. N. Endocrinology, 1964, 74, 800.
Residual body and plasma radioactivity in rabbit after injection
1261-I-thyroxine. x=Residual body radioactivity derived from serial subtraction of excreted counts and corrected for measured total-body iodide. 0= plasma protein-bound radioactivity per ml.
10% or 20% of total plasma radioactivity may be contributed by non-protein-bound counts. Since the total iodidedistribution space exceeds the thyroxine space, a considerable proportion of the whole-body activity may be accounted for by released iodide, and correction of both curves for free iodide may reduce the degree of divergence. (2) No allowance was made for fascal thyroxine. In the rat up to 60% of administered labelled thyroxine may be excreted in the faeces within 3 days 7; that portion of the dose which is non-exchangeable within the gut should be deducted from the whole-body activity curve to avoid spurious prolongation of its half-life. (3) In small animals it is unlikely that the final exponential term of the plasma-thyroxine-activity curve will have been reached by 72 hours (when the rat experiments of Harland and Orr ended), for the loss of thyroxine from plasma by excretion and degradation is rapid in comparison with the loss by equilibration with extravascular binding sites. This process of equilibration may materially contribute to the plasma curve in the first few days of a turnover study. As an example, a recent study in a rabbit provided a plasmathyroxine-radioactivity curve of the form to
At 60 hours the second term, presumably reflecting continued equilibration, contributes about 17% to the overall equation; even at 90 hours its contribution is over 7%-i.e., the final exponential term has not yet been reached. What is misleading is that the slope of plasma-radioactivity often appears to be linear (exponential) between 30 and 60 hours after intravenous administration of labelled thyroxine, due possibly to the balance between the contributions of the second and third terms over this period. The accompanying figure clearly shows this point. Had the experiment been stopped at 72 hours, whole-body and plasma radioactivity curves would have been seen to diverge; continuation for a further few days exposes the true curvilinear nature of the plasma slope, and parallelism between the two is approximated. It is always refreshing to find old concepts challenged, but further work is needed to clarify the relationship between plasma and tissue thyroxine. Division of Biophysics, National Institute for Medical Research, Mill Hill, London N.W.7. 7.
R. HOFFENBERG E. G. BLACK.
Albert, A., Keating, F. R. ibid. 1952, 51, 427.