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>While I am awaiting Dr. Vivienne Lyfar’s permission to redirect her >reply regarding TBG to you, I’d take the opportunity to say that my >surprise at the lack of goitre in TBG-deficiency and my assumption >of an increased binding of thyroid hormones to TBPA and albumin were >not based on anything I had read in any book but merely a by-product >of my wrong thought processes. If one accepted that one important >function of TBG was to decrease the loss of thyroid hormones from >the circulation, then I reasoned that in its absence, the rate of >production of the hormones from the thyroid gland should increase - >at a guess, probably quite significantly - in order to match their >increased loss. And this could only be brought about by a >significant increase in TSH, with the concomitant proliferation of >thyroid cells and an enlargement of the thyroid gland (different >from the increase in TSH in a dysfunctioning thyroid). This was >merely a production-should-equal-loss scenario in order to maintain >a steady state of thyroid hormones, and nothing to do with the fact >that free thyroid hormone concentrations remain the same. However, >the latter, i.e. a normal concentration of the free fraction, gives >me a headache. How can free hormone concentrations stay the same >(as suggested also by Hall and Besser) while neither the >concentrations of the binding proteins nor their affinities change >and at a time when the total thyroid hormone levels fall (because >there is no longer any TBG)?! The only possibility I could come up >with was that the fall in total thyroid hormones might not be that >large, and what necessitated this was an increased binding to TBPA >and albumin because there was now, without TBG, more thyroid >hormones ‘available’ for binding to them. It is all a fallacy of >course. >Many thanks. >Reza Morovat Well as I indicated in my earlier message on this subject of today's date, its an old myth that hormone binding proteins in blood prevent hormone loss from the microcirculation. The reality is that they increase it. Many years ago my colleagues and I showed (see Ekins R, Edwards P and Newman B, The role of binding proteins in hormone delivery. In Free Hormones in Blood, Eds A. Albertini and RP Ekins, Elsevier Biomedical, Amsterdam, 1982, 3-42) that assuming a FT4 concentration of [FT4]e as determined at equilibrium in vitro, the FT4 concentration in a capillary (at the capillary wall) traversing a target tissue is lower (due to T4 loss from the capillary), the reduction being dependent (amongst other things) on the target tissue clearance rate and the bound T4 concentration. In short, for a given value of [FT4]e, the greater the binding protein and bound T4 concentrations, the greater the capillary wall FT4 concentration, and the greater the T4 loss rate from the capillary. Common sense really, but, paradoxically, also counterintuitive. The maths are quite difficult, and I'm not clever enough to construct the equations describing the kinetics when three binding proteins are involved. Even one binding protein and one hormone are taxing, I attach figures 1 & 2 taken from Ekins R. The science of free hormone measurement. Proc UK NEQAS meeting 1998: 3 , 35-59. These indicate the density of free hormone molecules across a capillary lumen in which blood containing a single binding protein is flowing (without significant mixing), assuming free hormone molecules are being lost across the capillary wall. The equation in fig 2 describes the free hormone concentration (under steady state conditions) as a function of the distance r from the capillary axis. It shows that the FH concentration falls as the capillary wall is approached, the extent of the fall at the capillary wall depending, inter alia. on the free hormone diffusion constant, the free hormone permeation rate constant across the capillary wall and other parameters (including the total hormone concentration). I hesitate to pursue this matter further on this mailbase, but the bottom line is that one must be cautious about accepting a that the free hormone hypothesis is valid, b. the corollary that TBG has no physiological role and c. that the FT4 concentration as measured at equilibrium determines T4 action in all target tissues in the body - especially in young women such as the intended recipient of my Valentine. -- Regards Roger Ekins Molecular Endocrinology University College London Medical School London W1N 8AA Fax +44 20 7580 2737 Phone +44 20 7679 9410 ------ACB discussion List Information-------- This is an open discussion list for the academic and clinical community working in clinical biochemistry. Please note, archived messages are public and can be viewed via the internet. Views expressed are those of the individual and they are responsible for all message content. ACB Web Site http://www.acb.org.uk List Archives http://www.jiscmail.ac.uk/lists/ACB-CLIN-CHEM-GEN.html List Instructions (How to leave etc.) http://www.jiscmail.ac.uk/