Low serum thyroxine and high serum triiodothyronine in nephrotic rats: Etiology implications for unavailability of protein-bound hormone

Traditionally, it has been thought that the bioavailable fraction of circulating serum hormones, i.e. that which is available for cellular uptake and is physiologically active, is limited to the free (nonprotein bound) hormone. However, recent evidence, based on acute organ uptake of labeled hormone, suggests that the amount of hormone which is bioavailable in vivo may exceed that which is calculated to be free in vitro. To explore the bioavailability of circulating protein-bound thyroid hormones under steady state conditions in vivo, we altered serum thyroid hormone-binding proteins in rats by inducing nephrotic syndrome with puromycin aminonucleoside. Nephrotic rats (serum albumin, 1.1 g/dl) were found to have a marked reduction in serum T₄ [2.1 ± 0.2 (SEM) vs. 6.5 ± 0.3 µg/dl; P < 0.01] and an elevation of serum T₃ [141 ± 8 vs. 51 ± 2 ng/dl; P < 0.01]. Estimated T₄ production rate was normal in nephrotic rats, and the 3- to 4-fold increase in T₄ MCR appeared to account for the marked reduction in serum T₄. By contrast, increased serum T₃ levels in nephrotic rats reflected both a reduction (55%) in T₃ MCR and an increased rate of peripheral conversion of T₄ to T₃. A circulating inhibitor of T₄ binding to serum proteins appeared to be present in nephrotic rats. The changes in the various serum components of thyroid hormone [T₄-binding prealbumin (TBPA)-bound, albumin-bound, free] produced by nephrotic syndrome were compared with the corresponding changes in indices of thyroid hormone bioavailability (MCR, urinary excretion, hepatic content, TSH suppression, single pass extraction by liver). These comparisons suggested that nephrotic syndrome results in increased bioavailability of circulating T₄ and decreased bioavailability of circulating T₃. The bioavailable fraction of circulating T₃ in vivo seemed to include both free T₃ and that which is albumin bound in vitro. The bioavailable fraction of circulating T₄ resembled free T₄ more than non-TBPA-bound T₄ (=albumin bound + free), although a nephrosis-induced increase in bioavailability of TBPA-bound T₄ was also possible. We conclude that nephrotic rats have low serum T₄, which is related to accelerated T₄ clearance, and high serum T₃, which is related both to decreased T₃ clearance and increased peripheral conversion of T₄ to T₃. Under steady state conditions in vivo, bioavailable circulating T₃ appears to include both free T₃ and the T₃ that is bound to albumin in vitro.