Thyroxine distribution and metabolism in familial dysalbuminemic hyperthyroxinemia

We studied two families with familial dysalbuminemic hyperthyroxinemia (FDH), a recently described entity characterized by marked elevation of serum T4 due to increased binding of T4 to albumin. The seven affected subjects had elevated serum total T4 levels (range, 15.3-25.2 micrograms/dl; normal, 4.5-11.0 micrograms/dl), but normal serum free T4 levels, as measured by equilibrium dialysis. Their serum T3 levels ranged from 1.40-2.46 ng/ml (normal, 0.9-2.0 ng/ml). The proportion of T4 associated with serum albumin was increased approximately 4-fold in the affected subjects, as shown both by reverse flow paper electrophoresis and immunoprecipitation of albumin-bound T4 with antihuman serum albumin. In vivo T4 kinetic studies were performed in the two index subjects to assess the effects of the increased binding of T4 to albumin on the in vivo transport, distribution, and disposal of T4. Compared to values in normal subjects, the MCR of T4 was decreased by about 50%, and its total body (extrathyroidal) pool size was increased by approximately 50%; the T4 production rate was normal. The extracellular T4 pool size was increased by about 100% in the FDH subjects, but the rapidly exchangeable intracellular T4 pool size was normal. The unidirectional T4 clearance rate from plasma into the rapidly exchangeable cellular compartment was reduced by approximately 50%, but the absolute rate of T4 flux from plasma into the cellular compartment was normal. Thus, the in vivo kinetic data indicate that the increased plasma binding of T4 in FDH alters the distribution of T4 in favor of the extracellular compartment, retards the fractional rate of transfer of T4 into cells, and slows the metabolic clearance of T4. However, the absolute rate of T4 flux into the rapidly exchangeable cellular compartment, the intracellular T4 pool size, and the T4 disposal rate are all normal in FDH, consistent with the normal serum concentrations of free T4 and the eumetabolic state of these individuals.