Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine

Familial dysalbuminemic hyperthyroxinemia (FDH), is the most common cause o f inherited increase in serum total T-4 (TT4) in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, r esulting in 10-fold higher affinity for T-4 and, in heterozygous affected s ubjects, a TT4 level 2-fold higher than that in subjects expressing the wil d-type HSA only. We now report FDH in a Swiss family, caused by HSA R218P, previously reported in subjects of Japanese origin. In this form of FDH, se rum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurement s in serum extracts. TrT3 and TT3, concentrations are 7- and P-fold above t he mean, respectively. Thus, to maintain a normal free T-4 level, the calcu lated affinity constant (K-a) of HSA R218P should be about 16-fold higher t han that of HSA R218H. Surprisingly, the K-a values measured at saturation were similar: 5.4 x 10(6) and 0.4 x 10(6) mol/L-1 for HSA R218H, respective ly. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4, the concentration of dialyzable T-4 was measured at increasing amounts of TT4. At a TT4 level equivalent t o that found in the subjects with HSA R218P, the absolute FT4 concentration s were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T-4 must be hi gher than that of R218H to produce an 11-fold difference in FT4 at the same concentration of TT4. This difference was obliterated at saturating concen trations of TT4 used for the determination of K-a values by the method of S catchard.