The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 8: 2281-2285.
Familial Dysalbuminemic Hyperthyroxinemia in a Swiss Family Caused by a Mutant Albumin (R218P) Shows an Apparent Discrepancy between Serum Concentration and Affinity for Thyroxine
Silvana Pannain · Michael Feldman · Urs Eiholzer · Roy E. Weiss · Neal H. Scherberg · Samuel Refetoff
Familial dysalbuminemic hyperthyroxinemia (FDH), is the most common cause of inherited increase in serum total T4 (TT4 )in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, resulting in 10-fold higher affinity for T4 and, in heterozygous affected subjects, a TT4 level 2-fold higher than that in subjects expressing the wild-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, serum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurements in serum extracts. TrT3 and TT3 , concentrations are 7- and 2-fold above the mean, respectively. Thus, to maintain a normal free T4 level, the calculated affinity constant (Ka) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the Ka values measured at saturation were similar: 5.4 x 106 and 6.4 x 106 mol/L-1 for HSA R218H, respectively. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4 , the concentration of dialyzable T4 was measured at increasing amounts of TT4. At a TT4 level equivalent to that found in the subjects with HSA R218P, the absolute FT4 con-centrations were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T4 must be higher than that of R218H to produce an 11-fold difference in FT4 at the same concentration of TT4. This difference was obliterated at saturating concentrations of TT4 used for the determination of Ka values by the method of Scatchard. (J Clin Endocrinol Metab 85: 2786–2792, 2000)