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Familial Dysalbuminemic Hyperthyroxinemia in a Swiss Family Caused by a Mutant Albumin (R218P) Shows an Apparent Discrepancy between Serum Concentration and Affinity for Thyroxine¹

Departments of Medicine (S.P., M.F., R.E.W., N.H.S., S.R.), Pediatrics (S.R.); J. P. Kennedy, Jr., Mental Retardation Research Center (S.R.); and Clinical Endocrinology Laboratory (N.H.S., S.R.), University of Chicago, Chicago, Illinois 60637-1470; and Center for Adolescent Medicine and Foundation Growth Puberty Adolescence (U.E.), Zurich, Switzerland

Address all correspondence and requests for reprints to: Dr. Samuel Refetoff, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.bsd.uchicago.edu

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 (K_a) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the K_a 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 concentrations 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 TT_4. This difference was obliterated at saturating concentrations of TT₄ used for the determination of K_a values by the method of Scatchard.