Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

Abstract

Familial dysalbuminemic hyperthyroxinemia (FDH-T4) and hypertriiodothyroninemia (FDH-T3) are dominantly inherited syndromes characterized by a high concentration of thyroid hormone in the blood stream. The syndromes do not cause disease, because the concentration of free hormone is normal, but affected individuals are at risk of erroneous treatment. FDH-T4 is the most common cause of euthyroid hyperthyroxinemia in Caucasian populations in which its prevalence is about 1 in 10,000 individuals, but the prevalence can be much higher in some ethnic groups. The condition is caused by a genetic variant of human serum albumin (HSA); Arg218 is mutated to histidine, proline, or serine or Arg222 is changed to isoleucine. The disorder is characterized by greater elevation in serum l-thyroxine (T4) than in serum triiodothyronine (T3); T4 can be increased by a factor 8–15. The high serum concentration of T4 is due to modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Thus, mutating Arg218 or Arg222 for a smaller amino acid reduces the steric restrictions in the site and creates a high-affinity binding site. The mutations can also affect binding of other ligands and can perhaps cause modified pharmacokinetics of albumin-binding drugs. In normal HSA, the high-affinity site has another location (in subdomain IIIB). Different locations of these sites imply that persons with and without FDH-T4 can have different types of interactions, and thereby complications, when given albumin-binding drugs. FDH-T3 is caused by a leucine to proline mutation in position 66 of HSA, which results in a large increment of the binding affinity for T3 but not for T4. For avoiding unwanted treatment of euthyroid persons with hyperthyroxinemia or hypertriiodothyroninemia, protein sequencing and/or sequencing of the albumin gene should be performed.

Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity

“…Interestingly, our model did not use clinical variables such as goiter, showing that these variables were not as reliable predictors of RTHβ versus FDH as the fT3 levels. These results are coherent with the fact that FDH had already been described to yield artificially increased fT4 levels and are in agreement with in vitro assay results, since the variant R218H of the human serum albumin leads to an increased affinity for T4 but not T3, explaining the preferential interference in fT4 assays [17,18]. It largely depends on the technique used but does not necessarily correlate with the usage of one-or two-step methods, even if, in theory, the one-step method is more impacted by this interference [23,24].…”

Effect of Albumin Polymorphism on Thyroid Hormones: A Case Report and Literature Review

“…The mutation involves codon 218, which is normally arginine, and it gets replaced with histidine, proline, or serine (or codon 222), which is also arginine that gets replaced with isoleucine. These mutations in the codon 218 and codon 222 for a smaller amino acid reduces the steric hindrances and creates a high-affinity binding site for T4 [ 2 , 9 ]. Individuals with FDH are heterozygous for the mutation.…”

“…Our case report and TFT results fit the classic description of FDH, an autosomal dominant disorder characterized by an elevated TT4, elevated FT4 (as measured by one-step/two-step immunoassay but normal by equilibrium dialysis), a normal or rarely elevated T3, and normal TSH. The estimated prevalence of FDH among the Caucasian population is 1 in 10,000 individuals, and it is much higher in subjects of Hispanic origin, i.e., 1.0 - 1.8% [ 2 ].…”

“…Extracellular T4 and T3 are protein-bound by 99.97% and 99.7%, respectively. Because free thyroid hormones exist in equilibrium with the carrier proteins, any factor that affects the quantity/quality of the carrier invariably affects the pharmacokinetics and pharmacodynamics of the thyroid hormones [ 2 ]. This is best exemplified in familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal dominant disorder characterized by an elevated total T4 (TT4), elevated free T4 (FT4), normal thyroid stimulating hormone (TSH), and T3 level, as measured by a one/two-step immunoassay.…”

Hyperthyroxinemia with a non-suppressed TSH: how to confidently reach a diagnosis in this clinical conundrum

“…Changes affecting one of the thyroid hormone binding proteins, such as thyroid binding globulin (TBG), transthyretin, or albumin, can also affect the free T4 assay as is the case in familial dysalbuminemic hyperthyroxinemia (FDH). This is a rare genetic condition in which albumin has a preferential affinity for T4, which can lead to alterations in total and free T4 levels with non-suppressed TSH [2,5,6].…”