Euthyroid hyperthyroxinemia: relevance of albumin and transthyretin genetic variations in a single centre experience

Euthyroid Hyperthyroxinemia (EH) is a condition consisting of high total T4 (TT4), variable total T3 (TT3), endogenous free T4 (fT4) and free T3 (fT3) within the reference interval, normal TSH, absence of thyroid disease. EH may be due to genetic alterations of albumin (ALB), transthyretin (TTR) and thyroxine binding globulin (TBG) genes. Our study aimed to evaluate the frequency of inherited conditions affecting thyroid hormones transport proteins, associated with EH.

We retrospectively enrolled 42 patients with EH who underwent genetic testing for ALB and TTR mutations. A control group of 58 patients, having normal thyroid function tests, negative for ALB and TTR mutations, was selected. Direct sequencing of exons 1,2,3,4 of TTR gene (NM_000371.4), exon 7 of ALB gene (NM_000477.7) was performed.

In 42 patients with EH, ALB p.R218H (c.653G > A) variant was found in 20 subjects (47.6 %); 7 subjects (16.7 %) had TTR gene variants; 15 patients (35.7 %) were wild-type for ALB and TTR genetic testing. FT4 concentration was not dependent on the presence of sequence variants. We compared thyroid hormones levels of all carriers of ALB and TTR variants, including relatives positive for ALB and TTR variants, with 58 controls negative for ALB and TTR mutation. We observed a statistically significant difference between fT4 levels according to mutational status, being fT4 in ALB-mutated: 24.47 ± 2.58 pmol/L, in TTR-mutated: 20.65 ± 3.75 pmol/L; in controls: 14.50 ± 1.65 pmol/L (mean ± 1 standard deviation) (p < 0.000001).

After exclusion of secondary causes, genetic variation in thyroid hormones transport proteins is a common cause of EH.