Artifactually Elevated Serum-Free Thyroxine Levels Measured by Equilibrium Dialysis in a Pregnant Woman with Familial Dysalbuminemic Hyperthyroxinemia

Abstract

Familial dysalbuminemic hyperthyroxinemia (FDH) is a familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by radioimmunoassay (RIA) but not when determined by RIA after ultrafiltration of sera. These results indicate an increased T4 binding to TBG during pregnancy in the patients with FDH. Furthermore, our results suggest that normal serum FT4 determined by equilibrium dialysis is not an ultimate standard for the diagnosis of FDH in the patients with the mutant albumin R218P.

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

“…While this method has a better ability to accurately report true free T4 values in the face of confounding variables, false-positives may still occur [ 9 ]. Hoshikawa et al have reported false-positive results of elevated free T4 assays using equilibrium dialysis/radioimmunoassay (RIA), and they suggest that this assay is not an ultimate standard for diagnosing FDH, especially in patients with the R218P mutation of the ALB gene [ 10 ]. They further recommended ultrafiltration as an added measure to increase the accuracy of testing prior to RIA.…”

A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH)

“…Both of p.R218P and p.R218H mutations in the albumin genes cause hyperthyroxinemia, but the p.R218P mutation in the present patient was characterized by extremely high serum FT 4 levels when compared with those of patients with the p.R218H mutation. We expected that the affinity of albumin with the p.R218P mutation for T 4 would be much higher than that of albumin with the R218H mutation, but the affinity constants (Ka) for mutant albumin p.R218P and p.R218H were reported to be similar [5], and recombinant p.R218H and have been four reports of FDH in Japan [4,15,17,18]. So far, all of them harbored the p.R218P mutation in the albumin gene.…”

“…The authors do not have any potential conflicts of interest associated with this research except for SK, who received research funding support from Chugai Pharmaceutical Co., Ltd. min p.R218P during the equilibrium dialysis and that the structural change in the albumin 218P (but not in R218H) renders albumin more susceptible to the inhibitory effect of chloride ions in the dialysis buffer [15]. Fig.…”

Familial dysalbuminemic hyperthyroxinemia in a 4-year-old girl with hyperactivity, palpitations and advanced dental age: how gold standard assays may be misleading

“…While this method has a better ability to accurately report true free T4 values in the face of confounding variables, false positives may still occur. Hoshikawa et al (5) have reported false-positive results of elevated free T4 assays using equilibrium dialysis/RIA, and they suggest that this assay is not an ultimate standard for diagnosing FDH, especially in patients with the R218P mutation of the ALB gene. They further recommend ultrafiltration as an added measure to increase the accuracy of testing prior to RIA.…”

“…However, assays employing equilibrium dialysis followed by radioimmunoassay (RIA), liquid chromatography, and tandem mass spectrometry should give normal free T4 results. Lack of normalization of free T4 levels using these assays can be due to causes other than FDH, although false-positive results have been previously reported (5). This poses a challenge to the clinician, who may then undertake extensive additional and unnecessary evaluations.…”