Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests

Area of Science:

• Endocrinology
• Genetics
• Clinical Chemistry

Background:

• Discordant thyroid function tests (TFTs) are common, with differential diagnoses including thyroxine (T4) ingestion, lab interference, thyroid hormone resistance, TSH-secreting pituitary adenomas, and T4 protein binding abnormalities.
• Abnormalities in T4 binding proteins are a less recognized cause of discordant TFTs, particularly with the widespread use of free T4 (FT4) immunoassays.

Observation:

• A 69-year-old female presented with persistently elevated FT4 levels (25-34 pmol/L) and normal/low TSH (0.05-2.74 mU/L) while on levothyroxine.
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed a lower FT4 level (19.5 pmol/L).
• Exome sequencing identified a genetic variant in the *ALB* gene, confirming familial dysalbuminemic hyperthyroxinemia.

Findings:

• The *ALB* gene variant at residue 725 caused discordant TFTs, impacting FT4 immunoassay results.
• The variant affected Roche Cobas and Siemens Centaur platforms significantly, while Abbott Architect showed better agreement with LC-MS/MS.
• The patient's daughter exhibited similar TFT results and carried the same genetic variant.

Implications:

• Familial dysalbuminemic hyperthyroxinemia should be considered in patients with discordant TFTs.
• Reference methods like LC-MS/MS and equilibrium dialysis can help diagnose protein-binding abnormalities.
• Exome sequencing provides a cost-effective approach for identifying genetic variants causing discordant TFTs.