Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests

Matthew J M Ting; Rui Zhang; Ee Mun Lim; Bryan K Ward; Scott G Wilson; John P Walsh

doi:10.1210/jendso/bvab012

Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests

J Endocr Soc. 2021 Feb 1;5(4):bvab012. doi: 10.1210/jendso/bvab012. eCollection 2021 Apr 1.

Authors

Matthew J M Ting¹, Rui Zhang², Ee Mun Lim^{1

2}, Bryan K Ward^{1

3}, Scott G Wilson^{1

4

5}, John P Walsh^{1

6}

Affiliations

¹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia.
² PathWest Laboratory Medicine, Nedlands, Australia.
³ Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, University of Western Australia, Nedlands, Australia.
⁴ School of Biomedical Sciences, University of Western Australia, Crawley, Australia.
⁵ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁶ Medical School, University of Western Australia, Crawley, Australia.

Abstract

Introduction: Discordant thyroid function tests are routinely encountered in clinical practice. Differential diagnoses include acute thyroxine (T4) ingestion, laboratory interference from heterophilic antibodies, thyroid hormone resistance, thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, and T4 protein binding abnormalities. The impact of abnormal binding proteins may be less recognized since widespread use of free T4 (FT4) assays compared to older total T4 assays.

Case report: A 69-year-old female was referred for assessment of discordant thyroid function tests. Biochemistry since July 2015 showed persistently elevated FT4 levels by immunoassay ranging between 25 to 34 pmol/L with normal or slightly decreased TSH ranging between 0.05 to 2.74 mU/L. The patient was clinically euthyroid on 100 mcg daily of levothyroxine for Hashimoto's thyroiditis. FT4 measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was 19.5 pmol/L. Exome sequencing (confirmed by Sanger sequencing) detected a guanine to adenine substitution at residue 725 of the ALB gene previously associated with dysalbuminemic hyperthyroxinemia. The patient's daughter had similar thyroid function tests and the same genetic variant. FT4 results from 3 different automated immunoassays showed the Roche Cobas and Siemens Centaur platforms to be most affected by the variant, and Abbott Architect had the best agreement with LC-MS/MS.

Conclusion: Familial dysalbuminemic hyperthyroxinemia is a potential cause of discordant thyroid function tests. Clinicians suspecting protein-binding abnormalities may further investigate using reference methods such as LC-MS/MS and equilibrium dialysis if available. The increasing accessibility of exome sequencing offers a cost-effective method of diagnosing genetic variants that cause discordant thyroid function tests.

Keywords: albumin; euthyroid hyperthyroxinemia; thyroxine.

Publication types

Case Reports