FAMILIAL DYSALBUMINEMIC HYPERTHYROXINAEMIA (FDH): A diagnosis easily missed with sometimes subtle biochemical manifestation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 449-497-Thyroid Neoplasia & Case Reports
Clinical
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-468
Roshini Kulanthaivelu1, Carla M Moran*2, V Krishna K Chatterjee2 and Abbi Lulsegged3
1South London Healthcare NHS Trust, Orpington, United Kingdom, 2University of Cambridge & Addenbrooke's hospital, Cambridge, United Kingdom, 3South London NHS Trust, Bromley, United Kingdom
FDH is a recognised cause of discordant thyroid function and typically causes a raised FT4 in commercially available assays.  Here, we describe two related cases of confirmed FDH, one of whom had only subtle biochemical abnormalities.

CLINICAL CASE:

A 23 year old Caucasian man with reactive arthritis presented with a raised free T4 (38.9, Roche assay; ref range 10.5-24.5pmol/L) and non-suppressed TSH (0.93,  rr 0.3-4.0mU/L). Similar results were present a year earlier while well.  He was clinically euthyroid with a normal thyroid on clinical and ultrasound examination.  A maternal aunt had undergone a thyroidectomy for presumed thyrotoxicosis. 

Repeat fT4 measurement on another one step assay (Centaur) was 38.1 pmol/L; rr 10-19.8, however was 24.9pmol/L on a two step assay (DELFIA, rr 9-20), suggestive of interference in the FT4 measurement. FT3 in both assays was normal. FT4 by equilibrium dialysis was normal. Total T4 was raised (257 nmol/L, rr 69-141). TSH measured in dilution was normal.

Interestingly, his mother’s thyroid function was also abnormal, but with more subtle abnormalities (centaur TSH 2.6, FT4 19.5, FT3 4.8, rr 3.5-6.5, delfia fT4 15.7, TT4 181). Although the FT4 is within the normal range in both these assays, the discrepancy in the results suggested interference, and the raised TT4 is typical of FDH.

The biochemical and inheritance patterns suggested FDH. Molecular genetic analysis of the ALB gene in the proband and his mother confirmed a missense mutation in exon 7 (R218H or R242H), known to cause FDH, in both. 

The mutant albumin molecule has an increased affinity for T4. Total T4 is truly raised, but the mutated albumin binds labelled T4 analogs used in many FT4 assays and hence results in a falsely raised FT4 result. Two step assays reduce this interference since a wash step reduces the likelihood of the labelled analog coming into contact with mutated albumin. FT4 measured by equilibrium dialysis typically returns a normal FT4 result. Crucially, there is no abnormality in the thyroid axis and these patients do not require treatment.

CLINICAL LESSONS:

(1)  Not all unusual patterns of thyroid function in illness are due to non-thyroidal illness.

(2)  Typically in FDH the Total T4 is raised and the FT4 measured by equilibrium dialysis is normal.

(3)  FDH can be misdiagnosed as thyrotoxicosis. To avoid inappropriate treatment hyperthyroxinaemia with non-suppressed TSH should always be further investigated. Interestingly, the proband’s maternal aunt has had a thyroidectomy but may well have FDH.

(4)  Familial thyroid function with a similarly abnormal pattern suggests a genetic cause such as FDH, rather than other causes of interference, which are not inherited. 

Thyroid dysfunction in FDH may be more subtly abnormal than previously recognised; the proband’s mother’s results could be easily misinterpreted as normal and hence the “clue” in the family history would have been missed.

Nothing to Disclose: RK, CMM, VKKC, AL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm