Familial dysalbuminemic hyperthyroxinemia confounding management of coexistent autoimmune thyroid disease

[helvella]

We see a trickle of reports where patients have thyroid test results that are very difficult to understand.

This is one possible cause. Note the use of two different methods of assaying - which should be a standard first-step.

Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020. pii: EDM190161. doi: 10.1530/EDM-19-0161. [Epub ahead of print]

Familial dysalbuminemic hyperthyroxinemia confounding management of coexistent autoimmune thyroid disease.

Khoo S1, Lyons G1, Solomon A2, Oddy S3, Halsall D3, Chatterjee K1, Moran C1.

Author information

Abstract

Summary:

Familial dysalbuminemic hyperthyroxinemia (FDH) is a cause of discordant thyroid function tests (TFTs), due to interference in free T4 assays, caused by the mutant albumin. The coexistence of thyroid disease and FDH can further complicate diagnosis and potentially result in inappropriate management. We describe a case of both Hashimoto's thyroiditis and Graves' disease occurring on a background of FDH. A 42-year-old lady with longstanding autoimmune hypothyroidism was treated with thyroxine but in varying dosage, because TFTs, showing high Free T4 (FT4) and normal TSH levels, were discordant. Discontinuation of thyroxine led to marked TSH rise but with normal FT4 levels. She then developed Graves' disease and thyroid ophthalmopathy, with markedly elevated FT4 (62.7 pmol/L), suppressed TSH (<0.03 mU/L) and positive anti-TSH receptor antibody levels. However, propylthiouracil treatment even in low dosage (100 mg daily) resulted in profound hypothyroidism (TSH: 138 mU/L; FT4: 4.8 pmol/L), prompting its discontinuation and recommencement of thyroxine. The presence of discordant thyroid hormone measurements from two different methods suggested analytical interference. Elevated circulating total T4 (TT4), (227 nmol/L; NR: 69-141) but normal thyroxine binding globulin (TBG) (19.2 µg/mL; NR: 14.0-31.0) levels, together with increased binding of patient's serum to radiolabelled T4, suggested FDH, and ALB sequencing confirmed a causal albumin variant (R218H). This case highlights difficulty ascertaining true thyroid status in patients with autoimmune thyroid disease and coexisting FDH. Early recognition of FDH as a cause for discordant TFTs may improve patient management.

Learning points:

The typical biochemical features of familial dysalbuminemic hyperthyroxinemia (FDH) are (genuinely) raised total and (spuriously) raised free T4 concentrations due to enhanced binding of the mutant albumin to thyroid hormones, with normal TBG and TSH concentrations. Given the high prevalence of autoimmune thyroid disease, it is not surprising that assay interference from coexisting FDH may lead to discordant thyroid function tests confounding diagnosis and resulting in inappropriate therapy. Discrepant thyroid hormone measurements using two different immunoassay methods should alert to the possibility of laboratory analytical interference. The diagnosis of FDH is suspected if there is a similar abnormal familial pattern of TFTs and increased binding of radiolabelled 125I-T4 to the patient's serum, and can be confirmed by ALB gene sequencing. When autoimmune thyroid disease coexists with FDH, TSH levels are the most reliable biochemical marker of thyroid status. Measurement of FT4 using equilibrium dialysis or ultrafiltration are more reliable but less readily available.

KEYWORDS:

2020; Adult; Error in diagnosis/pitfalls and caveats; February; Female; Genetics; Thyroid; United Kingdom; White

PMID: 32101523

DOI: 10.1530/EDM-19-0161

ncbi.nlm.nih.gov/pubmed/321...

[diogenes Remembering]

Sopme time ago I collaborated with a biochemist at Northwick Park Hospital to better understand the thyroid hormone biochemistry in this (quite rare) class of patients. He had in his possession several mutant forms which interfered with FT4 (and sometimes FT3, but rarer) tests. The mutation(s) are in the high conentration but weaker T4/3 binder, albumin. The strength of binding by the mutation was about 100 fold higher than normal. This meant that for FT4, the albumin carried the majority of T4 round the system bound on to it and total T4 could be twice and three times the normal euthyroid level. He identified two sets of albumin mutation. One bound T4 strongly, but T3 at its normal weak strength, and the other bound both strongly (only 1 family had this one). Lesson for FDH diagnosis: test TSH, FT4 AND FT3. If the patient is euthyroid then the more common syndrome will show normal TSH, abnormally high FT4 (interference in the test) and normal FT3. The normal TSH and FT3 give the game away so there should be no misunderstanding if all test are used. Of course if FT3 is missed out the lack of sufficient evidence will cause flutters in the medical hencoop. It is ironic that these patients can easily be identified if FT3 is included in the measurements.

[HughH in reply to diogenes]

It is very disappointing that this research team included the top specialists from Addenbrooke's Hospital, Cambridge, UK and they did not look at FT3.

It is hard to fathom!