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      Familial dysalbuminaemic hyperthyroxinaemia interferes with current free thyroid hormone immunoassay methods


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          Familial dysalbuminaemic hyperthyroxinaemia (FDH), most commonly due to an Arginine to Histidine mutation at residue 218 (R218H) in the albumin gene, causes artefactual elevation of free thyroid hormones in euthyroid individuals. We have evaluated the susceptibility of most current free thyroid hormone immunoassay methods used in the United Kingdom, Europe and Far East to interference by R218H FDH.


          Different, one- and two-step immunoassay methods were tested, measuring free T4 (FT4) and free T3 (FT3) in 37 individuals with genetically proven R218H FDH.


          With the exception of Ortho VITROS, FT4 measurements were raised in all assays, with greatest to lowest susceptibility to interference being Beckman ACCESS > Roche ELECSYS > FUJIREBIO Lumipulse > Siemens CENTAUR > Abbott ARCHITECT > Perkin-Elmer DELFIA. Five different assays recorded high FT3 levels, with the Siemens CENTAUR method measuring high FT3 values in up to 30% of cases. However, depending on the assay method, FT4 measurements were unexpectedly normal in some, genetically confirmed, affected relatives of index FDH cases.


          All FT4 immunoassays evaluated are prone to interference by R218H FDH, with their varying susceptibility not being related to assay architecture but likely due to differing assay conditions or buffer composition. Added susceptibility of many FT3 assays to measurement interference, resulting in high FT4 and FT3 with non-suppressed TSH levels, raises the possibility of R218H FDH being misdiagnosed as resistance to thyroid hormone beta or TSH-secreting pituitary tumour, potentially leading to unnecessary investigation and inappropriate treatment.

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          Most cited references16

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          Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm

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            Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand?

            For a long time it has been known that both hypo- and hyperthyroidism are associated with an increased risk of morbidity and mortality. In recent years, it has also become clear that minor variations in thyroid function, including subclinical dysfunction and variation in thyroid function within the reference range, can have important effects on clinical endpoints, such as bone mineral density, depression, metabolic syndrome, and cardiovascular mortality. Serum thyroid parameters show substantial interindividual variability, whereas the intraindividual variability lies within a narrow range. This suggests that every individual has a unique hypothalamus-pituitary-thyroid axis setpoint that is mainly determined by genetic factors, and this heritability has been estimated to be 40-60%. Various mutations in thyroid hormone pathway genes have been identified in persons with thyroid dysfunction or altered thyroid function tests. Because these causes are rare, many candidate gene and linkage studies have been performed over the years to identify more common variants (polymorphisms) associated with thyroid (dys)function, but only a limited number of consistent associations have been found. However, in the past 5 years, advances in genetic research have led to the identification of a large number of new candidate genes. In this review, we provide an overview of the current knowledge about the polygenic basis of thyroid (dys)function. This includes new candidate genes identified by genome-wide approaches, what insights these genes provide into the genetic basis of thyroid (dys)function, and which new techniques will help to further decipher the genetic basis of thyroid (dys)function in the near future.
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              A point mutation in the human serum albumin gene results in familial dysalbuminaemic hyperthyroxinaemia.

              Using DNA samples obtained from two unrelated patients, diagnosed as having familial dysalbuminaemic hyperthyroxinaemia (FDH), exons 1-14 which span the entire coding region of the human serum albumin (HSA) gene were amplified by the polymerase chain reaction. The sequence of each of the 14 DNA fragments was then determined. In each case a point mutation was identified at nucleotide 653 which causes an Arg to His substitution at amino acid position 218. The substitution was confirmed by amino acid sequencing of a mutant peptide resulting from tryptic digestion of the protein. Abnormal affinity of FDH HSA for a thyroxine (T4) analogue was verified by an adaptation of the procedure used in routine free T4 measurement. The location of the mutation is discussed in relation to other studies on the binding properties of HSA.

                Author and article information

                Eur J Endocrinol
                Eur. J. Endocrinol
                European Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                June 2020
                26 March 2020
                : 182
                : 6
                : 533-538
                [1 ]University of Cambridge Metabolic Research Laboratories , Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
                [2 ]Department of Clinical Biochemistry , Addenbrooke’s Hospital, Cambridge, UK
                [3 ]Department of Internal Medicine , Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, Netherlands
                [4 ]Department of Clinical Chemistry , Erasmus MC, Rotterdam, Netherlands
                Author notes
                Correspondence should be addressed to K Chatterjee; Email: kkc1@ 123456medschl.cam.ac.uk
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                : 13 December 2019
                : 26 March 2020
                Clinical Study

                Endocrinology & Diabetes
                Endocrinology & Diabetes


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