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      Pitfalls in the measurement and interpretation of thyroid function tests

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          Abstract

          Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations in both primary and secondary care. Fortunately, most TFTs are straightforward to interpret and confirm the clinical impression of euthyroidism, hypothyroidism or hyperthyroidism. However, in an important subgroup of patients the results of TFTs can seem confusing, either by virtue of being discordant with the clinical picture or because they appear incongruent with each other [e.g. raised thyroid hormones (TH), but with non-suppressed thyrotropin (TSH); raised TSH, but with normal TH]. In such cases, it is important first to revisit the clinical context, and to consider potential confounding factors, including alterations in normal physiology (e.g. pregnancy), intercurrent (non-thyroidal) illness, and medication usage (e.g. thyroxine, amiodarone, heparin). Once these have been excluded, laboratory artefacts in commonly used TSH or TH immunoassays should be screened for, thus avoiding unnecessary further investigation and/or treatment in cases where there is assay interference. In the remainder, consideration should be given to screening for rare genetic and acquired disorders of the hypothalamic–pituitary–thyroid (HPT) axis [e.g. resistance to thyroid hormone (RTH), thyrotropinoma (TSHoma)]. Here, we discuss the main pitfalls in the measurement and interpretation of TFTs, and propose a structured algorithm for the investigation and management of patients with anomalous/discordant TFTs.

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          Most cited references61

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          Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.

          Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.
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            A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene.

            Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.
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              Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease.

              High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range.

                Author and article information

                Journal
                Best Pract Res Clin Endocrinol Metab
                Best Pract. Res. Clin. Endocrinol. Metab
                Best Practice & Research. Clinical Endocrinology & Metabolism
                Elsevier
                1521-690X
                1878-1594
                1 December 2013
                December 2013
                : 27
                : 6
                : 745-762
                Affiliations
                [a ]Metabolic Research Laboratories, Wellcome Trust – MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
                [b ]Department of Clinical Biochemistry, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
                [c ]School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
                Author notes
                []Corresponding author. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Tel.: +44 1223 348739; Fax: +44 1223 330598. mg299@ 123456medschl.cam.ac.uk
                Article
                S1521-690X(13)00153-X
                10.1016/j.beem.2013.10.003
                3857600
                24275187
                93f91a1e-80d5-4b04-9a0a-a58d435c557a
                © 2013 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                Categories
                1

                Endocrinology & Diabetes
                anomalous/discordant thyroid function tests (tfts),assay interference,acquired and genetic disorders of hypothalamic–pituitary–thyroid axis

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