Pitfalls in the measurement and interpretation of thyroid function tests

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.

Keywords: acquired and genetic disorders of hypothalamic–pituitary–thyroid axis; anomalous/discordant thyroid function tests (TFTs); assay interference.

Fig. 1

Schematic representation of the hypothalamic–pituitary–thyroid axis and the various factors governing thyroid hormone transport, metabolism and action at the tissue/cellular level. Key: α1, TRα1; β1, TRβ1; β2, TRβ2; CoA, coactivator; DNA, deoxyribonucleic acid; MCT8, monocarboxylate transporter 8; RXR, retinoid X receptor; SA, somatostatin; T3, triiodothyronine; T4, thyroxine; TR, thyroid receptor; TRE, thyroid response element; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone (thyrotropin).

Fig. 2

Different patterns of thyroid function tests and their causes. Key: ATDs, antithyroid drugs; FDH, familial dysalbuminaemic hyperthyroxinaemia; FT4, free thyroxine; FT3, free triiodothyronine; NTI, non-thyroidal illness; TKIs, tyrosine kinase inhibitors; TSH, thyroid-stimulating hormone/thyrotropin [*signifies that TSH may be either fully suppressed (for example as seen in classical primary hyperthyroidism) or partially suppressed (i.e. measurable, but below the lower limit of normal)]. Reproduced with permission from: Koulouri O, Gurnell M. How to interpret thyroid function tests. Clin Med 2013; 13:282–6. Copyright © 2013 Royal College of Physicians.

Fig. 3

Protocol for supervised thyroxine absorption test, followed by weekly supervised thyroxine administration. Key: ECG, electrocardiogram; FT4, free thyroxine; FT3, free triiodothyronine; TSH, thyrotropin (thyroid stimulating hormone).

Fig. 4

Schematic representation of an immunoradiometric assay for measurement of serum TSH. a. TSH is bound by both capture (immobilised) and detection (labelled) antibodies. b. The presence of a human anti-animal (HAA) or heterophilic antibody that is capable of cross-linking the capture and detection antibodies even in the absence of analyte (TSH), results in positive assay interference. c. In contrast, an HAA or heterophilic antibody that binds either the capture or detection antibody to prevent crosslinking (even in the presence of TSH) results in negative assay interference.

Fig. 5

Algorithm for the interpretation of discordant TFTs. Key: FT3, free triiodothyronine; FT4, free thyroxine; HPT, hypothalamic–pituitary–thyroid; RR, reference range; TFTs, thyroid function tests; TH, thyroid hormones; L-T4, levothyroxine; NTI, non-thyroidal illness, TT4, total thyroxine; TT3, total triiodothyronine; TSH, thyroid stimulating hormone (thyrotropin); TH, thyroid hormones; TBG, thyroxine binding globulin.