What Should Be Done When Thyroid Function Tests Do Not Make Sense?
What Should Be Done When Thyroid Function Tests Do Not Make Sense?
Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic–pituitary–thyroid axis are associated with anomalous TFTs. Failure to recognize these potential 'pitfalls' can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs.
Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations. Fortunately, in most patients the interpretation of TFTs is straightforward with the combination of thyroid hormone (TH) and thyrotropin (TSH) measurements confirming euthyroidism, thyrotoxicosis or hypothyroidism consistent with their clinical status. However, in a small but significant group of contexts the laboratory results either do not 'fit' with the clinical picture and/or form an unusual, nonphysiological pattern – so-called 'funny TFTs'. Establishing the correct diagnosis in these cases is critically dependent on careful clinical assessment combined with focused laboratory, radiological and genetic testing – failure to adopt a structured approach may result in an incorrect diagnosis and inappropriate management.
Figure 1a shows the pattern of TFTs typically seen in classical thyrotoxicosis and hypothyroidism, together with various 'deviations' from these patterns and possible causes. A detailed review of all of these anomalous profiles is beyond the scope of this article, and the reader is directed to other resources [e.g. Association for Clinical Biochemistry/British Thyroid Association/British Thyroid Foundation joint guidelines; National Academy of Clinical Biochemistry (NACB) guidelines; Thyroid Disease Manager] for a more general discussion of how to investigate/manage discrepant TFTs. Here, we focus on the differential diagnosis of conditions associated with elevated TH [thyroxine (T4) and/or triiodothyronine (T3)] together with nonsuppressed (inappropriate) thyrotropin levels and ask the question 'what should be done when TFTs do not make sense?' Our approach is based on two decades of experience investigating such cases and proposes an algorithm that combines clinical, laboratory, radiological and genetic analyses. Formulation of this algorithm has been guided by knowledge of the following: (i) physiology of the hypothalamic–pituitary–thyroid (HPT) axis and the factors that govern TH action at a tissue/cellular level; (ii) the principles underpinning laboratory measurement of T4, T3 and TSH, and potential mechanisms of assay interference; and (iii) causes of hyperthyroxinaemia with nonsuppressed TSH. Importantly, many of the guiding principles outlined here (e.g. exclusion of assay interference or confounding drug therapy) are also applicable to other clinical contexts where discordant TFTs are encountered.
(Enlarge Image)
Figure 1.
Relationship between free thyroid hormone and thyrotropin levels in physiological and pathological states. (a) Schematic representation of different patterns of thyroid function tests and their causes. FDH, familial dysalbuminaemic hyperthyroxinaemia; FT4, free thyroxine; FT3, free triiodothyronine; NTI, nonthyroidal illness; TSH, thyrotropin [*signifies that TSH may be either fully suppressed (for example as seen in classical primary hyperthyroidism) or partially suppressed (i.e. measureable but below the lower limit of normal); historically, the lower limit of detection of TSH assays was 0·1 mU/l, but modern assays can detect levels an order of magnitude lower than this]. (b) Schematic representation of the log-linear relationship between thyrotropin and free thyroxine, illustrating how relatively small changes in FT4 (even within the normal range) lead to marked excursions in TSH. Horizontal and vertical black dotted lines denote upper and lower limits of the respective reference ranges for FT4 and TSH, respectively. Grey dotted line indicates TSH 0·1 mU/l.
Abstract and Introduction
Abstract
Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic–pituitary–thyroid axis are associated with anomalous TFTs. Failure to recognize these potential 'pitfalls' can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs.
Introduction
Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations. Fortunately, in most patients the interpretation of TFTs is straightforward with the combination of thyroid hormone (TH) and thyrotropin (TSH) measurements confirming euthyroidism, thyrotoxicosis or hypothyroidism consistent with their clinical status. However, in a small but significant group of contexts the laboratory results either do not 'fit' with the clinical picture and/or form an unusual, nonphysiological pattern – so-called 'funny TFTs'. Establishing the correct diagnosis in these cases is critically dependent on careful clinical assessment combined with focused laboratory, radiological and genetic testing – failure to adopt a structured approach may result in an incorrect diagnosis and inappropriate management.
Figure 1a shows the pattern of TFTs typically seen in classical thyrotoxicosis and hypothyroidism, together with various 'deviations' from these patterns and possible causes. A detailed review of all of these anomalous profiles is beyond the scope of this article, and the reader is directed to other resources [e.g. Association for Clinical Biochemistry/British Thyroid Association/British Thyroid Foundation joint guidelines; National Academy of Clinical Biochemistry (NACB) guidelines; Thyroid Disease Manager] for a more general discussion of how to investigate/manage discrepant TFTs. Here, we focus on the differential diagnosis of conditions associated with elevated TH [thyroxine (T4) and/or triiodothyronine (T3)] together with nonsuppressed (inappropriate) thyrotropin levels and ask the question 'what should be done when TFTs do not make sense?' Our approach is based on two decades of experience investigating such cases and proposes an algorithm that combines clinical, laboratory, radiological and genetic analyses. Formulation of this algorithm has been guided by knowledge of the following: (i) physiology of the hypothalamic–pituitary–thyroid (HPT) axis and the factors that govern TH action at a tissue/cellular level; (ii) the principles underpinning laboratory measurement of T4, T3 and TSH, and potential mechanisms of assay interference; and (iii) causes of hyperthyroxinaemia with nonsuppressed TSH. Importantly, many of the guiding principles outlined here (e.g. exclusion of assay interference or confounding drug therapy) are also applicable to other clinical contexts where discordant TFTs are encountered.
(Enlarge Image)
Figure 1.
Relationship between free thyroid hormone and thyrotropin levels in physiological and pathological states. (a) Schematic representation of different patterns of thyroid function tests and their causes. FDH, familial dysalbuminaemic hyperthyroxinaemia; FT4, free thyroxine; FT3, free triiodothyronine; NTI, nonthyroidal illness; TSH, thyrotropin [*signifies that TSH may be either fully suppressed (for example as seen in classical primary hyperthyroidism) or partially suppressed (i.e. measureable but below the lower limit of normal); historically, the lower limit of detection of TSH assays was 0·1 mU/l, but modern assays can detect levels an order of magnitude lower than this]. (b) Schematic representation of the log-linear relationship between thyrotropin and free thyroxine, illustrating how relatively small changes in FT4 (even within the normal range) lead to marked excursions in TSH. Horizontal and vertical black dotted lines denote upper and lower limits of the respective reference ranges for FT4 and TSH, respectively. Grey dotted line indicates TSH 0·1 mU/l.