Time to Standardize Thyroid Function Testing

Thyroid disease is a highly prevalent and severe health problem that requires timely diagnosis and disease management. Whereas the diagnosis of overt hypo- or hyperthyroidism is rather easy, identification of subclinical dysfunction is not trivial and requires an integrated clinical laboratory approach (1, 2). Despite the importance of laboratory thyroid function testing (TFT), several confounding factors may hamper optimal use of the results; for example, if certain aspects, such as time of phlebotomy, analytical and biological variation, index of individuality, the patient’s setpoint and reference change values, are not properly accounted for, test results can be misinterpreted. But perhaps the factor with the highest clinical importance stems from the fact that today’s current assays for common TFT (thyrotropin [TSH], free thyroxine [FT4]/triiodothyronine [FT3]) generate results that differ by up to 30–40 percent (3-5). Admittedly, we can compensate for these differences using assay-specific reference intervals (RIs) and/or clinical decision limits, but is this really state-of-the art? After all, it does not allow the use of evidence-based clinical practice guidelines for application of consistent standards of medical care, nor the use of electronic patient records.

Before endocrinologists can agree on what constitutes “normal” thyroid hormone levels, we need to first accomplish comparability of laboratory testing results. Only through standardization or harmonization can we ensure that all TFT assays are fit to address modern clinical and public health needs (3–5). To that end, back in 2005 the IFCC established a task force to develop ISO 17511 conforming reference measurement systems that could be used to standardize/harmonize TSH and FT4/FT3 tests. Although we had to start the process from scratch, we are proud that we made some great achievements so far. We have established the key elements of the reference measurement systems for both TSH and FT4 (6, 7), and have developed a practical concept for implementation – the “step-up” approach (8). Step-up consists of performing a method comparison with as many assays as possible and the use of a panel of clinically relevant samples assigned with values by the FT4/FT3 reference measurement procedures (RMPs) or surrogate RMP (for TSH). These method comparison data are then used for recalibration of the assays, so that, after alignment, they generate comparable results.

We are particularly proud that we have formed close collaborations with all of the major in vitro diagnostic (IVD) manufacturers, who are extraordinarily committed. Together, we have established a relationship with the US FDA, which was very important, because recalibration of an assay can entail major regulatory activities. Making such relationships way ahead of the actual implementation of the process will hopefully limit delays to making the newly standardized/harmonized assays available for clinical use.

So, where do we go from here? We’re currently working to provide a clinically relevant serum panel for the final technical process of standardization/harmonization of the FT4 and TSH assays (this will happen in spring 2015), and to provide infrastructure for sustaining the status that we will have established. Although we would like to establish a network of competent reference laboratories, the laboratory at the University of Ghent is currently the only lab in the world that’s listed in the JCTLM database to offer the FT4 (FT3 coming soon) reference measurement services. We also want to define a platform that proves the applicability of a common RI after standardization/harmonization. To do this, we will determine the FT4 and TSH concentrations in a cohort of 120 individuals with the FT4 RMP and the TSH surrogate RMP, in parallel with the standardized IVD assays. After achieving this RI for common use, it will be up to the IVD manufacturers to establish reliable reference ranges from much bigger cohorts.

Once we get to that point, we will work with all key stakeholders (clinicians, patients, laboratories) to support the implementation of standardized/harmonized TFT in routine clinical practice. Indeed, in view of the significant change in values for TFT that will be introduced, healthcare providers/receivers need to be well prepared to avoid confusion. We will develop an outreach program to inform and educate them. Our plan is to act as a central coordinator to ensure that the switch happens globally and at the same time. The implementation process will also be preceded by a global benefit-risk analysis, which should result in an action plan to oversee and proactively avoid any causes of patient harm after standardization/harmonization. It’s a big challenge, but one that we believe we can achieve with confidence.

Linda Thienpont, professor of instrumental analytical chemistry, statistics and quality control, head of mass spectrometric reference laboratory, at the University of Ghent, Belgium, and chair of the IFCC committee for standardization of thyroid function test (C-STFT). Katleen van Uytfanghe is technical supervisor of the reference laboratory at the University of Ghent, Belgium, and scientific secretary of the C-STFT.

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