The World Health Organization (WHO), through its Expert Committee for Biological Standardisation (ECBS), provides an International Standard (IS) for Thyroid-Stimulating Hormone (TSH) diagnostic measurements. This product has been in existence since the 1970s, and it defines the International Unit (IU) of TSH activity. The product has been maintained throughout its lifespan by the UK Medicines and Healthcare products Regulatory Agency (MHRA) via its National Institute for Biological Standards and Control (NIBSC) catalogue. The current 4th WHO IS for TSH, coded 81/615,was established in 2023.
The current and previous iterations of the WHO International Standard have all comprised of pituitary TSH. However, the WHO IS has historically shown poor commutability with patient samples in clinical TSH immunoassays, which is likely due to differences in the glycosylation profiles of pituitary and serum TSH. This led to historically poor harmonisation of clinical TSH immunoassays, the improvement of which was one objective of C-STFT upon its creation. This led to the development of a TSH serum sample panel, aimed at harmonisation of clinical TSH immunoassays via recalibration to the panel, the components of which were value assigned in mIU/L (traceable to the WHO IS) using an All Procedure Trimmed Mean (APTM) approach.
In the early 2020s both the 3rd WHO IS for TSH, coded 81/565, and the 2nd C-STFT harmonisation panel needed replacement. These projects were undertaken simultaneously in a collaboration between C-STFT and MHRA/WHO. The 2nd C-STFT panel, the 3rd WHO IS, 81/565, and the candidate 4th WHO IS, 81/615, were all tested together in 16 different TSH immunoassays. This enabled value-assignment of the candidate 4th WHO IS, 81/615, in mIU per ampoule relative to its predecessor, and evaluation of its commutability with the C-STFT panel serum samples. Results of the 2nd C-STFT panel also enabled assay recalibration ahead of evaluation and APTM-assignment of the 3rd C-STFT panel at a later date.
The data obtained in this study confirmed a lack of commutability of WHO International Standards for TSH with patient samples in some TSH immunoassays. Through statistical analysis, it was demonstrated that re-calibration of C-STFT panel sample measurements using the WHO International Standards would result in reduced inter-assay harmonisation compared to results reported as per current assay/kit calibrations. This further indicated that the recent availability of the C-STFT panel for assay re-calibration has resulted in some improvement of the TSH immunoassay harmonisation status (31),(32).
Despite limitations in its commutability, pituitary TSH has continued to be used for the WHO International Standard largely due to its ease of availability; three preparations manufactured in the 1980s have been sequentially adopted as the 2nd, 3rd, and 4th WHO IS. On the contrary, obtaining high-TSH serum of sufficient volume to prepare a WHO IS would be extremely difficult. For example, the 4th IS is a batch of approximately 3,000 units, expected to last 15-20 years, each containing 11.7 mIU of TSH, allowing for small volumes with TSH concentrations of >10,000 mIU/L to be readily achieved. Meanwhile, the C-STFT panel can only be prepared in relatively small numbers yet involves the difficult and time-consuming process of sourcing sufficient volumes of clinical samples containing TSH levels across the clinical measurement range. For these reasons, the continued co-existence of the two resources is crucial at the current time; the WHO IS, as a long-term and widely available material (which continues to define the International Unit), and the C-STFT, as a more restricted resource available to manufacturers that is used to improve assay harmonisation.
In the future, C-STFT and MHRA aims to continue its collaboration to investigate the feasibility of developing a serum-derived WHO IS for TSH with improved commutability.