New TSH testing for early diagnosis of hypothyroidism including a therapeutic index for hormone treatment – TSH testing

Thyroid diseases are most frequent among endocrine disorders with 100Mn patients in Europe.TSH is the first protein marker prescribed by clinicians. Over the past decades, there has been a long standing debate to validate TSH levels within the normal range and detect the onset of hypothyroidism with high accuracy. The International Federation of Clinical Chemistry has recently estimated to approx. 36% discordance among existing tests. There has been also a need to develop assays calibrated on a molar basis to comply with new regulatory EU Directives. Since those issues are currently unsolved, the TSH testing project aims at establishing new tests and a working group with the IVD Industry to progress in early diagnosis.

A clinical validation of new procedures will be developed to measure early raise in TSH (4-10mIU/L) on a molar basis and for the first time, validate a clinical setting for thyroid hormone treatment at 7mIU/L. It is a truly innovative study which will deliver first-in-class tests since no strategic threshold has ever been established worldwide and no Reference Measurement Procedure is known for this marker.

Our past EU project showed that during the onset of the disease, TSH is turning to highly sialylated, hypofucosylated, long-lived forms which are more reactive to most monoclonal antibodies than the normal forms. These findings have been patented and a proof of concept (ANR EMPB) performed as a preliminary clinical study. We now aim at establishing a more accurate measurement of the early raise in TSH in subclinical hypothyroidism to develop an early diagnostic. Measuring such glycoforms will deliver a more accurate testing and as a result, will also be able to deliver a threshold that inclines the clinician to treat or not treat the patient with thyroid hormone.

The project will be conducted by Pr. C. Ronin - Siamed’Xpress, and organized in 3 main workpackages

Bood collections of hypothyroid patients (CHU Lyon Sud):
Blood samples will be collected in the Rhône Alpes Region and dispatched as 3 collections: TSH 0.5-4 mIU/L, TSH 4-10 mIU/L and TSH 10-50mIU/L. 1400 patients with slightly elevated TSH will be recruited and those with TSH> 7mIU/L will be treated with Levothyrox® over 1 month. TSH will be measured and collected again over a period of 1 to 6 months until their TSH is normalized. Appropriate pools will be prepared and sent out to the Manufacturers.

Design of new TSH calibrators and new tests (SiaMed’Xpress):
Hyperglycosylated TSH will be produced by Siamed based on a proprietary engineering of CHO cells equipped with a 6-sialyltransferase activity. This material will be sent to manufacturers for in house comparison in their analyzers. Monoclonal antibodies against this product will be developped and screened by the company to construct new assays to be validated on blood samples.
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Working Group with EDMA (Roche Diagnostics):
European Manufacturers will be represented through their European Association. This WP will clarify the right antigen detected by the current tests. To this aim, manufacturers will participate in testing new TSHs in automated assays using a common blood collection. Accordingly, a procedure may be developped to identify which antibodies detect best diseased TSHs. This WP will also seek for the participation of the IFCC Scientific Division and the IFCC-working group Standardization of Thyroid Function testing to help dissemination of the study worldwide
The project will deliver a clinical validation of outmost importance to validate new and existing assays according to the recent European Directives. It will provide the Manufacturers with the opportunity of optimizing existing tests or acquiring new tests at will. Since TSH is the first marker to be prescribed among serum protein markers, it is hoped that the project will also deliver a similar strategy to optimize other tests (30 markers).