Endocrine Abstracts

Introduction: Thyreotropin (TSH) is a glycoprotein containing an alpha-subunit similar to other glycoproteins (LH, FSH, ACTH, HCG) and a unique beta-subunit which reacts with the alpha-subunit in binding to the TSH-receptor. Low TSH levels are usually evidence of primary hyperthyreoidism as in Graves diseases/ toxic goiter or thyroiditis, or a result of secondary hypothyroidism in case of diseases of the pituitary gland. This case shows a rare variant causing apparently low TSH levels in a euthyroid patient due to altered immunoreactivity with the serum TSH measurement.

Case presentation: A 37-year old patient was referred to our clinic with subclinical hyperthyroidism and a discrepancy in TSH results from his general practitioner (Abbott assay at a contract). Clinically, there were no signs of hyperthyroidism. In the initial laboratory work-up he showed repeatedly low TSH (Siemens assay), negative Anti-TPO and TRAb. After excluding all primary and secondary causes we had the serum sample analyzed for TSH (Roche assay) in a third laboratory, using a different assay, resulting in slightly elevated levels. The following genetic test revealed a homozygous variant in the TSH-beta-subunit, 223A > G (P.Arg75Gly), leading to a reduced immunoreactivity with our TSH assay (Siemens Dimension Vista 1500 assay). This mutation was previously described to interfere with other detection assays. With worldwide only 5 cases of homozygous carriers and none in Europe, this sequence variant is very rare, according to genome databases.

Conclusion: This report shows a case of spuriously low TSH measurement in a euthyroid patient. An arginine to glycine substitution at amino acid position 75 in the TSH-beta-subunit reduced immunoreactivity ofthe Siemens Dimension Vista 1500 assay. Generally, state-of-the-art antibody based protein quantification assays offer high sensitivity and specificity; however, missense mutations (even if physiologically irrelevant) may result in falsely low values due to impeded antibody binding. Even if rare, it is important to question conflicting results, especially if they are not in agreement with the clinical findings, as otherwise they can lead to a false diagnosis and mistreatment of patients.