Falsely Undetectable TSH in a Cohort of South Asian Euthyroid Patients

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 4; pp. 1171 - 1179
• Main Authors: Drees, Julia C, Stone, Judith A, Reamer, C. Randy, Arboleda, Victoria E, Huang, Karl, Hrynkow, Jane, Greene, Dina N, Petrie, Matthew S, Hoke, Carolyn, Lorey, Thomas S, Dlott, Richard S
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.04.2014; Copyright by The Endocrine Society
• Subjects: Adult; Aged; Asian Continental Ancestry Group - statistics & numerical data; California - epidemiology; Cohort Studies; Diagnostic Errors - statistics & numerical data; False Negative Reactions; Female; Humans; Hypothyroidism - blood; Hypothyroidism - diagnosis; Hypothyroidism - epidemiology; Immunoassay - standards; Immunoassay - statistics & numerical data; Male; Middle Aged; Thyroid Function Tests - standards; Thyroid Function Tests - statistics & numerical data; Thyrotropin - blood; Young Adult; California
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-2092

Context: An index case of a clinically euthyroid woman of South Asian descent was identified with discordant TSH results: undetectable TSH on our routine assay and normal TSH on an alternate assay. Low TSH concentrations due to functionally compromising TSH mutations have been reported. Here we describe a new phenomenon of functional TSH that is undetectable by 4 widely used US Food and Drug Administration (FDA)–approved TSH immunoassays marketed by a single vendor. Objective: The purpose of this study was to identify additional cases and investigate the cause of the falsely undetectable TSH. Design: All samples with TSH results of <0.01 μIU/mL were retested with a second TSH assay. Discordant samples were evaluated on up to 8 FDA-approved TSH immunoassays and the TSHβ gene was sequenced. Retrospectively, thyroid function tests, diagnoses, and medications from 1.6 million individuals were analyzed. Results: Out of approximately 2 million individuals, we have identified a cohort of 20 hypothyroid and euthyroid patients of shared ethnicity with falsely undetectable TSH (<0.01 μIU/mL) in 4 of 8 commercially available TSH assays. Half of these individuals were initially treated based on repeated falsely undetectable TSH values (7 euthyroid patients were treated with methimazole and 2 hypothyroid patients had doses of levothyroxine decreased). In all cases, a retrospective chart review revealed that clinical assessments and free T4 and total T3 results were inconsistent with the undetectable TSH results. Specific antibodies failing to detect TSH in these cases were identified in the 4 affected assays. A novel TSHβ point mutation was identified. Conclusions: Our data suggest that these individuals have a previously unrecognized, functionally normal, TSH variant to which some monoclonal antibodies fail to bind. To assure appropriate patient management, clinicians and laboratorians need to be aware that certain TSH variants may be undetectable in some hyperselective TSH assays.