Variable Diagnoses in Cases Referred for Discordant Thyroid Function Tests: Focus on Lymphoproliferative Disorders

Background: Careful consideration of the differential diagnosis of discordant thyroid function tests (TFTs) is fundamental to prevent mismanagement, waste of resources, uncover rare thyroid disorders, or other underlying critical conditions in patients referred for the evaluation of this issue. Here, we describe the frequency of underlying diagnoses and focus on cases in which the identification of analytical interferences led to the discovery of lymphoproliferative disorders. Methods: This is a retrospective cross-sectional study including all consecutive patients referred to the Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano, for suspected central hyperthyroidism between January 2017 and February 2025. Inclusion criteria were based on laboratory findings of (1) elevated or inappropriately normal thyrotropin (TSH) with high FT4 and/or FT3, (2) elevated TSH with FT4 in the upper reference range, and (3) failure of TSH to normalize despite levothyroxine therapy, along with rising FT4 levels. The differential diagnosis was made by (1) reassessment of discrepant results in the hormone panel by different analytical methods or tandem mass spectrometry; (2) serum serial dilution or polyethylene glycol precipitation; (3) evaluation of rheumatoid factor, serum protein electrophoresis (SPEP), and cryoglobulins; and (4) deep clinical phenotyping and/or confirmatory genetic testing, as appropriate. Results: Among 144 patients referred for discordant TFTs mimicking central hyperthyroidism, 44% were genuine rare thyroid disorders—32% with resistance to thyroid hormone beta (RTHβ), 7% with TSH-secreting adenomas, and 5% other diagnosis—and 56% had assay interference. In this latter group, interfering clonal paraproteins were detected in 6/81 cases. One patient was ultimately diagnosed with multiple myeloma, another one with type 1 cryoglobulinemia due to indolent marginal zone B non-Hodgkin lymphoma, and the remaining four cases were found to have monoclonal gammopathy of uncertain significance. The clonal paraprotein was an IgM kappa/lambda in five cases and IgG kappa or IgA kappa in one case, respectively. Conclusions: In patients referred for discordant TFTs, RTHβ is the most prevalent thyroid disorder, but variable assay interferences represent the most frequent condition. In these cases, SPEP and hematological investigations are highly recommended.