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

Antonio Musolino1, Giacomo Fabio Antonio Grifoni1, Simone Rodolfi1

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Thyroid : Official Journal of the American Thyroid Association
|July 30, 2025
PubMed
Summary

Discordant thyroid function tests (TFTs) often stem from assay interference rather than rare thyroid disorders like resistance to thyroid hormone beta (RTHβ). Investigating paraproteins via serum protein electrophoresis (SPEP) is crucial for diagnosing underlying lymphoproliferative disorders.

Keywords:
PEG precipitationimmunoassay interferencemonoclonal gammopathy of uncertain significanceparaproteinresistance to thyroid hormonespurious hyperthyroxinemia

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Area of Science:

  • Endocrinology
  • Clinical Chemistry
  • Hematology

Background:

  • Discordant thyroid function tests (TFTs) require careful differential diagnosis to avoid mismanagement and identify critical underlying conditions.
  • Analytical interferences can mimic rare thyroid disorders, necessitating thorough investigation.

Purpose of the Study:

  • To determine the frequency of underlying diagnoses in patients with discordant TFTs suggestive of central hyperthyroidism.
  • To highlight cases where analytical interferences led to the discovery of lymphoproliferative disorders.

Main Methods:

  • Retrospective cross-sectional study of 144 patients with discordant TFTs.
  • Differential diagnosis involved reassessment of hormone assays, serum dilution/precipitation, and evaluation for paraproteins (rheumatoid factor, SPEP, cryoglobulins).
  • Clinical phenotyping and genetic testing were used for confirmation.

Main Results:

  • 44% had genuine rare thyroid disorders (32% resistance to thyroid hormone beta [RTHβ], 7% TSH-secreting adenomas).
  • 56% had assay interference, with interfering clonal paraproteins found in 6/81 cases.
  • Diagnoses included multiple myeloma, cryoglobulinemia, and monoclonal gammopathy of uncertain significance.

Conclusions:

  • Resistance to thyroid hormone beta (RTHβ) is the most prevalent thyroid disorder in this cohort.
  • Assay interferences are more frequent than rare thyroid disorders, with paraproteins being a significant cause.
  • Serum protein electrophoresis (SPEP) and hematological investigations are recommended for patients with discordant TFTs.