Introduction: We present the case of a young female patient referred for hyperthyroidism with persistently detectable TSH despite elevated free thyroxine (FT4) levels which, interestingly, failed to normalize following anti-thyroidal treatment. Further testing elucidated the underlying causation for detectable TSH in presence of hyperthyroxinemia to be due to interfering substances in the thyroid function assays.
Case: A 35-year-old female is evaluated for hyperthyroidism discovered in preparation for embryo transfer. History includes transient hyperthyroidism two years ago while undergoing in vitro fertilization. Prior workup included negative antibodies and nuclear uptake scan revealing a right-sided autonomously functioning thyroid nodule with 24-hour uptake of 40.7%. She was briefly treated with PTU in first trimester and lost to follow-up. While once again undergoing fertility treatment with clomiphene, the patient developed tremor and heat intolerance. She was found to have TSH 0.3 (0.45-4.12 mU/L) and analog FT4 of 6.4 (0.8-1.8 ng/dL). She denied use of OTC supplements. PTU 50 mg twice daily was initiated with minimal improvement with TSH 0.7 mU/L, FT4 3.7 ng/dL. On evaluation, slight tremor and mild thyroid enlargement were noted. Our differential expanded to include TSH-secreting pituitary adenoma, thyroid hormone resistance (no family history), and assay interference. Both MRI pituitary and an alpha-subunit level (0.36) were normal. Symptoms improved gradually with repeat TSH 1.79 mU/L, FT4 2.4 ng/DL by standard analog methods. We suspected ‘assay interference’ for which FT4 via direct equilibrium dialysis was obtained and was indeed normal at 0.76 ng/dL. Further lab testing verified interference in both in the standard TSH and FT4 assays presumed secondary to heterophile antibodies.
Discussion: Interpretation of thyroid studies discordant with the clinical picture or incongruent with each other requires understanding of thyroid physiology and the intricacies of commonly utilized assays. The differential of elevated thyroxine levels with detectable/normal TSH rests between thyroid hormone resistance syndromes, TSH secreting pituitary tumors and interfering substances in the assay. Most commercially available TSH assays are based on a ‘sandwich’ assay which is notoriously interfered with by heterophile antibodies and excess biotin. Determination of FT4 is also challenging as the assay must detect very low concentrations of free hormone relative to excess of protein-bound analyte. When in question, it is important consider utilization of laboratory expertise and retesting by alternative assays.