Approach to the Patient With Raised Thyroid Hormones and Nonsuppressed TSH

Abstract

Measurement of free thyroid hormones (THs) and thyrotropin (TSH) using automated immunoassays is central to the diagnosis of thyroid dysfunction. Using illustrative cases, we describe a diagnostic approach to discordant thyroid function tests, focusing on entities causing elevated free thyroxine and/or free triiodothyronine measurements with nonsuppressed TSH levels. Different types of analytical interference (eg, abnormal thyroid hormone binding proteins, antibodies to iodothyronines or TSH, heterophile antibodies, biotin) or disorders (eg, resistance to thyroid hormone β or α, monocarboxylate transporter 8 or selenoprotein deficiency, TSH-secreting pituitary tumor) that can cause this biochemical pattern will be considered. We show that a structured approach, combining clinical assessment with additional laboratory investigations to exclude assay artifact, followed by genetic testing or specialized imaging, can establish a correct diagnosis, potentially preventing unnecessary investigation or inappropriate therapy.

Keywords: assay interference; thyroid function tests; thyroid hormone action.

Figure 1.

Molecular (functional) pituitary imaging in a patient with an occult microthyrotropinoma. Standard clinical MRI (coronal T1SE before and after gadolinium) at diagnosis fails to demonstrate an adenoma. Similarly, volumetric (FSPGR) sequences are unremarkable. However, molecular imaging with Met-PET coregistered with FSPGR MRI reveals intense focal radiotracer uptake just to the left of the site of insertion of the infundibulum. Following 3 months of depot SRL therapy, with resultant normalization of thyroid function tests, there is no discernible change in anatomical imaging findings; however, in marked contrast, there is dramatic diminution in radiotracer uptake, thereby revealing the location of the occult microadenoma (subsequently confirmed at transsphenoidal surgery). Abbreviations: FSPGR, fast spoiled gradient recalled echo; Gad, gadolinium; Met-PET/MR^CR, ¹¹C-methionine PET/CT coregistered with FSPGR MRI; MRI, magnetic resonance imaging; PET, positron emission tomography; SE, spin echo; SRL, somatostatin receptor ligand; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

Figure 2.

Antibody interference in free T4/T3 measurement can be due to anti-iodothyronine or antireagent antibodies, and in TSH measurement due to anti-TSH (macroTSH) or antireagent antibodies Abbreviations: CH, congenital hypothyroidism; GFC, gel filtration chromatography; PEG, polyethylene glycol; RTHα, resistance to thyroid hormone α; RTHβ, resistance to thyroid hormone β; SHBG, sex hormone–binding globulin; SRL, somatostatin receptor ligand.