Abstract
Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHβ) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis.Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging.Results: 88 patients were correctly diagnosed as RTHβ with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHβ (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHβ (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHβ a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHβ showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 μUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHβ patients had small pituitary lesions, leading to unnecessary surgery in one case.Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.
Highlights
TSH secreting pituitary adenomas (TSHomas) and Resistance to Thyroid Hormone due to mutations in the THRB gene (RTHβ) are two possible underlying causes of the rare clinical entity of inappropriate secretion of TSH (IST), which is characterized by hyperthyroxinemia and non-suppressed TSH levels.The differential diagnosis of IST is often challenging [1]
This latter condition was accepted as a proof of TSHoma as thyroid function tests (TFTs) can be only transiently affected by the acute administration of somatostatin in RTHβ, but no normalization or even decreases of circulating free thyroid hormones can be seen in RTHβ patients on chronic somatostatin analogs [1, 20]
TRH Stimulation and T3 Suppression Tests. Both TSH peak and fold increase response to TRH were blunted in TSHoma patients compared with RTHβ or controls (p < 0.001), whilst RTHβ cases showed a greater fold increase in TSH compared with controls (p < 0.001; Table 1)
Summary
TSH secreting pituitary adenomas (TSHomas) and Resistance to Thyroid Hormone due to mutations in the THRB gene (RTHβ) are two possible underlying causes of the rare clinical entity of inappropriate secretion of TSH (IST), which is characterized by hyperthyroxinemia and non-suppressed TSH levels.The differential diagnosis of IST is often challenging [1]. TSH secreting pituitary adenomas (TSHomas) and Resistance to Thyroid Hormone due to mutations in the THRB gene (RTHβ) are two possible underlying causes of the rare clinical entity of inappropriate secretion of TSH (IST), which is characterized by hyperthyroxinemia and non-suppressed TSH levels. Laboratory artifacts resulting in discrepant thyroid function tests (TFTs) may arise due to anti-T4 or heterophile antibodies [5] or abnormal concentration or affinity of TH transport proteins (TBG, albumin, and transthyretin) [6]; these conditions are significantly more frequent than genuine IST, and as such, result in real potential for misdiagnosis [7]. Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHβ) due to THRB mutations. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis
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