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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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The clinical consequences of primary hypothyroidism include cardiovascular morbidity, increased mortality, and poor quality of life; therefore guidelines endorsed by several Scientific Societies recommend measuring circulating thyroid-stimulating hormone (TSH) in patients at risk. The assessment of serum TSH levels is also deemed to be the most robust and accurate biomarker during the management of replacement therapy in patients with a previous diagnosis of primary hypothyroidism. In line with a reflex TSH laboratory strategy, free thyroxine is measured only if the TSH falls outside specific cutoffs, in order to streamline investigations and save unjustified costs. This serum TSH-based approach to both diagnosis and monitoring has been widely accepted by several national and local health services; nevertheless, false-negative or -positive testing may occur, leading to inappropriate management or treatment. This review aims to describe several infrequent causes of increased circulating TSH, including analytical interferences, resistance to TSH, consumptive hypothyroidism, and refractoriness to levothyroxine replacement treatment. We propose a clinical flowchart to aid correct recognition of these various conditions, which represent important potential pitfalls in the diagnosis and treatment of primary hypothyroidism.
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Introduction
Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment.
Methods
Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR.
Results
All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively.
Conclusions
We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.
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Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy
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Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy
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Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Introduction: Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.
