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Tissue sensitivity to thyroid hormones may change over time.

Giorgio Radetti1, Franco Rigon2, Alessandro Salvatoni3

  • 1Marienklinik, Bolzano, Italy.

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PubMed
Summary

Some children with congenital hypothyroidism (CH) develop temporary pituitary resistance to levothyroxine (LT4). In some cases, thyroid-stimulating hormone (TSH) remains high despite adequate LT4 treatment, indicating acquired resistance.

Keywords:
Refetoff syndromehyperthyroidismhypothyroidismresistance to thyroid hormones

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Area of Science:

  • Endocrinology
  • Genetics
  • Pediatric Endocrinology

Background:

  • Congenital hypothyroidism (CH) patients may exhibit transient pituitary resistance to levothyroxine (LT4).
  • In some CH patients, thyroid-stimulating hormone (TSH) fails to normalize despite sufficient LT4 therapy, suggesting persistent resistance.

Purpose of the Study:

  • To investigate the phenomenon of acquired pituitary resistance to thyroid hormone (TH) in patients with congenital hypothyroidism.
  • To identify potential genetic or biochemical factors contributing to this resistance.

Main Methods:

  • Studied nine patients with CH who developed resistance to thyroid hormones.
  • Performed extensive biochemical and genetic analyses, including Sanger sequencing and next-generation sequencing of candidate genes.
  • Utilized tri-iodothyronine suppression and thyrotrophin-releasing hormone stimulation tests in select cases.

Main Results:

  • All patients initially had normal thyroid hormone sensitivity, developing resistance later in life.
  • TSH normalized only with elevated free thyroxine levels, consistent with central resistance to TH.
  • No genetic variants in TH action regulation genes were found; however, double heterozygous variants in TSHR/GLIS3 or DUOX2/SLC26A4 were identified in two patients.

Conclusions:

  • Identified congenital hypothyroidism patients with acquired, unexplained pituitary refractoriness to thyroid hormone action.
  • This acquired resistance can occur irrespective of the underlying cause of CH (ectopic, eutopic, or athyreosis).