Tissue sensitivity to thyroid hormones may change over time

Abstract

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 TSH fails to normalize despite adequate LT4 treatment. Methods: Nine patients with CH followed in three Academic Centre who developed over time a 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 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 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 FT4 levels. T3 suppression test followed by TRH stimulation was performed in two cases and was compatible with central resistance to thyroid hormones. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (N=2) or an eutopic gland (N=3) or in case of agenesis (N=1). None of the patients had genetic variants in genes involved in the regulation of thyroid hormone 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 thyroid hormone action.

Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone

“…Considering that the secretory capacity of the thyroid gland (the SPINA-GT index) seemed unaffected in the CFS patients, the suppressed serum T3 to T4 ratio in SELENOP-aAb positive patients is compatible with a defect in local deiodination of TH in Se-sensitive target tissues, like brain, bone, skeletal muscle and others [ 39 , 52 ]. This interpretation is supported by the hypothyroid-like clinical characteristics of , and it is tempting to speculate that SELENOP-aAb lead to an acquired form of resistance to thyroid hormone (A-RTH) with impaired local activation of T4 to T3 [ 53 , 54 ]. Collectively, the physiological consequences from SELENOP-aAb that can be deduced from the data would predict intracellular Se deficiency, low GPx and DIO biosynthesis rate, impaired TH activation in SELENOP-target cells with local hypothyroidism, reduced iodide liberation causing low urinary iodine, and elevated oxidative stress in kidney and elsewhere ( Fig.…”

Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism

“…The NKX2-5 gene is a member of the homeobox Nkx2 family that has been implicated in the pathogenesis of CH [25]. TSHB encodes the beta subunit of thyroid-stimulating hormone and a reduced methylation status at this level might favor the circulating TSH rise in CH patients and potentially explain the relative pituitary refractoriness in the normalization of circulating TSH occurring in some patients with CH during levothyroxine replacement [26][27][28][29].…”

Unusual causes of hyperthyrotropinemia and differential diagnosis of primary hypothyroidism: a revised diagnostic flowchart

“…Alternatively, they propose combined replacement therapy with T4 + T3 (55). Some of the patients reported by Lacámara were affected with congenital hypothyroidism (CH) and indeed earlier studies found that in 10-40% of neonates and children with CH the TSH fails to normalize despite an adequate LT4 treatment (56,58). In addition, a still unexplained degree of resistance to levothyroxine (LT4) persists also later in life, as adult CH patients maintain euthyroidism with higher L-T4 doses compared to postsurgical acquired hypothyroidism (59).…”