Neuropsychological Alterations in Patients with Congenital Hypothyroidism Treated with Levothyroxine: Linked Factors and Thyroid Hormone Hyposensitivity

Abstract

Eighty-five percent of the studies of patients with congenital hypothyroidism (CH) treated with Levothyroxine (L-T₄) report neuropsychological sequelae throughout life. In neonates and infants, there is a deficit in sensorimotor skills (impaired balance). In preschool and elementary school children and adolescents, there are alterations in intellectual quotient (low scores), language (delayed phonological acquisition), memory (visual, verbal, visuospatial, visuoconstructive, autobiographical, and semantic), sensorimotor skills (impaired fine and gross motor control), and visuoconstructive-visuospatial domain (low scores in spatial location, block design, and object assembly). These neuropsychological domains are also affected in young adults, except for language (adequate verbal fluency) and visuoconstructive-visuospatial domain (no data). The onset and severity of neuropsychological sequelae in patients with treated CH depend on several factors: extrinsic, related to L-T₄ treatment and social aspects, and intrinsic, such as severity and etiology of CH, as well as structural and physiological changes in the brain. In this review, we hypothesized that thyroid hormone hyposensitivity (THH) could also contribute to neuropsychological alterations by reducing the effectiveness of L-T₄ treatment in the brain. Thus, further research could approach the THH hypothesis at basic and clinical levels to implement new endocrinological and neuropsychological therapies for CH patients.

Keywords: IQ; adolescents; infants; language; learning; memory; preschoolers; school children; sensorimotor; visuoconstructive; visuospatial; young adults.

Figure 1

Worldwide distribution of scientific reports on neuropsychological profiles of CH-Tx patients. The red dots indicate reports of CH-Tx patients with a deficit in at least one neuropsychological domain. The green dots indicate reports of CH-Tx patients who did not present neuropsychological alterations.

Figure 2

Main neuropsychological alterations reported in CH-Tx patients at different ages. This figure summarizes the main alterations reported in CH-Tx patients; however, these alterations depend on several factors (see Section 4). The dotted line indicates that it is not possible to evaluate the neuropsychological domain in neonates and infants. * Scores are frequently within normal limits, but values are at inferior limit. + Optimum L-T₄ dose and early treatment are essential for better scores. # Alterations were found in 29–50% of children with CH. ** No impairment in verbal fluency.

Figure 3

Factors related to the neuropsychological alterations found in patients with congenital hypothyroidism treated with levothyroxine (L-T₄). The onset and severity of the neuropsychological alterations in patients with congenital hypothyroidism treated with L-T₄ are related to extrinsic (dotted yellow line) and intrinsic (dotted green line) factors. Extrinsic factors include those related to L-T₄ treatment (I) and social elements (II). Intrinsic factors correspond to severity and etiology of congenital hypothyroidism (III), and changes in the brain, such as structural and physiological alterations in specific brain regions (IV) and modifications in the thyroid physiology of the brain (V). This review proposes the hypothesis that modifications in the brain thyroid physiology lead to a state of mild thyroid hormone hyposensitivity that could also contribute to the onset of the neuropsychological sequelae (V).

Figure 4

Hypothesis of thyroid hormone hyposensitivity as a factor linked to neuropsychological alterations in patients with congenital hypothyroidism (CH) treated with levothyroxine (L-T₄). Reduced levels of thyroid hormones (THs) during perinatal period could lead to mild thyroid hormone hyposensitivity in the brain (A). Hyposensitivity may be caused by altered expression of molecules OATP1C, MCT8, DIO2, DIO3, and RXR and thyroid receptors (TRα1, TRβ1, TRβ2) (asterisks indicate molecules possibly affected). This leads to a deficit in L-T₄ transport from the periphery to the brain, a reduced transport of L-T₄ and T₃ between neural cells, impaired conversion of L-T₄ into T₃ or T₃ into T₂, and an impaired THs mechanism of action in the brain (B). It is hypothesized that the hyposensitivity is mild but enough to reduce effectiveness of L-T₄ treatment at cerebral level (C), which contributes to the incidence of neuropsychological alterations in CH patients under treatment (D). The mechanism of THs transport in this figure is based on that published by Alkemade et al. for human hypothalamus [118]. Abbreviations: BBB, Blood–brain barrier; OATP1CI, Organic anion-transporting polypeptide 1c1; MCT8, Monocarboxylate transporter 8; MCT10, Monocarboxylate transporter 10; DIO2, Type 2 deiodinase; DIO3, type 3 deiodinase; RXR, Retinoid X receptor; TR, thyroid receptors.