Thyroid Hormone Receptors and Resistance to Thyroid Hormone Disorders

Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre.

Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology.

These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic–pituitary–thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

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Overview of tissues and homeostatic functions affected in RTHα and RTHβ.

Source: NatureReviewsEndocrinology

Subclinical Hypothyroidism in Childhood — Current Knowledge and Open Issues

Subclinical hypothyroidism is defined as serum levels of TSH above the upper limit of the reference range, in the presence of normal concentrations of total T4 or free T4. This biochemical profile might be an indication of mild hypothyroidism, with a potential increased risk of metabolic abnormalities and cardiovascular disease recorded among adults. Whether subclinical hypothyroidism results in adverse health outcomes among children is a matter of debate and so management of this condition remains challenging. Mild forms of untreated subclinical hypothyroidism do not seem to be associated with impairments in growth, bone health or neurocognitive outcome. However, ongoing scientific investigations have highlighted the presence of subtle proatherogenic abnormalities among children with modest elevations in their TSH levels. Although current findings are insufficient to recommend levothyroxine treatment for all children with mild asymptomatic forms of subclinical hypothyroidism, they highlight the potential need for assessment of cardiovascular risk among children with this condition. Increased understanding of the early metabolic risk factors associated with subclinical hypothyroidism in childhood will help to improve the management of affected individuals.

Key points

• Subclinical hypothyroidism among children is often a benign and remitting condition, for which risk of progression to overt hypothyroidism depends on the underlying cause (for example, autoimmune disease)
• The optimum management of children with subclinical hypothyroidism depends on the aetiology and degree of TSH elevation and should be individually tailored
• The benefits of levothyroxine therapy are clear for the severe forms of subclinical hypothyroidism; however, uncertainty about this approach still exists for the mild forms of the condition
• In the absence of therapeutic intervention, clinical evaluation and thyroid function tests should be regularly performed to ensure early identification of children who might benefit from treatment
• Growth and neurocognitive outcomes do not seem to be affected in mild subclinical hypothyroidism; however, subtle proatherogenic abnormalities have been detected among children with modest elevations of TSH concentration
• Cardiovascular risk assessment among children and adolescents with subclinical hypothyroidism could help to prevent cardiovascular disease in adulthood

Read more: Subclinical Hypothyroidism in Childhood — Current Knowledge and Open Issues

Source: NatureReviewsEndocrinology