Thyroid function in childhood obesity

The progressive increase in childhood obesity worldwide has stimulated interest in the pathogenesis of obesity, including the relationship between thyroid function and obesity in overweight children. Although several studies have reported an association between body mass and function of the thyroid axis, the underlying mechanism linking obesity to subtle changes in circulating levels of thyroid hormones and thyroid-stimulating hormone (TSH) remains to be clarified. The favoured mechanism is a direct effect of leptin, the main hormone of adipose tissue, on the activity of the hypothalamic-pituitary-thyroid axis (HPT axis), which controls and modulates hormone production by the thyroid. The interaction between leptin, thyrotropin-releasing hormone (TRH), TSH and thyroid hormones creates a vicious circle that can be broken only by a reduction in adipose tissue, suggesting that changes in the thyroid axis observed in childhood obesity are a consequence rather than a cause of increased body mass. Management should therefore be directed towards normalization of body mass.

Background

Childhood obesity has become one of the most serious public health challenges of the 21st century. The 2010 WHO report states that 8.3% of children aged 5-14 years are obese, rising to 14.2% in adolescents and young adults aged 15-24 [1]. Clinical research conducted in overweight and obese children has demonstrated that a hormone profile typical of subclinical hypothyroidism, i.e. slightly raised TSH values with normal or slightly raised fT4 and/or fT3 levels, was observed in 10-23% of obese children. This pattern is seen in only about 2% of the overall teenage population. This increase in subclinical hypothyroidism emphasizes the influence of obesity upon thyroid function [2][3].

Hypothalamic-pituitary-thyroid (HPT) axis

Figure 1
Figure 1
Thyroid hormone production is controlled and modified by the HPT axis. TRH secreted from the hypothalamus stimulates TSH synthesis in the anterior pituitary gland. Subsequently TSH stimulates formation of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in the thyroid gland. This production is controlled by regulatory feedback loops at the level of hypothalamus and pituitary gland (Fig.1) [4].

Considering the connection between overweight and thyroid function, it is worth noticing that T3 (biologically more potent than T4) influences metabolic homeostasis, thermogenesis, lipolysis and metabolism of cholesterol. Moreover, TSH stimulates adipogenesis not only via thyroid hormones, but also directly via its receptors on the surface of adipocytes [5][6].

Although raised TSH level is the most commonly detected disorder, it is not the only indication of thyroid malfunction which has been observed in obese children. A positive correlation between the increase of fT3 level and the increase of body mass was also observed. A parallel increase of TSH and fT3 levels suggests that the patients in that group are strongly resistant to fT3. Moreover, moderately elevated fT3 level along with lower level of fT4 observed in obese children may be a consequence of nutrient-dependent T4 to T3 conversion [2][7].

Pathogenesis - the role of leptin

Since weight affects function of thyroid gland, the underlying mechanism linking obesity to the subtle changes in the levels of thyroid hormones and TSH still remains to be clarified. Possible explanations include

  1. Changes occurring in the hypothalamic-pituitary axis,
  2. Impaired feedback mechanism resulting from reduced numbers of T3 receptors in the hypothalamus (“T3 resistance”)
  3. Limited activity of peripheral deiodinase
  4. The most favoured hypothesis is that leptin causes an increase in pro-TRH levels [2][8][9].

The increase in leptin is positively correlated with body mass, and affects the neurons in the hypothalamus responsible for TRH synthesis, resulting in Figure 2
Figure 2
increased TRH secretion, increased of TSH, and thus increased stimulation of leptin production by adipocytes.

The relation between leptin and TSH is not unidirectional, as leptin also affects the action of pituitary gland by exerting an inhibitory effect on the activity of pituitary type 2 deiodinase, which causes disorders in the functioning of the fT3-TSH feedback mechanism (Fig.2) [2][10][11][12]. The resulting vicious circle can only be broken by reduction of the adipose tissue mass, suggesting that the thyroid axis alterations observed in childhood obesity represent the consequence rather than the cause of increased body mass.

The treatment dilemma

Subtle changes in the thyroid hormone axis, both in obese children and in children with normal body mass and possible subclinical hypothyroidism constitute a problem for experts who attempt to generate guidelines for the treatment of such cases [2].

In order to elucidate the natural history of subclinical hypothyroidism, 121 000 children with subclinical hypothyroidism were observed over 5 years. TSH levels normalized without any treatment in up to 70% of children with TSH 5.5-10 mIU/l. In contrast, TSH levels normalized only in 40% of those whose initial TSH was >10 mIU/l [13].

The hypothesis that body mass disorders are primary while changes in the thyroid axis are secondary to this suggests that optimal first-line treatment is life-style change rather than pharmacological treatment. Even a small decrease in body mass decrease often leads to normalization of thyroid hormone levels. This form of treatment is often successful, but it is worth monitoring the thyroid axis and considering the possibility of thyroid substitution at a later stage, especially if the hormone changes progress.

This does however require careful consideration and evaluation of the clinical status of the patient. Treatment seems to be unnecessary in obese children with a TSH from 5.5 - 10 mIU/l, except when normalization of thyroid axis function is not observed when body mass decreases. Hormone treatment should however be considered in children with TSH levels above 10 µIU/ml [2][14][15].

Practical points

  • Thyroid function tests should be performed in obese children to define their thyroid hormonal status.
  • Subclinical hypothyroidism appears to be the most common disturbance of the thyroid function in overweight children.
  • The most probable mechanism that links obesity to thyroid function is the increased level of leptin, which affects the hypothalamus and pituitary gland causing TRH and TSH secretion.
  • Thyroid axis alterations observed in childhood obesity seem to constitute a consequence rather than a cause of obesity.
  • Optimal first-line treatment is lifestyle change and body weight reduction, with hormone replacement as a supplementary option.

References

  1. ^ WHO 2010 the social report

  2. ^ Gertig AM, Niechciał E, Skowrońska B Thyroid axis alterations in childhood obesity. Pediatr Endocrinol Diabetes Metab. 2012;18(3):116-9.

  3. ^ Reinehr T Thyroid function in the nutritionally obese child and adolescent. Current Opinion in Pediatrics 2011;23:415-20.

  4. ^ Bursell JD, Warner JT Interpretation of thyroid function in children. Paediatrics and Child Health 2007, 17(9):361-66.

  5. ^ Sorisky A, Bell A, Gagnon A TSH receptor in adipse cells. Horm Metab Res 2000:32:468-74.

  6. ^ Pacifico L, Anania C, Ferraro F et al. Thyroid function in childhood obesity and metabolic comorbidity. Clinica Chimica Acta 2012 (413):396-405.

  7. ^ Marras V, Casini MR, Pilia S, et al. Thyroid function in obese children and adolescents. Horm Res Paediatr. 2010;73:193-7.

  8. ^ Rapa A, Monzani A, Moia S, et al. Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved. J Clin Endocrinol Metab. 2009;94:2414-20.

  9. ^ Santini F, Galli G, Maff ei M, et al. Acute exogenous TSH administration stimulates leptin secretion in vivo. Eur J Endocrinol. 2010;163:63-67.

  10. ^ Reinehr T, Isa A, de S ousa G, et al . Thyroid hormones and their relation to weight status. Horm Res. 2008;70:51-7.

  11. ^ Winter WE, Signorino MR. Review; molecular thyroidology. Ann Clin Lab Sci. 2001;31:221-44.

  12. ^ Ortiga-Carvalho TM, Oliveira KJ, Soares BA, Pazos-Moura CC. The role of leptin in the regulation of TSH secretion in the fed state: in viv o and in vitro studies. J Endocrinol. 2002;174:121 -125.

  13. ^ Reinehr T, Andler W. Thyroid hormones before and after weight loss in obesity. Arch Dis Child. 2002;87:320-3.

  14. ^ Arrigo T, Wasniewska M, Crisafulli G, et al . Subclinical hypothyroidism: the state of the art. J Endocrinol Invest. 2008;31:79-84.

  15. ^ De Luca F, Wasniewska M, Zirilli G, et al. At the end of a two-year follow-up elevated TSH levels normalize or remain unchanged in most the children with subclinical hypothyroidism. Ital J Pediatr. 2010;36:11.

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