Resistance to Thyroid Hormone in Childhood

Thyroid Factor

The Natural Thyroid Diet

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O. Bakker

Division of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands

Occasionally, a patient is seen in the clinic with apparent hypo- and/or hyperthyroid symptoms but with conflicting results of thyroid function tests: they have a nonsuppressed or even slightly increased TSH inappropriate for the invariably increased free T4 in serum. This combination of hormone levels can have several causes but there are two major ones namely a TSH-producing pituitary adenoma and resistance to thyroid hormone (RTH). The latter will be the subject of this chapter. The basic problem in RTH is a decreased sensitivity of tissues to thyroid hormone. The decreased sensitivity is also present in the pituitary, where it leads to a blunting of the feedback of thyroid hormone on the pituitary. This in turn results in the above mentioned increased secretion of TSH and thereby of T4. As will be explained below, the insensitivity is caused by mutations in the thyroid hormone receptor beta isoform that reduce thyroid hormone binding affinity. This does not just lead to a presentation resembling hypothyroidism as would be expected - many patients present with symptoms reminiscent of hyperthyroidism, especially with tachycardia.

Normally the net effects of thyroid hormone are brought about by the positive or negative changes it causes in the expression of T3-responsive genes in target tissues. For instance the rise in LDL-cholesterol found in hypothyroid patients can be attributed to a decrease in LDL-receptor protein expression. The gene for this protein is sensitive to thyroid hormone. The presence of thyroid hormone is signaled by nuclear thyroid hormone receptors (TR) of which at least five isoforms exist (fig. 1). These are members of the so-called nuclear receptor family of which the steroid, vitamin D and retinoic acid receptors are also a member. These receptors influence gene expression by binding to specific DNA elements as dimers. TR can bind as a homodimer (two identical monomers) or as a heterodimer (two different

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