Introduction
  Every now and then a patient is seen with apparent hypo- or hyperthyroid symptoms but with conflicting results of thyroid function tests: they have a non-suppressed or even slightly increased TSH inappropriate for the invariably increased free T4 in serum. A number of causes exist for this combination 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 overview. The main problem of RTH is a decreased sensitivity of tissues to thyroid hormone. This is also present in the pituitary, where it leads to a blunting of the feedback of thyroid hormone on the pituitary (Fig. 1) resulting in an 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 reminescent of hyperthyroidism, especially with tachycardia.

Fig. 1: Schematic representation of the hypothalamic-pituitary-thyroid axis



Under normal conditions the pituitary produces the peptide hormone TSH which stimulates (green) the thyroid to produce mainly thyroxine (T4). T4 is metabolized in the liver to T3 and both thyroid hormones feedback in a inhibitory fashion (red) on the pituitary thus maintaining an equilibrium. The active hormone T3 is released into the bloodstream and reaches the peripheral tissues where it binds to the thyroid hormone receptors which then become active. In the case of RTH the feedback (red) is inhibited due to decreased sensitivity of the pituitary to thyroid hormone, resulting in an increase of TSH and subsequently of T4 secretion. The higher T3 levels that result hyperactivate (big arrow) certain peripheral tissues that are not or less resistant, but "underactivate" (thin arrow) tissues that are prominently resistant, leading to a range of hyper- to hypothyroid symptoms respectively.


Under normal conditions the net effects of thyroid hormone are brought about by the 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 four isoforms exist (Fig. 2). 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 monomers) to these specific DNA elements which are called thyroid response elements (TRE), located in the promoter region of T3-responsive genes. There are three active TR namely TRa1, TRb1 and TRb2 which bind T3 and one inactive one, TRa2 which does not bind T3. They are derived from two different genes located on chromosomes 17 and 3 respectively and are expressed at different levels in different tissues (Fig. 2). Furthermore the receptors can bind to a number of different TRE, sometimes in specific combinations, so a plethora of regulatory possibilities is present. This explains how TR (after binding T3) can both activate a gene (i.e. the LDL receptor) or repress a gene. The latter happens in the case of the feedback to the pituitary where the ligand-bound TR binds to a special TRE of the TSHa and b-subunit genes and thereby shuts the gene down.

Fig. 2: Schematic representation of the four thyroid hormone receptor (TR) isoforms



The receptor isoforms are shown schematically with the tissues where their expression is most prominent. The black box represents the DNA binding domain and the red and dark green boxes the T3-binding domain. TRb1 and b2 differ in their N-terminal domain whereas TRa1 and a2 differ in their C-terminal domain. In both cases an mRNA is transcribed from one gene which upon alternative splicing yields the a or b isoform.


Thyroid hormone receptors are rather unique among their family in that they can influence gene expression whether bound by ligand or not. This is the result of the fact that the TR can bind to a TRE without hormone. When it does, it recruits a so-called co-repressor protein which causes the gene to be silent. The co-repressors for the TRs that have been identified are N-CoR and SMRT (Zhang and Lazar, 2000). Upon binding of the hormone, the receptor homodimer releases the co- repressor and then falls apart. The ligand-bound TR monomer now heterodimerises with the retinoic X receptor (RXR) and binds again to the same TRE but due to a conformational change is now able to recruit a coactivator and thereby increases transcription of the gene (Fig. 3). A number of co- activators for the TRs have been identified such as SRC-1 and TIF2/GRIP1 (Zhang and Lazar, 2000). Recently the three dimensional structure of the thyroid hormone receptor has been characterized (Wagner, 1995). From this it became apparent that thyroid hormone is tightly packed inside the receptor molecule and that the last few amino acids of the receptor protein (helix twelve) act as a kind of lid to close the box in which the hormone fits. From these studies it has also become clear that closure of the lid is necessary for the formation of the binding site of the co-activator.

Fig. 3: Model for gene activation by the TR



When the TR is unliganded it binds to the TRE of the gene as a homodimer (two identical TR monomers) and it represses gene expression by binding to a co-repressor. When hormone binds to TR, the corepressor is released and the homodimer falls apart. The TR receptor monomer then acquires another heterodimerisation partner RXR (the retinoic X receptor) and then binds again to the TRE as a heterodimer (two different monomers) and attracts a coactivator which will signal to the transcription machinery. As a result the gene is actively transcribed.