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For Some, L-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale

A Genetic Rationale

Although the thyroid gland secretes a very small amount of active thyroid hormone (triiodothyronine or T3[), the major circulating form is thyroxine (T4), and it is widely accepted that thyroid hormone replacement in patients with hypothyroidism can be fully accomplished with l-T4
monotherapy [see 1995 American Thyroid Association guidelines (Ref. 1)]. The mechanistic basis for this belief stems from the actions of the iodothyronine deiodinases, enzymes that activate thyroid hormone by conversion of T4[to T3 (or inactivate both forms via further deiodination) (2). Thanks to the actions of the type 2 deiodinase (D2) and to some extent the type 1 deiodinase (D1), both endogenous T4 and l-T4are converted to T3 at a rate sufficient to maintain normal serum T3 concentration. However, despite the extensive literature demonstrating that patients do well clinically on l-t4monotherapy, most clinicians have at least anecdotally seen benefits from combined T3[/T4[ therapy for some patients, prompting a search for the biological mechanism of the T3 requirement. In the current issue of JCEM, Panicker et al. (3) examine this question from a novel perspective, asking whether a polymorphism in the Dio2 gene could explain a differential psychological response to the type of thyroid hormone replacement seen in a subpopulation of the Weston Area T4/T3 Study (WATTS) from the United Kingdom (3, 4).

D2 was initially characterized in the pituitary gland and hypothalamus, where it plays an important role in the TSH/TRH feedback mechanism (2). Subsequent studies found that D2 is also an important source of plasma T3, i.e. plasma T3 largely originates from the thyroid gland as T4, to be converted to T3 by D2 in peripheral tissues (5, 6). To understand how a Dio2 gene polymorphism could explain a differential neurological response to T4as opposed to T3/T4 therapy, it is critical to understand two properties of D2 physiology. First, when thyroid hormone levels fall, D2 activity increases thanks to decreased ubiquitination of the enzyme (7). As D2 activity increases in the face of falling T4, the net effect is homeostatic, promoting maintenance of normal T3 levels. Second, D2 is expressed in the endoplasmic reticulum, and D2-generated T3can accumulate in the nucleus of specific tissues while plasma thyroid hormone levels remain unchanged; i.e. D2 allows for local control of thyroid hormone signaling. For example, sympathetic stimulation of brown adipose tissue leads to cAMP generation, which in turn induces D2 and fills up the tissue with T3, a crucial mechanism for adaptive thermogenesis (heat generation after exposure to cold or high caloric diet) (8). The example of D2 in brown adipose tissue also illustrates that dynamic changes in D2 activity can occur in settings beyond the realm of thyroid hormone homeostasis. Indeed novel proactive roles for D2 have been found in settings ranging from development to metabolism; for example, D2 ubiquitination is accelerated by the Hedgehog signaling pathway, linking deiodination to the development of the tibial growth plate (9), while at the same time D2 activity is increased via the G protein-coupled bile acid receptor 1-mediated (also known as TGR5) signaling cascade, which mediates some of the metabolic effects of bile salts (10). D2 activity is also induced by some dietary flavonols, suggesting the potential for nutritional or pharmacological manipulation of metabolism via control of D2 (11).

The homeostatic and proactive functions of D2 are both at work in the brain, where D2 is widely expressed (12, 13). Indirect evidence for a physiological role for D2 in the brain includes studies of thyroidectomized rats in which T4monoreplacement fails to normalize T3levels in some tissues but the cerebral cortex is spared (14). At the same time, D2 knockout mice exhibit a substantial reduction in brain T3 levels but, to the extent that they have been tested, do not demonstrate any overt neurological phenotype (15). Thus, whereas the effects of T3 on neurological function are well established, and an extensive literature regarding T3 therapy and mood exists (16), except for the TSH feedback mechanism, it remains to be proven that D2-generated T3 is important for neurological function in adult humans.

The observation of an unexpected spatial dichotomy currently prevents a full mechanistic accounting of the role of D2 in the brain: D2 is found in glial cells, whereas thyroid hormone receptors are predominantly expressed in neurons (17, 18). Thus, for D2-generated T3 to have its proposed effects, it must somehow transit from the glial cytoplasm to the nuclei of target neurons; it has been proposed that glial D2-generated T3 acts in a paracrine fashion in the brain (19). Indirect support for this hypothesis could be taken from the observation that the T3transporter monocarboxylate transporter 8 plays a critical role in brain development (20, 21), but the transit of iodothyronines in the brain remains to be elucidated. The supply-side situation is complex as well; in the mediobasal hypothalamus, D2 expression is concentrated in specialized glial cells known as tanycytes, located in the floor and infralateral walls of the third ventricles. This location suggests that the cerebrospinal fluid may be a source of T4 for hypothalamic D2 (22).

To date, there are no identified genetic syndromes involving mutations in the Dio2 gene. However, a number of single nucleotide polymorphisms (SNPs) have been identified, the best characterized being Thr92Ala, a common A-G polymorphism (T-C on the complementary forward strand) at codon 92 that predicts an Ala for Thr substitution (274 A-G, D2-G/A; GI 13654872; rs225014) (23). This SNP is common in various ethnic groups: its allele frequency is 0.35 in Caucasians and is particularly high at 0.75 in Pima Indians. A growing number of studies have examined correlations between the Thr92Ala polymorphism and disease or dysfunction in tissues where D2 is expressed, but the results have been mixed for metabolic endpoints (23, 24, 25, 26, 27) and for hypertension (28, 29, 30). Recently, the Thr92Ala D2 polymorphism was also linked to susceptibility for generalized osteoarthritis, a common late-onset articular joint disease (31); this is an interesting result, given the role of D2 in the developing growth plate (9). As for the brain, associations have been reported between the Thr92Ala polymorphism and TSH level as well as the dose of l-T4needed to normalize TSH (32, 33). However, investigators failed to find an association with response to paroxetine therapy in depressed patients (34), and a study from China found associations between other Dio2 SNPs and mental retardation but not Thr92Ala (35).

The publication by Panicker et al. (3) adds importantly to the literature because the WATTS data set represents one of the largest randomized studies of thyroid hormone replacement (4). The key findings are an association between the Thr92Ala polymorphism with lower baseline psychological well-being on l-T4 alone, as well as with improvement on combination T3/T4 therapy compared with l-t4 monotherapy. These results stand in contrast to a number of smaller trials that did not find associations with Thr92Ala and cognitive endpoints [see references in Panicker et al. (3)]. A complex clinical question arises from these findings: is the subset of patients with the Thr92Ala abnormal with respect to brain T3 levels, and thus susceptible to cognitive or mood defects?

A key point underlying this and other Thr92Ala studies is whether or not the polymorphism has functional implications for D2 protein. On this score, the jury is still out. Although the substitution is nonconservative (aliphatic for polar), codon 92 is not in the catalytic active site of the enzyme, and it is not phylogenetically conserved: the homologous position is proline in rodents and glycine in chicken D2 (23). In vitro analysis has shown that the Thr92Ala substitution does not change the kinetics of the transiently expressed D2 enzyme (32). One study suggested that Thr92Ala decreases the activity of the endogenously expressed enzyme in human thyroid and skeletal muscle tissue (24). However, two subsequent studies found much lower levels of D2 activity (two orders of magnitude) in human skeletal muscle (36, 37), calling these findings into question. Furthermore, whereas codon 92 is located in the 18-amino acid region of D2 known to be important for regulation of the enzymes ubiquitination, an in vitro mutational analysis failed to confirm any impact of Thr92Ala on protein stability (38). If the Thr92Ala substitution is relevant for D2 ubiquitination, the conditions or endogenous factors that bring out the phenotype must be identified and confirmed experimentally. Otherwise, one must consider the possibility that the positive findings of these genetic studies are based on linkage with another locus. What is also needed is a prospective trial studying the effect of the Thr92Ala substitution on the neuropsychiatric response to combined T3/T4vs. monotherapy with l-t4; this will be the true test of the fascinating implications raised in the current work.

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