The association between hyperthyroidism and lithium(Drug information on lithium) is less widely recognized than that of hypothyroidism. However, Barclay et al. (1994) documented a statistically significant increase in the incidence of hyperthyroidism in lithium-treated patients. The mechanism of this association remains unclear, especially in view of the many ways lithium impairs thyroid function. Enhanced immune stimulation is an unsatisfactory explanation since the bulk of cases were due to toxic multi-nodular goiter, not Graves' disease or other immune conditions (Barclay et al., 1994). Nonetheless, this relationship appears to be both real and relevant.Responsiveness to Thyroxine
An increasing body of research supports the hypothesis that lithium alters cellular responsiveness to thyroxine in addition to inducing significant changes in the function of the thyroid gland. The induction of cellular unresponsiveness to thyroxine may account for the apparent efficacy of lithium in treating thyrotoxicosis. My colleagues and I reported two cases in which cessation of lithium appeared to precipitate a thyroid crisis, presumably because the presence of lithium prevented clinical manifestations of thyroid excess (Oakley et al., 2000).
Bolaris et al. (1995) documented altered binding of T3 in the CNS of rats, implying that a state of cellular hypothyroidism developed. Hahn et al. (1999b) studied the effect of lithium on gene expression in response to T3 in different cells. In some cell lines, lithium reduced the transcription of mRNA in response to T3, while other cell lines were unaffected. This effect changed with duration of therapy and was deemed to be time-dependent and cell-line specific. Thus, the effect of lithium to alter cellular responsiveness to thyroxine is not uniform for all cells and may change with duration of lithium therapy.
The same group studied the effect of lithium on the expression of different subtypes of thyroid hormone receptors in rat brains (Hahn et al., 1999a). These studies showed that transcription of messenger RNA induced by thyroxine was actually enhanced by the presence of lithium in some cells and reduced in others, depending on the receptor subtype. As different receptor subtypes are distributed differently throughout the CNS, cellular responsiveness to thyroxine is enhanced by the presence of lithium in some areas of the brain and impaired in others. In this study, gene expression was enhanced by the presence of lithium in the cortex and reduced by its presence in the hypothalamus.
Overall, the picture is far more complicated than the initial proposal of cellular hypothyroidism induced by lithium, but the effect is likely to be clinically significant. How much this contributes to the therapeutic effect of lithium in treating BD is difficult to estimate, as lithium significantly alters the metabolism and effects of many neurotransmitters.Lithium Pharmacokinetics
Some alterations in thyroid function have been shown to significantly alter lithium excretion. Hyperthyroidism induces a reduction in renal lithium clearance of 10% to 15% (Owada et al., 1993). This is due to enhanced resorption of lithium by the proximal convoluted tubule and occurs despite the increases in renal blood flow and glomerular filtration rate (GFR) that occur in hyperthyroidism. Thus, the development of hyperthyroidism or overzealous use of thyroxine as augmentation for lithium may result in lithium toxicity.
Hypothyroidism has not been reported to alter lithium excretion or result in cases of lithium toxicity. It is conceivable that reduced GFR in hypothyroidism may reduce lithium excretion, but concomitant changes in tubular function may attenuate these changes. In view of the high incidence of hypothyroidism in lithium-treated patients and the lack of any reports of an interaction with lithium, it seems less likely that hypothyroidism precipitates lithium toxicity.
In a recent study of 97 patients with lithium toxicity, a significant association was found between abnormalities of the thyroid axis and the risk of chronic toxicity (Oakley et al., in press). Other factors found to be associated with chronic toxicity were age over 50 years, presence of nephrogenic diabetes insipidus and renal impairment. This study focused on the important contribution of chronic medical conditions, including endocrine disease induced by lithium, to the development of lithium poisoning and toxicity.
While lithium generally impairs thyroid function and has the potential to precipitate hypothyroidism, chronic therapy with this agent appears to increase the risk of thyrotoxicosis as well. In addition to affecting thyroid gland function, lithium alters the bioactivation of secreted thyroxine and alters the responsiveness of cells to thyroxine, enhancing it in some areas of the CNS and impairing it in others. Furthermore, alterations in the thyroid axis can substantially alter the pharmacokinetics of lithium and lead to toxicity.
Clinicians who prescribe lithium to their patients should be aware of these potential deletenous effects, at least in principle, and should regularly evaluate the thyroid health status of all of their patients receiving lithium.