Lithium is used as an integral component in the management of acute mania and unipolar and bipolar depressive disorder. It is also used as long-term prophylaxis of bipolar disorders. Thyroid abnormalities associated with lithium treatment have been widely reported in the medical literature over the last 5 decades. These include hypothyroidism, hyperthyroidism, unmasking or induction of autoimmune thyroiditis and goiter.
Like iodide, lithium inhibits thyroid hormone (TH) release. In supratherapeutic doses in rodents, as well as in vitro, lithium also inhibits thyroglobulin (Tg) iodination and coupling reactions.  The prevalence of lithium-induced goiter ranges from 20% in patients residing in iodine-replete areas to 87% in patients residing in or emigrating from iodine-deficient areas or who are on long-term lithium therapy. The latter statistic highlights the importance of susceptible individuals' iodine status, especially in view of the downward trends in iodine sufficiency of the US population over the last 2 decades, as reported in data analyses from the National Health and Nutrition Examination Survey (NHANES) III study and subsequent reports. [2, 3]
Goiter has been noted within several weeks of initiation of lithium therapy, although in most cases, months to several years elapse before detectable goiter develops. The latter point is pertinent because lithium therapy is usually prescribed long-term for the control or prophylaxis of bipolar illness. Lithium-induced goiter is usually characterized by small, smooth, and nontender nodules; in some cases, nodules may regress over time despite continuing lithium exposure. A smaller percentage of patients treated with lithium (5-20%) may actually develop hypothyroidism, with or without goiter development. In most of these cases, the hypothyroidism is subclinical. Thyrotoxicosis can also be observed in lithium-treated patients, but it is rare, with a prevalence of 0.7%.
Lithium is highly concentrated in the thyroid gland against a concentration gradient, probably by active transport. In clinically useful doses, lithium induces a marked decrease in the release of preformed thyroid hormone (TH) from the thyroid. Its primary effect seems to be the blockade of colloid droplet formation in the apical pole of the thyrocyte and hence, inhibition of TH release, a process stimulated by thyrotropin and mediated by cyclic adenosine monophosphate (cAMP) within the thyrocyte.
The exact mechanism of action of lithium at the molecular level remains unknown.  While reports suggested either (1) lack of lithium effects on cAMP synthesis or (2) lithium-induced inhibition of cAMP synthesis, later work in a strain of rat thyroid follicular cells (FRTL-5) and a cell line of Chinese hamster ovary fibroblasts stably transfected with the human thyrotropin receptor (CHO-TSHR) showed significant potentiation by lithium of the cAMP response to exogenous thyrotropin. More recent research has highlighted additional complex effects of lithium on thyroid hormonal homeostasis. Lithium alters the structure of thyroglobulin (Tg), thereby affecting protein conformation and function and resulting in a clinical picture of an acquired mild iodotyrosine coupling defect. Finally, lithium exposure is associated with reduced hepatic deiodination and clearance of free thyroxine (T4). The latter induces a decrease in the activity of type I 5’-deiodinase enzyme.
With regard to the effects of lithium on thyrocyte growth, in the FRTL-5 cell system, lithium was found to stimulate cell proliferation in the absence of thyrotropin stimulation, but surprisingly, under thyrotropin stimulation, lithium diminished thyrocyte proliferation, especially when used at higher concentrations.  Whether the above in vitro data gathered from nonhuman thyroid cell lines and using acute exposure to lithium reflect the situation in patients typically treated long-term with lithium remains speculative. Of note, although lithium stimulates thyrocyte proliferation via activation of assorted pro-proliferative tyrosine kinase cascades and the Wnt/beta-catenin signaling pathway, the aggregate in vitro evidence suggest that this drug is not a bona fide thyroid epithelial carcinogen.
In a pathophysiologic context, exposure to lithium causes a mild initial elevation of thyrotropin levels  as a compensatory pituitary response to the initial lithium-induced decline in TH release. Hormone stores eventually increase, thus leading, in most cases, to normal TH output despite a reduced fractional TH secretion capability. The tendency of the thyroid gland to "escape" the inhibitory effects of lithium is similar to that observed with iodine therapy, although it is less marked.
The above sequence may be the mechanism for the development of euthyroid goiter observed in these patients. Concomitant hypothyroidism probably occurs in individuals predisposed to thyroid failure, because most persons in this subgroup already have positive antithyroidal antibodies.  Additionally, lithium-induced hypothyroidism is observed more frequently in patients with a prior history of thyroid gland damage (eg, following external radiation or iodine-131 [131 I] therapy administered to treat previously diagnosed hyperthyroidism).
Although the cause of the rarely encountered condition of lithium-induced thyrotoxicosis is not clear, some authorities have speculated that lithium may directly stimulate autoimmune reactions. On the other hand, thyroid autoimmunity per se reportedly is highly prevalent in patients with bipolar disorder, probably more so than in normothymic control subjects. 
The prevalence of goiter in patients receiving lithium therapy is approximately 15-20%. Up to a third of patients on lithium therapy who develop goiter (ie, 5% of all patients on lithium therapy) also may develop hypothyroidism, which usually remains subclinical. The development of clinically evident thyrotoxicosis is rare.
The prevalence of goiter in patients receiving lithium therapy is higher in patients from iodine-deficient areas and in patients receiving long-term therapy (20-87%). Up to 20% of patients receiving lithium therapy who develop goiter (ie, 25-50% of all patients on lithium therapy) have concomitant hypothyroidism.
Neither lithium-induced goiter nor hypothyroidism causes mortality directly. Morbidity is mostly related to concomitant hypothyroidism and to local compressive symptoms from thyroid enlargement (eg, dysphonia, dysphagia, voice-quality changes, neck discomfort). Lithium is potentially toxic and can cause arrhythmias, atrioventricular block, nephrogenic diabetes insipidus, agranulocytosis, confusion, seizures, mental status changes, and coma. Lithium-induced heart atrioventricular block can be exacerbated by the hypothyroid state. However, these adverse effects occur at supratherapeutic serum lithium levels, which are avoided by serial monitoring of these levels, especially in the setting of renal impairment (creatinine clearance, < 40 mL/min).
No well-described racial differences have been reported for the development of lithium-induced goiter.
No differences in the incidence or prevalence of goiter formation have been reported between men and women, although lithium-induced hypothyroidism is more common in women. Further, because males generally have a larger thyroid gland volume than do females, lithium-induced global thyroid enlargement theoretically may lead to more compressive symptomatology in males than in females, although this has not been reported to date.
Older patients are more prone to the development of goiter. 
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