The thyroid gland produces two hormones, thyroxine (T4) and triiodothyronine (T3). These hormones are critical for cell differentiation during development and to maintain homeostasis in adults. TSH, secreted by the anterior pituitary gland plays an important role in controlling the thyroid axis and is the most useful physiologic marker for thyroid function. The thyroid axis is an endocrine feedback loop. Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates TSH release and TSH stimulates T4 and T3 release. TRH is the major regulator of TSH synthesis and secretion. When thyroid hormone levels are low, TRH-mediated secretion of TSH is enhanced and TSH levels rise. When thyroid hormone levels are high, TRH -mediated TSH secretion is reduced and TSH levels drop.

Iodine is necessary for thyroid hormone synthesis. Both thyroid hormones are produced by the thyroid gland but T4 is secreted at a much higher proportion than T3. Once released, most of the circulating hormones are bound to plasma proteins. Only the free hormones are biologically active in tissues. T4 is converted to the more potent T3 in the periphery. Circulating levels of free T3 are higher than free T4 though total T3 is less than total T4.

In the United States, autoimmune disease is the most common cause of hypothyroidism with Hashimotos disease being the common variant. Iodine deficiency is a common cause of hypothyroidism in iodine-deficient regions of the world. Secondary causes are due to TRH or TSH deficiencies.

See table for causes of hypothyroidism.Causes of hypothyroidism

The common causes of primary hyperthyroidism are Graves disease, toxic multinodular goiter, and toxic adenomas. Secondary causes of hyperthyroidism are TSH -secreting pituitary adenomas and thyroid hormone resistance syndrome. Subacute thyroiditis, silent thyroiditis, and drug-induced thyroiditis cause transient elevation of thyroid hormones due to follicular destruction. Some medications such as propranolol or salicylate displace thyroid hormone from serum binding protein and increase the free circulating hormone level; the thyroid axis transiently is perturbed but soon resets to the new steady state.

Lithium can affect thyroid function in a multitude of ways. It is concentrated in the thyroid gland and has the potential to disrupt both thyroid hormone formation and secretion. Lithium can also accelerate thyroid antibody formation. It does not cause but worsens thyroid autoimmunity . Studies have estimated clinical hypothyroidism in 8–19% patients versus 0.5–1.8% in the general population and subclinical hypothyroidism in 23% versus 10.4% in the general population [1]. In a large meta-analysis, the rate of hypothyroidism was about sixfold for those on lithium [2].

Lithium-induced hypothyroidism develops usually in weeks to months but can take years. Risk factors are female gender, older age, family history of thyroid disease. Most patients are asymptomatic and it is unclear if and when treatment should be initiated for hypothyroidism. There is no evidence that stopping lithium reverses the thyroid dysfunction but small studies have shown some normalization of TFTs upon lithium cessation [2]. It may be that in cases where lithium enhances thyroid autoimmunity, the thyroid dysfunction is irreversible.

Goiter , a diffuse enlargement of the thyroid gland, is reported in up to 40% patients on lithium [1]. The thyroid enlargement is in part due to the increase in TSH caused by thyroid hormone inhibition. Goiters are slow growing and may take years to develop. They can be asymptomatic or present with hypothyroidism or even hyperthyroidism. Lithium causes homogenous thyroid gland enlargement and these goiters are more like to cause hypo rather than hyperthyroidism. In late stages, goiters can become fibrotic at which point surgery may be the only treatment option. It is rare for lithium to be a cause of a clinically significant goiter.

Even though lithium generally has a suppressive effect on the thyroid, there are case reports of hyperthyroidism also. Compared to hypothyroidism, it is more likely to occur earlier in the treatment course. The mechanism is unclear. It is either due to direct damage of thyroid cells causing thyroiditis or lithium-induced autoimmune-mediated hyperthyroidism [1]. In the case of thyroiditis, it may convert later to hypothyroidism. If lithium is stopped, it may reverse especially if thyroiditis is the pathology.

Other psychotropics may also interfere with thyroid function [3]. Antipsychotic medications, especially phenothiazines, induce autoantibody formation and may cause a hypothyroid state. Antidepressants (TCAs, SSRIs) and mood stabilizers (carbamazepine, valproate) also interfere with thyroid function but have little clinical impact.

The onset of symptoms is insidious and patients often do not become aware of symptoms until later stages. Common features of hypothyroidism are constipation, weight gain, menstrual abnormalities, and reduced libido. Skin changes and nonpitting edema are seen in later stages of the disease. Reduced cardiac function can lead to bradycardia. Rarely, neurologic symptoms occur. If a goiter is present, patients may complain of neck swelling.

See table for a complete list of symptoms.

Symptoms and signs of hypothyroidism