Lithium and the thyroid

INTRODUCTION — The antithyroid actions of lithium were first investigated in detail when it was noted that patients with psychiatric disease treated with lithium carbonate developed hypothyroidism and goiter. Animal and human studies subsequently revealed that lithium increases intrathyroidal iodine content, inhibits the coupling of iodotyrosine residues to form iodothyronines (thyroxine [T4] and triiodothyronine [T3]) [1-3], and inhibits release of T4 and T3 [2-4].

The mechanism by which lithium inhibits thyroid hormone release is not well understood. In vitro, lithium decreases colloid droplet formation within thyroid follicular cells, a reflection of decreased pinocytosis of colloid from the follicular lumen [5]. The efficiency of proteolytic digestion of thyroglobulin within phagolysosomes also may be impaired.

This topic will review the clinical effects of lithium on thyroid function. In addition to inducing hypothyroidism, the magnitude of the lithium-induced inhibition of thyroid hormone secretion is sufficient to make lithium useful in the treatment of some patients with hyperthyroidism or thyroid cancer.

THYROID DISEASE IN LITHIUM-TREATED PATIENTS — Lithium can cause goiter and hypothyroidism, and its use has been associated with both thyroid autoimmunity and hyperthyroidism [6,7]. Because of the high incidence of thyroid dysfunction that occurs during lithium treatment, patients should have a careful thyroid physical examination and determination of serum thyroid-stimulating hormone (TSH) and antithyroid peroxidase antibody titers before lithium treatment is begun. Patients with normal thyroid function initially should be reevaluated every 6 to 12 months for several years, and thyroid dysfunction should be treated if diagnosed. The development of thyroid dysfunction does not typically require discontinuation of lithium. If thyroid function is abnormal at the initial evaluation, lithium can still be given, if necessary, but the thyroid dysfunction should be treated.

Goiter — Goiter is the most common thyroid abnormality in lithium-treated patients, occurring in approximately 40 to 50 percent [8-11]. The inhibition of thyroid hormone secretion that occurs during lithium treatment results in decreased serum T4 and T3 concentrations, a compensatory increase in pituitary secretion of TSH and, in a new steady state, secretion of a normal amount of thyroid hormone by an enlarged thyroid gland [2]. Thyroid enlargement may also occur as a result of lithium-induced alterations in the function of insulin-like growth factor, tyrosine kinase, and/or Wnt/beta-catenin signaling [11,12]. In affected patients, the thyroid is enlarged to approximately twice the normal size, and the goiter is usually diffuse, although nodular goiter has also been reported [13]. The goiters usually occur within the first two years of treatment.

The treatment of goiter in patients taking lithium is the same as for goiter of any etiology. Ultrasound evaluation is typically performed to assess for diffuse versus nodular enlargement. Further evaluation of nodular thyroid disease with fine-needle aspiration biopsy may be indicated. Levothyroxine (T4) treatment may stabilize or reduce thyroid enlargement in patients with lithium-induced goiter [11]. It is unusual for lithium to cause large obstructive goiter, but in such cases, surgery is an alternative treatment. The approach to the patient with thyroid nodules and goiter is reviewed separately. (See "Diagnostic approach to and treatment of thyroid nodules" and "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter" and "Treatment of benign obstructive or substernal goiter".)

Hypothyroidism — Hypothyroidism is also common in lithium-treated patients. In a review of 11 reports (over 1700 patients), the prevalence of hypothyroidism ranged from 6 to 52 percent [11]. In addition, a meta-analysis of eight case-control studies showed more hypothyroidism in patients treated with lithium than in controls (odds ratio [OR] 5.78, 95% CI 2.00-16.67) [14]. Hypothyroidism may occur in the presence or absence of goiter, and it is usually subclinical, ie, the patient has a high serum TSH and normal free T4 and T3 concentrations. A few patients have overt hypothyroidism with all of its usual symptoms and signs (see "Subclinical hypothyroidism in nonpregnant adults" and "Clinical manifestations of hypothyroidism"). As with goiter, hypothyroidism usually occurs during the first two years of lithium therapy [15]. It occurs more frequently in women over the age of 45, and the risk of hypothyroidism increases with increasing age [16,17].

When hypothyroidism develops, it should be treated with T4 according to the usual therapeutic guidelines. (See "Treatment of primary hypothyroidism in adults".)

Although lithium-induced hypothyroidism is reversible with discontinuation of lithium, there is no need to discontinue it, and it should not be discontinued without consultation with the patient's psychiatrist [18]. If lithium is subsequently discontinued, it is reasonable to reassess the need for continued thyroid hormone replacement. There are no standard protocols for reassessment. We measure TSH approximately two months after discontinuation of lithium.

●If the TSH is in the lower half of the normal range or below normal, we taper and discontinue levothyroxine over a one- to two-month period and reassess TSH and free T4 approximately six weeks later. If TSH rises above normal, levothyroxine may be reinstituted, depending on the free T4 level and clinical assessment. (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Candidates for T4 replacement' and "Treatment of primary hypothyroidism in adults", section on 'Goals of therapy'.)

●If the TSH is in the upper half of the normal range or above normal, we continue levothyroxine. For patients with TSH above normal, dose adjustments may be necessary. (See "Treatment of primary hypothyroidism in adults", section on 'Adjustment of maintenance dose'.)

Chronic autoimmune thyroiditis — It is likely that many patients who develop hypothyroidism during lithium treatment have underlying chronic autoimmune thyroiditis [1,2,13]. They have a greater prevalence of antithyroid antibodies before lithium is begun than those lithium-treated patients who remain euthyroid [19]. However, whether lithium itself can induce thyroid autoimmunity is unknown. In one study, the incidence of antithyroid antibodies was higher in depressed patients who were treated with lithium than in depressed patients who were treated with other drugs [20]. Other studies show fluctuations in antithyroid antibodies, both up and down, in patients pre- and post-lithium therapy [19,21].

Hyperthyroidism — In two retrospective studies, the frequency of hyperthyroidism in patients treated with lithium was more than two to three times greater than that of hyperthyroidism in the general population [22,23]. In one study, among 14 lithium-treated patients who developed hyperthyroidism, eight were thought to have Graves' disease, three toxic nodular goiter, and two painless (subacute lymphocytic) thyroiditis [22]. In another study of 300 patients with Graves' hyperthyroidism and 100 patients with painless thyroiditis, the odds of lithium exposure were higher in patients with painless thyroiditis as compared with those with Graves' disease (odds of exposure 4.7, 95% CI 1.3-17.1) [23].

The treatment of hyperthyroidism in lithium-treated patients depends upon the cause. Treatment is reviewed separately. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter" and "Painless thyroiditis".)

LITHIUM TREATMENT OF THYROID DISORDERS — Because of its ability to inhibit thyroid secretion, lithium has been used in the treatment of several thyroid diseases. However, it is not used as first-line therapy, because of side effects and the availability of other antithyroid drugs (eg, thionamides).

Hyperthyroidism — Lithium (in a dose of 600 to 1000 mg/day) is effective therapy for patients with hyperthyroidism [24,25]. Its effects on thyroid hormone secretion are quantitatively similar to those of iodide, and it therefore may be given in place of iodide in patients who would benefit from rapid correction of hyperthyroidism but are allergic to iodine (see "Iodine in the treatment of hyperthyroidism"). It also may be useful in patients with intolerance to thionamides [6]. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Other medications infrequently used'.)

Lithium may prolong the retention of radioiodine within the thyroid gland, which could increase the effectiveness of radioiodine therapy. In a retrospective cohort study, the cure rate was slightly higher in patients given lithium (900 mg/day) for 12 days starting 5 days before radioiodine (91 versus 85 percent; p = 0.03) [26], but there was no difference in a randomized trial of radioiodine alone versus radioiodine plus lithium (900 mg/day) [27]. Lithium given coincident with radioiodine can prevent the transient increase in serum thyroid hormone concentrations following radioiodine [28]. Because of inconsistent data and the toxicity of lithium, we do not recommend its use in conjunction with radioiodine. (See "Radioiodine in the treatment of hyperthyroidism".)

Lithium alone has been used to prepare patients for thyroidectomy [29,30]. This treatment led to a decrease in serum thyroid hormone concentrations and clinical improvement; subsequent surgery was successful.

Thyroid cancer — When patients with thyroid cancer are treated with iodine-131 (131-I), it is sometimes helpful to increase retention of the isotope by cancer tissue. Lithium can prolong 131-I retention by thyroid tissue. In one study of 15 patients who had diagnostic 131-I scans before and then again after receiving lithium for one to two days, 131-I retention was higher and more prolonged during lithium administration in metastatic lesions and the thyroid remnants in most patients, so that the estimated 131-I dose to the metastases was higher [31]. Whether these findings will result in improved eradication of metastases remains to be determined. In a study of 12 patients with metastatic differentiated thyroid cancer who had previously received radioiodine therapy without lithium and who did not have a response despite radioiodine accumulation in metastases, treatment with lithium immediately prior to another dose of radioiodine did not have any beneficial effects on the clinical course (assessed by thyroglobulin levels and radiographs) [32]. In the absence of clinical trial data showing a beneficial effect, we do not suggest using lithium as an adjunct to radioiodine. This approach is consistent with the American Thyroid Association clinical practice guidelines [33]. (See "Differentiated thyroid cancer: Radioiodine treatment".)

SUMMARY AND RECOMMENDATIONS

●Lithium and thyroid physiology – Lithium increases intrathyroidal iodine content, inhibits the coupling of iodotyrosine residues to form iodothyronines (thyroxine [T4] and triiodothyronine [T3]), and inhibits release of T4 and T3. (See 'Introduction' above.)

●Lithium and thyroid disease – Lithium can cause goiter and hypothyroidism, and its use has been associated with both thyroid autoimmunity and hyperthyroidism. Goiter and hypothyroidism are more common, occurring in approximately 40 to 50 and 20 to 30 percent, respectively, of patients treated with lithium. (See 'Thyroid disease in lithium-treated patients' above.)

•Evaluation – Because of the high incidence of thyroid dysfunction that occurs during lithium treatment, patients should have a careful thyroid physical examination and determination of serum thyroid-stimulating hormone (TSH) and antithyroid peroxidase antibody titers before lithium treatment is begun. If thyroid function is abnormal at the initial evaluation, lithium can still be administered, if necessary, but the thyroid dysfunction should be treated. (See 'Thyroid disease in lithium-treated patients' above.)

•Monitoring – Patients with normal thyroid function initially should be reevaluated every 6 to 12 months for several years, and thyroid dysfunction should be treated if diagnosed. The development of thyroid dysfunction does not typically require discontinuation of lithium. (See 'Thyroid disease in lithium-treated patients' above.)

●Lithium for the treatment of thyroid disorders – Because of its ability to inhibit thyroid secretion, lithium has been used in the treatment of several thyroid diseases. However, it is not used as first-line therapy, because of side effects and the availability of other antithyroid drugs. (See 'Lithium treatment of thyroid disorders' above.)