Lithium-Induced Goiter

Despite its place as the gold standard for maintenance treatment of bipolar disorder, recent prescription patterns demonstrate a decreasing use of lithium.[1, 2] Side effects, an important variable in both prescription patterns and adherence, include the thryroid abnormalities of hypothyroidism and goiter.[3]

Due to the inhibition of thyroid hormone secretion, an increase in the concentration of TSH is produced that stimulates the growth of the thyroid. Many patients with goiter are euthyroid in that the enlarged gland has been sufficiently stimulated to synthesize and release adequate amounts of thyroid hormone.[3, 4]

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.[5] 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, 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. In most of these cases, the hypothyroidism is subclinical. Thyrotoxicosis can also be observed in lithium-treated patients, but it is rare, with an incidence rate of approximately 2-7 cases per 1000 person-years.[6]

Symptoms of hypothyroidism or thyrotoxicosis do not differ from those observed in states of thyroid deficiency or excess due to other causes and include ethargy, cognitive difficulties, depression, weight gain, dry skin, and cold intolerance. In addition, a number of these symptoms overlap with depression symptoms of bipolar disorder, as well as side effects from lithium, making diagnosis difficult in the absence of thyroid function tests.[3, 7]

Levothyroxine (LT4) is the drug of choice for patients who develop lithium-induced hypothyroidism or goiter (when discontinuation of lithium therapy is not feasible).

For patient education resources, see the Thyroid & Metabolism Center and Thyroid Problems.

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.[8] 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.[9] 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[10] 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 antithyroid antibodies.[11] Additionally, lithium-induced hypothyroidism is observed more frequently in patients with a prior history of thyroid gland damage (eg, following external radiation of iodine-131 [131I] 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.[12]

Lithium carbonate is the direct cause of goiter formation. Contributing factors in goiter formation include the following:

• Iodide deficiency

• Prior or subclinical autoimmune thyroid disease

• Prior 131I-induced or external radiation –induced thyroid gland damage

• Possible concomitant exposure to environmental and dietary goitrogens other than lithium (eg, polychlorinated biphenyls [PCBs], thiocyanate, naturally occurring thioglycosides and glucosinolates found in vegetables in the Brassica species, such as Brussels sprouts).

Important risk factors for lithium-induced hypothyroidism include the following:

• Presence of antithyroid antibodies ^[3]
• Female sex ^[13]
• Older age ^[7]
• Family history of hypothyroidism ^[14]

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.[6]

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.

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.[15]

The long-term prognosis ranges from very good to excellent. 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).

Potential complications include the following:

• Hypothyroidism

• Hyperthyroidism (rare)

• Lithium toxicity

History

Patients are usually asymptomatic. Documenting the duration of lithium therapy is important. Symptoms of hypothyroidism or thyrotoxicosis do not differ from those observed in states of thyroid deficiency or excess due to other causes and include ethargy, cognitive difficulties, depression, weight gain, dry skin, and cold intolerance. In addition, a number of these symptoms overlap with depression symptoms of bipolar disorder, as well as side effects from lithium, making diagnosis difficult in the absence of thyroid function tests.[3, 7]

Physical Examination

The thyroid gland enlargement is smooth, symmetrical, and nontender. Because goiter nodules are usually small, dyspnea due to laryngotracheal pressure is usually absent. The physical signs of hypothyroidism or thyrotoxicosis do not differ from those observed in states of thyroid deficiency or excess, respectively, attributable to other causes.

Confirmation of the diagnosis of lithium-induced goiter is mostly derived from a positive history of prolonged lithium intake and a positive physical examination finding. Determining whether the patient originates from an iodine-deficient area and whether he or she has a positive family history of goiter or other thyroid disorders is important. Laboratory studies, as follow, are indicated to exclude concomitant hypothyroidism and the existence of a thyroid-specific autoimmune process:

• Serum thyrotropin[16, 17]

  • This is a first-level test.

  • Levels higher than normal indicate concomitant hypothyroidism.

• Circulating antithyroid peroxidase (anti-TPO) and anti-Tg antibodies

  • These are first-level tests.

  • These antibodies indicate the presence of a thyroid-specific autoimmune process and a higher likelihood of hypothyroidism in the future in cases in which thyroid-function test findings are normal. The frequency of positivity of antithyroid antibodies is higher in lithium-treated patients with either overt or subclinical hypothyroidism than in control subjects with comparable thyrotropin levels.

• Serum free thyroxine (T4) and total triiodothyronine (T3) tests[16, 17, 18]

  • These are second-level tests.

  • Low levels indicate hypothyroidism, although T3 (or even free T3) testing alone is usually insensitive for a diagnosis of hypothyroidism. Furthermore, serum thyrotropin testing is more sensitive for a diagnosis of hypothyroidism than is free T4 testing.

• Exaggerated response of thyrotropin to thyrotropin-releasing hormone (TRH) stimulation test[19]

  • This is a third-level test.

  • This test is usually unnecessary and is mostly reserved for research purposes. Findings are positive in patients with hypothyroidism (clinical or subclinical). Of note, TRH is no longer commercially available as a diagnostic agent in the United States, although it can be manufactured in pharmacies of certain academic centers engaged in clinical endocrinology research.

Imaging studies include the following:

• Thyroid ultrasonography[20, 21]

  • This is a first-level test.

  • Thyroid ultrasonography can be used to quantitate thyroid size and may show a small volumetric increase in persons with lithium-induced goiter.

• 123I uptake test

  • This is a second-level test.

  • 123I uptake may be slightly increased in some patients with euthyroid goiter because of compensation of the gland for decreased coupling and/or iodination despite normal serum thyrotropin levels.123I uptake is definitely increased in the small percentage of patients who develop lithium-induced thyrotoxicosis.

• Perchlorate discharge test

  • This is a third-level test.

  • Results are usually normal (negative), and the test is rarely performed outside an academic setting.

• Iodide-perchlorate discharge test

  • This is a third-level test.

  • This test is seldom indicated. Results are positive in almost all patients on long-term lithium therapy.

Biopsy of the thyroid gland is unnecessary in the vast majority of patients with lithium-induced goiter, although the histologic changes that occur in lithium-induced goiter have been studied in a research setting.

Studies of the effects of lithium administration on normal thyroid gland histology in rodents suggest that hyperplasia and colloid depletion occur early in the course of therapy. Eventually, cellular hyperplasia and accumulation of colloid and Tg in supranormal amounts occur. Because lithium inhibits colloid endocytosis (pinocytosis) and iodine efflux from the thyroid, nodules associated with colloid goiter observed in patients on lithium therapy tend to be rich in Tg. In patients with underlying thyroid pathology (eg, multinodular goiter, postthyroiditis changes), histologic features of the underlying pathology are evident.

Before the initiation of lithium therapy, identify patients at increased risk for the development of hypothyroidism (eg, patients originating from iodine-deficient areas, those with a strong family history of thyroid disorders, women, elderly patients, patients exposed to other goitrogens). Suspicion of goiter upon physical examination may prompt the physician to order ultrasonography to record the baseline dimensions of the thyroid gland and to exclude underlying structural thyroid disease. Baseline thyroid function tests, including thyrotropin, free T4, total T3, anti-TPO, and anti-Tg antibodies, also are important.

Whether all patients being treated with lithium for a long period require prophylactic therapy with levothyroxine (LT4) is debatable. Such prophylactic treatment is probably not indicated if goiter and hypothyroidism have been excluded prior to initiation of lithium therapy. Provide regular follow-up care for patients on long-term lithium therapy by regularly assessing their history, physical examination findings, and serum thyrotropin levels. Rising levels of thyrotropin should prompt the physician to repeat a full evaluation, including serum measurements of free T4, total T3, anti-TPO, and anti-Tg antibodies.

For all patients on long-term lithium therapy, regular follow-up with an endocrinologist is indicated, starting within 6 months immediately after the initiation of lithium therapy and continuing annually thereafter (with thyrotropin levels and neck palpation). Because as many as one fourth to one third of patients on long-term lithium therapy develop hypothyroidism, provide regular follow-up care on a clinical and biochemical basis for symptoms and signs of hypothyroidism and increased serum thyrotropin levels, respectively.

If the diagnosis of hypothyroidism is established, early initiation of LT4 therapy is indicated, especially when discontinuation of lithium is inadvisable because of the patient's psychiatric status.

For patients who develop goiter over time, even in the absence of hypothyroidism (clinical or subclinical), also consider LT4 therapy aimed at restoring normal serum thyrotropin levels.

Diagnose and treat rare cases of lithium-induced thyrotoxicosis as indicated for similar cases attributable to other causes of hyperthyroidism; discontinuing lithium therapy is not necessary, and it can also be dangerous (in the context of exacerbation of manic-depressive illness).

Although specific surgical treatment is not usually necessary, in rare cases, long-term lithium administration may induce hyperthyroidism that is difficult to control, necessitating thyroidectomy. Similarly, the underlying or concomitant thyroid disorder (eg, multinodular goiter, nontoxic endemic goiter) may dictate the need for surgical intervention.

A more expanded discussion of the indications, techniques, and complications of thyroid surgery in each of the above contingencies can be found in respective Medscape Drugs & Diseases articles (eg, Nontoxic Goiter and Hyperthyroidism).

In most cases, the treating psychiatrist or primary care physician may opt to consult with an endocrinology specialist, especially in cases of lithium-induced thyrotoxicosis.[5] The development of compressive local symptoms requires an evaluation by a surgical or ear, nose, and throat specialist.

In cases of lithium-induced thyrotoxicosis, consultation with a cardiologist may be necessary, especially in elderly patients who have a high prevalence of coronary artery disease, arrhythmias, and congestive heart failure.

For all patient referrals from psychiatrists, it is important for the consultant endocrinologist to establish and maintain appropriate regular bidirectional communication with the mental health provider(s) regarding clinical status and specific endocrine management on patients on long-term lithium therapy.

No restrictions in exercise or activity patterns are advisable or necessary, with the exception of patients who have severe lithium-induced thyrotoxicosis with cardiovascular symptoms, in which case any strenuous activity should be avoided (as in all cases of severe thyrotoxicosis).

A review of patient history, a physical examination, and an evaluation of thyrotropin levels are indicated within 6 months immediately after the initiation of lithium therapy and annually thereafter.

The treating physician must be aware that rare cases of thyrotoxicosis have been reported following discontinuation of lithium therapy.

Levothyroxine (LT4) is the drug of choice for patients who develop lithium-induced hypothyroidism or goiter (when discontinuance of lithium therapy is not feasible). Slightly higher doses (enough to keep the thyrotropin level in the range of 0.4 mIU/L) may be necessary if the patient has rapidly growing or large nodules from goiter, especially in the presence of local compressive symptoms. LT4 is the most commonly used pharmacologic preparation of thyroid hormone for treating goiter and other hypothyroid states. The rationale for thyrotropin suppression therapy in persons with goiter is that a reduction in thyrotropin secretion may decrease the growth and function of abnormal thyroid tissue.

Class Summary

A normally functioning thyroid gland produces and secretes the major thyroid hormones (THs) levothyroxine (LT4) and L-triiodothyronine. Complex feedback mechanisms of the hypothalamic-pituitary-thyroid axis regulate the rate of production and secretion.[22, 23] The action of thyrotropin, which is produced in the anterior pituitary gland, stimulates the thyroid gland to secrete THs.

Thyrotropin secretion is mainly controlled by TRH produced in the hypothalamus and by circulating THs that act as feedback inhibitors of thyrotropin and TRH. When concentrations of T4 and T3 are decreased, secretion of thyrotropin and TRH is increased and vice versa. When the thyroid gland fails to function, hypothyroidism develops and therapy with TH is absolutely indicated. Additionally, exogenous administration of TH to euthyroid individuals results in the suppression of endogenous TH secretion.

Levothyroxine (Synthroid, Levoxyl)

In active form, influences growth and maturation of tissues. LT4 is involved in normal growth, metabolism, and development. LT4 preparations contain synthetic crystalline L-3,3',5,5'-tetraiodothyronine sodium salt. Synthetic LT4 is identical to that produced in the human thyroid gland.

The mechanism of action is complex and only partially understood. Following absorption from the GI tract, a large proportion of circulating T4 is converted into T3, and both are transported into cells. T3, the proposed active form (from cell cytoplasm), and T3 and T4 (generated in situ) diffuse into the nucleus and bind to specific thyroid receptor proteins, which appear to be attached primarily to DNA. Receptor binding leads to the activation or repression of DNA transcription, altering the amounts of mRNA and resultant proteins. Changes in the concentration of proteins in various tissues and organs are responsible for metabolic changes.

THs enhance oxygen consumption of most body tissues and increase the basal metabolic rate and metabolism of carbohydrates, lipids, and proteins, thus exerting a profound influence on every organ system.