eMedicine Specialties > Endocrinology > Thyroid

Goiter, Lithium-Induced

Author: Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Coauthor(s): Boaz Hirshberg, MD, Associate Director, CVMD, Pfizer
Contributor Information and Disclosures

Updated: Dec 18, 2008

Introduction

Background

Lithium is used for the treatment of bipolar manic-depressive disorder. 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. Lithium treatment has been associated with the development of goiter. The prevalence of this condition 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 decade, as reported in data analyses from the National Health and Nutrition Examination Survey (NHANES) III study.1

Goiter has been described within several weeks of initiation of lithium therapy, although in most cases, months to several years elapse before goiter develops. The latter point is pertinent because lithium therapy is usually prescribed long-term for the control of bipolar illness. Lithium-induced goiter is usually characterized by small, smooth, and nontender nodules; in some cases, nodules may regress over time. 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%.

Related eMedicine topics:
Bipolar Affective Disorder
Goiter
Hypothyroidism [Endocrinology]
Hypothyroidism [Pediatrics: General Medicine]
Mood Disorder: Bipolar Disorder
Thyrotoxicosis

Pathophysiology

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.2 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-R) showed significant potentiation by lithium of the cAMP response to exogenous thyrotropin.

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.3 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.

In a pathophysiologic context, exposure to lithium causes a mild initial elevation of thyrotropin levels4 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.5 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.6

Frequency

United States

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.

International

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.

Mortality/Morbidity

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).

Related eMedicine topic:
Toxicity, Lithium

Race

No well-described racial differences have been reported for the development of lithium-induced goiter.

Sex

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.

Age

Older patients are more prone to the development of goiter.

Clinical

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; however, because patients have either bipolar affective disorder or mania, symptoms of thyroid dysfunction may be misinterpreted or missed altogether, because these 2 classes of conditions share several similarities with regard to clinical presentation.

Physical

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.

Causes

Lithium carbonate is the direct cause of goiter formation.

  • The following are contributing factors in goiter formation:
    • Iodide deficiency
    • Prior or subclinical autoimmune thyroid disease
    • Prior131 I-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).

More on Goiter, Lithium-Induced

Overview: Goiter, Lithium-Induced
Differential Diagnoses & Workup: Goiter, Lithium-Induced
Treatment & Medication: Goiter, Lithium-Induced
Follow-up: Goiter, Lithium-Induced
References
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References

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Further Reading

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Keywords

lithium-induced goiter, thyroid, bipolar, TSH, lithium, hypothyroidism, bipolar disorder, thyroid symptoms, goiter, hypothyroid, thyroid problems, thyroid nodules, thyroid gland, thyroid hormone, manic depression, hypothyroidism symptoms, mood disorders, mood disorder, manic depressive, bipolar treatment, lithium effects, lithium side effects, goiter lithium therapy, lithium treatment, thyroid-stimulating hormone, lithium toxicity, lithium-induced thyromegaly, thyrotropin, thyroglobulin, Tg, cyclic adenosine monophosphate, cAMP, euthyroid goiter, thyrotoxicosis, iodine, iodine deficiency, thyrocytes, bipolar manic-depressive disorder,

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Contributor Information and Disclosures

Author

Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Nicholas J Sarlis, MBBS, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Therapeutic Radiology and Oncology, American Society of Clinical Oncology, American Thyroid Association, Association for Psychological Science, Endocrine Society, European Society for Medical Oncology, New York Academy of Sciences, and Royal Society of Medicine
Disclosure: Sanofi-Aventis Salary Employment

Coauthor(s)

Boaz Hirshberg, MD, Associate Director, CVMD, Pfizer
Boaz Hirshberg, MD is a member of the following medical societies: American Dietetic Association
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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