Lithium-Induced Goiter

No Results

No Results

processing….

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. ^[1] 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. ^[4] 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. ^[5] 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 ^[6] 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. ^[7] 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. ^[8]

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. ^[9]

Kibirige D, Luzinda K, Ssekitoleko R. Spectrum of lithium induced thyroid abnormalities: a current perspective. Thyroid Res. 2013 Feb 7. 6(1):3. [Medline]. [Full Text].

Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab. 1998 Oct. 83(10):3401-8. [Medline]. [Full Text].

Chakrabarti S. Thyroid functions and bipolar affective disorder. J Thyroid Res. 2011. 2011:306367. [Medline]. [Full Text].

Perrild H, Hegedus L, Baastrup PC, et al. Thyroid function and ultrasonically determined thyroid size in patients receiving long-term lithium treatment. Am J Psychiatry. 1990 Nov. 147(11):1518-21. [Medline].

Gaberscek S, Kalisnik M, Pezdirc M, et al. Influence of lithium on growth and viability of thyroid follicular cells. Folia Biol (Praha). 2002. 48(5):200-4. [Medline].

Gracious BL, Findling RL, Seman C, et al. Elevated thyrotropin in bipolar youths prescribed both lithium and divalproex sodium. J Am Acad Child Adolesc Psychiatry. 2004 Feb. 43(2):215-20. [Medline].

Bocchetta A, Cocco F, Velluzzi F, et al. Fifteen-year follow-up of thyroid function in lithium patients. J Endocrinol Invest. 2007 May. 30(5):363-6. [Medline].

Kupka RW, Nolen WA, Post RM, et al. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry. 2002. 51:305-11. [Medline].

Faggiano A, Del Prete M, Marciello F, Marotta V, Ramundo V, Colao A. Thyroid diseases in elderly. Minerva Endocrinol. 2011 Sep. 36(3):211-31. [Medline].

Emerson CH, Dysno WL, Utiger RD. Serum thyrotropin and thyroxine concentrations in patients receiving lithium carbonate. J Clin Endocrinol Metab. 1973 Feb. 36(2):338-46. [Medline].

Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007 Dec. 17(12):1211-23. [Medline].

Caykoylu A, Capoglu I, Unuvar N, et al. Thyroid abnormalities in lithium-treated patients with bipolar affective disorder. J Int Med Res. 2002 Jan-Feb. 30(1):80-4. [Medline].

Lazarus JH. The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid. 1998 Oct. 8(10):909-13. [Medline].

Loviselli A, Bocchetta A, Mossa P, et al. Value of thyroid echography in the long-term follow-up of lithium-treated patients. Neuropsychobiology. 1997. 36(1):37-41. [Medline].

Bauer M, Blumentritt H, Finke R, et al. Using ultrasonography to determine thyroid size and prevalence of goiter in lithium-treated patients with affective disorders. J Affect Disord. 2007 Dec. 104(1-3):45-51. [Medline].

Lombardi G, Panza N, Biondi B, et al. Effects of lithium treatment on hypothalamic-pituitary-thyroid axis: a longitudinal study. J Endocrinol Invest. 1993 Apr. 16(4):259-63. [Medline].

Bschor T, Baethge C, Adli M, et al. Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression. J Psychiatry Neurosci. 2003. 28:210-216. [Medline]. [Full Text].

Andersen BF. Iodide perchlorate discharge test in lithium-treated patients. Acta Endocrinol (Copenh). 1973 May. 73(1):35-42. [Medline].

Bagchi N, Brown TR, Mack RE. Studies on the mechanism of inhibition of thyroid function by lithium. Biochim Biophys Acta. 1978 Aug 3. 542(1):163-9. [Medline].

Barclay ML, Brownlie BE, Turner JG, et al. Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence. Clin Endocrinol (Oxf). 1994 Jun. 40(6):759-64. [Medline].

Bartalena L, Bogazzi F, Martino E. Is thyroxine during lithium therapy necessary?. J Endocrinol Invest. 1999 Mar. 22(3):220-2. [Medline].

Berens SC, Bernstein RS, Robbins J, et al. Antithyroid effects of lithium. J Clin Invest. 1970 Jul. 49(7):1357-67. [Medline]. [Full Text].

Berens SC, Wolff J. The endocrine effects of lithium. Johnson FN, ed. Lithium Research and Therapy. New York, NY: Academic Press; 1975. 443-72.

Berens SC, Wolff J, Murphy DL. Lithium concentration by the thyroid. Endocrinology. 1970 Nov. 87(5):1085-7. [Medline].

Bocchetta A, Mossa P, Velluzzi F, et al. Ten-year follow-up of thyroid function in lithium patients. J Clin Psychopharmacol. 2001 Dec. 21(6):594-8. [Medline].

Bou Khalil R, Richa S. Thyroid adverse effects of psychotropic drugs: a review. Clin Neuropharmacol. 2011 Nov-Dec. 34(6):248-55. [Medline].

Burrow GN, Burke WR, Himmelhoch JM, et al. Effect of lithium on thyroid function. J Clin Endocrinol Metab. 1971 May. 32(5):647-52. [Medline].

Calabrese JR, Gulledge AD, Hahn K, et al. Autoimmune thyroiditis in manic-depressive patients treated with lithium. Am J Psychiatry. 1985 Nov. 142(11):1318-21. [Medline].

Clower CG. Effects of lithium on thyroid function. Am J Psychiatry. 1989 Oct. 146(10):1357. [Medline].

Deodhar SD, Singh B, Pathak CM, et al. Thyroid functions in lithium-treated psychiatric patients: a cross-sectional study. Biol Trace Elem Res. 1999 Feb. 67(2):151-63. [Medline].

Fauerholdt L, Vendsborg P. Thyroid gland morphology after lithium treatment. Acta Pathol Microbiol Scand [A]. 1981 Jul. 89(4):339-41. [Medline].

Gaberscek S, Kalisnik M, Pavlin K, et al. Influence of lithium on cell function in two different cell systems. Folia Biol (Praha). 2003. 49:110-4. [Medline].

Hoogenberg K, Beentjes JA, Piers DA. Lithium as an adjunct to radioactive iodine in treatment-resistant Graves thyrotoxicosis. Ann Intern Med. 1998 Oct 15. 129(8):670. [Medline].

Kirov G. Thyroid disorders in lithium-treated patients. J Affect Disord. 1998 Jul. 50(1):33-40. [Medline].

Kusalic M, Engelsmann F. Effect of lithium maintenance therapy on thyroid and parathyroid function. J Psychiatry Neurosci. 1999 May. 24(3):227-33. [Medline]. [Full Text].

Lakshmanan MC, Robbibs J. Thyroid hormones, thyroid stimulating hormone (TSH), thyrotropin releasing hormone (TRH), and antithyroid drugs: lithium. Munson PL, ed. Principles of Pharmacology. Basic Concepts and Clinical Applications. New York, NY: Chapman & Hall; 1995. 802-7.

Lazarus JH. Is thyroxine during lithium therapy necessary?. J Endocrinol Invest. 1998 Dec. 21(11):784-6. [Medline].

Lazarus JH. Effect of lithium on the thyroid gland. Weetman AP, Grossman A, eds. Pharmacotherapeutics of the Thyroid Gland. Berlin, Germany: Springer-Verlag; 1997. 207-23.

Lindstedt G, Nilsson LA, Walinder J, et al. On the prevalence, diagnosis and management of lithium-induced hypothyroidism in psychiatric patients. Br J Psychiatry. 1977 May. 130:452-8. [Medline].

Maes M, Song C, Lin AH, et al. In vitro immunoregulatory effects of lithium in healthy volunteers. Psychopharmacology (Berl). 1999. 143:401-7. [Medline].

Miloni E, Burgi H, Studer H, et al. Thyroglobulin-rich colloid goitres: a result of the combined action of lithium and methimazole on the rat thyroid. Acta Endocrinol (Copenh). 1983 Jun. 103(2):231-4. [Medline].

Myers DH, Carter RA, Burns BH, et al. A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. Psychol Med. 1985 Feb. 15(1):55-61. [Medline].

Oakley PW, Dawson AH, Whyte IM. Lithium: thyroid effects and altered renal handling. J Toxicol Clin Toxicol. 2000. 38(3):333-7. [Medline].

Ozpoyraz N, Tamam L, Kulan E. Thyroid abnormalities in lithium-treated patients. Adv Ther. 2002 Jul-Aug. 19(4):176-84. [Medline].

Persad E, Forbath N, Merskey H. Hyperthyroidism after treatment with lithium. Can J Psychiatry. 1993 Nov. 38(9):599-602. [Medline].

Pesce L, Kopp P. Iodide transport: implications for health and disease. Int J Pediatr Endocrinol. 2014. 2014(1):8. [Medline].

Reus VI, Gold P, Post R. Lithium-induced thyrotoxicosis. Am J Psychiatry. 1979 May. 136(5):724-5. [Medline].

Robbins J. Control of hyperthyroidism with lithium after 131-I therapy [abstract]. Proceedings of the International Symposium on Graves Disease (Nagasaki, Japan). 1978. 36.

Rogers MP, Whybrow PC. Clinical hypothyroidism occurring during lithium treatment: two case histories and a review of thyroid function in 19 patients. Am J Psychiatry. 1971 Aug. 128(2):158-63. [Medline].

Rosser R. Thyrotoxicosis and lithium. Br J Psychiatry. 1976 Jan. 128:61-6. [Medline].

Schou M. Lithium prophylaxis in perspective. Pharmacopsychiatry. 1992 Jan. 25(1):7-9. [Medline].

Shopsin B, Shenkman L, Blum M, et al. Iodine and lithium-induced hypothyroidism. Documentation of synergism. Am J Med. 1973 Nov. 55(5):695-9. [Medline].

Sierra P, Cámara R, Tobella H, Livianos L. What is the real significance and management of major thyroid disorders in bipolar patients?. Rev Psiquiatr Salud Ment. 2014 Apr-Jun. 7(2):88-95. [Medline].

Smigan L, Wahlin A, Jacobsson L, et al. Lithium therapy and thyroid function tests. A prospective study. Neuropsychobiology. 1984. 11(1):39-43. [Medline].

Spaulding SW, Burrow GN, Bermudez F, et al. The inhibitory effect of lithium on thyroid hormone release in both euthyroid and thyrotoxic patients. J Clin Endocrinol Metab. 1972 Dec. 35(6):905-11. [Medline].

Spaulding SW, Burrow GN, Ramey JN, et al. Effect of increased iodide intake on thyroid function in subjects on chronic lithium therapy. Acta Endocrinol (Copenh). 1977 Feb. 84(2):290-6. [Medline].

Wharton RN. Accidental lithium carbonate treatment of thyrotoxicosis as mania. Am J Psychiatry. 1980 Jun. 137(6):747-8. [Medline].

Williams JA, Berens SC, Wolff J. Thyroid secretion in vitro: inhibition of TSH and dibutyryl cyclic-AMP stimulated 131-I release by Li+1. Endocrinology. 1971 Jun. 88(6):1385-8. [Medline].

Wolff J. Iodide goiter and the pharmacologic effects of excess iodide. Am J Med. 1969 Jul. 47(1):101-24. [Medline].

Nicholas J Sarlis, MD, PhD, FACP Vice President, Head of Medical Affairs, Incyte Corporation

Nicholas J Sarlis, MD, PhD, FACP is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American Association of Clinical Endocrinologists, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Radiation Oncology, American Thyroid Association, Endocrine Society, New York Academy of Sciences, Royal Society of Medicine, Association for Psychological Science, American College of Endocrinology, European Society for Medical Oncology, American Society of Clinical Oncology

Disclosure: Received salary from Incyte Corporation for employment; Received ownership interest from Sanofi-Aventis for previous employment; Received ownership interest/ stock & stock option (incl. rsu) holder from Incyte Corporation for employment.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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 and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus 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, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American College of Physicians, American Geriatrics Society, Endocrine Society, Gerontological Society of America, Association of Professors of Medicine

Disclosure: Nothing to disclose.

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.

Acknowledgments

The author wishes to dedicate this article to the late Jacob Robbins, MD (1922-2008), a leading figure in international thyroidology and a force majeure within the Clinical Endocrinology Branch of NIDDK, National Institutes of Health. His legacy lives on.

Lithium-Induced Goiter

Research & References of Lithium-Induced Goiter|A&C Accounting And Tax Services
Source

Share on Facebook

Tweet

Follow us