Lithium-associated hypothyroidism and thyroid papillary carcinoma: a case report.

Abstract: Ionizing radiation, some hereditary factors, and chronic thyroid-stimulating hormone elevation increases the risk of differentiated thyroid carcinoma. Lithium salts are used in the treatment of affective (mood) disorders as well as a variety of other psychiatric conditions. There have been occasional reports of hematologic and solid neoplasms associated with lithium use. We report a patient who developed hypothyroidism and subsequently, thyroid papillary carcinoma while on lithium treatment for bipolar affective disorder.

Key Words: lithium, hypothyroidism, thyroid carcinoma

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Lithium salts are used in the treatment of affective (mood) disorders as well as a variety of other psychiatric conditions. The most well-known side effect of lithium is hypothyroidism. Adverse reactions to lithium generally involve the central nervous system (CNS), the gastrointestinal tract, and the kidneys. Forty to fifty percent of patients on lithium develop mild adverse CNS and neuromuscular effects, such as lethargy, fatigue, muscle weakness, and tremor. There have been occasional reports of hematologic and solid neoplasms associated with lithium use (1-4). Most patients receiving lithium develop a reversible leukocytosis, with leukocyte counts of 10,000 to 15,000/m[m.sup.3]. Increases in erythrocyte and platelet counts are less frequently observed. There have been occasional reports of lithium-induced hematologic neoplasms (eg, acute leukemia, chronic myeloid leukemia), but a causal relationship to the drug has not been established. To the best of our knowledge, only four cases of lithium-associated thyroid carcinoma have been reported. (1-5) We report a patient who developed hypothyroidism and subsequently, thyroid papillary carcinoma while on lithium treatment for bipolar affective disorder.

Case Report

A 45-year-old man was referred to our department for differentiated thyroid carcinoma. His past medical history included bipolar affective disorder since age 7, and he had been on lithium 300 mg b.i.d. (lithium carbonate capsules) for the previous 4 years. His physical examination revealed a normal thyroid and thyroid function tests before lithium treatment was begun. Although the patient did not have any symptoms suggesting hypothyroidism, routine thyroid functions tests, 14 months after initiation of lithium, revealed a thyroid-stimulating hormone (TSH) of greater than 100 uIU/mL (0.49-4.67), a T3 of 0.61 ng/dL (0.45-1.37), and a T4 of 3.21 [micro]g/dL (4.5-12). His serum lithium levels during this period were within normal limits and varied between 0.53 and 1.12 (0.6-1.00 mmol/L). Antimicrosomal antibody was 8.2 AU (0-1.1 AU) and antithyroglobulin antibody was negative. A diagnosis of lithium-induced hypothyroidism was established and levothyroxine sodium treatment was prescribed at a dose of 0.1 mg/d. During routine follow up after 3 years of lithium treatment, a 1 cm nodule was palpated in the right lobe of the thyroid. Ultrasonography showed a hypoechoic nodule with millimetric calcifications in the right lobe. Fine needle aspiration revealed papillary carcinoma.

Family history of malignancy was insignificant. No metastasis was documented at the time of diagnosis. Total thyroidectomy was performed. Histopathological examination showed multifocal papillary carcinoma and Hashimoto thyroiditis. Tumors were located in the right lobe and isthmus, and were 1.5 cm and 0.4 cm in size, respectively. They were encapsulated, confined to the thyroid and no lymphovascular invasion was detected. The neoplasm was thought to have developed on the grounds of Hashimoto thyroiditis.

Thyroxin suppression treatment was started and lithium therapy was switched to carbamazepine. Following 24 months of follow-up, the patient remains well and free of recurrence.

Discussion

Lithium inhibits thyroid hormone secretion by acting on the proteolysis of active hormone from the colloid. Although it has various effects on the thyroid gland, its principal effect is to block the release of thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]) mediated

by TSH. This results in a decrease in circulating [T.sub.4] and [T.sub.3] concentrations and a feedback increase in serum TSH concentration. Furthermore, lithium inhibits TSH-stimulated adenylate cyclase activity and TSH-induced release of thyroidal iodine 131, decreases intrathyroidal iodothyronine-iodotyrosine ratios, and inhibits colloid droplet formation. (6)

In therapeutic concentrations, lithium causes clinically evident hypothyroidism in about 1 to 4% of patients. The presentation of hypothyroidism may vary from mild symptoms to severe myxedema and may occur within weeks to years after initiation of lithium therapy. Rarely, hypothyroidism may persist after discontinuation of the drug. In addition about 5% of lithium-treated patients develop goiters, resulting from stimulation of the thyroid gland by an indirect lithium-induced increase in TSH release. Goiters may develop even in the absence of hypothyroidism in some patients. Lithium-induced goiters are usually diffuse, nontender and are often so small, they are only noticed on palpation. Geriatric patients and patients with antithyroglobulin antibody, a prior history of Graves disease or Hashimoto thyroiditis, or those receiving iodine may be more likely to develop hypothyroidism during lithium therapy. Paradoxically, a few cases of hyperthyroidism have been reported. (7,8)

It is not known if lithium is mutagenic or carcinogenic. An increased number of chromosomal breaks, gaps, and satellite associations, as well as a reduced percentage of replicating cells were found in one study on lithium-containing leukocyte cultures. Similar findings were not found in two other in vitro studies. Mice inoculated with viable sarcoma cells have shown an earlier incidence of tumor development, but no change in tumor size when treated with lithium. The number and size of induced mammary tumors in rats have not been enhanced by lithium. (9,10) There have been occasional reports of lithium-induced hematologic neoplasms (eg, acute, chronic myeloid leukemia) but a causal relationship to the drug has not been established. Studies have shown no changes in blast and mature neutrophil counts in patients with various blood dyscrasias who were receiving lithium. One study found that the incidence of leukemia was not increased in a group of manic-depressive patients receiving chronic lithium therapy. Hyperparathyroidism associated with long-term lithium therapy is well described. Lithium selectively stimulates growth of parathyroid adenomas in susceptible patients. (11) To our knowledge, there have been only 4 patients with lithium-associated thyroid carcinoma reported in the literature. (1,5) In the literature there are no large series concerning this finding. Lithium-associated malignancy has most frequently been presented as case reports with bipolar disorders. This association has not been reported with other medications. Alhough chromosome aberrations have been proposed as a possible mechanism, the exact process of lithium-induced carcinogenesis (if it even exists) remains unsettled. (9,12) However, in the case of thyroid cancers, even if lithium does not directly cause the disease, it is possible that elevated TSH levels secondary to hypothyroidism contribute to the propagation of incidental differentiated thyroid cancers.

This case shows that lithium salts may be associated with the development of thyroid papillary carcinoma, and that a history of lithium-induced hypothyroidism may be a risk factor for thyroid papillary carcinoma. All patients taking lithium should undergo close surveillance for thyroid dysfunction and neoplasia, and appropriate surgical and medical interventions should be carried out when necessary.

References

1. Brownlie BE, Turner JG, Millner GM, et al. Lithium associated thyroid cancer. Aust N Z J Med 1980;10:62-63.

2. Volf N, Crismon ML. Leukemia in bipolar mood disorder: is lithium contraindicated? DICP 1991;25:948-951.

3. Moreb J, Hershko C. Increased leucocyte alkaline phosphatase and transcobalamin III in chronic myeloid leukaemia associated with lithium therapy. Scand J Haematol 1985;34:238-241.

4. Lyskowski J, Nasrallah HA. Lithium therapy and the risk for leukemia. Br J Psychiatry 1981;139:256.

5. McHenry CR, Rosen IB, Rotstein LE, et al. Lithiumogenic disorders of the thyroid and parathyroid glands as surgical disease. Surgery 1990;108:1001-1005.

6. Yassa R, Saunders A, Nastase C, et al. Lithium-induced thyroid disorders: a prevalence study. J Clin Psychiatry 1988;49:14-16.

7. Engin A, Altan N, Isik E. Erythrocyte glutathione levels in lithium-induced hypothyroidism. Drugs R D 2005;6:35-40.

8. Kusalic M, Engelsmann F. Effect of lithium maintenance therapy on thyroid and parathyroid function. J Psychiatry Neurosci 1999;24:227-233.

9. Weiner ML, Batt KJ, Putman DL, et al. Genotoxicity evaluation of lithium hypochlorite. Toxicology 1990;65:1-22.

10. El-Domeiri AA, Messiha FS, Hsia WC. Effect of alkali metal salts on sarcoma I in A/J mice. J Surg Oucol 1981;18:423-429.

11. Awad SS, Miskulin J, Thompson N. Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy. World J Surg 2003;27:486-488.

12. Leonard A, Hantson P, Gerber GB. Mutagenicity, carcinogenicity and teratogenicity of lithium compounds. Mutat Res 1995;339:131-137.</p> <pre> A religious man is a person who holds God and man in one thought at one time, at all times, who suffers harm done to others, whose greatest passion is compassion, whose greatest strength is love and defiance of despair. --Abraham Joshua Heschel </pre> <p>Sercan Aksoy, MD, Saadettin Kilickap, MD, and Mustafa Erman, MD

From the Department of Medical Oncology, Hacettepe University Institute of Oncology, Ankara, Turkey.

Reprint requests to Sercan Aksoy M.D., Hacettepe University Institute of Oncology, 06100, Sihhiye, Ankara, Turkey. Email: [e-mail]

Accepted November 22, 2005.

RELATED ARTICLE: Key Points

* Ionizing radiation, some hereditary factors, and chronic thyroid-stimulating hormone elevation increase the risk for differentiated thyroid carcinoma.

* Lithium salts are used in the treatment of affective (mood) disorders as well as a variety of other psychiatric conditions.

* There have been occasional reports of lithium-induced hematologic neoplasms (eg, acute leukemia, chronic myeloid leukemia), but a causal relationship to the drug has not been established. So far, 4 cases of lithium-associated thyroid carcinoma have been reported.

* All patients taking lithium should undergo close surveillance for thyroid dysfunction and neoplasia, and appropriate surgical and medical interventions should be carried out when necessary.