Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Rifai, M. A. Articles by Harrington, D. P. Search for Related Content PubMed Citation Articles by Rifai, M. A. Articles by Harrington, D. P. General Topics in Psychiatry

Lithium-Induced Hypercalcemia and Parathyroid Dysfunction

Received October 18, 2000; revised March 2, 2001; accepted March 15, 2001. From the University of Virginia, School of Medicine, Roanoke-Salem Program and the Veterans Affairs Medical Center, Salem, Virginia. Address reprint requests to Dr. Rifai, VAMC, Medicine/Psychiatry 116A7, Salem, Virginia 24153.

Key Words: Lithium • Hypercalcemia • Hyperparathyroidism

Lithium remains a first-line treatment for acute manic states and bipolar affective disorders despite the introduction of newer alternative effective treatments.¹ Lithium therapy, however, is associated with a variety of side effects.^1–3 Although thyroid dysfunction is the most widely recognized endocrine side effect of lithium therapy, hypercalcemia and more rarely a biochemical picture resembling primary hyperparathyroidism may also develop.² Recognition of this less common, but potentially life-threatening side effect, is important as an increasing number of patients are receiving long-term lithium therapy.³ The following case illustrates the potential impact of lithium on parathyroid function.

Case Report

Mr. M. was a 59-year-old white man with a 30-year history of schizoaffective disorder who was admitted to our inpatient psychiatry unit with acute mania. Symptoms at that time included hyperactivity, hypersexuality, rapid pressured speech, racing thoughts, and delusions of grandeur. Prior to admission, Mr. M. had been maintained on fluphenazine decanoate (50 mg im every 2 weeks for approximately 10 years). Other medications at the time of admission included benztropine (1 mg bid) and aspirin (325 mg). His previous medical history was significant for chronic obstructive pulmonary disease (COPD) and mild tardive dyskinesia (AIMS score was 3). Admission physical examination was normal. Laboratory evaluation revealed a normal chemistry panel, including calcium (9.7 mg/dl; nl 8–10.7), phosphorus (2.8 mg/dl; nl 2.6–4.8), and magnesium (2.2 mg/dl; nl 1.6–2.2). Serum albumin and alkaline phosphatase levels were normal. His complete blood count was normal (WBC 10.000/cc, Hg 14.1 g/dl, Hct 43.2%, Plt 162.000/ml), and arterial blood gas revealed a pH 7.38, PCO₂ 53 mmHg, PO₂ 65 mmHg, and O₂ Sat. of 91%. Urinalysis and drug screening were negative. Chest X ray was consistent with COPD, and no masses were seen. Parathyroid hormone (PTH; intact molecule, radioimmunoassay=80 pg/ml; nl 20–80) and thyroid stimulating hormone (TSH; 1.9 uIU/ml; nl 0.35–5.5) were normal. Mr. M. was started on lithium carbonate (LiCO₃; 300 mg bid) and fluphenazine hydrochloride (5 mg bid). He rapidly responded to lithium therapy and was discharged 2 weeks after admission. Lithium level (Li 0.7 mEq/l) was therapeutic at the time of discharge on LiCO₃ (300 mg bid). After discharge, Mr. M. received close follow-up with biweekly review of lithium levels and chemistry panels. He remained clinically stable and the additional fluphenazine HCl was discontinued 1 month after discharge.

Mr. M. presented to our emergency room 3 months after his discharge with delirium, agitation, shortness of breath, nausea, dizziness, and headache. Physical examination was notable for tachycardia (pulse 110 bpm) and hypertension (blood pressure 190/110 mmHg). ECG revealed shortened QT interval (QTc 220 msec) and nonspecific ST-T changes. A chemistry panel revealed hypercalcemia with a total calcium of 14 mg/dl and ionized calcium of 1.55 mmol/l (nl 1.13–1.32). Mild hypophosphatemia (2.5 mg/dl) and hypermagnesemia (2.7 mg/dl) were also present. Mr. M.'s lithium level was therapeutic (0.8 mEq/l). A chest X ray and arterial blood gas were unchanged from prior testing. Mr. M.'s medications included LiCO₃ (300 mg bid), aspirin (325 mg qd), benztropine (1 mg bid), and fluphenazine decanoate (50 mg im every 2 weeks with the last dose given 5 days before admission). Mr. M. was admitted to the intensive care unit (ICU). Three sets of cardiac enzymes 8 hours apart ruled out myocardial infarction. Hypercalcemia was treated with normal saline infusion and furosemide (40 mg iv q6h), and serum calcium levels declined gradually. Delirium resolved on the third ICU day, when the total calcium level was 11.7 mg/dl, and ionized calcium was 1.44 mmol/l. Calcium levels returned to normal (9.8mg/dl) 1 week after admission. An evaluation to determine the etiology of hypercalcemia revealed an elevated PTH (101 pg/ml) and a normal 25 OH vitamin D level (17 ng/ml; nl 15–20). A skeletal survey and chest X ray did not reveal any evidence of malignancy or sarcoid. Diuretics and intravenous fluids were discontinued and a 24-h urine collection revealed polyuria (urine volume 4 liters/24 h), elevated urinary calcium (Ca²⁺ 450 mg/24 h; nl<300 mg/24 h), and a normal glomerular filtration rate (GFR 90 ml/min). Lithium was suspected as the potential etiology of Mr. M.'s hyperparathyroid state and was discontinued. The patient remained clinically stable on fluphenazine decanoate therapy alone, and he was discharged after 10 days of hospitalization.

Mr. M. remained asymptomatic with normal calcium levels over the next 2 months. His PTH level continued to increase to 138 pg/ml despite the discontinuation of lithium. A repeat 24-h urine collection showed normalization of urinary calcium (Ca²⁺ 250 mg/24 h) and a normal GFR. At that time, a tentative diagnosis of primary hyperparathyroidism was considered, and Mr. M. and his family were offered imaging studies and surgical neck exploration but declined. Mr. M.'s PTH level eventually returned to baseline at 80 pg/ml approximately 5 months after discontinuation of lithium therapy, and serum calcium levels remained in the normal range. His PTH and calcium levels remained normal 1 year later (PTH 65 pg/ml).

Discussion

Despite the extensive use of lithium since 1968, only 26 reports of lithium-induced hypercalcemia/hyperparathyroidism have appeared in the literature.^3–5 Most of these were published before 1991, and only five reports have appeared since 1991.^3,4 The case presented in this report is unique with regard to the extent in which the clinical and laboratory findings support the diagnosis. Serial PTH, calcium, and phosphate levels obtained prior to, during, and after lithium therapy all suggest a temporal relationship between lithium exposure and the hyperparathyroid state.^2–4,9 In addition, other medical conditions that might influence serum calcium levels and calcium excretion (i.e., medications, renal failure, and other medical illnesses) were not likely to be operative in this patient.^2,3,5,6,8 Consequently, it is highly probable that lithium caused the hyperparathyroid state in this case. This case also illustrates many of the clinical features of lithium-induced parathyroid dysfunction as well as some differences between the lithium-induced syndrome and primary hyperparathyroidism.^2,3,5,6,8 As with other forms of hypercalcemia, the association of lithium-induced parathyroid dysfunction with weakness, fatigue, delirium, hypertension, and arrhythmias (bradycardia, short QT interval, asystole) makes it a life-threatening condition that requires immediate treatment. Unlike primary hyperparathyroidism, lithium-induced parathyroid dysfunction is associated with a resolution of hypercalcemia and its accompanying symptoms when lithium therapy is discontinued. Other findings that would distinguish the hyperparathyroid state as lithium induced, and are unusual in primary hyperparathyroidism, include a normal serum phosphate level and elevated magnesium levels.^3,5,7 Skeletal surveys often reveal mild osteopenia or normal bone density in the lithium-induced parathyroid dysfunction, versus the more pronounced osteoporosis and Osteitis Fibrosa Cystica encountered in primary hyperparathyroidism.⁶ Renal caliculi and hypercalciuria are common with primary hyperparathyroidism, while caliculi and renal calcium excretion is variable in the lithium-induced state.⁶ In the present case, phosphate levels were slightly below normal, a finding that may be related to the patient's mild COPD. Magnesium levels were elevated and skeletal surveys were normal. It is notable that in the current case, approximately 5 months were required for PTH levels to return to normal after lithium discontinuation. This time frame is much longer than what is reported in other cases of lithium-induced hyperparathyroidism.³

Currently, there is no consensus on the prevalence, severity, or exact mechanism underlying lithium-induced hypercalcemia and parathyroid dysfunction. Garfinkel et al.⁹ reported the first case of lithium-induced hypercalcemia in 1973. Retrospective case series have reported the prevalence of lithium-induced parathyroid dysfunction to range from 5–40% in patients on long-term lithium therapy (10–20 years). However given the small number of case reports in the literature, the true prevalence cannot be determined at this time. Lithium may affect calcium homeostasis by several different mechanisms.⁵ First, lithium has been shown to block calcium influx into a variety of cells by competitively inhibiting calcium transport across cell membranes. Acute hypercalcemia may result from the competitive mechanism inhibition of calcium influx, leading to elevated calcium concentrations. Second, lithium may raise the threshold of the calcium-sensing mechanism within the parathyroid gland responsible for shutting-off the PTH secretion. Consequently, PTH secretion continues despite elevated calcium levels. Lithium inhibits the production of the cellular messenger inositol monophosphate (IMP),¹ which regulates the intracellular calcium exposure to the nuclear calcium-sensing receptor in parathyroid cells. IMP depletion makes less calcium available for the nuclear calcium-sensing receptor, altering the "set-point" to shut-off PTH gene transcription. Third, lithium may directly induce the overproduction of PTH by inhibiting the action of glycogen synthase kinase 3b (GSK-3b), which in turn inhibits PTH transcription.¹ PTH transcription thereby proceeds with reduced inhibition leading to an overproduction of PTH. Which of the above mechanisms predominates in clinical cases of lithium-induced parathyroid dysfunction remains unclear.

The case described in this report has several clinical implications. Total serum calcium, serum proteins, and ionized calcium are usually sufficient to exclude any abnormalities before lithium is instituted. Periodic monitoring of serum calcium levels during lithium therapy is warranted. Hypercalcemia should be considered in any patient who becomes delirious or who develops any of the symptoms noted above. Hypercalcemia should also be considered in any patient who becomes refractory to lithium after an initial response. Any patient who is noted to be hypercalcemic or to have hyperparathyroidism prior to initiation of mood stabilizer therapy should not receive lithium, and patients who develop lithium-induced parathyroid dysfunction should be switched to an alternate mood stabilizer. After discontinuation of lithium therapy, PTH levels may remain elevated for months but in most cases the hyperparathyroid state is reversible and should not prompt premature surgical intervention.

ACKNOWLEDGMENTS

This case was presented at the Association of Medicine and Psychiatry, annual meeting in New Orleans, November 16, 1999.

REFERENCES

1. Lenox R, McNamara R, Papke R, et al; Neurobiology of lithium: an update. J Clin Psychiatry 1998; 59(suppl 6):37-47
2. Kingsbury S, Salzman C: Lithium's role in hyperparathyroidism and hypercalcemia. Hosp Commun Psychiatry 1993; 44:1047-1048[Medline]
3. Brochier T, Adnet-Kessous J, Barillot M, et al; Hyperthyroidie sous lithium (French). L'Encephale 1994; 20:339-349
4. Gama R, Wright J, Ferns G: An unusual case of hypercalcemia. Postgrad Med J 1999; 75:769-770[Free Full Text]
5. McIntosh W, Horn E, Mathieson L, et al: the prevalence, mechanism and clinical significance of lithium-induced hypercalcemia. Med Lab Sci 1987; 44:115-118[Medline]
6. Nordenstrom J, Elvius M, Strindlund M, et al: Biochemical hyperparathyroidism and bone mineral status in patients treated long-term with lithium. Metabolism 1994; 43:1563-1567[CrossRef][Medline]
7. Christiansen C, Baastrup P: Development of "primary" hyperparathyroidism during lithium therapy: longitudinal study. Neuropsychobiology 1980; 6:280-283[Medline]
8. Franks R, Dubovsky S, Lifshitz M, et al: Long-term lithium carbonate therapy causes hyperparathyroidism. Arch Gen Psychiatry 1982; 39:1074-1077[Abstract/Free Full Text]
9. Garfinkel P, Ezrin C, Stancer H: Hypothyroidism and hyperparathyroidism associated with lithium. Lancet 1973; 3:331-332

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Rifai, M. A. Articles by Harrington, D. P. Search for Related Content PubMed Citation Articles by Rifai, M. A. Articles by Harrington, D. P. General Topics in Psychiatry

Get information about faster international access.

Privacy Policy

Copyright © 2001 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us