Normalization of Lithium-Induced Hypercalcemia and Hyperparathyroidism With Cinacalcet Hydrochloride

Normalization of Lithium-Induced Hypercalcemia and Hyperparathyroidism With Cinacalcet Hydrochloride James A. Sloand, MD, and Mark A. Shelly, MD ● An underrecognized side effect of long-term lithium carbonate therapy is hyperparathyroidism with associated hypercalcemia and hypocalciuria. Because cessation of lithium carbonate therapy usually does not correct the hyperparathyroidism and associated hypercalcemia, parathyroidectomy frequently is necessary. This is the initial report of 2 patients with lithium carbonate–induced hyperparathyroidism treated with cinacalcet hydrochloride (HCl), which normalized serum calcium levels and reduced intact parathyroid hormone (iPTH) secretion. The patients, both with bipolar disease and a 15- to 30-year history of lithium carbonate therapy, were evaluated for stage 3 chronic kidney disease, persistent hypercalcemia, and hyperparathyroidism. A 67-year-old woman was administered cinacalcet HCl, 30 mg/d, for 11 months. Mean serum calcium level decreased from 10.8 ⴞ 0.4 mg/dL (2.69 ⴞ 0.10 mmol/L) to 9.9 ⴞ 0.4 mg/dL (2.47 ⴞ 0.10 mmol/L; P < 0.001), and iPTH level decreased from 139 ⴞ 31 pg/mL (139 ⴞ 31 ng/L) to 114 ⴞ 39 pg/mL (114 ⴞ 39 ng/L; P ⴝ not significant). A 63-year-old man was administered 30 mg/d of cinacalcet HCl for 8 months, then 60 mg/d for another 2 months. Mean serum calcium and iPTH levels decreased from 11.0 ⴞ 0.5 mg/dL (2.74 ⴞ 0.12 mmol/L) to 10.3 ⴞ 0.4 mg/dL (2.57 ⴞ 0.10 mmol/L; P < 0.001) and 138 ⴞ 10 pg/mL (138 ⴞ 10 ng/L) to 73 ⴞ 7 pg/mL (73 ⴞ 7 ng/L; P ⴝ 0.03), respectively. Urinary fractional excretion of calcium was low for both patients before (<0.026 and <0.015) and after (0.026 and 0.008) treatment with cinacalcet HCl. These findings suggest that cinacalcet HCl can provide an alternative nonsurgical means to control this disorder in patients with hypercalcemia of variable severity for whom surgical treatment is not a consideration because of perceived mildness of disease or unsuitability of the patient for surgical intervention. Am J Kidney Dis 48:832-837. © 2006 by the National Kidney Foundation, Inc. INDEX WORDS: Lithium carbonate; hyperparathyroidism; hypercalcemia; hypocalciuria; cinacalcet hydrochloride; parathyroid hormone; loop of Henle; long-term lithium therapy; familial hypocalciuric hypercalcemia.

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ITHIUM CARBONATE has been considered a mainstay in the treatment of patients with bipolar disease and schizoaffective disorders since its first use in 1949.1 Although generally well tolerated, long-term administration can result in adverse effects, including nephrogenic diabetes insipidus and chronic tubulointerstitial disease.2,3 A less recognized side effect of lithium carbonate therapy is hyperparathyroidism with associated hypercalcemia and hypocalciuria.4 A proposed mechanism for this effect is an alteration in the calciumsensing receptor, resulting in a shift to the right of the calcium–parathyroid hormone (PTH) response curve. Although hypercalcemia resolves after disFrom the University of Rochester School of Medicine, Department of Medicine, Nephrology and Infectious Disease/ Epidemiology Divisions, Rochester, NY. Received May 30, 2006; accepted in revised form July 20, 2006. Originally published online as doi:10.1053/j.ajkd.2006.07.019 on September 15, 2006. Support: None. Potential conflicts of interest: None. Address reprint requests to James A. Sloand, MD, Highland Hospital Renal Unit, 1000 South Ave, Box 88, Rochester, NY 14620. E-mail: [email protected] © 2006 by the National Kidney Foundation, Inc. 0272-6386/06/4805-0017$32.00/0 doi:10.1053/j.ajkd.2006.07.019 832

continuation of lithium therapy in some cases, complete resolution more often requires total or partial parathyroidectomy.5,6 Uncorrected, persistent hyperparathyroidism and resulting hypercalcemia may exacerbate psychiatric dysfunction and negatively influence bone mineral density, vascular health, and renal excretory function.7-9 Cinacalcet hydrochloride (HCl) is an allosteric activator of the calcium-sensing receptor present in chief cells of parathyroid glands, kidneys, and other tissues.10 This calcimimetic action of cinacalcet HCl lowers the threshold for activation of the calcium-sensing receptor by extracellular calcium. In parathyroid cells, this results in decreased PTH secretion. Whereas salutary effects of cinacalcet HCl were shown clearly in patients with both primary and secondary hyperparathyroidism,11,12 its utility in the treatment of patients with lithium-induced hyperparathyroidism is unexplored. Two cases of lithium-induced hyperparathyroidism successfully treated with cinacalcet HCl are described. CASE REPORTS

Patient 1 A 67-year-old woman was referred for evaluation of chronic kidney disease in a setting of long-term lithium

American Journal of Kidney Diseases, Vol 48, No 5 (November), 2006: pp 832-837

LITHIUM, HYPERPARATHYROIDISM, AND CINACALCET

carbonate use. She had a history of bipolar disease for 45 years and was treated with lithium for the previous 30 years. The current dose of lithium carbonate was 300 mg twice daily. She was not administered exogenous calcium, vitamin D, or diuretic therapy. There was a history of hypothyroidism, for which the patient was on replacement therapy. There was no family history of hyperparathyroidism or endocrine adenomatosis. Prior history was significant for 1- to 2-year use of celecoxib, 200 mg/d, for degenerative joint disease. There also was a history of recurrent urinary tract infections for a 2-year period 20 years before presentation. Medications included estradiol transdermal, 0.025 mg/wk; amitriptyline, 50 mg/d; lithium carbonate, 300 mg twice daily; rabeprazole, 20 mg/d; celecoxib, 200 mg/d; verapamil extended release, 120 mg/d; atorvastatin, 10 mg/d; levothyroxine, 100 ␮/d; vitamin C, 1,000 IU/d; vitamin E, 400 IU/d; folic acid, 800 ␮g/d; and vitamin B12, 100 ␮g/d. Physical examination was unrevealing, except for mild hypertension with a blood pressure of 150/90 mm Hg present in both arms in the seated position. The patient was 165 cm tall and weighed 75 kg, with a body mass index of 27.5 kg/m2. There was no evidence of ciliary flush on ophthalmological examination. Neurological examination findings also were unremarkable. Urinalysis results were normal, with no proteinuria, hematuria, or evidence of crystalluria. Laboratory findings were significant for a creatinine level of 1.5 mg/dL (133 ␮mol/L) and estimated glomerular filtration rate of 37 mL/min/1.73 m2 (0.62 mL/s) based on the Modification of Diet in Renal Disease formula.13 Calcium level was increased at 10.6 mg/dL (2.64 mmol/L; normal, 8.5 to 10.2 mg/dL [2.12 to 2.54 mmol/L]). Repeated serum calcium level was 11.1 mg/dL (2.77 mmol/L), with phosphorus level of 3.1 mg/dL (1 mmol/L; normal, 2.5 to 4.25 mg/dL [0.81 to 1.45 mmol/L]) and ionized calcium level of 5.6 mg/dL (2.80 mmol/L; normal, 4.5 to 5.3 mg/dL [2.25 to 2.65 mmol/L]). Magnesium level was 2.3 mg/dL (0.95 mmol/L). Intact PTH (iPTH) level was 179 pg/mL (179 ng/L; normal, 14 to 72 pg/dL [14 to 72 ng/L]). All iPTH measurements were performed by using a solid-phase 2-site chemiluminescent immunoassay. 25-Hydroxy vitamin D and 1,25dihydroxy vitamin D levels were 35 ng/mL (87 nmol/L; normal, 20 to 57 ng/mL [50 to 142 nmol/L]) and 19 pg/mL (49 pmol/L; normal, 15 to 75 pg/mL [39 to 195 pmol/L]), respectively. Twenty-four–hour urine collection showed urinary creatinine level of 654 mg (57,814 ␮mol), phosphorus level of 774 mg (249 mmol; normal, 400 to 1,300 mg/d [129.16 to 419.77 mmol]), sodium level of 167 mEq (167 mmol), and urinary calcium less than the level of detection, reported by the laboratory as “less than 149 mg” (⬍37.18 mmol). Fractional excretion of calcium was less than 0.026. Lithium levels were in the therapeutic range at 0.69 mEq/L (0.7 mmol/L; normal, 0.6 to 1.2 mEq/L [0.6 to 1.2 mmol/L]). Total urinary protein was normal. Thyroid function was normal. Repeated serum calcium values remained in the 10.9- to 11.1-mg/dL (2.72- to 2.77-mmol/L) range during the next 19 months. Renal ultrasound showed mild cortical thinning on the right greater than the left. No evidence of obstruction was present. Dual-energy X-ray absorptiometry scan showed

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significant osteoporosis with a T score of ⫺2.5 at the right distal radius (high relative fracture risk). T Score about the right hip was ⫺1.8 with a moderate fracture risk. Ultrasound of the neck failed to show enlarged parathyroid glands. The patient subsequently was started on therapy with cinacalcet HCl, 30 mg/d, to be ingested with a meal. Calcium and phosphorus were measured every 2 weeks initially, followed by monthly and then every 3 months. Biochemical studies were completed at the end of 11 months of cinacalcet HCl treatment; however, she has continued therapy. Her psychotherapist maintained her lithium carbonate therapy.

Patient 2 A 63-year-old man was referred for evaluation and treatment of chronic kidney disease after 15 years of lithium use to manage a bipolar disorder of 27 years’ duration. There was a history of hypertension and benign prostatic hypertrophy. He had a remote history of tobacco use; he had quit cigarette smoking 27 years before. There was no family history of kidney disease or endocrine adenomatosis. Medications included valsartan, 160 mg/d; bupropion sustained release, 100 mg/d; imipramine, 25 mg/d; lithium sustained release, 450 mg/d; and albuterol for seasonal allergy and asthma. He was administered no exogenous calcium, vitamin D, or diuretic therapy. Physical examination showed a 63-year-old obese man who weighed 118 kg and was 178 cm tall (body mass index, 37 kg/m2), with blood pressure of 124/84 mm Hg. No thyroid abnormalities were present on examination. Cardiopulmonary examination findings were normal. Trace to 1⫹ peripheral edema was present. Serum creatinine level was 2.4 mg/dL (212 ␮mol/L), with an estimated glomerular filtration rate of 30 mL/min/1.73 m2 (0.50 mL/s) based on the Modification of Diet in Renal Disease equation. Serum albumin level was 4.3 g/dL (43 g/L), calcium level was 10.5 mg/dL (2.62 mmol/L; normal, 8.5 to 10.2 mg/dL [2.12 to 2.54 mmol/L]), phosphorus level was 3.2 mg/dL (1.03 mmol/L), and magnesium level was 2.1 mg/dL (0.86 mmol/L). Twentyfour–hour urine collection showed total calcium excretion less than the level of detection by the laboratory, reported as “less than 99 mg” (⬍24.70 mmol), in a urine sample containing 1.4 g (123,760 ␮mol) of creatinine, 850 mg (274.47 mmol/L) of phosphate (normal, 400 to 1,300 mg/d [129.16 to 419.77 mmol]), and 253 mg (2,530 g) of total protein. Fractional excretion of calcium was less than 0.015. iPTH level (solid-phase 2-site chemiluminescent immunoassay) was 139 pg/mL (139 ng/L; normal, 14 to 72 pg/mL [14 to 72 ng/L]). 1,25-Dihydroxy vitamin D level was 31 pg/mL (81 pmol/L; normal, 15 to 75 pg/mL [39 to 195 pmol/L]), and 25-hydroxy vitamin D level was 21 ng/mL (52 nmol/L; normal, 20 to 57 ng/mL [50 to 142 nmol/L]). Prostate-specific antigen level was 4.68 ng/mL (4.68 ␮g/L; normal, 0 to 4 ng/mL [0 to 4 ␮g/L]). Serum protein electrophoresis results were normal. Despite discontinuation of lithium carbonate therapy for 20 months, serum calcium values remained elevated and increased to 11.7 mg/dL (2.92 mmol/L). A renal ultrasound was obtained, showing 11.1-cm and 10.9-cm kidneys containing a few simple cysts. A slight increase in echogenicity of both kidneys was present. A sestamibi scan showed no evidence of parathyroid adenoma or enlargement.

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SLOAND AND SHELLY Table 1. Calcium and PTH Levels On and Off Cinacalcet Therapy

Patient 1 Total calcium (mg/dL) PTH (pg/mL) Ionized calcium (mg/dL) Patient 2 Total calcium (mg/dL) PTH (pg/mL) Ionized calcium (mg/dL)

Baseline

On Cinacalcet Therapy

P

10.8 ⫾ 0.4 (10) 139 ⫾ 31 (4) 5.6 ⫾ 0.1 (3)

9.9 ⫾ 0.4 (11) 114 ⫾ 39 (6) 5.1 ⫾ 0.1 (1)

⬍ 0.001 Not significant

11.0 ⫾ 0.5 (8) 138 ⫾ 10 (4) 5.6 ⫾ 0.1 (2)

10.3 ⫾ 0.4 (4) 73 ⫾ 7 (2) 5.2 ⫾ 0.1 (2)

⬍ 0.001 0.03

NOTE. Values expressed as mean ⫾ SD (number of measurements). Probabilities were calculated with 2-tailed t-test. There were too few points for statistical testing of ionized calcium. To convert serum and ionized calcium in mg/dL to mmol/L, multiply by 0.2495; PTH in pg/mL to ng/L, multiply by 1.

With persistent hypercalcemia and excess iPTH secretion 20 months after lithium therapy was discontinued, the patient was started on therapy with cinacalcet HCl, 30 mg/d. After 8 months at this dose, the patient elected to stop using the medication for 2 months. After counsel, he resumed cinacalcet HCl therapy at a dose of 60 mg/d. The higher dose was prescribed to provide greater suppression of iPTH. He continued on this treatment for another 2 months. Biochemical studies were completed at the end of this time. He has continued using the drug.

RESULTS

Calcium levels decreased significantly in both patients when they were administered cinacalcet HCl (Table 1; P ⬍ 0.001 by t-test). iPTH levels also decreased, although in the first patient, this difference did not reach statistical significance. The cost of medication precluded additional increases in cinacalcet HCl dosing for this patient. In the second patient, calcium and iPTH levels returned to baseline off therapy for a few months. Relationships between calcium and iPTH levels for both patients before and after treatment with cinacalcet HCl are shown in Fig 1. Mean serum phosphate

levels increased from 3.20 ⫾ 0.28 (SE) mg/dL (1.03 ⫾ 0.09 mmol/L) to 3.66 ⫾ 0.16 mg/dL (1.18 ⫾ 0.05 mmol/L; P ⫽ 0.18) in patient 1 and 3.20 ⫾ 0.07 mg/dL (1.03 ⫾ 0.02 mmol/L) to 3.55 ⫾ 0.06 mg/dL (1.15 ⫾ 0.02 mmol/L; P ⫽ 0.01) in patient 2. Twenty-four–hour urine collections were completed at the end of 11 and 10 months of active cinacalcet HCl treatment for patients 1 and 2, respectively. Urinary calcium levels (159 mg/d [39.67 mmol/d] and 54 mg/d [13.47 mmol/d]) and fractional calcium excretion (0.026 and 0.008) remained low in both patients compared with pretreatment levels. Urinary phosphate levels on therapy were 1,053 mg/d (340.01 mmol/d) and 604 mg/d (195.03 mmol/d) for patients 1 and 2, respectively. The mild nausea experienced by patient 1 when cinacalcet HCl was ingested with breakfast resolved when she ingested the medication with her larger dinner meal. The drug otherwise was well tolerated by both patients, who continue to use the medication for control of lithium-induced hyperparathyroid disease.

Fig 1. Calcium and iPTH levels with and without cinacalcet therapy. Each point represents an independent determination of simultaneous total calcium (mg/dL) and iPTH hormone (ng/mL). Hollow circles, baseline values; filled circles, on cinacalcet therapy; box, normal range for calcium and iPTH levels. To convert serum calcium in mg/dL to mmol/L, multiply by 0.2495; PTH in pg/mL to ng/L, multiply by 1.

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DISCUSSION

Abnormal calcium metabolism associated with long-term use of lithium carbonate has been recognized since the early 1970s.14 Although well described in the literature, lithium-induced hypercalcemia may be unrecognized in both actively and previously treated patients. Presne et al2 reported a 35% incidence of hypercalcemia related to hyperparathyroidism in their series of 74 lithium-treated patients, whereas lower incidence rates of 2.7% to 10% were observed in other series.6,15 Although abnormal PTH release was shown to occur in vitro after even short-term exposure,16 the clinical incidence appears to increase significantly with exposure times exceeding 15 years.5,6 Morphological evaluation of parathyroid tissue shows predominantly adenoma formation, although hyperplasia occurs in substantial numbers of patients.5,6 This phenotypic alteration of parathyroid tissue in lithium-treated patients undoubtedly accounts for the persistence of increased PTH and serum calcium levels, even after discontinuation of lithium therapy in patients treated long term. Because cessation of therapy usually does not correct the hyperparathyroidism and associated hypercalcemia,4,6,8,16 parathyroidectomy frequently is necessary.5,8,17 Untreated, persistent mild to moderate hypercalcemia may not only mimic or exacerbate bipolar disease and nephrogenic diabetes insipidus,4,6,7 but may cause or contribute to hypertension and its sequelae, bradycardia and other cardiac conduction defects, and osteoporosis.8,9,18 Longterm lithium therapy was shown to cause tubulointerstitial changes that can result in progressive loss of renal excretory function and the need for renal replacement therapy in some patients. The individual or additive tubulotoxic contributions of lithium itself compared with attendant lithiuminduced abnormal calcium metabolism to the development of renal functional loss are unclear, but concerning and provocative. Irrespective of the relative culpability of lithium or hypercalcemia to the development of loss of excretory function, hypercalcemia likely is exacerbated by decreased urinary calcium excretion when kidney function is compromised. Whereas lithium clearly stimulates the parathyroid gland and PTH release, the metabolic

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changes are distinct from primary hyperparathyroidism in that hypercalciuria does not occur. Conversely, the characteristic hypocalciuria and normal urinary cyclic adenosine monophosphate excretion associated with lithium-induced hyperparathyroid disease makes the metabolic derangements analogous to those seen with familial hypocalciuric hypercalcemia.19,20 In patients with familial hypocalciuric hypercalcemia, there is a mutation in the calcium-sensing receptor,20 expressed in multiple tissues, including parathyroid glands, osteoclasts, and kidneys. The function of the calcium-sensing receptor appears to be regulation of calcium balance mediated by changes in parathyroid and renal tissue. Phenotypic expression of mutant calcium-sensing receptors in parathyroid glands results in decreased calciumreceptor binding and resulting inappropriate PTH secretion despite developing hypercalcemia. In the kidney, downregulated binding of calcium to these aberrant receptors on basolateral membranes of cells of the thick ascending limb of the loop of Henle ultimately fails to decrease lumen positivity, resulting in continued calcium absorption and hypocalciuria. The mechanism by which lithium induces hyperplastic or adenomatous parathyroid lesions has not been elucidated, but one would anticipate a process similar to that occurring in patients with familial hypocalciuric hypercalcemia. Lithium presumably interferes with calciummediated transmembrane signal transduction by the calcium-sensing receptor, increasing the set point for inhibition of PTH release in parathyroid cells.4 One would suspect that lithium occupies, but does not stimulate, the calcium-sensing receptor, competitively inhibiting calcium from doing so. This would result in continued PTH secretion, promoting bone resorption and release of calcium into the bloodstream. Alternatively, lithium may directly stimulate PTH production by as yet unidentified mechanisms, including interference with other parathyroid cell-surface receptors participating in the regulation of intracellular calcium levels.21 Long-term lithium exposure and resulting unabated parathyroid stimulation may trigger expression of parathyroid cell mutations and adenoma formation, perhaps because of loss of tumor suppression genes.22,23 Similar competitive inhibition of this receptor by lithium in the ascending limb of the loop of

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Henle interferes with the inhibitory effects on potassium channels that usually prevent further calcium reabsorption there. Cinacalcet HCl corrected or ameliorated PTH and serum calcium levels in both patients described here. Hypocalciuria was not changed appreciably with cinacalcet HCl therapy, yet this abnormality also may persist in this population after parathyroidectomy. However, the latter never was investigated in surgically parathyroidectomized patients with this disorder. The persistence of hypocalciuria probably is caused by either differential binding affinity or receptor saturation versus irreversible effects of lithium on the calcium-sensing receptors or intracellular calcium signaling in the thick ascending limb of the loop of Henle. Low doses of drug were administered to both patients. Higher doses of cinacalcet HCl may have enhanced urinary calcium excretion. The exact interaction between lithium, cinacalcet HCl, and the calcium-sensing receptor is unknown. Calcium is the most common signal transduction element in cells. The calcium-sensing receptor is a G-protein–coupled receptor. When activated by its natural ligand (ie, calcium), increases in phospholipase C and intracellular inositol 1,4,5-triphosphate ensue. The receptor for the latter compound provides the principal signal to intracellular calcium-release channels,24 which increase intracellular calcium levels, decreasing PTH release. Cinacalcet HCl binds and allosterically modulates the calcium-sensing receptor, increasing receptor sensitivity to calcium and amplifying inhibitory signals for PTH release. This allosteric alteration in the receptor must at least partially either offset receptor affinity for lithium or amplify calcium-mediated effects enough to override any lithium-induced effects. This would be supported by the observed salutary effects of cinacalcet HCl seen in the first patient, who continued lithium therapy. We would have anticipated an additional decrease in PTH levels if greater doses of cinacalcet HCl had been administered. Alternatively, other research suggests the possibility that the role of lithium in attenuating intracellular calcium levels may not necessarily be caused exclusively by effects on the calcium-sensing receptor. Lithium may interfere with other divalent cation cell-surface receptors that influence intracellular calcium levels.21 Additionally, recent data suggested that lithium

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also may affect factors influencing more downstream intracellular calcium handling.24 Irrespective of the exact site(s) of the dysmetabolism induced by lithium, cinacalcet HCl offsets the intracellular calcium imbalance through enhanced activity of calcium-sensing receptors. There currently are no identified drug-drug interactions between lithium and cinacalcet HCl. Conversely, because cinacalcet HCl is metabolized by the liver and inhibits cytochrome P450 enzyme 2D6 activity, drug levels of amitriptyline and imipramine can increase.25 This would be particularly worrisome at greater doses of either tricyclic antidepressants or cinacalcet HCl. Our patients manifested no symptoms or signs of tricyclic antidepressant toxicity. In summary, lithium-induced hypercalcemia is a disorder of the calcium-sensing receptor that can occur in actively and previously treated patients. Persistence of the disorder irrespective of continued lithium use has required parathyroidectomy in the past to control hypercalcemia. The present findings suggest that cinacalcet HCl can provide an alternative nonsurgical means to control the disorder. This may provide better longterm outcomes in patients with hypercalcemia of variable severity for whom surgical treatment is not a consideration because of perceived mildness of disease or unsuitability of the patient for surgical intervention.17 ACKNOWLEDGMENT The authors thank Christine Carrier-Gray, MS, Melissa J. Schiff, MD, and Mary Ann Liebman, MSN, for their invaluable assistance.

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the effect of lithium withdrawal. J Intern Med 240:357-365, 1996 7. Pieri-Balandraud N, Hugueny P, Henry JF, Tournebise H, Dupont C: Hyperparathyroidism induced by lithium: A new case. Rev Med Interne 22:460-464, 2001 8. Wolf ME, Moffat M, Mosnaim J, Dempsey S: Lithium therapy, hypercalcemia and hyperparathyroidism. Am J Ther 4:323-325, 1997 9. Wolf ME, Ranade V, Molnar J, Somberg J, Mosnaim AD: Hypercalcemia, arrhythmia, and mood stabilizers. J Clin Psychopharmacol 20:260-264, 2000 10. Nemeth EF, Steffey ME, Hammerland LG, et al: Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 95:4040-4045, 1998 11. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90:135-141, 2005 12. Quarles LD, Sherrard DJ, Adler S, et al: The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14:575-583, 2003 13. Levey A, Bosch J, Lewis J, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461-470, 1999 14. Garfinkel PE, Ezrin C, Stancer HC: Hypothyroidism and hyperparathyroidism associated with lithium. Lancet 2:331-332, 1973 15. Mallette LE, Eichhorn E: Effects of lithium carbonate on human calcium metabolism. Arch Intern Med 146:770776, 1986 16. Birnbaum J, Klandorf H, Giulano A, Van Herle A: Lithium stimulates the release of human parathyroid hor-

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mone in vitro. J Clin Endocrinol Metab 66:1187-1191, 1988 17. Lions C, Precloux P, Burckard E, Soubirou JL, Escarment J: Important hypercalcaemia due to hyperparathyroidism induced by lithium. Ann Fr Anesth Reanim 24:270-273, 2005 18. Brochier T, Adnet-Kessous J, Barillot M, Pascalis JG: Hyperparathyroidism with lithium. Encephale 20:339-349, 1994 19. Brown EM: Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium. Endocrinol Metab Clin North Am 29:503-522, 2000 20. Poliak MR, Brown EM, Chou YH, et al: Mutations in the human calcium-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297-1303, 1993 21. Hershfinkel M, Moran A, Grossman N, Sekler I: A zinc-sensing receptor triggers the release of intracellular calcium and regulated ion transport. Proc Natl Acad Sci 98:11749-11754, 2001 22. Haven CJ, Howell VM, Eilers PH, et al: Gene expression of parathyroid tumors: Molecular subclassification and identification of the potential malignant phenotype. Cancer Res 64:7405-7411, 2004 23. Ho C, Conner DA, Pollak MR, et al: A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11:389394, 1995 24. Schlecker C, Boehmerle W, Jeromin A, et al: Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium. J Clin Invest 116:1668-1674, 2006 25. Poon G: Cinacalcet hydrochloride (Sensipar). Proc Baylor Univ Med Center 18:181-184, 2005