Correspondence

Hypocalciuric Hypercalcemia and Autoantibodies against the Calcium-Sensing Receptor

N Engl J Med 2004; 351:2237-2238November 18, 2004

Article

To the Editor:

Inappropriate elevation of serum parathyroid hormone is present in both acquired and familial hypocalciuric hypercalcemia, and as Pallais et al. (July 22 issue)1 note, a low ratio of urinary calcium to creatinine clearance separates these disorders from primary hyperparathyroidism. This point is extremely important, because glucocorticoids may control the acquired form,1 and parathyroidectomy is rarely necessary for familial hypocalciuric hypercalcemia.2

We recently diagnosed familial hypocalciuric hypocalcemia in a 26-year-old woman thought to have primary hyperparathyroidism. Hypercalcemia (calcium, 12.0 mg per deciliter) associated with an inappropriate elevation of serum intact parathyroid hormone (5.8 pmol per liter; normal range, 1.3 to 7.6) had led first to bilateral neck exploration and later to mediastinal dissection with thymectomy. She was scheduled for a third operation when she became pregnant and was referred to us. Her 24-hour urinary calcium excretion was low at the time of the original diagnosis (33 mg; normal range, 100 to 300), with a ratio of calcium to creatinine clearance of less than 0.01. Recognition of hypocalciuria as a potential contraindication to parathyroid surgery should prevent unnecessary operations in patients with acquired and familial3 hypocalciuric hypercalcemia.

Michael R. Rickels, M.D.
Susan J. Mandel, M.D., M.P.H.
Hospital of the University of Pennsylvania, Philadelphia, PA 19104
mrrickels@aol.com

3 References

1. 1

   Pallais JC, Kifor O, Chen YB, Slovik D, Brown EM. Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor. N Engl J Med 2004;351:362-369
   Full Text | Web of Science | Medline

2. 2

   Fuleihan Gel-H. Familial benign hypocalciuric hypercalcemia. J Bone Miner Res 2002;17:Suppl:N51-N56
   Web of Science | Medline

3. 3

   Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980;92:351-356
   Web of Science | Medline

To the Editor:

Pallais et al. suggest that autoantibodies against the calcium-sensing receptor are responsible for the clinical syndrome described and that glucocorticoid therapy relieves the condition by decreasing the level of circulating antibody. It is interesting, however, that the use of mycophenolate mofetil did not have an effect on the clinical course in the patient, despite its known ability to decrease antibody production.1-3 In addition, because glucocorticoids can decrease “exogenous,” active vitamin D production in hypercalcemic syndromes that are associated with granulomatous disorders (resulting in the subsequent correction of the hypercalcemia), one might postulate that the authors may be describing a patient in whom treatment with prednisone decreased excess production of 1,25-dihydroxyvitamin D independently of an effect on parathyroid hormone levels. Although this would not explain the patient's underlying hypocalciuria, an analysis of her calcitriol status, I think, would have been useful.

Nader Shakibai, M.D., Ph.D.
Hackensack University Medical Center, Hackensack, NJ 07601
nas9005@aol.com

3 References

1. 1

   Kimball J, Pescovitz MD, Book BK, Norman DJ. Reduced human IgG anti-ATGAM antibody formation in renal transplant recipients receiving mycophenolate mofetil. Transplantation 1995;60:1379-1383
   CrossRef | Web of Science | Medline

2. 2

   Broeders N, Wissing KM, Crusiaux A, Kinnaert P, Vereerstraeten P, Abramowicz D. Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients. J Am Soc Nephrol 1998;9:1521-1525
   Web of Science | Medline

3. 3

   Hu W, Liu Z, Chen H, et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl) 2002;115:705-709
   Web of Science | Medline

Author/Editor Response

Drs. Rickels and Mandel appropriately remind us to be cautious about diagnosing primary hyperparathyroidism and performing parathyroid explorations in patients with parathyroid hormone–dependent hypercalcemia and ratios of calcium to creatinine clearance of less than 0.01. These clinical features suggest an acquired or familial defect in the calcium-sensing receptor for which parathyroidectomy is of limited benefit. However, some patients with primary hyperparathyroidism can have ratios of calcium to creatinine clearance that are less than 0.01.1 In addition, a vitamin D deficiency, thiazide therapy, and a very low calcium intake can all reduce the ratio of calcium to creatinine clearance in patients with primary hyperparathyroidism. All these factors should be considered in the evaluation of patients with parathyroid hormone–dependent hypercalcemia.

As Dr. Shakibai points out, it is generally accepted that glucocorticoids can be used to treat hypercalemia due to excess production of 1,25-dihydroxyvitamin D in granulomatous disorders. However, the parathyroid hormone levels in such conditions are typically suppressed, and treatment of the hypercalcemia with corticosteroids causes them to rise.2-4 The reverse pattern was seen in our patient, who had frankly elevated parathyroid hormone values that subsequently normalized with the administration of corticosteroids; the most recent calcium and parathyroid hormone values were 8.7 mg per deciliter and 42 pg per milliliter, respectively — down from a peak of 13.4 mg per deciliter and 128 pg per milliliter, respectively. Furthermore, the patient's calcium and parathyroid hormone response to corticosteroids was correlated with decreasing titers of calcium-sensing–receptor autoantibodies but not with calcitriol levels, which were measured several times before and after the initiation of prednisone therapy (range of calcitriol values, 23 to 67 pg per milliliter; normal range, 15 to 75).

The difference in the clinical responses to corticosteroids and mycophenolate mofetil in our patient with autoimmune hyperparathyroidism most likely reflects differences in the immune-modulating activity of these agents. These differences would be useful to study in a prospective fashion, and such a study might provide valuable insights into the underlying immune dysfunction. Important lessons can be gleaned from the use of these agents in the treatment of myasthenia gravis, another autoantibody-mediated disorder, in which corticosteroids still constitute the mainstay of immune-directed therapy.5

J. Carl Pallais, M.D., M.P.H.
Massachusetts General Hospital, Boston, MA 02114
jpallais@partners.org

Edward M. Brown, M.D.
Brigham and Women's Hospital, Boston, MA 02115

5 References

1. 1

   Heath H III. Familial benign (hypocalciuric) hypercalcemia: a troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723-740
   Web of Science | Medline

2. 2

   Adams JS. Vitamin D metabolite-mediated hypercalcemia. Endocrinol Metab Clin North Am 1989;18:765-778
   Web of Science | Medline

3. 3

   Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993;82:1383-1394
   Web of Science | Medline

4. 4

   Bell NH. Renal and nonrenal 25-hydroxyvitamin D-1α-hydroxylases and their clinical significance. J Bone Miner Res 1998;13:350-353
   CrossRef | Web of Science | Medline

5. 5

   Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology 2003;61:1652-1661
   Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Patricia A. Schenck, Dennis J. Chew, Larry A. Nagode, Thomas J. Rosol. 2012. Disorders of Calcium. , 120-194.
   CrossRef

2. 2

   Maurizio Bevilacqua, Ligia J Dominguez, Velella Righini, Valeria Valdes, Tarcisio Vago, Ennio Leopaldi, Gabriella Baldi, Massimo Barrella, Mario Barbagallo. (2006) Dissimilar PTH, Gastrin, and Calcitonin Responses to Oral Calcium and Peptones in Hypocalciuric Hypercalcemia, Primary Hyperparathyroidism, and Normal Subjects: A Useful Tool for Differential Diagnosis. Journal of Bone and Mineral Research 21:3, 406-412
   CrossRef

3. 3

   Patricia A. Schenck, Dennis J. Chew, Larry Allen Nagode, Thomas J. Rosol. 2006. Disorders of Calcium: Hypercalcemia and Hypocalcemia. , 122-194.
   CrossRef