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Review Article

Laboratory approaches for the diagnosis and assessment of hypercalcemia

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Pages 107-119 | Received 19 Aug 2014, Accepted 24 Sep 2014, Published online: 20 Oct 2014

References

  • Palmer M, Jakobsson S, Akerstrom G, Ljunghall S. Prevalence of hypercalcaemia in a health survey: a 14-year follow-up study of serum calcium values. Eur J Clin Invest 1988;18:39–46
  • Frolich A. Prevalence of hypercalcaemia in normal and in hospital populations. Dan Med Bull 1998;45:436–9
  • Lumachi F, Motta R, Cecchin D, et al. Calcium metabolism & hypercalcemia in adults. Curr Med Chem 2011;18:3529–36
  • Risteli J, Winter WE, Kleerekoper M, Risteli L. Bone and mineral metabolism. In: Burtis C, Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. 5th ed. St. Louis: Elsevier, 2012:2896–3017
  • Aurbach G, Marx SJ, Speigel AM. Parathyroid hormone, calcitonin and the calciferols. In: Wilson J, Foster DW, eds. Williams Textbook of Endocrinology. 8th ed. Philadelphia: W.B. Saunders, 1992:1397–476
  • Endres DB. Investigation of hypercalcemia. Clin Biochem 2012;45:954–63
  • Fogh-Andersen N, Bjerrum PJ, Siggaard-Andersen O. Ionic binding, net charge, and Donnan effect of human serum albumin as a function of pH. Clin Chem 1993;39:48–52
  • Kragh-Hansen U, Vorum H. Quantitative analyses of the interaction between calcium ions and human serum albumin. Clin Chem 1993;39:202–8
  • Taniegra ED. Hyperparathyroidism. Am Fam Physician 2004;69:333–9
  • Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr 2008;88:491S–9S
  • Cranney A, Weiler HA, O’Donnell S, Puil L. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. Am J Clin Nutr 2008;88:513S–9S
  • Meng QH, Wagar EA. Severe hypophosphatemia in a 79-year-old man. Clin Chem 2014;60:928–31
  • DiGirolamo DJ, Clemens TL, Kousteni S. The skeleton as an endocrine organ. Nat Rev Rheumatol 2012;8:674–83
  • Ramasamy I. Recent advances in physiological calcium homeostasis. Clin Chem Lab Med 2006;44:237–73
  • Smellie WS, Vanderpump MP, Fraser WD, et al. Best practice in primary care pathology: review 11. J Clin Pathol 2008;61:410–8
  • Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998;352:306–11
  • Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician 2003;67:1959–66
  • Chan FK, Koberle LM, Thys-Jacobs S, Bilezikian JP. Differential diagnosis, causes, and management of hypercalcemia. Curr Probl Surg 1997;34:445–523
  • Renoe BW, McDonald JM, Ladenson JH. Influence of posture on free calcium and related variables. Clin Chem 1979;25:1766–9
  • Renoe BW, McDonald JM, Ladenson JH. The effects of stasis with and without exercise on free calcium, various cations, and related parameters. Clin Chim Acta 1980;103:91–100
  • Robertson WG, Marshall RW. Calcium measurements in serum and plasma – total and ionized. CRC Crit Rev Clin Lab Sci 1979;11:271–304
  • Husdan H, Rapoport A, Locke S, Oreopoulos D. Effect of venous occlusion of the arm on the concentration of calcium in serum, and methods for its compensation. Clin Chem 1974;20:529–32
  • Don BR, Sebastian A, Cheitlin M, et al. Pseudohyperkalemia caused by fist clenching during phlebotomy. N Engl J Med 1990;322:1290–2
  • Buckley BM, Russell LJ. The measurement of ionised calcium in blood plasma. Ann Clin Biochem 1988;25:447–65
  • Heath H III. Postural and venous stasis-induced changes in total calcium. Mayo Clin Proc 2005;80:1101
  • van der Wiel HE, Lips P, Nauta J, et al. Biochemical parameters of bone turnover during ten days of bed rest and subsequent mobilization. Bone Miner 1991;13:123–9
  • Smith FE, Reinstein H, Braverman LE. Cork stoppers and hypercalcemia. N Engl J Med 1965;272:787–8
  • Chan KM, Arriaga C, Landt M, et al. Interference by hemolysis with various methods for total calcium and its correction by trichloroacetic acid precipitation. Clin Chem 1983;29:1497–500
  • Corns CM. Interference by haemoglobin with the cresolphthalein complexone method for serum calcium measurement. Ann Clin Biochem 1990;27:152–5
  • Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res 1991;6:S51–9
  • Lee CT, Yang CC, Lam KK, et al. Hypercalcemia in the emergency department. Am J Med Sci 2006;331:119–23
  • Kallas M, Green F, Hewison M, et al. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab 2010;95:3111–17
  • Iqbal AA, Burgess EH, Gallina DL, et al. Hypercalcemia in hyperthyroidism: patterns of serum calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels during management of thyrotoxicosis. Endocr Pract 2003;9:517–21
  • Jacobs TP, Bilezikian JP. Clinical review: rare causes of hypercalcemia. J Clin Endocrinol Metab 2005;90:6316–22
  • Pellitteri PK. Evaluation of hypercalcemia in relation to hyperparathyroidism. Otolaryngol Clin North Am 2010;43:389–97
  • Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005;132:359–72
  • Felger EA, Kandil E. Primary hyperparathyroidism. Otolaryngol Clin North Am 2010;43:417–32
  • Silverberg SJ, Lewiecki EM, Mosekilde L, et al. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:351–65
  • Eastell R, Arnold A, Brandi ML, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:340–50
  • Lundgren E, Hagstrom EG, Lundin J, et al. Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago. World J Surg 2002;26:931–6
  • Lumachi F, Brunello A, Roma A, Basso U. Cancer-induced hypercalcemia. Anticancer Res 2009;29:1551–5
  • Hu MI, Glezerman I, Leboulleux S, et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst 2013;105:1417–20
  • Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005;352:373–9
  • Moseley JM, Gillespie MT. Parathyroid hormone-related protein. Crit Rev Clin Lab Sci 1995;32:299–343
  • Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med 2000;342:177–85
  • Hutchesson AC, Bundred NJ, Ratcliffe WA. Survival in hypercalcaemic patients with cancer and co-existing primary hyperparathyroidism. Postgrad Med J 1995;71:28–31
  • Cozzolino M, Gallieni M, Brancaccio D, et al. Vitamin D retains an important role in the pathogenesis and management of secondary hyperparathyroidism in chronic renal failure. J Nephrol 2006;19:566–77
  • Meric F, Yap P, Bia MJ. Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Am J Kidney Dis 1990;16:459–64
  • Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–71
  • Suliburk JW, Perrier ND. Primary hyperparathyroidism. Oncologist 2007;12:644–53
  • Bridgewater JA, Ratcliffe WA, Bundred NJ, Owens CW. Malignant phaeochromocytoma and hypercalcaemia. Postgrad Med J 1993;69:77–9
  • Wong RK, Gregory R, Lo TC. A case of isolated ACTH deficiency presenting with hypercalcaemia. Int J Clin Pract 2000;54:623–4
  • Montoli A, Colussi G, Minetti L. Hypercalcaemia in Addison’s disease: calciotropic hormone profile and bone histology. J Intern Med 1992;232:535–40
  • Fujikawa M, Kamihira K, Sato K, et al. Elevated bone resorption markers in a patient with hypercalcemia associated with post-partum thyrotoxicosis and hypoadrenocorticism due to pituitary failure. J Endocrinol Invest 2004;27:782–7
  • Giusti F, Marini F, Brandi ML. Multiple endocrine neoplasia type 1. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, 2005:1993–2014
  • Yamaguchi K, Abe K, Adachi I, et al. Clinical and hormonal aspects of the watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome due to vasoactive intestinal polypeptide (VIP)-producing tumor. Endocrinol Jpn 1980;27:79–86
  • Varghese J, Rich T, Jimenez C. Benign familial hypocalciuric hypercalcemia. Endocr Pract 2011;17:13–7
  • Nesbit MA, Hannan FM, Howles SA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet 2013;45:93–7
  • Shinall MC Jr, Dahir KM, Broome JT. Differentiating familial hypocalciuric hypercalcemia from primary hyperparathyroidism. Endocr Pract 2013;19:697–702
  • Schwartz SR, Futran ND. Hypercalcemic hypocalciuria: a critical differential diagnosis for hyperparathyroidism. Otolaryngol Clin North Am 2004;37:887–96
  • Laubach J, Richardson P, Anderson K. Multiple myeloma. Annu Rev Med 2011;62:249–64
  • Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med 2000;6:442–7
  • Fuss M, Pepersack T, Gillet C, et al. Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol 1992;11:28–36
  • Wermers RA, Kearns AE, Jenkins GD, Melton LJ III. Incidence and clinical spectrum of thiazide-associated hypercalcemia. Am J Med 2007;120:911 e9–15
  • Patel AM, Adeseun GA, Goldfarb S. Calcium-alkali syndrome in the modern era. Nutrients 2013;5:4880–93
  • Abreo K, Adlakha A, Kilpatrick S, et al. The milk-alkali syndrome. A reversible form of acute renal failure. Arch Intern Med 1993;153:1005–10
  • Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf) 2005;63:566–76
  • Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab 2014;99:1132–41
  • Araki T, Holick MF, Alfonso BD, et al. Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States. J Clin Endocrinol Metab 2011;96:3603–8
  • Hassler A, Lamy O, Rossier A, et al. Severe hypercalcemia after a single high dose of vitamin D in a patient with sarcoidosis. Rheumatol Int 2013;33:2955–6
  • Jacobs TP, Kaufman M, Jones G, et al. A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab 2014;99:708–12
  • Kimmoun A, Leheup B, Feillet F, et al. Hypercalcemia revealing iatrogenic hypervitaminosis A in a child with autistic troubles. Arch Pediatr 2008;15:29–32
  • Akiyama H, Nakamura N, Nagasaka S, et al. Hypercalcaemia due to all-trans retinoic acid. Lancet 1992;339:308–9
  • Niesvizky R, Siegel DS, Busquets X, et al. Hypercalcaemia and increased serum interleukin-6 levels induced by all-trans retinoic acid in patients with multiple myeloma. Br J Haematol 1995;89:217–18
  • McPherson ML, Prince SR, Atamer ER, et al. Theophylline-induced hypercalcemia. Ann Intern Med 1986;105:52–4
  • Khairallah W, Fawaz A, Brown EM, El-Hajj Fuleihan G. Hypercalcemia and diabetes insipidus in a patient previously treated with lithium. Nat Clin Pract Nephrol 2007;3:397–404
  • Saunders BD, Saunders EF, Gauger PG. Lithium therapy and hyperparathyroidism: an evidence-based assessment. World J Surg 2009;33:2314–23
  • Jones BJ, Twomey PJ. Requesting patterns for serum calcium concentration in patients on long-term lithium therapy. Int J Clin Pract 2009;63:170–2
  • Letavernier E, Rodenas A, Guerrot D, Haymann JP. Williams-Beuren syndrome hypercalcemia: is TRPC3 a novel mediator in calcium homeostasis? Pediatrics 2012;129:e1626–30
  • Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen’s metaphyseal chondrodysplasia. N Engl J Med 1996;335:708–14
  • Saarela T, Simila S, Koivisto M. Hypercalcemia and nephrocalcinosis in patients with congenital lactase deficiency. J Pediatr 1995;127:920–3
  • Camara-Lemarroy CR, Gonzalez-Moreno EI, Ortiz-Corona Jde J, et al. Posterior reversible encephalopathy syndrome due to malignant hypercalcemia: physiopathological considerations. J Clin Endocrinol Metab 2014;99:1112–16
  • Akmal M, Bishop JE, Telfer N, et al. Hypocalcemia and hypercalcemia in patients with rhabdomyolysis with and without acute renal failure. J Clin Endocrinol Metab 1986;63:137–42
  • Edelson GW, Kleerekoper M. Hypercalcemic crisis. Med Clin North Am 1995;79:79–92
  • Cannon J, Lew JI, Solorzano CC. Parathyroidectomy for hypercalcemic crisis: 40 years’ experience and long-term outcomes. Surgery 2010;148:807–12; discussion 12–3
  • Wong ET, Freier EF. The differential diagnosis of hypercalcemia. An algorithm for more effective use of laboratory tests. JAMA 1982;247:75–80
  • Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003;33:598–603
  • Bilezikian JP, Potts JT Jr, Fuleihan Gel H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Miner Res 2002;17:N2–11
  • Khan AA, Bilezikian JP, Potts JT Jr. The diagnosis and management of asymptomatic primary hyperparathyroidism revisited. J Clin Endocrinol Metab 2009;94:333–4
  • Pallan S, Rahman MO, Khan AA. Diagnosis and management of primary hyperparathyroidism. BMJ 2012;344:e1013
  • Reagan P, Pani A, Rosner MH. Approach to diagnosis and treatment of hypercalcemia in a patient with malignancy. Am J Kidney Dis 2014;63:141–7
  • Bowers GN Jr, Brassard C, Sena SF. Measurement of ionized calcium in serum with ion-selective electrodes: a mature technology that can meet the daily service needs. Clin Chem 1986;32:1437–47
  • Meng QH, Krahn J. Lithium heparinised blood-collection tubes give falsely low albumin results with an automated bromcresol green method in haemodialysis patients. Clin Chem Lab Med 2008;46:396–400
  • Endres DB, Villanueva R, Sharp CF Jr, Singer FR. Immunochemiluminometric and immunoradiometric determinations of intact and total immunoreactive parathyrin: performance in the differential diagnosis of hypercalcemia and hypoparathyroidism. Clin Chem 1991;37:162–8
  • Couchman L, Taylor DR, Krastins B, et al. LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations. Clin Chem Lab Med 2014;52:1251–63
  • Brossard JH, Lepage R, Cardinal H, et al. Influence of glomerular filtration rate on non-(1-84) parathyroid hormone (PTH) detected by intact PTH assays. Clin Chem 2000;46:697–703
  • Carter AB, Howanitz PJ. Intraoperative testing for parathyroid hormone: a comprehensive review of the use of the assay and the relevant literature. Arch Pathol Lab Med 2003;127:1424–42
  • Sturgeon CM, Sprague SM, Metcalfe W. Variation in parathyroid hormone immunoassay results--a critical governance issue in the management of chronic kidney disease. Nephrol Dial Transplant 2011;26:3440–5
  • Lepage R, Roy L, Brossard JH, et al. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998;44:805–9
  • Teal TK, Wood JL, Stevens PE, Lamb EJ. Stability of Bio-Intact (1-84) parathyroid hormone ex vivo in serum and EDTA plasma from hemodialysis patients. Clin Chem 2004;50:1713–14
  • Glendenning P, Laffer LL, Weber HK, et al. Parathyroid hormone is more stable in EDTA plasma than in serum. Clin Chem 2002;48:766–7
  • Hanon EA, Sturgeon CM, Lamb EJ. Sampling and storage conditions influencing the measurement of parathyroid hormone in blood samples: a systematic review. Clin Chem Lab Med 2013;51:1925–41
  • Stokes FJ, Ivanov P, Bailey LM, Fraser WD. The effects of sampling procedures and storage conditions on short-term stability of blood-based biochemical markers of bone metabolism. Clin Chem 2011;57:138–40
  • Wallace AM, Gibson S, de la Hunty A, et al. Measurement of 25-hydroxyvitamin D in the clinical laboratory: current procedures, performance characteristics and limitations. Steroids 2010;75:477–88
  • Shu I, Pina-Oviedo S, Quiroga-Garza G, et al. Influence of vitamin D2 percentage on accuracy of 4 commercial total 25-hydroxyvitamin D assays. Clin Chem 2013;59:1273–5
  • Binkley N, Krueger D, Cowgill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152–7
  • Singh RJ. Are clinical laboratories prepared for accurate testing of 25-hydroxy vitamin D? Clin Chem 2008;54:221–3
  • Strathmann FG, Sadilkova K, Laha TJ, et al. 3-epi-25 hydroxyvitamin D concentrations are not correlated with age in a cohort of infants and adults. Clin Chim Acta 2012;413:203–6
  • Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. J Clin Endocrinol Metab 2006;91:3055–61
  • Schilling T, Pecherstorfer M, Blind E, et al. Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy. J Clin Endocrinol Metab 1993;76:801–3
  • Ramachandran R, Benfield P, Dhillo WS, et al. Need for revision of diagnostic limits for medullary thyroid carcinoma with a new immunochemiluminometric calcitonin assay. Clin Chem 2009;55:2225–6
  • Ubl P, Gincu T, Keilani M, et al. Comparison of side effects of pentagastrin test and calcium stimulation test in patients with increased basal calcitonin concentration: the gender-specific differences. Endocrine 2014;46:549–53
  • Machens A, Hauptmann S, Dralle H. Medullary thyroid cancer responsiveness to pentagastrin stimulation: an early surrogate parameter of tumor dissemination? J Clin Endocrinol Metab 2008;93:2234–8
  • Wu TJ, Taylor RL, Kao PC. Parathyroid-hormone-related peptide immunochemiluminometric assay. Developed with polyclonal antisera produced from a single animal. Ann Clin Lab Sci 1997;27:384–90
  • Burtis WJ. Parathyroid hormone-related protein: structure, function, and measurement. Clin Chem 1992;38:2171–83
  • Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet 1992;339:164–7
  • Kremer R, Shustik C, Tabak T, et al. Parathyroid-hormone-related peptide in hematologic malignancies. Am J Med 1996;100:406–11
  • Brown EM. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991;71:371–411
  • Pocotte SL, Ehrenstein G, Fitzpatrick LA. Regulation of parathyroid hormone secretion. Endocr Rev 1991;12:291–301
  • Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55:1517–22
  • Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008;69:713–20
  • Christensen SE, Nissen PH, Vestergaard P, et al. Plasma 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone in familial hypocalciuric hypercalcemia and primary hyperparathyroidism. Eur J Endocrinol 2008;159:719–27
  • Jayasena CN, Mahmud M, Palazzo F, et al. Utility of the urine calcium-to-creatinine ratio to diagnose primary hyperparathyroidism in asymptomatic hypercalcaemic patients with vitamin D deficiency. Ann Clin Biochem 2011;48:126–9
  • Foley K, Boccuzzi, L. Urine calcium: laboratory measurement and clinical utility. Lab Med 2010;41:683–6

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