Hypercalcemia

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Hypercalcemia is an elevated circulating blood calcium level.

Calcium is a vital intracellular and extracellular ion involved in neuronal activation, muscle contraction, enzymatic reactions, hormone secretion, and bone matrix.

Normal calcium homeostatic mechanisms maintain extracellular calcium concentrations within a narrow normal range of 9 - 11.4 mg/dL.

Extracellular calcium exists in three forms: ionized (the biologically active form), complexed (to plasma buffers), and protein-bound (mainly to albumin). Most commonly, total calcium is measured on serum biochemical analyses and represents the sum of all calcium fractions. Serum-ionized calcium (iCa) concentration is a more accurate measure of hypercalcemia than total serum calcium or corrected serum calcium concentrations[1].

The most common causes of ionized hypercalcemia are neoplasia (termed hypercalcemia of malignancy), followed by renal failure, hyperparathyroidism, and hypoadrenocorticism. Dogs with lymphoma and anal sac adenocarcinoma have higher serum iCa concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia. Chronic metabolic acidosis associated with chronic renal disease changes the ionized calcium (i-Ca) fraction, usually increasing its concentration[2].

Hypercalcemia of malignancy manifests as a result of three underlying pathological processes associated with neoplasia:

  • interference with 1 alpha-hydroxylase activity, leading to unregulated conversion of calcidiol to active calcitriol and enhanced intestinal absorption of calcium[3][4]
  • hypersecretion of parathyroid releasing protein (PTHrP), a polypeptide structurally similar to intact parathyroid hormone[5][6]
  • heightened activity of interleukin-1, interleukin-6 and tumor necrosis factor[7]. The production and secretion of these humoral mediators lead to pathologic increases in osteoclastic resorption, often without visible radiographic bone lesions.

A list of causes of ionized hypercalcemia include, in order of importance:

- Lymphoma[8], polyostotic lymphoma[9]
- Thymoma[10]
- Osteosarcoma
- Anal sac adenocarcinoma
- Hepatoid gland carcinoma
- Multiple myeloma[11]
- Hypoadrenocorticism
- Hypoaldosteronism[12]
- Hypothyroidism[13]
- Hyperparathyroidism[14]
- Vitamin D toxicosis
- Waldenström's macroglobulinemia[15]
- Schistosoma japonicum[16]
- Heterobilharzia americana[17]
- Leishmania spp[18]
- Hepatozoon canis[19]
- Pythium insidiosum gastric granuloma[20]
- Blastomyces spp[21]

This can be summarized by the common mnemonic - 'HARD IONS':

A tentative diagnosis of hypercalcemia can be established from blood levels showing a persistent, fasting total calcium >12 mg/dL, but elucidation of underlying disease processes must be investigated to accurately diagnose the cause.

Vitamin D toxicosis is associated with hypercalcemia as well as hyperphosphatemia.

Because the most commonly reported cause of hypercalcemia is lymphoma, evaluation of peripheral lymph nodes with aspiration cytology (even if they are normal on palpation) is warranted in patients with unexplained hypercalcemia[25].

Thoracic radiographs may be indicated to assess the presence of a mediastinal mass (lymphoma, thymoma), metastatic neoplasia, fungal pneumonia, osteopenia, orlytic bone lesions. Abdominal radiographs may have evidence of mass effect, hepatosplenomegaly, bony changes, uroliths, or renal mineralization.

A parathyroid ultrasound is indicated to evaluate size and shape of the parathyroid glands for evidence of primary or secondary hyperparathyroidism.

Treatment is dependent upon underlying cause, but management of hypercalcemia involves aggressive intravenous fluid therapy. To reverse increased calciuresis through an improved glomerular filtration rate, fluids devoid of calcium such as physiologic saline (isotonic saline solution - 0.9% sodium chloride) is recommended.

Other drugs which may assist include loop diuretics such as furosemide, insulin and aminobisphosphonates, chiefly zoledronate and pamidronate[26].

In cases of vitamin D toxicosis, calcitonin also reduces osteoclastic activity and hypercalcemia.

References

  1. Messinger JS et al (2009) Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). J Vet Intern Med 23(3):514-519
  2. Kogika MM et al (2006) Serum ionized calcium in dogs with chronic renal failure and metabolic acidosis. Vet Clin Pathol 35(4):441-445
  3. Rosol TJ et al (1992) Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 131:1157-1164
  4. Seymour JF & Gagel RF (1993) Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 82:1383-1394
  5. Bae BK et al (2007) Hypercalcemia and high parathyroid hormone-related peptide concentration in a dog with a complex mammary carcinoma. Vet Clin Pathol 36(4):376-378
  6. Rankin W et al (1997) Parathyroid hormone-related protein and hypercalcemia. Cancer 80(8):1564-1571
  7. Morrison WB (2002) Paraneoplastic syndromes and the tumors that cause them. In: Morrison WB. Cancer in dogs and cats: medical and surgical management. 2nd ed. Jackson, Wyo: Teton NewMedia. pp:731-735
  8. Marconato L et al (2011) Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc 238(4):480-485
  9. Vascellari M et al (2007) Vertebral polyostotic lymphoma in a young dog. J Vet Diagn Invest 19(2):205-208
  10. Downs MO & Houghton JO (2009) What is your diagnosis? Thymoma. J Am Vet Med Assoc 234(3):327-328
  11. Tripp CD et al (2009) Presumptive increase in protein-bound serum calcium in a dog with multiple myeloma. Vet Clin Pathol 38(1):87-90
  12. Kreissler JJ & Langston CE (2011) A case of hyporeninemic hypoaldosteronism in the dog. J Vet Intern Med 25(4):944-948
  13. Lobetti RG et al (2011) Hypercalcaemia in a dog with primary hypothyroidism. J S Afr Vet Assoc 82(4):242-243
  14. Sawyer ES et al (2012) Outcome of 19 dogs with parathyroid carcinoma after surgical excision. Vet Comp Oncol 10(1):57-64
  15. Jaillardon L & Fournel-Fleury C (2011) Waldenström's macroglobulinemia in a dog with a bleeding diathesis. Vet Clin Pathol 40(3):351-355
  16. Hanzlicek AS et al (2011) Canine schistosomiasis in Kansas: five cases (2000-2009). J Am Anim Hosp Assoc 47(6):e95-e102
  17. Corapi WV et al (2011) Multi-organ involvement of Heterobilharzia americana infection in a dog presented for systemic mineralization. J Vet Diagn Invest 23(4):826-831
  18. Freeman KS et al (2010) Leishmaniasis in a dog native to Colorado. J Am Vet Med Assoc 237(11):1288-1291
  19. Marchetti V et al (2009) Hepatozoonosis in a dog with skeletal involvement and meningoencephalomyelitis. Vet Clin Pathol 38(1):121-125
  20. LeBlanc CJ et al (2008) Hypercalcemia associated with gastric pythiosis in a dog. Vet Clin Pathol 37(1):115-120
  21. Crews LJ et al (2007) Evaluation of total and ionized calcium status in dogs with blastomycosis: 38 cases (1997-2006). J Am Vet Med Assoc 231(10):1545-1549
  22. Gow AG et al (2009) Calcium metabolism in eight dogs with hypoadrenocorticism. J Small Anim Pract 50(8):426-430
  23. Ferguson DC & Hoenig M (2003) Endocrine system. In: Latimer KS, Mahaffey EA, Prasse KW, eds. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 4th ed. Ames, Iowa: Iowa State Univ Pr. pp:270–303
  24. Feldman EC & Nelson RW (2004) Canine and Feline Endocrinology and Reproduction, 3rd ed. Philadelphia: Saunders. pp:660–715
  25. Barber P (2001) Disorders of calcium homeostasis in small animals. In Pract 23(5):262–267
  26. de Lorimier LP & Fan TM (2005) Bone metabolic effects of single-dose zoledronate in healthy dogs. J Vet Intern Med 19(6):924-927
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