Cancer associated hypercalcaemia

Cancer-Associated Hypercalcaemia

• hypercalcaemia is defined as an increase in the serum calcium level above the upper limit of normal for a given reference value used in a laboratory
  • differential diagnosis of hypercalcemia includes multiple pathologic entities but is focused primarily on primary hyperparathyroidism and hypercalcemia of malignancy given the highest prevalence of these aetiologies
    
    
• malignancy as a cause of hypercalaemia
  
  
  • malignancy accounts for 20-30% of cases (1) and is frequently accompanied by hypoalbuminaemia
    
    
  • suggested by rapidly increasing hypercalcaemia (1)
    
    
  • metastases with osteolytic deposits e.g. breast
    
    
  • osteoclast activating factors e.g. multiple myeloma
    
    
  • ectopic parathyroid hormone like peptide e.g. hypernephroma, ovarian tumour, bronchial carcinoma
    
    
  • hypercalcemia in the context of cancer may have nonmalignant causes, such as primary hyperparathyroidism; this possibility should be ruled out with the use of appropriate clinical assessment and laboratory testing
    
    
  • 10-15% of hypercalcaemia caused by malignancy have associated hyperparathyroidism (2)
    • hypercalcemia has been reported in association with most cancers, but it is most common in patients with non–small-cell lung cancer, breast cancer, multiple myeloma, squamous-cell cancers of the head and neck, urothelial carcinomas, or ovarian cancers (3)
    • prevalence of cancer-associated hypercalcemia appears to be declining owing to the prophylactic use of bisphosphonates or denosumab in patients with bone metastases (3)
    • increased osteoclastic bone resorption is almost always responsible for hypercalcemia, regardless of tumor type or mediator; after hydration, the use of bone-resorption inhibitors (most commonly intravenous bisphosphonates) to lower calcium levels is the mainstay of treatment
      
      
  • cancer-associated hypercalcemia has been classified into four subtypes:
    • humoral
      • humoral hypercalcemia of malignancy is usually caused by tumor secretion of PTHrP (parathyroid hormone-related protein )
        • usually, PTHrP is a locally produced growth factor, but its dysregulated, systemic secretion by tumors increases osteoclastic bone resorption and renal tubular reabsorption of calcium by binding the PTH-PTHrP type 1 receptor in the bones and kidneys
        • approximately 80% of malignancy-related hypercalcemia, is mediated by the production of PTHrP (4)
      • typically associated with squamous tumors of the lung and the head and neck, urothelial carcinomas, and breast cancers, although almost any tumor type may produce PTHrP
      • patients with humoral hypercalcemia of malignancy typically have few or no bone metastases.
        
    • local osteolytic
      • local osteolytic hypercalcemia have extensive bone metastases, most often resulting from breast cancer or multiple myeloma
    • 1,25-dihydroxyvitamin D-mediated
      • some tumors up-regulate the expression of Cyp27B1, which encodes 1-alpha-hydoxylase, the enzyme responsible for converting 25-hydroxyvitamin D to the active hormone 1,25-dihydroxyvitamin D
        • excess 1,25- increases intestinal calcium absorption as well as bone resorption, leading to hypercalcemia
        • 1,25- decreases the renal excretion of calcium and phosphate
        • 1,25-dihydroxyvitamin D is deactivated by the 24,25-hydroxylase enzyme in the kidneys.
    • ectopic hyperparathyroidism
      • caused by rare tumors that produce PTH instead of PTHrP
      • parathyroid cancers also cause hypercalcemia by secreting PTH
        
• cancer-associated hypercalcemia often occurs late in the course of solid-tumor development and portends a poor prognosis
  • patients with hypercalcemia of malignancy tend to have limited survival of several months, and it is not clear whether this poor prognosis is related to the advanced stage of malignancy associated hypercalcemia or just simply a marker of underlying cancer (4)
    
    
• patients with cancer-associated hypercalcemia typically present with profound dehydration, the initial treatment should involve the administration of intravenous fluids
  • patients with hypercalcemia are dehydrated by default due to poor oral intake secondary to nausea, vomiting, altered mental status, and hypercalcemia-induced nephrogenic diabetes insipidus (4)
    • furthermore, volume contraction in itself compromises renal clearance of calcium due to hypovolemia-mediated increased calcium reabsorption in the kidneys
      
      
• successful treatment of cancer-associated hypercalcemia ultimately depends on treatment of the underlying cancer

Reference:

• (1) Joshi D, Center JR, Eisman JA. Investigation of incidental hypercalcaemia. BMJ. 2009;339:b4613
• (2) Barth, J.H., Butler, G.E. and Hammond, P.J. 2008. Hypercalcaemia. Biochemical Investigations in Laboratory Medicine. Leeds Teaching Hospitals.
• (3) Guise TA et al. Cancer-Associated Hypercalcemia N Engl J Med 2022; 386:1443-1451. DOI: 10.1056/NEJMcp2113128
• (4) Mirrakhimov AE. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci. 2015;7(11):483-493. doi:10.4103/1947-2714.170600