Hypercalcaemia Of Malignancy

Question 1

Definition and types of hypercalcaemia of malignancy

Answer 1

High calcium levels associated with malignancy
• Different types/causes:
• Humoral hypercalcaemia of malignancy: Tumour secretion of PTH related peptide (PTHrP)

					• Local osteolytic hypercalcaemia: Boney metastases that promotes osteoclast activity 

					• Caclitriol mediated hypercalcaemia: Autonomous production of calcitriol by lymphoma cells

Question 2

Aetiology of types of hypercalcaemia of malignancy

Answer 2

• Humoral hypercalcaemia of malignancy is most associated with:
◦ Renal cancer
◦ Ovarian cancer
◦ Breast cancer
◦ Endometrial cancer
• Local osteolytic hypercalcaemia:
◦ Breast cancer
◦ Multiple myeloma
• Calcitriol mediated hypercalcaemia:
◦ All types of lymphoma
◦ Granulomatous disease (active sarcoidosis, TB)

Question 3

Pathophysiology of types of hypercalcaemia of malignancy

Answer 3

• Humoral hypercalcaemia of malignancy: An increase in PTH related peptide secretion by the tumour would result in an activation of osteoclastic bone resorption and suppression of osteoblastic bone formation. Would result in the release of calcium. Would also lead to hypophosphataemia

• Local osteolytic hypercalcaemia: Metastases to the bone would lead to an inflammatory response that would activate osteoclastic resorption of the bone; hence releasing calcium

• Calcitriol mediated hypercalcaemia: Overexpression of 1-alpha hydroxylase leads to an increase in calcitriol levels (active Vitamin D). The vitamin D would increase intestinal absorption of calcium and activate osetoclastic resorption of bone. This would lead to hypercalcaemia

Question 4

History and Examination of hypercalcaemia of malignancy

Answer 4

• History of malignancy: hypercalcaemia occurs in 20-30% of patietns with cancer
• Hypercalcaemia signs/symptoms:
◦ Confusion
◦ Fatigue
◦ Constipation
◦ Nausea
◦ Abdominal pain
◦ Loss of appetite
◦ Polyuria
◦ Bone pain
• Use of hypercalcaemia inducing medication: thiazide diuretics, lithium
• Weight loss
• Dehydration: reduced skin turgor, dry mucous membranes

Question 5

Investigations for hypercalcaemia of malignancy

Answer 5

• Total serum calcium: Hypercalcaemia present
• Parathyroid hormone: would be elevated in primary, secondary and tertiary hyperparathyroidism, but would be SUPPRESSED in malignancy associated hypercalcaemia (except if ectopic PTH)
• PTH related peptide (PTHrP): elevated in humoral hypercalcaemia of malignancy
• Phosphorus/phosphate: would be decreased in humoral hypercalcaemia of malignancy due to PTHrP
• Serum calcitriol: would be elevated in calcitriol mediated hypercalcaemia
• Serum 25-hydroxyvitamin D: needs to be checked if IV Bisphosphonates are being considered

• LOW PTH, high calcium, ALP may be high if bone damage

Question 6

Treatment for hypercalcaemia of malignancy

Answer 6

Mild hypercalcaemia or asymptomatic:
1) Treat underlying malignancy + supportive measures + monitoring: avoid medications that can worsen hypercalcaemia (thiazide diuretics, calcitriol supplements)

Moderate/severe hypercalcaemia or symptomatic:
1) IV normal saline: reverses dehydration due to hypercalcaemia
+ IV Bisphosphonates or Denosumab (monoclonal antibody):
◦ IV Bisphosphonates are the most effective way to treat malignancy associated hypercalcaemia
◦ They would block the osteoclastic bone resorption
◦ Response takes 2-4 days
◦ E.g Zoledronic acid, Pamidronate disodium
◦ Side-effects: AKI, flu, hypocalcaemia if Bisphosphonates given to hypercalcaemic patient with severe vitamin D deficiency

+ treat underlying malignancy, avoid exacerbating medications

Question 7

Complications and prognosis of hypercalcaemia of malignancy

Answer 7

• Bisphosphonate side effects
• Coma: due to hypercalcaemia
• Acute pancreatitis: due to stone formation as a result of hypercalcaemia

IV hydration and pharmacological therapy can restore to normocalcaemia, but eradication of underlying malignancy needed for permanent reversal