Question 6

How  would  you  determine the  aetiology of  severe hypercalcaemia? List  the  treatments appropriate for each aetiology.

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College Answer

Major causes of hypercalcaemia are: Increased calcium release from bone
•  erosion of  bone (malignant neoplasms eg. lung, breast, haematologic (include multiple myeloma), head & neerenal, prostate)
•  release of calcium from bone with immobilization
. •  humoral stimulation of calcium release (mainly PTH but also other hoonones)

Increased calcium intake
•  calcium supplements.milk alkali syndrome

Both of these are augmented by the presence of renal impairment.

Aetiology determined by combination of history.examination and investigations.

History and Examination
• clinical  features relate  to  symptoms  due  to  hypercalcaemia (protean)  and  those  due
underlying cause (specific or general of malignancy, immobilization, diet and medications)

•  to confirm malignancy or bony involvement (Xrays of chest, spine etc.)
•  to assess bone turnover (alkaline phosphatase, urinary hydroxyproline)
•  to assess level of PTII

Treatment is dependent on underlying aetiology, but general measures are aimed at minimising calcium entry into and maximising exit from the circulation :

1.  Increased calcium excretion
•  volume resuscitation  to restore intravascular volume and tissue perfusion (usually normal saline, also inhibits calcium reabsorption in renal tubule)
•  frusemide (increase calcium filtration and decreased reabsorption). Aim? 200-300 m1/hr.
2.  Reducing calcium release
•  biphosphonates (eg. etidronate) are absorbed to hydroxyapatite crystals and inhibit bone resorption and formation and inhibit osteoclast activity. Administered intravenously; onset of action 24-48 hours.
•  calcitonin is less effective. Inhibits osteoclast activity and  increases calcium excretion.
Parenteral administration but faster onset of .11ction (6-24 hours).
•  plicamycin, gallium also used. Inorganic phosphate may be effective (multiple mechanisms)
but risks calcium precipitation
•  glucocorticoids  useful  in  some  scenarios   (excess  intake  or   production  of  Vit   D;
haematologic malignancies [tumouricidal effects])
3.  Others
•  correction of other electrolyte abnormalities (eg. K, Mg)
•  removal of offending drugs (eg. thiazides, Vitamins A & D, calcium)
• restriction of calcium intake
•  mobilisation (to reduce calcium release from bone)


This question closely resembles Question 7 from the first paper of 2001 (A patient is admitted to ICU because of severe symptomatic hypercalcaemia. List the manifestations and common causes) and Question 9 from the second paper of 2013 (List the clinical features of severe symptomatic hypercalcaemia and outline the treatment of this condition).

Question 18.1 from the the first paper of 2011 also deals with hypercalcaemia of malignancy, but in the context of a clinical scenario.

Causes and consequences of hypercalcemia are treated in slightly greater detail elsewhere.


Causes of Hypercalcemia

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens 
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis
Clinical Manifestations of Hypercalcemia

Early manifestations (levels < 3.5mmol/L)

  • Constipation
  • Peptic ulcer exacerbation
  • Polyuria
  • Nephrogenic diabetes insipidus
  • Nephrolithiasis
  • Type 1 (distal) renal tubular acidosis
  • Shortened QT interval
  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis
  • Renal failure (due to vasoconstriction)
  • Hypertension
  • Delirium, progressing to coma
  • Arrhythmia
  • Muscle weakness

Investigation of hypercalcemia

Causes such as renal failure and prolonged immobility can usually be ruled out (or in) immediately after meeting the patient. Similarly, one can easily look at their drugs and see whether something iatrogenic is responsible. Then, one is left with primary endocrine disturbances and malignancy.

Thus, one may wish to launch the following investigations:

  • Alkaline phosphatase
  • Serum PTH level
  • CK
  • Parathyroid hormone related peptide (PTHrp)
  • Serum Vitamin D metabolite levels
  • CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

Management of hypercalcemia

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)


UpToDate has a nice chapter on this topic, for the paying customer.


Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.


Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.


Shane, Elizabeth, and I. Dinaz. "Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management." Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Favus MJ (ed.). Philadelphia: Lippincott, Williams &Wilkins (1999): 183-87.


Endres, David B. "Investigation of hypercalcemia." Clinical biochemistry 45.12 (2012): 954-963.