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)

Investigations
•  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)

Discussion

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.

Thus:

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)