Case Presentation:

In our Morning Report at WCH, we discussed a case of a patient presenting with mild, asymptomatic hypercalcemia. Clinical assessment and investigations were compatible with PTH-dependent hypercalcemia due to primary hyperparathyroidism.

Learning Points:

1. Rationale for calcium correction and shortcuts for calculating
2. Clinical manifestations of hypercalcemia
3. Differential diagnosis of hypercalcemia
4. Multiple Endocrine Neoplasia (MEN) syndrome features
5. Causes of secondary hyperparathyroidism
6. Surgical indications for primary hyperparathyroidism

Calcium Correction:

• only ionized calcium is physiologically active
• Major calcium roles: cardiac contractility, neuroconduction, muscle function, coagulation cascade (cofactor)
• Most of calcium is ionized (~45%) or albumin-bound (~40%)
• Low albumin levels increase the amount of ionized calcium
• Shortcuts:
  • For every reduction in serum albumin by 10, add 0.2 to the serum calcium level
  • Calculate the albumin difference: Normal-patient albumin; multiply by 2; move the decimal point 2 to the left, then add to serum calcium
    • example: calcium 2.87 albumin 36 (normal albumin 40)
    • 40-36=4 x 2=8 move decimal point over 2 to the left=0.08 + 2.87 =2.95

Clinical Manifestations of Hypercalcemia:

• two “symptom” categories:
  • related to the hypercalcemia itself (Moans, bones, stones, groans)
    
    • related to the cause of the hypercalcemia (next section)

Differential Diagnosis of Hypercalcemia:

Multiple Endocrine Neoplasia Features:

Causes of Secondary Hyperparathyroidism:

1. Reduced intake of calcium
2. Calcium malabsorption (vitamin D deficiency, Bariatric surgery, Celiac disease, Pancreatic insufficiency)
3. Kidney-related
   • Renal calcium losses
   • Impaired calcitriol production
   • Hyperphosphatemia (triggers PTH secretion to promote phosphaturia)

Surgical Indications for Primary Hyperparathyroidism:

• Benefits of surgery: curative, decreases nephrolithiasis, improves bone mineral density, may decrease fracture risk
• All symptomatic patients should be considered for surgical parathyroidectomy
• Asymptomatic patients who have any of the following should be considered for surgical parathyroidectomy:
  1. Age<50 years
  2. Serum calcium > 0.25 mmol/L above the upper-limit of normal
  3. 24 hour urine calcium > 10 mmol
  4. eGFR <60
  5. BMD T score <-2.5 and/or prior asymptomatic vertebral fracture by imaging
  6. Evidence of nephrolithiasis or nephrocalcinosis on imaging
• Note: parathyroid imaging/localization is NOT needed to establish diagnosis or determine management. Imaging is indicated only if surgery is being planned.

Final Take Home Point:

• Thiazide diuretics are a common cause of mild hypercalcemia (usually up to ~2.9)
• The first step in a patient with mild hypercalcemia who is on a thiazide is to stop the diuretic and repeat the serum calcium level
• Persistently elevated calcium after cessation accompanied by elevated PTH level are suggestive of primary hyperparathyroidism.
• It is not uncommon for a thiazide diuretic to “unmask” underlying hyperparathyroidism