✕ exit

Hypercalcaemia

juniordoctornotes.com

Aetiology

  • Most common causes:
    • Primary hyperparathyroidism ⇒ rarely causes severe hypercalcaemia
    • Malignancy ⇒ more common cause of severe hypercalcaemia
      • PTHrP e.g. in squamous cell lung cancer
      • Bone metastases
      • Myeloma
  • Other causes
    • Sarcoidosis
    • Vitamin D intoxication
    • Acromegaly
    • Thyrotoxicosis
    • Milk-alkali syndrome
      • Typically occurs in patients with chronic kidney disease who are on calcium supplementation and vitamin D supplementation for treatment of osteoporosis
    • Drugs
      • Thiazides
      • Calcium-containing antacids
    • Dehydration
    • Addison disease
    • Paget’s disease of the bone with prolonged immobolisation

Mnemonic

  • C: Cancer (PTHrP, mets, myeloma)
  • H: Hyperparathyroidism
  • A: Addison’s disease, Acromegaly
  • M: Milk-alkali syndrome, Medications (thiazides, Ca-antacids)
  • P: Paget’s disease (immobilisation-related)
  • S: Sarcoidosis & other granulomas (TB, histoplasmosis)
  • D: Dehydration
  • VIT: Vitamin A or D toxicity, thyrotoxicosis

Physiology of Calcium Homeostasis

Physiology of Calcium Homeostasis

Parathyroid Hormone

  • Secreted by chief cells of the parathyroid glands
  • Most regulatory influences on PTH are inhibitory influences (inorganic phosphate is the only proper stimulatory release factor)
  • Calcium level and PTH secretion relation is not linear; high calcium can never completely suppress PTH secretion and PTH secretion reaches a peak at calcium concentration of around 0.90 mmol/L
  • Effects of PTH
    • Osteoclastic:
      • Direct effect on decreasing osteoblast activity
      • Increased osteoclast activity
      • Thus, increased release of calcium and phosphate from bone, and decreased bone deposition
    • Renal:
      • Decreased reabsorption of inorganic phosphate at the proximal tubule
      • Increased reabsorption of calcium at the thick ascending limb of the loop of Henle
      • Increased production of production of calcitriol in the kidney, through the stimulation of renal 1α-hydroxylase.

Physiology of Calcium Homeostasis

Calcitonin

  • Secreted from parafollicular cells of the thyroid gland
    • Osteoclastic:
      • Direct effect on decreasing osteoclast activity1
      • This decreases the resorption of bone, and therefore limits the entry of bone calcium and phosphate into the blood
    • Renal:
      • Calcitonin acts as a weak diuretic, increasing the elimination of sodium, chloride, phosphate and calcium. The effect on calcium is mainly due to inhibited reabsorption.
      • It also increases production of production of calcitriol in the kidney, through the stimulation of renal 1α-hydroxylase.
    • Intestinal:
      • Calcitonin increases gastric acid and pepsin secretion and decreases pancreatic amylase secretion.
      • It has no direct effect on calcium absorption in the intestine, but it can increase it indirectly by stimulating renal calcitriol synthesis

Physiology of Calcium Homeostasis

Action of Biphosphonates

  • Inhibition of osteoclast and osteoblast activity
    • Osteoclasts:
      • Inhibition of osteoclast recruitment and adhesion
      • Shortening of the life span of osteoclasts
      • Inhibition of osteoclast activity by inhibiting several essential parts of the cholesterol synthesis pathway
    • Inhibition of calcification by inhibiting the formation of calcium phosphate salts
      • Mainly seen in high doses
      • A totally physicochemical effect: they bind to the calcium of calcium phosphate
      • The result is inhibition of formation and aggregation of calcium phosphate crystals and inhibition of the transformation of amorphous calcium phosphate into hydroxyapatite.

Presentation

  • Stones, bones, groans and psychic moans
  • GI symptoms of smooth muscle relaxation: constipation, anorexia, nausea and vomiting
  • Neuro: Lethargy, hypotonia, confusion, coma
  • Renal: Polyuria, dehydration, stones
  • ECG Changes
    • Shortened QT interval
    • Osborne J waves

Investigations

  • Parathyroid hormone
  • Review FBC and film for bone marrow malignancies and metastases
  • TSH
  • Vitamin D (25-hydroxy) level
  • Vitamin A level
  • Malignancy related tests
    • Parathyroid hormone related protein
    • Serum protein electrophoresis
    • Prostate specific antigen
    • Skeletal survey
    • Alkaline phosphoatase
  • Calcium urine for familial hypocalciuric hypercalcaemia
  • Correcting for albumin, however evidence demonstrates that formulas actually perform worse than uncorrected calcium levels

Management

  • Rehydration therapy with sodium chloride 0.9% 4-6 L by IV infusion over 24 hours
    • IV furosemide can be used to treat fluid overload following rehydration but routine use has not been proved as beneficial
    • Avoid hartmann’s solution, thiazide diuretics
    • Plasmalyte is often preferred to sodium chloride 0.9% because it causes acidosis and patients with hypercalcaemia often have pre-existing acidosis
    • Aim for urine output of 150-200 mL/hour, but importantly the ongoing infusion of fluid must be balanced to the urine output
  • In acute life-threatening hypercalcaemia consider parenteral calcitonin salmon (salcatonin) in addition to biphosphonates to achieve a rapid effect
    • Note that calcitonin causes a temporary reduction in calcium (effect does not work after ~2 days)
  • If persisting severe hypercalcaemia after rehydration consider biphosphonate infusion
    • Do not give in milk-alkali syndrome (should resolve without biphosphonate therapy) and pre-menopausal women
    • Zoledronic acid is usually preferred dose-reduced in renal failure
    • Takes time to take effect, hence calcitonin and biphosphonates are oten started simultaneously
  • Hypercalcaemia caused by vitamin D toxicity, sarcoidosis or other granulomatous disease consider oral prednisolone
  • Galium nitrate can also be considered but requires expert opinion

Sources

Footnotes

  1. Their motility is affected within one minute, which is followed by a more gradual retraction