Aetiologies

• Increased binding of calcium to protein
• Magnesium is required for the release of PTH ⇒ hypomagnesaemia can precipitate hypocalcaemia

• Low parathyroid hormone
  • Primary Hypoparathyroidism (i.e. destruction of parathyroid glands)
  • Dysregulation of PTH secretion (e.g. congenital, Hypomagnesaemia, Sepsis)
• High or normal parathyroid hormone
  • Vitamin D deficiency (e.g. true deficiency as that in malabsorption, insufficient synthesis as in renal failure)
  • Altered protein binding (e.g. alkalosis)
  • PTH resistance (e.g. Hypomagnesaemia)
  • Chelation or depletion
    • Hyperphosphotaemia
    • Tumour lysis syndrome
    • Acute pancreatitis
    • Consumption by osteoclastic bone metastases
  • Drugs
    • Citrate
    • Phosphate
    • Biphosphonates
    • Phenytoin
• Causes of hypocalcaemia categorised by acid base balance:
  • Metabolic alkalosis – citrate toxicity
  • Metabolic acidosis – acute renal failure, tumour lysis, rhabdomyolysis, pancreatitis, ethylene glycol poisoning, hydrofluoric acid, sepsis, burns
• Citrate toxicity is probably the only cause of low ionised calcium with normal total calcium
  • This is because measurement instruments which detect calcium will also measure citrate-calcium complexes in the serum, but the electrode which measures ionised calcium will only measure the free fraction, which decreases with citrate chelation

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.

Clinical Features

• Mild hypocalcaemia
  • Generalised myalgia
  • Twitching, fasciculations
  • QT prolongation
  • Chvostek sign is the twicth elicited by tapping over the facial nerve.
  • Confusion, delirium psychosis
• Severe hypocalcaemia
  • Trousseau is the carpopedal spasm in response to overlong BP cuff inflation.
  • Tetany and seizures
  • Papilloedema and raised intracranial pressure
  • Cardiac arrhythmias (e.g. Torsades)
  • Hypotension

Investigations

• ECG
• PTH
  • PTH normally rises in resposne to hypocalcaemia
  • Low PTH suggests dysregulation of PTH secretion which can be due to primary Hypoparathyroidism (e.g. surgical destruction), PTH secretion suppression as in sepsis or congenital mutations
• Serum 25-hydroxyvitamin D
  • Low vitamin D can cause hypocalcaemia
  • Low vitamin D can be secondary to lack of UV light, dietary deficiency or renal failure (hence urea and creatinine)
• Urea and creatinine
• Magnesium and phosphate level
  • Hypomagnesaemia causes both decreased PTH secretion and impaired tissue response to PTH but requires Mg levels < 0.4 mmol/L
  • Hyperphosphataemia can be associated with low calcium
    • Primary Hypoparathyroidism disorders are associated with a raised serum phosphate
    • Secondary Hyperparathyroidism (e.g. in Vitamin D deficiency) are associated with a low phosphate
    • High phosphate will also chelate calcium; forming insoluble calcium phosphate
• Amylase and lipase
• Albumin
• CK and urate level to observe for rhabdomyolysis
• Correcting $\mathrm{Ca}{}^{+}$ for albumin, however evidence demonstrates that formulas actually perform worse than uncorrected calcium levels

Management

• Acute replacement
  • IV replacement with calcium salt (chloride has more calcium per 10mL)
    • 10mL gluconate = 2.3mmol = 93mg, 10mL chloride = 6.8mmol = 272mg
    • Calcium chloride has more significant phlebitis risk and tissue necrosis if extravasation; only give via a central line
    • Calcium gluconate is preferred in peripheral access
    • Calcium chloride is preferred in cardiac arrest, severe hepatic impairment or when central access already exists
  • Ensure magnesium and phosphate replacement also occurs accordingly
• Medium term placement
  • Oral replacement with either calcium citrate or carbonate¹
  • Vitamin D replacement
  • With intact parathyroid function (i.e. PTH appropriately high) cholecalciferol (converted to calcitriol in the kidney when parathyroid function is normal)
  • With impaired parathyroid function give calcitriol
• Recalcitrant hypocalcaemia
  • Thiazide diuretics
  • Recombinant PTH

Sources

• Hypocalcaemia • LITFL • CCC Electrolytes
• Hypocalcaemia - Deranged physiology

Footnotes

1. Perhaps calcium citrate is better as it does not need to be taken after food as it does not require a normal gastric pH to dissolve; calcium citrate might therefore be appropriate for fasted patients