Hypocalcaemia

Aetiologies

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

Factor	Effect on Ionised Calcium
Albumin	increased albumin = decreased ionised calcium
pH	increased pH = decreased ionised calcium
Lactate	increased lactate = decreased ionised calcium
Phosphate	increased phosphate = decreased ionised calcium
Bicarbonate	increased bicarbonate = decreased ionised calcium
Citrate	increased citrate = decreased ionised calcium
Heparin	Presence of heparin in the sample = decreased ionised calcium
Free fatty acids	Increase in free fatty acids = decreased ionised calcium

• 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

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.

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

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.

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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

$$\mathrm{Corrected}\mathrm{Calcium}=0.8\times (40-\mathrm{Albumin})+\mathrm{Ca}{}^{2+}$$

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 ↩