69. Hypocalcemia, hypercalcemia

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Calcium homeostasis

Calcium in the serum exists in one of two forms; it’s either in the free, ionized Ca²⁺ form or bound to proteins, especially albumin. The proportion is approximately 1:1, meaning that 50% of serum calcium is free while 50% of serum calcium is bound. Only the free calcium is biologically active; if 100% of serum calcium was bound it would be equal to having no calcium in the serum, functionally speaking.

The normal calcium level in the serum is 2.1 – 2.6 mM. Approximately half of it (1.3 mM) is in ionized form, while the other half (approx. 1.2 mM) is in bound form.

A factor that’s important in calcium homeostasis is the blood pH. In alkalosis the pH increases, so the number of H⁺ in the serum decreases. H⁺ is normally bound to proteins, so when the number of H⁺ ions decreases, more proteins are available to bind free Ca²⁺. This causes the amount of free calcium to decrease, mimicking hypocalcaemia. The opposite occurs in acidosis, where symptoms of hypercalcaemia occur.

Phosphate and calcium also form complexes in the serum. Therefore will hyperphosphataemia cause a decrease in free calcium and therefore hypocalcaemia. The opposite occurs in the case of hypophosphataemia.

Free calcium is important for stabilizing the resting membrane potential of cells. When hypocalcaemia occurs, the resting membrane potential increases and so the membrane excitability increases and vice versa.

Three hormones are involved in regulating the calcium level:

• PTH, which increases the calcium level
• Vitamin D (especially calcitriol, the active form), which increases the calcium level
• Calcitonin, which decreases the calcium level

Of these three only the first two are important in humans. Calcitonin has been determined to not influence calcium homeostasis significantly in humans.

Hypocalcaemia

Hypocalcaemia is defined as serum calcium level < 2.1 mM or free serum calcium < 1.2 mM.

Etiology:

• Due to hypoparathyroidism
  • Surgical removal of parathyroid glands
  • Autoimmune destruction of parathyroid glands
• Vitamin D deficiency
  • Malnutrition
  • Malabsorption
  • Inadequate sun exposure
  • Chronic renal failure
• Hyperphosphataemia
  • Chronic renal failure
  • Severe tissue breakdown
    • Tumor lysis syndrome
    • Rhabdomyolysis
• Necrotizing pancreatitis
• Drugs
  • Loop diuretics
  • Glucocorticoids
• Hyperventilation

Any condition that causes alkalosis will also cause hypocalcaemia. The most common causes are chronic renal failure, vitamin D deficiency or hypoparathyroidism.

Pathomechanism:

When adiponecrosis occurs in pancreatitis, calcium will combine with fatty acids to form soap. This decreases the calcium level in the serum.

Loop diuretics increase calcium excretion in the kidney.

Hyperventilation causes alkalosis, which in turn causes hypocalcaemia.

Clinical features:

All symptoms of hypocalcaemia are related to the increased neuromuscular excitability.

• Acute hypocalcaemia
  • Tetany
  • Paraesthesia
  • Muscle spasm
  • Seizures
  • Abdominal cramping
  • Diarrhoea
• Chronic hypocalcaemia
  • Arrhythmias

Tetany of the laryngeal muscles may be fatal and is a lethal complication of hypocalcaemia and hyperventilation.

On the long run, hypocalcaemia will cause secondary hyperparathyroidism, which increases calcium resorption from the bones.

Diagnosis:

Chvostek’s sign can be seen by tapping the facial nerve where it passes in front of the ear. In those with hypocalcaemia this will trigger contraction of the facial muscles.

Trousseau’s sign can be seen by inflating a blood pressure cuff around the upper arm. In those with hypocalcaemia this will trigger spasm of the muscles of the hand and the forearm. The result is flexion of the wrist, forming the characteristic “obstetrician’s hand”.

Hypercalcaemia

Hypercalcaemia is defined as serum calcium level > 2.6 mM or free serum calcium > 1.3 mM.

Etiology:

• Due to primary hyperparathyroidism
  • Parathyroid adenoma
• Hypercalcaemia of malignancy
  • Pseudohyperparathyroidism
    • PTHrP-producing cancers
  • Osteolytic metastases to bone
  • Multiple myeloma
• Thiazide diuretics
• Vitamin D overdose
• Sarcoidosis
• Milk-alkali syndrome

Primary hyperparathyroidism and hypercalcaemia of malignancy account for 90% of cases of hypercalcaemia.

Pathogenesis:

Metastases to bone and multiple myeloma causes osteolytic lesion in the bones. This releases calcium from those bones.

The granulomas in sarcoidosis have the necessary enzyme to convert inactive vitamin D to the active form of vitamin D (calcitriol).

Thiazide diuretics decrease renal calcium excretion.

Milk-alkali syndrome occurs when a person ingests too much calcium and absorbable alkali. It frequently occurs when people take alkali antacids and milk or other sources of calcium together. It causes hypercalcaemia and metabolic alkalosis. The pathomechanism is not known.

Calcium is involved in intracellular signalling of several hormones. In hypercalcaemia the effect of these hormones can be potentiated or inhibited.

Hypercalcaemia stimulates secretion of gastrin, increasing the production of stomach acid and causing peptic ulcer disease.

Hypercalcaemia decreases the effect of ADH on the kidney, causing nephrogenic diabetes insipidus.

Clinical features:

• Metastatic calcification
  • Nephrocalcinosis
  • Nephrolithiasis
  • Chondrocalcinosis – calcification of the joints
  • Acute pancreatitis
• Abdominal pain
• Bone pain
• Peptic ulcer disease
• Constipation
• Muscle weakness
• Nephrogenic diabetes insipidus -> polyuria
• Psychiatric symptoms
  • Depression
  • Psychosis
  • Coma
• Arrhythmias