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Ionized calcium – Ca2+ 

Physiological role and pathophysiology, reference intervals and the most likely causes of abnormalities

Ionized calcium – Ca2+ 

Reference interval Ca2+ – example
Distribution and physiological significance of calcium
Why measure calcium ?
Regulation of calcium
Terms used in interpretation of calcium
Causes of hypocalcemia
Symptoms of hypocalcemia
Causes of hypercalcemia
Symptoms of hypercalcemia

The calcium ion (Ca2+) is one of the most prevalent cations in the body, where approximately 1 % is present in the extracellular fluid of blood. Ca2+ plays a vital role for bone mineralization and many cellular processes, e.g. contractility of the heart and the skeletal musculature, neuromuscular transmission, hormone secretion and action in various enzymatic reactions such as, e.g. blood coagulation.

Reference interval Ca2+ – example

Distribution and physiological significance of calcium

Practically all (99 %) of the approximately 1 kg of calcium present in the human body is contained within bones and teeth. The remaining 1 % is distributed between intracellular fluid of all cells and extracellular fluid. Only 8.7 mmol (350 mg) calcium circulates in blood plasma at a total concentration of ∼2.5  mmol/L (10 mg/dL). Of these 350 mg, around 40 %, is bound to protein (mostly albumin) and 10 % is complexed with a range of anions (bicarbonate, lactate, phosphate, etc.). The remaining 50 % circulates as ”free” ionized calcium (Ca2+) at a concentration of ∼1.25  mmol/L (5 mg/dL). The three fractions of calcium present in blood plasma are in equilibrium, but only the Ca2+ fraction is physiologically active [142]. A very small proportion of the calcium in bone is exchangeable with that in plasma; this is important for the regulation of cCa2+ (Fig.14).The maintenance of cCa2+ within normal limits is not only important for the structural integrity of bones but for a range of physiological functions, including:

  • Hemostasis (calcium is an essential co-factor in the blood coagulation cascade)
  • Cardiac and skeletal muscle cell contraction
  • Neuromuscular transmission
  • Action of many hormones (calcium-signaling)

 

Why measure calcium?

Disturbance of calcium metabolism and resulting abnormal calcium concentration (cCa2+) is common among hospitalized patients, particularly the critically ill patients in whom prevalence has been estimated to be as high as 85 % [140]. Both increased and decreased cCa2+ have significant symptomatic effects, and if severe, they are both potentially life-threatening conditions. Even mild abnormality, if not identified and treated, has the potential for detrimental impact on health in the long term. “In patients undergoing massive transfusion, it is critically important to frequently monitor Ca2+ levels and keep them within the normal range” [141].

Regulation of calcium

In broad terms cCa2+ reflects the balance between dietary-derived calcium absorbed via the gastrointestinal tract and that lost from the body in urine. In addition, as outlined above, calcium can move between plasma and bone. Urinary excretion and the movement of calcium from bone is regulated by the parathyroid hormone (PTH), and absorption of dietary calcium from the gastrointestinal tract is regulated by the vitamin D-derived hormone calcitriol (1,25-dihydroxy cholecalciferol). PTH is released from the parathyroid glands in response to reducing Ca2+ (Fig. 14); it has effect on the kidneys, where it decreases renal excretion of calcium, and on bone, where it promotes release of calcium from bone to plasma. PTH also promotes release of calcitriol secretion from the kidneys, which in turn promotes increased absorption of dietary calcium. The net effect of both PTH and calcitriol is to raise cCa2+ to a level that halts by feedback mechanism PTH secretion and thereby calcitriol secretion. By the integrated action of PTH and calcitriol, cCa2+ is maintained within normal limits [143].

 

FIG. 14: Regulation of plasma Ca2+ level. Modified from [144]. PTH: Parathyroid hormone

To summarize, maintaining cCa2+ within reference intervals depends on:

  • Normal diet containing adequate amounts of calcium and vitamin D
  • Normal gastrointestinal function for dietary absorption of both
  • Exposure to sunlight for adequate endogenous production of vitamin D
  • Normal parathyroid function for appropriate secretion of PTH
  • Normal liver and renal function for conversion of vitamin D to calcitriol
  • Normal renal function for secretion of calcitriol and appropriate adjustment of calcium loss in urine
  • Normal bone metabolism for appropriate movement of calcium between blood and bone

 

Disturbance of any of the above can potentially lead to abnormal cCa2+.

Terms used in interpretation of calcium 

Reduced plasma cCa2+ (i.e. <1.15  mmol/L (4.6 mg/dL)) is called hypocalcemia. Clinically, hypocalcemia is never a singular finding; it may occur in the context of coexisting acidosis, hypothermia and dilution [145].

Increased plasma cCa2+ (i.e. >1.30  mmol/L (5.2 mg/dL)) is called hypercalcemia.

Causes of hypocalcemia [146] 

  • Hypoparathyroidism (reduced PTH due to disease/damage of the parathyroid glands)
  • Vitamin D deficiency (reduced production, dietary deficiency, malabsorption)
  • Chronic kidney disease
  • Chronic liver disease
  • Critical illness, e.g.:
    • Sepsis
    • Acute kidney injury (AKI)
    • Acute pancreatitis
    • Rhabdomyolysis
    • Severe burns
    • Massive red cell transfusion 
  • Neonatal prematurity (e.g. immature parathyroid glands)

 

Preserving normal plasma cCa2+ is more important for survival than preserving normal amounts of calcium in bone, and if calcium is in short supply, the body sacrifices bone mineralization in order to maintain plasma cCa2+.

Symptoms of hypocalcemia

Mild hypocalcemia may be associated with no symptoms

Symptoms reflect the role of calcium in neural signaling and neuromuscular transmission include [146]:

  • Muscle twitching
  • Carpopedal spasm – positive Trousseau’s sign
  • Parasthesia (tingling, numbness)

 

Severe hypocalcemia can cause:

  • Tetany with laryngeal spasm and breathing difficulty
  • Convulsions, seizures, fits
  • Cardiac arrhythmia with characteristic ECG changes

 

In the long term chronic hypocalcemia can cause:

  • Neuropsychiatric symptoms
  • Cataracts
  • Heart failure

 

Causes of hypercalcemia

The three most common causes, accounting for 90 % of cases, are [147]:

  • Primary hyperparathyroidism (excessive uncontrolled secretion of PTH)
  • Malignant disease: most cancer types can be associated with hypercalcemia, especially such diseases as lung, breast and esophagus cancer with excessive production of PTH-similar peptide
  • Drugs (e.g. thiazide diuretics, lithium, excessive use of antacids, excessive vitamin D)

 

Rare causes include:

  • Tuberculosis
  • Sarcoidosis
  • Hyperthyroidism
  • Inherited hypercalcemia

 

Symptoms of hypercalcemia [147]

Mild hypercalcemia can occur without symptoms

  • Abdominal pain
  • Nausea
  • Muscle weakness
  • Constipation
  • Thirst and polyuria
  • Tiredness, fatigue, depression
  • Palpitations – ECG changes
  • Renal (calcium) stones
  • Severe hypercalcemia can cause convulsions and coma
  • Chronic (long-standing) hypercalcemia can cause irreversible chronic kidney disease

 

 

References

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Ref.: Acute care testing handbook. Radiometer Medical ApS, 2700 Brønshøj, Denmark, 2014.

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ABOUT THIS POLICY

Radiometer values your privacy and the protection of your personal data. This policy (“Policy”) explains how Radiometer its affiliates, subsidiaries or related companies, a full list of which can be located here (together, “Radiometer”, “our”, “us”, or “we”), collects, uses, shares, transfers and processes data collected from or about you.


“Personal Data” is any information that can be used to directly or indirectly identify an individual or that can be reasonably expected to link to an individual. This can include items such as name, address, telephone number, credit card details, email address, ID number, Internet Protocol (“IP”) address of an electronic device used by an individual, or other identifying code (even absent of other identifying information). Statistical and non-identifiable metric data are not considered Personal Data.

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