By Adam George
- Hypocalcaemia indicates a total serum calcium (Ca) concentration corrected for albumin of <2.1 mmol/L (normal range 2.1-2.6mmol/L). Hypocalcaemia can loosely be stratified as follows:
- Mild/moderate (<2.1-1.9 mmol/L)
- Severe (<1.9 mmol/L)
- Approximately 99% of calcium in vivo is stored in bone as hydroxyapatite. Of the remaining 1%, 0.99% is extracellular, and 0.01% intracellular. This is necessitated by the fact that high intracellular calcium levels generate apoptosis – thus cells die if intracellular calcium levels rise excessively.
- Calcium is also involved in maintaining cellular resting membrane potential, cell signalling, hormone release, and coagulation.
- The serum concentration of calcium is monitored by the calcium-sensing receptors in parathyroid cells. This, in turn, determines how much parathyroid hormone (PTH) is released by the parathyroid gland. PTH is responsible for discharging calcium from bones, resorbing calcium at the kidneys, and synthesizing calcitriol (active vitamin D). Calcitriol successively boosts calcium absorption in the gastrointestinal tract. The net effect in homeostasis is maintenance of a total serum concentration between 2.1-2.6 mmol/L.
- Serum protein and acid-base status: Additionally, calcium homeostasis is affected by both serum protein levels (particularly albumin), and acid-base status. These factors influence the ratio of serum protein-bound Ca to ionized Ca. Albumin contains acidic amino acids. Thus, in alkalosis, albumin’s carboxyl groups exist largely in their COO- rather than their COOH state. A larger number of negatively charged carboxyl groups attract the doubly positively charged Ca molecules. This results in more bound and less free ionized serum calcium. This can lead to the symptoms of hypocalcaemia.
- Hypoalbuminemia: Similarly, conditions resulting in reduced albumin levels can lead to decreased bound Ca, whereas the hormone-regulated ionized Ca remains predominantly stable. Accordingly, the total serum Ca concentration may not provide an accurate impression of the physiologically meaningful ionized Ca concentration. Common causes of this phenomenon (often referred to as pseudohypocalcaemia) include volume overload, malnutrition, chronic disease, and nephrotic syndrome. It is important to note that total serum Ca concentration falls 0.25mmol/L for every 10g/L reduction in serum albumin concentration.
- Hypocalcaemia can be divided into two pathophysiological pathways:
- PTH-mediated hypocalcaemia, whereby a deficiency of PTH causes direct insufficient release of calcium from bones
- Non-PTH-mediated hypocalcaemia
PTH-mediated causes of hypocalcaemia
- Low PTH (hypoparathyroidism): can be caused by a number of factors, such as
- Surgical removal of the parathyroid glands (thyroidectomy, parathyroidectomy)
- Automimmune destruction of the parathyroid glands (autoimmune polyglandular syndrome)
- Congenital causes (DiGeorge syndrome)
- High PTH (secondary hyperparathyroidism): can be due to several reasons, such as
- Vitamin D deficiency, which can be caused by malnutrition/malabsorption, lack of exposure to sunlight, and reduced enzymatic hydroxylation to metabolically active form (eg liver disease)
- Chronic kidney disease, which can precipitate decreased renal hydroxylation of vitamin D – leading to weakened intestinal Ca absorption, and restricted renal excretion of phosphate – leading to hyperphosphatemia
- Hyperphosphatemia, which can be induced by: lowered renal excretion of phosphate, elevated intake of phosphate, increased tissue breakdown (eg rhabdomyolysis, crush injury)
- Pseudohypoparathyroidism: as a derivative of PTH resistance
Non-PTH-mediated causes of hypocalcaemia
- Hypomagnesemia: leads to decreased PTH secretion or engenders PTH resistance, both of which lead to hypocalcaemia.
- Multiple blood transfusions and haemolysis: can cause hypocalcaemia due to the citrate in blood products chelating calcium.
- Osteoblastic metastasis: of primary malignancies (such as breast, kidney, lung, and prostate cancers) into bone can prompt aggressive bone deposition.
- Bisphosphonates and denosumab limit osteoclast-induced bone resorption, and can contribute to hypocalcaemia
- Loop diuretics increase calcium excretion at the kidneys, potentially precipitating hypocalcaemia
- Calcitonin directly opposes the actions of the parathyroid gland, lowering total serum calcium concentrations
- Medications that provoke vitamin D resistance or deficiency (ie: phenobarbital, phenytoin, theophylline, isoniazid, rifampin, and glutethimide) can occasion in hypocalcaemia
- Proton pump inhibitors and H2-blockers can cutail calcium absorption due to reduced gastric acid production
- Hyperventilation: can increase blood pH via respiratory alkalosis, causing a reduction in free ionized calcium
- Gadolinium-based contrast agents: (gadoversetamide and gadodiamide) can incite spurious hypocalcaemia due to their interference with the colorimetric determination of serum calcium levels if blood samples are obtained soon after MRI
Symptoms of hypocalcaemia generally correlate with the severity of decreases in total serum calcium concentration and differ between acute and chronic manifestations. Mild hypocalcaemia can be asymptomatic, whereas severe hypocalcaemia can be a serious, life-threatening condition.
The clinical features of acute severe hypocalcaemia can include
- Tetany (latent tetany can be elicited with manoeuvres to produce the Chvostek or Trousseau signs)
- Cardiac arrythmias
- Hypotension (rare)
- Congestive heart failure (rare)
- Angina (rare)
The clinical features of chronic hypocalcaemia can include
- Basal ganglia calcifications
- Skin changes (dermatitis, eczema, psoriasis, hyperpigmentation)
- Hair changes (brittle hair with patchy alopecia)
- Dental changes (dental enamel hypoplasia, altered morphology)
- Brittle nails with characteristic transverse grooves
- Osteomalacia and growth plate abnormalities
- Parkinsonism (extrapyramidal effects)
Initial blood testing
- Total serum calcium: generally adequate for the diagnosis of hypocalcaemia alone, unless a notably diminished plasma protein concentration is observed. Normal range is 2.1-2.6 mmol/L
- Ionised calcium: is the physiologically significant form of calcium involved in cellular processes. Calcium, as a doubly positively charged ion (Ca2+) is repellent to albumin (the most abundant protein in the blood, accounting for 50% of plasma proteins). As such, protein concentration shifts can affect the ionised calcium concentration. If there is any protein concentration abnormality, then ionised calcium should be measured discretely. Normal range is 1.15-1.25 mmol/L
- Serum PTH level: Distinguishing between PTH-mediated and non-PTH mediated causes of hypocalcaemia is crucial. Elevated PTH suggests preservation of parathyroid function, renal disease, vitamin D deficiency, or pseudohypoparathyroidism. Low or inappropriately normal PTH indicates hypoparathyroidism. Serum PTH is the principal initial investigation to determine confirmed hypocalcaemia of an unknown aetiology
- Albumin: as in hypoalbuminemia the total serum calcium concentration changes in concert with albumin concentration and may not accurately reflect the physiologically important ionized calcium concentration
- Other electrolyte abnormalities: especially phosphate (PO₄³⁻) and magnesium (Mg2+)
- EUC: to investigate renal failure and hyperkalaemia
Additional blood testing
- Alkaline phosphatase: if elevated can signal osteomalacia generated via vitamin D deficiency
- Amylase: to rule out acute pancreatitis (which can cause intra-abdominal precipitation of calcium
- 25-hydroxyvitamin D (calcidiol): to determine a potential vitamin D deficiency
- ECG: in cases of prolonged, severe, or acute hypocalcaemia to investigate
- prolonged QT interval
- ventricular arrythmias (VT, VF, torsades de pointes)
- QRS and ST segment changes (can mimic myocardial infarction)
- AV block
- ECG: in cases of prolonged, severe, or acute hypocalcaemia to investigate
- X-rays: should be taken if multiple fractures or signs of osteomalacia are present
- Isotope bone scans: should be done for patients with possible malignant metastasis.
Mild/moderate (2.1-1.9 mmol/L albumin-corrected) or chronic asymptomatic hypocalcaemia
- In adults, oral calcium supplements are usually adequate to treat mild/moderate hypocalcaemia. In cases of hypoparathyroidism, calcitriol may also be required. If there is a vitamin D deficiency, then oral cholecalciferol can be administered. In children, calcium and calcitriol are generally used together.
- Initial treatment regimen (adults): is 1.25-1.5 g oral calcium carbonate (500-600 mg), twice daily, with food OR 2.38 g oral calcium citrate (500 mg), twice daily PLUS (if hypoparathyroidism) oral calcitriol 0.25-0.5 mcg, twice daily additionally to either option above
- Initial treatment regimen (children): is 100 mg/kg oral calcium, daily in 4-6 divided doses; increase as required (doses up to 300-500 mg/kg may be required)
Acute severe (<1.9 mmol/L albumin-corrected) or symptomatic hypocalcaemia
- Gradual correction via IV injection of calcium should be the treatment of severe symptomatic hypocalcaemia of any cause. In adults, follow this with a continuous IV infusion of calcium. In children, repeat IV injections as required (infusions are not normally used). The goal of treatment is the maintenance of calcium within the normal range.
- IV injection (adults): is 20ml calcium gluconate 0.22 mmol/mL in 100ml sodium chloride 0.9% IV over 20 minutes; repeat if required.
- IV infusion (adults): is 100ml calcium gluconate 0.22 mmol/mL in 900ml sodium chloride 0.9% by IV infusion at an initial rate of 1.1 mmol/hour (50 mL/hour). Titrate to maintain a corrected serum total calcium concentration of 2.0 to 2.3 mmol/L.
- IV injection (children): is 0.5 mL/kg (up to 20 mL) calcium gluconate 0.22 mmol/mL diluted in sodium chloride 0.9%, IV over 30 to 60 minutes; repeat as required PLUS 0.015 mcg/kg oral calcitriol, daily.
- NB: extravasation of calcium can generate localised skin necrosis. To prevent this, IV access must be secure and continually monitored. Calcium gluconate is preferred to calcium chloride as it is less toxic to peripheral veins. Calcium should never be administered by IM or SC injection.
- Via oral calcium supplementation AND vitamin D supplementation (calcitriol or colecalciferol) may be required if the cause of hypocalcaemia is permanent (eg: non-functioning parathyroid gland). Clinical and biochemical monitoring 6 monthly is recommended in these instances.
- Symptom control rather than a target calcium concentration is the goal of long-term management. As such, it is recommended to aim for a serum calcium concentration at the lower limit or slightly below the reference range to avoid hypercalciuria and nephrocalcinosis.
- Renal ultrasound to screen for nephrocalcinosis is recommended for all children who require ongoing treatment, and for adults if clinically indicated.
- Amboss. (2022, September 19). Hypocalcemia – Knowledge @ amboss. Amboss. Retrieved june 6, 2023, from https://www.amboss.com/us/knowledge/Hypocalcemia/
- Desai, R., & Marshall, T. (n.d.). Hypocalcemia | Osmosis. Osmosis. Retrieved February 28, 2023, from https://www.osmosis.org/learn/Hypocalcemia
- eTG. (n.d.). Therapeutic guidelines > therapeutic guidelines: Therapeutic guidelines. Therapeutic guidelines > Therapeutic Guidelines | Therapeutic Guidelines. Retrieved February 28, 2023, from https://tgldcdp.tg.org.au/searchAction?appendedinputbuttons=electrolyte+abnormalities
- Evaluation of hyocalcaemia. Evaluation of hypocalcaemia – Differential diagnosis of symptoms | BMJ Best Practice. (n.d.). Retrieved June 6, 2023, from https://bestpractice.bmj.com/topics/en-us/160
- Goltzman, D., Rosen, C. J., & Mulder, J. E. (2023, May 30). Diagnostic approach to hypocalcemia. UpToDate. https://www.uptodate.com/contents/etiology-of-hypocalcemia-in-adults
- Goltzman, D., Rosen, C. J., & Mulder, J. E. (2022, August 2). Etiology of hypocalcemia in adults. UpToDate. https://www.uptodate.com/contents/etiology-of-hypocalcemia-in-adults
- Goltzman, D., Rosen, C. J., & Mulder, J. E. (2023, March 8). Treatment of hypocalcemia. UpToDate. https://www.uptodate.com/contents/etiology-of-hypocalcemia-in-adults
- Kanbayashi, Y., Sakaguchi, K., Hongo, F., Ishikawa, T., Tabuchi, Y., Ukimura, O., Takayama, K., & Taguchi, T. (2021). Predictors for development of denosumab-induced hypocalcaemia in cancer patients with bone metastases determined by ordered logistic regression analysis. Scientific Reports, 11(1). https://doi.org/10.1038/s41598-020-80243-y
- Liamis, G., Milionis, H. J., & Elisaf, M. (2009). A review of drug-induced hypocalcemia. Journal of Bone and Mineral Metabolism, 27(6), 635–642. https://doi.org/10.1007/s00774-009-0119-x
- Nickson, C. (2020, November 3). Hypocalcaemia. Life in the Fast Lane • LITFL. https://litfl.com/hypocalcaemia/