Aetiology

The aetiologies of hypocalcaemia may be classified on the basis of parathyroid hormone (PTH) levels, or, alternatively, physiologically (e.g., insufficient entry into or increased loss of calcium from the circulation). Aetiologies may be interrelated.

Classification based on PTH level

Hypocalcaemia with inappropriately low serum PTH

  • Destruction of parathyroid glands

    • Surgery, autoimmune, radiation, infiltration (iron, copper, tumour)

  • Developmental parathyroid disorders

    • Isolated hypoparathyroidism

    • Autosomal recessive, autosomal dominant, or X-linked

    • Syndromes of hypoparathyroidism associated with complex developmental anomalies (e.g., DiGeorge sequence)

    • Reduced PTH secretion/function

    • Constitutively activating calcium sensing receptor (CaSR) mutations/autoimmune activation of the CaSR

  • Hypomagnesaemia

  • Hungry bone disease following parathyroidectomy.

Hypocalcaemia with secondary hyperparathyroidism

  • Vitamin D deficiency

    • Inadequate ultraviolet B light exposure, poor diet, malabsorption

  • Chronic renal disease, enzyme-induced drug resistance to PTH

  • Pseudohypoparathyroidism

  • Hypomagnesaemia

  • Resistance to vitamin D

  • Mutations in vitamin D receptor (mutations in 1-alpha hydroxylase enzyme).

Miscellaneous

  • Following drug treatment

    • Intravenous bisphosphonates (and other drugs that inhibit bone turnover) in untreated vitamin D deficiency

    • Gadolinium salts used in magnetic resonance imaging

    • Foscarnet

  • Osteoblastic metastases

  • Hyperphosphataemia

  • Severe illness

    • Acute pancreatitis

    • Acute rhabdomyolysis

    • Tumour lysis

    • Post massive transfusion.

Decreased entry of calcium into the circulation

  • Hypoparathyroidism is a well recognised cause of hypocalcaemia. It is often caused by accidental removal of all the parathyroid glands during surgery or radiation-induced parathyroid destruction. Low levels of parathyroid hormone (PTH) secretion are sometimes congenital (as in DiGeorge syndrome and velocardiofacial syndrome); hypoparathyroidism may also be autosomal dominant (hypocalcaemia with hypercalciuria) or autoimmune (occurring as an isolated entity or as part of polyglandular failure type 1, which is seen in association with adrenal insufficiency and mucocutaneous candidiasis).[7]

  • Repeated blood transfusions for chronic anaemia, or defects of iron metabolism (e.g., haemochromatosis) or copper metabolism (e.g., Wilson's disease), and less commonly a current malignancy, could suggest an infiltrative process in the parathyroid glands.[8][9]​​

  • Nutritional: vitamin D deficiency is the most common cause of hypocalcaemia.[10][11] Circulating vitamin D levels may be reduced by lack of exposure to sunshine and reduced vitamin D intake, resulting in calcium malabsorption.[11]

  • Magnesium imbalance: the presence of hypomagnesaemia can cause hypocalcaemia by interfering with the secretion and action of PTH. Hypomagnesaemia generally occurs as a primary disorder that is secondary to defects in intestinal absorption and renal absorption or as a secondary disorder due to nutritional deficiency, as seen in patients with chronic alcoholism.[12]​

  • PTH resistance, or pseudohypoparathyroidism, encompasses a group of hereditary disorders that involve resistance to the effects of PTH (e.g., renal and bone unresponsiveness to PTH). In contrast to hypoparathyroidism, pseudohypoparathyroidism is characterised by high levels of PTH and phosphorus in conjunction with hypocalcaemia.[13]​ Pseudohypoparathyroidism has other phenotypes such as Albright's hereditary osteodystrophy (associated with short stature, round facies, short digits, and intellectual impairment) and pseudopseudohypoparathyroidism (a condition where the individual has the physical appearance associated with pseudohypoparathyroidism but has normal biochemistry).[14]

Increased loss of calcium from the circulation

  • The 'hungry bone syndrome' refers to a state of severe hypocalcaemia that can be seen after parathyroidectomy (or thyroidectomy).[15][16]​​ Calcium is rapidly taken from the circulation and deposited in stores in the bones. In severe cases patients may develop cardiovascular collapse, arrhythmias, and hypotension unresponsive to fluids and vasopressors.

  • Acute pancreatitis can lead to hypocalcaemia, which is associated with a poor prognosis.[17]

  • Extensive osteoblastic skeletal metastases, such as those that occur in breast or prostate cancer, can result in hypocalcaemia.[18][19]

  • Hyperphosphataemia occurs after massive tissue breakdown in rhabdomyolysis, after accidental ingestion of phosphate-containing drugs, in tumour lysis syndrome, or in critically ill patients.[20][21][22]​​​​ Phosphate binds to calcium, leading to acute hypocalcaemia.

  • Chelating agents such as citrate, EDTA (ethylenediaminetetraacetic acid), lactate, and foscarnet can increase loss of calcium from the circulation.

Drug-induced hypocalcaemia and other causes

  • Hypocalcaemia can be induced by certain drugs (particularly if there is co-existing vitamin D deficiency): these include bisphosphonates, particularly when given intravenously; denosumab; chemotherapies; glucocorticoids; anticonvulsants; and chelating agents such as citrate, EDTA (ethylenediaminetetraacetic acid), lactate, and foscarnet.[23][24] ​Cinacalcet, which is usually given to patients with renal failure to inhibit PTH release, can also cause hypocalcaemia.[25]​ Proton-pump inhibitors may cause hypomagnesaemia, which in turn causes hypocalcaemia.

  • Critically ill patients may have transient hypocalcaemia, as seen in conditions such as sepsis or extensive burns, or after multiple blood transfusions. Hypocalcaemia is extremely common in patients admitted to hospital (occurring in up to 88% of patients admitted to medical, surgical, trauma, neurosurgical, burn, respiratory, and coronary intensive care units); the likelihood of hypocalcaemia occurring correlates with severity of illness, but not with a specific illness per se.[26][27]​​ The low serum calcium levels seen in these patients can be caused by the citrate content of transfused blood, receiving large quantities of fluids, and/or hypoalbuminaemia. Any condition that lowers plasma protein levels can also cause hypocalcaemia. For more information on sepsis, see Sepsis in adults and Sepsis in children.

  • Use of gadolinium-based magnetic resonance imaging contrast agents, such as gadodiamide and gadoversetamide, can interfere with the colorimetric assay of serum calcium levels leading to falsely lowered results.[28]

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