Hypocalcemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]Vindhya BellamKonda, M.B.B.S [3]

Hypocalcemia is the presence of low serum calcium levels in the blood, usually taken as less than 3.5 mmol/L or 8.8 mg/dl or an ionized calcium level of less than 1.1 mmol/L (4.5 mg/dL). It is a type of electrolyte disturbance. In the blood, about half of all calcium is bound to proteins such as serum albumin, but it is the unbound, or ionized, calcium that the body regulates. If a person has abnormal levels of blood proteins then the plasma calcium may be inaccurate. The ionized calcium level is considered more clinically accurate in this case.

Calcium is the most abundant mineral in the body. 99% of the body’s calcium is stored in bone. Calcium is found in plasma and is either protein-bound or ionized and readily available.

The association between thyroid and parathyroid surgery and hypocalcemia was made by Billroth, Kocher, Mayo, and Halsted.

There is a functional classification of hypocalcemia which includes complete absent of PTH gland, PTH insufficiency, and PTH overactivity.

Hypocalcemia may develop in disorders associated with insufficient parathyroid hormone or vitamin D production or resistance to hormonal activities. Perturbations of calcium homeostasis can be caused by environmental factors or occur as a result of genetic mutations in the calcium-sensing receptor (as in type 1 autosomal dominant hypocalcemia), G_s α subunit (as in type 1A and 1B pseudohypoparathyroidism), vitamin D hydroxylase (as in type 1 vitamin D-dependent rickets , and calcitriol receptor (as in type 2 vitamin D-dependent rickets).

Hypocalcemia can be the consequence of multiple disease processes, some of which will be mentioned in the following discussion. Common causes of hypocalcemia include Vitamin D insufficiency, hypoparathyroidism, renal disease, pseudohypoparathyroidism, hypomagnesemia, drugs and fanconi syndrome etc.

Hypocalcemia must be differentiated from tetanus, Neuroleptic Malignant Syndrome, Viral Meningitis, Stiff man syndrome, Strychnine poisoning and Parkinson’s disease.

Hypocalcaemia, is having a low calcium concentrations in the blood.The normal range of serum calcium lies between 8.8–10.7 mg/dl, 4.3–5.2 mEq/l.In the past 20 years quantification of serum and ionized calcium and PTH concentrations, helps in easier diagnosis. It is difficult to quantify the incidence of ionized hypocalcemia.

The most common risk factors of hypocalcemia are vitamin D deficiency. Other common causes of hypocalcemia include magnesium, newborn babies, parathyroid hormone (PTH), hyperphosphatemia and renal causes.

There is insufficient evidence to recommend routine screening for hypocalcemia.

The clinical features of hypocalcemia may vary widely, which ranges from asymptomatic symptoms to life-threatening complications.The main factors that influence the serum calcium levels are parathyroid hormone (PTH), vitamin D, the calcium ions, and phosphate.Hypocalcemia is commonly encountered in patients who are hospitalized. Undertreatment or improper treatment of hypocalcemic emergencies can lead to significant morbidity.Death is rare but has been reported in hypocalcemia patients.

Clinical presentation of hypocalcemia reflects the serum level of ionized calcium and depends on the severity of any concurrent electrolyte imbalance. Overt symptoms occur when ionized calcium falls below 3.2 mg/dL (0.8 mmol/L).An abrupt fall in the serum calcium level typically manifests as neuromuscular excitability in the form of tetany and tingling. Patients who develop hypocalcemia gradually may be asymptomatic.In addition to fatigue and muscle weakness, longstanding hypocalcemia is usually associated with neuropsychiatric symptoms.

The clinical manifestations of hypocalcemia depend on the degree of hypocalcemia. Common physical examination findings of hypocalcemia include Chvostek’s sign, Trousseau’s sign, and circumoral numbness.

Measurement of the serum albumin concentration is essential to distinguish pseudohypocalcemia from true hypocalcemia. Laboratory investigations that detect alterations in parathyroid hormone, vitamin D, and phosphate in the serum or urine aid in the differential diagnosis of the underlying etiologies. Other laboratory tests include serum alkaline phosphatase, liver function tests, coagulation profile, blood urea nitrogen, creatinine, and urinary cAMP levels at baseline or after PTH challenge.

An x-ray may be helpful in the diagnosis of hypocalcemia. Findings on an x-ray suggestive of hypocalcemia include trabeculation and femoral changes.Head CT scan may be helpful in the diagnosis of hypocalcemia. Findings on CT scan suggestive hypocalcemia include basal ganglia calcification.There are no MRI findings associated with hypocalcemia.

There are no other imaging findings associated with hypocalcemia.

Cause, severity and the presence of symptoms decide the treatment of hypocalcemia. In mild to moderate cases hypocalcemia can be treated by giving oral calcium and vitamin D supplements but in severe cases intravenous (IV) calcium gluconate is preferred. Most of the hypocalcemic cases are mild and require only supportive treatment and laboratory evaluation

Surgical intervention is not recommended for the management of hypocalcemia.

Effective measures for the primary prevention of hypocalcemia include the increase in dietary calcium and increase exposure to the sun.

There are no established measures for the secondary prevention of hypocalcemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Hypocalcemia may develop in disorders associated with insufficient parathyroid hormone or vitamin D production or resistance to hormonal activities. Perturbations of calcium homeostasis can be caused by environmental factors or occur as a result of genetic mutations in the calcium-sensing receptor (as in type 1 autosomal dominant hypocalcemia), G_s α subunit (as in type 1A and 1B pseudohypoparathyroidism), vitamin D hydroxylase (as in type 1 vitamin D-dependent rickets , and calcitriol receptor (as in type 2 vitamin D-dependent rickets).

The normal physiology of Hypocalcemia can be understood as follows:^[1][2]

• The normal concentrations of calcium in the body is maintained within the narrow range and that is required for the optimal activity of the many extra- and intracellular processes that calcium regulates. 
• Calcium transport within the blood is mainly via bound to plasma proteins such as albumin (45%), phosphate and citrate (15%) and ionized state (40%).
• Only the ionized form of calcium is active but most laboratories show report of total serum calcium concentrations.
• The normal concentration of calcium ranges between 8.5 and 10.5 mg/dL.
• The normal range of ionized calcium in the plasma is 4.65 to 5.25 mg/dL.

It is understood that hypocalcemia may result through any of the following mechanisms:

• One of the common causes of hypocalcemia is underproduction of vitamin D.^[3]
• The consequence of low serum calcium levels is an increase in serum PTH (to allow the calcium levels to return within normal range- mainly via increased release of calcium from bone tissue).
• Causes of vitamin D deficiency include:^[4]
  • Poor intake of vitamin D
  • Malabsorption
  • Reduced ultraviolet light exposure
  • Decrease in 25-hydroxylation to convert vitamin D into 25-hydroxyvitamin D
  • Decreased 1-hydroxylation of 25-hydroxyvitamin D (primarily occurrs in the kidney– so chronic kidney disease is one of the causes of reduced active form of vitamin D and hence hypocalcemia)

Hypoalbuminemia

• When there is a fluctuation in serum protein concentrations, especially albumin, total calcium levels in the blood may change.^[5][6]
• Whereas the levels of ionized calcium (free form) remains mostly constant, because it is hormonally regulated.
• In cases of hypoalbuminemia, total serum calcium levels may not accurately reflect the physiologically important ionized calcium concentration.
• Therefore, a correction may be required in order to arrive at the corrected calcium levels. (Corrected calcium = Measured calcium + 0.02 x [40 – Albumin])

• Parathyroid hormone (PTH) and vitamin D play an important role in regulating serum calcium.^[7]
• Calcium auto-regulates its own serum levels via a calcium-sensing receptor (CaSR) in the parathyroid gland to inhibit parathyroid hormone (PTH) secretion and on a CaSR in the loop of Henle of the kidney to stimulate renal calcium excretion.^{[8][9][10][11]}
• Whenever the serum ionized calcium decreases below normal (even in small amounts) PTH (parathyroid hormone) is secreted to aid in return of serum calcium levels within normal range. This is achieved by 3 major actions of PTH: ^{[12][13][14][15]}
  • 1)PTH (parathyroid hormone) stimulation of calcium reabsorption in the distal tubule of the kidney results in decreased urinary calcium excretion by the kidney.^[16]
  • 2)PTH (parathyroid hormone) increases renal production of 1,25-dihydroxyvitamin D which is also called as calcitriol which in turn increases the intestinal calcium absorption.^[17]
  • 3)PTH (parathyroid hormone) increases bone resorption which in turn increases the serum calcium levels.^[18]
• When PTH secretion is insufficient hypokalemia may occur, which is classically seen in hypoparathyroidism.

• Hypocalcemia can be caused by both hypomagnesemia or by severe hypermagnesemia.^[19][20]
• Magnesium depletion can lead to hypocalcemia by increasing parathyroid hormone (PTH) resistance.
• Parathyroid hormone (PTH) resistance occurs especially when serum magnesium concentrations fall below 0.8 mEq/L.
• In this patients hypocalcemia can be corrected by only correcting magnesium levels and by not giving calcium.
• Hypomagnesemia can be caused mostly by^[21][22]
  • Malabsorption
  • Chronic alcoholism
  • Cisplatin when combined with 5-fluorouracil and leucovorin
  • Diuretics
  • Aminoglycosides

• In alkalosis, hydrogen ions dissociate from the negatively charged albumin, which allows for increased calcium binding and leads to a decreased concentration of free calcium.

• For an increase in pH of 0.1 unit, there is an approximately 0.05 mmol/L (0.1 mEq/L) fall in the serum level of ionized calcium.

• Reduced ionized calcium concentration and hypocapnia associated with hyperventilation may contribute to symptoms of vasoconstriction including lightheadedness, fainting, and paresthesia.

• Calcium binding to globulin is relatively small (1.0 g of globulin binds 0.2–0.3 mg of calcium) and generally does not influence the total serum calcium concentration.^[23]

• Hypoparathyroidism which is acquired but not related to any surgery is most often an autoimmune disease.^[24]
• Autoimmune destruction of parathyroid glands results in permanent hypoparathyroidism .

The development of hypocalcemia is the result of genetic mutations such as

• Mutations in the transcription factor glial-cell missing B (GCMB).
• Mutations in the calcium-sensing receptor, results in autosomal dominant hypocalcemia (ADH).which is of 2 types^[25][26][27]
  • Type 1: Autosomal dominant hypocalcemia (ADH) 1 is due to activating mutation in the CaSR.^{[28][29][30][31]}
    • This mutation leads in shifting the set points of CaSR which results in no PTH release with altered changes in the levels of serum calcium.
  • Type 2: Autosomal dominant hypocalcemia (ADH) 2 is due to activating mutation in the guanine nucleotide binding protein, alpha 11 gene(GNA11).^[32][33]
    • This mutation leads to downstream CaSR signaling.

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