The amount of calcium in the blood (more specifically, in blood plasma) can be measured as total calcium, which includes both protein-bound and free calcium. In contrast, ionized calcium is a measure of free calcium. An abnormally high level of calcium in plasma is termed hypercalcemia and an abnormally low level is termed hypocalcemia, with "abnormal" generally referring to levels outside the reference range.

Hypercalcaemia, also spelt hypercalcemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

Most cases are due to primary hyperparathyroidism or cancer. Other causes include sarcoidosis, tuberculosis, Paget disease, multiple endocrine neoplasia (MEN), vitamin D toxicity, familial hypocalciuric hypercalcaemia and certain medications such as lithium and hydrochlorothiazide. Diagnosis should generally include either corrected calcium or ionized calcium level and be confirmed after a week. Specific changes, such as a shortened QT interval and prolonged PR interval, may be seen on an electrocardiogram (ECG).

Treatment may include intravenous fluids, furosemide, calcitonin or pamidronate in addition to treating the underlying cause. The evidence for furosemide use, however, is poor. In those with very high levels, hospitalization may be required. Haemodialysis may be used in those who do not respond to other treatments. In those with vitamin D toxicity, steroids may be useful. Hypercalcemia is relatively common. Primary hyperparathyroidism occurs in 1–7 per 1,000 people, and hypercalcaemia occurs in about 2.7% of those with cancer.

Signs and symptoms.

The neuromuscular symptoms of hypercalcaemia are caused by a negative bathmotropic effect due to the increased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibres, increased calcium raises the threshold for depolarization. This results in diminished deep tendon reflexes (hyporeflexia), and skeletal muscle weakness. There is a general mnemonic for remembering the effects of hypercalcaemia: "stones, bones, groans, moans, thrones, tones, and psychiatric overtones".

Stones (kidney or biliary) (see calculus)

Bones (bone pain)

Groans (abdominal pain, nausea and vomiting)

Moans (may complain about other non-specific symptoms)

Thrones (polyuria) resulting in dehydration due to nephrogenic diabetes insipidus from nephrocalcinosis

Muscle tone (hypotonia, muscle weakness, hyporeflexia)

Psychiatric overtones (Depression 30–40%, anxiety, cognitive dysfunction, insomnia, coma).

Other symptoms include cardiac arrhythmias (especially in those taking digoxin), fatigue, nausea, vomiting (emesis), loss of appetite, abdominal pain, constipation, & paralytic ileus. If kidney impairment occurs as a result, manifestations can include increased urination, urination at night, and increased thirst. Psychiatric manifestation can include emotional instability, confusion, delirium, psychosis, and stupor. Limbus sign is seen in the eye due to hypercalcemia.

Symptoms are more common at high calcium blood values (12.0 mg/dl or 3 mmol/l). Severe hypercalcaemia (above 15–16 mg/dl or 3.75–4 mmol/l) is considered a medical emergency: at these levels, coma and cardiac arrest can result. The high levels of calcium ions decrease the neuron membrane permeability to sodium ions, thus decreasing excitability, which leads to hypotonicity of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups. The sluggish nerves also explain drowsiness, confusion, hallucinations, stupor or coma. In the gut this causes constipation. Hypocalcaemia causes the opposite by the same mechanism.

Hypercalcaemic crisis

A hypercalcemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/l).

The main symptoms of a hypercalcemic crisis are oliguria or anuria, as well as somnolence or coma. After recognition, primary hyperparathyroidism should be proved or excluded.

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death. The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium. Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have an effect on calcium levels after one or two days).

Hypocalcaemia is low calcium levels in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dl, 4.3–5.2 mEq/L) with levels less than 2.1 mmol/l defined as hypocalcemia. Mildly low levels that develop slowly often have no symptoms. Otherwise, symptoms may include numbness, muscle spasms, seizures, confusion, or cardiac arrest.

Common causes include hypoparathyroidism and vitamin D deficiency. Others causes include kidney failure, pancreatitis, calcium channel blocker overdose, rhabdomyolysis, tumour lysis syndrome, and medications such as bisphosphonates. Diagnosis should generally be confirmed with corrected calcium or ionized calcium level. Specific changes may be seen on an electrocardiogram (ECG).

Initial treatment for severe disease is with intravenous calcium chloride and possibly magnesium sulfate. Other treatments may include vitamin D, magnesium, and calcium supplements. If due to hypoparathyroidism, hydrochlorothiazide, phosphate binders, and a low salt diet may also be recommended. About 18% of people who are being treated in the hospital have hypocalcemia.

Signs and symptoms

Purpura

The neuromuscular symptoms of hypocalcemia are caused by a positive bathmotropic effect (i.e. increased responsiveness) due to the decreased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibres, reduced calcium lowers the threshold for depolarization. The symptoms can be recalled by the mnemonic "CATs go numb" - convulsions, arrhythmias, tetany, and numbness in the hands and feet and around the mouth.

Petechiae which appear as on-off spots, then later become confluent, and appear as purpura (larger bruised areas, usually independent regions of the body).

Oral, perioral and acral paresthesias, tingling or 'pins and needles' sensation in and around the mouth and lips, and in the extremities of the hands and feet. This is often the earliest symptom of hypocalcaemia.

Carpopedal and generalized tetany (unrelieved and strong contractions of the hands, and in the large muscles of the rest of the body) are seen.

Latent tetany.

Trousseau sign of latent tetany (eliciting carpal spasm by inflating the blood pressure cuff and maintaining the cuff pressure above systolic)

Chvostek's sign (tapping of the inferior portion of the cheekbone will produce facial spasms)

Tendon reflexes are hyperactive

Life-threatening complications

Laryngospasm

Cardiac arrhythmias

Effects on cardiac output

The negative chronotropic effect, or a decrease in heart rate.

The negative inotropic effect, or a decrease in contractility

ECG changes include the following:

Intermittent QT prolongation or intermittent prolongation of the QTc (corrected QT interval) on the EKG (electrocardiogram) is noted. The implications of intermittent QTc prolongation predisposes to life-threatening cardiac electrical instability (and this is, therefore, a more critical condition than constant QTc prolongation). This type of electrical instability puts the person at high risk of torsades de pointes, a specific type of ventricular tachycardia which appears on an EKG (or ECG) as something which looks a bit like a sine wave with a regularly increasing and decreasing amplitude. (Torsades de pointes can cause death unless the person can be medically or electrically cardioverted and returned to a normal cardiac rhythm.)

An ECG of a person with hypocalcemia

Causes

Hypoparathyroidism is a common cause of hypocalcemia. Calcium is tightly regulated by the parathyroid hormone (PTH). In response to low calcium levels, PTH levels rise, and conversely, if there are high calcium levels then PTH secretion declines. However, in the setting of absent, decreased, or ineffective PTH hormone, the body loses this regulatory function, and hypocalcemia ensues. Hypoparathyroidism is commonly due to surgical destruction of the parathyroid glands. Hypoparathyroidism may also be due to autoimmune problem. Some causes of hypocalcaemia are as follows:

        ·         Hyperphosphatemia.

        ·         Vitamin D deficiency.

        ·         Chronic liver disease.

        ·         Edetate disodium.

        ·         Magnesium deficiency.

        ·         Prolonged use of medications/laxatives (magnesium).

        ·         Osteomalacia.

        ·         Chronic kidney failure.

        ·         Ineffective active vitamin D.

        ·         Hypoparathyroidism/genetic.

        ·         After surgery hypoparathyroidism.

        ·         Hungry bone syndrome.

        ·         Tumour lysis syndrome.

        ·         Acute kidney injury.

        ·         Rhabdomyolysis (initial stage).

        ·         A gain of function mutations of the calcium-sensing receptor.

        ·         Foscarnet use.

        ·         Loop diuretic use.

        ·         Crohn disease.

        ·         High level of lactic acid in the blood.

        ·         Pseudohypoparathyroidism.

        ·         As a complication of pancreatitis.

        ·         Alkalosis.

        ·         Massive red blood cell transfusion due to excess citrate in the blood.

        ·         As blood plasma hydrogen ion concentration decreases, caused by respiratory or metabolic alkalosis, the concentration of freely ionized calcium, the biologically active component of blood calcium, decreases. Because a portion of both hydrogen ions and calcium are bound to serum albumin, when blood becomes alkalotic, the bound hydrogen ions dissociate from albumin, freeing up the albumin to bind with more calcium and thereby decreasing the freely ionized portion of total serum calcium. For every 0.1 increase in pH, ionized calcium decreases by about 0.05 mmol/L. This hypocalcaemia related to alkalosis is partially responsible for the cerebral vasoconstriction that causes the lightheadedness, fainting, and paraesthesia often seen with hyperventilation.

        ·         Neonatal hypocalcemia.