Hypocalcemia

Hypocalcemia is a total plasma calcium concentration of less than 8.8 mg/dL (<2.20 mmol/L) with normal plasma protein concentrations, or an ionized calcium concentration of less than 4.7 mg/dL (<1.17 mmol/L). Possible causes include hypoparathyroidism, vitamin D deficiency, and kidney disease.

Manifestations include paresthesia, tetany, and in severe cases - epileptic seizures, encephalopathy, heart failure. Diagnosis is based on determining the level of calcium in the plasma. Treatment of hypocalcemia includes the introduction of calcium, sometimes in combination with vitamin D.

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Causes hypocalcemia

Hypocalcemia has a number of causes, some of which are listed below.

Hypoparathyroidism

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia, often causing chronic tetany. Hypoparathyroidism occurs when parathyroid hormone (PTH) is deficient, often due to removal or injury of the parathyroid glands during thyroidectomy. Transient hypoparathyroidism occurs after subtotal thyroidectomy. Permanent hypoparathyroidism occurs in less than 3% of thyroidectomies performed by experienced surgeons. Symptoms of hypocalcemia usually develop within 24 to 48 hours after surgery, but may not become apparent for months or years. PTH deficiency is more common after radical thyroidectomy for cancer or as a result of surgery on the parathyroid glands themselves (subtotal or total parathyroidectomy). Risk factors for severe hypocalcemia after subtotal parathyroidectomy include severe preoperative hypercalcemia, removal of a large adenoma, and elevated alkaline phosphatase.

Idiopathic hypoparathyroidism is a rare sporadic or inherited condition in which the parathyroid glands are absent or atrophied. It appears in childhood. The parathyroid glands are sometimes absent in thymic aplasia and in abnormalities of the arteries arising from the bronchial branches ( DiGeorge syndrome ). Other inherited forms include X-linked genetic hypoparathyroidism syndrome, Addison's disease, and mucocutaneous candidiasis.

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Pseudohypoparathyroidism

Pseudohypoparathyroidism comprises a group of disorders characterized not by hormone deficiency but by target organ resistance to PTH. Complex genetic transmission of these disorders is observed.

Patients with pseudohypoparathyroidism type Ia (Albright hereditary osteodystrophy) have a mutation in the Gsa1-stimulating protein of the adenylate cyclase complex. This results in a failure of the normal renal phosphaturic response or an increase in urinary cAMP to PTH. Patients usually develop hypocalcemia as a result of hyperphosphatemia. Secondary hyperparathyroidism and bone disease may develop. Associated abnormalities include short stature, round facies, mental retardation with basal ganglia calcification, shortened metatarsals and metacarpals, mild hypothyroidism, and other minor endocrine abnormalities. Because only the maternal allele of the mutated gene is expressed in the kidney, patients with the abnormal paternal gene will not develop hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism despite having somatic features of the disease; This condition is sometimes described as pseudohypoparathyroidism.

Less information is available about pseudohypoparathyroidism type lb. These patients have hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism but no other associated abnormalities.

Pseudohypoparathyroidism type II is even less common than type I. In these patients, exogenous PTH increases urinary cAMP but has no effect on increasing plasma calcium or urinary phosphate. Intracellular resistance to cAMP is suggested.

Vitamin D deficiency

Vitamin D deficiency may develop as a result of inadequate dietary intake or decreased absorption due to hepatobiliary disorders or intestinal malabsorption. It may also develop as a result of altered vitamin D metabolism, which is observed when taking certain medications (e.g. phenytoin, phenobarbital, rifampin) or as a result of insufficient sun exposure. The latter is a common cause of acquired vitamin D deficiency in institutionalized elderly people and in people living in northern climates who wear protective clothing (e.g. Muslim women in England). In type I vitamin D-dependent rickets (pseudovitamin D-deficiency rickets), which is an autosomal recessive disease, a mutation occurs in the gene encoding the enzyme 1 hydroxylase. Normally, this enzyme in the kidneys is involved in the conversion of the inactive form of 25-hydroxycholecalciferol into the active form 1,25-dihydroxycholecalciferol (calcitriol). In type II vitamin D-dependent rickets, target organs are resistant to the active form of the enzyme. Vitamin D deficiency, hypocalcemia, and severe hypophosphatemia are observed. Muscle weakness, pain, and typical bone deformities develop.

Kidney diseases

Renal tubular diseases, including proximal tubular acidosis due to nephrotoxins (e.g., heavy metals) and distal tubular acidosis, can cause severe hypocalcemia due to abnormal renal calcium loss and decreased renal calcitriol formation. Cadmium, in particular, causes hypocalcemia by damaging proximal tubular cells and impairing vitamin D conversion.

Renal failure can lead to hypocalcemia by decreasing calcitriol formation due to direct renal cell injury and by suppressing 1-hydroxylase in hyperphosphatemia.

Other causes of hypocalcemia

Decreased magnesium levels, as occurs with intestinal malabsorption or inadequate dietary intake, can cause hypocalcemia. There is a relative deficiency of PTH and end-organ resistance to the action of PTH, resulting in plasma magnesium concentrations of less than 1.0 mg/dL (< 0.5 mmol/L); replacement of the deficiency improves PTH levels and renal calcium retention.

Acute pancreatitis causes hypocalcemia because lipolytic substances released by the inflamed pancreas chelate calcium.

Hypoproteinemia may reduce the protein-bound fraction of plasma calcium. Hypocalcemia due to decreased protein binding is asymptomatic. Since the ionized calcium level remains unchanged, this condition is called factitious hypocalcemia.

Increased bone formation with impaired calcium uptake is observed after surgical correction of hyperparathyroidism in patients with generalized fibrous osteodystrophy. This condition is called hungry bone syndrome.

Septic shock can cause hypocalcemia by suppressing the release of PTH and decreasing the conversion of the inactive form of the vitamin to calcitriol.

Hyperphosphatemia causes hypocalcemia by mechanisms that are not fully understood. Patients with renal failure and subsequent phosphate retention are usually in the supine position.

Drugs that cause hypocalcemia include mainly those used to treat hypercalcemia: anticonvulsants (phenytoin, phenobarbital) and rifampin; transfusion of more than 10 units of citrated blood; radiocontrast agents containing the bivalent chelating agent ethylenediaminetetraacetate.

Although excess calcitonin secretion should theoretically cause hypocalcemia, patients with large amounts of calcitonin circulating in the blood due to medullary thyroid cancer rarely have low plasma calcium levels.

Symptoms hypocalcemia

Hypocalcemia is often asymptomatic. Hypoparathyroidism is often suspected based on clinical manifestations (eg, cataracts, basal ganglia calcifications, chronic candidiasis in idiopathic hypoparathyroidism).

Symptoms of hypocalcemia are due to disturbance of membrane potential, which leads to neuromuscular irritability. Muscle cramps of the back and legs are most often observed. Gradually developing hypocalcemia may cause mild diffuse encephalopathy, it should be suspected in patients with unexplained dementia, depression or psychosis. Sometimes there is swelling of the optic nerve, with prolonged hypocalcemia cataracts may develop. Severe hypocalcemia with plasma calcium level less than 7 mg/dl (< 1.75 mmol/l) may cause tetany, laryngospasm, generalized seizures.

Tetany develops with severe hypocalcemia, but may develop as a result of a decrease in the ionized fraction of plasma calcium without significant hypocalcemia, which is observed in severe alkalosis. Tetany is characterized by sensory symptoms, including paresthesia of the lips, tongue, fingers, feet; carpopedal spasm, which can be prolonged and painful; generalized muscle pain, spasm of the facial muscles. Tetany can be overt with spontaneous symptoms or latent, requiring provocative tests to detect. Latent tetany is more often observed at plasma calcium levels of 7-8 mg / dL (1.75-2.20 mmol / L).

The Chvostek and Trousseau signs are easily performed at the bedside to detect latent tetany. The Chvostek sign is an involuntary contraction of the facial muscles in response to a gentle tap with a mallet in the area of the facial nerve anterior to the external auditory canal. It is positive in < 10% of healthy individuals and in most patients with acute hypocalcemia, but is often negative in chronic hypocalcemia. The Trousseau sign is a finding of carpopedal spasm when blood flow to the arm is reduced with a tourniquet or sphygmomanometer cuff placed on the forearm for 3 minutes with air inflated to 20 mmHg above the blood pressure. The Trousseau sign is also seen in alkalosis, hypomagnesemia, hypokalemia, hyperkalemia, and in about 6% of people without electrolyte imbalance.

Patients with severe hypocalcemia sometimes experience arrhythmias or heart blocks. In hypocalcemia, the ECG usually shows prolongation of the QT and ST intervals. There are also repolarization changes in the form of a peaked T wave.

Chronic hypocalcemia may cause many other problems, such as dry, flaky skin, brittle nails, and coarse hair. Candidiasis is sometimes seen with hypocalcemia, but more often in patients with idiopathic hypoparathyroidism. Long-term hypocalcemia leads to the development of cataracts.

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Diagnostics hypocalcemia

Hypocalcemia - diagnosis is based on finding a total plasma calcium level < 8.8 mg/dL (< 2.20 mmol/L). However, given the fact that low plasma protein levels may reduce total but not ionized calcium, ionized calcium should be estimated using albumin (Box 1561). If low ionized calcium is suspected, it should be measured directly despite normal total plasma calcium. In patients with hypocalcemia, renal function (eg, blood urea nitrogen, creatinine), serum phosphate, magnesium, and alkaline phosphatase should be assessed.

If the cause of hypocalcemia is not obvious (eg, alkalosis, renal failure, massive transfusion), further investigation is necessary. Because hypocalcemia is the major stimulus for PTH secretion, PTH levels should be elevated in hypocalcemia. Low or normal PTH levels suggest hypoparathyroidism. Hypoparathyroidism is characterized by low plasma calcium, high plasma phosphate, and normal alkaline phosphatase. Hypocalcemia with high plasma phosphate suggests renal failure.

Pseudohypoparathyroidism type I can be distinguished by the presence of hypocalcemia despite normal or elevated circulating PTH levels. Despite the presence of high circulating PTH levels, cAMP and phosphate are absent from the urine. Provocative testing with injections of parathyroid extracts or recombinant human PTH does not cause increases in plasma or urinary cAMP. Patients with pseudohypoparathyroidism type Ia also often have skeletal abnormalities, including short stature and shortening of the first, fourth, and fifth metacarpals. Patients with type Ib have renal manifestations without skeletal abnormalities.

In pseudohypoparathyroidism type II, exogenous PTH increases urinary cAMP levels but does not cause phosphaturia or increase plasma calcium concentrations. Vitamin D deficiency must be excluded before diagnosing pseudohypoparathyroidism type II.

In osteomalacia or rickets, typical skeletal changes are seen on radiographs. Plasma phosphate levels are often mildly decreased and alkaline phosphatase levels are elevated, reflecting increased mobilization of calcium from bone. Plasma levels of active and inactive vitamin D may help differentiate vitamin D deficiency from vitamin D-dependent conditions. Familial hypophosphatemic rickets is recognized by the associated renal phosphate loss.

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Treatment hypocalcemia

Tetany is treated with 10 ml of 10% calcium gluconate solution intravenously. The response may be complete, but lasts only a few hours. Repeated infusions of 20-30 ml of 10% calcium gluconate solution in 1 liter of 5% dextrose solution or the addition of a continuous infusion may be required for the next 12-24 hours. Calcium infusions are dangerous in patients receiving digoxin and should be given slowly with constant ECG monitoring. If tetany is associated with hypomagnesemia, a transient response to calcium or potassium may occur, but complete recovery can occur only with replacement of the magnesium deficit.

In transient hypoparathyroidism following thyroidectomy and partial parathyroidectomy, oral calcium may be sufficient. However, hypocalcemia may be particularly severe and prolonged after subtotal parathyroidectomy in patients with chronic renal failure or end-stage renal disease. After surgery, prolonged parenteral calcium administration may be required; 1 g daily of calcium may be needed for 5 to 10 days. An increase in plasma alkaline phosphatase in these circumstances may indicate rapid uptake of calcium into bone. The need for large amounts of parenteral calcium usually continues until the alkaline phosphatase level has decreased.

In chronic hypocalcemia, oral calcium and sometimes vitamin D are usually sufficient. Calcium can be given as calcium gluconate (90 g elemental calcium/1 g) or calcium carbonate (400 mg elemental calcium/1 g) to provide one to two grams of elemental calcium per day. Although any form of vitamin D can be used, the most effective are analogues of the active form of the vitamin: 1-hydroxylated compounds, as well as synthetic calcitriol [1,25(OH)2D] and pseudohydroxylated analogues (dihydrotachysterol). These preparations are more active and are cleared from the body more quickly. Calcitriol is especially useful in renal failure because it does not require metabolic changes. Patients with hypoparathyroidism usually respond to doses of 0.5-2 mcg/day orally. In pseudohypoparathyroidism, oral calcium alone may sometimes be used. The effect of calcitriol is achieved by taking 1-3 mcg/day.

Vitamin D supplementation is ineffective without adequate calcium (1–2 g elemental calcium/day) and phosphate intake. Vitamin D toxicity with severe symptomatic hypercalcemia may be a serious complication of treatment with vitamin D analogs. Once calcium levels have stabilized, plasma calcium levels should be monitored daily for the first month and then at 1–3 monthly intervals. The maintenance dose of calcitriol or dihydrotachysterol is usually tapered over time.

Rickets due to vitamin D deficiency is usually treated with 400 IU/day of vitamin D (as vitamin D2 or D3); if osteomalacia is present, 5000 IU/day of vitamin D is given for 6 to 12 weeks and then tapered to 400 IU/day. An additional 2 g of calcium/day is advisable in the initial stages of treatment. In patients with rickets or osteomalacia due to insufficient sun exposure, sun exposure or the use of ultraviolet lamps may be sufficient.

In vitamin D-dependent rickets type I, 0.25-1.0 mcg calcitriol per day is effective. In patients with vitamin D-dependent rickets type II, vitamin D is not effective for treatment [a more understandable term is hereditary resistance to 1,25(OH)2D].

Hypocalcemia is treated depending on the severity of bone damage. In severe cases, up to 6 mcg/kg body weight or 30-60 mcg/day of calcitriol with the addition of up to 3 g of elemental calcium per day is necessary. When treating with vitamin D, plasma calcium levels must be monitored; hypercalcemia, which sometimes develops, usually responds quickly to changes in the vitamin D dose.