Hypocalcemia

Hypocalcemia is the total plasma calcium concentration of less than 8.8 mg / dl (<2.20 mmol / L) at 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, kidney disease.

The manifestations include paresthesia, tetany, as well as in severe conditions - epileptic seizures, encephalopathy, heart failure. Diagnosis is based on determining the level of calcium in the plasma. Treatment of hypocalcemia involves the administration of calcium, sometimes in combination with vitamin D.

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Causes of the hypocalcemia

Hypocalcemia is caused by a number of reasons. Some of them are listed below.

Hypoparathyroidism

Hypoparathyroidism is  characterized by hypocalcemia and hyperphosphatemia, often causing chronic tetany. Hypoparathyroidism develops with a deficiency of parathyroid hormone (PTH), often due to the removal or damage of parathyroid glands during thyroidectomy. Transient hypoparathyroidism is observed after subtotal thyroidectomy. Permanent hypoparathyroidism develops as a result of less than 3% of thyroidectomy performed by experienced surgeons. Symptoms of hypocalcemia usually develop 24-48 hours after the operation, but can manifest themselves in months and years. Deficiency of PTH is more often observed after radical thyroidectomy for cancer or as a result of surgical interventions on the parathyroid glands themselves (subtotal or total parathyroidectomy). The risk factors for severe hypocalcemia after subtotal parathyroidectomy include severe preoperative hypercalcemia, removal of a large adenoma, and an increase in alkaline phosphatase.

Idiopathic hypoparathyroidism is a rare sporadic or hereditary condition in which parathyroid glands are absent or atrophied. It appears in childhood. Parathyroid glands are sometimes absent in thymic aplasia and in anomalies of arteries that extend from the bronchial branches ( DiGeorge syndrome ). Other hereditary forms include the X-linked genetic syndrome of hypoparathyroidism, Addison's disease and skin-mucosal candidiasis.

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Pseudohypoparathyroidism

Pseudohypoparathyroidism combines a group of disorders characterized not by hormone deficiency, but by the resistance of the target organ to PTH. There is a complex genetic transmission of these disorders.

In patients with pseudohypoparathyroidism of type la (hereditary Albright osteodystrophy), there is a mutation in the stimulating Gsa1 protein of the adenylate cyclase complex. As a result, there is a disturbance in the normal renal phosphaturic response or an increase in urinary cAMP levels in PTH. In patients, usually as a result of hyperphosphataemia, hypocalcemia develops. Secondary hyperparathyroidism and bone tissue damage can develop. Associated anomalies include low growth, round face, mental retardation with calcification of basal ganglia, shortening of metatarsal and metacarpal bones, mild hypothyroidism and other less significant endocrine disorders. Since only the maternal allele of the mutated gene is expressed in the kidneys, hypocalcemia, hyperphosphataemia or secondary hyperparathyroidism will not develop in patients with an abnormal paternal gene, despite the presence of somatic signs of the disease; this state is sometimes described as pseudo pseudohypoparathyroidism.

There is less information about pseudohyparotyreosis of type lb. Such patients have hypocalcemia, hyperphosphataemia and secondary hyperparathyroidism, but there are no other associated anomalies.

Type II pseudohypoparathyroidism is even less common than type I. In such patients, exogenous PTH increases the level of urinary cAMP, but does not affect the increase in calcium levels of plasma or urinary phosphate. Intracellular resistance to cAMP is assumed.

Vitamin D deficiency

Deficiency of vitamin D can develop due to inadequate intake from food or a reduction in absorption due to hepatobiliary disorders or intestinal malabsorption. It can also develop due to a change in the metabolism of vitamin D, which is observed when taking certain drugs (for example, phenytoin, phenobarbital, rifampin), or as a result of lack of exposure to the sun. The latter is a common cause of the development of the acquired vitamin D deficiency in elderly people placed in special institutions, and in people living in countries with a northern climate and wearing closed clothing (for example, 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 hydroxycholecalciferol to 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. There is a deficiency of vitamin D, hypocalcemia and severe hypophosphataemia. Muscle weakness, pain and typical bone deformities develop.

Kidney Diseases

Tubular kidney diseases involving acidosis of the proximal renal tubules due to the action of nephrotoxins (eg, heavy metals) and acidosis of the distal renal tubules can cause severe hypocalcemia due to abnormal renal calcium loss and decreased calcitriol formation in the kidneys. Cadmium, in particular, causes hypocalcemia by damaging the cells of the proximal tubules and disrupting the conversion of vitamin D.

Renal failure can lead to hypocalcemia by reducing the formation of calcitriol due to direct damage to the kidney cells and inhibition of 1 hydroxylase in hyperphosphataemia.

Other causes of hypocalcemia

Reducing the level of magnesium, which is observed with intestinal malabsorption or inadequate intake from food, can cause hypocalcemia. There is a relative deficiency of PTH and resistance of target organs to the action of PTH, which leads to a concentration of magnesium in the plasma of less than 1.0 mg / dl (<0.5 mmol / l); reimbursement of deficiency improves PTH levels and renal calcium retention.

Acute pancreatitis causes hypocalcemia, since the lipolytic substances released by the inflamed pancreas form chelate compounds with calcium.

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

Increased formation of bone tissue with a violation of calcium capture is observed after surgical correction of hyperparathyroidism in patients with generalized fibrous osteodystrophy. This condition was called the syndrome of the hungry bone.

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

Hyperphosphatemia causes hypocalcemia due to mechanisms that are not yet fully understood. Patients with renal insufficiency and subsequent phosphate retention are usually in a prone position.

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

Although excessive calcitonin secretion theoretically must cause hypocalcemia, in patients with a large amount of calcitonin circulating in the blood due to medullary thyroid cancer, low plasma calcium levels are rarely observed.

Symptoms of the hypocalcemia

Hypocalcemia often occurs asymptomatically. The presence of hypoparathyroidism is often assumed by clinical manifestations (for example, cataracts, calcification of basal ganglia, chronic candidiasis in idiopathic hypoparathyroidism).

Symptoms of hypocalcemia are caused by a violation of the membrane potential, which leads to neuromuscular irritability. Cramps of muscles of the back and legs are more common. Gradually developing hypocalcemia can cause mild diffuse encephalopathy, it must be suspected in patients with unexplained dementia, depression or psychosis. Sometimes there is edema of the optic nerve, with prolonged hypocalcemia can develop cataracts. Severe hypocalcemia with a plasma calcium level of less than 7 mg / dL (<1.75 mmol / L) can cause tetany, laryngospasm, generalized convulsions.

Aetania develops with severe hypocalcemia, but it can develop as a result of a decrease in the ionized calcium plasma fraction without significant hypocalcemia, which is observed in severe alkalosis. Theta is characterized by sensory symptoms, including paresthesia of lips, tongue, fingers, feet; carpopedic spasm, which can be long and painful; generalized muscular pain, spasm of facial musculature. A tetany can be expressed with spontaneous symptoms or latent, requiring provocative tests to identify. Latent flow of tetany is more often observed at plasma calcium levels of 7-8 mg / dl (1.75-2.20 mmol / l).

The symptoms of Khvostek and Tissaur are easily performed at the patient's bed to detect latent tetany. The symptom of the tail is the involuntary contraction of the facial muscles in response to a light hammer blow in the area of the passage of the facial nerve in front of the external ear canal. Positive in <10% of healthy people and in most patients with acute hypocalcemia, but often negative for chronic hypocalcemia. The Trusso symptom is the detection of carp-pedal spasm with a decrease in blood flow in the hand with the help of a tourniquet or a cuff of a tonometer applied to the forearm for 3 minutes with an air pumping above the blood pressure of 20 mm Hg. Art. The Trusso symptom is also observed in alkalosis, hypomagnesemia, hypokalemia, hyperkalemia and in about 6% of people without disturbance of the electrolyte balance.

In patients with severe hypocalcemia, arrhythmias or cardiac blockages are sometimes observed. When hypocalcemia on the ECG is usually observed lengthening of the itervalov QT and ST. There are also changes in repolarization in the form of a sharpened tooth T.

With chronic hypocalcemia, many other disorders can occur, such as dryness and flaky skin, brittle nails, hard hair. With hypocalcemia, candidiasis is sometimes observed, but more often in patients with idiopathic hypoparathyroidism. Long-term hypocalcemia leads to the development of cataracts.

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Diagnostics of the hypocalcemia

Hypocalcemia - diagnosis is based on the determination of total plasma calcium level <8.8 mg / dl (<2.20 mmol / l). However, in view of the fact that a low level of plasma proteins can reduce total but not ionized calcium, the level of ionized calcium should be determined by the level of albumin (box 1561). If a low level of ionized calcium is suspected, its direct measurement is necessary, despite the normal level of total plasma calcium. In patients with hypocalcemia, renal function (eg blood urea nitrogen, creatinine), serum phosphate levels, magnesium, alkaline phosphatase should be evaluated.

If the cause of hypocalcemia is not obvious (eg, alkalosis, kidney failure, massive blood transfusion), further research is needed. Since hypocalcemia is the main stimulus of PTH secretion, the level of PTH in hypocalcemia should be increased. At a low or normal level of PTH, hypoparathyroidism can be assumed. Hypoparathyroidism is characterized by low plasma calcium, high plasma phosphate levels and normal alkaline phosphatase. Hypocalcemia with high plasma phosphate levels indicates renal failure.

Type I pseudohypoparathyroidism can be distinguished by the presence of hypocalcemia, despite normal or elevated levels of circulating PTH. Despite the presence of high levels of circulating PTH, cAMP and phosphates are absent in the urine. Provocative tests with injections of parathyroid gland extracts or recombinant human PTH do not cause an increase in the level of cAMP in the plasma or urine. In patients with pseudohypoparathyroidism of the type, skeletal anomalies are often observed, including low growth, shortening of the first, fourth and fifth metacarpal bone. In patients with the lb type, there are kidney manifestations without skeletal anomalies.

In pseudohypoparathyroidism of type II, exogenous PTH raises the level of cAMP in the urine, but does not cause phosphaturia or an increase in the calcium concentration in the plasma. Before diagnosis of type II pseudohypo- parathyroidism, vitamin D deficiency should be eliminated.

When osteomalacia or rickets on the radiograph, typical changes in the skeleton are noticeable. The plasma phosphate level is often slightly reduced, the level of alkaline phosphatase is increased, reflecting the increased mobilization of calcium from the bone. Determining the level of active and inactive forms of vitamin D in plasma can help differentiate vitamin D deficiency from vitamin D-dependent states. Family hypophosphatemic rickets are identified by an associated renal loss of phosphate.

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Treatment of the hypocalcemia

In tetany, 10 ml of a 10% calcium gluconate solution is intravenously administered. The answer can be complete, but lasts only a few hours. Repeated infusions of 20-30 ml of 10% calcium gluconate solution in 1 L of 5% dextrose solution or the addition of a permanent infusion may be required within the next 12-24 hours. Calcium infusions are dangerous in patients receiving digoxin, and should be administered slowly with constant ECG monitoring. If tetany is associated with hypomagnesemia, a transient response to the administration of calcium or potassium may develop, but complete recovery can only occur if magnesium deficiency is compensated.

With transient hypoparathyroidism after thyroidectomy and partial parathyroidectomy, oral administration of calcium may be sufficient. However, hypocalcemia can be particularly severe and prolonged after subtotal parathyroidectomy in patients with chronic renal failure or the last stage of kidney disease. After the operation, long-term parenteral administration of calcium may be required; for 5-10 days, it may be necessary to administer 1 g per day of calcium. An increase in plasma alkaline phosphatase in such conditions can be evidence of rapid calcium uptake by bone tissue. The need for large amounts of parenteral calcium administration is usually maintained until the level of alkaline phosphatase decreases.

With chronic hypocalcemia, the intake of calcium and sometimes vitamin D inside is usually sufficient. Calcium can be taken in the form of 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 it is possible to use any form of vitamin D, analogues of the active form of the vitamin have the best effect: 1 hydroxylated compounds, as well as synthetic calcitriol [1,25 (OH) 2D] and pseudohydroxylated analogs (dihydrotachysterol). These drugs have a more active effect and are quickly eliminated from the body. Calcitriol is especially useful in renal failure, since it does not require metabolic changes. In patients with hypoparathyroidism, the response usually develops at doses of 0.5-2 μg / day orally. With pseudohypoparathyroidism, only calcium intake can sometimes be used. The effect of calcitriol is achieved when taking 1-3 μg / day.

The intake of vitamin D is not effective without adequate intake of calcium (1-2 grams of elemental calcium per day) and phosphate. Vitamin D toxicity with severe symptomatic hypercalcemia can be a serious complication of treatment with vitamin D analogues. After stabilizing the calcium level, the plasma calcium concentration should be monitored daily during the first month and then at 1-3 month intervals. The maintenance dose of calcitriol or dihydrotachysterol usually decreases with time.

In rickets caused by vitamin D deficiency, a dose of 400 IU per day of vitamin D (in the form of vitamin D2 or D3) is usually used; in the presence of osteomalacia within 6-12 weeks, a dose of 5000 IU per day of vitamin D is prescribed, and then decreases to 400 IU per day. At the initial stages of treatment, an additional 2 g of calcium per day is desirable. In patients with rickets or osteomalacies caused by inadequate sun exposure, exposure to sunlight or the use of ultraviolet lamps may be sufficient.

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

Hypocalcemia is treated depending on the severity of bone tissue damage. In severe cases, it is necessary to administer up to 6 μg / kg of body weight or 30-60 μg / day of calcitriol supplemented with up to 3 g of elemental calcium per day. When treating vitamin D, it is necessary to control the level of calcium in the plasma; Hypercalcemia, which sometimes develops, usually responds quickly to a change in the dose of vitamin D.