Disorders of Calcium and Magnesium Metabolism

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112 Disorders of Calcium and Magnesium Metabolism

image Serum Calcium Concentration

The calcium concentration is essential to many physiologic phenomena, including preservation of the integrity of cellular membranes, neuromuscular activity, regulation of endocrine and exocrine secretory activities, blood coagulation, activation of the complement system, and bone metabolism.

image Hypocalcemia

Disorders associated with hypocalcemia can be classified into disorders related to vitamin D and disorders related to parathyroid hormone.

Disorders Related to Vitamin D Deficiency

Vitamin D Deficiency

Hypocalcemia is a common feature of vitamin D deficiency. The common causes of vitamin D deficiency are listed in Box 112-1. Lack of sunlight exposure impairs endogenous vitamin D synthesis. Because vitamin D is a fat-soluble vitamin, nutritional osteomalacia usually is associated with a deficient intake of food products containing fatty substances. Gastrectomy may lead either to dietary deficiency due to avoiding fatty products and/or due to malabsorption of vitamin D, as noted with Billroth type II surgery, in which a vitamin D–absorbing bowel segment is bypassed. Deficiency of bile salts impairs vitamin D absorption. Small-bowel diseases, laxative abuse, and certain anticonvulsants (phenytoin) interfere with absorption. Urinary losses of vitamin D were linked to Fanconi’s syndrome and nephrotic syndrome.7 Because hepatic formation of 25(OH) vitamin D from vitamin D is not tightly controlled and depends primarily on the availability of vitamin D, the serum level of 25(OH) vitamin D3 is utilized as a measurement of body stores of vitamin D; low levels of 25(OH) vitamin D indicate vitamin D deficiency.1

Impaired Metabolism of Vitamin D

Hypocalcemia in patients ingesting phenobarbital is associated with low levels of circulating 25(OH) vitamin D. Half-life of vitamin D and 25(OH) vitamin D are shortened by barbiturates, owing to induction of microsomal enzymes in the liver. Low circulating levels of 25(OH) vitamin D also have been observed in patients with hepatic failure due to reduced transformation of vitamin D to 25(OH) vitamin D in the liver.8

Dietary calcium deprivation increases the clearance and inactivation of 25(OH) vitamin D and causes vitamin D deficiency. This variety of vitamin D deficiency may be caused by secondary hyperparathyroidism, which augments renal synthesis of 1,25(OH)2 vitamin D and in turn enhances the degradation of 25(OH) vitamin D to inactive metabolites.

Hypothetically, this mechanism may account for vitamin D deficiency in clinical states of calcium malabsorption, including gastrointestinal (GI) diseases, anticonvulsant therapy (e.g., phenytoin), and certain drugs such as colchicine, fluoride, and theophylline. Likewise, increased intake of foods rich in phytate, oxalate, and citrate that chelate calcium in the GI tract and render it nonabsorbable may cause vitamin D deficiency.1,9

Vitamin D–dependent rickets type I (VDDR-1), also designated as pseudovitamin D deficiency, is inherited as an autosomal recessive disorder in which 25(OH) vitamin D-hydroxylase in the proximal tubules is deficient due to defects in the 1α-hydroxylase gene. It is manifested by early hypocalcemia, hypophosphatemia, severe secondary hyperparathyroidism, and severe rickets. The serum 1,25(OH)2 vitamin D is undetectable or very low, whereas 25(OH) vitamin D levels are normal. The clinical abnormality can be reversed completely by the administration of pharmacologic doses of vitamin D or physiologic doses of 1,25(OH)2 vitamin D. Linkage analysis in families with VDDR-1 mapped the disease locus to chromosome 12q13-14.10

Disorders Related To Parathyroid Hormone

Reduced Production of PTH

Secondary Hypoparathyroidism

Hypoparathyroidism may be caused by surgery. This variety of hypoparathyroidism may result from accidental removal of parathyroids or traumatic interruption of their blood supply. Hypocalcemia that appears after excision of parathyroid adenoma results from functional suppression and hypofunctioning of the remaining normal glands and is frequently transient. “Hungry bone syndrome” can develop following parathyroidectomy in patients with markedly elevated preoperative PTH levels. Decreased postoperative levels of PTH cause a “rebound” recalcification of bones secondary to unbalanced osteoblast and osteoclast activity. This results in profound hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase. Similarly, hypocalcemia has been reported to occur in 15% of patients after thyroidectomy.11

Hypoparathyroidism may be a component of multiple endocrine dysfunctions, including adrenal insufficiency, pernicious anemia, thalassemia, and Wilson’s disease. In the last two disorders, the deposition of iron and copper, respectively, in the parathyroid glands is the likely underlying mechanism.12

Hypocalcemia may occur in magnesium depletion.13 It has been shown that the chronic state of low serum magnesium diminishes the release of PTH.13 Hypomagnesemia has been reported to induce skeletal resistance to PTH.14 Magnesium level should always be checked during the workup of profound refractory hypocalcemia. The mechanisms that underlie the effects of hypomagnesemia on serum calcium are poorly understood. It may be speculated, however, that magnesium depletion may impair the activity of the calcium pump and thus alter the distribution of calcium between the extracellular and intracellular spaces.

Hypocalcemia in association with hypomagnesemia has been reported in 60% of patients with severe acute respiratory syndrome.15 Hypocalcemia may follow therapeutic use of magnesium sulfate (e.g., in preeclampsia) secondary to magnesium-induced suppression of PTH. Aminoglycosides and cytotoxic agents may exert a toxic effect on parathyroid glands, leading to hypocalcemia.1,13 Symptomatic hypoparathyroidism has been observed in association with HIV infection.1

Primary (Idiopathic) Hypoparathyroidism

Primary hypoparathyroidism may occur in association with other endocrine disorders or as an isolated entity. The latter is termed isolated hypoparathyroidism, and it may occur as a sporadic or familial disorder, inherited as both an autosomal dominant and recessive form.14

Aplasia or hypoplasia of the parathyroids is most commonly caused by the DiGeorge velocardiofacial syndrome, associated with deletions of chromosome 22q11.2. Most cases are sporadic, but familial cases with autosomal dominant inheritance have been reported. Affected patients have abnormalities in organs derived from the third and fourth branchial arches including the parathyroid glands, thymus, and outflow tract of the heart. These patients typically present in the first week after birth with signs of hypocalcemia such as tetany and seizures. They have characteristic facial features, an upturned nose, and a widened distance between the inner canthi (telecanthus), with short palpebral fissures. Cardiac defects include truncus arteriosus, tetralogy of Fallot, or interrupted aortic arch. Thymic hypoplasia leads to immune deficiencies. CATCH 22 syndrome is an acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia caused by chromosome 22q11 deletions.16

Autoimmune hypoparathyroidism is commonly a part of polyglandular autoimmune syndrome type I, which is a familial syndrome. It occurs during childhood, is inherited as an autosomal recessive trait, and is associated with mucocutaneous candidiasis and adrenal insufficiency. It can present as hypoparathyroidism in the absence of the two other disorders. Adrenal insufficiency is a late phenomenon in this syndrome. The acronym APECED stands for autoimmune polyglandular endocrinopathy with candidiasis and ectodermal dystrophy, including vitiligo, alopecia, nail dystrophy, enamel hypoplasia of teeth, and corneal opacities.17

Hypoparathyroidism was also reported in association with two mitochondrial cytopathies with mitochondrial DNA mutations: Kearns-Sayre syndrome and Kenny-Caffey syndrome.18

Impaired Action of PTH Due to Peripheral Resistance

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a rare inheritable disorder characterized by mental retardation, moderate obesity, short stature, brachydactyly with short metacarpal and metatarsal bones, exostoses, radius curvus, and an expressionless face.19 The biochemical abnormalities are hypocalcemia and hyperphosphatemia. Some patients exhibit only the biochemical abnormalities. Thus, the disorder may be subdivided into pseudohypoparathyroidism type IA, which is also known as Albright’s hereditary osteodystrophy, and type IB. Pseudohypoparathyroidism type IA is associated with both the somatic and biochemical abnormalities, and type IB presents as the biochemical defect without the somatic abnormalities. Because of the hypocalcemic stimulus, secondary hyperparathyroidism may develop in some patients, leading to osteitis fibrosa cystica. Failure of the kidney to form 1,25(OH)2 vitamin D3 in response to PTH results in a low circulating level of this metabolite.

Calcitonin

Calcitonin binds to specific cell membrane receptors on bone-resorbing osteoclasts and depresses their activity. In this regard, it antagonizes the effect of PTH on bone.

Medullary carcinoma of the thyroid is derived from parafollicular cells of ultimobranchial organ, which secrete calcitonin. It may present as a familial and autosomal dominant or sporadic disorder. Patients with this tumor have high circulating levels of calcitonin, and hypocalcemia has been reported in some patients.20

Hypocalcemia has been described in critically ill patients admitted to intensive care units (ICUs).21 The degree of hypocalcemia correlated with the severity of the disease and was most commonly detected in patients who were septic. The mechanism of this abnormality is unknown. Circulating levels of calcitonin precursors (CTpr) increase up to several thousandfold in response to microbial infections, and this increase correlates with the severity of the infection and mortality. The relationship of elevated CTpr to the emergence of hypocalcemia needs to be investigated.22

Bisphosphonates

Hypocalcemia has been reported in patients with bone metastases of solid tumors who were treated with pamidronate23 and in a patient treated with alendronate for osteoporosis. In both cases, bisphosphonate induced skeletal resistance, and PTH was proposed as a possible mechanism. Hypomagnesemia may cause hypocalcemia by a similar mechanism.24

Rapid Removal of Calcium from the Circulation

Hyperphosphatemia

The various causes of hyperphosphatemia that may lead to hypocalcemia are listed in Box 112-2. The oral or intravenous (IV) administration of phosphate lowers serum calcium concentration in normal animals and hypercalcemic human subjects, which formed the basis for the clinical use of phosphate administration in states of hypercalcemia. The association of hyperphosphatemia and hypocalcemia has been reported to occur in a variety of circumstances. Hyperphosphatemia has been observed in persons ingesting large quantities of phosphate-containing laxatives or receiving enemas with phosphate. Hyperphosphatemia and hypocalcemia with tetany may develop in infants fed cow’s milk, which contains 1220 mg of calcium and 940 mg of phosphorus per liter (human milk contains 340 mg of calcium and 150 mg of phosphorus per liter).25,26 The mechanism responsible for lowering serum calcium concentration by the administration of phosphate is not entirely understood. One possibility is that the decrease in serum calcium concentration is caused by deposition of calcium phosphate in the bone, soft tissues, or both.

In chronic renal failure, a constant increase in serum phosphorus concentration is observed when the glomerular filtration rate is 30 mL/min or less, and hyperphosphatemia is a common accompaniment of acute renal failure.

In patients undergoing chemotherapy for neoplastic diseases, particularly of lymphatic origin, large quantities of phosphates may be released into the circulation as a result of the cytolysis. Spontaneous tumor lysis may cause hyperphosphatemia and, consequently, hypocalcemia.

Citrate, Lactate, Bicarbonate, Na-EDTA, Foscarnet, and Poisoning with Ethylene Glycol

Citrate is present in stored blood products (such as plasma and platelets) as an anticoagulant that exerts its action through the binding of ionized calcium. Patients receiving a massive transfusion frequently experience hypocalcemia; however, this is usually transient secondary to the rapid hepatic metabolism of citrate.28 The ionized hypocalcemia (with a normal total calcium concentration) can lead to tetany, myocardial dysfunction, or hypotension. The same applies to IV lactate and Na-EDTA, which causes ionized hypocalcemia. Bicarbonate may directly complex calcium or may increase protein binding of calcium from the resulting alkalosis. Low serum ionized calcium may be a complication of ethylene glycol (antifreeze) poisoning because of calcium binding by oxalic acid, which is the metabolite of the poison. An analog of the pyrophosphate, foscarnet, used to treat cytomegalovirus infection in HIV-infected patients causes ionized hypocalcemia secondary to chelation of calcium by foscarnet.1

Clinical Consequences of Hypocalcemia

The clinical presentation of hypocalcemia depends on its severity, rapidity of the fall in serum calcium concentration, age of the patient, chronicity of hypocalcemia, and comorbid conditions.

Most infants with hypocalcemia are asymptomatic. Among those who become symptomatic, the characteristic sign is increased neuromuscular irritability. Generalized or focal clonic seizures may be the first indication of hypocalcemia. Other manifestations may include stridor caused by laryngospasms and wheezing caused by bronchospasms. Vomiting may be caused by pylorospasm.

Neuromuscular manifestations in adults with hypocalcemia are variable (Table 112-1). The characteristic symptom is tetany, which includes perioral numbness and tingling, paresthesias in the extremities, carpopedal spasm, laryngospasm, and focal and generalized seizures. The spasms of the diaphragm and of intercostal muscles may cause respiratory arrest and asphyxia.

TABLE 112-1 Clinical Manifestations of Abnormalities in Magnesium and Calcium

Increased Serum Levels
System Magnesium Calcium
Gastrointestinal Nausea/vomiting Anorexia, nausea/vomiting, abdominal pain, constipation
Neuromuscular Weakness, lethargy, ↓ reflexes Depression, confusion, coma, muscle weakness, back and extremity pain
Cardiovascular Hypotension, cardiac arrest Hypotension, arrhythmias
Renal Polydipsia, polyuria
Decreased Serum Levels
System Magnesium Calcium
Gastrointestinal
Neuromuscular Hyperactive reflexes, muscle tremors, tetany, delirium, seizures Hyperactive reflexes, paresthesias, weakness, paralysis, tetany, seizures, carpopedal spasm, seizures
Cardiovascular Arrhythmia Heart failure

The characteristic physical findings in patients with hypocalcemia that are indicative of latent tetany are Trousseau’s sign (carpal spasm) and Chvostek’s sign (facial muscle contraction). Visual impairment may by caused acutely by papilledema, whereas usually chronic hypocalcemia, when due to hypoparathyroidism, causes cataracts. Myocardial functional and anatomic abnormalities have been associated with hypocalcemia. Acute hypocalcemia may be associated with hypotension. Very often the absence of the compensatory reflex tachycardia aggravates the condition. The typical ECG change consists of prolongation of the QT interval. Hypocalcemia prolongs phase 2 of the action potential and thus prolongs repolarization time, because inward calcium currents are one of the factors determining the plateau configuration of the action potential. QT prolongation is associated with a variety of ventricular arrhythmias, most characteristically torsades de pointes. These abnormalities can be reversed with calcium replacement. Calcium therapy significantly shortens the repolarization intervals and decreases the frequency of ventricular premature contractions.29 Chronic hypocalcemia may infrequently cause hypocalcemic cardiomyopathy, which is a dilated cardiomyopathy. Partial recovery of cardiac function has been reported after restoration of normocalcemia.30

Treatment of Hypocalcemia

Symptomatic hypocalcemia generally responds promptly to IV administration of calcium. The commonly used preparations are 10% calcium gluconate (10-mL ampules containing 90 mg of elemental calcium) and 10% calcium chloride (10-mL ampules containing 360 mg of elemental calcium). The treatment should be instituted immediately, because delay may be associated with further aggravation of tetany and lead to generalized seizures and even cardiac arrest.

The IV administration of 100 to 200 mg elemental calcium (5-10 mEq) should be slow to avoid complications. Then the administration of calcium can be continued as a slow drip of 100 to 200 mg of elemental calcium, diluted in 250 to 500 mL of 0.45% NaCl or D5W, given over several hours until oral calcium takes over. Calcium extravasation should be avoided because it causes local irritation and thrombophlebitis.

Chronic treatment with oral calcium should follow the IV therapy in patients with chronic hypocalcemia due to irreversible causes such as hypoparathyroidism. Oral calcium administration constitutes the best initial therapy in mild cases. The commonly used preparations are in tablet form: calcium lactate, 300 mg (60 mg of elemental calcium); chewable calcium gluconate, 1 g (90 mg of elemental calcium); calcium carbonate (Os-Cal), 250 mg of elemental calcium; calcium carbonate, 650 mg (250 mg of elemental calcium); and calcium citrate, 950 mg (200 mg of elemental calcium).

Oral calcium also may be used for patients for whom the diagnosis of irreversible hypoparathyroidism has not been established with absolute certainty. In patients who fail to respond to oral calcium, vitamin D in large doses is the only available treatment. The commonly used preparations are capsules containing 1.25 mg (50,000 units) of vitamin D2 (ergocalciferol). The average dose ranges between 1.25 and 3.75 mg/d. DHT3 is three times as potent as vitamin D2 in raising serum calcium concentration. Each capsule contains 0.125 mg of DHT3. The average daily dose ranges between 0.25 and 1 mg of DHT3. Both vitamins are available in liquid oil solutions as well. Both hypoparathyroidism and pseudohypoparathyroidism respond to physiologic doses of 1,25(OH)2 vitamin D3 and 1α(OH) vitamin D3 with restoration of serum calcium concentration to normal. Calcitriol is marketed as Rocaltrol and is dispensed in capsules containing 0.25 and 1 µg. Chlorothiazides may enhance the calcemic action of vitamin D and its analogs, whereas furosemide may aggravate the hypocalcemia through its hypercalciuric action.

Patients in whom hypocalcemia is associated with hypomagnesemia respond poorly to IV calcium, but the serum calcium concentration is restored to normal levels with correction of the hypomagnesemia.

Symptoms rarely develop in patients with chronic renal failure and hypocalcemia. However, very often reduction of elevated serum phosphorus with phosphate-binding antacids causes an increase in serum calcium concentrations.

Hypocalcemia associated with osteomalacia resulting from vitamin D deficiency is rarely symptomatic. It usually responds to physiologic doses of vitamin D and increased oral calcium intake.

image Hypercalcemia

Primary hyperparathyroidism and malignancy account for 80% to 90% of all cases of hypercalcemia.31 Primary hyperparathyroidism is the leading cause of hypercalcemia in the outpatient setting. Its incidence is 1% in the normal population.32

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