112 Disorders of Calcium and Magnesium Metabolism
Serum Calcium Concentration
Total Serum Calcium Concentration
The normal range for total serum calcium must be established for each laboratory and varies according to the method used. Calcium exists in three forms: protein-bound calcium, ionized calcium, and nonionized calcium.1
Protein-Bound Calcium
Approximately 40% of total calcium is bound to serum proteins, and 80% to 90% of this calcium is bound to albumin. Variations in serum protein alter proportionately the concentration of the protein-bound and total serum calcium. An increase in serum albumin concentration of 1 g/dL increases protein-bound calcium by 0.8 mg/dL, whereas an increase of 1 g/dL of globulin increases protein-bound calcium by 0.16 mg/dL. However, the validity of this correction in critical illness has been questioned, with multiple authors emphasizing the importance of directly measuring serum ionized calcium concentration in this patient population.2,3 Marked changes in serum sodium concentration also affect the protein binding of calcium. Hyponatremia increases, whereas hypernatremia decreases, protein-bound calcium. Changes in pH also affect protein-bound calcium, and an increase or decrease of 0.1 pH, respectively, increases or decreases protein-bound calcium by 0.12 mg/dL. In vitro, freezing and thawing serum samples may decrease the binding of calcium as well.
Cytosolic Free Calcium
The normal concentration of cytosolic calcium is 100 nM/L, which is 10,000-fold lower than the concentration of extracellular calcium. This very steep gradient is maintained by an energy-driven calcium pump known as the plasma membrane Ca++-ATPase (PMCA). In certain types of cells a Na+/Ca++ exchanger energized by Na+ gradient helps drive cytosolic calcium into the extracellular space. Part of cellular calcium is sequestered in intracellular organelles including endoplasmic reticulum, sarcoplasmic reticulum in muscle cells, and mitochondria. These organelles are endowed with their own calcium pumps that help preserve the very low free cytosolic calcium. The calcium-dependent intracellular signaling generally requires a 10-fold increase in free cytosolic calcium. With each heartbeat, the cytosolic calcium concentration in cardiac myocytes is elevated 10-fold, from a resting level of 100 nM to 1000 nM. Likewise, in other signaling events such as T-cell activation, which triggers the transcription of interleukin (IL)-2, a 10-fold increase in cytosolic calcium serves as the signal for the response. Elevation in cytosolic calcium is mediated by the activation of calcium channels, which allows passive calcium flux down its electrochemical gradient.4
Vitamin D Metabolism
Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorous, and bone metabolism.5
Calcium Homeostasis
Calcium is regulated by a combination of bone exchange, renal excretion, and intestinal absorption. Decreased ionized calcium increases PTH (parathyroid hormone) and 1,25-dihydroxyvitamin D2, both of which increase osteoclastic activity and thus stimulate bone resorption. Renal excretion of calcium is regulated by PTH and vitamin D, which increase distal tubular reabsorption of calcium, and by calcitonin, which inhibits calcium reabsorption. Intestinal absorption of calcium depends primarily on 1,25-dihydroxyvitamin D2, which stimulates calcium absorption from all parts of the small intestine.6
Hypocalcemia
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
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 D1α-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
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.
Acute Pancreatitis
The hypocalcemia associated with acute pancreatitis is not well understood. The precipitation of calcium soaps in the abdominal cavity, which results from the release of lipolytic enzymes and fat necrosis, has been suggested as the mechanism of hypocalcemia. Recently, endotoxemia has been implicated.27
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
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
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 Hypercalcemia is most often detected in routinely tested blood specimens. Malignancy is the prevalent cause of hypercalcemia in hospitalized patients. The most common iatrogenic hypercalcemia is milk-alkali syndrome, which ranks third after malignancy and hyperparathyroidism and accounts for 10% to 15% of cases with hypercalcemia. The free over-the-counter access to the generic brands of calcium carbonate and their widespread use for heartburn, osteoporosis, and as an alleged prevention of colon cancer may be the underlying cause for the rise in the incidence of milk-alkali syndrome.33
Hypercalcemia presents a challenge to every clinician. In some instances, the cause of hypercalcemia is self-evident on the basis of the circumstantial clinical findings, whereas extensive efforts are required to establish the etiology in other situations. The important causes of hypercalcemia are listed in Box 112-3.
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