Calcium, phosphorus, and magnesium serve critical functions in skeletal growth, bone strength, and neuromuscular excitation. Each of these electrolytes is also essential for the most fundamental of intracellular biochemical reactions. Calcium ion (Ca2+) acts as an intracellular "second messenger" to transmit activation of intracellular enzyme reactions. The intracellular transfer of phosphate groups mediates storage and release of energy from adenosine triphosphate (ATP), and phosphorylation activates latent proteins for diverse cellular functions. Magnesium ion (Mg2+) is a cofactor for more than 300 enzymes, including ATPase and adenylate cyclase. Early recognition and correction of inherited or acquired disorders of these electrolytes will prevent growth failure, bone deformity, or muscle wasting and may avoid or reverse acute life-threatening complications.
PHYSIOLOGY OF CALCIUM, PHOSPHORUS, AND MAGNESIUM HOMEOSTASIS
Extracellular calcium and phosphorus are maintained at normal levels by the action of 1,25-dihydioxyvitamin D (1,25[OH]2D) on the intestine and bones and by parathyroid hormone (PTH) on kidneys and bones. Synthesis of 1,25(OH)2D and secretion of PTH are, in turn, directly stimulated or suppressed by blood levels of ionized calcium or phosphorus.1
If blood levels of ionized calcium drop by as little as 0.1 mg/dL, the parathyroid glands secrete PTH, which stimulates the enzyme 25-hydroxyvitamin D3-Iahydroxylase in renal proximal tubular epithelial cells. This enzyme converts the less active 25-hydroxyvitamin D into its most active 1,25(OH)2D form. Both PTH and 1,25(OH)2D act on the bone mineral pool to release calcium and phosphorus. Parathyroid hormone also increases reabsorption of filtered urinary calcium by activating calcium channels in the distal convoluted tubules. In addition, 1,25(OH)2D promotes active transport of calcium across intestinal and renal distal tubular epithelia by stimulating synthesis of the calcium-binding protein, calbindinD. Conversely, elevations of blood calcium result in suppression of PTH secretion and 1 a-hydroxylase activity. Mechanisms that transport ionized calcium from bone, kidney, and intestine therefore are reversed.
Elevation in serum phosphorus, as in early renal insufficiency, is another inducer of PTH secretion. Parathyroid hormone acts on renal proximal tubules to reduce reabsorption of phosphorus from glomerular filtrate. Action of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemia while hypophosphatemia is a strong stimulus for 1,25(OH)2D production. Action of 1,25(OH)2D on the duodenum and jejunum increases phosphorus as well as calcium absorption. The resulting rise in calcium suppresses PTH release, and proximal tubules thereby increase their rate of phosphorus reabsorption from urinary filtrate.
Magnesium appears to be absorbed through the jejunum and ileum in the absence of vitamin or hormone control. Regulation of magnesium homeostasis occurs mainly in the kidney by alterations in the reabsorption of filtered Mg2+.2 The mechanisms that control reabsorption have not yet been elucidated, but appear to be inhibited by increased urinary calcium, sodium, and protein. Intracellular levels of magnesium are critical to calcium and phosphorus homeostasis because Mg2+ must be present as a cofactor for PTH secretion and the activity of many enzymes through which PTH and 1,25(OH)2D exert their effects.
In normal conditions, blood calcium is divided between three fractions: 40% is bound to protein (primarily albumin), 12% is complexed to anions such as phosphate, citrate, or bicarbonate, and 48% exists in the free ionized state necessary for most metabolic functions. One gram per deciliter of albumin binds approximately 0.8 mg/dL calcium. Therefore, in the hypoalbuminemic state, plasma concentrations of total calcium are reduced accordingly. In the critically ill or edematous child, calcium and protein stores may both be diminished, and parenteral administration of albumin will further bind already marginal levels of ionized calcium and place the child at risk for seizures, tetany, and laryngospasm. Furthermore, the affinity of calcium for albumin varies with pH; binding of calcium to albumin increases by 0.12 mg/dL for each 0.1 unit rise in pH. Thus, correction of metabolic acidosis in the hypocalcemie patient also may precipitate tetany. In addition to albumin, accumulation of blood anions such as phosphate (eg, in uremia) or citrate (after multiple transfusions) will complex with and deplete ionized calcium.
Respiratory or metabolic acidosis increases urinary losses of calcium, phosphorus, and magnesium, while respiratory or metabolic alkalosis tend to enhance reabsorption of all three. Increases in dietary sodium chloride or protein also will promote urine calcium and magnesium excretion. Loop diuretics, such as furosemide, or osmotic agents, such as mannitol or glucose, increase urinary excretion of magnesium and calcium.
EVALUATION OF CALCIUM, MAGNESIUM, OR PHOSPHORUS IMBALANCE
Table 1 lists the physical signs and symptoms for conditions in which derangements of calcium, magnesium, or phosphorus may be the primary etiology.2'4 Because the homeostatic mechanisms that govern these three electrolytes are interrelated, a derangement of one ion is likely to be accompanied by abnormalities of the other two.
Tables 2 and 3 list laboratory tests and causes of calcium, phosphorus, and magnesium abnormalities. Although ionized calcium may be roughly estimated from measurements of total calcium and serum albumin, direct measurement of ionized calcium is recommended when available for the evaluation of sick patients with suspected hypocalcemia.5 Because the kidneys play a key role in the regulation of these ions, assessment of renal function and urinary electrolyte losses is an important component of evaluation. For example, serum magnesium may be normal despite abnormal tissue and bone levels. Measurement of reduced urinary Mg2+ excretion may be necessary to diagnose systemic magnesium deficiency.4
The first etiology to be considered for persistent hypocalcemia is nutritional deficiency of vitamin D and/or calcium. Inadequate intake of vitamin D provides reduced substrate for 25a-hydroxylase in the liver and 1 a-hydroxylase activity in the kidneys. Chronic hypocalcemia from vitamin D deficiency leads to secondary hyperparathyroidism, hypophosphatemia, and rickets. Blood levels of 25(OH)D and 1,25(OH)2D are low. Although chronic vitamin D deficiency is uncommon in developed countries, the pediatrician may encounter patients with acute deficiencies in calcium and vitamin D in the hospital intensive care unit.
Clinical Features Associated With Abnormal Calcium, Phosphorus, or Magnesium Regulation
Hypocalcemia is seen in patients with decreased glomerular filtration rate (GFR) from acute tubular necrosis, severe glomerulonephritis, or chronic renal failure.6 Glomerular inflammation or injury reduces filtration of dietary phosphorus, and the resulting hyperphosphatemia depresses blood ionized calcium and induces compensatory (secondary) hyperparathyroidism. Damage to renal tubule cells diminishes activity of 1 a-hydroxylase, and the secondary deficiency in 1,25(OH)2D further exacerbates hypocalcemia and PTH secretion. Bone stores thus become the major source of Ca2+, and the duration of renal insufficiency can be estimated from the degree of serum PTH and alkaline phosphatase elevation. Children with renal failure are managed with dietary phosphorus restriction, calcium supplementation, and 1,25(OH)2D (calcitriol).7
Children with nephrotic proteinuria are at risk for mild to moderate hypocalcemia.8,9 Total calcium levels are reduced in relation to hypoalbuminemia, but the fraction of ionized calcium also may be low from reduced absorption through edematous intestinal mucosa, increased urinary tosses of cholecalciterol binding globulin, and decreased levels of 25(OH)D. In addition, prednisone therapy increases urinary calcium losses. Low-dose calcium supplement may be necessary to treat osteopenia in patients with frequently relapsing or steroid-dependent nephrotic syndrome. The clinician should check and correct ionized calcium before administering parenteral albumin and furosemide to the nephrotic patient with severe anasarca.
Absent or diminished PTH in the presence of severe hypocalcemia indicate primary or acquired hypoparathyroidism.3 Patients with this disorder also have hyperphosphatemia from inappropriate tubular reabsorption of phosphorus in the absence of PTH. The differential diagnosis for parathyroid gland failure includes primary aplasia, hypoplasia, or DiGeorge syndrome in the infant and mitochondrial myopathy syndromes or autoimmune polyglandular disease in the older child.
The patient with normal renal function who has hypocalcemia and hyperphosphatemia but normal to elevated PTH may have peripheral resistance to endogenous PTH or pseudohypoparathyroidism. This may be inherited with a distinct phenotype that includes dysmorphic facies, short stature, mild mental retardation, and subcutaneous ossification. Patients with clinical hypoparathyroidism are treated with aggressive supplementation of calcium and 1,25(OH)2D, and moderate restriction of dietary phosphorus.
Vitamin D-Dependent Rickets
Inherited defects in the ability to produce or respond to 1,25(OH)2D are very rare causes for hypocalcemia in children.
Initial evaluation of the child with persistently elevated serum calcium should exclude primary hyperparathyroidism. This disorder is rare in early childhood. Presenting symptoms in the neonate or infant are those of acute hypercalcemia with lethargy, coma, cardiac dysrhythmia with reduced QT interval on EKG, hypertension, or renal failure. The latter symptoms are thought to be due to direct vasoconstrictor action of Ca2+ on peripheral and renal arteriolar smooth muscle cells10 and to renal tubular obstruction from calcium precipitation. Chronic symptoms in the older child are osteodystrophy, anemia, renal calculi, nephrocalcinosis with diabetes insipidus and renal tubular acidosis, chronic renal failure, myopathy, peptic ulcer, lethargy, and depression.2,3 Hypercalcemia is accompanied by elevated PTH and 1,25(OH)2D, hypophosphatemia, calciuria, phosphaturia, and nyperchloremic metabolic acidosis. Several autosomal dominant syndromes must be considered in the differential diagnosis of the child with primary hyperparathyroidism.3
Intoxication with vitamin D or calcium must be considered as an etiology of hypercalcemia. The cause is commonly iatrogenic, as in the child who is treated with calcitriol and calcium carbonate for renal osteodystrophy. However, intoxication with vitamin D, calcium, or vitamin A also may occur when a family gives excessive vitamins. Calcium elevations associated with hypervitaminosis A are due to increased bone resorption. Thiazide diuretics can be a rare cause of hypercalcemia in children because of reduced urinary calcium losses.
Hypercalcemia occurs less commonly in childhood malignancies than in adult malignancies. Pathogenic mechanisms are lytic resorption of bone metastases, ectopic production of parathyroid hormone-related peptides, or ectopic production of 1,25(OH)D. Table 3 lists other uncommon but potential causes for hypercalcemia in children.
This is likely to be the most common disorder of calcium metabolism encountered in the pediatrician's outpatient practice. Symptoms include dysuria, frequency, recurrent abdominal pain, recurrent micro- or macroscopic hematuria, and nephrolithiasis.11 However, a common presentation for normocalcemic hypercalciuria is isolated, persistent, asymptomatic microhematuria. The mechanism causing the hypercalciuria is unknown. Affected children may have overabsorption of intestinal calcium or reduced resorption of filtered urinary calcium. Urine calcium excretion exceeds 350 mg/24 hours. Diagnosis often can be confirmed with a calcium to creatinine ratio (mg/mg) that exceeds 0.21 on a spot urine sample. Urinalysis, urine culture, BUN, creatinine, electrolytes, calcium, phosphorus, and renal ultrasound also should be performed to exclude infection, glomerulonephritis, renal tubular disease, or obstructive uropathy. Symptoms are managed by mild to moderate restriction of sodium chloride (since urinary sodium excretion is coupled with calcium excretion) and by avoidance of dietary calcium intake in excess of the recommended daily allowance.
Diagnostic Evaluation of Divalent Ion Imbalance
Vitamin D deficiency results in hypophosphatemia but dietary phosphorus deficiency is unusual in children because of their proclivity for dairy products. However, in the critically or chronically ill child, inadequate phosphate in total parenteral nutrition, frequent dosing of phosphate-binding antacids, or excessive stool losses can cause hypophosphatemia.
"Hungry Bone" Syndrome
Initial therapy to correct chronic hyperparathyroidism may be accompanied by a dramatic fall in both phosphorus and calcium levels in the serum and urine. Severely demineralized, rachitic bones suddenly become a "sink" into which calcium and phosphorus are rapidly absorbed. Therefore, careful monitoring and aggressive replenishment of phosphorus or calcium may be needed for several weeks after parathyroidectomy, renal transplantation, or institution of vitamin D replacement.3
Hypophosphatemia due to excessive urinary losses of phosphorus is often caused by a renal tubulopathy such as Fanconi's syndrome.12 Urinary excretion is increased for other solutes as well, including potassium, sodium, uric acid, bicarbonate, amino acids and glucose, and the patient may require substantial supplementation of many electrolytes. Observation of hypophosphatemia in this setting should prompt an investigation for an underlying disorder.
Common and Uncommon Causes off Calcium, Phosphorus, and Magnesium Imbalance
Other rare causes of phosphaturia and hypophosphatemia are inherited defects in synthesis or target organ response to 1,25(OH)2D. Patients with x-linked hypophosphatemic rickets ("vitamin Dresistant" rickets) have urinary phosphate wasting and an inability to increase baseline 1 a-hydroxylase activity and 1,25(OH)2D production in the face of hypophosphatemia. These individuals have normal serum levels of calcium, parathyroid hormone, and 1,25(OH)2D. Treatment to prevent rickets and growth failure depends on phosphate supplementation and large doses of calcitriol.
Hyperphosphatemia may be caused by a decrease in urinary phosphorus excretion or by sudden release of intracellular phosphate into the extracellular space.
Renal insufficiency is a relatively common etiology. Mild phosphate accumulation begins when the GFR is compromised to 50% of normal, but pronounced serum phosphorus elevations do not usually occur until the GFR falls below 20%?6·7 Hyperphosphatemia should be sought and treated in acute and transient as well as chronic and progressive renal diseases.
Cell Lysis Syndromes
Sudden lysis of a large volume of cells may result in a burden of extracellular phosphate that exceeds maximal urinary excretion. Exertional or metabolic rhabdomyolysis, severe hemolytic anemia, and chemotherapy for lymphomas or leukemias can produce this. Early recognition is necessary in order to avoid precipitation of phosphate and urate and subsequent renal failure.
Low magnesium levels may account for a significant proportion of apneic episodes, seizures, jitteriness, or lethargy in sick newborns. Hypocalcemia is often associated with these symptoms and treated, but the possibility of an underlying magnesium deficiency is less commonly recognized.4
Gluten enteropathy, steatonhea, and short gut syndrome can cause significant magnesium depletion.2,13 Since bile salts play an important role in the absorption of Mg2+, plasma magnesium levels also should be checked in children with obstructive jaundice from biliary atresia, neonatal hepatitis, or choledochal cyst. Infectious diarrhea can exacerbate subclinical magnesium deficiency in infants with predisposing conditions.
Renal Tubular Losses\
The most common disorders of renal magnesium wasting are induced by drugs (cisplatin, aminoglycosides, amphotericin B, and diuretics); observed during renal recovery after acute obstruction, acute tubular necrosis, or renal transplantation2·'3; or occur in rare tubulopathies such as nephropathic cystinosis, and Bartter's and Gitelman's syndromes.
Hypomagnesemia may be caused by shift of Mg2 + from the extracellular space, as in rapid correction of chronic acidosis, or by binding of Mg2+ by anions in a child who requires infusion of multiple citratecontaining blood products,
The causes of hypermagnesemia in childhood are limited and rarely require intervention. Most children with chronic renal failure have hypermagnesemia. Plasma elevations only become significant (>5 mg/dL) when the patient fails to comply with the standard restricted diet or is inadvertently treated with dialysate containing excess magnesium. Severe and symptomatic hypermagnesemia (5 to 15 mg/dL) may be encountered in the infant bom to an eclamptic mother treated with magnesium sulfate. Hypotonia and lethargy may necessitate temporary ventilatory support.
MANAGEMENT OF DISORDERS OF CALCIUM, PHOSPHORUS, AND MAGNESIUM
Before instituting therapy for low serum total calcium, the clinician should determine serum albumin or ionized calcium to confinn hypocalcemia. Measurement of serum phosphorus is also essential because a calcium (mg/dL) X phosphorus (mg/dL) product >63 is associated with tissue calcification on further administration of calcium. In the alert asymptomatic child, oral supplement in a dose of 1 g elemental calcium/m2 divided into three or four doses per day is the preferred method of administration.
Calcium carbonate is a useful oral supplement for the child with renal insufficiency, moderate hyperphosphatemia, and metabolic acidosis, because the drug weakly binds ingested phosphorus and provides some bicarbonate. Calcium gluconate may be used if the serum phosphorus is low or normal or if the child is alkalotic. Patients symptomatic with hypocalcemia may require parenteral Ca2 + . Centrai intravenous access is preferred. If the clinician must use a peripheral IV, he or she must be certain intravenous placement is secure because extravasation of calcium into soft tissues will cause necrosis. Calcium chloride given as 10 mg/kg IV (maximum of 1000 mg) or calcium gluconate given as 30 mg/kg IV (maximum 1000 mg) are indicated to relieve cardiac dysrhythmia, tetany, seizures, or respiratory failure.
In the child with chronic hypocalcemia and vitamin D deficiency, calcitriol is used to maintain normal calcium levels. The initial dose is 0.25 µg orally each day, but the eventual dose may need to be quite high and will vary according to underlying disease. Serum calcium and phosphorus levels should be measured frequently to avoid iatrogenic vitamin D toxicity and hypercalcemia.
Treatment of hypercalcemia in the medicated or hospitalized child requires review of all intravenous fluids, drugs, and diet to remove sources of calcium and vitamin D. In a child with normal renal function, severe or symptomatic hypercalcemia (exceeding 14 to 15 mg/dL) may be treated with 10 to 20 cc/kg saline bolus followed by 0.5 to 1 mg/kg furosemide to increase urine excretion. Blood pressure should be monitored as the hypercalcémie child may be hypertensive. Severe hypercalcemia in renal insufficiency may require dialysis with a low Ca2+ bath. In infants or children with chronic, severe hypercalcémie syndromes or malignancy, glucocorticoids or diphosphonate therapy have helped reduce calcium.
It is uncommon to need phosphate supplementation because children enjoy milk and those with hypophosphatemia often crave it. However, serum phosphate levels <2 mg/dL must be treated to avoid symptoms. The child can be treated with 2 to 6 mg/kg phosphate in oral supplements divided three to four times daily. Phosphate supplements should be administered at times when they will not antagonize other medications.
Attention must be given to exogenous sources of phosphorus. For example, a child with renal failure may be ingesting phosphorus in excess of the ability of dialysis to clear this. Calcium carbonate, combined with dietary restriction, is used to treat hyperphosphatemia. Antacids containing aluminum hydroxide as phosphate binders are strongly discouraged in kidney failure because of aluminum toxicity for bones, bone marrow, and the brain. Extreme phosphate elevations as a result of cell lysis can be treated with saline bolus and IV mannitol to increase urinary excretion if renal function is normal. However, extreme elevations of phosphorus (>10 to 12 mg/dL) and continued cell lysis make it prudent to prepare for dialysis because renal function may deteriorate.
Children with symptomatic and severe magnesium deficiency may require parenteral magnesium supplementation, particularly if they have severe diarrhea. Standard magnesium therapy is 50% magnesium sulfate solution at a dose of 0.1 mL/kg (maximum of 4 mL), diluted in intravenous crystalloid solution, and administered over 1 hour. The child without severe diarrhea or acute symptoms may receive oral supplement in the form of 10% magnesium chloride solution, magnesium gluconate, or magnesium protein complex. Initial dose may start at 1 to 2 mEq/kg/day but advanced if the child has malabsorption.
Magnesium elevations in the child with renal insufficiency are best treated with dietary restriction and dialysis with a low magnesium bath. In the neonate whose mother has received tocolytic therapy, ventilatory support may be necessary until the magnesium burden is excreted. Intravenous calcium also may be used as a temporary antagonist of magnesium. Parenteral glucose and insulin drip has been used to shift magnesium intracellularly, but if such measures are needed to treat extreme magnesium elevations, it is wise to prepare for hemodialysis.
1 . Pönale AA. Calcium and phosphorus. In: Holliday MA, Barrate TM, Avner ED, cd*. Pediatric Nephrology. 3rd cd. Baltimore. Md: Williams 6k Wilkins; 1994:247-266.
2. Sutton RAL1 Dirks JH. Calcium and magnesium: renal handling and disorders of metabolism. In: Brenner BM, Rector FC, eds. The Kidney. ìrd ed. Philadelphia, Pa: WB Saunders Co; 1986:551-618.
3. Langnun CB. Disorders of phosphorus, calcium, and vitamin D. Jn: Holliday MA1 Barran TM, Avner ED, eds. Pediatric NephroUigy. 3rd ed. Baltimore, Md: Williams & Wilkins; 1994:611-624.
4. Caddell JL. Magnesium in perinatal care and infant health. Magnes Trace Elan. 1992;10:229-250.
5. Lynch RE. Ionized calcium: pediatric perspective. PediarrClin North Am. 1990;37:373389.
6. Mehls O. Renal osteodystrophy in children: etiology and clinical aspects. In: Fine RN. Gruskin AB, eds, End Stage Renal Disease m Children. Philadelphia, Pa: WB Saunders Qi; 1984:227-250.
7. Dabhagh S, Chesney RW. Treatment of renal osteodystrophy during childhood. In: Fine RN. Gruskin AB, eds. End Stage Renal Disease m Children. Philadelphia, Pa: WB Saunders G.; 1984:251-270.
8. Lim P, Jacob E, Tock EPC, Pwee HS. Calcium and phosphorus metabolism in nephrotic syndrome. QJ Med. 1977;46:327-338.
9. Glassock RJ, Adler SG. Ward HJ, Cohen AH. Primary glomerular diseases. In: Brenner BM, Rector FC eds. The Kidney. 3rd ed. Philadelphia. Pa: WB Saunders Co; 1986:929-1013.
10. Campcsc VM. Calcium, parathyroid hormone, and blood pressure. Am } Hypertension. 1989;2:34S-44S.
11. Stapleton FB, Roy S, Noe HN , Jerkins G. Hypercalciuria in children with hematuria. N Engl J Med. 1 984;3 1 0: 1 345- 1 348.
1 2. Foreman JW. Fanconi syndrome and cystinosis. In: Holliday MA, Barrati TM, Avner ED, eds. Pediatric Nephrology. 3rd ed. Baltimore. Md: Williams & Wilkins; 1994:537557.
13. Geven WB, Monnens LAH, Willems JL. Magnesium metabolism in childhood. Miner Electrolyte Mené. 1 99 3; 1 9:308- 313.
Clinical Features Associated With Abnormal Calcium, Phosphorus, or Magnesium Regulation
Diagnostic Evaluation of Divalent Ion Imbalance
Common and Uncommon Causes off Calcium, Phosphorus, and Magnesium Imbalance