++
++
Calcium is the most abundant mineral in the body and is required for proper functioning of numerous intracellular and extracellular processes, including muscle contraction, nerve conduction, hormone release, and blood coagulation. Calcium also plays a unique role in intracellular signaling and is involved in the regulation of enzyme activity. Maintenance of calcium homeostasis is therefore critical. Ionized calcium, which is responsible for the physiologic effects, is maintained under normal conditions within a narrow normal range of approximately 4.5 to 5.3 ng/dL (1.12–1.32 mmol/L), with higher levels in neonates and infants.
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The majority of total body calcium exists as bone mineral, with serum calcium representing less than 1% of total body calcium. Although total serum calcium levels are routinely measured, it is the ionized fraction that is biologically active. Total serum calcium levels include both ionized and bound calcium. The total calcium level reflects serum changes in albumin, pH, phosphate, magnesium, and bicarbonate. Ionized calcium may be reduced by exogenous factors such as citrate from transfused blood or free fatty acids from total parenteral nutrition. At physiologic pH, 40% of total serum calcium is bound to albumin, 10% can be bound to bicarbonate, phosphate, or citrate, and the remaining 50% exists in the ionized form.
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Calcium absorption and regulation involves a complex interplay between multiple organ systems and regulatory hormones. This tight regulation of circulating calcium is controlled through constant adjustment of parathyroid hormone (PTH) secretion, 1,25-dihydroxyvitamin D (1,25(OH)2D) production, and renal handling of calcium.
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The three major targets for calcium regulation include bone, kidney, and intestine. In bone, PTH stimulates calcium resorption, thereby increasing total and ionized calcium levels. PTH increases intestinal absorption of calcium via activation of 1-α-hydroxylase in the kidney leading to conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)2D. Increased levels of 1,25(OH)2D will increase intestinal absorption of calcium and phosphorus. Without vitamin D-dependent calcium absorption, only 10% of ingested calcium will be absorbed through passive, concentration-dependent absorption. PTH increases renal calcium reabsorption and phosphorus excretion. The majority (60%–70%) of calcium is reabsorbed passively in the proximal tubule driven by a gradient that is generated by sodium and water reabsorption. Individuals with normal kidney function have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium by actions of PTH and 1,25(OH)2D.1
++
Calcitonin plays a minor role in decreasing serum calcium levels via its effect on bone and the kidney. Serum calcium levels are detected by calcium-sensing receptors (CaSR) located on the parathyroid glands and renal tubule cells resulting in regulation of PTH secretion and renal reabsorption of calcium, respectively.2
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CLINICAL PRESENTATION
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Hypocalcemia is frequently observed in the inpatient setting, and incidentally noted biochemical hypocalcemia is often asymptomatic. Symptomatic hypocalcemia occurs in response to a rapid decrease in calcium concentration, as well as in response to the absolute calcium level. Symptoms tend to be more severe if hypocalcemia develops acutely.
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The predominant clinical symptoms and signs in children and adolescents include perioral paresthesias, tingling of the fingers and toes, spontaneous or latent tetany, carpopedal spasms, and seizures.3 In neonates, manifestations of hypocalcemia are more nonspecific and include jitteriness, feeding intolerance, lethargy, apnea, and seizures. Physical examination may reveal hyperreflexia, a positive Chvostek sign (twitching of facial muscles after tapping the facial nerve anterior to the ear), or the Trousseau sign (carpopedal spasm after maintaining a blood pressure cuff above systolic blood pressure for 3 to 5 minutes). Less often seen are cataracts, papilledema, rachitic deformities, and abnormal dental development. Chronic mucocutaneous candidiasis and other ectodermal abnormalities in the setting of hypoparathyroidism may suggest autoimmune polyglandular syndrome type 1, whereas other physical findings may suggest pseudohypoparathyroidism type la or DiGeorge syndrome4 (Table 71-1).
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++
Hypocalcemia is generally defined as a total serum calcium level of less than 8.5 mg/dL (ionized calcium <4.6 mg/dL or <1.15 mmol/L) in children and adolescents, less than 8 mg/dL (ionized calcium <4.4 mg/dL or 1.1 mmol/L) in term neonates, and less than 7 mg/dL (ionized calcium < 3.2 mg/dL or 0.8 mmol/L) in preterm neonates. If ionized calcium is not available, the corrected calcium can be calculated by adding 0.8 mg/dL to the total calcium for every 1-mg decrease in the serum albumin below 4 mg/dL. Individual laboratory norms should be used when available.5
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In childhood, hypercalcemia is less common than hypocalcemia and is frequently discovered incidentally on a routine chemistry profile. Because of the potential clinical significance of a slight elevation in serum calcium levels, it is important to obtain an accurate measure by taking the serum albumin concentration and acid–base status into account.
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Symptoms of hypercalcemia vary little with age. Lethargy, weakness, inability to concentrate, and depression may develop. Many patients have nausea, vomiting, anorexia, constipation, and weight loss. Patients may become hypertensive with extreme elevations in calcium. Neonates may manifest symptoms of gastroesophageal reflux, lethargy, poor weight gain, and a decrease in linear growth. Elevations in extracellular calcium impair the ability of the distal tubule of the nephron to respond to ADH; therefore hypercalcemic patients may present with polyuria, dehydration, and azotemia.6
++
The normative values for calcium are age dependent. A total serum calcium level of greater than 9.2 mg/dL (ionized Ca >5.8 mg/dL or 1.42 mmol/L) in a premature infant, greater than 10.4 mg/dL (ionized Ca >5.0 mg/dL or 1.22 mmol/L) in a full-term infant, and greater than 10.8 mg/dL (ionized Ca >5.0 mg/dL or 1.22 mmol/L) in a child or adolescent is considered elevated.
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DIFFERENTIAL DIAGNOSIS
++
The etiology of hypocalcemia in pediatrics can vary by the age of the child at presentation. Table 71-1 highlights the clinically important categories of hypocalcemia and associated laboratory findings.
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Early Neonatal Hypocalcemia
++
In infants presenting with hypocalcemia within 48 to 72 hours of birth, the differential diagnosis includes prematurity, birth asphyxia, maternal diabetes, and maternal hyperparathyroidism. In preterm infants, hypocalcemia is essentially due to an insufficient increase in PTH secretion along with a relative resistance to 1,25(OH)2D. In addition, premature infants have limited intake of milk, which contributes to hypocalcemia.7 In infants of diabetic mothers, magnesium deficiency may also play an important role in the development of early neonatal hypocalcemia.8 Whenever neonatal hypocalcemia occurs in the absence of these risk factors, the diagnosis of congenital hypoparathyroidism must be considered.
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Late Neonatal Hypocalcemia
++
Late neonatal hypocalcemia presents clinically at 5 to 10 days of life in healthy full-term infants. The three major causes of late neonatal hypocalcemia are phosphate loading, hypoparathyroidism, and magnesium deficiency. Other causes include vitamin D deficiency, PTH resistance, inborn errors of metabolism, and iatrogenic causes (e.g. diuretics, glucocorticoids, and citrated blood products).9 Historically, infant formulas with a high phosphorus content have contributed to the development of late neonatal hypocalcemia, but this is seen less commonly with current infant formulas. Phosphate-induced hypocalcemia should be differentiated from congenital hypoparathyroidism. In both situations serum calcium is low and serum phosphorus is high. PTH is appropriately elevated in phosphate-induced neonatal hypocalcemia, however, and the hypocalcemia resolves spontaneously when the neonate is placed on a low-phosphorus formula such as PM 60/40.10
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Childhood Hypocalcemia
++
Causes of hypocalcemia in children include PTH deficiency, calcium sensing receptor defects, vitamin D deficiency, and resistance to the biologic effects of these calcium-regulating hormones. The differential diagnosis includes vitamin D deficiency, vitamin D resistance, hypoparathyroidism, pseudohypoparathyroidism, metabolic bone disease, and drug effect. Abnormalities in vitamin D metabolism can be seen with renal disease and liver disease. In patients with renal failure, 1α-hydroxylation of 25(OH)D is impaired, and as a consequence, the stored form of vitamin D (25(OH)D) cannot be converted to the biologically active form 1,25(OH)2D. Hyperphosphatemia may further aggravate hypocalcemia in renal failure and lead to secondary hyperparathyroidism and renal osteodystrophy.
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Vitamin D deficiency may be a primary nutritional deficiency or may be secondary to malabsorption. Nutritional deficiency is more common in infants 3 to 36 months of age, with dark skin or from northern latitudes, and in premature or exclusively breastfed infants. Conditions predisposing to malabsorption of vitamin D include celiac disease, cystic fibrosis, pancreatic insufficiency, intestinal bypass, and laxative abuse. Children on anti-seizure medication such as phenobarbital and phenytoin are at increased risk for vitamin D deficiency because of increased hepatic metabolism of vitamin D into inactive metabolites. Biochemical features of rickets are often seen with vitamin D deficiency, including secondary hyperparathyroidism, low serum phosphorus, phosphaturia, high serum alkaline phosphatase, and low 25(OH)D. Clinical features of vitamin D deficiency vary with severity, ranging from a normal exam to severe features seen with rickets including deformities of weight-bearing limbs, growth retardation, frontal bossing of the skull, rachitic rosary, Harrison sulcus, or delayed dentition.11 Radiographic evidence of rickets may also be present on radiographs if fusion of the epiphyses has not yet occurred.
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To prevent vitamin D deficiency, the American Academy of Pediatrics (AAP) and the Institute of Medicine have established recommended daily intake guidelines for vitamin D. The current recommended daily intake for infants age 0 to 12 months is 400 international units (IU) daily and for children age 1 to 21 years is 600 IU daily. Any breastfeeding infant, regardless of amount of formula supplementation, should receive a daily supplement of 400 IU per day. If infants are exclusively formula-fed, they do not require vitamin supplementation, as they should receive their daily recommended dose of vitamin D in the formula.12
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Hypoparathyroidism may be secondary to surgery, polyglandular autoimmune disease, infiltrative disease, neck irradiation, or an idiopathic process. The diagnosis of hypoparathyroidism is suggested by low calcium levels, high phosphorus levels, an inappropriately low PTH level, and absence of bone disease on radiographs. Hypomagnesemia may be a causative factor in the development of hypoparathyroidism. Severe hypomagnesemia will suppress PTH secretion, and mild hypomagnesemia will interfere with PTH activity.13
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Autosomal Dominant Hypocalcemia
++
is due to a gain of function mutation in the calcium sensing receptor on the parathyroid gland leading to a lowering of the calcium set-point and resulting in hypocalcemia with an inappropriately normal PTH.
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Pseudohypoparathyroidism
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The diagnosis of pseudohypoparathyroidism (PHP) is characterized by hypocalcemia, hyperphosphatemia, and elevated PTH concentrations. PHP type 1 is a result of a dominantly inherited mutation in GNAS1, the gene that encodes the alpha subunit of the G protein coupled to the PTH receptor, which leads to a failure of signal transduction and end-organ resistance to PTH. The alpha subunit of the G protein is also required for signal transduction for thyroid-stimulating hormone, growth hormone–releasing hormone, luteinizing hormone, and follicular-stimulating hormone. PHP type 1a is the result of an inactivating mutation in GNAS1 on the maternal allele (either maternally inherited or de novo) resulting in characteristic biochemical findings of hypocalcemia, hyperphosphatemia, and elevated PTH, and a phenotype known as Albright’s hereditary osteodystrophy (AHO). The AHO phenotype includes short stature, round face, shortened fourth metacarpal bones, obesity, subcutaneous ossifications, and developmental delay. PHP type 1b has the biochemical findings of PHP but not the AHO phenotype. Patients with PHP type 1c have both the biochemical profile and phenotype similar to 1a, but via a different mechanism. PHP type 2 has hypocalcemia but does not have the AHO phenotype. Pseudopseudohypoparathyroidism is the result of a mutation in GNAS1 on the paternal allele leading to an AHO phenotype, but with normal calcium and phosphorus.14 Elevated PTH levels, hypocalcemia, and hyperphosphatemia can also be seen in children with renal failure or those who have received treatment with phosphate enemas.
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Other conditions associated with hypocalcemia include renal failure, hungry bone syndrome, tumor lysis syndrome, rhabdomyolysis, acute illness, and hypoproteinemia medications (furosemide, calcitonin, bisphosphonates, antineoplastic agents).
++
Because serum calcium regulation is dependent on PTH, vitamin D, calcium intake, and renal calcium excretion, derangements in any of these systems can produce hypercalcemia. It can be useful to separate the causes into two broad categories: hypercalcemia with inappropriate PTH secretion and hypercalcemia despite appropriate PTH suppression. The causes of hypercalcemia in childhood, along with associated biochemical findings, are summarized in Table 71-2.
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Williams syndrome is the result of a large contiguous deletion on chromosome 7q11.23 involving approximately 28 different genes. Patients with Williams syndrome may have hypercalcemia in addition to characteristic features including elfin facies, congenital cardiovascular anomalies, and cognitive impairment. The cause of the hypercalcemia is not currently understood. The hypercalcemia may respond to a diet low in calcium and usually remits between 9 and 18 months of age. It is important to consider Williams syndrome in the setting of hypercalcemia in an infant because of the associated cardiac defects.
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Idiopathic Hypercalcemia of Infancy
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Idiopathic hypercalcemia of infancy was initially described by Kenny et al. in 1963 in a report of an infant with asymptomatic hypercalcemia.15 The hypercalcemia improved when vitamin D intake was limited and would recur when given replacement doses of only 400 IU daily, suggesting a problem with the removal or deactivation of vitamin D. The CYP24A1 gene encodes the 24-hydroxylase that breaks down vitamin D metabolites, and recently, loss of function mutations in the CYP24A1 gene has been described in patients with idiopathic hypercalcemia of infancy confirming that the mechanism of hypercalcemia is due to problems with deactivation of vitamin D.16
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Familial Hypocalciuric Hypercalcemia
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Familial hypocalciuric hypercalcemia (FHH) is a usually asymptomatic condition of parathyroid insensitivity to the normal suppressive effect of calcium on PTH secretion due to a loss of function mutation in the CaSR. This mutation results in an elevation in the normal calcium set-point, leading to hypercalcemia with an inappropriately normal PTH. It is inherited in an autosomal dominant fashion. A homozygous CaSR mutation is characterized by severe and often lethal neonatal hyperparathyroidism.17
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Hyperparathyroidism is very rare in childhood. It is characterized by autonomous PTH secretion independent of the serum calcium level. Affected children are hypercalcemic as a result of increased calcium resorption from bone, increased renal reabsorption, and increased intestinal absorption. Serum phosphorus is usually reduced but may be normal. The skeletal erosion is best evidenced in the phalanges and clavicle. Sporadic cases may result from either a parathyroid adenoma or chief cell hyperplasia.
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Any child with hyperparathyroidism should be evaluated for multiple endocrine neoplasia (MEN) syndromes. Ninety percent of patients with MEN-I have parathyroid hyperplasia along with a pituitary adenoma or a pancreatic tumor (or both). In MEN-IIA, medullary thyroid carcinoma and pheochromocytoma are the main features, and chief cell hyperplasia is sometimes associated.18
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Hypercalcemia of Malignancy
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Hypercalcemia may be caused by an elevation of PTH-related protein (PTH-rp) in patients with malignancies or from increased osteoclastic activity at the tumor site.19 PTH-rp is secreted by many types of malignant tumors, most notably leukemia, lymphoma, rhabdomyosarcoma, and Ewing sarcoma. Hypercalcemia results from activation of the PTH receptor by PTH-rp.12
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Hypercalcemia Associated with Granulomatous Disease
++
Hypercalcemia from excessive extrarenal production of 1,25(OH)2D may occur in diseases presenting with granulomas. It common in sarcoidosis (present in about half of symptomatic cases) but has also been reported in tuberculosis, fungal diseases (eg. Berylliosis, coccidiomycosis, histoplasmosis, or candidiasis), inflammatory bowel disease, Wegener granulomatosis, and even cat-scratch disease.
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Vitamin D intoxication is uncommon but can arise from chronic overdosage of vitamin D given for therapeutic purposes or self-administration of vitamin preparations. The resultant hypercalcemia can be severe and prolonged because of storage of vitamin D in fat. Specific therapy includes discontinuation of vitamin D and ingestion of a low-calcium diet.
++
Excessive intake of vitamins may result in vitamin A excess in addition to vitamin D excess. Excess amounts of the fat-soluble vitamin A also increase bone resorption, which may result in hypercalcemia.
++
Hypercalcemia of immobilization occurs more commonly in children and adolescents than in adults because of a higher rate of bone remodeling at this age. It is seen most frequently after leg fractures, spinal cord injuries, and burns. Hypercalciuria and substantial bone loss are more common than hypercalcemia. PTH and 1,25(OH)2D are suppressed, and bone biopsy specimens show increased resorption of bone and decreased formation of bone.20
++
Thiazides may cause hypercalcemia as a result of increased renal resorption of calcium and increased calcium binding protein levels.
++
Other conditions associated with hypercalcemia include adrenal insufficiency, hyperthyroidism, subcutaneous fat necrosis, and high calcium intake.
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DIAGNOSTIC EVALUATION
++
The diagnosis of hypocalcemia or hypercalcemia should be based on the total serum calcium concentration corrected for albumin or on measurements of ionized calcium (if the appropriate tools are available for rapid processing). The evaluation of calcium abnormalities should include total calcium, ionized calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone, 25(OH)D, 1,25(OH)2D, electrolytes, BUN, creatinine, albumin, and a urine calcium to creatinine ratio. The phosphate level can greatly aid in narrowing the differential as a high phosphate concentration suggests a deficiency of PTH action, whereas a low phosphate concentration favors increased PTH effect. Other laboratory tests to consider if warranted include PTHrp or N-terminary telopeptide, a marker of bone turnover. An electrocardiogram should be performed to monitor for QT prolongation (QTc >0.45s).9 The algorithms shown in Figures 71-1 (hypocalcemia) and 71-2 (hypercalcemia) will assist in diagnosis. The diagnostic workup for calcium abnormalities involves a detailed history, examination, and laboratory investigation, as listed in Table 71-3.
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++
++
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Although mild hypocalcemia may not require therapy, any neonate with a serum calcium less than 7.5 mg/dL or any older child with a serum calcium less than 8 to 8.5 mg/dL should be treated to prevent tetany and other symptoms. Oral therapy is preferable whenever possible.
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In acute symptomatic hypocalcemia (tetany, seizures), intravenous therapy (IV) is required. For patients with acute life-threatening symptoms of hypocalcemia, IV calcium gluconate is the treatment of choice. Calcium gluconate 10% solution (9.4 mg elemental calcium/mL) can be given by slow intravenous push.21 A cardiac monitor must be used because rapid injection can cause serious cardiac dysrhythmias. All calcium salts are locally toxic and can lead to tissue damage if accidental extravasation occurs. A freely running intravenous line should be used to avoid extravasation. When symptoms of hypocalcemia resolve, serial calcium determinations will determine the need for and route of further therapy. Because serum calcium levels may fall gradually after the initial infusion, ongoing treatment may be necessary, and continuous infusions will typically yield better results than multiple boluses.
++
Mildly symptomatic patients who are unable to take calcium enterally may need calcium gluconate by slow intravenous infusion (every 6–8 hours, depending on subsequent calcium levels). IV calcium infusion is preferred to IV calcium bolus therapy, to reduce the risk of cardiac dysrhythmias.22
++
In the absence of tetany or seizures, oral therapy will suffice.
++
Calcium glubionate is the most suitable agent for infants and young children because it is dispensed as palatable syrup. In older children, tablets of calcium gluconate, carbonate, or lactate can be given. A dosage of 50 mg elemental calcium/kg/day is generally prescribed, with a maximum adult dose of 2000 mg of elemental calcium per day.
++
If children are vitamin D–deficient, they will require vitamin D supplementation. Two preparations are currently available: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). According to the AAP, the recommendations for supplementation are as follows: 1000 IU per day for infants <1 month of age, 1000–5000 IU per day for children age 1 to 12 months, and > 5000 IU per day for children 1 year of age and older. Guidelines for weekly vitamin D supplementation have been provided by the Endocrine Society, at a dose of 50,000 IU once per week for children ages 0 to 18 years. Treatment should continue for 6 weeks, at which time children should be continued on a maintenance dose of vitamin D based on recommended daily intake.23,24
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Calcitriol may be used if the patient is unable to produce 1,25(OH)2D because of renal disease or severe hypoparathyroidism. However, calcitriol bypasses the body’s ability to regulate vitamin D activity and therefore carries the risk of hypercalcemia and hypercalciuria. It has a short half-life and persists in the body for only 1 to 2 days. Because calcitriol will not replenish vitamin D stores, 25(OH)D should be given as well if a true deficiency of vitamin D is suspected. The usual dosage of calcitriol is 0.25 μg/day but varies with body weight and the disorder for which it is being used. The dosage may be adjusted until calcium levels have improved. Children with significant malabsorption, 1-α hydroxylase deficiency, and vitamin D receptor defects may require high dose calcitriol and/or chronic intravenous calcium therapy.
++
Individualization of therapy is essential. It is crucial to monitor serum and urinary calcium and creatinine levels frequently to adjust the doses of medications. The goal is to maintain eucalcemia and avoid hypercalcemia and hypercalciuria. Annual renal sonography is also recommended to detect nephrocalcinosis.
++
Appropriate management of a patient with hypercalcemia depends on the severity and cause of the hypercalcemia. When the calcium concentration is less than 12 mg/dL in an asymptomatic subject, treatment may be delayed until the cause of the hypercalcemia is known. If the total serum calcium concentration exceeds 12 mg/dL or the child is symptomatic, efforts to lower calcium levels should be instituted to prevent the adverse effects of hypercalcemia while awaiting the laboratory results. After initial stabilization, attention should turn to treatment of the underlying cause of the hypercalcemia.
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The mainstay of initial therapy for acute symptomatic hypercalcemia is vigorous hydration with normal saline. Twice the maintenance infusion rate is recommended initially, if tolerated. Urine output must be closely monitored, and any net fluid deficit should be replaced on an ongoing basis. The goal is to maintain an increased urinary rate and to have input exceed urinary output.
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In cases of severe hypercalcemia, calcitonin (2–4 U/kg) via subcutaneous injection can be given every 6 to 12 hours as needed, but rapid tachyphylaxis to this medication is common and limits its utility.25
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Oral glucocorticoids decrease calcium, principally by decreasing absorption from the intestine by inhibiting synthesis of 1,25(OH)2D from 25(OH)D.26 They also have a role in treating hypercalcemia that arises from granulomatous disease by treating the underlying disease.
++
Once adequate hydration has been achieved, furosemide (1–2 mg/kg) may be administered intravenously to increase urinary calcium excretion if the serum calcium level is not improving. However, diuretics must be used with caution, as they may lead to fluid losses and worsening dehydration and can increase the risk of nephrocalcinosis with long-term use.
++
Oral phosphate may be used to bind calcium in the intestine, but its efficacy is limited and its use may result in nausea, abdominal cramps, and diarrhea.
++
Bisphosphonate therapy should be reserved for refractory cases in which the underlying cause of hypercalcemia is not amenable to other therapies. These agents act via inhibition of osteoclastic bone resorption. Pamidronate (0.5 to 1 mg/kg per dose) may be given intravenously over a period of 4 to 5 hours. The peak effect will not be seen for 48 hours or longer and effects may last up to 24 weeks. Other electrolyte imbalances are frequently seen with bisphosphonate therapy, and patients must therefore be monitored for hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia.27 If renal failure coexists, bisphosphonate therapy may only be indicated in severe cases and at reduced doses. Renal dialysis may be necessary to decrease calcium levels in these patients (severe cases).
++
Cinacalcet is a calcimimetic drug that binds the CaSR to reduce PTH secretion and is used in the treatment of FHH and may be used in cases of hyperparathyroidism (off-label use) to suppress PTH levels in children who are symptomatic and not candidates for surgery.28,29
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Parathyroidectomy may be indicated for patients with primary hyperparathyroidism. Surgery should be performed by an experienced surgeon to avoid injury to recurrent laryngeal nerve and hypoparathyroidism. If malignancy-derived PTH-rp is the cause of hypercalcemia, treatment of the underlying malignancy is the treatment of choice.
++
Dialysis using a low-calcium dialysate is generally reserved for those patients with life-threatening hypercalcemia that is resistant to medical therapy.
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ADMISSION AND DISCHARGE CRITERIA
++
Symptomatic hypocalcemia (unless the diagnosis is hyperventilation)
Severe hypocalcemia; specifically, a serum calcium level less than 7 to 7.5 mg/dL
Any newborn with hypocalcemia should be monitored in the neonatal intensive care unit (NICU)
++
Symptomatic hypercalcemia
Severe hypercalcemia, specifically, serum calcium greater than 12 mg/dL (except familial hypocalciuric hypercalcemia)
Any newborn with hypercalcemia should be monitored in the NICU
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++
++
KEY POINTS
The concentration of calcium in serum is modulated through a delicate interplay between PTH and vitamin D via their actions on target organs such as bone, kidney, and the gastrointestinal tract.
Pediatric reference ranges should be used to interpret levels of total serum calcium, ionized calcium, and phosphorus because levels differ significantly with age.
Pediatric units should have a protocol for the diagnostic workup of patients with hypercalcemia and hypocalcemia.
PTH and vitamin D levels should be checked before any intervention.
Hypocalcemia may develop as a result of decreased calcium intake or absorption, excessive urinary loss of calcium, abnormal parathyroid gland development-destruction of the gland by antibodies or surgical procedures, synthesis of an abnormal form of PTH, impaired cellular responsiveness to PTH, restricted exposure to sunlight, or abnormal intake, absorption, or activity of vitamin D and its metabolites.
Hypercalcemia in children can occur when there is increased resorption of calcium from bone (excessive secretion of PTH or PTH-rp), when the intestinal rate of calcium absorption exceeds renal excretory capacity (vitamin D intoxication), or when there is augmented renal tubular absorption of calcium (thiazide diuretics).
Treatment of hypocalcemia is mainly calcium replacement (intravenously or orally, depending on the severity of symptoms). Concurrent administration of vitamin D may be required, depending on the cause of the hypocalcemia.
Treatment of hypercalcemia typically begins with saline administration to produce volume expansion and increase urinary calcium excretion. Correction of the underlying cause should be the next focus, but administration of bisphosphonates to reduce bone resorption may be considered in certain severe cases.
Drugs acting on the CaSR may play an important role in the management of primary and secondary hyperparathyroidism in the future.
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