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.
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.
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.
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
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.
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).
| Category | Phosphorus | 25(OH)D | 1,25(OH)2D | PTH | Comments |
|---|---|---|---|---|---|
| Neonate | |||||
| Early hypocalcemia | N | N | N or L | N or L | Prematurity, IUGR, birth asphyxia, diabetic mother |
| Late hypocalcemia | H | N | L | L | Low GFR, intake of high-phosphate milk |
| Older Child | |||||
| Congenital hypoparathyroidism | H | N | L | L | DiGeorge syndrome |
| Autoimmune hypoparathyroidism | H | N | L | L | Part of polyendocrinopathy syndrome, type 1 |
| Pseudohypoparathyroidism | H | N | L | H | Peripheral resistance to PTH |
| Vitamin D deficiency | L, N, or H | L | L, N, or H | H | Exclusively breastfed with maternal vitamin D deficiency, sunlight avoidance, fat malabsorption |
| Vitamin D dependent | L | N | H | H | Caused by loss-of-function mutation of 1α-hydroxylase gene |
| Critical illness | N | N | N | L | PTH dysfunction and increase in cortisol |
| Magnesium deficiency | H | N | N/L | L | May be part of Bartter syndrome, malabsorption, renal disease |
| Renal disease | H | N | L | H | Abnormal renal function, metabolic acidosis |
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
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.
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.
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.
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.
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
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.
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.
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
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
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.
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.
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).
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