Chapter 542. Calcium, Phosphorus, and Magnesium Metabolism

Calcium

Calcium (Ca) is present largely (99%) in the skeleton as the hydroxyapatite crystal of calcium phosphate [Ca10(PO4)10(OH)2]. Only the 1% to 2% that resides in recently deposited and rapidly exchangeable surface bone, blood, and extracellular fluid is readily mobilized. Calcium serves as an inter- and intracellular messenger and is necessary for neuronal and neuromuscular communication, muscular contraction, cardiac rhythmicity, enzyme function, clotting, protein synthesis and secretion, and cellular proliferation. Intracellularly, calcium is a second messenger that propagates signals that control cellular activities such as gene transcription, cell division, growth, movement, and function. Total serum calcium is composed of about 50% ionized calcium (Ca2+), the physiologically active form, about 40% calcium bound to albumin and globulins where it is inert, and 10% is complexed to citrate, lactate, bicarbonate, phosphate, or sulfate. Systemic acidosis decreases calcium binding to albumin thus increasing serum Ca2+ levels, while alkalosis increases calcium binding to albumin and lowers Ca2+ values.

Serum Ca2+ levels are maintained within narrow limits by a complex integration of the plasma membrane Ca2+ sensing receptor (CaSR); parathyroid hormone (PTH) and its receptor (PTH/PTH-related protein [PTHrP]-R-PTHR1; calcitonin, the product of the thyroidal parafollicular (C) cell and its receptor; and the vitamin D hormone system acting upon the intestinal tract, bone, and kidney (Fig. 542-1).1-3 As the serum Ca2+ concentration increases, the CaSR on the chief cell of the parathyroid gland (PTG) is activated and decreases PTH synthesis and release. Activation of the CaSR in the distal renal tubule decreases reabsorption of calcium and increases its urinary excretion. PTH stimulates osteoclastic bone reabsorption and increases renal tubular synthesis of 1,25 dihydroxyvitamin D3 (calcitriol) and intestinal absorption of calcium.

Ca2+ enters cells through transmembrane calcium channels. Intracellularly, Ca2+ is bound to calbindin and calmodulin. Ca2+ leaves the cell through adenosine triphosphate (ATP)-driven Ca2+ pumps and by exchange for sodium (Na+) through H+-ATPase and Na+-Ca2+ exchangers. In the intestinal tract, calcium is absorbed in the duodenum, jejunum, ileum, and colon through the enterocyte’s calcium transport protein 1 (TRPV6), whose synthesis is stimulated by calcitriol. Ca2+ is released from the enterocyte through a Na+-Ca2+ exchanger (SLC8A1) or a Ca2+-magnesium (Mg2+)-dependent ATPase calcium channel. There are paracellular protein channels in the intestinal tract through which Ca2+ is passively transported when dietary calcium intake is excessive. The absorption of calcium increases during adolescence, pregnancy, and lactation. PTH increases calcium absorption by stimulating expression of CYP27B1—the gene-encoding renal 25-hydroxyvitamin D-1 hydroxylase—and the synthesis of calcitriol. Estrogens and growth hormone (GH) increase, and thyroid hormones, glucocorticoids, vitamin D deficiency, chronic renal disease, and hypoparathyroidism impair intestinal calcium absorption. The bioavailability of calcium is influenced by the form of food ingested (eg, in human breast milk, 60% of calcium is bioavailable, while in cow milk formulas its bioavailability is 40%). Intestinal calcium absorption is impaired by ingestion of foods containing large amounts of phytates (soy or whole grains), oxalates (citrus, spinach, green beans), or phosphate (cola drinks). Currently recommended intakes of calcium range from 200 mg/day in infancy to 1300 mg/day in adolescents (see Table 23-3). However, when calcium intake exceeds 500 mg/day in children and adolescents, further increase in calcium intake exerts only a transient effect on bone mineralization and has no long-term beneficial effect on fracture rate or risk of osteoporosis.4-6

Calcium is primarily excreted by the kidney and the intestinal tract. After crossing the renal glomerular membrane, 70% of ultrafiltrable serum calcium is reabsorbed in the proximal renal tubule, 20% in the thick ascending loop of Henle, and 8% in the distal convoluted tubule.7 In the thick ascending loop of Henle, calcium is also reabsorbed through a paracellular channel—paracellin-1. When peritubular levels of Ca2+ increase, the CaSR is activated and depresses reabsorption of calcium. In the distal convoluted tubule, Ca2+ is actively transported through a renal epithelial calcium channel encoded by TRPV5, the expression of which is increased by a low calcium diet, calcitriol, and estradiol. Calcium leaves the cell by exchange for Na+ at its serosal surface. Renal calcium excretion is increased by excessive intake, hypercalcemia of various causes, expansion of extracellular volume, metabolic acidosis, and loop diuretics such as furosemide, glucocorticoids, and mineralocorticoids.

In utero, calcium is actively transported across the placenta under the control of calcitriol and PTHrP. Fetal serum calcium concentrations are high (12 to 13 mg/dL) but quickly fall during the first 24 to 48 hours after delivery in the full-term neonate to a nadir value of 9 mg/dL and then increase to approximately 10 mg/dL. In preterm infants, low-birth-weight (LBW) infants, or full-term ill infants, the fall in calcium concentrations may be exaggerated resulting in hypocalcemia. In the child and adolescent, serum calcium concentrations vary slightly with age and the analytical laboratory (total calcium concentrations: 1 to 5 years, 9.4 to 10.8; 6 to 12 years, 9.4 to 10.2; > 20 years, 8.8 to 10.2 mg/dL.8

The calcium sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) whose ligands are Ca2+ and Mg2+. The CaSR regulates the serum concentration of Ca2+ by determining the rates of secretion and synthesis of PTH and of calcium reabsorption in the renal tubule. The CaSR is expressed by the parathyroid chief cells, the renal thick ascending loop of Henle and collecting ducts, and the C cells of the thyroid, cartilage, and bone.9 In thyroid C cells, increases in serum Ca2+ concentrations release calcitonin, a hypocalcemic peptide. Calcimimetics (eg, cinacalcet) are synthetic compounds that are agonists, and calcilytics are antagonists of the CaSR.10

Phosphorus

In vivo, 55% of phosphorus is present as free orthophosphate anions (HPO42– or H2PO4–); 35% is complexed to calcium, sodium, or magnesium; and 10% is bound to protein. Bone hydroxyapatite accounts for 85% of body phosphate stores. Intracellularly, phosphate is an essential component of membrane phospholipids, ribonucleic (RNA) and deoxyribonucleic (DNA) acids, ATP, and phosphorylated metabolic intermediate compounds that are critical to the function of all intracellular signal transduction systems. The concentration of serum phosphate is governed by its intake, intestinal absorption, excretion, and renal tubular reabsorption. Intestinal absorption of dietary phosphate occurs primarily in the duodenum and jejunum by both passive paracellular diffusion and by calcitriol-dependent active transport with sodium through a Na+-HPO42– cotransporter protein (SLC34A2). Excessive amounts of calcium and aluminum precipitate intraluminal phosphate and impede its absorption as do primary malabsorption disorders. Phosphate is excreted by the kidney. After glomerular filtration, 85% of phosphate is reabsorbed in the proximal and distal convoluted tubules by active transfer through 2 Na+-HPO42– transporters (NPT2a-SLC34A1; NPT2c-SLC34A3). Renal tubular reabsorption of phosphate is augmented by hypophosphatemia, hypercalcemia, decreased extracellular fluid volume, and metabolic alkalosis. Its renal tubular reabsorption is decreased by high phosphate intake, PTH, PTHrP, and fibroblast growth factor (FGF)-23, calcitriol, glucocorticoids, and thiazide diuretics. Serum phosphate levels peak in infancy and early childhood and decline during later childhood and adolescence to adult values.

Phosphatonins are phosphaturic substances that inhibit renal tubular phosphate uptake by downregulating expression of SLC34A1.11 They also suppress renal tubular synthesis of calcitriol by inhibiting expression of CYP27B1, thus decreasing intestinal absorption of calcium and phosphate. In osteoblasts and osteocytes, expression and secretion of FGF23 are stimulated by calcitriol.12,13 FGF23 is inactivated by enzymatic cleavage between amino acids Arg179 and Ser180. FGF23 acts through the tyrosine kinase FGF receptors (FGFR) 1, 2, and 3. In adults, the mean serum FGF23 concentration is 29 pg/mL and is inversely related to that of phosphate.14 Serum values of FGF23 are increased in patients with X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, tumor-induced osteomalacia, and fibrous dysplasia. Other phosphatonins are FGF7, matrix extracellular phosphoglycoprotein, and serum frizzled related protein-4.15

Magnesium

Magnesium (Mg2+) is the second most common cation in the intracellular fluid. It is important for normal bone formation and is an essential component of critical enzymatic reactions including many kinases, ATPase and GTPase. Body magnesium is distributed such that 54% is in the skeleton as a component of bone, 45% is in the intracellular fluid, and only 1% is in the extracellular space. Approximately 0.3% Mg2+ is distributed in plasma; about 30% is bound to protein. Normal serum concentrations of Mg2+ range from 1.5 to 2.3 mg/dL (0.7 to 1.0 mmol/L). Serum concentrations of magnesium in neonates have been reported to be somewhat lower, with total serum magnesium levels of 1.4 to 2.0 mg/dL (0.58 to 0.83 mmol/L) and ionized Mg2+ levels of 0.97 to 1.26 mg/dL (0.40 to 0.56 mmol/L).

Magnesium is ubiquitous in foods, but it is particularly abundant in dairy products, bread, cereals, leafy vegetables, and meat. Intake varies between 200 and 600 mg per day in normal adults. Thirty percent to 50% is absorbed, predominantly in the distal small bowel. The mechanism of absorption is unclear (either a saturable carrier-mediated mechanism or a paracellular route), but rare genetic isolated defects in intestinal magnesium absorption suggest a specific magnesium transport mechanism exists. Vitamin D enhances intestinal Mg2+ absorption but to a much lesser extent than for Ca2+ absorption. The efficiency of Mg2+ absorption decreases with increasing intake. Absorption increases following magnesium depletion, during periods of rapid growth, and with ingestion of large quantities of phosphate.

Magnesium is primarily excreted by the kidney. In the adult, the proximal tubule reabsorbs only 10% of the filtered magnesium (fractional reabsorption of sodium and calcium is in excess of 70%), but in the neonate, the proximal tubule reabsorbs about 70% of the filtered magnesium. The permeability of the proximal tubule changes during development so that less Mg2+ is reabsorbed in the proximal tubule. In the adult, about 70% of filtered magnesium is reabsorbed in the thick ascending limb of the loop of Henle by a passive mechanism through a paracellular pathway. The remaining 5% to 10% of filtered Mg2+ is absorbed in the distal convoluted tubule by active transcellular transport through selective channels on the apical membrane. Magnesium entry across the apical membrane is the rate-limiting step in transepithelial reabsorption. Cellular Mg2+ is extruded at the basolateral membrane by a sodium-dependent exchange mechanism. Changes in distal tubular absorption of Mg2+ provide for selective magnesium conservation when intake decreases or if there are increased losses due to intestinal malabsorption. Increased serum Mg2+ or Ca2+ inhibits Mg2+ uptake through activation of the extracellular Ca2+/Mg2+-sensing receptor (CASR).

Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNSALP) is synthesized by osteoblasts, liver, kidney, and skin fibroblasts. The osteoblast also synthesizes a specific bone isoform of alkaline phosphatase (BSAP) that is anchored to the osteoblast’s cell surface. BSAP binds to collagen type I and prepares the skeletal matrix for mineralization, increases local concentrations of phosphate by dephosphorylating protein-bound phosphates, enables the transport of inorganic phosphate and Ca2+ into the cell, and inactivates inhibitors of mineralization by removing phosphate groups. Endogenous substrates for alkaline phosphatase are pyrophosphate, phosphoethanolamine, and pyridoxal-5′-phosphate.

Circulating Hormones and Receptors

Parathyroid Hormone

PTH is synthesized, stored, and secreted by the chief cells of 4 paired parathyroid glands, derived from the third (inferior) and fourth (superior) pharyngeal pouches. The synthesis and secretion of PTH is increased by low and suppressed by high Ca2+ concentrations. Elevated phosphate values increase and low phosphate levels depress PTH production and secretion. High calcitriol concentrations also inhibit PTH synthesis and secretion. Both hypomagnesemia and hypermagnesemia suppress PTH release but not its synthesis. PTH is synthesized as a 115 amino acid propeptide and processed to PTH1-84 that is secreted. PTH1-34 possesses the full biological activity of intact PTH1-84. The parathyroid glands release intact PTH1-84 and carboxyl terminal PTH fragments of varying length, making accurate immunological measurement of circulating PTH complex. In the circulation, the half-life of PTH1-84 is approximately 2 minutes. PTH raises serum calcium concentrations by increasing its renal tubular reabsorption, mobilization from bone, and intestinal absorption, and depresses phosphate levels by inhibiting its renal tubular reabsorption. PTH increases renal tubular synthesis of calcitriol, thus augmenting intestinal absorption of calcium. Acting through the osteoblast, PTH also stimulates osteoclastogenesis and bone resorption.

Parathyroid Hormone-Related Protein

PTHrP is a 141-amino-acid peptide that is homologous with PTH at its amino terminal region and is recognized by the type 1 PTH receptor. PTHrP was originally identified as a product secreted by tumor cells that caused “hypercalcemia of malignancy,” a syndrome that can mimic primary hyperparathyroidism PTHrP. It is synthesized in fetal and adult tissues (placenta, PTGs, cartilage, bone, muscle, skin) and functions mainly as a tissue growth and differentiation factor at the local level, and a regulator of smooth muscle tone. It is essential for chondrocyte differentiation and maturation, endochondral bone formation, mammary gland development, tooth eruption, and epidermal and hair follicle growth acting primarily as a paracrine or juxtacrine messenger.16 In the fetus, PTHrP increases calcium transport across the placenta from mother to fetus. PTHrP has effects similar to those of PTH on calcium, phosphate, and vitamin D metabolism. Postnatally, serum levels of PTHrP are low. PTHrP values are high in breast milk.

PTH/PTHrP Receptors

PTH and PTHrP utilize PTHR1 to exert their cellular effects in osteoblasts, renal tubules, skin, and breast. In turn, PTHR1 activates stimulatory G proteins (Gs, Gq) and their respective adenylyl cyclase and phospholipase C signal transduction pathways. After activation of the G-protein, PTHR1 enters the cell through the process of endocytosis where it may be recycled to the cell membrane, guided to the nucleus where it may influence gene transcription, or degraded.

Calcitonin

Calcitonin is a 32 amino acid hypocalcemic peptide secreted by the C cells of the thyroid gland which lowers serum calcium levels by inhibiting osteoclastic bone resorption.17 Because the calcitonins of many species have similar amino acid compositions, several are also active in humans. Salmon calcitonin has been useful for the emergent treatment of hypercalcemia and as long-term therapy for patients with low bone mass. The secretion of calcitonin is primarily stimulated by increasing serum concentrations of Ca2+. Gastrin and glucagon also provoke calcitonin secretion. Somatostatin, calcitriol, and chromogranin inhibit calcitonin secretion. Calcitonin concentrations are high in the (hypercalcemic) fetus, and fall rapidly after birth, paralleling the decline in serum Ca2+ values. Calcitonin values are relatively constant (< 12 pg/mL) after 3 years of age. However, immunoassays for calcitonin yield inconsistent measurements. Calcitonin activates its specific GPCR and its effects are transmitted through the G-protein-adenylyl cyclase signal transduction pathway.

Vitamin D

Cholecalciferol (vitamin D3) is a prohormone produced in skin by exposure to sunlight and is also ingested in egg yolk, salmon, herring, and mackerel; ergocalciferol (vitamin D2) is derived from plants and yeast18 (Fig. 542-2). The cutaneous synthesis of cholecalciferol is influenced by the latitude (the farther north the fewer ultraviolet photons reach the skin), season of the year (the duration of sunlight is longer in the summer; time of day—the sun is at its zenith in midday), and skin pigmentation (the darker is the skin, the longer must it be exposed to sunlight for comparable biologic effect). Sunscreening agents partially inhibit the cutaneous production of cholecalciferol. After endogenous synthesis or oral ingestion, vitamin D is linked to vitamin D-binding protein and carried to the liver where it is hydroxylated to form 25-hydroxyvitamin D (calcidiol is 25OHD3) by vitamin D-25 hydroxylase (CYP2R1). Bound to vitamin D-binding protein, 25OHD moves to the proximal convoluted and straight renal tubules where it is hydroxylated to the biologically potent metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 = calcitriol] by mitochondrial 25OHD-1α-hydroxylase (CYP27B1). 25OHD-1α-hydroxylase is also found in keratinocytes and hair follicles, osteoblasts, placental cells, monocytes, and macrophages. PTH stimulates production of 25OHD-1α-hydroxylase in the kidney as do hypocalcemia, hypophosphatemia, PTHrP, GH, IGF-I, and prolactin. Synthesis of 25OHD-1α-hydroxylase is suppressed by increased levels of Ca2+ and phosphate, FGF23, and indirectly by calcitriol through inhibition of PTH secretion. In monocytes, expression of this enzyme is stimulated by inflammatory cytokines. Bone, intestine, liver, and kidney inactivate calcitriol and increase its excretion in urine and bile. Many drugs (eg, phenobarbital, phenytoin, carbamazepine) increase hydroxylation of calcitriol and its urinary excretion.

Calcitriol can assume trans and cis configurations, thereby permitting it to exert both slow (trans form—genomic) and rapid (cis form—nongenomic) actions.19-21 Acting through the nuclear vitamin D receptor (VDR), the major effect of calcitriol is to increase intestinal and renal absorption of calcium and phosphate and to maintain normal serum concentrations of these ions by enhancing expression of genes that encode calcium transporters and channels. Calcitriol also stimulates formation of cortical, trabecular, and endochondral bone. Calcitriol inhibits synthesis of PTH. Vitamin D has noncalcemic effects as well; it is important for normal muscle development, inhibition of T lymphocyte differentiation into Th1 cells, suppression of tumor cell growth in vitro, and pancreatic β cell secretion of insulin. Synthetic analogues of vitamin D3 have been developed with reduced calcemic effects (eg, alfacalcidiol). Calcitriol exerts rapid, nongenomic effects by binding to the Vitamin D receptor present in the cell plasma membrane. The rapid effects of vitamin D may enhance its genomic effects by phosphorylation of factors utilized by the Vitamin D receptor-transcriptional complex.

Serum concentrations of 25OHD reflect body stores of vitamin D. Currently defined normal serum 25OHD levels (10 to 55 ng/mL) are likely too low; a more physiologic range of normal values is 32 to 80 ng/mL. Serum 25OHD concentrations below 15 ng/mL indicate vitamin D deficiency, and levels between 15 and 31 ng/mL are “insufficient.” Normal ranges of calcitriol concentrations are as follows: neonates 8 to 72 pg/mL; infants and children 15 to 90 pg/mL; and adults 21 to 65 pg/mL. Current recommendations for daily oral vitamin D intake range from 200 IU in infants to 400 IU in children and adolescents to 1000 IU during pregnancy and lactation, but there is substantial evidence to indicate that these doses are inadequate and that there is a high incidence of subclinical vitamin D deficiency.19,20

Vitamin D Receptor (VDR)

The VDR has 5 domains: the amino-terminal domains (A/B) have a ligand-independent transcription activating function (AF-1); the DNA binding domain (C) has 2 zinc fingers that recognize specific DNA sites termed VDR response elements (VDRE); the AhingeA domain (D) connects to the carboxyl terminal ligand-binding domain (E) that also has 2 ligand-dependent transactivating sites (E1 and AF2). The VDR is found in the intestinal tract, distal renal tubule, osteoblast, keratinocyte, hair follicle, fibroblast, muscle, thyroid, PTG, pancreas, placenta, activated T and B lymphocytes, macrophages, and monocytes. The synthesis of the VDR is stimulated by calcitonin, retinoic acid, estrogen, and β-catenin. After binding to calcitriol, the VDR pairs with the retinoid X receptor (RXRα) to form a heterodimer that binds the target genes.

Hypocalcemia is the consequence of either too little calcium entering the circulation from the gastrointestinal tract, bone, or kidney, or its excessive loss into urine, stool, or bone. The causes of hypocalcemia are most easily considered when divided into neonatal causes, hypoparathyroidism, vitamin D deficiency, and miscellaneous disorders as listed in Table 542-1. These are discussed below. The approach to evaluation and management is then discussed. A large number of disorders due to specific gene mutations are also associated with disorders of mineral and skeletal homeostasis and are shown in eTable 542.1.

Disorders Associated with Neonatal Hypocalcemia

Causes of neonatal hypocalcemia include a blunted post natal secretion of PTH, decreased renal tubular excretion of phosphate in response to PTH with resultant hyperphosphatemia, excessive and prolonged secretion of calcitonin, hypomagnesemia, resistance to the intestinal calcium absorptive and skeletal calcium reabsorptive actions of calcitriol, and rapid deposition of calcium into bone.

Hypocalcemia developing within the first 72 hours after delivery (early hypocalcemia) occurs in full-term ill newborns, low-birth-weight (both premature or small-for-gestational-age) neonates, and in those born to women with vitamin D deficiency, diabetes mellitus, chronic renal disease, or other illnesses. If the mother had hyperparathyroidism or ingested large quantities of calcium-containing antacids during gestation, increased placental transfer of calcium suppresses PTH secretion, and return of normal parathyroid function after birth may require weeks or months.22-52

Hypocalcemia appearing after 72 hours of age (late neonatal hypocalcemia) results from increased dietary intake of calcium-binding agents such as phosphate (evaporated milk or modified cow milk formulas) or fiber, hypomagnesemia, hypoparathyroidism, or vitamin D deficiency. Hyperphosphatemia and hypocalcemia may be due to hypoparathyroidism if PTH levels are low, or to renal insufficiency (renal hypoplasia or obstructive uropathy) if PTH and creatinine values are elevated. Neonatal vitamin D deficiency is characterized by hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase. It occurs as a consequence of maternal vitamin D deprivation (especially in the older breastfed infant with a vegetarian mother and who has little sun exposure), altered activity of renal 25-hydroxyvitamin D-1 hydroxylase, or inactivating mutations of the vitamin D receptor.53 At 3 to 4 months of postnatal age, if the LBW infant has only marginal ingestion of calcium, phosphate, and vitamin D, the infant can develop hypocalcemia with osteopenia due to calcium depletion.

Hypoparathyroidism

Hypoparathyroidism may be due to dysgenesis of the parathyroid glands or to their destruction by inflammatory, infiltrative, surgical, or radiation insults, to errors in the synthesis of PTH, or to abnormalities of tissue responsiveness to PTH.54,55 In neonates and infants, hypoparathyroidism is often transient due to delayed maturation of parathyroid gland activity and resolves a few weeks after birth.

Parathyroid Dysgenesis

DiGeorge syndrome is the most common form of parathyroid gland dysgenesis with an incidence of 1:4000 to 1:10,000 births, is present in approximately 70% of children with isolated hypoparathyroidism, and may occur sporadically or be inherited as an autosomal dominant disorder.56,57 The characteristic clinical triad in patients with this syndrome includes hypocalcemia due to PTG hypoplasia; increased frequency of viral and fungal infections due to impaired cell-mediated immunity and defective T lymphocyte function—the result of partial or complete absence of thymic differentiation; and conotruncal defects of the heart or aortic arch (tetralogy of Fallot, truncus arteriosis, interrupted or right aortic arch, aberrant right subclavian artery). It is further discussed in Chapter 176. Microdeletions of chromosome 22q11.2 (associated with haplosufficiency of the gene TBX1) result in impaired development of structures derived from the third and fourth pharyngeal pouches and first to fifth branchial arches including the parathyroid glands.58 Other multiorgan disorders associated with dysgenesis of the parathyroid glands are listed in Table 542-1.

Other Genetic Causes

Isolated familial neonatal or childhood-onset hypoparathyroidism may be transmitted as autosomal dominant, autosomal recessive, or X-linked recessive traits due to loss-of-function mutations in GCM2, PTH, and SOX3, and gain-of-function mutations in CASR. Autosomal dominant and recessive forms of dyshormonogenic hypoparathyroidism have been ascribed to synthesis of abnormal forms of pre-pro-PTH. Autosomal dominant hypoparathyroidism has been associated with hypercalciuric hypocalcemia due to an activating mutation in CASR.59,60 Because there is increased “sensitivity” to Ca2+, PTH synthesis and secretion are depressed, and renal tubular reabsorption of calcium (and magnesium) is impaired. This disorder is suspected because of inappropriately increased urine calcium excretion in the presence of hypocalcemia and hypomagnesemia and confirmed by genotyping of CASR. Administration of recombinant human PTH1-34 and supplemental magnesium has increased serum calcium levels and normalized urinary excretion of calcium in affected children.61,62 Transmitted as a lethal autosomal recessive trait, Blomstrand osteochondrodysplasia is due to inactivating mutations in PTHR1 and insensitivity to the calcemic effects of PTH.63

Pseudoparathyroidism (PHP) should be suspected in the hypocalcemic term neonate in whom elevated serum levels of thyrotropin have been detected in the neonatal screening program for congenital hypothyroidism.64 Inactivating mutations in GNAS (encoding the Gαs subunit of G-protein essential for intracellular signal transduction through GPCR) cause resistance to PTH resulting in pseudohypoparathyroidism. GNAS is composed of 13 exons with 4 alternative first exons upstream (5) of exon 2. Linkage of exon 1 to exons 2 to 13 generates active Gαs. This isoform of GNAS is expressed in most tissues by both maternal and paternal GNAS alleles. However, in the renal proximal tubules, thyroid, pituitary, and ovaries, Gs is expressed principally by the maternal allele.65 Pseudohypothyroidism is classified into types IA, IB, IC, and II, and pseudopseudohypoparathyroidism (PPHP). PHP-IA, also known as Albright hereditary osteodystrophy, is characterized by short stature, husky to obese body habitus, brachydactyly, round face, flat nasal bridge, short neck, subcutaneous calcifications, cataracts, and developmental delay, as well as hypocalcemia, hyperphosphatemia, hyperphosphaturia, and elevated serum concentrations of PTH. Exogenous PTH1-34 does not increase serum concentrations of calcium, lower serum levels of phosphate, or increase urinary excretion of phosphate or nephrogenous cyclic AMP. Patients with the Albright heriditary osteodystrophy phenotype but with normal serum calcium, phosphate, and PTH concentrations and normal response to exogenous PTH1-34 have PPHP. The heterozygous inactivating mutations in GNAS in patients with PHP-IA and PPHP result in approximately 50% of normal Gαs activity in most cells, sufficient to sustain normal cellular function except in chondrocytes. Chondrocyte differentiation is impaired because in chondrocytes GNAS is normally expressed by both maternal and paternal alleles. When levels of Gsα activity are only one-half normal, the AHO skeletal deformities appear.66 If the maternal GNAS allele is inactivated, then there are also very low levels of Gαs in and impaired function of the kidneys, thyroid, pituitary, and ovary leading to PTH resistance in renal tubules, insensitivity to thyrotropin in the thyroid, somatotroph resistance to GH-releasing hormone, and ovarian resistance to gonadotropins (ie, PHP-IA).67-69 Transmission of a mutated GNAS allele from father to child results in PPHP, because the levels of Gαs activity in the proximal renal tubule, thyroid gland, pituitary somatotroph, and ovary derived from the intact maternal GNAS allele are normal.

The skeleton is normal in patients with PHP-IB, but Gαs activity is decreased, primarily in the proximal renal tubule. These patients are hypocalcemic and hyperphosphatemic and resistant to the renal effects of exogenous PTH.1-34 PHP-IB is due to an imprinting error that results in loss of the maternal pattern of GNAS expression. In patients with PHP type IB, both GNAS alleles have a paternal imprinting pattern. Thus, there are normal amount of Gαs in most tissues (including the osteoblast and chondrocyte accounting for the normal skeletal phenotype) but deficient quantities of Gαs in the kidney. When familial, PHP-IB develops only in the offspring of female obligate carriers. PHP-IB may also arise by paternal disomy for chromosome 20 or familial mutations within GNAS. Patients with PHP type II have no skeletal deformities but are hypocalcemic and hyperphosphatemic, and PTH levels are elevated. In response to exogenous PTH, the urinary cyclic AMP excretion increases, but phosphate excretion does not. The pathogenesis of this disorder is unknown.

Acquired Hypoparathyroidism

In children and adolescents, hypoparathyrodism is most often due to autoimmune disease that either destroys the parathyroid gland chief cell or inhibits its secretion of PTH. Antibodies that activate the CaSR and simulate the effect of Ca2+ cause an acquired form of hypoparathyroidism that may be isolated or part of a complex autoimmune endocrinopathy.70,71 Other causes of acquired hypoparathyroidism include surgical removal or operative injury to the vascular supply of the PTGs, infiltration of the PTGs by iron or copper, granulomatous diseases, or cervical radiation therapy for lymphoma or radioiodine therapy of hyperthyroidism.72-76

As many as 30% of patients with acquired isolated idiopathic hypoparathyroidism have blocking antibodies directed against the extracellular domain of the CaSR. In other patients, autoimmune hypoparathyroidism is due to the development of cytotoxic antibodies that destroy the parathyroid gland. Autoimmune hypoparathyroidism is one component of autoimmune polyendocrinopathy syndrome (APS) type I, an autosomal recessive disorder, with almost 100% penetrance, due to homozygous or compound heterozygous inactivating mutations in AIRE (autoimmune regulator) causing autoimmune polyendocrinopathy, mucocutaneous candidiasis, and ectodermal dystrophy (APECED). Mucocutaneous candidiasis affects the nails and mouth and is usually the first clinical sign of APS-I; it develops in almost all patients, sometimes appearing at 2 months of age and usually by 2 years of age. Hypoparathyroidism (between 2 and 10 years of age) and hypoadrenocorticism (between 5 and 10 years of age) ensue in 80% to 90% of affected subjects.73 Other autoimmune endocrinopathies that occur in patients with APS-I include oophoritis, orchitis, type 1 diabetes mellitus, thyroiditis, and hypophysitis. In addition to mucocutaneous candidiasis, dermatologic manifestations of APS-I include alopecia, vitiligo, and febrile rashes. Pernicious anemia, hepatitis, chronic diarrhea, and keratoconjunctivitis also develop in patients with APS-I. AIRE encodes a transcription promoting factor with expression limited to the thymus, lymph nodes, spleen, and other immune sites and cells; AIRE also acts within the ubiquitin-proteasomal system of protein processing and degradation.74,75 AIRE promotes immune self-tolerance by impairing development of self-reactive thymocytes. The diagnosis of APS-I is established by the presence of 2 of its 3 primary clinical manifestations—mucocutaneous candidiasis, hypoparathyroidism, hypoadrenocorticism—and confirmed by identification of the mutation(s) in AIRE.

Vitamin D Deficiency

Vitamin D deficiency due to suboptimal intake, impaired absorption or synthesis of calcitriol, or an abnormality of the tissue response to calcitriol leads to hypocalcemia and hypophosphatemia.77 When vitamin D deficiency is marked, administration of vitamin D may precipitously lower the serum calcium concentration as the cation is rapidly “sucked” into bone (the hungry bone syndrome). Management of Vitamin D deficiency is discussed in more detail in Chapter 243.

Other Causes of Hypocalemia

Medications that impair secretion of PTH (magnesium), osteoclastic bone resorption (bisphosphonates), or renal tubular calcium resorption (furosemide) may lead to hypocalcemia. Rectal instillation or intravenous infusion of phosphate, acute cellular destruction during tumor cell lysis or rhabdomyolysis, and acute and chronic renal failure increase serum phosphate levels resulting in reciprocal decline in calcium values. Serum levels of calcium fall in patients who have been transfused with many units of citrated blood or during plasmapheresis. Acute pancreatitis leads to hypocalcemia by deposition in necrotic tissue of calcium complexed to free fatty acids. The hypocalcemia that develops in patients with acute and serious illnesses is related to hypoalbuminemia, functional hypoparathyroidism, hypercalcitonemia, hypomagnesemia, decreased calcitriol synthesis, alkalosis, elevated serum concentrations of free fatty acids, and increased cytokine activity.78 Hypocalcemia may also occur with administration of phosphate containing enemas or oral laxatives leading to hyperphosphatemia and hypocalcemic tetany.54

Clinical Features

In neonates, hypocalcemia (total calcium < 7.5 mg/dL, Ca2+ < 1.20 mmol/L) is manifested by neuromuscular irritability—tremulousness, tetany, laryngospasm, seizures—or by systemic symptoms—apnea, emesis, difficulty feeding.51 In the child or adolescent, hypocalcemia may be asymptomatic or identified by chemical screening. Presenting symptoms often are muscular cramping at rest or during exercise (hyperventilation increases systemic pH and the amount of calcium bound to albumin, thereby lowering the level of Ca2+) or paresthesias of the digits or circumoral region. Tetany (uncontrollable muscular contractions leading to carpopedal spasm, laryngospasm, bronchospasm), carpal-pedal spasm (flexion of the elbow and wrist, adduction of the thumb, flexion of the metacarpal/metatarsal-phalangeal joints, and extension of the interphalangeal joints), or seizures (grand mal, focal, petit mal, adynamic, syncopal) may be seen at presenation.

In a hypocalcemic neonate, a directed history seeks complications of pregnancy (eg, maternal diabetes mellitus, toxemia of pregnancy, retarded fetal growth) or delivery (prematurity, LBW, asphyxia), or early postnatal complications (sepsis) and relevant family history (relatives with renal calculi, rickets, or hypocalcemia). The mother’s diet and sunlight exposure history should also be queried. Physical examination may reveal abnormalities (facial features, cardiac murmur) that suggest a complex form of hypocalcemia such as DiGeorge syndrome.

In the child the past medical history may reveal insults known to be associated with hypoparathyroidism (recurrent infections, congenital cardiac anomalies, surgical procedures in the neck, cervical radiation, infiltrative diseases). Physical examination may disclose a phenotype characteristic of DGS, PHP-IA, or of APS-I. The presence of rickets implies hypovitaminosis D.

Physical examination may or may not reveal a positive Chvostek or Trousseau sign and hyperreflexia.Tetany is also observed in patients with hypo- and hypernatremia, hypo- and hyperkalemia, and hypomagnesemia, and a positive Chvostek sign may be elicited in normal adolescents.

Diagnostic Approach for Hypocalcemia

Figure 542-3 outlines the approach to evaluation of a patient with hypocalcemia. Measurement of serum levels of total calcium, Ca2+, magnesium, phosphate, creatinine, intact PTH, calcidiol, and calcitriol, and urinary calcium and creatinine concentrations in a spot urine are useful. The electrocardiographic (ECG) hallmark of hypocalcemia is prolongation of the QTc interval because of lengthening of the ST segment, which is directly proportional to the degree of hypocalcemia.

All of the disorders listed in Table 542-1 and discussed above should be considered. In neonates with early onset hypocalcemia, low serum concentrations of PTH are common; persistently low PTH levels suggest hypoparathyroidism. In the latter instance, the diagnosis of the DiGeorge syndrome should be considered and fluorescent in situ hybridization (FISH) for chromosome segment 22q11 undertaken. When PTH concentrations are high in the hypocalcemic neonate, vitamin D deficiency or insensitivity, PTH resistance due to inactivating mutations in PTHR1 or GNAS, or impaired renal function should be suspected. In vitamin D deficiency, low serum levels of calcidiol suggest decreased maternal (and hence fetal) stores of vitamin D (or rarely a defect in synthesis of calcidiol). When calcidiol values are normal and calcitriol concentrations are inappropriately low, compromised renal function, hypoparathyroidism, or deficiency of 25OHD-1α-hydroxylase may be suspected. When calcitriol values are high, vitamin D resistance should be considered. In full-term neonates with unexplained hypocalcemia, serum levels of calcium, Ca2+, phosphate, and PTH should be measured in the mother who may have undiagnosed hyperparathyroidism.

In the child or adolescent, hypocalcemia is often first identified by a multiassay chemical profile performed for an unrelated problem or during evaluation of a patient with a long QT interval noted by electrocardiography obtained because of a (functional) heart murmur or arrhythmia.79 The child may also present with the physical findings noted above. After the hypocalcemic state has been confirmed, urine calcium excretion is assayed. In the majority of hypocalcemic patients, there is low urine calcium excretion; if urine calcium excretion is inappropriately normal or elevated, autosomal dominant hypoparathyroidism due to an activating mutation in CASR should be considered, CASR analyzed, and antibodies to CaSR determined as clinically indicated. Hypoparathyroidism is present in the child or adolescent with hypocalcemia, hypocalciuria, hyperphosphatemia, and low or undetectable serum PTH concentrations (and normal or slightly low serum magnesium level). The cause of hypoparathyroidism must then be elucidated. DGS may be identified by abnormal FISH of chromosome 22q11.2 or TBX1 genotyping. The diagnosis of APS-I is based on clinical and laboratory findings and genotyping of AIRE. In patients with isolated, idiopathic hypoparathyroidism, antibodies to the CaSR or to parathyroid tissue may be sought. In hypomagnesemic patients, magnesium and PTH levels are low; the release of PTH occurs immediately after intravenous administration of magnesium. If the serum PTH concentration is elevated in a hypocalcemic subject, then either the patient is synthesizing an abnormal, bioinactive PTH molecule, is resistant to PTH, or has a compensatory PTH secretory response to hypocalcemia. In the patient with AHO, analysis of GNAS and its imprinting pattern will identify the specific genetic defect in many patients with PHP-IA, PHP-IB, or PPHP. Vitamin D deficiency is identified by subnormal serum levels of calcidiol. In the rare patient with decreased renal 25OHD3-1α-hydroxylase activity, the serum concentration of calcidiol is normal but that of calcitriol is low. When the concentration of calcitriol is increased, the presence of a mutation in VDR should be sought. The patient with chronic renal failure is azotemic.

Management of Hypocalcemia

Preparations used to administer calcium are listed in eTable 542.2. Treatment of early neonatal hypocalcemia is indicated if the newborn is symptomatic or if the total serum calcium concentration is less than 6 mg/dL in the preterm infant and below 7 mg/dL in the term infant. Restoration of eucalcemia is most easily accomplished in the asymptomatic neonate by increasing the oral intake of calcium to a level such that the overall (formula plus supplement) ratio of the calcium to phosphate intake is 4:1. Calcium glubionate or calcium carbonate administered in divided doses every 4 to 6 hours is usually effective (eTable 542.2). These infants are usually able to maintain eucalcemia without supplementation by 3 weeks of age. When the hypocalcemic infant has tetany or seizures, 10% calcium gluconate (elemental calcium 9.3 mg/mL) at a dose of 1 to 3 mg/kg and rate not to exceed 1 mL/minute (total dose not greater than 20 mg of elemental calcium/kg) may be administered by intravenous infusion and discontinued when the seizures cease. Calcium should not be administered intravenously with either phosphate or bicarbonate, because these salts may coprecipitate. Extravascular extravasation of calcium will cause local tissue injury and should be avoided. Monitoring of cardiac rate and rhythm is important during administration of intravenous calcium. Following intravenous admninistrationm, the infants should receive supplemental oral calcium as outlined above. Additional intravenous bolus doses of calcium (~10 mg/kg at 6 hour intervals) should be used sparingly, as they lead to wide excursions in serum calcium values.

Depending on the cause of the hypocalcemia, supplemental vitamin D or calcitriol may also be needed to restore eucalcemia. It is important to measure serum and urine calcium and creatinine levels frequently and to modify therapy to maintain eucalcemia and the urine calcium/creatinine ratio < 0.2 in order to prevent iatrogenic hypercalcemia, hypercalciuria, nephrocalcinosis, and renal insufficiency. Hypomagnesemic hypocalcemia is treated acutely by the intravenous infusion or intramuscular injection of 50% magnesium sulfate (0.1 to 0.2 mL/kg) while monitoring cardiac status.

In the hypocalcemic child or adolescent, immediate intervention may not be required if asymptomatic and the total serum calcium value is above 7.5 mg/dL. However, if serum calcium levels are very low or if the patient has tetany or seizures, 10% calcium gluconate should be administered intravenously at a rate not to exceed 2 mL/kg over 10 minutes while monitoring pulse rate and the QT interval. After resolution of the acute symptoms, calcium gluconate (10 mL in 100 mL 5% dextrose/0.25 N saline) may be temporarily infused intravenously at a rate sufficient to maintain calcium levels in the asymptomatic low-normal range while the cause of the hypocalcemia is identified. If there is marked hyperphosphatemia, infusion of normal saline sufficient to maintain urine output at or above 2 mL/kg per hour is also necessary. Serum calcium and phosphate concentrations must be measured frequently to permit rapid adjustment of fluid and electrolyte therapy. In patients with hypoparathyroidism or PHP, calcitriol (20 to 60 ng/kg/day) and supplemental calcium (calcium glubionate or calcium citrate 30 to 75 mg elemental calcium/kg/day in divided doses are administered in order to restore and maintain the serum calcium concentration within the low-normal range. (Future therapy of children with diverse forms of primary hypoparathyroidism is likely to include rhPTH1-34.80) Children with PHP-IA have associated abnormalities in the secretion of a number of peptide hormones, so periodic assessment of pituitary-thyroid and pituitary-ovarian function and GH secretion is indicated with hormone replacement therapy instituted when needed. On occasion, transient hypoparathyroidism of infancy may herald the later onset of hypoparathyroidism that may become manifest during acute illness or other stress. Therefore, periodic assessment of calcium levels is indicated in these children.

Hypercalcemia

Hypercalcemia is defined as a total blood calcium concentration greater than 10.8 to 11.3 mg/dL and ionized Ca2+ level exceeding 1.4 mmol/L (depending on the norms of the analytical laboratory). Causes of hypercalcemia are listed in Table 542-2,81,82 and the management of specific disorders is discussed below.

Disorders Associated with Hypercalcemia

Hypervitaminosis D due to excessive amounts in formula or milk, its increased intake in vitamin preparations, or augmented endogenous synthesis of calcitriol by monocytes at inflammatory sites result in hypercalcemia. Subcutaneous fat necrosis (firm, violaceous nodules on the cheeks, trunk, buttocks and legs) occurs in severely asphyxiated neonates and in older children who have sustained major injuries, or with acute pancreatitis.

Neonatal severe hyperparathyroidism (NSHPT) often presents with a serum calcium concentrations greater than 15 mg/dL, and PTH values are inappropriately elevated. NSHPT is usually the consequence of homozygous or compound heterozygous inactivating mutations of CASR, but also may develop in a heterozygous fetus who has inherited a paternal mutation and who has been relatively hypocalcemic in utero resulting in hyperplasia of the fetal parathyroid glands.83,84 There is relative hypocalciuria and low renal tubular reabsorption of phosphate. Hypermagnesemia, low serum phosphate levels, hyperphosphatasemia, and elevated calcitriol values are also present. Identification of an inactivating mutation in CASR confirms the diagnosis. In infants with NSHPT treatment may be emergent and includes sodium and calcium diuresis (fluids, furosemide) and intravenous administration of a bisphosphonate to lower serum calcium values (see below). Occasionally, parathyroidectomy may be necessary.

Hereditary hypocalciuric hypercalcemia type 1 (HHC1) is an autosomal dominant, usually asymptomatic, trait with hypercalcemia (11 to 12 mg/dL), hypocalciuria (ratio of calcium clearance/creatinine clearance < 0.01), hypermagnesemia, hypomagnesuria, and hypophosphatemia. It is due to heterozygous loss-of-function mutations in CASR that result in amplified secretion of PTH because of an elevated set-point for Ca2+-mediated inhibition of PTH synthesis and increased renal tubular reabsorption of calcium.83 In children, HCC1 is usually unsuspected until the serum calcium concentration is found to be mildly elevated in a chemistry profile or during family screening for hypercalcemia. In children and adolescents with HHC1, the diagnosis is established by demonstrating that one of the parents is also mildly hypercalcemic and hypocalciuric, and by identifying the heterozygous mutation in CASR. HHC1 may be differentiated from primary hyperparathyroidism in which there is hypercalciuria. No intervention is indicated in children and adolescents with typical HHC1.

In Williams syndrome, hypercalcemia is seen in 15% of infants with the syndrome (see Chapter 176) which is suspected by the characteristic clinical phenotype (with or without hypercalcemia) and confirmed by identifying the microdeletion at chromosome 7q11.23 or of ELN, although negative studies do not eliminate this diagnosis. The associated hypercalcemia is managed by ingestion of a low calcium diet, and a vitamin-D-free formula. The hypercalcemia usually is self-limited and remits by 1 year of age.

Primary hyperparathyroidism occurs in 2 to 5 per 100,000 children and adolescents with equal frequency in boys and girls. It is most often sporadic due to a solitary parathyroid adenoma (60%) or due to hyperplasia of the thyroid glands (30%).

Primary hyperparathyroidism may also be transmitted as an autosomal dominant trait, either as an isolated disease, or as one manifestation of a complex of disorders such as multiple endocrine neoplasia (MEN) (see Chapter 537) or the hypoparathyroidism-jaw tumor syndrome.85,86

Physical examination of the youngster with primary hyperparathyroidism is usually unremarkable, although the physical characteristics of the child with MEN type IIB are distinctive. A parathyroid adenoma may be visualized by ultrasonography, magnetic resonance imaging, computed tomography, or radionuclide scans (^ch542ref99mTc-SestaMIBI). One may occasionally be sited within the thymus, thyroid gland, or mediastinum. In the pediatric population, a parathyroid adenoma should be localized before it is removed by an experienced surgeon.87-99 If hyperparathyroidism is due to diffuse parathyroid hyperplasia, subtotal (3.5 glands) or total parathyroidectomy may be undertaken with autotransplantation of small fragments of one gland to a forearm pocket. Transient hypocalcemia may follow removal of a parathyroid adenoma and is managed by administration of oral calcium. If osteitis fibrosa cystica and demineralization are marked, significant hypocalcemia may be anticipated due to the acute deposition of calcium into “hungry bone.” If permanent hypoparathyroidism develops postoperatively, it may be managed with calcitriol and supplemental calcium (or PTH1-34). Calcimimetic agents (eg, cinacalcet) find major use in the management of secondary hyperparathyroidism of chronic renal disease if lowering serum phosphate concentrations and maintaining serum Ca2+ levels prove unsuccessful.100

Hypervitaminosis D may be due to ingestion of excessive amounts of vitamin D or calcitriol for nutritional or therapeutic reasons, or inappropriate fortification of milk.88,89 Topical application of vitamin D or analogue-containing preparations for treatment of psoriasis may lead to hypercalcemia.90 Patients with granulomatous diseases (eg, sarcoidosis, tuberculosis) and neoplastic disorders (eg, B-cell lymphoma, Hodgkin disease) develop hypercalcemia due to monocyte synthesis of calcitriol, a process suppressible by glucocorticoids.91 Hypercalcemia has been observed in children with acquired immunodeficiency disease, congenital hypothyroidism, and juvenile rheumatoid arthritis.92

The sudden immobilization of an active, rapidly growing child or adolescent abruptly decreases the rate of bone formation while bone resorption continues resulting in hypercalciuria, hypercalcemia, and “acute disuse osteoporosis.”93 Hypercalcemia occurs with the milk-alkali syndrome that results from the intake of calcium and absorbable alkali (milk or calcium carbonate) for treatment of peptic ulcer disease or as dietary supplements. Intestinal absorption of calcium is increased, but renal calcium excretion may not increase appropriately because of hypovolemia and renal vasoconstriction.94 In the hyperthyroid child, hypercalcemia develops as a consequence of thyroid-hormone-mediated stimulation of osteoclast function and increase in the rate of bone resorption. Hypercalcemia may occur during recovery from acute renal failure as calcium is mobilized from ectopic sites. In children with chronic renal failure, hypercalcemia is due to immobilization, aluminum toxicity, or excessive intake of calcium-containing antacids or vitamin D. After renal transplantation, hypercalcemia is a consequence of prolonged secondary hyperparathyroidism that may result in autonomous parathyroid hyperfunction (tertiary hyperparathyroidism). Secondary and tertiary hyperparathyroidism have been recorded in patients with long-term nutritional vitamin D deficiency and in subjects with X-linked hypophosphatemic rickets receiving large amounts of phosphate.95

Clinical Features

Hypercalcemic symptoms and signs include fatigue, headache, polyuria, anorexia, abdominal pain and emesis, constipation, irritability and seizures, hypotonia, hypertension, and behavioral changes (particularly depression). These usually occur when the total calcium level is greater than 12 to 13 mg/dL.81 The Q-Tc segment is shortened in hypercalcemia. In infants and children, chronic hypercalcemia may be manifested by impaired weight gain and growth. Hypercalcemia due to any cause is usually accompanied by hypercalciuria leading to nephrocalcinosis and nephrolithiasis. Pathologic fractures may occur due to osteopenia or lesions of osteitis fibrosa cystica.98

Diagnostic Approach for Hypercalcemia

The approach to the evaluation of hypercalcemia is outlined in Figure 542-4. Specific diagnostic approaches for some disorders are discussed above. The history should evaluate the intake of calcium, phosphate, and vitamin D, and determine if there is any family history of mineral disorders. Physical examination searches for characteristic findings such as the cutaneous firm masses of subcutaneous fat necrosis, or the facial and behavioral characteristics of Williams syndrome. Determination of serum levels of total calcium and Ca2+, phosphate, alkaline phosphatase, PTH, PTHrP, calcidiol, calcitriol, and creatinine and urine calcium and creatinine excretion are obtained as appropriate.

Management of Hypercalcemia

Initially, patients with hypercalcemia are managed with a low calcium diet and elimination of dietary vitamin D while a diagnostic evaluation is pursued. When required by very high calcium values and symptoms of hypercalcemia, an infusion of 0.9% saline (10 to 20 mL/kg over 1 hour) should be administered followed by furosemide (1 to 2 mg/kg intravenously). Calcitonin (10 units/kg subcutaneously), glucocorticoids (1 mg/kg intravenously, repeated every 6 hours as needed), or bisphosphonate (pamidronate, 0.5 to 1.0 mg/kg in 30 mL intravenously over 4 to 6 hours) may also be employed to lower serum calcium concentrations.96

Treatment of the underlying disorders causing hypercalcemia (eg, thyrotoxicosis, hypoadrenocorticism) usually restores the eucalcemic state. Hypercalcemia due to excessive intake of vitamin D or uncontrolled synthesis of calcitriol by granulomatous and chronic inflammatory tissues usually responds to treatment with glucocorticoids. The hypercalcemia of immobilization is prevented by limitation of calcium intake, avoidance of vitamin D, copious fluid intake, and early mobilization, if possible.

Disorders of Magnesium Metabolism

Hypomagnesemia

Symptoms of hypomagnesemia mimic those of hypocalcemia because they result primarily from decreased parathyroid hormone secretion and target-tissue resistance to the actions of parathyroid hormone due to hypomagnesemia. Because magnesium is required for Na,K ATPase activity, Mg2+ deficiency can cause potassium deficiency by inhibiting K+ reabsorption in the proximal tubule.

A variety of inherited or acquired conditions can lead to hypomagnesemia (Table 542-3). Decreased intake rarely causes hypomagnesemia because magnesium is present in many foods; if intake is reduced, the kidney compensates by increasing absorption. Administration of parenteral nutrition without added magnesium or prolonged protein-calorie malnutrition may result in hypomagnesemia. Endocrine disorders including hyperparathyroidism, hypothyroidism, and diabetes mellitus may cause hypomagnesemia. Most alterations in magnesium balance are due to congenital or acquired disorders that decrease gastrointestinal absorption or increase renal losses of magnesium. Disorders such as short bowel syndrome, celiac disease, and chronic pancreatitis are all associated with hypomagnesemia. Biliary or small bowel fistulas may also result in increased losses of magnesium because the secreted Mg2+ is not reabsorbed in the distal small intestine. Renal causes of hypomagnesemia are discussed in Chapter 466.

Familial Hypomagnesemia

This disorder, also known as hypomagnesemia with secondary hypocalcemia (HSH), is due to a primary defect in intestinal magnesium absorption, from mutations in TRPM6, a member of the melastatin-related subfamily of transient receptor potential (TRP) ion channels.97 The disorder is characterized by extremely low levels of serum concentrations of magnesium and by hypocalcemia. The usual age of presentation is within the first months of life, when severe hypomagnesemia results in hypocalcemia. Intestinal magnesium absorption is impaired, but urinary magnesium absorption is normal. Genetic linkage mapping has identified a mutation of chromosome 9 (9q12-9q22.2) associated with this disorder in 3 Bedouin kindreds. Patients treated with oral supplementation of magnesium sulfate in doses of 0.5 to 0.75 mmol/kg/day have had normal growth and development but have a life-long requirement for Mg2+ supplementation.

Evaluation and Management

Identification of the underlying cause of hypomagnesemia is often obvious following recognition of the disorder. Secondary causes are far more common than primary defects in magnesium metabolism. Routine monitoring of serum concentrations of magnesium during administration of parenteral nutrition, in patients with malabsorptive disorders, or who are at risk for hungry bone syndrome allows therapy before patients are symptomatic (usually at serum levels below 0.65 mmol/L or 1.5 mg/dL). Mild or asymptomatic cases of hypomagnesemia can be treated with oral supplementation using magnesium oxide, magnesium chloride, or magnesium hydroxide (see eTable 542.2). Overly aggressive oral supplementation will lead to diarrhea. Severe symptomatic hypomagnesemia may be treated with magnesium sulfate given intravenously. Adult doses of 2 to 4 g of 50% magnesium sulfate (16.6 to 33 meq) diluted in dextrose can be safely administered over 30 to 60 min. With life-threatening arrhythmias, the same dose may be given by intravenous push. Pediatric doses of 1 meq/kg are effective. Subsequent doses of 0.5 meq/kg/d should be given over the following 3 to 5 days to replete body stores (1.0 mL/kg/day of 50% magnesium sulfate [USP]). In neonatal hypomagnesemia, intravenous administration of 6 mg elemental magnesium sulfate over 1 hour has been shown to be effective.

Hypermagnesemia

Symptomatic hypermagnesemia is infrequent and usually iatrogenic. Manifesting with neuromuscular blockade and respiratory depression, hypermagnesemia is most common in patients with renal impairment but can occur with administration of magnesium-containing antacids, purgatives, or rectal administration of magnesium-containing solutions. Hypermagnesemia can also occur in Addison disease, hypothyroidism, lithium therapy, and with the milk-alkali syndrome.

Symptoms can be transiently reversed by the intravenous administration of calcium chloride. Insulin and dextrose can be administered to promote influx of magnesium into the intracellular space, similar to therapy for hyperkalemia. In severe cases, dialysis may be necessary.