Pediatric Hypercalcemia

Calcium absorption and regulation involve a complex interplay between multiple organ systems and regulatory hormones.[1] The 3 predominant sources of calcium and targets for regulation are the bones, renal filtration and reabsorption, and intestinal absorption. The major regulators of calcium levels are parathyroid hormone (PTH) and vitamin D, which target the bones, intestine, and kidney to increase serum calcium. Calcitonin, a more minor player in regulation, decreases serum calcium by its effects on bone and kidney. Cyclically, high levels of calcium suppress PTH and thereby decrease levels of the active form of vitamin D by decreasing the activity of renal 1 α -hydroxylase.

The kidney serves as the rapid regulator of calcium fluxes but has limited capacity to handle large swings in the serum calcium levels. Sixty-five percent of the calcium filtered through the glomeruli is reabsorbed in the proximal tubule by a process linked to sodium reabsorption. Although dependent on concentration and voltage, this process is independent of PTH. Approximately 20-25% of filtered calcium is reabsorbed in the ascending limb of the loop of Henle, whereas the remaining 10% is reabsorbed under the influence of PTH and vitamin D in the distal tubule.

The bones serve as a reservoir, storing 99% of the body's calcium. Bony remodeling can engineer large, but slower, alterations in the serum calcium by a slow change in the balance between osteoblastic bone formation and osteoclastic bone resorption. However, deposition and release from hydroxyapatite can also provide slightly faster regulation. The intestine serves as a long-term homeostatic mechanism for calcium. Although the major source of calcium is dietary, seven eighths of dietary calcium is excreted unabsorbed in feces. Absorption occurs primarily in the ileum and jejunum by means of active transport and facilitated diffusion.

Investigations flowchart.

Half the plasma calcium is ionized and freely diffusible, whereas 10% is bound to citrate and phosphate but able to diffuse into cells. The remaining 40% is plasma protein bound and not diffusible into cells. In the setting of a calcium increase in a person with normal regulatory mechanisms, hypercalcemia suppresses the secretion of PTH. This plays a prominent role in calcium maintenance, however, only in the narrow range of serum calcium levels from 7.5-11.5 mg/dL. levels above or below this range are relatively ineffective at further stimulating or suppressing PTH and rely on direct exchange of calcium between bone and extracellular fluid.

Normally, PTH stimulates release of calcium from bone by direct osteolytic action and via osteoclast up-regulation. Therefore, a decline in serum PTH concentration decreases the flux of calcium from bone to extracellular fluid. PTH also acts to reabsorb calcium in the loop of Henle and distal tubule in the kidney and; when PTH is absent, much of the filtered calcium is excreted in the urine. Finally, PTH stimulates enzymatic conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D.

Ultraviolet (UV) light converts 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D-3). Alternatively, previtamin D is directly ingested and transported by proteins to the liver, where it is converted to 25-hydroxyvitamin D. In the kidney, 25-hydroxyvitamin D (calcidiol) is converted to the active metabolite 1,25-dihydroxyvitamin D by a PTH-stimulated process. 1,25-dihydroxyvitamin D (calcitriol) serves to promote intestinal absorption of calcium. When PTH is suppressed because of hypercalcemia, levels of 1,25-dihydroxyvitamin D decline, and thus intestinal calcium absorption declines.

The calcium sensing receptor (CaSR) is a regulator of calcium metabolism that has recently received significant attention.[2] Primarily expressed by the kidney and parathyroid gland, it controls parathyroid secretion and renal calcium reabsorption based on the extracellular calcium levels it senses. Inactivation of this receptor can cause hypercalcemia.

Regulators of calcium metabolism

The primary action of PTH is to increase serum calcium by the following mechanisms:

• Directly causes rapid resorption of calcium from the bone into the plasma, elevating serum calcium both by directly stimulating the osteolytic calcium pump and by osteoclast up-regulation

• Directly causes renal tubular reabsorption of calcium in the loop of Henle and distal tubule

• Inhibits phosphate reabsorption, as well as that of sodium, water, and bicarbonate in the kidney

• Promotes renal conversion of 25-hydroxyvitamin D to the more active form 1,25-dihydroxyvitamin D by stimulating renal 1 hydroxylase activity

• Lowers serum phosphate

• Is stimulated by increases in phosphate, decreases in calcium, adrenergic agents, magnesium, and certain vitamin D metabolites

• Is suppressed by hypercalcemia and high levels of 1,25-dihyroxyvitamin D

Vitamin D in its active form of 1,25-dihydroxyvitamin D (also known as calcitriol [Rocaltrol]) increases serum calcium levels by the following mechanisms:

• Increases calcium and phosphate absorption from the intestines

• Increases mineralization of bone, possibly by increasing intracellular transport of calcium ions and by increasing circulating concentrations of calcium and phosphate

• Increases calcium reabsorption in the distal tubule of the kidney

• Is inhibited by phosphate and corticosteroids

Calcitonin causes an overall decrease in serum calcium by the following mechanisms:

• Impairs osteoclast and bone osteolytic activity

• Prevents osteoclast formation

• Increases urinary excretion of calcium

Other factors altering serum calcium include the following:

• Metabolic alkalosis, which causes an increase in tubular calcium reabsorption

• Phosphate-induced decrease of serum calcium levels and increase of PTH

• Stimulation of osteoclasts by cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6

• Stimulation of osteoclasts by prostaglandins

• Effect of glucocorticoids on bone formation and intestinal absorption of calcium

• Inhibition of bone resorption by estrogens

• CaSR

Etiologies vary by age and other factors.

• Neonates

  • Neonatal primary hyperparathyroidism can begin as soon as the parathyroid glands, functional in the first trimester of pregnancy, become hyperplastic.

    • Infants have malaise, constipation, and vomiting; serum calcium and parathyroid hormone (PTH) concentrations are elevated, and serum phosphate concentration is decreased. Aminoaciduria occurs. Rarification of bones leads to easier fracturing.

    • Rehydration with isotonic sodium chloride solution and forced diuresis with furosemide are urgently required, as well as administration of subcutaneous calcitonin. Common side effects of subcutaneous calcitonin include facial flushing, nausea, and vomiting.

    • Definitive treatment is performed by means of surgical resection, often with reimplantation of a small amount of tissue into a more accessible ectopic site (eg, forearm).

    • Neonatal primary hyperparathyroidism stems from a homozygous inactivating mutation in a calcium-sensing receptor.

  • Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant heterozygous mutation of the same calcium receptor-sensing gene (CASR) that is abnormal in the homozygous state in neonatal primary hyperparathyroidism.

    • If symptoms are observed (eg, chondrocalcinosis, pancreatitis, renal disease, neuropsychiatric disease), they generally begin in the neonatal period; however, patients are often asymptomatic. If the patient is asymptomatic, no treatment is required.

    • Because of the mutation, levels of calcium that are higher than usual are required to decrease secretion of PTH. The serum PTH concentration, although within the reference range, is inappropriately high for the degree of hypercalcemia.

    • Other laboratory findings include a decreased or normal serum phosphorus level, an increased magnesium level in 50% of babies, normal levels of alkaline phosphatase and serum 25-hydroxyvitamin D, and an appropriate level (to the PTH) of 1,25-dihydroxyvitamin D. Serum calcium levels rarely rise above 14 mg/dL. Urine calcium excretion is decreased to less than 200 mg/d, but the level of urine cyclic adenosine monophosphate (cAMP) is normal.

    • Radiographic findings are normal.

  • Excessive supplementation of calcium causes hypercalcemia.

  • Williams syndrome, which is associated with a deletion of elastin genes on chromosome 7, occurs as transient neonatal hypercalcemia, perhaps secondary to increased sensitivity to vitamin D.[3]  The syndrome is associated with characteristic elfin facies, mental retardation, and supravalvar aortic stenosis. Generally, hypercalcemia is symptomatic, with poor feeding and constipation, and spontaneously remits by age 9-18 months. Treatment is a dietary restriction of calcium to 100 mg/d and limited vitamin D intake. Hydrocortisone at 10-25 mg/kg/d or calcitonin is sometimes helpful.

  • Severe autosomal recessive hypophosphatasia is a disease of bone mineralization due to a deficiency in tissue nonspecific alkaline phosphatase (TNSALP). Associations vary from rachitic changes to fetal death. These children require a low-calcium high-phosphate diet.

  • Secondary hyperparathyroidism is a neonatal response to maternal hypocalcemia with similar symptoms to primary hyperparathyroidism, except that the child undergoes a progression from hypocalcemia to normocalcemia to hypercalcemia quickly after birth. PTH is generally elevated. During the first few months, the parathyroid glands and skeletal lesions normalize; therefore, only symptomatic nonsurgical treatment is required.

  • Idiopathic infantile hypercalcemia (IIH) is a poorly understood disorder possibly related to non–malignancy-associated PTH-related protein (PTHrP), which spontaneously resolves by age 12 months. In a study of 20 children with mild IIH who were followed up for a median of 21 months, dietary calcium and vitamin D restriction reduced serum and urinary calcium levels; however, serum concentrations of 1,25 dihydroxyvitamin D remained elevated. In addition, renal calcification worsened in 2 of the children in the study.[4]

  • Blue diaper syndrome is a selective defect in the intestinal transport of tryptophan. The diagnosis is confirmed by analyzing urine indoles.

  • Jansen metaphyseal chondrodysplasia is a rare disease of endochondral bone formation characterized by short stature, leg bowing, short-limbed dwarfism, and a waddling gait. Neonatally, these children appear normal but have radiographic and laboratory abnormalities. In early childhood, the external changes become more obvious. The condition arises from an activating mutation in the PTH/PTHrP receptor. Radiographic findings reveal cupped and ragged metaphyses and osteitis fibrosa cystica, and laboratory findings reveal a serum calcium level of 13-15 mg/dL, a low phosphate level, a high level of 1,25-dihydroxyvitamin D, a high alkaline phosphatase level, and urine hydroxyproline.

• Infants: Subcutaneous fat necrosis, which manifests in neonate as violaceous plaques or nodules overlying fatty areas, can lead to life-threatening hypercalcemia at age 1-6 months. It is likely mediated by prostaglandin E (PGE) or due to macrophage production of 1,25-dihydroxyvitamin D. Treatment includes corticosteroids and symptomatic support of patient.

• School-aged children

  • Hyperparathyroidism secondary to parathyroid adenoma or autosomal dominant hereditary hyperparathyroidism is a rare problem in older children. Children may be asymptomatic or symptomatic with constipation and personality changes. Levels of urine and serum calcium are high, whereas the serum phosphorus level is low and urine phosphorus level is high. Unlike in most forms of hypercalcemia, which are associated with systemic alkalosis, patients with hyperparathyroidism tend to have acidosis. This acidosis is due to a loss of bicarbonate in the urine, giving a picture consistent with renal tubular acidosis. Radiographic findings of osteitis fibrosa cystica may be present. Treatment is surgical, and corticosteroids have no role.[5]

  • Multiple endocrine neoplasia (MEN) type 1 (ie, Wermer syndrome) is a rare autosomal dominant constellation of hyperparathyroidism, pancreatic tumors, and pituitary tumors treated by subtotal parathyroidectomy. Molecular diagnosis is now available for MEN types 1 and 2.

• General factors

  • Malignancies produce hypercalcemia much less frequently in the pediatric patients than in adults. However, pediatric malignancies that can elevate calcium include the following:

    • Non-Hodgkin lymphoma or Hodgkin lymphoma

    • Ewing sarcoma

    • Neuroblastoma

    • Langerhans cell histiocytosis[6]

    • Rhabdomyosarcoma with metastases to breast or bone marrow in adolescents

    • Ovarian small cell carcinoma in adolescents

    • Renal tumors with rhabdoid histology in infants

  • Three different mechanisms are responsible, and resultant laboratory abnormalities slightly differ.

    • Primarily in leukemia, PTHrP increases osteoclast resorption of bone, renal reabsorption of calcium, and renal loss of phosphorous, leading to decreased serum phosphate levels, increased urinary cAMP, and detectable PTHrP.

    • Burkitt lymphoma and multiple myeloma, as well as bony tumors or sarcomas with bony metastases, can cause cytokine-mediated bone resorption.

    • Hodgkin and non-Hodgkin lymphoma may cause increased intestinal absorption of calcium via production of 1,25-dihydroxyvitamin D by macrophages, which contain 1-alpha-hydroxylase activity, and may maintain a normal serum phosphorus level.

  • Generally, patients with malignancy-induced hypercalcemia have decreased chloride levels, alkalosis, increased BUN levels, increased uric acid levels, urine calcium levels higher than 400 mg/dL, and increased urine cAMP levels. Serum alkaline phosphatase levels may be elevated, and serum PTH levels are decreased, except in the uncommon setting of direct stimulation of PTH production by the tumor. Serum calcium levels greater than 14 require treatment, primarily with hydration and steroids at a dose of 1.5-2 mg prednisone equivalent/kg/d for several days.

  • Thyrotoxicosis can cause sufficient bone resorption to increase serum calcium in 20% of cases. In these patients, thyrotoxicosis can also decrease serum PTH and increase urine excretion of cAMP and calcium. Although hypercalcemia is rarely subjectively symptomatic to the patient, it can lead to nephrocalcinosis and renal failure. This condition is rare in childhood, but it is possible in neonates of mothers with Graves disease or in older children who develop Graves disease.

  • Granulomatous disease, including sarcoidosis, tuberculosis (TB), Wegener disease, berylliosis, and Pneumocystis carinii pneumonia, may cause hypercalcemia via overproduction of 1,25-dihydroxyvitamin D by macrophages and increased extrarenal alpha1-hydroxylase activity.

  • Adrenal insufficiency can decrease the renal clearance of calcium.

  • Hypercalcemia may appear in the oliguric phase of acute renal failure due to the PTH increase stimulated by hyperphosphatemia. Also, children with renal failure treated with calcitriol for secondary hyperparathyroidism can develop a mild hypercalcemia.[7]

  • Immobilization can cause hypercalcemia.

• Medication and iatrogenic causes

  • Total parenteral nutrition may cause hypercalcemia.

  • Vitamin D intoxication due to ingestion of more than 50 mcg/d in infants or more than 500 mcg/d in adults can cause hypercalcemia, even in the absence of a markedly elevated 1,25-dihydroxyvitamin D. Symptoms of hypercalcemia, including hypertension, aortic valvular sclerosis, retinopathy, renal damage, and bony abnormalities, can also occur 1-3 months after a large overdose of vitamin D. Serum PTH is decreased. Levels of water-soluble preparations can drop quickly, but hypercalcemia from an excess intake of fat-soluble preparations may persist for months.

  • Vitamin A in high doses, such as those found in retinoid therapy for acne, can directly stimulate bone resorption by functioning as a transcription factor in osteoclast stimulation. Trans -retinoic acid, used for treatment of some leukemias, can elevate calcium with this mechanism, particularly when coupled with voriconazole.[8]

  • Thiazide diuretics (eg, Diuril) may cause hypercalcemia because of their action on the distal tubule.

  • Lithium causes a mild increase in serum calcium, which can occasionally increase further in the few months after cessation of the drug secondary to parathyroid hyperplasia or adenoma.

  • Tamoxifen and oral contraceptives can exacerbate existing hypercalcemia.

  • Milk-alkali syndrome (ie, Burnett syndrome) from exogenous ingestion of calcium-containing antacids leads to renal insufficiency and metastatic calcinosis with increased phosphorus levels, increased levels of 1,25-dihyroxyvitamin D, decreased PTH levels, normal levels of serum alkaline phosphatase, normal urine calcium levels, and decreased urine phosphate levels.[9]  If continued over time, this may lead to osteomalacia. This condition is particularly sensitive to the development of hypocalcemia following treatment with bisphosphonates.

  • Theophylline can cause increases in calcium via beta-adrenergic stimulation. This may be treated with propranolol.

  • Oral dietary phosphate deficiency may cause hypercalcemia.

  • Vitamin-D receptor modulators (eg, paricalcitol) are newer medications used to treat malignancy and hyperparathyroidism, which can increase serum calcium levels.

United States statistics

Hypercalcemia is not a common pediatric problem; the actual incidence in children is unknown, although it is less common than in adults. In adults, hypercalcemia is the primary malignancy-associated endocrine/electrolyte disorder; it is present in 5% of all malignancies, or in 15 per 100,000 total patients. Cancer-related hypercalcemia in adults most often occurs in later-stage malignancies.[10]

Hypercalcemia is frequently noted during laboratory testing while the patient is asymptomatic or mildly symptomatic. Prognosis depends on the underlying disorder.

Morbidity/mortality

Mortality from hypercalcemia itself is rare, although cardiovascular collapse and neonatal seizures are reported. The survival rate is more than 80%, even with malignancy-associated hypercalcemia in adults requiring ICU admission. Clearly, in certain disorders associated with hypercalcemia (eg, Williams syndrome, cancer), the underlying disorder may prove fatal or provide significant morbidity.

Complications

Primarily ectopic calcifications may occur.

Hypercalcemia can cause symptoms at levels as low as 12 mg/dL and consistently causes symptoms at 15 mg/dL. Hypercalcemia initially and predominantly affects the GI and nervous systems. Symptoms include the following:

• Nervous system

  • Personality changes

  • Malaise

  • Headache

  • Hallucinations

  • Unsteady gait

  • Proximal muscle weakness

  • CNS depression

  • Irritability

  • Confusion

• GI system

  • Hypercalcemia can cause a paralytic ileus, with resultant abdominal cramping, constipation, anorexia, nausea, and vomiting.

  • Ectopic calcification can lead to symptoms of pancreatitis, with epigastric pain and vomiting.

  • Increased gastric acid secretion may produce symptoms consistent with gastritis.

• Renal symptoms

  • Renal stones

  • Nephrogenic diabetes insipidus (DI) with polyuria and polydipsia

  • Renal failure

• Musculoskeletal system - Bone pain

• Ectopic calcification

  • Pruritus

  • Conjunctivitis

• Miscellaneous symptoms

  • Congenital deformity

  • Other symptoms of malignancy

  • Symptoms of other underlying causes of hypercalcemia

  • Hypercalcemia-associated acute respiratory distress syndrome (rare)[11]

Vital signs include the following:

• Bradycardia

• Possible hypertension

Neurologic examination findings include the following:

• Depressed sensorium

• Confusion

• Gait disturbances

• Hyporeflexia

• Proximal muscle weakness

Even at lower levels, patients can have renal failure and ectopic calcification, including renal stones and pancreatitis.

Ectopic calcification can also manifest as conjunctivitis or band keratopathy on eye examinations.

Neonates may be asymptomatic or may have vomiting, hypotonia, hypertension, or seizures.

At levels of 17 mg/dL, calcium phosphate precipitation through the blood and soft tissues can lead to coma or lethal cardiac arrest.

Hypercalcemia is often asymptomatic. If hypercalcemia is symptomatic, the differential diagnosis rests heavily on the predominating symptom.

Weakness and altered sensorium may be symptomatic of a myriad of neurologic disorders, as well as toxins (eg, organophosphate poisoning), lupus, or thyroid dysregulation.

Weakness alone may be confused with hypokalemia, whereas ataxia is found in phenytoin overdoses, mass lesions, stroke syndromes, and encephalitides.

Hypertension may indicate a cardiac or renal problem.

Many manifestations of hypercalcemia (eg, pancreatitis, renal stones, gastritis, conjunctivitis) may be caused by etiologies different from hypercalcemia.

Overall, creating an all-encompassing algorithm for diagnosing the etiology of hypercalcemia is difficult. Clearly, the differential diagnosis widely varies on the basis of the child's age. Much of the laboratory workup should be guided by the history and physical examination. In infancy, a syndromic appearance of a child or dietary review may lead to very different diagnostic paths. If the history and physical examination yield no clear direction, a laboratory workup may reveal the diagnosis.

• Initially, a physician must verify that the hypercalcemia is not a laboratory error. The most common reasons for falsely elevated serum calcium levels are hemoconcentration and elevated serum protein levels (eg, multiple myeloma). Acidosis increases the level of ionized calcium (but not total calcium) by changing plasma protein binding. A high intake of phosphate may also falsely elevate the serum calcium level.

• In the neonate, in addition to calcium, determine serum protein, phosphate, and parathyroid hormone (PTH) levels as well as the levels of maternal calcium and maternal PTH. Serum calcium levels from other family members may also be helpful. In a baby with hypercalcemia, the serum PTH level should be lower than 10 pg/mL. A definitive diagnosis of hyperparathyroidism is confirmed by a PTH level higher than 50 pg/mL. In the situation of inappropriately normal or high PTH, consider hyperparathyroidism, familial hypocalciuric hypercalcemia, secondary hyperparathyroidism, and, rarely, malignancy. When PTH is suppressed, malignancy, granulomatous disease, iatrogenic causes, adrenal insufficiency, thyrotoxicosis, and vitamin D intoxication are possibilities.

  A study on the failure to diagnose primary hyperparathyroidism by Balentine et al reviewed data on 10,432 patients diagnosed with hypercalcemia and reported that only 31% of hypercalcemic patients had PTH levels measured and only 22% of 2666 patients with classic hyperparathyroidism were referred to surgeons. ^[12]

• Other laboratory findings that may be abnormal include sodium, potassium, and magnesium measurements. The reabsorption of these electrolytes is decreased in the proximal tubule, lowering their serum levels. Sensitivity to digitalis is increased, and a level should be assessed if the patient is taking digoxin. Perform BUN and creatinine tests to evaluate renal function, pancreatic enzyme tests to evaluate for pancreatitis, and stool hemoccult tests to evaluate for gastritis or a peptic ulcer if symptoms point toward these possibilities.

• In childhood, the history and physical examination are extremely important. Inquire about symptoms or family history consistent with a multiple endocrine neoplasia (MEN) syndrome and perform molecular testing if appropriate. Consider the possibility of a malignancy, and direct the diagnostic evaluation toward that if symptoms or results from a CBC count point to this direction. Review the history and chest radiography for the possibility of granulomatous disease. Query about a history of signs or symptoms of thyrotoxicosis, and assess the level of thyroid-stimulating hormone (TSH) if indicated. Use history and creatinine clearance to eliminate renal failure. Ensure no medications, herbal preparations, or recent immobilizations are responsible. If this initial screen does not reveal the etiology, begin with serum PTH and phosphate, urine calcium, and serum bicarbonate measurements, and consider the other studies listed in the table below.

• High PTH levels usually indicate primary hyperparathyroidism if the urine calcium–to–creatinine ratio is high and indicates familial hypocalciuric hypercalcemia if the urine calcium–to–creatinine ratio is low (confirm with DNA sequence analysis for CASR gene). Low PTH levels usually indicate hypervitaminosis D if 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are high and indicate malignancy if they are low (confirm with high PTHrP level).

• All laboratories have different reference-range values, examples of which are listed in the table below. Table 1. Normal Laboratory Values

  Table. (Open Table in a new window)

  Laboratory Test	Reference Range	Normal Response to Increased Calcium
  Serum calcium	8.5-10.2 mg/dL	NA
  Ionized calcium	1-1.3 mmol/L	NA
  PTH (intact)	10-55 pg/mL*	Decrease
  Serum phosphate	Age-dependent	Increase
  1,25-dihydroxyvitamin D	36-108 pmol/L	Decrease
  Alkaline phosphatase	68-217 U/L	Normal
  Urine calcium	4 mg/kg/d	Increase
  Urine Ca/Cr ratio	See note†	Increase
  Urine cAMP‡	< 5 mol	Decrease
  *Note that 1 mmol/L equals 4 mg/dL. †In infants younger than 7 months, the reference range is less than 0.86; in infants aged 7-18 months, the reference range is less than 0.6. By age 6-7 years, the adult reference range of less than 0.21 is reached.‡The urine cAMP level generally parallels the PTH level.

• Depending on the age of the patient and history obtained, consider all of the above tests.

• When testing for hypervitaminosis D, assess the serum levels of 25-hydroxyvitamin D because they reflect the intake of vitamin D better than levels of 1,25-dihydroxyvitamin D. The exception to this is when 1,25-dihydroxyvitamin D is overingested or overproduced. Table 2. Additional Laboratory Values

  Table. (Open Table in a new window)

  Condition	Serum Phosphorus	Serum Alkaline Phosphatase	Urine Calcium	Urine Phosphate	PTH
  Hyperparathyroidism	Low	Normal-high	High*	High	High
  Vitamin D excess	Normal-high	Low	High	High
  Malignancy	Often low	High †	Variable	High
  Granulomatous disease	Normal-high	Normal-high	High	Normal
  Milk alkali syndrome	Normal-high	Normal	Normal	Normal
  FHH	Normal or low	Normal	Low (< 200mg/d)	Normal	Low
  *67% of the time † Except hematologic malignancies, in which alkaline phosphatase is normal

Plain radiography may reveal demineralization, pathologic fractures, bone cysts, and bony metastases.

Renal imaging, ultrasonography, CT urography, or intravenous pyelography (IVP) may reveal evidence of calcifications or stones.

Perform ultrasonography of the parathyroid glands if hyperplasia or adenoma is a primary diagnosis. A sestamibi nuclear scan may be helpful in locating a parathyroid adenoma.

Other imaging tests may be necessary to exclude alternative diagnoses (eg, gallstone vs hypercalcemic pancreatitis) or to find a primary or associated malignancy if the laboratory tests or history produce suspicious findings.

Other tests include the following:

• ECG

  • Shortened QT interval

  • Bradycardia

  • Coving of ST-T wave

  • Widened T wave

• Ophthalmologic examination

  • Band keratopathy

  • Conjunctivitis

Localization of a parathyroid adenoma may be assisted by catheterization of the appropriate veins and measurements of PTH.

Initial treatment of hypercalcemia involves hydration to improve urinary calcium output. Isotonic sodium chloride solution is used, because increasing sodium excretion increases calcium excretion. Addition of a loop diuretic inhibits tubular reabsorption of calcium, with furosemide having been used up to every 2 hours. Attention should be paid to other electrolytes (eg, magnesium, potassium) during saline diuresis. These treatments work within hours and can lower serum calcium levels by 1-3 mg/dL within a day.

Bisphosphonates serve to block bone resorption over the next 24-48 hours by absorbance into the hydroxyapatite and by shortening the life span of osteoclasts. Administered intravenously (IV), they decrease serum calcium in 2-4 days with a nadir at 4-7 days. These medications have been studied more in adults than in children; however, many studies have established safety and efficacy in children, particularly with etidronate and pamidronate.[13]

• Etidronate (Didronel), a first-generation bisphosphonate, may result in hyperphosphatemia and a transient increase in creatinine. It is given as 7.5 mg/kg/d IV over 2 hours for 3-7 days and lowers serum calcium in 2 days; maximal action is reached in 7 days. Oral etidronate doses are 5-20 mg/kg/d. Oral dosing of etidronate for 3-12 months can inhibit bone mineralization, leading to bony pain and fractures, and occasionally nephrotic syndrome.

• Clodronate (Bonefos), is an orphan drug in the United States and is used for increased bone resorption or hypercalcemia of malignancy. It acts similarly to etidronate.

• Pamidronate (Aredia) in IV and oral formulation has been used successfully in children. To lower serum calcium levels over a period of days to months, intravenous doses of 1-1.5 mg/kg (to an adult dose of 90 mg) are administered. Redosing is based on a rise in serum calcium levels and should not be done more than once a month. Oral doses are 4-8 mg/kg/d. Fever, musculoskeletal discomfort, and vomiting are common side effects.

• Alendronate (Fosamax), tiludronate (Skelid), and risedronate (Actonel) are newer, more potent bisphosphonates that carry the uncommon but potential toxicities of lowering serum phosphorus, acute phase response with low grade fever, myalgia, lymphopenia, increased cAMP receptor protein (CRP), GI upset, gastritis, bone pain, and reversible hepatotoxicity. Additionally, some believe that the tensile strength of bones formed while on these medications may be less than that of native bone. Mineralization defects may occur, particularly in pediatric patients before growth plates are fused. Ibandronate (Boniva) and zoledronate (Zometa) are believed to be even more potent medications. Adult literature contains the preponderance of studies involving these medications.

• Neridronic acid is an IV/intramuscular (IM) bisphosphonate currently licensed in Europe; some pediatric data are available, including some in neonates.[14]

Calcitonin at subcutaneous (SC) or IM doses of 3-6 mcg/kg every 6 hours, works within hours to decrease skeletal reabsorption of calcium and inhibit renal reabsorption, but it lowers serum calcium concentration only for 2-3 days because of tachyphylaxis. It can be expected to lower serum calcium only 0.5 mmol/L. Adverse effects include nausea, cramping, abdominal pain, and flushing. One benefit of calcitonin is that it has analgesic properties.

Other options include 200 mg/m2/d of gallium nitrate for 5 days as a continuous infusion. Gallium nitrate inhibits bone resorption by reducing the solubility of hydroxyapatite, but it is potentially nephrotoxic.

Plicamycin (ie, mithramycin) lowers calcium by inhibiting RNA synthesis to kill osteoclasts. The manufacture and distribution of plicamycin was discontinued in the United States in 2000. A dose of 25 mcg/kg/d is given IV over 3-4 days; the onset of action is within 24-48 hours. Mithramycin is associated with many reversible adverse effects, such as thrombocytopenia, hepatocellular necrosis with increased lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), decreased clotting factors with resultant bleeding, azotemia, proteinuria, hypokalemia, hypophosphatemia, nausea, vomiting, and facial swelling. These adverse effects are more common with repeated dosing.

Peritoneal dialysis or hemodialysis can be used in extreme situations, particularly in patients with renal failure; careful attention must be given to the phosphorus level following dialysis.

Cinacalcet hydrochloride (Sensipar) is the first medication approved from the calcimimetic class. It changes the configuration of the transmembranal calcium-sensing receptor in a manner that makes it more sensitive to serum calcium. It is primarily indicated for chronic renal disease and secondary hyperparathyroidism. No large pediatric studies have been done to date, but its efficacy has been substantiated in adults.

Several newer medications that do not acutely lower serum calcium levels and may raise them have been developed for hyperparathyroidism. These include calcitriol and its more potent forms (eg, DN-101) and other vitamin D analogues, such as paricalcitol (Zemplar). By binding to vitamin D receptors, they chronically inhibit the secretion of parathyroid hormone (PTH). However, their use in patients with severe or symptomatic hypercalcemia is limited by their ability to increase serum calcium and the calcium x phosphate product. One report of a long-acting depot form of octreotide demonstrated efficacy in patients with multiple endocrine neoplasia (MEN) 1 who also had hyperparathyroidism.[15]

Surgical intervention may be needed in patients with hyperparathyroidism, particularly with recurrent renal stones or persistent serum calcium levels higher than 12.5 mg/dL.

Subtotal parathyroidectomy can be performed, or complete parathyroidectomy can be chosen with reimplantation of a small amount of tissue in the forearm.

Consultations include the following:

• Endocrinologist

• Nephrologist

• Oncologist

A low-calcium diet is indicated. Restriction of vitamin D (sunlight, dairy) may be warranted in some disorders.

Class Summary

These agents increase sensitivity of the calcium-sensing receptor to extracellular calcium by changing the configuration.

Cinacalcet (Sensipar in the US, Mimpara in Europe)

Directly lowers iPTH levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant decrease of serum calcium levels by affecting renal reabsorption. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease. Pediatric data are limited.

Class Summary

These augment urinary elimination.

Furosemide (Lasix)

Used to induce calciuresis. First line for hypercalcemia with concomitant intense hydration. For IV dosing, diuretic effect begins within 5 min and peaks at 2 h.

Administer IV for emergency treatment of hypercalcemia.

Class Summary

These agents decrease serum calcium levels. They inhibit bone resorption and, thus, have a hypocalcemic effect. Used in the treatment of conditions associated with increased bone resorption, such as osteoporosis, Paget disease of bone, and management of hypercalcemia (especially that associated with malignancy). Recent reports have linked these medications with osteonecrosis of the jaw, delayed oral wound healing, and renal compromise.[16]

Etidronate (Didronel)

Bisphosphonate that inhibits formation, growth, and dissolution of hydroxyapatite crystals by chemisorption to calcium phosphate surfaces; can be used IV short term or PO long term.

Pamidronate (Aredia)

A bisphosphonate. Same mechanism as etidronate. Inhibits formation, growth, and dissolution of hydroxyapatite crystals by chemisorption to calcium phosphate surfaces. Only IV use is approved, although a few studies have attempted PO.

Gallium nitrate (Ganite)

A naturally occurring heavy metal. The mechanism by which it inhibits calcium resorption from bone is unclear but may involve reducing increased bone turnover.

Class Summary

These are secreted by the thyroid gland and help maintain calcium homeostasis by increasing calcium mineral stores in bone and increasing calcium renal excretion.

Calcitonin (Calcimar, Miacalcin)

Acts primarily on bone but also on the kidney and GI tract to decrease serum calcium levels. Also lowers serum alkaline phosphatase levels by inhibiting bony turnover. Calcium-lowering effect begins 2 h after the first injection and lasts 6-8 h. The effect is maintained for 5-8 d.

Daily calcium intake should be limited, and restriction of vitamin D (sunlight, dairy) may be warranted in certain disorders.

Admit any patient requiring treatment for hypercalcemia.

• Continue the previously mentioned medications as needed.

• Continue an appropriate workup for the etiology of hypercalcemia.

For neonates, specifically, Oski recommends 5% dextrose (D5) in one-half isotonic sodium chloride solution with 30 mEq/L potassium chloride at 2 times the maintenance dose along with 2-3 mg/kg/d furosemide and adequate phosphate supplementation to maintain normal levels.[17] Strongly consider surgical correction of primary hyperparathyroidism.

Long-term therapy can begin while the patient is in the hospital and continue following discharge.

Corticosteroids are helpful in certain disorders, particularly malignancy-associated hypercalcemia, granulomatous disease, or vitamin D ingestion; and they can be given either IV or orally as prednisone in doses of 40-60 mg/m2/d or 1.5-2 mg/kg/d to inhibit osteoclast action and decrease intestinal calcium absorption.

Aminohydroxypropylidene (APD) can induce remissions of malignancy-associated hypercalcemia.

If serum phosphate is low, intravenous (IV) phosphorus is no longer recommended because of the risk of intravascular precipitation with calcium; however, oral phosphate supplementation is recommended because this binds calcium in the intestine and diminishes calcium absorption. The dose is 1-3 g/d for an adult-sized person. Phosphate is contraindicated in renal failure and requires 2-3 days before it becomes effective.

Bisphosphonates may also be continued as outpatient medications. One should consider alendronate as an oral preparation. However, note that no pediatric experience is noted.

Indocin may be of some use in certain disorders that lead to hypercalcemia.

As in any patient, transfer is acceptable when patient is stable or when a higher level of care is required. However, consider the possibility of coma or cardiovascular collapse in a patient with an excessively high calcium level. Begin close observation/therapy before transfer.

Carefully monitor patients with risk factors for hypercalcemia, such as known malignancy, thiazide diuretic use, total parenteral nutrition, retinoid use for acne, or lithium use.

Counsel patients to consume adequate phosphate and to avoid excessive calcium-containing antacids, vitamin D, and herbal preparations with vitamin A.