Pediatric Hypercalcemia

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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.

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.

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

United States

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.

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.

See Causes for an extensive discussion of causes of hypercalcemia by age group.

[Guideline] Hawley C, Elder G. Calcium. Westmead NSW (Australia): CARI – Caring for Australasians with Renal Impairment; 2005 Oct. [Full Text].

Vezzoli G, Soldati L, Gambaro G. Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport. Curr Pharm Biotechnol. Apr 2009. 10(3):302-10. [Medline].

Hsu YH, Chen HI. Acute respiratory distress syndrome associated with hypercalcemia without parathyroid disorders. Chin J Physiol. Dec 2008. 51(6):414-8. [Medline].

Sangun O, Dundar BN, Erdogan E. Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy. J Pediatr Endocrinol Metab. 2011. 24(1-2):69-70. [Medline].

Roizen J, Levine MA. A meta-analysis comparing the Biochemistry of Primary Hyperparathyroidism in Youths to the Biochemistry of Primary Hyperparathyroidism in Adults. J Clin Endocrinol Metab. 2014 Sep 2. jc20142268. [Medline].

Arico M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998 Apr. 12(2):247-58. [Medline].

De Sanctis V, Fiscina B, Ciccone S. Severe hypercalcemia in a patient treated for hypoparathyroidism with calcitriol. Pediatr Endocrinol Rev. 2010 Jun. 7(4):363-5. [Medline].

Bennett MT, Sirrs S, Yeung JK, Smith CA. Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Leuk Lymphoma. 2005 Dec. 46(12):1829-31. [Medline].

Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). 2005 Nov. 63(5):566-76. [Medline].

Balentine CJ, Xie R, Kirklin JK, Chen H. Failure to Diagnose Hyperparathyroidism in 10,432 Patients With Hypercalcemia: Opportunities for System-level Intervention to Increase Surgical Referrals and Cure. Ann Surg. 2017 Jul 3. [Medline].

Baroncelli GI, Bertelloni S. The Use of Bisphosphonates in Pediatrics. Horm Res Paediatr. 2014 Nov 6. 290-302. [Medline].

Gatti D, Viapiana O, Idolazzi L, Fracassi E, Adami S. Neridronic acid for the treatment of bone metabolic diseases. Expert Opin Drug Metab Toxicol. Oct 2009. 5(10):1305-11. [Medline].

Faggiano A, Tavares LB, Tauchmanova L, Milone F, Mansueto G, Ramundo V et al. Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism in MEN1 patients. Clin Endocrinol. May 2008. Epub:[Medline].

Landesberg R, Cozin M, Cremers S, Woo V, Kousteni S, Sinha S, et al. Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg. May 2008. 66(5):839-47. [Medline].

Oski F, DeAngelis CD, Feigin RD. Principles and Practice of Pediatrics. 2nd ed. 1994.

Laboratory Test

Reference Range

Normal Response to Increased Calcium

Serum calcium

8.5-10.2 mg/dL

Ionized calcium

1-1.3 mmol/L

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.

Condition

Serum Phosphorus

Serum Alkaline Phosphatase

Urine Calcium

Urine Phosphate

PTH

Hyperparathyroidism

Low

Normal-high

High*

High

Vitamin D excess

Normal-high

Low

High

Malignancy

Often low

High †

Variable

High

Granulomatous disease

Normal-high

High

Normal

Milk alkali syndrome

Normal-high

Normal

FHH

Normal or low

Normal

Low (< 200mg/d)

Normal

Low

*67% of the time

† Except hematologic malignancies, in which alkaline phosphatase is normal

Pisit (Duke) Pitukcheewanont, MD Associate Professor of Clinical Pediatrics, University of Southern California, Keck School of Medicine, Childrens Hospital Los Angeles

Pisit (Duke) Pitukcheewanont, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, American Society for Bone and Mineral Research, Endocrine Society, Pediatric Endocrine Society