Background
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. Pathophysiology
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
Epidemiology
Frequency
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/Morbidity
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.
Age
See Causes for an extensive discussion of causes of hypercalcemia by age group.
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| 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. | ||
| 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 | |||||
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