Hypercalcemia: a consultant’s approach
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Due to their daily involvement in mineral metabolism, nephrologists are often asked to consult on children with hypercalcemia. This might become even more pertinent when the hypercalcemia is associated with acute kidney injury and/or hypercalciuria and renal calcifications. The best way to assess the severity of hypercalcemia is by measurement of plasma ionized calcium, and if not available by adjusting serum total calcium to albumin concentration. The differential diagnosis of the possible etiologies of the disturbance in the mineral homeostasis starts with the assessment of serum parathyroid hormone concentration, followed by that of vitamin D metabolites in search of both genetic and acquired etiologies. Several tools are available to acutely treat hypercalcemia with the current main components being fluids, loop diuretics, and antiresorptive agents. This review will address the pathophysiologic mechanisms, clinical manifestations, and treatment modalities involved in hypercalcemia.
KeywordsAcute kidney injury Parathyroid hormone PTH-related peptide Vitamin D Calcitriol Bisphosphonates
Of total body calcium, 98–99% resides in the skeleton and the other 1–2% is present in the extracellular and intracellular compartments. Of circulating calcium, 45% is bound to protein (mainly albumin) and the other 55% is regarded as “ultrafiltrable” . The latter is obtained by applying pressure on serum against a semipermeable membrane, and is further divided between 10% complex calcium (bound to anions like phosphate, bicarbonate, and citrate) and 45% free (ionized) calcium, which is the fraction of this mineral participating in various crucial physiologic processes.
Serum calcium concentration is usually reported as total calcium. This fact requires further attention, as total calcium is never a reflection of ionized calcium concentration. The major factor affecting total calcium concentration is serum albumin. A change in serum albumin concentration by 1 g/dl will change total serum calcium by 0.8 mg/dl. A typical example is the child with early nephrotic syndrome with low serum albumin and low serum total calcium, at a time when serum ionized calcium concentration is normal. On the other hand, “pseudo-hypercalcemia” is seen in the face of high serum albumin concentration.
Assuming average serum albumin concentration of 4.0 g/dl, the equation to calculate “corrected” serum calcium is:
Corrected calcium (mg/dl) = measured total calcium (mg/dl) + [4.0 – serum albumin (g/dl)] × 0.8.
A factor that will shift calcium from being protein-bound to a free one is blood pH. Increase or decrease by 0.1 pH increases or decreases protein-bound calcium by 0.12 mg/dl, respectively. Thus in an individual with normal total serum calcium concentration, metabolic acidosis may lead to ionized hypercalcemia, whereas metabolic alkalosis to ionized hypocalcemia. An example of the latter is the patient with anxiety-induced hyperventilation, respiratory alkalosis, and consequently tetany, namely at the time total serum calcium is normal, ionized calcium concentration is low. Another reason for low serum ionized calcium is when concentrations of complexed calcium are high as it happens when high doses of phosphate or citrate are introduced. The former can be seen in patients with hypophosphatemia treated with intermittent high oral doses of phosphate and the latter is typically seen in patients receiving large quantities of blood transfusions anti-coagulated with citrate, as happens during liver transplant operations. It is thus evident that the best way to assess physiologically relevant serum calcium concentration is by directly measuring the ionized fraction. As this is not always available, one can still use total calcium for clinical purposes taking into account the above considerations.
Hypercalcemia is defined as serum ionized calcium concentration above 1.4 mmol/l (5.6 mg/dl) or total calcium concentration higher than 10.6 mg/dl, with possible variations among laboratories. Hypercalcemia is usually mild and asymptomatic, but at times can be severe with potential serious manifestations, as detailed below.
Physiology of calcium homeostasis and pathophysiology of hypercalcemia
Calcium homeostasis is tightly regulated by the interplay of three processes: absorption from the small intestine and renal tubular reabsorption, bone remodeling, and disposal through the gut and the kidney [2, 3, 4]. These processes are regulated by local and circulating factors. The two main hormones influencing the homeostasis of calcium are PTH and calcitriol. Additional factors include phosphate, 25(OH)-vitamin D, calcitonin, calcium sensing receptor (CaSR), fibroblast growth factor 23 (FGF-23); PTH related peptide (PTHrP), and weight bearing .
Serum-ionized calcium concentration is tightly maintained within a very narrow range and its regulation is conducted by PTH . This is governed by a sigmoid curve in which a small change in serum-ionized calcium concentration instantly results in a change in serum PTH. This is executed through binding of serum-ionized calcium to the calcium-sensing receptor (CaSR, vide infra), which regulates the release of PTH; high serum calcium will suppress its secretion and vice versa. PTH actions are mediated by binding to the PTH receptor in bone and kidney. When activated in bone, PTH receptor indirectly increases osteoclast activity, which causes bone resorption and release of calcium to the circulation. In the kidney, PTH increases reabsorption of calcium in the distal tubules and stimulates 1-alpha hydroxylation of 25(OH)-vitamin D to 1,25(OH)2-vitamin D in the proximal renal tubules, which in turn increases calcium absorption from the gut (vide infra). Overall, the role of PTH is to “recruit calcium” from all possible sources. In addition, in order to prevent the creation of too high serum Ca X P product, due to phosphate released from bone together with calcium, PTH activity decreases proximal tubular phosphate reabsorption by reducing NPT2a and NPT2c expression. Thus, over-activity of the gland in the patient with normal kidney function results in high serum calcium and low phosphate, but in the face of renal failure, serum phosphate is high due to the inability of the kidneys to eliminate it. Besides the effect of calcium, PTH secretion is affected by serum magnesium, calcitriol, FGF-23, and possibly serum phosphate, although the search for a “phosphate-sensing-receptor” is still elusive.
Calcitriol promotes calcium and phosphate absorption from the intestine, and possibly increases calcium reabsorption in the distal renal tubule, both actions contributing to bone mineralization by maintaining serum minerals at their optimal levels. However, when dietary calcium intake or serum calcium is low, the calcitriol interacts with the vitamin D receptor in osteoblasts to induce the expression of the plasma membrane protein receptor activator of factor k beta ligand (RANKL), which binds to RANK on osteoclast precursors, causing their differentiation to mature osteoclasts, which in turn cause bone resorption and release of calcium into the circulation. Thus, in cases of hypocalcemia, calcitriol acts on bone like PTH, namely increasing bone resorption to maintain serum calcium. Calcitriol suppresses PTH secretion and stimulates FGF-23 production. Calcitriol levels are low during hyperphosphatemia because of reduced activity of 1-alpha hydroxylase, which is mediated by phosphate-induced increase in circulating FGF-23. On the other hand, hypophosphatemia leads to increased calcitriol production [2, 5]. In cases of excessive calcitriol production or decreased degradation, resulting in elevated blood calcitriol levels, hypercalcemia will develop.
Calcium sensing receptor
The CaSR, a G protein coupled receptor is expressed in the cells of organs that participate in calcium homeostasis such as parathyroid, kidney, osteoblasts, and intestinal cells. The CaSR is the main regulator of PTH secretion. When calcium binds to the extracellular domain, it induces a conformational change in the intracellular domain, resulting in second messenger signaling, which reduces PTH production and secretion. Thus, the receptor serves to apply negative feedback in which hypercalcemia suppresses PTH release, and vice versa. Serum magnesium has a similar effect but its potency is about one-third that of calcium. Interestingly though, profound hypomagnesemia can be associated with hypoparathyroidism and hypocalcemia due to a yet unknown mechanism. In the thick ascending limb of the loop of Henle (TAL), the CaSR is present in the basolateral side and its activation leads to suppression of the Na-K-2Cl symporter (SLC12A1). Its activation results in decreased sodium reabsorption, and coupled with that decreased calcium reabsorption, leading to hypercalciuria. A genetic mutation leading to loss of function of the CaSR (discussed later) will result in hypercalcemia and hypocalciuria [2, 8, 9].
PTH-related peptide (PTHrP)
The PTHrP is produced by a variety of tissues and acts in paracrine and autocrine manners to control local tissue calcium concentration. PTHrP has a role in calcium homeostasis during fetal life and is involved in placental calcium transport and fetal chondrocyte maturation. PTHrP may also have some role in mobilizing calcium from maternal bone during lactation. The PTHrP is homologous in configuration to the PTH and acts on the same type I PTH/PTHrP receptor. Having a PTH-like effect induces osteoclastic activity and increases bone resorption, production of calcitriol, and renal reabsorption of calcium. Its main clinical significance is as a mediator of humoral hypercalcemia of malignancy as discussed below [10, 11, 12].
This is an endogenous polypeptide secreted by the parafollicular C cells of the thyroid gland. Its secretion is stimulated by hypercalcemia and it opposes many of the effects of PTH. By inhibiting osteoclastic activity its final effect is of deposition of calcium in bone [1, 13].
Serum phosphate and fibroblast growth factor 23 (FGF-23)
Hypophosphatemia, indirectly can cause hypercalcemia, by stimulating 1,25(OH)2-vitamin D production either directly or via a decrease in FGF-23 production. A lower level of FGF-23 will result in increased 1-alpha-hydroxylase and decreased 24-hydroxylase activities [3, 11].
Loss of weight bearing almost instantaneously results in increased osteoclasts and decreased osteoblasts activity leading to bone demineralization and release of calcium into the circulation. Besides in non-ambulatory patients, this phenomenon may become a problem in astronauts who consequently are at risk for development of kidney stones due to the ensuing hypercalciuria . Indeed most patients will first develop hypercalciuria and if the kidneys are able to clear the calcium released from bone they will stay normocalcemic, but if the released quantity of calcium surpasses the kidneys’ ability to excrete it, the patient will develop hypercalcemia. Of note, the above scenario is true for the newly bedridden patient. In chronic immobilization, once a new steady state of osteopenia occurs, the patients may exhibit none of the above perturbations.
Clinical manifestations of hypercalcemia
Mild: serum calcium < 12.0 mg/dl. Usually carries asymptomatic presentation.
Moderate: serum calcium 12.0–14.0 mg/dl. The presentation may include fatigue, malaise, anorexia, impaired mental concentration ability, constipation, polyuria, polydipsia.
Severe: serum calcium > 14.0 mg/dl. The presentation may include, in addition to the above, nausea, vomiting, dehydration, pancreatitis, peptic ulcers, arrhythmias, cardiac arrest, impaired mental capacity, stupor, coma, death.
Symptoms and signs of hypercalcemia
Corneal and other ectopic calcification
Central nervous system
Impaired mental abilities
Altered consciousness (confusion, lethargy, stupor, coma)
Abdominal pain (pancreatitis, peptic ulcer)
Low urinary specific gravity
Reduced glomerular filtration rate
Naturally, the presentation may include also symptoms of the underlying disease causing the hypercalcemia like bone pain, fractures, or urolithiasis in patients with hyperparathyroidism.
The causes of hypercalcemia can be divided between PTH-mediated and non-PTH-mediated (Fig. 2). Enhanced calcium mobilization from bone is the most common mechanism leading to hypercalcemia. In the adult population, the most common causes of hypercalcemia are hyperparathyroidism and malignancies. In neonates and infants, one should look first at genetic and iatrogenic etiologies. In children and adolescents, the most common causes of hypercalcemia are primary hyperparathyroidism, immobilization, and malignancy [13, 16, 17].
High serum parathyroid hormone
Primary, secondary, and tertiary hyperparathyroidism
Primary hyperparathyroidism is rare during childhood and represents 1% of hypercalcemia cases. The autonomous secretion of PTH can be due to parathyroid hyperplasia, adenoma (80% of cases), or carcinoma (less than 1% of cases). Children at presentation are usually symptomatic, having the above symptoms of moderate hypercalcemia, and in addition they may have band keratopathy, skeletal manifestations as subperiosteal resorption, osteopenia, slipped upper femoral epiphysis and pathologic fractures, and renal involvement expressed as polyuria, renal failure, kidney stones, or nephrocalcinosis. Besides high levels of calcium, the elevated level of PTH induces hyperchloremic metabolic acidosis, elevated serum calcitriol concentration and alkaline phosphatase activity, and decreased TP/GFR (tubular threshold for phosphate per glomerular filtration rate) [18, 19].
In addition to isolated hyperparathyroidism, one should consider the etiologies of hyperparathyroidism as part of multiple endocrine neoplasia type I that involves also the pancreas and anterior pituitary, type II that involves also the adrenal and thyroid glands, or type IV that involves also the anterior pituitary. Whereas type I can be found in adolescents, the other two are rare in childhood [11, 20].
Tertiary hyperparathyroidism is the result of advancement of untreated secondary hyperparathyroidism to an autonomous state of uncontrolled release of the hormone in the face of hypercalcemia. Imaging studies and histopathology will usually show the glands to be hyperplastic. Tertiary hyperparathyroidism can be seen in patients with long-standing ESRD and poor control of their hyperphosphatemia, and may continue into the post-transplant period . Less commonly, this condition is seen in patients exposed to prolonged periods of stimulation of the gland by frequent and repeat episodes of ionized hypocalcemia, as occurs in some patients with X-linked dominant hypophosphatemic rickets treated with high oral doses of phosphate [22, 23].
Familial hypocalciuric hypercalcemia (FHH)
Various types of genetic mutations transmitted in an autosomal dominant mode have been described in FHH resulting in inactivating mutations or in impaired signaling of the CaSR [24, 25]. Consequently, the parathyroid glands become less sensitive to circulating levels of calcium resulting in hypercalcemia and either normal or elevated levels of PTH. Naturally, the “normal” level of PTH is inappropriate for the degree of hypercalcemia and practically indicates a higher “set point” of the parathyroid glands to the extracellular calcium concentration. In the kidney, the defect leads to an increase in tubular calcium and magnesium reabsorption with final result of hypocalciuria manifested by fractional excretion of calcium of less than 1% [24, 25].
Severe neonatal hyperparathyroidism
Low Serum PTH
Elevated vitamin D metabolites
Elevated 25(OH)-vitamin D - vitamin D intoxication
Hypervitaminosis D is one of the more common causes of hypercalcemia in children. It is caused by excessive intake of vitamin D by either the infant or the breast-feeding mother. The excess vitamin D leads to increased intestinal calcium and phosphate absorption, enhanced bone resorption, and consequently both hypercalcemia and hyperphosphatemia. Serum levels required to cause hypercalcemia are believed to need to be quite high (>250 ng/ml) in order to cause the hypercalcemia due to decreased affinity of the metabolite to the receptor. Interestingly, 1,25(OH)2-vitamin D levels in such condition are not elevated, which is thought to be due to the hypercalcemia and suppressed PTH . Due to its liposoluble qualities, vitamin D overdose leads to long-lasting (weeks to months) hypercalcemia and hypercalciuria, in contrast to hypercalcemia seen secondary to ingestion of shorter-acting vitamin D analogs such as calcitriol or alfacalcidol, which usually last only a few days because of their short half-lives [33, 34].
Elevated 1,25(OH) 2 -vitamin D
Inappropriately high production
In principal, granulomatous diseases can be divided between infectious and non-infectious, which have an impact on diagnostic work up, treatment, and prognosis, but the mechanism of hypercalcemia seems to be the same [35, 36]. Granulomas are caused by macrophage activation due either to an inability to clear the initial source (intracellular bacteria, foreign material, or inefficient microbial killing in chronic granulomatous disease) or an abnormality in the processes that turn off the macrophages, with consequent over-activation of this phagocytic cells, which leads to endogenous production of calcitriol (they have an autonomous 1-alpha hydroxylase) and in turn hypercalcemia develops. While the most studied granulomatous disease is sarcoidosis, other conditions include Pneumocystis jirovecii pneumonia, Wegener’s granulomatosis, necrobiotic xanthogranuloma, and paraffin-associated granuloma [37, 38]. The conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D is substrate-dependent; namely, a higher presence of the former will result in higher levels of the latter. In addition, in contrast to the kidney where production of 1,25 (OH)2 –vitamin D by 1-alpha-hydroxylase is tightly regulated by Ca, PTH, FGF-23, and 1,25 (OH)2 –vitamin D itself by a negative feedback loop, it is not regulated in the macrophages. The treatment of these diseases may take several weeks to months, and with that the need to manage the hypercalcemia [35, 36]. In immunocompromised patients, like those following kidney transplantation, and hypercalcemia associated with suppressed PTH, one should be looking for opportunistic infections like the one caused by Pneumocystis jirovecii pneumonia [39, 40].
Low phosphate intake
Inappropriate degradation of 1,25 (OH)2–vitamin D
Idiopathic infantile hypercalcemia (IHH)
Previously named IHH is now known to be an autosomal recessive disorder caused by inactivating mutation in the CYP24A1 gene that encodes for vitamin D 24-hydroxylase, resulting in high serum levels of 1,25(OH)2-vitamin D. Biallelic disease individuals (homozygous or compound heterozygote mutation) are usually symptomatic, whereas patients with monoallelic mutations can often be asymptomatic. Hypercalcemia presents between 4 and 12 months of age and usually resolves spontaneously by age 2 years. Infants afflicted with this disease can develop significant hypercalcemia when supplemented with a standard dose of vitamin D [34, 50]. Patients have no characteristic dysmorphic features, and exhibit failure to thrive, vomiting, and dehydration. Typically, nephrocalcinosis is already present at presentation. Following normalization of serum calcium, nephrocalcinosis and hypercalciuria may persist and patients may have reduced bone mineral density [34, 50].
Normal-low vitamin D metabolites
Elevated parathyroid-hormone related peptide (PTHrP)
Normal parathyroid-hormone related peptide (PTHrP)
Jansen metaphyseal chondrodysplasia
As discussed earlier, besides the production of humoral factors such as PTHrP and 1,25 (OH)2–vitamin D that lead to hypercalcemia, tumors can produce hypercalcemia by direct invasion of the bone and its distraction, releasing calcium to the circulation. As such, evaluation of children with hypercalcemia should include skeletal survey in search for bone lesions. In acute lymphoblastic leukemia with hypercalcemia, skeletal survey often shows osteolytic lesions. In some of these patients, the initial complete blood cell count might be normal with no blasts seen in the peripheral blood smear, and only bone marrow aspiration may disclose the malignancy. The presence of hypercalcemia by itself does not necessarily indicate a worse oncologic prognosis .
Rare causes of hypercalcemia (reference)
1. Excessive calcium intake 
2. Ovarian tumors 
3. Blue diaper syndrome 
4. Osteopetrosis 
5. Milk-alkali syndrome 
6. Congenital lactase deficiency 
7. Diabetic ketoacidosis 
8. IMAGe syndrome 
9. Hypothyroidism and thyrotoxicosis 
10. Down syndrome 
11. Manganese toxicity 
13. Primary hyperoxaluria 
14. Partial duplication of chromosome 2p 
15. Medications – lithium, omeprazole, theophylline, foscarnet 
16. Adrenal insufficiency 
17. Gum Arabic 
Kidney involvement in hypercalcemia
Patients with hypercalcemia are often polyuric due to the development of a renal concentrating defect resulting from tubular resistance to the effect of antidiuretic hormone (ADH). The mechanism likely involves activation of the cortical tubule CaSR that impairs the trafficking and expression of vasopressin-dependent aquaporin 2 water channel . Consequently, patients are often dehydrated. Since activation of the CaSR in the TAL results in losses of sodium, replenishment of these patients requires the administration of both water and sodium, namely, normal saline [79, 80].
Hypercalcemia can result in more permanent damage to the kidneys in the form of nephrocalcinosis. The renal calcifications can result from the high serum calcium itself settling in the interstitial compartment or from hypercalciuria resulting in calcium deposits in the tubules. Advanced nephrocalcinosis can then cause permanent kidney damage.
The investigation of the origin of hypercalcemia and its management are often done simultaneously. Besides history and physical examination the laboratory studies include serum creatinine, electrolytes, phosphate, magnesium, alkaline phosphatase, ionized and total calcium, albumin, PTH, 25-hydroxy vitamin D, 1,25(OH)2-vitamin D, complete blood count, urinalysis with microscopy and urine calcium, phosphate and creatinine. Routine imaging studies include skeletal survey and urinary tract ultrasound. Second line of the evaluation includes PTHrP, serum vitamin A, and genetic evaluation. Additional imaging studies utilizing various techniques may be directed at specific organs like the parathyroid glands or lesions like pulmonary infiltrates.
In the interpretation of laboratory data, it is important to remember to look at blood levels of hormones in the context of the associated axis and feedback. For example, in the face of hypercalcemia, “normal” serum PTH is actually inappropriately high as under normal physiologic conditions it should be suppressed.
The treatment of hypercalcemia proceeds in two avenues complementing each other; the normalization of serum calcium and correction of the source of hypercalcemia, namely the underlying disorder. Symptomatic hypercalcemia requires immediate treatment due to potential cardiac toxicity. In addition, consequences of untreated hypercalcemia can include kidney damage and neurologic sequelae.
Treatment of acute hypercalcemia
Intravenous fluids – Hydration with 0.9% normal saline at 1.5 maintenance
Furosemide – IV 1 mg/kg/dose, q6-8 h
Calcitonin - 3–6 units/kg/dose subcutaneously q6-12 h
Pamidronate - 0.5 to 1 mg/kg/dose (decrease dose by 50% in patients with impaired renal function); can be repeated after 24–48 h
Zoledronic acid - 0.025 mg/kg/dose (decrease dose by 50% in patients with impaired renal function); can be repeated after 24–48 h
Nutrition and mobilization
In some cases of hyperparathyroidism, parathyroidectomy, either complete or partial is indicated. Following parathyroidectomy, a “hungry bone” syndrome may develop and patients might require calcium and vitamin D replacement .
Serum calcium concentration is best assessed by measuring the ionized calcium concentration. If unavailable, then serum total calcium should be adjusted to that of albumin.
Hypercalcemia is mostly caused by increased bone resorption and to a lesser extent by increased intestinal calcium absorption and tubular reabsorption.
Severe hypercalcemia can result in cardiac, renal, and CNS mortality and morbidity.
The evaluation of the etiology of hypercalcemia starts with determination of serum PTH. If normal, serum levels of 25(OH)-D, 1,25(OH)2D, PTHrP and genetic studies should follow.
Patients with severe hypercalcemia are often polyuric, dehydrated and at some stage of non-oliguric AKI.
Acute treatment should start with IV hydration with 0.9% normal saline. More sustained control of the hypercalcemia can be achieved with bisphosphonates.
Questions: (Answers can be found after the references).
1. Pseudohypercalcemia can be seen in:
a) Low-serum ionized calcium concentration.
e) Severe combined immune deficiency.
2. Elevated Ca concentrations induce the following CaSR-mediated effect:
a) Water reabsorption is reduced by inhibiting the tubular response to ADH.
b) Water reabsorption is reduced by inhibiting the CaSR mesangial transporters.
c) Water reabsorption is enhanced by inhibiting the tubular response to ADH.
d) Water reabsorption is unaffected.
e) Water reabsorption is reduced by stimulating proximal tubular sodium reabsorption.
3. Post-renal transplant hypercalcemia may occur as a result of:
a) Calcineurin inhibitor induced PTH production.
b) Delayed graft function induced 1,25 (OH)2 vitamin D production.
c) Pre-transplant hyperplastic parathyroid glands.
d) Dietary non-compliance.
e) Hidden parathyroid adenoma.
4. Following hydration, the drug of choice in addressing most cases of hypercalcemia is:
5. To exert their effect, calcimimetics;
a) Have to have extracellular calcium present.
b) Have to have 1,25 (OH)2 vitamin D present.
c) Have to have an abnormal CaSR present.
d) Have to have high serum phosphate present.
e) Have to be given concomitantly with bisphosphonates.
We would like to thank Ms. Andrea Fontana for her administrative assistance. This work was supported by the Sam and Helen Kaplan Research Fund in Pediatric Nephrology and the Eric McClure Research Fund in Bone and Mineral Metabolism.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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