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Pediatric Nephrology

, Volume 33, Issue 9, pp 1475–1488 | Cite as

Hypercalcemia: a consultant’s approach

  • Ari Auron
  • Uri S. Alon
Educational Review

Abstract

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.

Keywords

Acute kidney injury Parathyroid hormone PTH-related peptide Vitamin D Calcitriol Bisphosphonates 

Introduction

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” [1]. 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 [2].

Parathyroid hormone

Serum-ionized calcium concentration is tightly maintained within a very narrow range and its regulation is conducted by PTH [5]. 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

Vitamin D undergoes hydroxylation by a 25 hydroxylase in the liver, which leads to formation of 25(OH)-vitamin D (Fig. 1). The activity of the liver enzyme is poorly regulated and serum 25(OH)-vitamin D level indicates the status of body stores of the vitamin. A second hydroxylation by 1-alpha hydroxylase in the kidney (CYP27B1) converts it to 1,25(OH)2 -vitamin D (calcitriol), which is the active hormone. Although the kidney is the major source of circulating 1,25(OH)2-vitamin D, it can be produced by extra-renal cells like monocytes/macrophages, skin cells, and placenta cells [5]. The renal production of 1,25(OH)2-vitamin D is stimulated by low serum calcium and phosphate, and high PTH, and suppressed by FGF-23 and by 1,25(OH)2-vitamin D itself. The latter two, as well as serum calcium, stimulate 24-hydroxylase enzyme (CYP24A1). Its activity catabolizes 25(OH)D to 24,25 (OH)2D and 1,25(OH)2D to 1,24,25(OH)3D [6, 7]. Both 24 metabolites are regarded as inert.
Fig. 1

Principles of vitamin D metabolism

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].

Calcitonin

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].

Weight bearing

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 [14]. 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.

As will be detailed later, one can look at hypercalcemia as either caused by excess PTH activity or from influx of calcium into the circulation from other reasons, in which case serum PTH will be suppressed (Fig. 2). In most patients, the hypercalcemia is due to excessive osteoclastic activity. Cytokines such as TNF alpha, IL-1, and IL-6 stimulate the osteoclast directly. PTH and other osteoclast-stimulating factors interact with receptors on osteoblasts to increase the expression of RANKL and to decrease production of osteoprotegerin, which is a circulating decoy receptor for RANKL. RANKL stimulates activation, migration, differentiation, and fusion of hematopoietic cells of the osteoclast lineage to stimulate bone resorption [15]. In other cases, hypercalcemia can be due to high levels of vitamin D causing increased intestinal absorption of the mineral. Less commonly, decreased renal tubular reabsorption may result in higher serum calcium levels.
Fig. 2

Algorithm for evaluation of hypercalcemia

Clinical manifestations of hypercalcemia

The clinical features can be nonspecific and hypercalcemia is often discovered during routine blood work. The symptoms and signs of hypercalcemia are detailed in Table 1, and to some degree may go along with the degree of its severity, as follows:
  1. a)

    Mild: serum calcium < 12.0 mg/dl. Usually carries asymptomatic presentation.

     
  2. b)

    Moderate: serum calcium 12.0–14.0 mg/dl. The presentation may include fatigue, malaise, anorexia, impaired mental concentration ability, constipation, polyuria, polydipsia.

     
  3. c)

    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.

     
Table 1

Symptoms and signs of hypercalcemia

General

 Weakness

 Dehydration

 Corneal and other ectopic calcification

Central nervous system

 Impaired mental abilities

 Depression

 Psychosis

 Altered consciousness (confusion, lethargy, stupor, coma)

Gastrointestinal tract

 Anorexia

 Nausea

 Vomiting

 Abdominal pain (pancreatitis, peptic ulcer)

 Constipation

Renal system

 Polydipsia

 Polyuria

 Low urinary specific gravity

 Reduced glomerular filtration rate

 Nephrolithiasis

 Nephrocalcinosis

Cardiovascular system

 Hypertension

Naturally, the presentation may include also symptoms of the underlying disease causing the hypercalcemia like bone pain, fractures, or urolithiasis in patients with hyperparathyroidism.

Etiology

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].

  1. I.

    High serum parathyroid hormone

     
  1. a)

    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 [21]. 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].

  1. b)

    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].

The diagnosis is made either because of history of an affected family member or incidentally. Patients present in childhood with hypercalcemia, inappropriately normal or mildly elevated PTH and very low urine calcium. Affected individuals are usually asymptomatic although pancreatitis, chondrocalcinosis, or mental changes may develop in adulthood. Most patients tend to have normal bone mineral density. This condition usually requires no intervention but if indicated may respond well to calcimimetics [12, 19, 26].
  1. c)

    Severe neonatal hyperparathyroidism

     
This autosomal recessive disorder is caused by a homozygous inactivating mutation in the CaSR gene (chromosome 3q13.3-q21). The genetic anomaly results in a complete or near-complete absence of functional CaSR in the parathyroid glands and other cells in the body. Afflicted patients often have severe metabolic bone disease and life-threatening hypercalcemia. The presentation, usually in the first few weeks of life, includes vomiting, feeding difficulties, failure to thrive, respiratory distress due to muscle hypotonia, elevated PTH in the face of severe hypercalcemia accompanied by hypophosphatemia, relative hypocalciuria (although some cases present with hypercalciuria), bone demineralization (osteopenia), subperiosteal resorption, rickets and fractures. A neck ultrasound will localize a parathyroid abnormality in only one-third of the cases. Parathyroidectomy has been the therapeutic approach in cases of life-threatening hypercalcemia refractory to medical treatment [27, 28].
  1. d)

    Maternal hypocalcemia

     
Chronic maternal hypocalcemia can be seen in the untreated or undertreated mother with hypoparathyroidism or pseudohypoparathyroidism, vitamin D deficiency, and renal tubular acidosis. The induced fetal hypocalcemia leads to development of secondary hyperparathyroidism and post-natal hypercalcemia. The presentation includes hypercalcemia, elevated PTH, bone deformities, respiratory failure due to rib cage deformities, hepatosplenomegaly, and anemia [29, 30]. The secondary hyperparathyroidism and hypercalcemia usually resolve spontaneously within a few months [31].
  1. II.

    Low Serum PTH

     
  1. (i)

    Elevated vitamin D metabolites

     
  1. A

    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 [32]. 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].

  1. B.

    Elevated 1,25(OH) 2 -vitamin D

     
  1. 1.

    Inappropriately high production

     
  1. a)

    Granulomatous diseases

     

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].

One of the pediatric types of granulomatous diseases is subcutaneous fat necrosis, which is a form of panniculitis seen in term infants. Patients develop a violaceous rash composed of hard, indurated, painful nodules over the trunk, arms, buttocks, thighs, and back. It appears that there is a defect in fat metabolism resulting in granulomatous reaction to the inflamed necrotic fat. Hypercalcemia can occur in the first few weeks of life. The hypercalcemia can be often asymptomatic but can cause symptoms including irritability, vomiting, failure to thrive, hypotonia, myopathy, fever, eosinophilia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure [41, 42, 43].
  1. b)

    Low phosphate intake

     
Errors in parenteral nutrition manufacturing with low phosphate can lead to hypophosphatemia, which in turn promotes calcitriol production. Hypercalcemia and hypophosphatemia may occur in premature infants fed a low-phosphate diet or in full-term infants fed a low-phosphate-containing breast milk when the mother has known hypophosphatemia, and the metabolic abnormalities correct upon addition of phosphate supplementation to the enteral or parenteral nutrition [31, 44, 45]. A clue to this entity will be low serum phosphate accompanied by very low urine phosphate quantities, namely the TP/GFR is normal and the intact kidney is avidly reabsorbing the phosphate filtered in the glomerulus.
  1. c)

    Phosphate-losing tubulopathies

     
Caused by homozygous or compound heterozygous mutation in the SLC34A1 gene (5q35), which encodes for the renal cotransporter Na-Pi IIa, rendering the latter to be defective. The resulting renal phosphate wasting induces inappropriate production of calcitriol. Besides hypercalcemia, these patients may present with hypercalciuria-induced nephrocalcinosis and urolithiasis. Characteristic to this condition are low serum phosphate concentration and low TP/GFR, in the face of normal FGF-23 [46].
  1. d)

    Tumors

     
Hypercalcemia is a common finding in adult with malignancies but relatively rare in children. The hypercalcemia may be life-threatening and generally requires urgent intervention [47]. Pediatric malignancies associated with hypercalcemia include acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphoma, myeloid leukemia, brain tumors, rhabdomyosarcoma and hepatoblastoma [47, 48]. In children with leukemia, hypercalcemia is more likely to happen at the time of initial diagnosis, whereas in patients with solid tumors, hypercalcemia usually occurs later in the course of the disease. In malignancy-associated hypercalcemia, PTHrP can be either normal or elevated, as might be the case with calcitriol, and PTH will be suppressed [49]. As shown in Fig. 2, there are three mechanisms of hypercalcemia caused by tumors: (a) bone invasion of tumor cells causing bone resorption/destruction due to osteoclasts activated by the tumoral cells, (b) osteoclastic factors released from tumor cells, mainly PTHrP and/or other factors/pro-inflammatory cytokines like leukotrienes, prostaglandin E, IL-1, IL-6, TGF-beta and TNF alpha, that stimulate osteoclast proliferation through their interaction with RANKL, and (c) increased ectopic production of 1,25(OH)2-vitamin D, similar to the one described above in granulomatous disorders. Hypercalcemia has also been described during treatment of neuroblastoma as a toxic side effect from one of the chemotherapy medications, 13 cis-retinoic acid due to an unknown mechanism [48, 49].
  1. 2.

    Inappropriate degradation of 1,25 (OH)2–vitamin D

     
  1. a.

    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].

  1. (ii)

    Normal-low vitamin D metabolites

     
  1. A.

    Elevated parathyroid-hormone related peptide (PTHrP)

     
  1. a)

    Tumors

     
As discussed earlier, elevated PTHrP is commonly seen in adults with tumor-induced hypercalcemia. Nonetheless, also in the child, the finding of high PTHrP level requires a thorough investigation to identify or rule out the presence of a tumor. Interestingly, also benign conditions such as mesoblastic nephroma and multicystic dysplastic kidney have been reported to be associated with the development of hypercalcemia, suppressed PTH, and elevated PTHrP [51, 52]. Elevated serum PTHrP has also been rarely reported in association with pheochromocytoma [53].
  1. B.

    Normal parathyroid-hormone related peptide (PTHrP)

     
  1. a)

    Maternal hypercalcemia

     
Maternal hypercalcemia can lead to neonatal calcium overload. The source of the maternal hypercalcemia can vary and may be due to some of the causes detailed in Fig. 2. The neonatal hypercalcemia will have a tendency to resolve on its own. Attention should be paid to the possibility that the parathyroid gland has become temporarily suppressed [31].
  1. b)

    Williams syndrome

     
Autosomal dominant condition that is caused by a deletion on chromosome 7q11.23 that encodes for the elastin gene. The deletion of the elastin is the culprit of the vascular and connective tissue abnormalities seen in this condition. Most infants are born small for gestational age and may have multisystem manifestations including depressed nasal bridge, epicanthal folds, characteristic facial appearance (elfin facies), dental decay, enamel hypoplasia, neurocognitive problems, cardiac malformations including supravalvular aortic stenosis and peripheral pulmonary stenosis. The hypercalcemia, which is usually mild, presents in 15–40% of patients during infancy/early childhood, and resolves between 2 and 4 years of age, and can recur during puberty. There is no exact known specific mechanism for the hypercalcemia but vitamin D receptor hypersensitivity is regarded as a possibility [54, 55].
  1. c)

    Hypophosphatasia

     
Autosomal recessive disorder is characterized by a loss-of-function mutation in the ALPL gene (1p34–36) that encodes for tissue non-specific alkaline phosphatase. Patients develop bone and teeth hypo-mineralization. It is classified into several clinical forms depending on the age at diagnosis and the severity of the symptoms (the most severe presentation is in the infantile form). Low-alkaline phosphatase impairs skeletal mineralization and calcium uptake, leading to hypercalcemia, hypercalciuria, nephrocalcinosis, severe bone demineralization, and fractures. Serum PTH, phosphate, and vitamin D levels are usually within normal range [56].
  1. d)

    Jansen metaphyseal chondrodysplasia

     
This autosomal dominant disorder is due to a heterozygous mutation in the PTHR1 gene encoding type 1 PTH/PTHrP receptor, which leads to gain-of-function of the receptor in the kidney, bone, and growth plate. This results in hypercalcemia in the face of low or undetectable serum PTH presenting as early as 3 months of age. The abnormal receptor in the growth plate causes delay chondrocyte differentiation, which results in postnatal short limbs, short stature (there is usually normal growth during infancy and short stature becomes apparent during mid-childhood), and diffuse demineralization. Choanal atresia and rib fractures may result in respiratory distress after birth. Bone lesions seen on plain roentgenograms include rachitic changes, radiolucencies, and irregular metaphyses of the long bone and sclerotic changes in the base of the skull [57].
  1. e)

    Hypervitaminosis A

     
Receptors for retinoic acid are located on both osteoclasts and osteoblasts. In vitro, retinoic acid suppresses osteoblast activity and stimulates osteoclast formation, resulting in increased bone resorption and decreased bone formation. Vitamin A has been shown also to stimulate PTH secretion. The clinical presentation of vitamin A overdose may include anorexia, pruritus, irritability, bone pain, osteopenia, and fractures [58, 59, 60].
  1. f)

    Immobilization

     
Immobility-induced hypercalcemia occurs due to uncoupling of bone remodeling, resulting in a decrease in osteoblastic activity and increase in osteoclastic activity, which cause calcium and phosphate release from the skeleton and loss of bone mass. Serum PTH and calcitriol are usually suppressed. The hypercalcemia is observed in acute immobilization cases such as seen in head injuries, fractures, spinal cord injuries, and burns. Long-term immobilization leads to decreased bone density and possible fractures. The hypercalcemia and hypercalciuria resolve with the onset of weight bearing [61, 62, 63].
  1. g)

    Thiazide diuretics

     
This group of sulfonamide-derivate diuretics act on the distal tubules to increase calcium reabsorption, an effect that is useful in the treatment of patients with hypercalciuria, nephrocalcinosis, and urolithiasis [64]. Hypercalcemia is rarely seen but can be present in patients with an underlying increase in bone resorption such as in patients with hyperparathyroidism, namely the treatment with high-dose thiazide diuretic unmasks the endocrinopathy [31].
  1. h)

    Bartter syndrome

     
Commonly associated with hypercalciuria. Hypercalcemia can be seen in infants with homozygous inactivation in the gene for either the furosemide sensitive Na-K 2Cl cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1) [65, 66].
  1. i)

    Tumors

     

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 [12].

Additional, less common causes of hypercalcemia are detailed in Table 2. Due to their rarity and for cost-effectiveness, one should be looking for them after excluding the more common etiologies.
Table 2

Rare causes of hypercalcemia (reference)

1. Excessive calcium intake [31]

2. Ovarian tumors [67]

3. Blue diaper syndrome [68]

4. Osteopetrosis [69]

5. Milk-alkali syndrome [31]

6. Congenital lactase deficiency [70]

7. Diabetic ketoacidosis [71]

8. IMAGe syndrome [72]

9. Hypothyroidism and thyrotoxicosis [2]

10. Down syndrome [73]

11. Manganese toxicity [31]

12. Extracorporeal membrane oxygenation, plasmapheresis [74, 75]

13. Primary hyperoxaluria [31]

14. Partial duplication of chromosome 2p [76]

15. Medications – lithium, omeprazole, theophylline, foscarnet [31]

16. Adrenal insufficiency [77]

17. Gum Arabic [78]

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 [9]. 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].

Acute kidney injury (AKI) and hypercalcemia can be pathophysiologically associated in two different ways. (a) Hypercalcemia can cause AKI, which is typically non-oliguric. The decrease in GFR is thought to be secondary to a combination of the aforementioned dehydration and arterial vasoconstriction caused by the hypercalcemia, as was demonstrated by Doppler renal ultrasound before and after alleviation of the hypercalcemia (Fig. 3). As discussed later, the first step in the treatment of hypercalcemia is the restoration of intravascular volume by administration of 0.9% normal saline. The AKI is usually reversible once the hypercalcemia is corrected [81]. (b) On the other hand, hypercalcemia is at times seen during the recovery phase of AKI, in particular if the etiology of the AKI was rhabdomyolysis. This is due to the fact that during AKI calcium was settled in soft tissues to be mobilized from them during the recovery phase. This is usually a transient phenomenon of mild hypercalcemia that requires no intervention besides maintenance of adequate hydration [21].
Fig. 3

Doppler renal ultrasound in a 7-year-old girl with acute lymphoblastic leukemia, before (a) and after (b) correcting her hypercalcemia (16.2 mg/dl) due to bone lesions. Note normalization of abnormal arterial blood flow, likely due to hypercalcemia-induced vasoconstriction (from reference 81 with permission)

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.

Evaluation

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.

Treatment

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.

The main components of the treatment of hypercalcemia are detailed in Table 3. In principle, they include enhancement of urinary calcium excretion and its incorporation to bone, and when indicated decrease in its absorption from the gut. In the rare occasion of life-threatening hypercalcemia hemodialysis or peritoneal dialysis can be considered.
  1. a)

    Calcium diuresis

     
Table 3

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

Volume expansion with normal saline decreases calcium reabsorption. As previously discussed, due to hypercalcemia-induced polyuria, these patients are invariably dehydrated and volume expansion should always be the immediate first step in addressing them. Normal saline is the fluid of choice. Not only does it induce hypercalciuria but by causing volume expansion it improves kidney perfusion and function [11, 82].
  1. b)

    Loop diuretics

     
By blocking the Na-K 2Cl channel in the TAL, loop diuretics block sodium reabsorption and with that paracellular calcium reabsorption. This actually mimics the normal physiologic response to hypercalcemia that takes place via the CaSR. In the setting of treatment of hypercalcemia, furosemide should be administered only once the patient is well hydrated [13, 82]. Chronic furosemide therapy should be avoided as much as possible due to its known adverse effects of nephrocalcinosis and urolithiasis [83].
  1. c)

    Calcitonin

     
Calcitonin inhibits bone-resorbing activity of osteoclasts and inhibits tubular reabsorption of calcium, promoting renal excretion of calcium. Thus, it has a dual beneficial effect in treating hypercalcemia [84]. Another advantage is its rapid effect within hours, relative to bisphosphonates that take days. It can be given intravenously, subcutaneously, intramuscularly, or intranasally. Its effect on hypercalcemia is moderate, and side effects may include nausea, flushing, paresthesias, and local inflammation. It is metabolized by the kidneys so it may accumulate in renal failure. It cannot be used long term as tachyphylaxis develops, namely its effect decreases over time presumably due to down-regulation of the involved receptors [11].
  1. d)

    Bisphosphonates

     
Targeting the osteoclasts is likely the most effective approach since in most cases osteoclastic bone resorption is the cause of hypercalcemia. Bisphosphonates are regarded nowadays as the drug of choice in treating hypercalcemia of various etiologies. Since they act by suppressing osteoclastic activity the effect on serum calcium is not immediate but may take a few days to be fully manifested, hence in cases of hypercalcemic emergency the immediate treatment is by fluids, loop diuretics and calcitonin while awaiting the effect of bisphosphonates that may be delayed by 24–48 h. The bisphosphonates should be introduced intravenously. Due to the fact that the drug is cleared through the kidneys and patients often have a degree of AKI, it is recommended to start with half the recommended dose. If not enough improvement is seen in 24–48 h, another dose can be given. The main potential adverse effects include “flu-like” symptoms and development of hypocalcemia. The latter is especially true in cases of “hungry bones” [85].
  1. e)

    Dialysis

     
Considered in very ill patients in whom there is renal failure or heart failure, or when hypercalcemia is refractory to other conventional treatment measures. Hemodialysis or peritoneal dialysis with a low-calcium dialysate should be prescribed.
  1. f)

    Nutrition and mobilization

     
IV calcium intake should be assessed and adjusted as appropriate. The enteral calcium intake should be reviewed, and calcium and vitamin D supplementation should be avoided. Low-calcium and vitamin D formulas are available. It is important to resume recommended vitamin D supplementation once hypercalcemia and its underlying disorder have been brought under control. Weight bearing should be encouraged.
  1. g)

    Specific treatments

     
For some specific conditions, additional modes of intervention are helpful as follows.
  1. i.

    Corticosteroids

     
Corticosteroids suppress 1-alpha hydroxylase activity, thus decreasing calcitriol synthesis in conditions where an excessive activation of vitamin D exists, such as seen in granulomatous diseases and 1,25(OH)2-vitamin D producing tumors. In some of these conditions, corticosteroids play a role also in the treatment of the underlying disease as in sarcoidosis and lymphoma [13, 82].
  1. ii.

    Ketoconazole

     
Like corticosteroids, ketoconazole inhibits 1-alpha hydroxylase activity. The antifungal has been used to treat hypercalcemia in infantile idiopathic hypercalcemia, primary hyperparathyroidism, granulomatous disorders. Adverse effects include liver and renal toxicity [86].
  1. iii.

    Cinacalcet

     
Calcimimetics modulate the CaSR by lowering its threshold to extracellular calcium resulting in decreased secretion of PTH, thus lowering Ca concentration. In essence, they can be used in all cases in which the hypercalcemia is caused by increased secretion of PTH. This has be shown to be the case in primary, secondary, and tertiary hyperparathyroidism, in the face of normal and abnormal kidney function [87, 88]. They are primarily used to treat chronic hypercalcemia. It is important to remember that besides their effect on the CaSR in the parathyroid glands calcimimetics exert their effect also on the CaSR in the TAL and may cause hypercalciuria. The latter responds well to thiazide diuretics [26].
  1. iv.

    Denosumab

     
The monoclonal antibody inhibits RANKL, thus suppressing osteoclast activity. It may present as an alternative to bisphosphonates in controlling the dramatic hypercalcemia seen at times after bone marrow transplantation [89]. One of its advantages is its convenient administration by sub-cutaneous injection.
  1. v.

    Surgical intervention

     

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 [19].

Key summary points
  1. 1.

    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.

     
  2. 2.

    Hypercalcemia is mostly caused by increased bone resorption and to a lesser extent by increased intestinal calcium absorption and tubular reabsorption.

     
  3. 3.

    Severe hypercalcemia can result in cardiac, renal, and CNS mortality and morbidity.

     
  4. 4.

    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.

     
  5. 5.

    Patients with severe hypercalcemia are often polyuric, dehydrated and at some stage of non-oliguric AKI.

     
  6. 6.

    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.

b) Hypoalbuminemia.

c) Pseudohypoparathyroidism.

d) Hyperalbuminemia.

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:

a) Furosemide.

b) Calcitonin.

c) Corticosteroids.

d) Bisphosphonates.

e) Phosphate.

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.

Notes

Acknowledgements

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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Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.Bone and Mineral Disorders Clinic, Division of Pediatric Nephrology, Children’s Mercy HospitalUniversity of Missouri at Kansas City School of MedicineKansas CityUSA

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