Etiology of hypercalcemia

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Official reprint from UpToDate

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Etiology of hypercalcemia
Author
Elizabeth Shane, MD

Section Editor
Clifford J Rosen, MD

Deputy Editor
Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2016. | This topic last updated: Apr 29, 2015.
INTRODUCTION Hypercalcemia is a relatively common clinical problem. It results when the entry of
calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone. This occurs
when there is accelerated bone resorption, excessive gastrointestinal absorption, or decreased renal
excretion of calcium. In some disorders, however, more than one mechanism may be involved. As
examples, hypervitaminosis D increases both intestinal calcium absorption and bone resorption, and primary
hyperparathyroidism increases bone resorption, tubular calcium reabsorption, and renal synthesis of
calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D), and intestinal calcium
absorption.
Among all causes of hypercalcemia, primary hyperparathyroidism and malignancy are the most common,
accounting for greater than 90 percent of cases (table 1).
This topic card will review the etiology of hypercalcemia. The clinical manifestations, diagnostic approach,
and treatment are reviewed separately. (See "Clinical manifestations of hypercalcemia" and "Diagnostic
approach to hypercalcemia" and "Treatment of hypercalcemia".)
BONE RESORPTION
Primary hyperparathyroidism Hypercalcemia in primary hyperparathyroidism is due to parathyroid
hormone (PTH)-mediated activation of osteoclasts leading to increased bone resorption. In addition,
intestinal calcium absorption is elevated. Primary hyperparathyroidism is most often due to a parathyroid
adenoma. Patients typically have only small elevations in serum calcium concentrations (less than 11 mg/dL
or 2.75 mmol/L), and many have mostly high-normal values with intermittent hypercalcemia. Thus, when one
suspects primary hyperparathyroidism, as with high-normal serum calcium values in a patient with calcium
nephrolithiasis, it may be necessary to obtain a series of serum calcium measurements to detect
hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
Secondary and tertiary hyperparathyroidism Patients with severe chronic kidney disease and
secondary hyperparathyroidism usually have low or normal serum calcium concentrations, but with
prolonged disease, may develop hypercalcemia. The rise in plasma calcium most often occurs in patients
with adynamic bone disease and markedly reduced bone turnover. In such patients, hypercalcemia is due to
a marked reduction in the bone uptake of calcium after a calcium load, as with calcium carbonate to treat
hyperphosphatemia [1]. (See "Overview of chronic kidney disease-mineral bone disease (CKD-MBD)",
section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)
In other patients with advanced renal failure, hypercalcemia is due to progression from appropriate
parathyroid hyperplasia to autonomous overproduction of PTH, a disorder called tertiary
hyperparathyroidism.
If the patient with end-stage renal disease undergoes renal transplantation, the parathyroid gland
hyperplasia subsides over a period of months to years. In some patients, hypercalcemia may develop after
renal transplantation, because correction of the renal failure normalizes phosphate balance and increases
calcitriol production, thereby raising serum calcium concentrations transiently until the parathyroid
hyperplasia subsides. Often, parathyroid hyperplasia may not resolve completely. (See "Persistent
hyperparathyroidism after renal transplantation", section on 'Hypercalcemia'.)
Malignancy Hypercalcemia occurs in patients with many tumors, both solid tumors and leukemias.

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Values above 13 mg/dL (3.25 mmol/L) are less commonly seen in primary hyperparathyroidism and, in the
absence of another apparent cause, are more likely due to malignancy.
The mechanism of increased bone resorption with malignancy depends upon the cancer. In patients with
bone metastases, direct induction of local osteolysis by the tumor cells is common. Cytokines such as tumor
necrosis factor and interleukin-1 appear to play an important role by stimulating the differentiation of
osteoclast precursors into mature osteoclasts.
In patients with multiple myeloma, hypercalcemia is similarly due to the release of osteoclast activating
factors such as lymphotoxin, interleukin-6, hepatocyte growth factor, and receptor activator of nuclear factor
kappa B ligand (RANK ligand). (See "Clinical features, laboratory manifestations, and diagnosis of multiple
myeloma" and "Normal skeletal development and regulation of bone formation and resorption", section on
'Osteoclasts'.)
The most common cause of hypercalcemia in patients with nonmetastatic solid tumors is secretion of
PTH-related protein (PTHrP). In contrast, hypercalcemia is caused by PTH-independent extrarenal
production of calcitriol from calcidiol by activated mononuclear cells (particularly macrophages) in patients
with lymphoma. Although rare, a few patients with ectopic non-parathyroid cancers that secreted PTH, not
PTHrP, have been reported.
Hypercalcemia of malignancy is reviewed in more detail elsewhere. (See "Hypercalcemia of malignancy".)
Thyrotoxicosis Mild hypercalcemia occurs in up to 15 to 20 percent of thyrotoxic patients, due to a
thyroid hormone mediated increase in bone resorption [2,3]. It typically resolves following correction of
hyperthyroidism [2,4]. If the hypercalcemia persists after the restoration of euthyroidism, serum PTH should
be measured to assess for concomitant hyperparathyroidism.
Other Other less common causes of hypercalcemia due to increased bone resorption include:
Immobilization [5-7].
Paget disease of bone, primarily if the patient is at bed rest. (See "Clinical manifestations and
diagnosis of Paget disease of bone".)
The administration of estrogen or an antiestrogen (such as tamoxifen) to patients with breast cancer
and extensive skeletal metastases [8,9].
Hypervitaminosis A (in which there is prolonged ingestion of more than 50,000 International Units per
day) [10,11] or the administration of retinoic acid to patients with certain tumors, as either cis-retinoic
acid [12] or all-trans retinoic acid [13,14]. Retinoic acid causes a dose-dependent increase in bone
resorption, resulting in an overall incidence of hypercalcemia of approximately 30 percent [12]. All-trans
retinoic acid inhibits cell growth in part by downregulation of interleukin-6 receptors; the subsequent
rise in serum interleukin-6 concentrations may be responsible for increased bone resorption and
hypercalcemia [13]. (See "Differentiation (retinoic acid) syndrome".)
CALCIUM ABSORPTION Calcium is absorbed in the small intestine via both active and passive
transport. The former is more important physiologically and is stimulated by vitamin D metabolites. On the
other hand, when calcium intake is greater than 1 to 2 grams daily or more, substantial amounts of calcium
are absorbed passively.
Increased calcium intake A high calcium intake alone is rarely a cause of hypercalcemia, because the
initial elevation in serum calcium concentration inhibits both the release of parathyroid hormone (PTH) and in
turn the synthesis of calcitriol. In patients who also have reduced urinary excretion, however, increased
intake can cause hypercalcemia. This combination of high calcium intake and low urine calcium excretion
occurs in two clinical situations: chronic kidney disease and the milk-alkali syndrome.
Chronic kidney disease Renal failure alone, although associated with decreased calcium excretion,
does not lead to hypercalcemia because of the calcium-lowering effects of concurrent hyperphosphatemia
and decreased calcitriol synthesis. However, hypercalcemia is not unusual in patients who are given calcium

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carbonate or calcium acetate to bind dietary phosphate, particularly if they have adynamic bone disease or
are also treated with calcitriol (or another form of vitamin D) in an attempt to reverse both hypocalcemia and
secondary hyperparathyroidism [1]. (See "Treatment of hyperphosphatemia in chronic kidney disease",
section on 'Calcium-containing binders'.)
Milk alkali syndrome In the absence of renal failure, hypercalcemia can be induced by a high intake
of milk or more commonly, calcium carbonate, leading to hypercalcemia, metabolic alkalosis, and renal
insufficiency (the milk-alkali syndrome) [15,16]. The metabolic alkalosis augments the hypercalcemia by
directly stimulating calcium reabsorption in the distal tubule, thereby diminishing calcium excretion. A
calcium-induced decline in renal function, due to renal vasoconstriction and, with chronic hypercalcemia,
structural injury, can also contribute to the inability to excrete the excess calcium. Renal function usually
returns to baseline after cessation of milk or calcium carbonate intake, but irreversible injury can occur in
patients who have prolonged hypercalcemia. (See "The milk-alkali syndrome".)
The milk-alkali syndrome typically occurs in the setting of excess calcium carbonate supplementation to treat
osteoporosis or dyspepsia [15,16]. One study found that the milk-alkali syndrome accounted for 2 percent of
hospitalized patients with hypercalcemia between 1985 and 1989, as compared with 12 percent between
1990 and 1993 [15]. In another study, milk-alkali syndrome accounted for 8.8 percent of hypercalcemia
cases between 1998 and 2003 [17].
Hypervitaminosis D High serum concentrations of either 25-hydroxyvitamin D (25[OH]D; calcidiol) or
1,25-dihydroxyvitamin D (calcitriol) can cause hypercalcemia by increasing calcium absorption and bone
resorption. (See "Overview of vitamin D", section on 'Metabolism'.)
Intestinal transport of calcium is primarily regulated by 1,25-dihydroxyvitamin D, which is more potent than
25(OH)D. However, hypercalcemia does occur in patients with markedly elevated serum 25(OH)D
concentrations, for example, those who ingest high doses of either vitamin D (which is converted to calcidiol
in the liver), calcidiol itself, or use topical calcipotriol, a vitamin D analog used in the treatment of some
dermatologic disorders [18-20]. In some patients with hypervitaminosis D, the excess intake was unknown to
the patients because milk was inadvertently excessively fortified with vitamin D [18].
High serum 1,25-dihydroxyvitamin D concentrations are usually due to ingestion of calcitriol as treatment for
hypoparathyroidism or for the hypocalcemia and secondary hyperparathyroidism of renal failure. Calcitriolinduced hypercalcemia usually lasts only one to two days because of the relatively short biologic half-life of
calcitriol. Thus, stopping the calcitriol, increasing salt and fluid intake, or perhaps hydration with intravenous
saline may be the only therapy that is needed.
Hypercalcemia caused by vitamin D or calcidiol lasts longer. More aggressive therapy such as
glucocorticoids and intravenous bisphosphonates may be necessary [21].
Hypercalcemia can also be caused by increased endogenous production of 1,25-dihydroxyvitamin D, as can
occur in patients with malignant lymphoma (see "Hypercalcemia of malignancy"), chronic granulomatous
disorders (especially sarcoidosis) (see "Hypercalcemia in granulomatous diseases"), and less frequently in
other illnesses characterized by granuloma formation, such as Wegener's granulomatosis [22].
Finally, a rare cause of hypercalcemia is spontaneous idiopathic excess production of calcitriol in the
apparent absence of granulomatous disease. These patients have high serum concentrations of angiotensin
converting enzyme and calcitriol, and a presumed increase in calcitriol production by macrophages. The
hypercalcemia responds to prednisone but continuous therapy is required [23].
MISCELLANEOUS CAUSES Other causes of hypercalcemia include:
Lithium Patients receiving chronic lithium therapy often develop mild hypercalcemia, most likely due to
increased secretion of parathyroid hormone (PTH) due to an increase in the set point at which calcium
suppresses PTH release. The hypercalcemia usually, but not always, subsides when the lithium is stopped.
Lithium can also unmask previously unrecognized mild hyperparathyroidism. Conversely, lithium can also
raise serum PTH concentrations without raising serum calcium concentrations. (See "Pathogenesis and

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etiology of primary hyperparathyroidism", section on 'Lithium therapy'.)

Thiazide diuretics Thiazide diuretics lower urinary calcium excretion, an effect that is useful in the
treatment of patients with hypercalciuria and recurrent calcium nephrolithiasis (see "Prevention of recurrent
calcium stones in adults" and "Diuretics and calcium balance"). This effect rarely causes hypercalcemia in
otherwise normal persons but can lead to hypercalcemia in patients with an underlying increase in bone
resorption, such as those with hyperparathyroidism. (See "Pathogenesis and etiology of primary
hyperparathyroidism", section on 'Thiazide therapy'.)
Pheochromocytoma Hypercalcemia is a rare complication of pheochromocytoma. It can be due to
concurrent hyperparathyroidism (in multiple endocrine neoplasia type 2 [MEN2]) [24] or to the
pheochromocytoma itself [25,26] (see "Clinical manifestations and diagnosis of multiple endocrine neoplasia
type 2"). The hypercalcemia in the latter patients appears to be due to tumoral production of PTH-related
protein (PTHrP). Serum PTH-related protein concentrations in these patients can be reduced by alphaadrenergic blockers, suggesting a mediating role for alpha-stimulation [27].
Adrenal insufficiency Hypercalcemia occurs in occasional patients with Addisonian crisis [28,29].
Multiple factors appear to contribute to the hypercalcemia including increased bone resorption, volume
contraction and increased proximal tubular calcium reabsorption, hemoconcentration, and perhaps
increased binding of calcium to serum proteins. Cortisol administration reverses the hypercalcemia within
several days [28]. Hypercalcemia has also been reported in patients with secondary adrenal insufficiency
due to lymphocytic hypophysitis [30,31]. The increased release of calcium from bone occurs despite
appropriate suppression of PTH and calcitriol release and appears to be mediated, at least in part, by thyroid
hormone via a process normally inhibited by glucocorticoids [30].
Rhabdomyolysis and acute renal failure Hypercalcemia has been described during the diuretic phase
of acute renal failure, most often in patients with rhabdomyolysis [32,33]. Hypercalcemia in this setting is
primarily due to the mobilization of calcium that had been deposited in the injured muscle. Correction of
hyperphosphatemia (induced by the rise in glomerular filtration rate), mild secondary hyperparathyroidism
induced by the renal failure, and an unexplained increase in serum calcitriol concentrations all appear to
contribute to the hypercalcemia. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and
"Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)", section
on 'Calcium'.)
A similar mechanism of mobilization of calcium phosphate as renal failure-induced hyperphosphatemia is
corrected plus persistent secondary hyperparathyroidism may account for the transient hypercalcemia that
can occur after successful renal transplantation. (See "Overview of chronic kidney disease-mineral bone
disease (CKD-MBD)".)
Theophylline toxicity Theophylline toxicity has been associated with mild hypercalcemia [22]. As in
hyperthyroidism, the hypercalcemia usually subsides in response to administration of a beta-adrenergic
antagonist. (See "Theophylline poisoning".)
Familial hypocalciuric hypercalcemia Familial hypocalciuric hypercalcemia is a rare autosomal
dominant disorder characterized by mild hypercalcemia, hypocalciuria (suggesting a contribution from
increased renal tubular calcium reabsorption), normal to moderately elevated serum magnesium
concentrations, and normal to slightly increased serum PTH concentrations. The majority of these patients
has few if any symptoms of hypercalcemia and requires no therapy; subtotal parathyroidectomy does not
correct the hypercalcemia.
The primary defect in this disorder is a loss-of-function mutation in the calcium-sensing sensor on the
parathyroid cells and in the kidneys so that higher than normal serum calcium concentrations are needed to
suppress PTH release. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric
hypercalcemia and autosomal dominant hypocalcemia".)
A rare acquired form of hypocalciuric hypercalcemia due to autoantibodies directed against the calciumsensing receptor has been described. (See "Disorders of the calcium-sensing receptor: Familial

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hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Acquired disorders of the
calcium-sensing receptor'.)
Metaphyseal chondrodysplasia A rare form of dwarfism, Jansen-type metaphyseal chondrodysplasia, is
associated with asymptomatic but significant hypercalcemia and hypophosphatemia. The parathyroid glands
are normal and serum PTH and PTHrP concentrations are normal or low. The primary defect in this
condition is a mutation in the PTH-PTHrP receptor gene, resulting in continuous activation of the receptor at
normal or low levels of PTH secretion [34].
Congenital lactase deficiency Hypercalcemia and medullary nephrocalcinosis have been described in
infants with congenital lactase deficiency [35]. The hypercalcemia resolves rapidly after institution of a
lactose-free diet but the nephrocalcinosis may persist. The hypercalcemia may be due to an increase in
calcium absorption in the ileum in the presence of nonhydrolyzed lactose.
SUMMARY AND RECOMMENDATIONS
Hypercalcemia is a relatively common clinical problem. Among all causes of hypercalcemia,
hyperparathyroidism and malignancy are the most common. (See 'Primary hyperparathyroidism' above
and 'Malignancy' above.)
The many other causes of hypercalcemia occur less frequently but are important to consider in clinical
situations when hypercalcemia is not caused by hyperparathyroidism or malignancy (table 1).
The diagnostic approach to hypercalcemia is reviewed separately. (See "Diagnostic approach to
hypercalcemia".)
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REFERENCES
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3. Iqbal AA, Burgess EH, Gallina DL, et al. Hypercalcemia in hyperthyroidism: patterns of serum calcium,
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4. Alikhan Z, Singh A. Hyperthyroidism manifested as hypercalcemia. South Med J 1996; 89:997.
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6. Alborzi F, Leibowitz AB. Immobilization hypercalcemia in critical illness following bariatric surgery.
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7. Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after
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8. Legha SS, Powell K, Buzdar AU, Blumenschein GR. Tamoxifen-induced hypercalcemia in breast
cancer. Cancer 1981; 47:2803.
9. Valentin-Opran A, Eilon G, Saez S, Mundy GR. Estrogens and antiestrogens stimulate release of bone
resorbing activity by cultured human breast cancer cells. J Clin Invest 1985; 75:726.
10. Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused by iatrogenic hypervitaminosis A. J Am Diet
Assoc 2005; 105:119.
11. Fishbane S, Frei GL, Finger M, et al. Hypervitaminosis A in two hemodialysis patients. Am J Kidney
Dis 1995; 25:346.
12. Villablanca JG, Khan AA, Avramis VI, Reynolds CP. Hypercalcemia: a dose-limiting toxicity associated

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with 13-cis-retinoic acid. Am J Pediatr Hematol Oncol 1993; 15:410.

13. Niesvizky R, Siegel DS, Busquets X, et al. Hypercalcaemia and increased serum interleukin-6 levels
induced by all-trans retinoic acid in patients with multiple myeloma. Br J Haematol 1995; 89:217.
14. Akiyama H, Nakamura N, Nagasaka S, et al. Hypercalcaemia due to all-trans retinoic acid. Lancet
1992; 339:308.
15. Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of
7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized
with hypercalcemia. Medicine (Baltimore) 1995; 74:89.
16. Abreo K, Adlakha A, Kilpatrick S, et al. The milk-alkali syndrome. A reversible form of acute renal
failure. Arch Intern Med 1993; 153:1005.
17. 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; 63:566.
18. Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med
1992; 326:1173.
19. Scanlon KS, Blank S, Sinks T, et al. Subclinical health effects in a population exposed to excess
vitamin D in milk. Am J Public Health 1995; 85:1418.
20. Hoeck HC, Laurberg G, Laurberg P. Hypercalcaemic crisis after excessive topical use of a vitamin D
derivative. J Intern Med 1994; 235:281.
21. Selby PL, Davies M, Marks JS, Mawer EB. Vitamin D intoxication causes hypercalcaemia by increased
bone resorption which responds to pamidronate. Clin Endocrinol (Oxf) 1995; 43:531.
22. Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab
2005; 90:6316.
23. Evron E, Goland S, von der Walde J, et al. Idiopathic calcitriol-induced hypercalcemia. A new disease
entity? Arch Intern Med 1997; 157:2142.
24. Heath DA. Primary hyperparathyroidism. Clinical presentation and factors influencing clinical
management. Endocrinol Metab Clin North Am 1989; 18:631.
25. Stewart AF, Hoecker JL, Mallette LE, et al. Hypercalcemia in pheochromocytoma. Evidence for a novel
mechanism. Ann Intern Med 1985; 102:776.
26. Bridgewater JA, Ratcliffe WA, Bundred NJ, Owens CW. Malignant phaeochromocytoma and
hypercalcaemia. Postgrad Med J 1993; 69:77.
27. Mune T, Katakami H, Kato Y, et al. Production and secretion of parathyroid hormone-related protein in
pheochromocytoma: participation of an alpha-adrenergic mechanism. J Clin Endocrinol Metab 1993;
76:757.
28. Muls E, Bouillon R, Boelaert J, et al. Etiology of hypercalcemia in a patient with Addison's disease.
Calcif Tissue Int 1982; 34:523.
29. Montoli A, Colussi G, Minetti L. Hypercalcaemia in Addison's disease: calciotropic hormone profile and
bone histology. J Intern Med 1992; 232:535.
30. Vasikaran SD, Tallis GA, Braund WJ. Secondary hypoadrenalism presenting with hypercalcaemia. Clin
Endocrinol (Oxf) 1994; 41:261.
31. Fujikawa M, Kamihira K, Sato K, et al. Elevated bone resorption markers in a patient with
hypercalcemia associated with post-partum thyrotoxicosis and hypoadrenocorticism due to pituitary
failure. J Endocrinol Invest 2004; 27:782.
32. Llach F, Felsenfeld AJ, Haussler MR. The pathophysiology of altered calcium metabolism in
rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone,
25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol. N Engl J Med 1981; 305:117.
33. Akmal M, Bishop JE, Telfer N, et al. Hypocalcemia and hypercalcemia in patients with rhabdomyolysis
with and without acute renal failure. J Clin Endocrinol Metab 1986; 63:137.
34. Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone

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and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med

1996; 335:708.
35. Saarela T, Simil S, Koivisto M. Hypercalcemia and nephrocalcinosis in patients with congenital
lactase deficiency. J Pediatr 1995; 127:920.
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GRAPHICS
Causes of hypercalcemia
Parathyroid mediated
Primary hyperparathyroidism (sporadic)
Inherited variants
Multiple endocrine neoplasia (MEN) syndromes
Familial isolated hyperparathyroidism
Hyperparathyroidism-jaw tumor syndrome
Familial hypocalciuric hypercalcemia
Tertiary hyperparathyroidism (renal failure)

Non-parathyroid mediated
Hypercalcemia of malignancy
PTHrp
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
Osteolytic bone metastases and local cytokines
Vitamin D intoxication
Chronic granulomatous disorders
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)

Medications
Thiazide diuretics
Lithium
Teriparatide
Excessive vitamin A
Theophylline toxicity

Miscellaneous
Hyperthyroidism
Acromegaly
Pheochromocytoma
Adrenal insufficiency
Immobilization
Parenteral nutrition
Milk alkali syndrome
PTHrp: PTH-related peptide.
Adapted from: Khairallah W, Fawaz A, Brown EM, and El-Hajj Fuleihan G. Hypercalcemia and
diabetes insipidus in a patient previously treated with lithium. Nat Clin Pract Nephrol 2007; 3:397.
Graphic 66865 Version 7.0

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Contributor Disclosures
Elizabeth Shane, MD Nothing to disclose. Clifford J Rosen, MD Grant/Research/Clinical Trial Support:
Alexion [Hypophosphatasia (Recombinant alkaline phosphatase)]. Jean E Mulder, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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