Hypercalcemia in Emergency Medicine
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https://emedicine.medscape.com/article/766373-overview
Practice Essentials
Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism.  [1, 2, 3, 4, 5, 6] Other,
less common causes of elevated calcium include increased intake or absorption, granulomatous disease, immobilization, and
thiazide diuretic use. However, the primary diagnostic approach should be to first rule out underlying malignancy and
parathyroid disease. [7]
Hypercalcemic crisis does not have an exact definition, although marked elevation of serum calcium, usually more than 14
mg/dL, is associated with acute signs and symptoms of hypercalcemia. Treatment of the elevated calcium level may resolve
the crisis.
The reference range of serum calcium levels varies among laboratories but generally is 8.7-10.4 mg/dL, with somewhat
higher levels present in children. Approximately 50% of calcium is bound to protein, primarily albumin, and the remaining
50% is ionized and is in physiologic active form. [7]
Signs and symptoms of hypercalcemia
Mild elevations in calcium levels are usually asymptomatic and typically discovered on routine laboratory diagnostic testing
(usually up to 11.5 mg/dL). [8]
As calcium levels increase, the following symptoms may occur:
 Nausea
 Vomiting
 Alterations of mental status
 Abdominal or flank pain - The workup of patients with a new kidney stone occasionally reveals an elevated
calcium level
 Constipation
 Lethargy
 Depression
 Weakness and vague muscle/joint aches
Pathophysiology
Plasma calcium is maintained within the reference range by a complex interplay of 3 major hormones, parathyroid hormone
(PTH), 1,25-dihydroxyvitamin D (ie, calcitriol), and calcitonin. These 3 hormones act primarily at bone, kidney, and small
intestine sites to maintain appropriate calcium levels.
Calcium enters the body through the small intestine and eventually is excreted via the kidney. Bone can act as a storage
depot. This entire system is controlled through a feedback loop; individual hormones respond as needed to increase or
decrease the serum calcium concentration.
For hypercalcemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol,
some other serum factor that can mimic these hormones, or a huge calcium load.
Hypercalcemia can result from a multitude of disorders. The causes are divided into PTH-mediated hypercalcemia and non–
PTH-mediated hypercalcemia.
PTH-mediated hypercalcemia
Primary hyperparathyroidism originally was the disease of "stones, bones, and abdominal groans." In most primary
hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by
the PTH-induced calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase
in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is
excreted than might be expected. Hypercalcemia of this disorder may remain mild for long periods because some
parathyroid adenomas respond to the feedback generated by the elevated calcium levels.
Non–PTH-mediated hypercalcemia
Malignancy-associated hypercalcemia occurs in up to 20-30% of patients at some course within their disease. Most episodes
occur with advanced disease and patients typically have a poor prognosis (with up to a 50% 30-day mortality). There are two
generally recognized forms of this disorder, one in which hypercalcemia is the result of tumor secretion of a humoral factor
(usually PTHrP) and one is the result of excessive bone metastases.  [9] Common malignancies include multiple

Polyuria, polydipsia, nocturia
Headache
 Confusion
Severe elevations in calcium levels may cause coma.
Workup in hypercalcemia
When calcium levels are reported as abnormal, the first step is to measure the albumin level. The following is a common
formula used in calculating a corrected calcium level  [8] :
Corrected total calcium (mg/dL)
= (measured total calcium mg/dL) + 0.8 (for every decrement in the serum albumin of 1 g/dL below the reference value
[in many cases 4.1 g/dL]; subsequently, subtract 0.8 for every increment in the serum albumin of 1 g/dL above the
reference value)
If the corrected serum calcium level still is not accurate, it is possible to measure the free calcium ion activity (ie, ionized
calcium level).
Hypercalcemia may produce electrocardiographic abnormalities related to altered transmembrane potentials that affect
conduction time.
After a diagnosis of hypercalcemia is established, the next step is to determine the cause. Initial testing is directed at
malignancy, hyperparathyroidism, and hyperthyroidism, the most common causes of hypercalcemia.
Emergency department care
The initial step in the care of severely hypercalcemic patients is hydration and forced calciuresis. Because most of these
patients are profoundly dehydrated, 0.9 normal saline is the crystalloid of choice for rehydration.
A loop diuretic (eg, furosemide) may be used with hydration to increase calcium excretion.
This may also prevent volume overload during therapy.
Bisphosphates will inhibit osteoclast activity for up to a month. However, these agents may
take 48-72 hours before reaching full therapeutic effect. [7]
myeloma, breast cancer, or lung cancer. Multiple factors for osteolysis are responsible for this action, which is produced by
or in response to the myeloma cells in the marrow. These are collectively referred to osteoclast-activating factors.  [10]
Multiple endocrine neoplasia (MEN) are a group of disorders associated with hyperfunction of two or more endocrine
glands and can be a cause of hypercalcemia (which may be milder and even asymptomatic). Finally, tamoxifen-linked
hypercalcemia is hypercalcemia in association with the use of estrogen or antiestrogen therapy for therapy for carcinoma of
the breast. The severity of hypercalcemia is variable, but it can be fatal. The mechanism by which tamoxifen and similar
agents cause hypercalcemia is unclear but prostaglandins may be the main mediator of the response.  [11] Other causes that
are non-malignancy-related include milk-alkali syndrome (which involves large intake of calcium in association with volume
contraction, systemic alkalosis and renal insufficiency) and medication-induced hypercalcemia (especially chronic lithium
therapy). [9]
The emergency physician should be concerned about any patient with a history of cancer who presents with lethargy or
altered mental status. Granulomatous disorders with high levels of calcitriol may be found in patients with sarcoidosis,
berylliosis, tuberculosis, leprosy, coccidioidomycosis, and histoplasmosis.  [4]
Epidemiology
Frequency
United States
Hypercalcemia is a fairly common metabolic emergency. Between 20-40% of patients with cancer develop hypercalcemia at
some point in their disease (this may be decreasing with the use of bisphosphates, but data are lacking), and it is the most
common serious electrolyte presenting in adults with malignancies. [12]
A study by Gastanaga et al estimated that between 2009 and 2013, 2.0-2.8% of all cancer patients in the United States were
affected by hypercalcemia of malignancy, with the highest rates of such hypercalcemia found in multiple myeloma patients
(7.5-10.2% between 2010 and 2012), and the lowest rates found in patients with prostate cancer (1.4-2.1% between 2011 Hypercalcemia has few physical examination findings specific to its diagnosis. Often it is the symptoms or signs of underlying
and 2012).  [13] malignancy that bring the patient with hypercalcemia to seek medical attention. The primary malignancy may be suggested
Primary hyperparathyroidism occurs in 25 per 100,000 persons in the general population and in 75 per 100,000 hospitalized by lung findings, skin changes, lymphadenopathy, or liver or spleen enlargement.
patients. This condition is the most common cause of mild hypercalcemia, which can be treated on an outpatient basis. In Hypercalcemia can produce a number of nonspecific findings, as follows:
the United States, more than 50,000 new cases occur each year.  Hypertension and bradycardia may be noted in patients with hypercalcemia, but this is nonspecific.
International
A retrospective cohort study by Lapointe that looked at adult emergency department patients in two hospitals in Québec  Abdominal examination may suggest pancreatitis or the possibility of an ulcer.
City, including one specializing in oncology and nephrology, found the prevalence of hypercalcemia to be 3.8%.  [14]  Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more
A Scottish study, by McNeilly et al, estimated that in a general hospital setting, the rate of sustained hypercalcemia prominent in the lower extremities; they also may have bony tenderness to palpation.
(hypercalcemia on 2 or more consecutive days) is 1 in 500 children, with the greatest frequency found in neonates.
Etiologies varied with age among pediatric patients.  [15]  Hyperreflexia and tongue fasciculations may be present.
Mortality/Morbidity  Anorexia or nausea may occur.
Prognosis of hypercalcemia associated with malignancy is poor; the 1-year survival rate is 10-30%. In one study, 50% of
patients died within 30 days of beginning treatment; 75% died within 3 months.
 Polyuria and dehydration are common.
In a study by Ramos et al of patients with solid tumors suffering from malignancy-related hypercalcemia, univariable analysis  Lethargy, stupor, or even coma may be observed.
showed significantly poorer survival in those with an Eastern Cooperative Oncology Group performance status of over 2, Long-standing hypercalcemia may cause band keratopathy, but this is rarely recognized in the ED.
altered mental status, a C-reactive protein level above 30 mg/L, an albumin concentration of less than 2.5 g/dL, or a body If hypercalcemia is caused by sarcoidosis, vitamin D intoxication, or hyperthyroidism, patients may have physical
mass index below 18 kg/m2. [16] examination findings suggestive of those diseases.
Prognosis related to many of the other causes of hypercalcemia can be excellent once the underlying disease is addressed. Causes
Sex Hypercalcemia is divided into PTH-mediated hypercalcemia (primary hyperparathyroidism) and non–PTH-mediated
The incidence of primary hyperparathyroidism is considerably higher in women. The annual incidence in women older than hypercalcemia. [17, 18, 19]
65 years is 250 per 100,000. PTH-mediated hypercalcemia is related to increased calcium absorption from the intestine.
Elevations in calcium levels related to cancer have no sex predominance. Non–PTH-mediated hypercalcemia includes the following:
Age  Hypercalcemia associated with malignancy: Unlike PTH-mediated hypercalcemia, the elevation of calcium that
The incidence of primary hyperparathyroidism increases with age.
results from malignancy generally worsens until therapy is provided. Hypercalcemia caused by malignancy is
The rate of malignancy and, thus, of malignancy-associated hypercalcemia increases with age.
the result of increased osteoclastic activity within the bone. This results from one or both of the mechanisms
History
that follow:
Symptoms of hypercalcemia depend on the underlying cause of the disease, the time over which it develops (rapid increases
in calcium cause more severe symptoms), and the overall physical health of the patient. o Extensive localized bone destruction may result from osteolytic metastasis of solid tumors.
Mild elevations in calcium levels are usually asymptomatic and typically discovered on routine laboratory diagnostic testing Evidence indicates that many malignant cells may release local osteoclastic activating factors.
(usually up to 11.5 mg/dL). [8] o Increased calcium levels resulting from malignancy caused by a PTH-related protein (PTH-rp) is a
As calcium levels increase, the following symptoms may occur: second mechanism. This protein is a humeral factor that acts on the skeleton to increase bone
 Nausea reabsorption; it acts on the kidney to decrease excretion of calcium. The gene that produces this
protein is present in many malignant tissues.
 Vomiting
 Granulomatous disorders: High levels of calcitriol may be found in patients with sarcoidosis and other
 Alterations of mental status granulomatous diseases. In these disorders, the increased level of calcitriol results from production within the
 Abdominal or flank pain (The workup of patients with a new kidney stone occasionally reveals an elevated macrophages, which constitute a large portion of some granulomas.
calcium level.)  Iatrogenic: In some cases, elevation of calcium is a known adverse effect of appropriate dosage. In other cases,
 Constipation large ingestions must be taken to induce the increase in calcium levels. Obtain a complete review of current
medications for patients presenting with hypercalcemia. Record any vitamin use.
 Lethargy
Other causes of hypercalcemia
 Depression These include the following:
 Weakness and vague muscle/joint aches  Neoplasms (nonparathyroid) - Metastasis to the bone from breast, multiple myeloma, and hematologic
malignancies (Breast cancer is one of the most common malignancies responsible for hypercalcemia.)
 Polyuria, polydipsia, nocturia
 Headache
 Nonmetastatic (humoral-induced) - Ovary, kidney, lung, head and neck, esophagus, cervix, lymphoproliferative
disease, multiple endocrine neoplasia, pheochromocytoma, and hepatoma
 Confusion
 Pharmacologic agents - Thiazide, calcium carbonate (antacid), hypervitaminosis D, hypervitaminosis A, lithium,
Severe elevations in calcium levels may cause coma.
milk-alkali syndrome, and theophylline toxicity
Elderly patients are more likely to be symptomatic from only moderate elevations of calcium levels.
Hypercalcemia of malignancy may lack many of the features commonly associated with hypercalcemia caused by  Endocrinopathies (nonparathyroid) - Hyperthyroidism, adrenal insufficiency, and pheochromocytoma
hyperparathyroidism. In addition, the symptoms of elevated calcium level may overlap with the symptoms of the patient's  Familial hypocalciuric hypercalcemia
malignancy.
Hypercalcemia associated with renal calculi, joint complaints, and ulcer disease is more likely to be caused by  Tertiary hyperparathyroidism - Post–renal transplant and initiation of chronic hemodialysis
hyperparathyroidism.  Miscellaneous - Immobilization, hypophosphatasia, primary infantile hyperparathyroidism, AIDS, and advanced
Physical chronic liver disease
A study by Meehan et al found that 26.2% of patients with bipolar disorder undergoing lithium treatment had
hypercalcemia. Out of a study population consisting of patients with bipolar disorder being treated with lithium, patients
with bipolar disorder not being treated with lithium, and controls, hypercalcemia occurred in 87 individuals, including 82
(94.3%) of those undergoing lithium therapy. [20]
In a retrospective, observational study from Australia of emergency department patients, Taylor et al reported that risk
variables for hypercalcemia included not only aforementioned factors—vomiting, polyuria, confusion, hyperparathyroidism,
and cancer—but also female sex and type 1 diabetes mellitus.  [21]
The aforementioned study by Lapointe et al, which looked at adult emergency department patients in two hospitals in
Québec City, indicated that bone pain, the use of medications containing vitamin D, and hallucinations are risk factors for
hypercalcemia. [14]
Differential Diagnoses
 Acute Complications of Sarcoidosis
 Hyperparathyroidism in Emergency Medicine
 Lithium Toxicity
 Malignancy
 Rapid HIV Testing
 Salicylate Toxicity
 Theophylline Toxicity
 Toxicity, Thyroid Hormone
 Tuberculosis (TB)
 Vitamin Toxicity
Laboratory Studies
When calcium levels are reported as abnormal, the first step is to measure the albumin level. The following is a common
formula used in calculating a corrected calcium level [8] :
Corrected total calcium (mg/dL) = (measured total calcium mg/dL) + 0.8 (for every decrement in the serum albumin of 1
g/dL below the reference value [in many cases 4.1 g/dL]; subsequently, subtract 0.8 for every increment in the serum
albumin of 1 g/dL above the reference value)
If the corrected serum calcium level still is not accurate, it is possible to measure the free calcium ion activity (ie, ionized
calcium level).
Other nonspecific laboratory abnormalities commonly found in patients with hypercalcemia result from disordered renal
function. Patients commonly have significant azotemia at presentation.
Hypercalcemia may produce electrocardiographic abnormalities related to altered transmembrane potentials that affect
conduction time. QT interval shortening is common, and, in some cases, the PR interval is prolonged. At very high levels, the
QRS interval may lengthen, T waves may flatten or invert, and a variable degree of heart block may develop. Digoxin effects
are amplified.
After a diagnosis of hypercalcemia is established, the next step is to determine the cause. Initial testing is directed at
malignancy, hyperparathyroidism, and hyperthyroidism, the most common causes of hypercalcemia.
The measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid gland function. A
reference range is 2-6 mol/L. A nonsuppressed PTH level in the presence of hypercalcemia suggests a diagnosis of primary
hyperparathyroidism. If the PTH level is suppressed in the face of an elevated calcium level, hyperparathyroidism is unlikely.
Parathyroid hormone-related peptide (PTHrP) is thought to mediate the hypercalcemia that develops with many
malignancies. Assays to measure this peptide are available. [22]
Measurement of calcitriol is difficult but can be accomplished. This laboratory value is useful in diagnosing hypercalcemia
secondary to a granulomatous disease such as sarcoidosis. It is often elevated in primary hyperparathyroidism.
Other electrolytes also may be disturbed in hypercalcemia. Serum phosphate levels tend to be low or normal in primary
hyperparathyroidism and hypercalcemia of malignancy. Phospate levels are elevated in hypercalcemia secondary to vitamin
D–related disorders or thyrotoxicosis. Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and
less than this value in other forms of hypercalcemia.
A study by Balentine et al suggested that a large percentage of patients with hypercalcemia are not appropriately evaluated
for hyperparathyroidism, while many of those who are diagnosed with hyperparathyroidism do not get a surgical referral.
Looking at figures from a tertiary referral center, the investigators found that only 3200 (31%) of 10,432 patients with
hypercalcemia underwent parathyroid hormone measurement, with a hypercalcemia diagnosis documented in just 2914
patients (28%) and a hyperparathyroidism diagnosis found in the medical records of 880 patients (8%). Of 2666 patients
with classic hyperparathyroidism (ie, abnormal calcium and parathyroid hormone levels), only 592 (22%) received a surgical
referral. [23]
Imaging Studies
No imaging studies definitively diagnose hypercalcemia. However, the chest radiograph may reveal malignancy or
granulomatous disease. [7]
Consider hypercalcemia in patients with multiple nonspecific complaints and an associated lung mass.
If laboratory evidence of primary hyperparathyroidism is present, CT scan of the head, MRI, ultrasound, or nuclear
parathyroid scans may be helpful. Preoperative diagnostic imaging is essential in patients with previous neck surgery.
Prehospital Care
Prehospital care is primarily supportive with management of the ABCs. If a patient has a history of hypercalcemia and
displays evidence of acute hypercalcemia, immediately begin IV hydration.
Emergency Department Care
The treatment of hypercalcemia depends on the level, the clinical presentation, and (if known) the underlying cause of the
problem. In mild to moderate elevations of calcium, few treatment options may be available in the ED. A physical evaluation
to help delineate the source of the elevation is always appropriate, as is a subsequent timely follow-up visit.
 Initial goals of treatment
o Assessment and maintenance of airway, breathing, and circulation (ABCs)
o Stabilization and reduction of the calcium level
o Adequate hydration
o Increased urinary calcium excretion
o Inhibition of osteoclast activity in the bone
o Discontinuation of pharmacologic agents associated with hypercalcemia
o Treatment of the underlying cause (when possible)
 The initial step in the care of severely hypercalcemic patients is hydration and forced calciuresis. Because most
of these patients are profoundly dehydrated, 0.9 normal saline is the crystalloid of choice for rehydration.
Hydration helps decrease the calcium level through dilution. The expansion of extracellular volume also
increases the renal calcium clearance. The rate of fluid therapy is based upon the following  [7] :
o Degree of hypercalcemia
o Severity of dehydration
o Ability of the patient to tolerate rehydration - Vigilance to prevent volume overload is critical.
o Hydration is ineffective in patients with kidney failure because diuresis is impossible. Dialysis is
necessary to correct hypercalcemia in patients with renal failure.
 Loop diuretics
o A loop diuretic (eg, furosemide) may be used with hydration to increase calcium excretion. This
may also prevent volume overload during therapy.
o In contrast to loop diuretics, avoid thiazide diuretics because they increase the reabsorption of
calcium.
  Bisphosphates - These agents will inhibit osteoclast activity for up to a month. However, these agents may take
48-72 hours before reaching full therapeutic effect. [7]

Consultations
Patients with renal failure or heart failure may not be able to tolerate fluid hydration or some of the other medications.
Patients in this group who present with severe elevations of calcium may require urgent dialysis. Consult a nephrologist
immediately in such cases.
Patients with primary hyperparathyroidism may require surgery to eliminate the condition,  [24] but surgery usually does not
need to be performed on an urgent basis.
Patients with malignancy may require surgery, chemotherapy, or radiation treatment. Appropriate consultation should be
undertaken.