Hypercalcemia can result when too much calcium enters the extracellular fluid or when there is insufficient calcium excretion from the kidneys. Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism.[26]
The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Mild prolonged hypercalcemia may produce mild or no symptoms, or recurring problems such as kidney stones. Sudden-onset and severe hypercalcemia may cause dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.
Hypercalcemia affects nearly every organ system in the body, but it particularly affects the central nervous system (CNS) and the kidneys. CNS effects include the following:
Renal effects include the following:
Gastrointestinal effects include the following:
Cardiac effects include syncope from arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.
Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:
Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy. Hypercalcemia from hyperparathyroidism is usually mild, asymptomatic, and sustained for years. Immunoreactive parathyroid hormone (PTH) and ionized calcium should be simultaneously measured.
Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, urinary calcium, and thyroid function may be useful in some cases.
Treatment of hypercalcemia includes the following:
Calcium plays an important role in intracellular and extracellular metabolism controlling such processes as nerve conduction, muscle contraction, coagulation, electrolyte and enzyme regulation, and hormone release. Calcium metabolism, in turn, is tightly regulated by a series of hormones that affect not only the entry of calcium into the extracellular space from bone and the GI tract but also control its excretion from the kidneys.
Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.
Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms: (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.
Very little evidence suggests that intracellular stores of calcium contribute in any way to plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which in turn alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.
A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:
Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.
For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.
A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:
Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)
Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.
Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. The image below reviews vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.
View Image | Vitamin D metabolism. |
The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca++ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca++ on the calcium receptor.[1]
The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemia with hypercalciuria.[2, 3]
Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its occurrence may signify an unfavorable prognosis. Of the cases that result from malignancy, approximately 80% are due to the effects of parathyroid hormone–related peptide (PTHrP), while the other 20% are due to bony metastases. Hypercalcemia secondary to malignancy may be classified into the following four types, based on the mechanism involved:
The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and in rare cases, familial disorders. Treatment with recombinant human PTH for postmenopausal osteoporosis is also a cause.[4]
Causes of hypercalcemia that are related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:
Causes of hypercalcemia that are related to the parathyroid include the following:
Causes related to vitamin D include the following:
Causes related to high bone turnover include the following:
Other causes related to particular mechanisms are as follows:
Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed. A review of cancer-related hypercalcemia found that rates varied by tumor type, being highest in multiple myeloma (7.5–10.2%) and lowest in prostate cancer (1.4–2.1%).[9]
Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.
Morbidity and mortality from hypercalcemia depend entirely on the cause.
Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.
Some studies suggest that up to 20% of patients who present to the ED with hypercalcemia are ultimately diagnosed with hyperparathyroidism. Royer et al performed a retrospective review from 2012 to 2013 of patients with hypercalcemia in the ED, and a definitive diagnosis of hyperparathyroidism was identified in 3.5% (6 of 168). According to the authors, 24% (41 of 168) identified with mild hypercalcemia were discharged from the ED with no definitive follow-up plan, and although mild hypercalcemia found during ED workup rarely requires immediate medical treatment, many of those patients may have hyperparathyroidism amenable to surgical correction. The authors therefore suggested that an appropriate mechanism for outpatient hypercalcemia workup should be integrated into the patient's ED discharge plan.[10]
Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Cancers that produce PTHrP include breast cancer, lung cancer, prostate cancer, and multiple myeloma.[11]
PTHrP increases the expression of receptor activator of nuclear factor kappa B ligand (RANKL) in bone. RANKL in turn contributes to the development of hypercalcemia by binding to receptor activator of nuclear factor kappa B (RANK) on the surface of osteoclast precursors, leading to bone osteolysis.
Hypercalcemia is often the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.
Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.
Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.
Hypercalcemia from nearly all causes increases with advancing age. That is especially true of hypercalcemia from the two most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.
Cancer-related hypercalcemia most often occurs in later-stage malignancies and it predicts a poor prognosis for patients with it.[12]
In a study of 90 patients with advanced head and neck squamous cell carcinoma (HNSCC), Alsirafy et al compared outcomes for those patients in the cohort who had hypercalcemia (46 patients) with those of patients who did not. The authors found that inpatients with hypercalcemia had a higher rate of palliative care referrals. Moreover, during the final 3 months of patient follow-up, a greater percentage of individuals with hypercalcemia paid more than 1 visit to the emergency room and a larger proportion of hypercalcemic patients were hospitalized for at least 14 days.
The authors also determined that among the study's patients who were referred for palliative care, the median postreferral survival time for those with hypercalcemia was 43 days, while that for nonhypercalcemic patients was 128 days. Alsirafy et al concluded that if hypercalcemia in patients with HNSCC is detected and managed early, this may help to prevent hypercalcemia-associated symptoms and to reduce hospitalization time.[13]
The mnemonic "stones, bones, abdominal moans, and psychic groans" describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeletal changes.
The presentation in a patient with hypercalcemia varies with how fast and how far the calcium level rises, as well as the sensitivity of the individual to elevated calcium levels. Mild prolonged hypercalcemia may produce mild or no symptoms, or recurring problems such as kidney stones. Sudden-onset and severe hypercalcemia may cause dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.
Central nervous system effects include the following:
Renal effects include the following:
Gastrointestinal effects include the following:
Cardiac effects include syncope from arrhythmias.
Most patients with hypercalcemia do not have any specific findings on physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.
Nervous system findings include the following:
Renal findings include the following:
Gastrointestinal findings include the following:
Cardiovascular findings include the following:
Ophthalmic findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.
Malignancy is one of the most common causes and must be excluded. Hyperparathyroidism and other causes of hypercalcemia can coexist with malignancy. If calcium levels have been mildly elevated for months or years, malignancy is an unlikely cause.
Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy. If calcium levels have been elevated for an unknown duration, the patient should be evaluated for the presence of malignancy. Breast, lung, and kidney cancers should be considered, as should multiple myeloma, lymphoma, and leukemia. Testing in such cases might include a peripheral blood smear and/or serum and urine immunofixation electrophoresis. Biopsy samples may be taken from a solid tumor or from bone marrow for tissue histology studies.
Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive parathyroid hormone (PTH) and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the combination of normal PTH levels and elevated calcium levels suggests mild hyperparathyroidism. Hyperparathyroidism may be part of multiple endocrine neoplasia type 1, (ie, Wermer syndrome).
Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, and urinary calcium may be useful in some cases. Renal function should be evaluated and thyroid-stimulating hormone should be checked to help rule out hyperthyroidism. In rare cases, measurement of vitamin D and its metabolites and measurement of parathyroid hormone–related peptide (PTHrP) may be necessary.
A flowchart of investigations is depicted in the image below.
View Image | Investigations flowchart. |
rction.
Chest radiographs always should be performed to help rule out lung cancer or sarcoidosis. Other radiographs should be considered to help evaluate for possible malignancies, metastases, or Paget disease.
Mammograms should be considered to help rule out breast cancer. Computed tomography (CT) and ultrasound should be considered to help rule out renal cancer.
When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, magnetic resonance imaging (MRI), and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.
On electrocardiography (ECG), characteristic changes in patients with hypercalcemia include shortening of the QT interval. ECG changes in patients with very high serum calcium levels include the following[14, 15, 16] :
Treatment depends on the severity of symptoms and the underlying cause.[17]
Volume depletion results from uncontrolled symptoms leading to decreased intake and enhanced renal sodium loss. This tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle (TALH). Thus, appropriate volume repletion with isotonic sodium chloride solution is an effective short-term treatment for hypercalcemia.
Once volume is restored, simultaneous administration of loop diuretics blocks Na+ and calcium reabsorption in the TALH. Replacing ongoing sodium, potassium, chloride, and magnesium losses is important if prolonged sodium chloride and loop diuretic therapy is contemplated.
Immobilization aggravates hypercalcemia. Whenever possible, weightbearing mobilization should be encouraged.
Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption (eg, in idiopathic infantile hypercalcemia, ie, Williams syndrome). In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 (eg, in sarcoidosis), prednisone may help reduce plasma calcium levels by reducing intestinal calcium absorption. Oral phosphate also can be used to form insoluble calcium phosphate in the gut.
Bisphosphonates inhibit osteoclastic bone resorption and are effective in the treatment of hypercalcemia due to conditions causing increased bone resorption and malignancy-related hypercalcemia. Pamidronate and etidronate can be given intravenously, while risedronate and alendronate may be effective as oral therapy. Calcitonin can be given intramuscularly or subcutaneously, but it becomes less effective after several days of use. Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia. It has significant hepatic, renal, and marrow toxicity.
The US Food and Drug Administration (FDA) approved denosumab (Xgeva) for treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy in December 2014.[18] Approval was based on results from an open-label, single-arm study that enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L.
The study achieved its primary endpoint with a response rate at day 10 of 63.6% in the 33 patients evaluated. The estimated median time to response (CSC < 11.5 mg/dL) was 9 days, and the median duration of response was 104 days.[19]
Peritoneal dialysis or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.
Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage, as follows[20, 21] :
The first therapy for symptomatic hypercalcemia is volume repletion. More severe cases require saline infusion with concomitant loop diuretics (eg, furosemide) to increase calcium excretion and lower levels rapidly. Other therapies, outlined below, are for longer-term management. Note, however, that no current therapies generally are effective for long-term outpatient therapy. Definitive treatment often requires surgical management of the underlying cause.[17]
Bisphosphonates are effective in the treatment of malignancy-related hypercalcemia and hypercalcemia due to conditions causing increased bone resorption. Zoledronic acid is 100-850 times more potent than pamidronate and may be given as a bolus rather than an infusion. Clodronate (not available in the United States) can be given either intravenously or orally and may represent a better alternative in the future. The monoclonal antibody denosumab is approved for the treatment of hypercalcemia of malignancy that is refractory to bisphosphonate therapy.
Clinical Context: Used after initial hydration to inhibit bone reabsorption and maintain low serum calcium levels, especially in hypercalcemia of malignancy and Paget disease.
Clinical Context: Reduces bone formation and does not alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Clinical Context: Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.
Clinical Context: Denosumab is a monoclonal antibody that specifically targets RANKL. It binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. It is indicated for hypercalcemia of malignancy refractory to bisphosphonate therapy.
Binds RANKL and thereby prevents osteoclast formation resulting in decreased bone resorption and decreased calcium release from bone.
Clinical Context: Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Expect higher response when serum calcium levels are high.
Onset of action is approximately 2 h following injection, and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by approximately 9% if given q12h. IM route is preferred at multiple injection sites with dose > 2 mL.
Clinical Context: Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Inhibit cytokine release and have a direct cytolytic effect on some tumor cells.
Clinical Context: Increases urinary pyrophosphate and complexes with calcium, thus decreasing urinary calcium level, while pyridoxine results in a reduction of urinary oxalate excretion. All dosage forms must be mixed in 6-8 oz of water. Never give IV. Never give if renal function is abnormal or if serum phosphorous levels are > 3 mg/dL.
Phosphate inhibits calcium absorption and promotes calcium deposition. Theorized to help bind dietary calcium, thus rendering it an unabsorbable calcium-phosphorous product, but used rarely.
Clinical Context: Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and in hypercalcemia with parathyroid carcinoma.
Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.[1, 22]
Marcocci et al performed an open-label, single-arm study to determine how effectively cinacalcet, a calcimimetic, reduces hypercalcemia in patients with intractable persistent primary hyperparathyroidism.[23] The investigation, performed on 17 patients, included a 2- to 16-week titration phase and a maintenance phase of up to 136 weeks. By the end of the titration phase, serum calcium had been reduced in 15 patients by at least 1 mg/dL. Although 15 patients suffered adverse events related to treatment (most commonly, nausea, vomiting, and paresthesias), none of these were considered to be serious.
In most cases, follow-up care is dictated by the etiology of hypercalcemia. If the hypercalcemia is related to malignancy, efforts are directed towards treating the neoplasm.
Oral phosphates have only a limited role in the treatment of hypercalcemia and are increasingly replaced by bisphosphonates. However, when phosphates are used, especially for treating chronic hypercalcemia, attention should be paid to hyperphosphatemia and the calcium and phosphate product because this tends to increase the risk of metastatic calcification.
Restriction of dietary calcium and administration of glucocorticoids remains the preferred treatment for hypercalcemia due to sarcoidosis and vitamin D intoxication.