AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Calcium (Ca) plays an important role in intracellular and extracellular metabolism that controls processes, such 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. Hypercalcemia can be the result of excess entry of calcium into the extracellular fluid (ECF) or of insufficient excretion.

Calcium hemostasis

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 towards 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:

• Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)
• Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)
• Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)

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. Media file 1 shows a review of 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.

Role of the calcium-sensing receptor

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.

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.

Pathophysiology

Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensure. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.

Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.

High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.

The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.

The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.

Frequency

United States

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.

International

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.

Mortality/Morbidity

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.
• 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. Often, the hypercalcemia is 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.

Sex

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.

Age

Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

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 skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.

• Central nervous system effects include the following:
• • Lethargy
  • Weakness
  • Confusion
  • Coma
• Renal effects include the following:
• • Polyuria
  • Nocturia
  • Dehydration
  • Renal stones
  • Renal failure
• Gastrointestinal effects include the following:
• • Constipation
  • Nausea
  • Anorexia
  • Pancreatitis
  • Gastric ulcer
• Cardiac effects include syncope from arrhythmias.

Physical

Most patients with hypercalcemia do not have any specific findings upon 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:
• • Confusion
  • Hypotonia
  • Hyporeflexia
  • Paresis
  • Coma
• Renal findings include the following:
• • Volume depletion
  • Signs of renal failure
• Gastrointestinal findings include the following:
• • Fecal impaction (from constipation)
  • Signs of pancreatitis
  • Signs of malignancy (eg, enlarged liver or masses)
• Cardiac findings include the following:
• • Arrhythmias
  • Hypotension
  • Shortened QT interval
• General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.

Causes

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 detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into 4 types based on the mechanism involved, as follows:

1. Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP. This is the most common form, accounting for up to 80% of cases.
2. Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue. This is the second most common mechanism, accounting for about 20% of cases.
3. Secretion of active vitamin D by some lymphomas may be seen.
4. Ectopic PTH secretion is very rarely seen.

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 causes.

• Those related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:
• • Solid tumor metastases
  • Solid tumors with humoral effects
  • Hematologic malignancies
• Those related to the parathyroid include the following:
• • Primary hyperparathyroidism
    • Solitary adenoma
    • Generalized hyperplasia
    • Multiple endocrine neoplasia type 1 or type 2A
  • Lithium-related release of PTH
  • Familial cases of high PTH
• Those related to vitamin D include the following:
• • Vitamin D toxicity
  • Granulomatous disease (especially sarcoidosis)
• Those related to high bone turnover include the following:
• • Hyperthyroidism
  • Immobilization (especially in Paget disease)
  • Thiazides
  • Vitamin A intoxication
• Renal failure (milk-alkali syndrome)
• Other causes related to particular mechanisms are as follows:
• • Increased intestinal calcium absorption
    • Idiopathic infantile hypercalcemia (Williams syndrome)
    • Vitamin D intoxication
    • Vitamin A intoxication
    • Granulomatous disorders, eg, sarcoidosis
  • Decreased renal calcium excretion
    • Hyperparathyroidism
    • Familial hypocalciuric hypercalcemia
    • Thiazide diuretics
  • Increased bone resorption
    • Immobilization
    • Hyperparathyroidism
    • Malignancy
  • Mutations of the calcium-sensing receptor
    • Familial benign hypocalciuric hypercalcemia
    • Neonatal severe hyperparathyroidism
  • Uncertain mechanism
    • Hypophosphatasia
    • Subcutaneous fat necrosis
    • Blue diaper syndrome
    • Dietary phosphate deficiency

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• 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. 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. Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy.
• Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive PTH and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the presence of normal PTH levels with 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 PTHrP may be necessary.

Imaging Studies

• 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, and CT scan and ultrasound should be considered to help rule out renal cancer.
• When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, MRI, and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.

Other Tests

• Miscellaneous
• • Peripheral smear
  • Serum and urine immunofixation electrophoresis

Procedures

• Tissue histology
• • Biopsy of solid tumor
  • Biopsy of bone marrow

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment depends on the severity of symptoms and the underlying cause.

• Volume expansion and saline diuresis
• • 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.
• Mobilization
  • Immobilization aggravates hypercalcemia.
  • Whenever possible, weightbearing mobilization should be encouraged.
• Reduction of gastrointestinal calcium absorption
  • 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.
• Inhibition of bone resorption
  • 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.
• Dialysis: Peritoneal or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.

Surgical Care

Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage.

• Prolonged hypercalcemia due to hyperparathyroidism may warrant surgical neck exploration and removal of one or more parathyroid glands. This is particularly appropriate if evidence of nephrolithiasis, osteoporosis, reduction of renal function, neuromuscular symptoms, or radiographic bone disease is present.
• Hypercalcemia due to malignancy, especially if due to a tumor that is producing PTHrP, may require surgical resection of the tumor.
• Orthopedic complications of prolonged hypercalcemia (eg, osteoporosis), complications of Paget disease, or complications of bony metastases may require orthopedic or neurosurgical intervention.

Consultations

Consultation with a surgeon or orthopedist may be required, as indicated.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

Clodronate (not available in the United States) can be given either IV or PO and may represent a better alternative in the future at a dose 1600-2400 mg/d. Ibandronate (not available in the United States) is approximately 50 times more potent than pamidronate and may be given as a single bolus rather than an infusion. Zoledronic acid is 100-850 times more potent than pamidronate and may be given as a bolus rather than an infusion.

Drug Category: Bisphosphonates

Inhibit bone reabsorption.

Drug Name	Etidronate (Didronel)
Description	Reduces bone formation and does not alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Adult Dose	7.5 mg/kg/d IV for 3 consecutive d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia, renal impairment
Interactions	Coadministration with calcium-containing products and other multivalent cations decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women

Drug Name	Alendronate (Fosamax)
Description	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.
Adult Dose	Not established; usual starting dose is 40 mg PO qam
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment

Drug Category: Antineoplastic drugs

Some agents in this drug class can reduce bone turnover.

Drug Name	Plicamycin (Mithracin)
Description	No longer manufactured and distributed in the United States. Inhibits bone resorption. Used only in cases of hypercalcemia due to malignancy; treatment can be repeated if necessary.
Adult Dose	25 mcg/kg IV over 4-6 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; thrombocytopenia, coagulation disorders, impairment of bone marrow function
Interactions	Coadministration with glucagon, calcitonin, and etidronate may increase toxicity
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor platelets, prothrombin, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment

Drug Category: Antidote, hypercalcemia agents

Inhibit bone resorption and increase renal calcium excretion.

Drug Category: Glucocorticoids

Inhibit cytokine release and have a direct cytolytic effect on some tumor cells.

Drug Category: Minerals

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.

Drug Category: Calcimimetic agent

Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• In most cases, follow-up care is dictated by the etiology of hypercalcemia.
• • If the hypercalcemia is related to malignancy, the cause may be obvious in most cases and efforts are directed towards treating the neoplasm.
  • The role of oral phosphates in the treatment of hypercalcemia is limited and now is 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.
  • Dietary restriction of calcium and glucocorticoid administration remains the preferred treatment for hypercalcemia due to sarcoidosis and vitamin D intoxication.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Hypercalcemia frequently is undiagnosed.
• • All cases of hypercalcemia should be investigated.
  • Hyperparathyroidism often coexists with other, more serious problems.
  • Any sudden change or rise in calcium levels should trigger consideration for a more serious condition.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Hypercalcemia. Vitamin D metabolism.
	View Full Size Image
Media type:  Graph

Media file 2:  Hypercalcemia. Investigations flowchart.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Allerheiligen DA, Schoeber J, Houston RE. Hyperparathyroidism. Am Fam Physician. Apr 15 1998;57(8):1795-802, 1807-8. [Medline].
• Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. May 1 2003;67(9):1959-66. [Medline].
• Falk S, Fallon M. ABC of palliative care. Emergencies. BMJ. Dec 6 1997;315(7121):1525-8. [Medline].
• Ganong CA, Kappy MS. Hypercalcemia. In: Berman S, ed. Pediatric Decision Making. 3rd ed. St. Louis, Mo: Mosby-Year Book; 1996:. 128-31.
• Hay WW Jr, Hayward AR, Levin MJ, Sondheimer JM, eds. Current Pediatric Diagnosis and Treatment. 14th ed. Stamford, Conn: Appleton & Lange; 1999:. 830-1.
• Hoenderop JG, Nilius B, Bindels RJ. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol. 2002;64:529-49. [Medline].
• Inzucchi SE. Management of hypercalcemia. Diagnostic workup, therapeutic options for hyperparathyroidism and other common causes. Postgrad Med. May 2004;115(5):27-36. [Medline].
• Lteif AN, Zimmerman D. Bisphosphonates for treatment of childhood hypercalcemia. Pediatrics. Oct 1998;102(4 Pt 1):990-3. [Medline].
• Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med. Aug 1997;103(2):134-45. [Medline].
• Pearce SH. Calcium homeostasis and disorders of the calcium-sensing receptor. J R Coll Physicians Lond. Jan-Feb 1998;32(1):10-4. [Medline].
• Postlethwaite RJ. Clinical Pediatric Nephrology. 2nd ed. New York, NY: Butterworth Heinemann; 1994.
• Renton P. Radiology of rickets, osteomalacia and hyperparathyroidism. Hosp Med. May 1998;59(5):399-403. [Medline].
• Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer. Oct 15 1997;80(8 Suppl):1652-60. [Medline].
• Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest. 1996;109(2):535-539. [Medline].
• Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. Jan 27 2005;352(4):373-9. [Medline].
• Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med. Jan 20 2000;342(3):177-85. [Medline].
• al Zahrani A, Levine MA. Primary hyperparathyroidism. Lancet. Apr 26 1997;349(9060):1233-8. [Medline].

Article Last Updated: Oct 6, 2006