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| {{Infobox_Disease |
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| Name = {{PAGENAME}} |
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| Image = Ca-TableImage.png |
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| Caption = [[Calcium]] |
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| DiseasesDB = 6196 |
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| ICD10 = {{ICD10|E|83|5|e|70}} |
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| ICD9 = {{ICD9|275.42}} |
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| ICDO = |
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| OMIM = |
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| MedlinePlus = 000365 |
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| eMedicineSubj = med |
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| eMedicineTopic = 1068 |
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| eMedicine_mult = {{eMedicine2|emerg|260}} {{eMedicine2|ped|1062}} |
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| MeshID = D006934 |
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| }}
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| {{SI}}
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| {{CMG}}
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| __NOTOC__ | | __NOTOC__ |
| '''Associate Editor-In-Chief:''' {{CZ}}
| | {{Hypercalcemia}} |
| | {{CMG}}; {{AE}}, {{Anmol}}, {{CZ}} |
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| {{Editor Join}} | | {{SK}} Increased calcium in serum, Increased calcium in blood |
| | '''For patient information click [[Hypercalcemia (patient information)|here]]''' |
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| '''Hypercalcaemia''' (in US English '''Hypercalcemia''') is an elevated [[calcium in biology|calcium]] level in the [[blood]]. (Normal range: 9-10.5 mg/dL or 2.2-2.6 mmol/L). It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a diagnosis should be undertaken if it persists. It can be due to excessive skeletal calcium release, increased intestinal calcium absorption, or decreased renal calcium excretion. | | {| class="infobox" style="float:right;" |
| * Calcium is the most abundant mineral in the the body
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| * 99% of the calcium in the body is stored in the bone
| | | [[File:Siren.gif|30px|link=Hypercalcemia resident survival guide]]|| <br> || <br> |
| * Calcium in the plasma is either ionized or protein-bound and readily available for use
| | | [[Hypercalcemia resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']] |
| * An increase in total plasma [[calcium]] concentration above 10.4 mg/dL signifies [[hypercalcemia]]
| | |} |
| * Serum concentration is regulated through [[parathyroid hormone]] (PTH), [[vitamin D]] and [[calcitonin]]
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| ==Causes== | | ==[[Hypercalcemia overview|Overview]]== |
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| ===Main causes=== | | ==[[Hypercalcemia historical perspective|Historical Perspective]]== |
| ''hyperparathyroidism and malignancy account for ~90% of cases''
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| * [[Drugs]]
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| * Exogenous [[vitamin D]]
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| * Humoral hypercalcemia of [[malignancy]]
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| * Immobilization
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| * Primary [[hyperparathyroidism]]
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| * [[Sarcoidosis]]
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| * Secondary [[hyperparathyroidism]]
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| ===Complete Differential Diagnosis of the Causes of Hypercalcemia=== | | ==[[Hypercalcemia classification|Classification]]== |
| (In alphabetical order)
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| * Abnormal [[parathyroid gland]] function
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| * [[Acromegaly]]
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| * [[Osteoporosis|Acute osteoporosis]]
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| * [[Acute renal failure]]
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| * [[Addison's disease]]
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| * [[Adrenal insufficiency]]
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| * After [[kidney transplant]]
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| * [[Aluminum]] intoxication
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| * [[Aspirin]] (in large amounts)
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| * Autonomous [[hyperparathyroidism]] (post long-term [[renal failure]])
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| * [[Bartter's Syndrome]]
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| * [[Berylliosis]]
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| * Bone [[fracture]]
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| * [[Breast cancer]]
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| * [[Bronchial carcinoma]]
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| * [[Carcinoma]]
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| * [[Chronic renal failure]]
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| * [[Coccidioidomycosis]]
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| * [[Cushing's syndrome]]
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| * [[Dehydration]]
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| * [[Drugs]]
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| * Familial hypocalcuric hypercalcemia
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| * Familial isolated [[hyperparathyroidism]] ({{OMIM|146200}})
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| * [[Gitelman syndrome]]
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| * Granulomatous diseases with [[tuberculosis]]
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| * [[Hematologic]] [[malignancy]] ([[multiple myeloma]], [[lymphoma]], [[leukemia]])
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| * [[Hepatocellular carcinoma]]
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| * [[Histoplasmosis]]
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| * [[Hodgkin's Lymphoma]]
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| * [[Hyperparathyroidism]] (in the preceding oliguric-anuric phase)
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| * [[Hyperthyroidism]]
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| * [[Hypervitaminosis D]] (vitamin D intoxication)
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| * [[Idiopathic]] hypercalcemia (in infants)
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| * Immobilization
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| * Isolated or multinodal adenoma
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| * [[Kidney cancer]]
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| * [[Leprosy]]
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| * [[Leukemia]]
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| * [[Lithium]]
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| * [[Lymphoma]]
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| * [[Malignancy]]
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| * [[Medullary sponge kidney]]
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| * [[Milk-alkali syndrome]]
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| * [[Multiple endocrine neoplasia]] (MEN)
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| * [[Multiple myeloma]]
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| * [[Oral candidiasis]]
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| * [[Osteomalacia]]
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| * [[Ovarian cancer]]
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| * [[Paget's disease]]
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| * [[Paraplegia]]
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| * Parathyroid [[carcinoma]] ({{ICD10|C|75|0|c|73}})
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| * [[Parathyroid]] hyperplasia
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| * [[Pheochromocytoma]]
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| * [[Plasma cell]] [[granuloma]]
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| * [[Polycythemia]]
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| * [[Primary hyperparathyroidism]]
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| * Primary Parathyroid [[hyperplasia]]
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| * Rebound hypercalcemia after [[rhabdomyolysis]]
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| * [[Renal failure]]
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| * [[Sarcoidosis]]
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| * Secretion of [[prostaglandin]]s
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| * Severe [[secondary hyperparathyroidism]]
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| * [[Silicone]]-induced [[granuloma]]
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| * [[Sjogren's syndrome]]
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| * Solid tumor with humoral mediation of hypercalcemia (e.g. [[lung cancer|lung]] or [[renal cell carcinoma|kidney cancer]], [[pheochromocytoma]])
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| * Solid tumor with metastasis (e.g. [[breast cancer]])
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| * Solitary parathyroid [[adenoma]]
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| * [[Thiazide]] [[diuretic]]s
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| * [[Total parenteral nutrition]]
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| * [[Tuberculosis]]
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| * [[Vasoactive intestinal polypeptide-producing tumor]] ([[VIPoma]])
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| * [[Vitamin A]] intoxication
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| * [[Vitamin D]] intoxication
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| * [[Vitamin D]] [[metabolic disorders]]
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| * [[William's syndrome]]
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| ===Complete Differential Diagnosis of the Causes of Hypercalcemia=== | | ==[[Hypercalcemia pathophysiology|Pathophysiology]]== |
| (By organ system)
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| {|style="width:80%; height:100px" border="1"
| | ==[[Hypercalcemia causes|Causes]]== |
| |style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
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| |style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Chemical / poisoning'''
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| |bgcolor="Beige"| [[Aluminum]] intoxication, [[Hypervitaminosis D]], [[Vitamin A]] intoxication, [[Vitamin D]] intoxication
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Dermatologic'''
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| |bgcolor="Beige"| [[Leprosy]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Drug Side Effect'''
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| |bgcolor="Beige"| [[Lithium]], [[Thiazide]] [[diuretic]]s
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Ear Nose Throat'''
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| |bgcolor="Beige"| [[Oral candidiasis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Endocrine'''
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| |bgcolor="Beige"| Abnormal [[parathyroid gland]] function, [[Acromegaly]], [[Osteoporosis|Acute osteoporosis]], [[Addison's Disease]], [[Adrenal insufficiency]], Autonomous [[hyperparathyroidism]] (post long-term [[renal failure]]), [[Bartter's Syndrome]], [[Cushing's syndrome]], Familial isolated [[hyperparathyroidism]], [[Hyperparathyroidism]] (in the preceding oliguric-anuric phase), [[Hyperthyroidism]], Isolated or multinodal [[adenoma]], [[Multiple endocrine neoplasia]] (MEN), Parathyroid [[carcinoma]], [[Parathyroid]] hyperplasia, [[Pheochromocytoma]], [[Primary hyperparathyroidism]], Primary Parathyroid [[hyperplasia]], Secretion of [[prostaglandin]]s, Severe [[secondary hyperparathyroidism]], Solitary parathyroid [[adenoma]], [[Vasoactive intestinal polypeptide-producing tumor]] ([[VIPoma]])
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| |-bgcolor="LightSteelBlue"
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| | '''Environmental'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Gastroenterologic'''
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| |bgcolor="Beige"| [[Hepatocellular carcinoma]], [[Hypervitaminosis D]], [[Oral candidiasis]], [[Total parenteral nutrition]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Genetic'''
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| |bgcolor="Beige"| Familial hypocalcuric hypercalcemia, Familial isolated [[hyperparathyroidism]], [[Gitelman syndrome]], [[William's syndrome]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Hematologic'''
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| |bgcolor="Beige"|[[Hodgkin's lymphoma]], [[Leukemia]], [[Lymphoma]], [[Multiple myeloma]], [[Plasma cell]] [[granuloma]], [[Polycythemia]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Iatrogenic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Infectious Disease'''
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| |bgcolor="Beige"| [[Coccidioidomycosis]], [[Leprosy]], [[Oral candidiasis]]
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| |-bgcolor="LightSteelBlue"
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| | '''Musculoskeletal / Ortho'''
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| |bgcolor="Beige"| [[Osteoporosis|Acute osteoporosis]], Bone [[fracture]], [[Paget's Disease]], Rebound hypercalcemia after [[rhabdomyolysis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Neurologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Nutritional / Metabolic'''
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| |bgcolor="Beige"| [[Dehydration]], [[Milk-alkali syndrome]], [[Osteomalacia]], [[Total parenteral nutrition]], [[Vitamin A]] intoxication, [[Vitamin D]] intoxication, [[Vitamin D]] [[metabolic disorders]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Obstetric/Gynecologic'''
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| |bgcolor="Beige"| [[Breast cancer]], [[Ovarian cancer]], [[Paget's Disease]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Oncologic'''
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| |bgcolor="Beige"| [[Breast cancer]], [[Bronchial carcinoma]], [[Carcinoma]], [[Hematologic]] [[malignancy]] ([[multiple myeloma]], [[lymphoma]], [[leukemia]]), [[Hepatocellular carcinoma]], [[Hodgkin's lymphoma]], Isolated or multinodal [[adenoma]], [[Kidney cancer]], [[Leukemia]], [[Lymphoma]], [[Malignancy]], [[Multiple endocrine neoplasia]] (MEN), [[Multiple Myeloma]], [[Ovarian cancer]], [[Paget's Disease]], Parathyroid [[carcinoma]], [[Pheochromocytoma]], [[Plasma cell]] [[granuloma]], [[Silicone]]-Induced [[granuloma]], Solid tumor with humoral mediation of hypercalcemia (e.g. [[lung cancer|lung]] or [[renal cell carcinoma|kidney cancer]], [[pheochromocytoma]]), Solid tumor with metastasis (e.g. [[breast cancer]]), Solitary parathyroid [[adenoma]], [[Vasoactive intestinal polypeptide-producing tumor]] ([[VIPoma]])
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Opthalmologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Overdose / Toxicity''' | |
| |bgcolor="Beige"| , [[Aluminum]] intoxication, [[Aspirin]] (in large amounts), [[Drugs]], [[Hypervitaminosis D]], [[Vitamin A]] intoxication, [[Vitamin D]] intoxication
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Psychiatric'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Pulmonary'''
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| |bgcolor="Beige"| [[Berylliosis]], [[Bronchial carcinoma]], Granulomatous diseases with [[tuberculosis]], [[Histoplasmosis]], [[Sarcoidosis]], [[Tuberculosis]], [[Tuberculosis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Renal / Electrolyte'''
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| |bgcolor="Beige"| [[Acute renal failure]], After [[kidney transplant]], [[Bartter's Syndrome]], [[Chronic renal failure]], Familial hypocalcuric hypercalcemia, [[Kidney cancer]], [[Medullary sponge kidney]], [[Milk-alkali syndrome]], Rebound hypercalcemia after [[rhabdomyolysis]], [[Renal failure]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Rheum / Immune / Allergy'''
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| |bgcolor="Beige"| [[Osteoporosis|Acute osteoporosis]], [[Sarcoidosis]], [[Sjogren's syndrome]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Sexual'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Trauma'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Urologic'''
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| |bgcolor="Beige"| [[Acute renal failure]], [[Chronic renal failure]], [[Milk-alkali syndrome]], [[Renal failure]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Miscellaneous'''
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| |bgcolor="Beige"| [[Idiopathic]] hypercalcemia (in infants), Immobilization, [[Paraplegia]]
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| |-
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| |}
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| ==Diagnosis== | | ==[[Hypercalcemia differential diagnosis|Differentiating Hypercalcemia from other Diseases]]== |
| ===Signs and symptoms===
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| Hypercalcemia ''per se'' can result in [[Fatigue (physical)|fatigue]], [[clinical depression|depression]], [[confusion]], [[anorexia (symptom)|anorexia]], [[nausea]], [[vomiting]], [[constipation]], [[pancreatitis]] or [[polyuria|increased urination]] "Bones, stones, groans, and psychic moans" is a saying which will help you remember the signs and symptoms of hypercalcemia; if it is chronic it can result in urinary calculi ([[kidney stones|renal stones]] or bladder stones). Abnormal [[cardiac arrhythmia|heart rhythms]] can result, and [[EKG]] findings of a short [[QT interval]] and a widened T wave suggest hypercalcemia.
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| Symptoms are more common at high calcium [[blood values]] (12.0 mg/dL or 3 mmol/l). Severe hypercalcemia (above 15-16 mg/dL or 3.75-4 mmol/l) is considered a [[medical emergency]]: at these levels, [[coma]] and [[cardiac arrest]] can result.
| | ==[[Hypercalcemia epidemiology and demographics|Epidemiology and Demographics]]== |
| ==== Complete List of Possible Symptoms ==== | |
| * Renal stones
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| * [[Ddx:Headache|Headaches]]
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| * [[Ddx:Bone Pain|Bone pain and/or weakness]]
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| * Abdominal pain
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| * [[Ddx:Confusion|Confusion]]
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| * [[Ddx:Nausea and Vomiting|Nausea/vomiting]]
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| * [[Constipation]]
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| * Peptic ulcer disease
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| * Hallucinations
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| * [[Ddx:Bradycardia|Bradycardia]]
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| * Insulin resistance
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| * Glucose intolerance
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| * Muscle weakness
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| * [[Hyporeflexia]]
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| * [[Polyuria]]
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| * Shortened QT interval
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| * [[Pancreatitis]]
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| * Psychosis
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| * Depression
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| * [[Anxiety]]
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| == Physical Examination ==
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| * Evaluate for increased urination and/or renal stones
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| * Mental status changes
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| * Confusion
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| * Tiredness
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| * Hyporeflexia
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| * Arrhythmias
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| * Coma
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| == Laboratory Findings == | | ==[[Hypercalcemia risk factors|Risk Factors]]== |
| * Complete blood count (CBC)
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| * Serum and urinary calcium
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| * Blood urea nitrogen (BUN)/creatinine
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| * Parathyroid hormone (PTH)
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| * PTH-related peptide
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| * Albumin
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| * Phosphate
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| * Alkaline phosphatase
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| * Vitamin D
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| * Magnesium
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| ===Electrocardiographic Findings===
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| # A shortening of the [[QTc]] interval
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| # The decrease is at the expense of the [[ST segment]] which becomes shortened or absent.
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| # This is true for Ca of up to 16 meq/li, after this [[QTc]] prolongation occurs
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| [[image:Ganseman.Hypercalcemia.jpg|center|400px|thumb|12 lead EKG:Hypercalcemia. [http://www.ganseman.com/ecgbibnl.htm#_top000 Courtesy of Dr Jose Ganseman]]]
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| ==Treatment== | | ==[[Hypercalcemia screening|Screening]]== |
| The goal of therapy is to treat the hypercalcemia first and subsequently effort is directed to treat the underlying cause.
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| ===Initial therapy: fluids and diuretics=== | | ==[[Hypercalcemia_natural_history,_complications_and_prognosis|Natural History, Complications, and Prognosis]]== |
| *hydration, increasing salt intake, and [[forced diuresis]].
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| **hydration is needed because many patients are dehydrated due to vomiting or renal defects in concentrating urine.
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| **increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion (In other words, calcium and sodium (salt) are handled in a similar way by the kidney. Anything that causes increased sodium (salt) excretion by the kidney will, ''en passant'', cause increased calcium excretion by the kidney)
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| **after rehydration, a [[loop diuretic]] such as [[furosemide]] can be given to permit continued large volume intravenous salt and water replacement while minimizing the risk of blood volume overload and thence [[pulmonary edema]]. In addition, [[loop diuretics]] tend to depress renal calcium reabsorption thereby helping to lower blood calcium levels
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| **can usually decrease serum calcium by 1-3 mg/dL within 24 h
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| **caution must be taken to prevent potassium or magnesium depletion
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| ===Additional therapy: bisphosphonates and calcitonin=== | | ==Diagnosis== |
| *[[bisphosphonates]] are [[pyrophosphate]] analogues with high affinity for bone, especially areas of high bone-turnover.
| | [[Hypercalcemia diagnostic study of choice|Diagnostic Study of Choice]] | [[Hypercalcemia history and symptoms|History and Symptoms]] | [[Hypercalcemia physical examination|Physical Examination]] | [[Hypercalcemia laboratory findings|Laboratory Findings]] | [[Hypercalcemia electrocardiogram|Electrocardiogram]] | [[Hypercalcemia x ray|X Ray]] | [[Hypercalcemia CT|CT]] | [[Hypercalcemia MRI|MRI]] | [[Hypercalcemia echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Hypercalcemia other imaging findings|Other Imaging Findings]] | [[Hypercalcemia other diagnostic studies|Other Diagnostic Studies]] |
| **they are taken up by [[osteoclast]]s and inhibit osteoclastic bone resorption
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| **current available drugs include (in order of potency): (1st gen) [[etidronate]], (2nd gen) [[tiludronate]], IV [[pamidronate]], [[alendronate]], [[risedronate]], and (3rd gen) zolendronate
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| **all patients with cancer-associated hypercalcemia should receive treatment with [[bisphosphonates]] since the 'first line' therapy (above) cannot be continued indefinitely nor is it without risk. Further, even if the 'first line' therapy has been effective, it is a virtual certainty that the hypercalcemia will recur in the patient with hypercalcemia of malignancy. Use of bisphoponates in such circumstances, then, becomes both therapeutic and preventative
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| **patients in [[renal failure]] and [[hypercalcemia]] should have a risk-benefit analysis before being given [[bisphosphonates]], since they are relatively contraindicated in [[renal failure]].
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| *[[Calcitonin]] blocks bone resorption and also increases urinary calcium excretion by inhibiting renal calcium reabsorption
| | ==Treatment== |
| **Usually used in life-threatening hypercalcemia along with rehydration, diuresis, and bisphosphonates
| | [[Hypercalcemia medical therapy|Medical Therapy]] | [[Hypercalcemia surgery|Surgery]] | [[Hypercalcemia primary prevention|Primary Prevention]] | [[Hypercalcemia secondary prevention|Secondary Prevention]] | [[Hypercalcemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hypercalcemia future or investigational therapies|Future or Investigational Therapies]] |
| **Helps prevent recurrence of hypercalcemia
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| **Dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely
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| ===Other therapies=== | | ==Case Studies== |
| *rarely used, or used in special circumstances
| | [[Hypercalcemia case study one|Case #1]] |
| **[[plicamycin]] inhibits bone resorption (rarely used)
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| **[[gallium]] [[nitrate]] inhibits bone resorption and changes structure of bone crystals (rarely used)
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| **[[glucocorticoids]] increase urinary calcium excretion and decrease intestinal calcium absorption
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| ***no effect in calcium level in normal or 1' hyperparathyroidism
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| ***effective in hypercalcemia due to osteolytic malignancies ([[multiple myeloma]], [[leukemia]], [[Hodgkin's lymphoma]], [[breast cancer|carcinoma of the breast]]) due to antitumor properties
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| ***also effective in [[hypervitaminosis D]] and [[sarcoidosis]]
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| **[[dialysis]] usually used in severe hypercalcemia complicated by [[renal failure]]. Supplemental phosphate should be monitored and added if necessary
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| **[[phosphate]] therapy can correct the hypophosphatemia in the face of hypercalcemia and lower serum calcium
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| ==See also== | | ==See also== |
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| *[[Disorders of calcium metabolism]] | | *[[Disorders of calcium metabolism]] |
| *[[ATC code V03#V03AG Drugs for treatment of hypercalcemia]] | | *[[ATC code V03#V03AG Drugs for treatment of hypercalcemia]] |
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| | ==References== |
| | {{reflist|2}} |
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| {{Endocrine, nutritional and metabolic pathology}} | | {{Endocrine, nutritional and metabolic pathology}} |
| {{Electrocardiography}} | | {{Electrocardiography}} |
| {{SIB}}
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| [[Category:Electrolyte disturbances]] | | [[Category:Disease]] |
| [[Category:Calcium]]
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| [[Category:Diseases]]
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| [[Category:Emergency medicine]] | | [[Category:Emergency medicine]] |
| [[Category:Kidney diseases]]
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| [[Category:Blood tests]]
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| [[Category:Cardiology]] | | [[Category:Cardiology]] |
| [[Category:Intensive care medicine]] | | [[Category:Endocrinology]] |
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| [[de:Hyperkalzämie]] | | [[de:Hyperkalzämie]] |
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| [[sv:Hyperkalcemi]] | | [[sv:Hyperkalcemi]] |
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