Editing Hypercalcaemia

{{Short description|High calcium (Ca2+) level in the blood serum}}
{{cs1 config|name-list-style=vanc}}
{{For|the disorder of low blood calcium|Hypocalcemia}}
{{Use British English|date=January 2021}}
{{Infobox medical condition (new)
| name            = Hypercalcemia
| synonyms        = Hypercalcaemia
| image           = Ca-TableImage.svg
| caption         = Calcium within the [[periodic table]]
| field           = [[Endocrinology]]
| symptoms        = [[Abdominal pain]], bone pain, [[confusion]], [[Depression (mood)|depression]], [[weakness]]<ref name=BMJ2015/><ref name=EU2010/>
| complications   = [[Kidney stones]], [[Heart arrhythmia|abnormal heart rhythm]], [[cardiac arrest]]<ref name=BMJ2015/><ref name=EU2010/>
| onset           =
| duration        =
| types           =
| causes          = [[Primary hyperparathyroidism]], [[cancer]], [[sarcoidosis]], [[tuberculosis]], [[Paget's disease of bone|Paget disease]], [[multiple endocrine neoplasia]], [[vitamin D toxicity]]<ref name=BMJ2015/><ref name=PMH2016/>
| risks           =
| diagnosis       = [[Blood serum]] level > 2.6&nbsp;mmol/L ([[corrected calcium]] or [[ionized calcium]])<ref name=BMJ2015/><ref name=EU2010/>
| differential    =
| prevention      =
| treatment       = Underlying cause, [[intravenous fluids]], [[furosemide]], [[calcitonin]], [[pamidronate]], [[hemodialysis]]<ref name=BMJ2015/><ref name=EU2010/>
| medication      = See article
| prognosis       =
| frequency       = 4 per 1,000<ref name=BMJ2015/>
| deaths          =
}}
<!-- Definition and symptoms -->
'''Hypercalcemia''', also spelled '''hypercalcaemia''', is a high [[calcium]] (Ca<sup>2+</sup>) level in the [[blood serum]].<ref name=BMJ2015/><ref name=PMH2016>{{cite web|title=Hypercalcemia - National Library of Medicine|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024710/|website=PubMed Health|access-date=27 September 2016|url-status=live|archive-url=https://web.archive.org/web/20170908183336/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024710/|archive-date=8 September 2017}}</ref> The normal range for total calcium is 2.1–2.6&nbsp;[[mmol/L]] (8.8–10.7&nbsp;mg/dL, 4.3–5.2 [[mEq/L]]), with levels greater than 2.6&nbsp;mmol/L defined as hypercalcemia.<ref name=BMJ2015/><ref name=EU2010/><ref name=SI2005>{{cite book |doi=10.1002/047009057X.app01 |chapter=Appendix 1: Conversion of SI Units to Standard Units |title=Principles and Practice of Geriatric Medicine |volume=2 |pages=i–ii |no-pp=yes |year=2005 |isbn=978-0-470-09057-2 }}</ref> Those with a mild increase that has developed slowly typically have no symptoms.<ref name=BMJ2015/> In those with greater levels or rapid onset, symptoms may include [[abdominal pain]], bone pain, [[confusion]], [[Depression (mood)|depression]], [[weakness]], [[kidney stones]] or an [[Heart arrhythmia|abnormal heart rhythm]] including [[cardiac arrest]].<ref name=BMJ2015/><ref name=EU2010/>

<!-- Cause and diagnosis -->
Most outpatient cases are due to [[primary hyperparathyroidism]] and inpatient cases due to [[cancer]].<ref name="BMJ2015" /> Other causes of hypercalcemia include [[sarcoidosis]], [[tuberculosis]], [[Paget's disease of bone|Paget disease]], [[multiple endocrine neoplasia]] (MEN), [[vitamin D toxicity]], [[familial hypocalciuric hypercalcaemia]] and certain [[medications]] such as [[Lithium (medication)|lithium]] and [[hydrochlorothiazide]].<ref name="BMJ2015" /><ref name="EU2010">{{cite journal |doi=10.1016/j.resuscitation.2010.08.015 |pmid=20956045 |title=European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution |journal=Resuscitation |volume=81 |issue=10 |pages=1400–33 |year=2010 |last1=Soar |first1=Jasmeet |last2=Perkins |first2=Gavin D |last3=Abbas |first3=Gamal |last4=Alfonzo |first4=Annette |last5=Barelli |first5=Alessandro |last6=Bierens |first6=Joost J.L.M |last7=Brugger |first7=Hermann |last8=Deakin |first8=Charles D |last9=Dunning |first9=Joel |last10=Georgiou |first10=Marios |last11=Handley |first11=Anthony J |last12=Lockey |first12=David J |last13=Paal |first13=Peter |last14=Sandroni |first14=Claudio |last15=Thies |first15=Karl-Christian |last16=Zideman |first16=David A |last17=Nolan |first17=Jerry P }}</ref><ref name="PMH2016" /> Diagnosis should generally include either a [[corrected calcium]] or [[ionized calcium]] level and be confirmed after a week.<ref name=BMJ2015>{{cite journal |doi=10.1136/bmj.h2723 |pmid=26037642 |title=The diagnosis and management of hypercalcaemia |journal=BMJ |volume=350 |pages=h2723 |year=2015 |last1=Minisola |first1=S |last2=Pepe |first2=J |last3=Piemonte |first3=S |last4=Cipriani |first4=C |s2cid=28462200 }}</ref> Specific changes, such as a shortened [[QT interval]] and prolonged [[PR interval]], may be seen on an [[electrocardiogram]] (ECG).<ref name=EU2010/>

<!-- Treatment and epidemiology -->
Treatment may include [[intravenous fluids]], [[furosemide]], [[calcitonin]], intravenous bisphosphonate, in addition to treating the underlying cause.<ref name=BMJ2015/><ref name=EU2010/> The evidence for furosemide use, however, is poor.<ref name=BMJ2015/> In those with very high levels, hospitalization may be required.<ref name=BMJ2015/> [[Haemodialysis]] may be used in those who do not respond to other treatments.<ref name=BMJ2015/> In those with vitamin D toxicity, [[steroids]] may be useful.<ref name=BMJ2015/> Hypercalcemia is relatively common.<ref name=BMJ2015/> Primary hyperparathyroidism occurs in 1–7 per 1,000 people, and hypercalcaemia occurs in about 2.7% of those with cancer.<ref name=BMJ2015/>

==Signs and symptoms==
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|+ Mnemonic for symptoms
|-
| Stones || [[Nephrolithiasis|Kidney]] or biliary
|-
| Bones || Bone pain
|-
| Groans || Abdominal discomfort
|-
| Moans || Complaints of [[non-specific symptoms]]
|-
| [[toilet|Thrones]] || [[Constipation]] and [[polyuria|excessive urination volume]]
|-
| Muscle tone || Muscle weakness, decreased reflexes
|-
| Psychiatric overtones  || [[Depression (mood)|Depression]], [[anxiety]], cognitive dysfunction
|}

The neuromuscular symptoms of hypercalcaemia are caused by a negative [[bathmotropic]] effect due to the increased interaction of calcium with [[sodium channel]]s. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, increased calcium raises the threshold for depolarization.<ref name=CMArmstrong1999>{{cite journal |doi=10.1073/pnas.96.7.4154 |pmid=10097179 |pmc=22436 |title=Calcium block of Na+ channels and its effect on closing rate |journal=Proceedings of the National Academy of Sciences |volume=96 |issue=7 |pages=4154–7 |year=1999 |last1=Armstrong |first1=C. M |last2=Cota |first2=G |bibcode=1999PNAS...96.4154A |doi-access=free }}</ref> This results in decreased [[deep tendon reflexes]] ([[hyporeflexia]]), and skeletal [[muscle weakness]].<ref name=Merck2017>{{cite web |url= http://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/electrolyte-disorders/hypercalcemia |title= Hypercalcemia |publisher= Merck Manual |access-date= June 10, 2017 |url-status= live |archive-url= https://web.archive.org/web/20170713041445/https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/electrolyte-disorders/hypercalcemia |archive-date= July 13, 2017 }}</ref>

Other symptoms include [[cardiac arrhythmias]] (especially in those taking [[digoxin]]), [[fatigue (physical)|fatigue]], [[nausea]], [[vomiting]] (emesis), [[loss of appetite]], abdominal pain, & paralytic [[ileus]]. If [[kidney impairment]] occurs as a result, manifestations can include [[polyuria|increased urination]], [[nocturia|urination at night]], and [[polydipsia|increased thirst]].<ref name=Merck2017/> Psychiatric manifestation can include emotional instability, [[confusion]], [[delirium]], [[psychosis]], and [[stupor]].<ref name=Merck2017/> Calcium deposits known as [[limbus sign]] may be visible in the eyes.<ref>Orient, Dr. Jane M. (2011). [https://www.amazon.com/gp/product/B0052TGRBK/ Amazon Sapira's Art & Science of Bedside Diagnosis (Kindle Edition)] Lippincott Williams & Wilkins. Retrieved January 7, 2012.</ref>

Symptoms are more common at high calcium [[blood values]] (12.0&nbsp;mg/dL or 3&nbsp;mmol/L).<ref name=Merck2017/> Severe hypercalcaemia (above 15–16&nbsp;mg/dL or 3.75–4&nbsp;mmol/L) is considered a [[medical emergency]]: at these levels, [[coma]] and [[cardiac arrest]] can result. The high levels of calcium ions decrease the neuron membrane permeability to sodium ions, thus decreasing excitability, which leads to [[hypotonicity]] of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups. The sluggish nerves also explain [[drowsiness]], confusion, hallucinations, [[stupor]] or coma. In the gut this causes [[constipation]]. Hypocalcaemia causes the opposite by the same mechanism.<ref>{{cite web |url=https://www.lecturio.com/concepts/hypercalcemia/| title=Hypercalcemia|website=The Lecturio Medical Concept Library |access-date= 25 July 2021}}</ref>

===Hypercalcaemic crisis {{anchor|crisis}}===
A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14&nbsp;mg/dL (or 3.5&nbsp;mmol/L).<ref>[http://emedicine.medscape.com/article/766373-overview Hypercalcemia in Emergency Medicine] {{webarchive|url=https://web.archive.org/web/20110425092016/http://emedicine.medscape.com/article/766373-overview |date=2011-04-25 }} at Medscape. Author: Robin R Hemphill. Chief Editor: Erik D Schraga. Retrieved April 2011</ref>

The main symptoms of a hypercalcaemic crisis are [[oliguria]] or [[anuria]], as well as [[somnolence]] or [[coma]].<ref name=Ziegler2001>{{cite journal |author=Ziegler R |title=Hypercalcemic crisis |journal=J. Am. Soc. Nephrol. |volume=12 |pages=S3–9 |date=February 2001 |issue=Suppl 17 |doi=10.1681/ASN.V12suppl_1s3 |pmid=11251025 |doi-access=free }}</ref> After recognition, primary [[hyperparathyroidism]] should be proved or excluded.<ref name=Ziegler2001/>

In extreme cases of primary hyperparathyroidism, removal of the [[parathyroid gland]] after surgical neck exploration is the only way to avoid death.<ref name=Ziegler2001/> The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium.<ref name=Ziegler2001/> Treatment of choice for acutely lowering calcium is extensive hydration and [[calcitonin]], as well as [[bisphosphonate]]s (which have effect on calcium levels after one or two days).<ref>[https://books.google.com/books?id=LngD6RFXY_AC&pg=PA394 Page 394] {{webarchive|url=https://web.archive.org/web/20170908183336/https://books.google.com/books?id=LngD6RFXY_AC&pg=PA394 |date=2017-09-08 }} in: {{cite book |author1=Roenn, Jamie H. Von |author2=Ann Berger |author3=Shuster, John W. |title=Principles and practice of palliative care and supportive oncology |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |isbn=978-0-7817-9595-1 }}</ref>

==Causes==
[[Primary hyperparathyroidism]] and malignancy account for about 90% of cases of hypercalcaemia.<ref name=Kumar>Table 20-4 in: {{cite book |author1=Mitchell, Richard Sheppard |author2=Kumar, Vinay |author3=Abbas, Abul K. |author4=Fausto, Nelson |title=Robbins Basic Pathology|publisher=Saunders |location=Philadelphia |isbn=978-1-4160-2973-1 |edition=8th |year=2007 }}{{page needed|date=June 2018}}</ref><ref name="isbn0-07-147247-9">{{cite book |author1=Tierney, Lawrence M. |author2=McPhee, Stephen J. |author3=Papadakis, Maxine A. |title=Current Medical Diagnosis and Treatment 2007 (Current Medical Diagnosis and Treatment) |publisher=McGraw-Hill Professional |year=2006 |page=[https://archive.org/details/currentmedicaldi0046unse/page/901 901] |isbn=978-0-07-147247-0 |url=https://archive.org/details/currentmedicaldi0046unse/page/901 }}</ref>

Causes of hypercalcemia can be divided into those that are PTH dependent or PTH independent.

===Parathyroid function===
* Primary hyperparathyroidism
** [[Solitary parathyroid adenoma]]<ref>{{cite journal |vauthors=Sekine O, Hozumi Y, Takemoto N, Kiyozaki H, Yamada S, Konishi F |title=Parathyroid adenoma without hyperparathyroidism |journal=Japanese Journal of Clinical Oncology |volume=34 |issue=3 |pages=155–8 |date=March 2004  |pmid=15078912 |doi=10.1093/jjco/hyh028|doi-access=free }}</ref>
** Primary parathyroid hyperplasia<ref name="Ranaghan 2018">{{Cite journal |last1=Renaghan |first1=Amanda DeMauro |last2=Rosner |first2=Mitchell H |date=2018-04-01 |title=Hypercalcemia: etiology and management |url=https://academic.oup.com/ndt/article/33/4/549/4958946 |journal=Nephrology Dialysis Transplantation |language=en |volume=33 |issue=4 |pages=549–551 |doi=10.1093/ndt/gfy054 |issn=0931-0509|doi-access=free }}</ref>
** [[Parathyroid carcinoma]]<ref>Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. [http://www.cancernetwork.com/cancer-management-11/chapter05/article/10165/1402668 "Thyroid and Parathyroid Cancers"] {{Webarchive|url=https://web.archive.org/web/20100228072652/http://www.cancernetwork.com/cancer-management-11/chapter05/article/10165/1402668 |date=2010-02-28 }} in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) [http://www.cancernetwork.com/cancer-management-11/ Cancer Management: A Multidisciplinary Approach] {{Webarchive|url=https://web.archive.org/web/20131004224102/http://www.cancernetwork.com/cancer-management-11/ |date=2013-10-04 }}. 11 ed. 2008.</ref>
** [[Multiple endocrine neoplasia]] (MEN1 & MEN2A)<ref>{{cite web |url= https://www.lecturio.com/concepts/multiple-endocrine-neoplasia/| title= Multiple Endocrine Neoplasia
|website=The Lecturio Medical Concept Library |access-date= 11 August 2021}}</ref>
** [[Familial isolated hyperparathyroidism]]<ref>{{OMIM|146200}}</ref>
* [[Lithium (medication)|Lithium]] use
* [[Familial hypocalciuric hypercalcemia]]/familial benign hypercalcemia<ref>{{OMIM|145980}}</ref><ref>{{OMIM|145981}}</ref><ref>{{OMIM|600740}}</ref>

===Cancer===
Hypercalcemia of malignancy (cancer) is due to a variety of mechanisms. The two most common are humoral hypercalcemia of malignancy and local osteolytic hypercalcemia due to bony metastasis. Humoral hypercalcemia of malignancy involves the tumor releasing a hormone which increases calcium mobilization (most commonly [[parathyroid hormone-related protein]] (PTHrP)) into the circulation.<ref name="Guise 2022">{{cite journal |last1=Guise |first1=Theresa A. |last2=Wysolmerski |first2=John J. |title=Cancer-Associated Hypercalcemia |journal=New England Journal of Medicine |date=14 April 2022 |volume=386 |issue=15 |pages=1443–1451 |doi=10.1056/NEJMcp2113128|pmid=35417639 |s2cid=248155661 }}</ref> PTHrP acts similarly to [[parathyroid hormone]] in that it binds to the [[parathyroid hormone 1 receptor]]s on the kidneys and bones and causes an increased [[renal tubule|tubular]] reabsorption of calcium and activation of [[osteoclast]] activity, respectively.<ref name="Guise 2022" /> Osteoclasts are a type of bone cell which cause bone resorption, releasing calcium into the bloodstream. PTHrP also acts by activating [[rank ligand]] and inhibiting [[osteoprotegerin]] which activates [[nuclear factor kappa B]], which causes further activation of osteoclast activity.<ref name="Guise 2022" /> The combination of PTHrP driven osteoclast activation and calcium reabsorption by the kidneys causes hypercalcemia associated with malignancy (humoral type).<ref name="Guise 2022" />

Another mechanism in which cancer causes hypercalcemia is via local osteolysis due to [[metastasis]] to bone.<ref name="Guise 2022" /> Tumor bone metastasis releases local cytokines including [[interleukin-6|IL-6]], [[interleukin-8|IL-8]], [[interleukin-11|IL-11]], [[interleukin-1 beta]], [[TNF alpha]] and [[macrophage inflammatory protein]]. These cytokines activate osteoclasts and inhibit [[osteoblasts]] (the cell type responsible for laying down new bone) via the [[rank ligand]] pathway leading to bone resorption and calcium release into the bloodstream.<ref name="Guise 2022" /> The massive release of calcium from bone metastasis and osteoclast activation usually overwhelms the kidney's ability to secrete calcium, thus leading to hypercalcemia.<ref name="Guise 2022" />

Hypercalcemia of malignancy may also occur due to tumor production of [[vitamin D]] or [[parathyroid hormone]]. These causes are rare and constitute about 1% of all causes of hypercalcemia of malignancy.<ref name="Guise 2022" />

Hypercalcemia of malignancy usually portends a poor prognosis, and the medial survival is 25–52 days of its development.<ref name="Guise 2022" /> It has an incidence of 30% in those with cancer, and the prevalence is estimated to be about 2-3% in the United States.<ref name="Guise 2022" />

[[Image:Small cell carcinoma of the ovary hypercalcemic type - high mag.jpg|thumb|right|[[Micrograph]] of ovarian small cell carcinoma of the hypercalcemic type. [[H&E stain]].]]

Common cancer types that are associated with hypercalcemia of malignancy include:
* Solid tumor with metastasis via local osteolytic hypercalcemia: which can be due to any tumor that metastasizes to the bone. But common causes include [[breast cancer]], [[lung cancer]], [[kidney cancer]], and [[myeloma]] or [[lymphoma]] of the bone<ref name="Guise 2022" />
* Solid tumor with humoral mediation of hypercalcemia: [[lung cancer]] (especially squamous cell tumors, a type of [[non-small cell lung cancer]]), [[squamous cell cancer]]s of the head and neck, [[renal cell carcinoma|kidney cancer]] or other [[urothelial cancer]]s, and breast cancer.<ref name="Guise 2022" />
* [[hematology|Hematologic]] [[malignancy|cancers]]: including [[multiple myeloma]], [[lymphoma]], [[leukemia]]
* Ovarian small cell carcinoma of the hypercalcemic type

===Vitamin-D disorders===
* [[Hypervitaminosis D]] (vitamin D intoxication)
* Elevated [[1,25(OH)2D|1,25(OH)<sub>2</sub>D]] (see calcitriol under [[Vitamin D]]) levels (e.g., [[sarcoidosis]] and other granulomatous diseases such as [[tuberculosis]], [[berylliosis]], [[histoplasmosis]], [[Crohn's disease]], and [[granulomatosis with polyangiitis]])
* [[Idiopathic hypercalcaemia of infancy]]<ref>{{OMIM|143880}}</ref>
* Rebound hypercalcaemia after [[rhabdomyolysis]]

===High bone-turnover===
* [[Hyperthyroidism]]
* [[Multiple myeloma]]
* Prolonged immobilization
* [[Paget's disease of bone|Paget's disease]]
* [[Thiazide]] use
* [[Vitamin A]] intoxication<ref name="Ranaghan 2018"/>

===Kidney failure===
* [[Tertiary hyperparathyroidism]]
* [[Aluminium]] intoxication
* [[Milk-alkali syndrome]]<ref name="Ranaghan 2018"/>

===Other===
* [[Acromegaly]]
* [[Adrenal insufficiency]]
* [[Zollinger–Ellison syndrome]]
* [[Williams Syndrome]]
* Excessive calcium consumption

==Diagnosis==
Diagnosis should generally include either a calculation of [[corrected calcium]] or direct measurement of [[ionized calcium]] level and be confirmed after a week.<ref name=BMJ2015/> This is because either high or low serum [[albumin]] levels does not show the true levels of ionised calcium.<ref name="Ranaghan 2018"/> There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium.<ref>{{cite book |last1=Thomas |first1=Lynn K. |last2=Othersen |first2=Jennifer Bohnstadt |title=Nutrition Therapy for Chronic Kidney Disease |date=2016 |publisher=CRC Press |isbn=978-1-4398-4950-7 |page=116 |url=https://books.google.com/books?id=o3bRBQAAQBAJ&pg=PA116 |language=en}}</ref>

Once calcium is confirmed to be elevated, a detailed history taken from the subject, including review of medications, any vitamin supplementations, herbal preparations, and previous calcium values. Chronic elevation of calcium with absent or mild symptoms often points to primary hyperparathyroidism or [[Familial hypocalciuric hypercalcemia]]. For those who has underlying malignancy, the cancers may be sufficiently severe to show up in history and examination to point towards the diagnosis with little laboratory investigations.<ref name="Ranaghan 2018"/>

If detailed history and examination does not narrow down the differential diagnoses, further laboratory investigations are performed. Intact PTH (iPTH, biologically active [[parathyroid hormone]] molecules) is measured with immunoradiometric or immunochemoluminescent assay. Elevated (or high-normal) iPTH with high urine calcium/creatinine ratio (more than 0.03) is suggestive of primary hyperparathyroidism, usually accompanied by low serum phosphate. High iPTH with low urine calcium/creatinine ratio is suggestive of familial hypocalciuric hypercalcemia. Low iPTH should be followed up with [[Parathyroid hormone-related protein]] (PTHrP) measurements (though not available in all labs). Elevated PTHrP is suggestive of malignancy. Normal PTHrP is suggestive of multiple myeloma, vitamin A excess, milk-alkali syndrome, thyrotoxicosis, and immobilisation. Elevated [[Calcitriol]] is suggestive of lymphoma, sarcoidosis, granulomatous disorders, and excessive calcitriol intake. Elevated [[calcifediol]] is suggestive of vitamin D or excessive calcifediol intake.<ref name="Ranaghan 2018"/>

The normal range is 2.1–2.6&nbsp;[[mmol/L]] (8.8–10.7&nbsp;mg/dL, 4.3–5.2 [[mEq/L]]), with levels greater than 2.6&nbsp;mmol/L defined as hypercalcaemia.<ref name=BMJ2015/><ref name=EU2010/><ref name=SI2005/> Moderate hypercalcaemia is a level of 2.88–3.5&nbsp;mmol/L (11.5–14&nbsp;mg/dL) while severe hypercalcaemia is > 3.5&nbsp;mmol/L (>14&nbsp;mg/dL).<ref>{{cite book |last1=Stack |first1=Brendan C. Jr. |last2=Bodenner |first2=Donald L. |title=Medical and Surgical Treatment of Parathyroid Diseases: An Evidence-Based Approach |date=2016 |publisher=Springer |isbn=978-3-319-26794-4 |page=99 |url=https://books.google.com/books?id=p1C7DQAAQBAJ&pg=PA99 |language=en}}</ref>

===ECG===
[[File:Osborn wave.gif|thumb|An Osborn wave, an abnormal EKG tracing that can be associated with hypercalcemia.]]
Abnormal [[cardiac arrhythmia|heart rhythms]] can also result, and [[ECG]] findings of a short [[QT interval]]<ref>{{cite web |url=http://lifeinthefastlane.com/ecg-library/basics/hypercalcaemia/ |title=Life in the Fast Lane • LITFL |access-date=2014-10-19 |url-status=live |archive-url=https://web.archive.org/web/20141216085448/http://lifeinthefastlane.com/ecg-library/basics/hypercalcaemia |archive-date=2014-12-16 }}</ref> suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute [[myocardial infarction]].<ref>{{Cite journal | doi = 10.7861/clinmedicine.9-2-186 | last1 = Wesson | first1 = L | last2 = Suresh | first2 = V | last3 = Parry | first3 = R | title = Severe hypercalcaemia mimicking acute myocardial infarction | journal = [[Clinical Medicine (journal)|Clinical Medicine]] | volume = 9 | issue = 2 | pages = 186–7 | year = 2009 | pmid = 19435131| pmc = 4952678 }}</ref> Hypercalcaemia has also been known to cause an [[ECG]] finding mimicking hypothermia, known as an [[Osborn wave]].<ref>{{cite journal |doi=10.3402/jchimp.v1i4.10742 |pmid=23882340 |pmc=3714046 |title=Osborn waves in a hypothermic patient |journal=Journal of Community Hospital Internal Medicine Perspectives |volume=1 |issue=4 |pages=10742 |year=2012 |last1=Serafi |first1=Sami W |last2=Vliek |first2=Crystal |last3=Taremi |first3=Mahnaz }}</ref>

==Treatments==
The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause. In those with a calcium level above 13&nbsp;mg/dL, calcium level that is rising rapidly or those with altered mental status, urgent treatment is required.<ref name="Guise 2022" />

===Fluids and diuretics===
Initial therapy:{{citation needed|date=November 2021}}
** [[IV fluids]] is the initial therapy.<ref name="Guise 2022" /> Hypercalcemia usually causes symptoms that lead to chronic dehydration, such as nausea, vomiting, anorexia, and [[nephrogenic diabetes insipidus]] (inability of the kidney to concentrate the urine). IV fluid rehydration allows the kidneys to excrete more calcium, and usually lowers the calcium level by 1–2&nbsp;mg/dL.<ref name="Guise 2022" />
** increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion.
** 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 [[pulmonary edema|pulmonary oedema]]. In addition, [[loop diuretics]] tend to depress calcium reabsorption by the kidney thereby helping to lower blood calcium levels
** caution must be taken to prevent [[Potassium#Supplementation|potassium]] or [[Magnesium deficiency (medicine)|magnesium]] depletion

===Bisphosphonates and calcitonin===
Additional therapy:{{citation needed|date=November 2021}}
* [[bisphosphonates]] are [[pyrophosphate]] analogues with high affinity for bone, especially areas of high bone-turnover.
** they are taken up by [[osteoclast]]s and inhibit osteoclastic bone resorption, therefore inhibiting calcium release from osteoclasts
** current available drugs include: (1st generation) [[etidronate]], (2nd generation) [[tiludronate]], IV [[pamidronate]], [[alendronate]] (3rd generation) [[zoledronate]] and [[risedronate]]
** Bisphosphonates are used as a first line therapy for those with hypercalcemia of malignancy. They are used as both an acute therapy and are usually continued long term to prevent hypercalcemia.<ref name="Guise 2022" />
** Bisphosphonates are not recommended in those with [[chronic kidney disease]] or those who are severely dehydrated as they may worsen or cause kidney disease.<ref name="Guise 2022" />
** Bisphosphonates caused normalization of calcium levels in 60-90% of patients who were treated for hypercalcemia of malignancy.<ref name="Guise 2022" />
* [[Denosumab]] is a bone anti-resorptive agent that can be used to treat hypercalcemia in patients with a [[contraindication]] to bisphosphonates such as severe kidney failure or allergy.
** Denosumab is a monoclonal antibody that inhibits osteoclasts. It acts by binding [[RANK ligand]] preventing it from activating osteoclasts via [[NFKB]].<ref name="Guise 2022" />
** Denosumab caused normalization of calcium levels in 70% in those with hypercalcemia of malignancy.<ref name="Guise 2022" />
* [[Calcitonin]] blocks bone resorption by inhibiting osteoclasts and also increases urinary calcium excretion by the kidneys.<ref name="Guise 2022" />
** Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
** Due to its limited duration of action (it works for 48–96 hours, then efficacy decreases as the calcitonin receptors are downregulated) its use is limited to acute hypercalcemia as a bridge therapy until more long-term treatments can be initiated.<ref name="Guise 2022" />

===Other therapies===
* rarely used, or used in special circumstances:
** [[plicamycin]] inhibits bone resorption (rarely used)
** [[gallium nitrate]] inhibits bone resorption and changes structure of bone crystals (rarely used)
** [[glucocorticoids]] increase urinary calcium excretion and decrease intestinal calcium absorption
*** no effect on calcium level in normal or primary hyperparathyroidism
*** effective in hypercalcemia due to malignancy with elevated vitamin D levels (many types of malignancies raise the vitamin D level).<ref name="Guise 2022" />
*** also effective in [[hypervitaminosis D]] and [[sarcoidosis]]
** [[Kidney dialysis|dialysis]] usually used in severe hypercalcaemia complicated by [[kidney failure]]. Supplemental phosphate should be monitored and added if necessary
** [[phosphate]] therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium, but this can further increase the risk for kidney stones and [[nephrocalcinosis]]

==Other animals==
Research has led to a better understanding of hypercalcemia in non-human animals. Often the causes of hypercalcemia have a correlation to the environment in which the organisms live. Hypercalcemia in house pets is typically due to disease, but other cases can be due to accidental ingestion of plants or chemicals in the home.<ref name="Hypercalcemia in Dogs and Cats" /> Outdoor animals commonly develop hypercalcemia through [[Hypervitaminosis D|vitamin D toxicity]] from wild plants within their environments.<ref name="Enzootic Calcinosis">[http://www.merckmanuals.com/vet/musculoskeletal_system/dystrophies_associated_with_calcium_phosphorus_and_vitamin_d/enzootic_calcinosis.html Enzootic Calcinosis] {{webarchive|url=https://web.archive.org/web/20140728125957/http://www.merckmanuals.com/vet/musculoskeletal_system/dystrophies_associated_with_calcium_phosphorus_and_vitamin_d/enzootic_calcinosis.html |date=2014-07-28 }} Gruenberg MS, PhD, DECAR DECBHM. W.G., April 2014. Enzootic Calcinosis. The Merck Veterinary Manual. Merck Sharp & Dohme, Whitehouse Station, NJ, USA.</ref>

===Household pets===
Household pets such as dogs and cats are found to develop hypercalcemia. It is less common in cats, and many feline cases are [[idiopathic]].<ref name="Hypercalcemia in Dogs and Cats" /> In dogs, [[lymphosarcoma]], [[Addison's disease]], [[primary hyperparathyroidism]], and chronic [[kidney failure]] are the main causes of hypercalcemia, but there are also environmental causes usually unique to indoor pets.<ref name="Hypercalcemia in Dogs and Cats">[http://www.merckmanuals.com/vet/endocrine_system/the_parathyroid_glands_and_disorders_of_calcium_metabolism/hypercalcemia_in_dogs_and_cats.html Hypercalcemia in Dogs and Cats] {{webarchive|url=https://web.archive.org/web/20140728125538/http://www.merckmanuals.com/vet/endocrine_system/the_parathyroid_glands_and_disorders_of_calcium_metabolism/hypercalcemia_in_dogs_and_cats.html |date=2014-07-28 }} Peterson DVM, DACVIM. M. E., July 2013. Hypercalcemia in Dogs and Cats. The Merck Veterinary Manual. Merck Sharp & Dohme, Whitehouse Station, NJ, USA.</ref> Ingestion of small amounts of [[Calcipotriol|calcipotriene]] found in psoriasis cream can be fatal to a pet.<ref name="Topical Agents (Toxicity)">[http://www.merckmanuals.com/vet/toxicology/toxicities_from_human_drugs/topical_agents_toxicity.html Topical Agents (Toxicity)] {{webarchive|url=https://web.archive.org/web/20140728125702/http://www.merckmanuals.com/vet/toxicology/toxicities_from_human_drugs/topical_agents_toxicity.html |date=2014-07-28 }} Khan DVM, MS, PhD, DABVT, S.A., March 2012. Topical Agents (Toxicity). The Merck Veterinary Manual. Merck Sharp & Dohme, Whitehouse Station, NJ, USA.</ref> [[Calcipotriol|Calcipotriene]] causes a rapid rise in calcium ion levels.<ref name="Topical Agents (Toxicity)" /> Calcium ion levels can remain high for weeks if untreated and lead to an array of medical issues.<ref name="Topical Agents (Toxicity)" /> There are also cases of hypercalcemia reported due to dogs ingesting [[rodenticide]]s containing a chemical similar to [[Calcipotriol|calcipotriene]] found in [[psoriasis]] cream.<ref name="Topical Agents (Toxicity)" /> Additionally, ingestion of household plants is a cause of hypercalcemia. Plants such as ''[[Cestrum diurnum]]'', and ''[[Solanum malacoxylon]]'' contain [[ergocalciferol]] or [[cholecalciferol]] which cause the onset of hypercalcemia.<ref name="Hypercalcemia in Dogs and Cats" /> Consuming small amounts of these plants can be fatal to pets. Observable symptoms may develop such as [[polydipsia]], [[polyuria]], extreme fatigue, or constipation.<ref name="Hypercalcemia in Dogs and Cats" />

===Outdoor animals===
[[File:Trisetum.flavescens2.-.lindsey.jpg|thumb|''[[Trisetum flavescens]]'' (yellow oat grass)]]
In certain outdoor environments, animals such as horses, pigs, cattle, and sheep experience hypercalcemia commonly. In southern [[Brazil]] and Mattewara [[India]], approximately 17 per cent of sheep are affected, with 60 per cent of these cases being fatal.<ref name="Enzootic Calcinosis" /> Many cases are also documented in [[Argentina]], [[Papua New Guinea]], [[Jamaica]], [[Hawaii]], and [[Bavaria]].<ref name="Enzootic Calcinosis" /> These cases of hypercalcemeia are usually caused by ingesting ''[[Trisetum flavescens]]'' before it has dried out.<ref name="Enzootic Calcinosis" /> Once ''Trisetum flavescens'' is dried out, the toxicity of it is diminished.<ref name="Enzootic Calcinosis" /> Other plants causing hypercalcemia are ''[[Cestrum diurnum]]'', ''[[Nierembergia veitchii]]'', ''[[Solanum esuriale]]'', ''[[Solanum torvum]]'', and ''[[Solanum malacoxylon]]''.<ref name="Enzootic Calcinosis" /> These plants contain [[calcitriol]] or similar substances that cause rises in calcium ion levels.<ref name="Enzootic Calcinosis" /> Hypercalcemia is most common in grazing lands at altitudes above 1500 meters where growth of plants like ''Trisetum flavescens'' is favorable.<ref name="Enzootic Calcinosis" /> Even if small amounts are ingested over long periods of time, the prolonged high levels of calcium ions have large negative effects on the animals.<ref name="Enzootic Calcinosis" /> The issues these animals experience are muscle weakness, and [[calcification]] of blood vessels, heart valves, liver, kidneys, and other soft tissues, which eventually can lead to death.<ref name="Enzootic Calcinosis" />

==See also==
* [[Calcium metabolism]]
* [[Dent's disease]]
* [[Electrolyte disturbance]]
* [[Disorders of calcium metabolism]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
| DiseasesDB      = 6196
| ICD10           = {{ICD10|E|83|5|e|70}}
| ICD9            = {{ICD9|275.42}}
| ICDO            =
| OMIM            =
| MedlinePlus     = 000365
| eMedicineSubj   = med
| eMedicineTopic  = 1068
| eMedicine_mult  = {{eMedicine2|emerg|260}} {{eMedicine2|ped|1062}}
| MeshID          = D006934
| SNOMED CT       = 66931009
}}

{{Electrolyte abnormalities}}
{{Mineral metabolic pathology}}
{{Paraneoplastic syndromes}}
{{Authority control}}

[[Category:Electrolyte disturbances]]
[[Category:Calcium]]
[[Category:Abnormal clinical and laboratory findings for blood]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]
[[Category:Medical mnemonics]]