Hypercalcemia differential diagnosis: Difference between revisions

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{{Hypercalcemia}}
[[Image:Home_logo1.png|right|250px|link=https://www.wikidoc.org/index.php/Hypercalcemia]]
{{CMG}}; {{AE}}
{{CMG}}; {{AE}} {{Anmol}}
 
{{PleaseHelp}}


==Overview==
==Overview==
Various common causes of hypercalcemia should be differentiated from each other. Causes of [[hypercalcemia]] to be differentiated include [[hyperparathyroidism]], [[familial hypocalciuric hypercalcemia]], [[hypercalcemia]] related to [[malignancy]], [[medication-induced]] [[hypercalcemia]], [[hypercalcemia]] due to [[nutritional]] disorders, and [[hypercalcemia]] related to [[Granulomatous|granulomatous diseases]].


==Differential Diagnosis==
==Differential Diagnosis==
(In alphabetical order)
Different causes of hypecalcemia should be differentiated from each other. Common causes of hypercalcemia to be differentiaetd include:
* Abnormal [[parathyroid gland]] function
*'''Parathyroid related'''
* [[Acromegaly]]
**Hyperparathyroidism
* [[Osteoporosis|Acute osteoporosis]]
***Primary hyperparathyroidism
* [[Acute renal failure]]
***Secondary hyperparathyroidism
* [[Addison's disease]]
***Tertiary hyperparathyroidism
* [[Adrenal insufficiency]]
**[[Familial hypocalciuric hypercalcemia]]
* After [[kidney transplant]]
*'''Non-parathyroid related'''
* [[Aluminum]] intoxication
**[[Malignancy]]
* [[Aspirin]] (in large amounts)
***Humoral [[hypercalcemia]] of [[malignancy]]
* Autonomous [[hyperparathyroidism]] (post long-term [[renal failure]])
***[[Osteolytic metasteses|Osteolytic tumors]]
* [[Bartter's Syndrome]]
***Production of [[calcitriol]] by [[Tumor|tumors]]
* [[Berylliosis]]
***[[Ectopia|Ectopic]] [[parathyroid hormone]] production
* Bone [[fracture]]
**[[Medication-induced]]
* [[Breast cancer]]
***[[Thiazide diuretics]]
* [[Bronchial carcinoma]]
***[[Lithium]]  
* [[Carcinoma]]
**[[Nutritional]]
* [[Chronic renal failure]]
***[[Milk-alkali syndrome]]
* [[Coccidioidomycosis]]
***[[Hypervitaminosis D|Vitamin D toxicity]]
* [[Cushing's syndrome]]
**[[Granulomatous]] disease
* [[Dehydration]]
***[[Sarcoidosis]]
* [[Drugs]]
**Surgical
* Familial hypocalcuric hypercalcemia
***Immobization
* Familial isolated [[hyperparathyroidism]] ({{OMIM|146200}})
 
* [[Gitelman syndrome]]
 
* Granulomatous diseases with [[tuberculosis]]
<br>
* [[Hematologic]] [[malignancy]] ([[multiple myeloma]], [[lymphoma]], [[leukemia]])
* [[Hepatocellular carcinoma]]
* [[Histoplasmosis]]
* [[Hodgkin's Lymphoma]]
* [[Hyperparathyroidism]] (in the preceding oliguric-anuric phase)
* [[Hyperthyroidism]]
* [[Hypervitaminosis D]] (vitamin D intoxication)
* [[Idiopathic]] hypercalcemia (in infants)
* Immobilization
* Isolated or multinodal adenoma
* [[Kidney cancer]]
* [[Leprosy]]
* [[Leukemia]]
* [[Lithium]]  
* [[Lymphoma]]
* [[Malignancy]]
* [[Medullary sponge kidney]]
* [[Milk-alkali syndrome]]
* [[Multiple endocrine neoplasia]] (MEN)
* [[Multiple myeloma]]
* [[Oral candidiasis]]
* [[Osteomalacia]]
* [[Ovarian cancer]]
* [[Paget's disease]]
* [[Paraplegia]]
* Parathyroid [[carcinoma]] ({{ICD10|C|75|0|c|73}})
* [[Parathyroid]] hyperplasia
* [[Pheochromocytoma]]
* [[Plasma cell]] [[granuloma]]
* [[Polycythemia]]
* [[Primary hyperparathyroidism]]
* Primary Parathyroid [[hyperplasia]]
* Rebound hypercalcemia after [[rhabdomyolysis]]
* [[Renal failure]]
* [[Sarcoidosis]]
* Secretion of [[prostaglandin]]s
* Severe [[secondary hyperparathyroidism]]
* [[Silicone]]-induced [[granuloma]]
* [[Sjogren's syndrome]]
* 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]]
* [[Thiazide]] [[diuretic]]s
* [[Total parenteral nutrition]]
* [[Tuberculosis]]
* [[Vasoactive intestinal polypeptide-producing tumor]] ([[VIPoma]])
* [[Vitamin A]] intoxication
* [[Vitamin D]] intoxication
* [[Vitamin D]] [[metabolic disorders]]
* [[William's syndrome]]


Hypercalcemia must be differentiated from other causes of diabetes insipidus.
{|
{| class="wikitable"
! colspan="9" style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Differential diagnosis of hypercalcemia}}
!Type of DI
|-
!Subclass
! colspan="2" rowspan="2" style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Disorder}}
!Disease
! rowspan="2" style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Mechanism of hypercalcemia}}
!Defining signs and symptoms
! rowspan="2" style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Clinical features}}
!Lab/Imaging findings
! colspan="4" style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Laboratory findings}}
! rowspan="2" style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Imaging & diagnostic modalities}}
|-
|-
| rowspan="5" |Central
! style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|PTH}}
| rowspan="3" |Acquired
! style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Calcium}}
|[[Histiocytosis]]
! style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Phosphate}}
|
! style="background: #7d7d7d; text-align: center;" |{{fontcolor|#FFF|Other findings}}
* Bone lysis and [[Bone fracture|fracture]]
* Purulent [[otitis media]]
* [[Diabetes insipidus]] and delayed puberty
* [[Maxillary]], [[mandibular]], and [[gingival]] disease
* [[Rash]] and [[Erythematous|maculoerythematous]] skin lesions
* Scaly, [[erythematous]] scalp patches
* [[Lung]] involvement
* [[GI bleeding]]
* [[Lymphadenopathy|Lymph node enlargement]]<ref name="pmid1340034">{{cite journal| author=Ghosh KN, Bhattacharya A| title=Gonotrophic nature of Phlebotomus argentipes (Diptera: Psychodidae) in the laboratory. | journal=Rev Inst Med Trop Sao Paulo | year= 1992 | volume= 34 | issue= 2 | pages= 181-2 | pmid=1340034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1340034  }} </ref>
|
* CD1a and CD45 +
* Interleukin-17 (ILITA)
[[Image:Langerhans Skull X ray.jpg|center|300px|thumb|Skull x-ray of a patient with Langerhan's histiocytosis showing lytic lesions - Case courtesy of Dr Hani Salam, Radiopaedia.org, rID: 9459]]
|-
|-
|[[Craniopharyngioma]]
! rowspan="3" style="background: #DCDCDC; text-align: center;" |'''Hyperparathyroidism'''
|
! style="background: #DCDCDC; text-align: center;" |Primary hyperparathyroidism
* [[Headache]]
| style="background: #F5F5F5;" |Increase in [[secretion]] of [[parathyroid hormone]] ([[PTH]]) from a primary process in [[parathyroid gland]]. [[Parathyroid hormone]] causes increase in [[serum]] [[calcium]].
* [[Endocrine disorders|Endocrine dysfunction]]
| style="background: #F5F5F5;" |
** [[Diabetes insipidus]]
* Usually asymptomatic
** [[Hypothyroidism]]  
* [[Hypercalcemia]] detected on routine biochemical  panel
** [[Adrenal failure]]
| style="background: #F5F5F5; text-align: center;" |↑
** [[Diabetes insipidus]] (e.g., excessive fluid intake and urination)
| style="background: #F5F5F5; text-align: center;" |↑
** Growth failure and [[delayed puberty]]
| style="background: #F5F5F5; text-align: center;" |↓/Normal
|
| style="background: #F5F5F5; text-align: center;" |Normal/↑ calcitriol
* [[Suprasellar]] calcified cyst on [[MRI]]
| rowspan="3" style="background: #F5F5F5;" |Findings of bone resorption:
[[Image:Craniopharyngioma-papillary-1.jpg|center|300px|thumb|Brain MRI showing suprasellar mass consistent with the diagnosis of craniopharyngioma - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 16812]]
* [[X-ray]]
* [[Dual energy X-ray absorptiometry]] ([[DXA]])
Preoperative localization of hyperfunctioning [[parathyroid gland]]:
* Non-Invasive
** [[Tc-99m sestamibi scintigraphy]]
** Neck [[ultrasound]]
** 4D-CT
** [[SPECT]](P-SPECT)
** [[Positron emission tomography|PET]]
** [[MRI]]
* Invasive:
** Super sensitive [[venous]] sampling
** Selective [[arteriography]]
** [[Angiogram|Angiography]]
Predicting post-operative success:
* [[Intraoperative parathyroid hormone]] monitoring
|-
|-
|[[Sarcoidosis]]
! style="background: #DCDCDC; text-align: center;" |Secondary hyperparathyroidism
|
| style="background: #F5F5F5;" |Increase in [[secretion]] of [[parathyroid hormone]] ([[PTH]]) from a secondary process. [[Parathyroid hormone]] causes increase in [[serum]] [[calcium]] after long periods.
* Systemic complaints
| style="background: #F5F5F5;" |
** [[Fever]]
* May present with history of:
** [[Anorexia]]
** [[Chronic renal failure]]
** [[Arthralgias]]
** [[Vitamin D deficiency]]
* Pulmonary complaints
| style="background: #F5F5F5; text-align: center;" |↑
** [[Dyspnea on exertion]]
| style="background: #F5F5F5; text-align: center;" |↓/Normal
** [[Cough]]
| style="background: #F5F5F5; text-align: center;" |↑
** Chest pain,
| style="background: #F5F5F5; text-align: center;" | --
** [[Hemoptysis]] (rare)
|-
* [[Diabetes mellitus]]
! style="background: #DCDCDC; text-align: center;" |Tertiary hyperparathyroidism
|
| style="background: #F5F5F5;" |Continuous elevation of [[parathyroid hormone]] (PTH) even after successful treatment of the secondary cause of  elevated [[parathyroid hormone]]. [[Parathyroid hormone]] causes increase in serum calcium.
* [[Hypercalcemia]]  
| style="background: #F5F5F5;" |
* [[Hypercalciuria]] ([[Granulomas|noncaseating granulomas]])
* Usually present with history of [[kidney transplant]]
* Elevated [[alkaline phosphatase]]
* Usually [[hyperplasia]] of all four [[parathyroid glands]]
* [[Serum amyloid A]] (SAA)
| style="background: #F5F5F5; text-align: center;" |↑
* [[Angiotensin-converting enzyme|ACE]] levels may be elevated
| style="background: #F5F5F5; text-align: center;" |↑
[[Image:Neurosarcoidosis.jpg|center|300px|thumb|Contrast-enhanced patches in a patient previously diagnosed with lung sarcoidosis - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 10930]]
| style="background: #F5F5F5; text-align: center;" |↑
| style="background: #F5F5F5; text-align: center;" | --
|-
|-
| rowspan="2" |Congenital
! colspan="2" style="background: #DCDCDC; text-align: center;" |[[Familial hypocalciuric hypercalcemia]]
|[[Hydrocephalus]]
| style="background: #F5F5F5;" |This is a [[genetic disorder]] caused my [[mutation]] in [[calcium-sensing receptor]] gene.
|
| style="background: #F5F5F5;" |
* Cognitive deterioration
* A benign condition
* [[Headaches]]
* Does not require treatment
* [[Neck pain]]
| style="background: #F5F5F5; text-align: center;" |Normal/↑
* [[Blurred vision]]
| style="background: #F5F5F5; text-align: center;" |Normal/↑
* [[Unsteady gait]]
| style="background: #F5F5F5; text-align: center;" | --
* [[Incontinence]] such as [[polyuria]]
| style="background: #F5F5F5; text-align: center;" | --
|Dilated [[ventricles]] on [[Computed tomography|CT]] and [[Magnetic resonance imaging|MRI]]
| style="background: #F5F5F5;" |
[[Image:Obstructive-hydrocephalus.jpg|center|300px|thumb|Obstructive hydrocephalus showing dilated lateral ventricles - Case courtesy of Dr Paul Simkin, Radiopaedia.org, rID: 30453]]
* Urinary calcium/creatinine clearance ratio
|-
|-
|[[Wolfram syndrome|Wolfram Syndrome]] (DIDMOAD)
! rowspan="4" style="background: #DCDCDC; text-align: center;" |'''Malignancy'''<ref name="pmid26713296">{{cite journal |vauthors=Mirrakhimov AE |title=Hypercalcemia of Malignancy: An Update on Pathogenesis and Management |journal=N Am J Med Sci |volume=7 |issue=11 |pages=483–93 |year=2015 |pmid=26713296 |pmc=4683803 |doi=10.4103/1947-2714.170600 |url=}}</ref><ref name="pmid15673803">{{cite journal| author=Stewart AF| title=Clinical practice. Hypercalcemia associated with cancer. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 4 | pages= 373-9 | pmid=15673803 | doi=10.1056/NEJMcp042806 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15673803  }} </ref>
|
! style="background: #DCDCDC; text-align: center;" |Humoral hypercalcemia of malignancy<ref name="pmid1346019">{{cite journal |vauthors=Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG |title=Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia |journal=Lancet |volume=339 |issue=8786 |pages=164–7 |year=1992 |pmid=1346019 |doi=10.1016/0140-6736(92)90220-W |url=}}</ref><ref name="pmid7962324">{{cite journal |vauthors=Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T |title=Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma |journal=J. Clin. Endocrinol. Metab. |volume=79 |issue=5 |pages=1322–7 |year=1994 |pmid=7962324 |doi=10.1210/jcem.79.5.7962324 |url=}}</ref><ref name="pmid12679445">{{cite journal |vauthors=Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF |title=Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers |journal=J. Clin. Endocrinol. Metab. |volume=88 |issue=4 |pages=1603–9 |year=2003 |pmid=12679445 |doi=10.1210/jc.2002-020773 |url=}}</ref><ref name="pmid7085851">{{cite journal| author=Stewart AF, Vignery A, Silverglate A, Ravin ND, LiVolsi V, Broadus AE et al.| title=Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity. | journal=J Clin Endocrinol Metab | year= 1982 | volume= 55 | issue= 2 | pages= 219-27 | pmid=7085851 | doi=10.1210/jcem-55-2-219 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7085851  }} </ref>
* [[Diabetes insipidus|Diabetes Insipidus]]
| style="background: #F5F5F5;" |[[Tumor]] cells secretes [[parathyroid hormone-related protein]] ([[PTHrP]]) which has similar action as [[parathyroid hormone]].
* [[Diabetes mellitus|Diabetes Mellitus]]
| style="background: #F5F5F5;" |
* [[Optic atrophy|Optic Atrophy]]
* Most common cause of [[malignancy]] related [[hypercalcemia]]
* [[Deafness]]
* Usually present with [[solid tumors]]
|
| style="background: #F5F5F5; text-align: center;" | --
* Negative [[islet cell]] antibodies
| style="background: #F5F5F5; text-align: center;" |↑
* [[Optic atrophy]] on [[electroretinogram]]
| style="background: #F5F5F5; text-align: center;" |↓/Normal
* [[Deafness]] on [[audiogram]]
| style="background: #F5F5F5; text-align: center;" |↑ [[PTHrP]]
* [[Atrophy]] of brain stem on [[Magnetic resonance imaging|MRI]]
 
Normal/↑ calcitriol
| style="background: #F5F5F5;" |
* [[Chest X-rays|Chest X-ray]]
* [[CT scan]]
* [[MRI]]
|-
|-
| rowspan="5" |[[Nephrogenic diabetes insipidus|Nephrogenic]]
! style="background: #DCDCDC; text-align: center;" |Osteolytic tumors<ref name="pmid15084698">{{cite journal| author=Roodman GD| title=Mechanisms of bone metastasis. | journal=N Engl J Med | year= 2004 | volume= 350 | issue= 16 | pages= 1655-64 | pmid=15084698 | doi=10.1056/NEJMra030831 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15084698  }} </ref><ref name="pmid8833902">{{cite journal| author=Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF et al.| title=Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. | journal=J Clin Invest | year= 1996 | volume= 98 | issue= 7 | pages= 1544-9 | pmid=8833902 | doi=10.1172/JCI118947 | pmc=507586 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8833902  }} </ref>
| rowspan="5" |[[Acquired disorder|Acquired]]
| style="background: #F5F5F5;" |[[Multiple myeloma]] produces [[osteolysis]] of [[bones]] causing [[hypercalcemia]]. [[Osteolytic metasteses]] can cause [[bone resorption]] causing [[hypercalcemia]].
|Drug-induced ([[demeclocycline]], [[lithium]])
| style="background: #F5F5F5;" |
|
* Commonly present in [[multiple myeloma]] and [[breast cancer]]
* [[Polyuria]]
| style="background: #F5F5F5; text-align: center;" |↓
* [[Polydipsia]]
| style="background: #F5F5F5; text-align: center;" |↑
* [[Nocturia]]
| style="background: #F5F5F5; text-align: center;" | --
|
| style="background: #F5F5F5; text-align: center;" | --
* [[Urine osmolality]] <100 mmol/
| style="background: #F5F5F5;" |
* [[Arginine vasopressin]] level >4.6 pmol/
* [[DXA]]
* Little or no response to administration of  exogenous [[arginine vasopressin]]
* [[X-ray]]
* [[Mammography]]
* [[Ultrasound]]
* [[ESR]]
* [[Serum protein electrophoresis]]
|-
|-
|[[Hypercalcemia]]
! style="background: #DCDCDC; text-align: center;" |Production of calcitirol<ref name="pmid7944070">{{cite journal| author=Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F| title=Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. | journal=Ann Intern Med | year= 1994 | volume= 121 | issue= 9 | pages= 633-40 | pmid=7944070 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7944070  }} </ref>
|
| style="background: #F5F5F5;" |Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of [[calcitriol]]. [[Calcitriol]] is active form of [[vitamin D]] and causes [[hypercalcemia]].
* [[Polyuria]]
| style="background: #F5F5F5;" |
* [[Polydipsia]]
* Commonly present in [[lymphomas]] and in some [[Ovarian cancer|ovarian germ cell tumors]]
* [[Gastrointestinal]] disturbances
| style="background: #F5F5F5; text-align: center;" | --
* [[Bone fracture|Pathological fractures]]
| style="background: #F5F5F5; text-align: center;" |↑
* [[Confusion]]
| style="background: #F5F5F5; text-align: center;" | --
* [[Palpitations]] and [[cardiac arrhythmias]]
| style="background: #F5F5F5; text-align: center;" |↑ [[Calcitriol]]
|
| style="background: #F5F5F5;" |
* Ca levels greater than 11 meq/L
* [[CT scan]]
* [[MRI]]
|-
|-
|[[Hypokalemia]]
! style="background: #DCDCDC; text-align: center;" |Ectopic parathyroid hormone<ref name="pmid16263810">{{cite journal |vauthors=VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R |title=Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene |journal=J. Clin. Endocrinol. Metab. |volume=91 |issue=2 |pages=580–3 |year=2006 |pmid=16263810 |doi=10.1210/jc.2005-2095 |url=}}</ref>
|
| style="background: #F5F5F5;" |Some tumors leads to [[Ectopia|ectopic]] production of [[parathyroid hormone]].
* [[Polyuria]]
| style="background: #F5F5F5;" |
* [[Hyporeflexia]]
* In rare instances, [[small cell carcinoma of lung]] may produce [[hypercalcemia]] by this process
* [[Palpitations]] and [[cardiac arrhythmias]]
| style="background: #F5F5F5; text-align: center;" |↑
|
| style="background: #F5F5F5; text-align: center;" |↑
* K levels less than 3meq/L on CBC
| style="background: #F5F5F5; text-align: center;" |↓/Normal
| style="background: #F5F5F5; text-align: center;" |Normal/↑ [[calcitriol]]
| style="background: #F5F5F5;" |
* [[Chest X-rays|Chest X-ray]]
* [[CT scan]]
* [[MRI]]
|-
|-
|[[Multiple myeloma]]
! rowspan="2" style="background: #DCDCDC; text-align: center;" |'''Medication induced'''
|
! style="background: #DCDCDC; text-align: center;" |Lithium<ref name="pmid2918061">{{cite journal |vauthors=Mallette LE, Khouri K, Zengotita H, Hollis BW, Malini S |title=Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume |journal=J. Clin. Endocrinol. Metab. |volume=68 |issue=3 |pages=654–60 |year=1989 |pmid=2918061 |doi=10.1210/jcem-68-3-654 |url=}}</ref>
* Pathologic [[bone fractures]]
| style="background: #F5F5F5;" |[[Lithium]] lowers [[Urinary System|urinary]] [[calcium]] and causes [[hypercalcemia]]. [[Lithium]] has been reported to cause an increase in [[parathyroid hormone]] and enlargement if [[parathyroid gland]] after weeks to months of therapy.
* [[Bleeding]]
| style="background: #F5F5F5;" |
* [[Hypercalcemia]] leading to [[polyuria]]
* History of [[mood disorder]]
* [[Infection]]
| style="background: #F5F5F5; text-align: center;" |↑
* [[Hyperviscosity]]
| style="background: #F5F5F5; text-align: center;" |↑
* [[Anemia]]
| style="background: #F5F5F5; text-align: center;" | --
|
| style="background: #F5F5F5; text-align: center;" | --
* [[IgG]] or [[IgA]] spike on [[serum protein electrophoresis]]
| style="background: #F5F5F5;" |
* [[Monoclonal antibody|Monoclonal M spike]]
* [[Lithium]] levels
* Disordered [[plasma cell]] proliferation on [[bone marrow biopsy]]
[[Image:Multiple-myeloma-skeletal-survey.jpg|center|300px|thumb|Skeletal survey in a patient with multiple myeloma showing multiple lytic lesions - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 7682]]
|-
|-
|[[Sickle-cell disease|Sickle cell disease]]
! style="background: #DCDCDC; text-align: center;" |Thiazide diuretics<ref name="pmid26751196">{{cite journal| author=Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ et al.| title=Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 3 | pages= 1166-73 | pmid=26751196 | doi=10.1210/jc.2015-3964 | pmc=4803175 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26751196  }}</ref>
|
| style="background: #F5F5F5;" |[[Thiazide diuretics]] lowers [[urinary]] [[calcium]] [[excretion]] and causes [[hypercalcemia]].
* [[Chronic pain]]
| style="background: #F5F5F5;" |
* [[Anemia]]
* History of [[cardiac]] disorder
* [[Aplastic crisis]]
* Rarely causes [[hypercalcemia]]
* Splenic sequestration
| style="background: #F5F5F5; text-align: center;" | --
* [[Infection]]
| style="background: #F5F5F5; text-align: center;" |↑
* [[Isosthenuria]] presenting with [[polyuria]]
| style="background: #F5F5F5; text-align: center;" | --
|
| style="background: #F5F5F5; text-align: center;" | --
* [[Hemoglobin]] level is 5-9 g/dL
| style="background: #F5F5F5;" | --
* [[Hematocrit]] is decreased to 17-29%
* [[Peripheral blood smear|Peripheral blood smears]] demonstrate [[Target cell|target cells]], elongated cells, and characteristic sickle erythrocytes
* MRI can demonstrate [[avascular necrosis]] of the [[femoral]] and [[humeral]] heads
[[Image:Sickle cells.jpg|center|300px|thumb|Blood film showing the sickle cells - By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18421017]]
|-
|-
| colspan="2" |Primary polydipsia
! rowspan="2" style="background: #DCDCDC; text-align: center;" |'''Nutritional'''
|[[Psychogenic]]
! style="background: #DCDCDC; text-align: center;" |Milk-alkali syndrome
|
| style="background: #F5F5F5;" |[[Hypercalcemia]] is be caused by high intake of [[calcium carbonate]].
* [[Polyuria]]
| style="background: #F5F5F5;" |
* [[Polydipsia]]
* History of
* [[Nocturia]]
** High milk intake
|
** Excess calcium intake for treating:
* Dry mucus membrane
*** [[Osteoporosis]]
* History of [[psychiatric disorders]]
*** [[Dyspepsia]]
* May lead to [[metabolic alkalosis]] and [[renal insufficiency]].
| style="background: #F5F5F5; text-align: center;" | --
| style="background: #F5F5F5; text-align: center;" |↑
| style="background: #F5F5F5; text-align: center;" | --
| style="background: #F5F5F5; text-align: center;" |↓ [[calcitriol]]
| style="background: #F5F5F5;" |
* [[Renal function tests]]
|-
|-
| colspan="3" |Gestational diabetes insipidus
! style="background: #DCDCDC; text-align: center;" |Vitamin D toxicity<ref name="pmid81205272">{{cite journal |vauthors=Hoeck HC, Laurberg G, Laurberg P |title=Hypercalcaemic crisis after excessive topical use of a vitamin D derivative |journal=J. Intern. Med. |volume=235 |issue=3 |pages=281–2 |year=1994 |pmid=8120527 |doi= |url=}}</ref><ref name="pmid13135472">{{cite journal |vauthors=Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW |title=Hypervitaminosis D associated with drinking milk |journal=N. Engl. J. Med. |volume=326 |issue=18 |pages=1173–7 |year=1992 |pmid=1313547 |doi=10.1056/NEJM199204303261801 |url=}}</ref><ref name="pmid8620732">{{cite journal| author=Sharma OP| title=Vitamin D, calcium, and sarcoidosis. | journal=Chest | year= 1996 | volume= 109 | issue= 2 | pages= 535-9 | pmid=8620732 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8620732  }}</ref>
|
| style="background: #F5F5F5;" |Excess [[vitamin D]] causes increased [[absorption]] of [[calcium]] from [[intestine]] causing [[hypercalcemia]].
* [[Polyuria]]  
| style="background: #F5F5F5;" |
* [[Polydipsia]]
* History of:
* [[Nocturia]]
** Excess intake [[vitamin D]]
* [[Pregnancy]]
** Excess milk fortified with [[vitamin D]]<ref name="pmid1313547">{{cite journal |vauthors=Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW |title=Hypervitaminosis D associated with drinking milk |journal=N. Engl. J. Med. |volume=326 |issue=18 |pages=1173–7 |year=1992 |pmid=1313547 |doi=10.1056/NEJM199204303261801 |url=}}</ref>
|
** Topical application of vitamin D analogue [[calcipotriol]]<ref name="pmid8120527">{{cite journal |vauthors=Hoeck HC, Laurberg G, Laurberg P |title=Hypercalcaemic crisis after excessive topical use of a vitamin D derivative |journal=J. Intern. Med. |volume=235 |issue=3 |pages=281–2 |year=1994 |pmid=8120527 |doi= |url=}}</ref>
* Dry mucus membranes
| style="background: #F5F5F5; text-align: center;" | --
* [[Pregnancy]]
| style="background: #F5F5F5; text-align: center;" |↑
| style="background: #F5F5F5; text-align: center;" | --
| style="background: #F5F5F5; text-align: center;" |↑ [[Vitamin D]] ([[calcidiol]] and/or [[calcitriol]])
| style="background: #F5F5F5;" | --
|-
|-
| colspan="3" |[[Diabetes mellitus]]
! style="background: #DCDCDC; text-align: center;" |'''Granulomatous disease'''
|
! style="background: #DCDCDC; text-align: center;" |Sarcoidosis<ref name="pmid9215298">{{cite journal |vauthors=Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E |title=gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue=7 |pages=2222–32 |year=1997 |pmid=9215298 |doi=10.1210/jcem.82.7.4074 |url=}}</ref>
* [[Polyuria]]  
| style="background: #F5F5F5;" |[[Hypercalcemia]] is causes by endogeous production of [[calcitriol]] by disease-activated [[Macrophage|macrophages]].
* [[Polydipsia]]
| style="background: #F5F5F5;" |
* [[Nocturia]]
* History of:
* [[Weight gain (patient information)|Weight gain]]
** [[Cough]]
|
** [[Dyspnea]]
* Elevated blood sugar levels >126
** [[Chest pain]]
* Elevated [[HbA1c]] > 6.5
** [[Tiredness]] or [[weakness]]
** [[Fever]]
** [[Weight loss]]
| style="background: #F5F5F5; text-align: center;" | --
| style="background: #F5F5F5; text-align: center;" |↑
| style="background: #F5F5F5; text-align: center;" | --
| style="background: #F5F5F5; text-align: center;" |↑ [[Calcitriol]]
 
↑ [[ACE]] levels
| style="background: #F5F5F5;" |
* [[Chest X-ray]]
* [[Biopsy]]
|}
|}


Latest revision as of 21:37, 13 February 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Various common causes of hypercalcemia should be differentiated from each other. Causes of hypercalcemia to be differentiated include hyperparathyroidism, familial hypocalciuric hypercalcemia, hypercalcemia related to malignancy, medication-induced hypercalcemia, hypercalcemia due to nutritional disorders, and hypercalcemia related to granulomatous diseases.

Differential Diagnosis

Different causes of hypecalcemia should be differentiated from each other. Common causes of hypercalcemia to be differentiaetd include:



Differential diagnosis of hypercalcemia
Disorder Mechanism of hypercalcemia Clinical features Laboratory findings Imaging & diagnostic modalities
PTH Calcium Phosphate Other findings
Hyperparathyroidism Primary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.
  • Usually asymptomatic
  • Hypercalcemia detected on routine biochemical panel
 ↑ ↑ ↓/Normal Normal/↑ calcitriol Findings of bone resorption:

Preoperative localization of hyperfunctioning parathyroid gland:

Predicting post-operative success:

Secondary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods. ↑ ↓/Normal ↑ --
Tertiary hyperparathyroidism Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium. ↑ ↑ ↑ --
Familial hypocalciuric hypercalcemia This is a genetic disorder caused my mutation in calcium-sensing receptor gene.
  • A benign condition
  • Does not require treatment
 Normal/↑ Normal/↑ -- --
  • Urinary calcium/creatinine clearance ratio
Malignancy[1][2] Humoral hypercalcemia of malignancy[3][4][5][6] Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone. -- ↑ ↓/Normal ↑ PTHrP

Normal/↑ calcitriol

Osteolytic tumors[7][8] Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia. ↓ ↑ -- --
Production of calcitirol[9] Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia. -- ↑ -- ↑ Calcitriol
Ectopic parathyroid hormone[10] Some tumors leads to ectopic production of parathyroid hormone. ↑ ↑ ↓/Normal Normal/↑ calcitriol
Medication induced Lithium[11] Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormone and enlargement if parathyroid gland after weeks to months of therapy. ↑ ↑ -- --
Thiazide diuretics[12] Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia. -- ↑ -- -- --
Nutritional Milk-alkali syndrome Hypercalcemia is be caused by high intake of calcium carbonate. -- ↑ -- ↓ calcitriol
Vitamin D toxicity[13][14][15] Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia. -- ↑ -- ↑ Vitamin D (calcidiol and/or calcitriol) --
Granulomatous disease Sarcoidosis[18] Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages. -- ↑ -- ↑ Calcitriol

↑ ACE levels

References

  1. ↑ Mirrakhimov AE (2015). "Hypercalcemia of Malignancy: An Update on Pathogenesis and Management". N Am J Med Sci. 7 (11): 483–93. doi:10.4103/1947-2714.170600. PMC 4683803. PMID 26713296.
  2. ↑ Stewart AF (2005). "Clinical practice. Hypercalcemia associated with cancer". N Engl J Med. 352 (4): 373–9. doi:10.1056/NEJMcp042806. PMID 15673803.
  3. ↑ Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG (1992). "Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia". Lancet. 339 (8786): 164–7. doi:10.1016/0140-6736(92)90220-W. PMID 1346019.
  4. ↑ Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T (1994). "Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma". J. Clin. Endocrinol. Metab. 79 (5): 1322–7. doi:10.1210/jcem.79.5.7962324. PMID 7962324.
  5. ↑ Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF (2003). "Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers". J. Clin. Endocrinol. Metab. 88 (4): 1603–9. doi:10.1210/jc.2002-020773. PMID 12679445.
  6. ↑ Stewart AF, Vignery A, Silverglate A, Ravin ND, LiVolsi V, Broadus AE; et al. (1982). "Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity". J Clin Endocrinol Metab. 55 (2): 219–27. doi:10.1210/jcem-55-2-219. PMID 7085851.
  7. ↑ Roodman GD (2004). "Mechanisms of bone metastasis". N Engl J Med. 350 (16): 1655–64. doi:10.1056/NEJMra030831. PMID 15084698.
  8. ↑ Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF; et al. (1996). "Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis". J Clin Invest. 98 (7): 1544–9. doi:10.1172/JCI118947. PMC 507586. PMID 8833902.
  9. ↑ Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F (1994). "Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma". Ann Intern Med. 121 (9): 633–40. PMID 7944070.
  10. ↑ VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R (2006). "Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene". J. Clin. Endocrinol. Metab. 91 (2): 580–3. doi:10.1210/jc.2005-2095. PMID 16263810.
  11. ↑ Mallette LE, Khouri K, Zengotita H, Hollis BW, Malini S (1989). "Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume". J. Clin. Endocrinol. Metab. 68 (3): 654–60. doi:10.1210/jcem-68-3-654. PMID 2918061.
  12. ↑ Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ; et al. (2016). "Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades". J Clin Endocrinol Metab. 101 (3): 1166–73. doi:10.1210/jc.2015-3964. PMC 4803175. PMID 26751196.
  13. ↑ Hoeck HC, Laurberg G, Laurberg P (1994). "Hypercalcaemic crisis after excessive topical use of a vitamin D derivative". J. Intern. Med. 235 (3): 281–2. PMID 8120527.
  14. ↑ Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.
  15. ↑ Sharma OP (1996). "Vitamin D, calcium, and sarcoidosis". Chest. 109 (2): 535–9. PMID 8620732.
  16. ↑ Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.
  17. ↑ Hoeck HC, Laurberg G, Laurberg P (1994). "Hypercalcaemic crisis after excessive topical use of a vitamin D derivative". J. Intern. Med. 235 (3): 281–2. PMID 8120527.
  18. ↑ Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E (1997). "gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses". J. Clin. Endocrinol. Metab. 82 (7): 2222–32. doi:10.1210/jcem.82.7.4074. PMID 9215298.

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