Hypercalcemia

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

Hypercalcemia (in UK English Hypercalcaemia) is an elevated 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.

• Calcium is the most abundant mineral in the the body
• 99% of the calcium in the body is stored in the bone
• Calcium in the plasma is either ionized or protein-bound and readily available for use
• 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

In 1932, L. I. Pugsley AND Hans Selye, described the histological changes in the bone due to parathyroid hormone action and calcium metabolism in rat experiments. In the same year, Iftakhar Jahan and Robert F. Pitts described effect of parathyroid hormone in decreasing calcium and magnesium excretion.

There are several ways in which hypercalcemia may be classified. Common Terminology Criteria for Adverse Events (CTCAE) grade classifies hypercalcemia into 4 grades on the basis of corrected serum calcium (CSC). Hypercalcemia may be classified according to severity into 3 groups including mild, moderate, and severe hypercalcemia. Hypercalcemia associated with malignancy may be classified according to mechanism of increased production of calcium.

Normal calcium homeostasis is maintained by parathyroid hormone and vitamin D. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedbackfor secretion of parathyroid hormone. Hypercalcemia may result due to increase in secretion of parathyroid hormone (PTH), most common cause. Other mechanism of hyperlcacemia include secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, which has similar action as parathyroid hormone, excess intake of calcium or vitamin D, and production of vitamin D by macrophages in granulomatous diseases.

Hypercalcemia is most commonly caused by hyperparathyroidism and malignancy. Other causes of hypercalcemia include hyperthyroidism, vitamin D toxicity, increased calcium intake, granulomatous diseases ( such sarcoidosis), and various renal disorders.

Various common causes of hypercalcemia should be differentiated from each other.

The prevalence of hypercalcemia in the cancer patient is approximately 3286.23 per 100,000 individuals over the period of 2009 to 2013 in the United States.

Common risk factors in the development of hypercalcemia include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, history of familial syndromes, and renal diseases.

There is insufficient evicence to recommend routine screening for hypercalcemia.

Mild hypercalcemia is usually asymptomatic and goes undetected in a large number of patients. Furthermore, it commonly reflects in routine laboratory exams. Hypercalcemia may complicated various organ systems including renal (most commonly), gastrointestinal, and skelatal. Prognosis of hypercalcemia is usually excellent after treatment.

Serum calcium levels is the study of choice for the diagnosis of hypercalcemia. However, a panel of tests may be required to reach the underlying cause of hypercalcemia.

The symptoms of hypercalcemia are same irrespective of etiology. Neurological symptoms are common in hypercalcemia as normal neurological processes requires optimal serum extracellular concentration. The patient may have a positive history of kidney stones, bone pain and tenderness, gastrointestinal symptoms. “Bones, stones, groans, and psychic moans” is a saying which may help remember the signs and symptoms of hypercalcemia.

Physical examination of patients with hypercalcemia is usually unremarkable. Patients may have physical findings due to severe hypercalcemia and other complications.

Routine panel is recommended for patients suspected of hypercalcemia to diagnosed the underlying cause.

Most common finding on ECG due to hypercalcemia is short QT interval.

X-ray is essential to rule out various causes of hypercalcemia such as hyperparathyroidism, malignancy, and sarcoidosis.

CT scan may be helpful in the diagnosis of hypercalcemia due to malignancy such as renal cell carcinoma.

MRI is not useful in diagnosis of hypercalcemia. However, MRI may be helpful in the diagnosis of causes of hypercalcemia including hyperparathyroidism, renal cell carcinoma, and lung cancer.

Ultrasound is not useful in diagnosis of hypercalcemia. However, ultrasound may be helpful in the diagnosis of causes of hypercalcemia including renal cell carcinoma and hyperparathyroidism.

There are no other imaging findings associated with hypercalcemia.

There are no other diagnostic studies associated with hypercalcemia.

Parathyroidectomy is usually indicated for patients with hypercalcemia due to hyperparathyroidism.

There is no establish method for primary prevention of hypercalcemia.

There is no establish method for secondary prevention of hypercalcemia. However, effective measures should be applied for secondary prevention primary hyperparathyroidism, which is the most common cause of hypercalcemia.

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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]

In 1932, L. I. Pugsley AND Hans Selye, described the histological changes in the bone due to parathyroid hormone action and calcium metabolism in rat experiments. In the same year, Iftakhar Jahan and Robert F. Pitts described effect of parathyroid hormone in decreasing calcium and magnesium excretion.

• In 1909, William George MacCallum and Carl Voegtlin, demonstrated association between parathyroid gland, calcium, and tetany.^[1]
• In 1932, L. I. Pugsley AND Hans Selye, described the histological changes in the bone due to parathyroid hormone action and calcium metabolism in rat experiments. ^[2]
• In the same year, Iftakhar Jahan and Robert F. Pitts described effect of parathyroid hormone in decreasing calcium and magnesium excretion.^[3]

• In 1925, Felix Mandl, a viennese surgeon, was the first who performed parathyroidectomy to treat a patient suffering from osteitis fibrosa cystica.^[4]

• Garry Shandling, a famous comedian suffered from hyperparathyroidism.^[5]

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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]

There are several ways in which hypercalcemia may be classified. Common Terminology Criteria for Adverse Events (CTCAE) grade classifies hypercalcemia into 4 grades on the basis of corrected serum calcium (CSC). Hypercalcemia may be classified according to severity into 3 groups including mild, moderate, and severe hypercalcemia. Hypercalcemia associated with malignancy may be classified according to mechanism of increased production of calcium.

Common Terminology Criteria for Adverse Events (CTCAE) grade classifies hypercalcemia into 4 grades on the basis of corrected serum calcium (CSC):^[1]

Grade	Corrected serum calcium (CSC)
Grade 1	Corrected serum calcium of >ULN – 11.5 mg/dL; >ULN – 2.9 mmol/L; Ionized calcium >ULN – 1.5 mmol/L
Grade 2	Corrected serum calcium of >11.5 – 12.5 mg/dL; >2.9 – 3.1 mmol/L; Ionized calcium >1.5 – 1.6 mmol/L; symptomatic
Grade 3	Corrected serum calcium of >12.5 – 13.5 mg/dL; >3.1 – 3.4 mmol/L; Ionized calcium >1.6 – 1.8 mmol/L; hospitalization indicated
Grade 4	Corrected serum calcium of >13.5 mg/dL; >3.4 mmol/L; Ionized calcium >1.8 mmol/L; life-threatening consequences
ULN= Upper limit of normal (10.8 mg/dL) “Corrected calcium” may lead to confusion that the result is due to error and shall be corrected. So, the term “adjusted” calcium is preferred over “corrected” calcium.[2] Adjusted total calcium(mg/dL) = Total calcium(mg/dL) + 0.8 [4−Albumin(g/dL)] or Adjusted total calcium(mmol/L) =Total calcium (mmol/L) + 0.02 [40−Albumin(g/L)][2][3]

Hypercalcemia may be classified according to severity into 3 groups:^[4]

Severity	Calcium concentration	Key Points
Mild hypercalcemia	<3.0 mmol/L	Often asymptomatic No urgent correction needed
Moderate hypercalcemia	3.0–3.5 mmol/L	Tolerated well if there is a slow rise Symptoms may be present Treatment indicated in symptomatic cases
Severe hypercalcemia	>3.5 mmol/L	Urgent correction is recommended Risk of dysrhythmia and coma if not corrected

Hypercalcemia associated with malignancy may be classified according to mechanism of increased production of calcium into four types:^[5][6]

Disorder	Mechanism of hypercalcemia	Clinical features	Laboratory findings
			PTH	Calcium	Phosphate	Other findings
Humoral hypercalcemia of malignancy[7][8][9][10]	Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors	—	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol
Osteolytic tumors[11][12]	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer	↓	↑	—	—
Production of calcitirol[13]	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.	Commonly present in lymphomas and in some ovarian germ cell tumors	—	↑	—	↑ Calcitriol
Ectopic parathyroid hormone[14]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process	↑	↑	↓/Normal	Normal/↑ calcitriol

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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]

Normal calcium homeostasis is maintained by parathyroid hormone and vitamin D. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedbackfor secretion of parathyroid hormone. Hypercalcemia may result due to increase in secretion of parathyroid hormone (PTH), most common cause. Other mechanism of hyperlcacemia include secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, which has similar action as parathyroid hormone, excess intake of calcium or vitamin D, and production of vitamin D by macrophages in granulomatous diseases.

Effect of minerals and vitamin D on parathyroid hormone:^[1][2]

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

The effect of parathyroid hormone on mineral metabolism is as follows:

• Effect on parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
  • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Parathyroid hormone

Kidney

Bone

Decreased excretion of magnesium

Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin D

Increase excretion of inorganic phosphate

Decrease excretion of calcium

Increased resorption of bone

Increased serum concentration of magnesium

Increased absorption of calcium from gut

Decreased serum concentration of inorganic phosphate

Prevents precipitation of calcium phosphate in bones

Increased serum concentration of calcium

Mechanism of hypercalcemia in various diseases
Disorder		Mechanism of hypercalcemia	Clinical features
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
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.	May present with history of: Chronic renal failure Vitamin D deficiency
	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.	Usually present with history of kidney transplant Usually hyperplasia of all four parathyroid glands
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused my mutation in calcium-sensing receptor gene.	A benign condition Does not require treatment
Malignancy[3][4]	Humoral hypercalcemia of malignancy[5][6][7][8]	Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors
	Osteolytic tumors[9][10]	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer
	Production of calcitirol[11]	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.	Commonly present in lymphomas and in some ovarian germ cell tumors
	Ectopic parathyroid hormone[12]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process
Medication induced	Lithium[13]	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.	History of mood disorder
	Thiazide diuretics[14]	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.	History of cardiac disorder Rarely causes hypercalcemia
Nutritional	Milk-alkali syndrome	Hypercalcemia is be caused by high intake of calcium carbonate.	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.
	Vitamin D toxicity[15][16][17]	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D[18] Topical application of vitamin D analogue calcipotriol[19]
Granulomatous disease	Sarcoidosis[20]	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss

• Hypercalcemia is most commonly caused by hyperparathyroidism. For gross pathology of hyperparathyroidism, click here.

• Hypercalcemia is most commonly caused by hyperparathyroidism. For microscopic pathology of hyperparathyroidism, click here.

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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], Luke Rusowicz-Orazem, B.S.

Hypercalcemia is most commonly caused by hyperparathyroidism and malignancy. Other causes of hypercalcemia include hyperthyroidism, vitamin D toxicity, increased calcium intake, granulomatous diseases ( such sarcoidosis), and various renal disorders.

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Severity of hypercalcemia is more related to life-threatening situations rather that particular cause.

Common causes of hypercalcemia include:^[1]

• Hyperparathyroidism^[2][3]
  • Primary hyperparathyroidism
    • Parathyroid adenoma^[4]
    • Parathyroid hyperplasia
    • Parathyroid carcinoma
  • Secondary hyperparathyroidism (long standing)^[5]
  • Tertiary hyperparathyroidism^[6]
  • Neonatal severe hyperparathyroidism
• Hypercalcemia of malignancy^[7][8]
• Hyperthyroidism^[9][10]
• Hypervitaminosis D^[11][12][13]
• Chronic kidney disease^[14]
• Milk-alkali syndrome
• Hypokalaemic distal renal tubular acidosis
• Sarcoidosis^[15][16]
• Post renal transplantation

Less common causes of hypercalcemia include:^[1]

• Immobilization
• Pagets disease of bone
• Hypervitaminosis A
• Pheochromocytoma
• Adrenal insufficiency
• Rhabdomyolysis
• Acute renal failure
• Familial hypocalciuric hypercalcemia^[17]
• Methphysial chondrodysplasia
• Conenital lactase deficienccy
• Idiopathic infantile hypercalcemia (Williams syndrome)
• Mutations of the calcium-sensing receptor
• Subcutaneous fat necrosis
• Blue diaper syndrome
• Hypophosphataemia
• Hypophosphatasia 
• Dietary phosphate deficiency
• Medication-induced
  • Lithium^[18]
  • Thiazide^[19]
  • Theophylline toxicity
  • Teriparatide
  • Estrogen
  • Cidofovir
  • Danazol
  • Dexlansoprazole
  • Fluoxymesterone
  • Gestrinone
  • Nandrolone
  • Paricalcitol
  • Tamoxifen
  • Toremifene

Cardiovascular	Beuren-Williams syndrome, Vasoactive intestinal polypeptide-producing tumor
Chemical / poisoning	Aluminium antacid overuse, Aluminum intoxication, Calcium acetate, Caspofungin acetate, Cefepime, Chlortalidone, Theophylline toxicity
Dermatologic	Leprosy, Subcutaneous fat necrosis of newborn
Drug Side Effect	Cidofovir, Danazol, Dexlansoprazole, Diuretics, Fluoxymesterone, Gestrinone, Lithium, Nandrolone, Paricalcitol, Tamoxifen, Teriparatide, Thiazide, Toremifene
Ear Nose Throat	Oral candidiasis, Sjogren’s syndrome
Endocrine	Abnormal parathyroid gland function, Acromegaly, Addison’s disease, Adenoma, Adrenal cortex insufficiency, Adrenal insufficiency, Adult T-cell leukemia, Bartter’s syndrome, Cushing’s syndrome, Familial hypocalciuric hypercalcemia, Familial isolated hyperparathyroidism, Growth hormone-secreting pituitary adenoma, Hypercalcemia of malignancy, Hyperparathyroidism , Hyperthyroidism, Multiple endocrine neoplasia, Neonatal severe primary hyperparathyroidism, Paget’s disease of bone, Parathyroid adenoma, Parathyroid carcinoma, Parathyroid hormone-related peptide, Parathyroid hyperplasia, Pituitary tumour, Tryptophan malabsorption syndrome
Environmental	No underlying causes
Gastroenterologic	Hepatocellular carcinoma, Vipoma
Genetic	Activation of extra-renal 1 alpha-hydroxylase, Beuren-Williams syndrome, Familial isolated hyperparathyroidism, Metaphyseal chondrodysplasia, Phosphoethanolaminuria, Pseudophosphatasia, William’s syndrome
Hematologic	Acute adult T-cell leukemia, Adult T-cell leukemia, Chronic adult T-cell leukemia, Cuffed blood sample, Cushing’s syndrome, Familial hypocalciuric hypercalcemia, Hematologic malignancy, Hodgkin’s lymphoma, Hypervitaminosis A, Hypervitaminosis D, Hypokalaemic distal renal tubular acidosis, Hypophosphataemia, Hypophosphatasia, Leukemia, Lymphoma, Multiple myeloma, Plasma cell granuloma, Polycythemia, Pseudophosphatasia, Smoldering adult T-cell leukemia
Iatrogenic	Kidney transplant
Infectious Disease	Coccidioidomycosis, Histoplasmosis, Oral candidiasis, Tuberculosis
Musculoskeletal / Ortho	Bone cancer, Bone fracture, Immobilization, Osteolytic bone metastases and local cytokines, Osteomalacia, Osteoporosis, Paget’s disease of bone, Paraplegia
Neurologic	Adrenal cortex insufficiency, Brown-Sequard syndrome
Nutritional / Metabolic	Milk-alkali syndrome, Parenteral nutrition
Obstetric/Gynecologic	Breast cancer, Ovarian cancer, Subcutaneous fat necrosis of newborn
Oncologic	Acute adult T-cell leukemia, Adenoma, Adult T-cell leukemia, Adult T-cell lymphoma, Bone cancer, Breast cancer, Bronchial carcinoma, Chronic adult T-cell leukemia, Growth hormone secreting pituitary adenoma, Hematologic malignancy, Hepatocellular carcinoma, Hodgkin’s lymphoma, Hypercalcemia of malignancy, Renal cancer, Lymphoma, Metastatic neoplasm, Multiple endocrine neoplasia, Multiple myeloma, Osteolytic bone metastases and local cytokines, Osteomalacia, Ovarian cancer, Paraneoplastic syndrome, Parathyroid adenoma, Parathyroid carcinoma, Parathyroid hyperplasia, Pheochromocytoma, Pituitary tumour, Plasma cell granuloma, Silicone-induced granuloma, Smoldering adult T-cell leukemia, Vasoactive intestinal polypeptide-producing tumor
Ophthalmologic	No underlying causes
Overdose / Toxicity	Aluminum intoxication, Aspirin (in large amounts), Drugs, Hypervitaminosis A, Hypervitaminosis D
Psychiatric	No underlying causes
Pulmonary	Berylliosis, Bronchial carcinoma, Coccidioidomycosis, Histoplasmosis, Sarcoidosis, Tuberculosis
Renal / Electrolyte	Acute renal failure, Bartter’s syndrome, Gitelman syndrome, Hypokalaemic distal renal tubular acidosis, Hypophosphataemia, Hypophosphatasia, Renal cancer, Kidney transplant, Milk-alkali syndrome, Renal failure, Rhabdomyolysis
Rheum / Immune / Allergy	Chronic granulomatous disorders, Sarcoidosis
Sexual	No underlying causes
Trauma	Bone fracture, Dehydration
Urologic	Acute renal failure, Chronic renal failure, Milk-alkali syndrome, Renal failure
Miscellaneous	Idiopathic hypercalcemia (in infants), Immobilization, Paraplegia

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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]

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.

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

• Parathyroid related
  • Hyperparathyroidism
    • Primary hyperparathyroidism
    • Secondary hyperparathyroidism
    • Tertiary hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
• Non-parathyroid related
  • Malignancy
    • Humoral hypercalcemia of malignancy
    • Osteolytic tumors
    • Production of calcitriol by tumors
    • Ectopic parathyroid hormone production
  • Medication-induced
    • Thiazide diuretics
    • Lithium
  • Nutritional
    • Milk-alkali syndrome
    • Vitamin D toxicity
  • Granulomatous disease
    • Sarcoidosis
  • Surgical
    • Immobization

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: 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) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/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.	Usually present with history of kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	—
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.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors	—	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors[7][8]	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer	↓	↑	—	—	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	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.	Commonly present in lymphomas and in some ovarian germ cell tumors	—	↑	—	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone[10]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process	↑	↑	↓/Normal	Normal/↑ calcitriol	Chest X-ray CT scan MRI
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.	History of mood disorder	↑	↑	—	—	Lithium levels
	Thiazide diuretics[12]	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.	History of cardiac disorder Rarely causes hypercalcemia	—	↑	—	—	—
Nutritional	Milk-alkali syndrome	Hypercalcemia is be caused by high intake of calcium carbonate.	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	—	↑	—	↓ calcitriol	Renal function tests
	Vitamin D toxicity[13][14][15]	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D[16] Topical application of vitamin D analogue calcipotriol[17]	—	↑	—	↑ Vitamin D (calcidiol and/or calcitriol)	—
Granulomatous disease	Sarcoidosis[18]	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	—	↑	—	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy

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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]

The prevalence of hypercalcemia in the cancer patient is approximately 3286.23 per 100,000 individuals over the period of 2009 to 2013 in the United States.

Primary hyperparathyroidism is the most common cause of hypercalcemia. For epidemiology and demographics of hyperparathyroidism, click here.

• The prevalence of hypercalcemia in the cancer patient is approximately 3286.23 per 100,000 individuals over the period of 2009 to 2013 in the United States.^[1]

Template:WS Template:WH

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]

Common risk factors in the development of hypercalcemia include postmenopausal women, age group 50-60 year, family history of hyperparathyroidism, history of familial syndromes, and renal diseases.

Common risk factors in the development of hypercalcemia include:

• Postmenopausal women
• Age group 50-60 years
• Family history of hyperparathyroidism
• History of familial syndromes such as multiple endocrine neoplasia type 1, type 2A or type 4; familial hypocalciuric hypercalcemia, hyperparathyroid-jaw tumor syndrome

Common risk factors in the development of hypercalcemia in chronic renal failure include:^[1]

• High serum phosphorus expression levels
• Low serum creatinine expression levels
• Low serum calcium expression levels
• Female gender
• Hypertension

Common risk factors in the development of hypercalcemia post renal transplantation include:^[2]

• Elderly individuals
• Longer duration of dialysis

Less common risk factors in the development of hypecalcemia include:

• History of current or past lithium use^[3]
• Exposure to head and neck radiation

Less common risk factors in the development of secondary hyperparathyroidism in chronic renal failure include:^[1]

• Acidosis
• Anemia
• Hyperlipidemia
• Micro-inflammation (C reactive protein)

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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]

There is insufficient evicence to recommend routine screening for hypercalcemia.

There is insufficient evicence to recommend routine screening for hypercalcemia.

Template:WS Template:WH

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]

Mild hypercalcemia is usually asymptomatic and goes undetected in a large number of patients. Furthermore, it commonly reflects in routine laboratory exams. Hypercalcemia may complicated various organ systems including renal (most commonly), gastrointestinal, and skelatal. Prognosis of hypercalcemia is usually excellent after treatment.

• Mild hypercalcemia is usually asymptomatic and goes undetected in a large number of patients.^[1]
• Hypercalcemia may present in any age group depending on etiology and severity and presents initially with concentration and sleep abnormalities.

Possible complications include:^[1]

Gastrointestinal:

• Pancreatitis
• Peptic ulcer disease

Kidney:

• Calcium deposits in the kidney (nephrocalcinosis)
• Dehydration
• High blood pressure
• Kidney failure
• Kidney stones

Psychological:

• Depression
• Difficulty concentrating or thinking

Skeletal:

• Bone cysts
• Fractures
• Osteoporosis

These complications of long-term hypercalcemia are uncommon today.

• Prognosis of hypercalcemia is usually excellent after treatment.
• However, untreated hypercalcemia may be fatal.^[2]

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