Hypercalcaemia
Encyclopedia
Hypercalcaemia is an elevated calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...

 level in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

. (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 workup should be undertaken if it persists. It can be due to excessive skeletal calcium release, increased intestinal calcium absorption, or decreased renal calcium excretion.

Signs and symptoms

There is a general mnemonic for remembering the effects of hypercalcaemia: "groans (constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

), moans (psychiatric symptoms (e.g., fatigue, lethargy, depression, confusion)), bones (bone pain
Bone pain
Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it...

, especially if PTH is elevated), and stones (kidney stones)."

Other symptoms can include fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...

 and increased urination
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...

.

Abnormal heart rhythms can result, and ECG findings of a short QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...

 and a widened T wave
T wave
In electrocardiography, the T wave represents the repolarization of the ventricles. The interval from the beginning of the QRS complex to the apex of the T wave is referred to as the absolute refractory period. The last half of the T wave is referred to as the relative refractory period...

 suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

.

Hypercalcemia can increase gastrin
Gastrin
In humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...

 production, leading to increased acidity so Peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

s may also occur.

Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/l). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/l) is considered a medical emergency
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...

: at these levels, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

 and cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...

 can result.

Causes

Primary hyperparathyroidism
Primary hyperparathyroidism
Primary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...

 and malignancy account for about 90% of cases of hypercalcaemia.

Abnormal parathyroid gland function

  • primary hyperparathyroidism
    Primary hyperparathyroidism
    Primary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...

    • solitary parathyroid adenoma
    • primary parathyroid hyperplasia
    • parathyroid carcinoma
      Parathyroid carcinoma
      Parathyroid carcinoma is a rare cause of hypercalcemia. It forms in tissues of one or more of the parathyroid glands ....

    • multiple endocrine neoplasia
      Multiple endocrine neoplasia
      The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...

       (MEN)
    • familial isolated hyperparathyroidism
  • lithium
    Lithium
    Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...

     use
  • familial hypocalciuric hypercalcaemia
    Familial hypocalciuric hypercalcemia
    -Causes:Types include:Most cases are associated with loss of function mutations in the CASR gene, which encodes a calcium-sensing receptor, expressed in parathyroid and kidney tissue...

    /familial benign hypercalcaemia

Malignancy

  • solid tumour with metastasis (e.g. breast cancer
    Breast cancer
    Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

     or classically squamous cell carcinoma
    Squamous cell carcinoma
    Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...

    , which can be PTHrP-mediated)
  • solid tumour with humoral mediation of hypercalcaemia (e.g. lung cancer
    Lung cancer
    Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

     [most commonly non-small cell lung cancer] or kidney cancer
    Renal cell carcinoma
    Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...

    , phaeochromocytoma
    Pheochromocytoma
    A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...

    )
  • haematologic
    Hematology
    Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...

     malignancy (multiple myeloma
    Multiple myeloma
    Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...

    , lymphoma
    Lymphoma
    Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

    , leukaemia
    Leukemia
    Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

    )

Vitamin-D metabolic disorders

  • hypervitaminosis D
    Hypervitaminosis D
    Hypervitaminosis D is a state of vitamin D toxicity.The recommended daily allowance is 400 IU per day. Overdose has been observed at 1925 µg/d...

     (vitamin D intoxication)
  • elevated 1,25(OH)2D (see calcitriol under Vitamin D
    Vitamin D
    Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

    ) levels (e.g. sarcoidosis
    Sarcoidosis
    Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

     and other granulomatous diseases)
  • idiopathic hypercalcaemia of infancy
  • rebound hypercalcaemia after rhabdomyolysis
    Rhabdomyolysis
    Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...


Disorders related to high bone-turnover rates

  • hyperthyroidism
    Hyperthyroidism
    Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...

  • prolonged immobilization
  • thiazide
    Thiazide
    Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....

     use
  • vitamin A
    Vitamin A
    Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...

     intoxication
  • Paget's disease of the bone
  • multiple myeloma
    Multiple myeloma
    Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...


Renal failure

  • severe secondary hyperparathyroidism
    Secondary hyperparathyroidism
    Secondary hyperparathyroidism refers to the excessive secretion of parathyroid hormone by the parathyroid glands in response to hypocalcemia and associated hypertrophy of the glands. This disorder is especially seen in patients with chronic renal failure...

  • aluminium
    Aluminium
    Aluminium or aluminum is a silvery white member of the boron group of chemical elements. It has the symbol Al, and its atomic number is 13. It is not soluble in water under normal circumstances....

     intoxication
  • milk-alkali syndrome
    Milk-alkali syndrome
    In medicine, milk-alkali syndrome, also called Burnett's syndrome in honour of Charles Hoyt Burnett, the American physician who first described it, is characterized by hypercalcemia caused by repeated ingestion of calcium and absorbable alkali...


Treatments

The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause.

Initial therapy: fluids and diuretics

  • hydration, increasing salt intake, and forced diuresis
    Forced diuresis
    Forced diuresis may enhance the excretion of certain drugs in urine and is used to treat drug overdose or poisoning of these drugs and hemorrhagic cystitis.-Diuretics:...

    .
    • hydration is needed because many patients are dehydrated due to vomiting or renal defects in concentrating urine.
    • increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion (In other words, calcium and sodium (salt) are handled in a similar way by the kidney. Anything that causes increased sodium (salt) excretion by the kidney will, en passant, cause increased calcium excretion by the kidney)
    • after rehydration, a loop diuretic
      Loop diuretic
      Loop diuretics are diuretics that act on the ascending loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency...

       such as furosemide
      Furosemide
      Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...

       can be given to permit continued large volume intravenous salt and water replacement while minimizing the risk of blood volume overload and pulmonary oedema
      Pulmonary edema
      Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...

      . In addition, loop diuretics tend to depress renal calcium reabsorption thereby helping to lower blood calcium levels
    • can usually decrease serum calcium by 1–3 mg/dL within 24 h
    • caution must be taken to prevent potassium or magnesium
      Magnesium deficiency (medicine)
      Magnesium deficiency refers to an intake of dietary magnesium below minimal levels, which can result in numerous symptoms and diseases. These can generally be remedied by an increase of magnesium in diet or oral supplements...

       depletion

Additional therapy: bisphosphonates and calcitonin

  • bisphosphonates are pyrophosphate
    Pyrophosphate
    In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...

     analogues with high affinity for bone, especially areas of high bone-turnover.
    • they are taken up by osteoclast
      Osteoclast
      An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...

      s and inhibit osteoclastic bone resorption
    • current available drugs include (in order of potency): (1st gen) etidronate, (2nd gen) tiludronate, IV pamidronate, alendronate
      Alendronate
      Alendronic acid or alendronate sodium — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...

       (3rd gen) zoledronate
      Zoledronate
      Zoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...

       and risedronate
      Risedronate
      Risedronic acid or risedronate sodium is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Warner Chilcott, Sanofi-Aventis, and in Japan by Takeda under the trade names Actonel, Atelvia, and Benet...

    • all patients with cancer-associated hypercalcaemia should receive treatment with bisphosphonates since the 'first line' therapy (above) cannot be continued indefinitely nor is it without risk. Further, even if the 'first line' therapy has been effective, it is a virtual certainty that the hypercalcaemia will recur in the patient with hypercalcaemia of malignancy. Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative
    • patients in renal failure
      Renal failure
      Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

       and hypercalcaemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in renal failure
      Renal failure
      Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

      .

  • Calcitonin
    Calcitonin
    Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...

     blocks bone resorption and also increases urinary calcium excretion by inhibiting renal calcium reabsorption
    • Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
    • Helps prevent recurrence of hypercalcaemia
    • Dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely

Other therapies

  • rarely used, or used in special circumstances
    • plicamycin
      Plicamycin
      Plicamycin is an antineoplastic antibiotic produced by Streptomyces plicatus. It is an RNA synthesis inhibitor...

       inhibits bone resorption (rarely used)
    • gallium nitrate
      Gallium nitrate
      Gallium nitrate is the gallium salt of nitric acid with the chemical formula Ga3. It is a drug used to treat symptomatic hypercalcemia secondary to cancer. It works by preventing the breakdown of bone through the inhibition of osteoclast activity, thus lowering the amount of free calcium in the...

       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 hypercalcaemia due to osteolytic malignancies (multiple myeloma
        Multiple myeloma
        Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...

        , leukaemia
        Leukemia
        Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

        , Hodgkin's lymphoma
        Hodgkin's lymphoma
        Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...

        , carcinoma of the breast
        Breast cancer
        Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

        ) due to antitumor properties
      • also effective in hypervitaminosis D
        Hypervitaminosis D
        Hypervitaminosis D is a state of vitamin D toxicity.The recommended daily allowance is 400 IU per day. Overdose has been observed at 1925 µg/d...

         and sarcoidosis
        Sarcoidosis
        Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

    • dialysis
      Dialysis
      In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...

       usually used in severe hypercalcaemia complicated by renal failure
      Renal failure
      Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

      . Supplemental phosphate should be monitored and added if necessary
    • phosphate
      Phosphate
      A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

       therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium

Hypercalcaemic crisis

A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/l).

The main symptoms of a hypercalcaemic crisis are oliguria
Oliguria
Oliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...

 or anuria
Anuria
Anuria means nonpassage of urine, in practice is defined as passage of less than 50 milliliters of urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur because of some severe obstruction like kidney stones or tumours. It may occur with end stage renal...

, as well as somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

 or coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

. After recognition, primary hyperparathyroidism should be proved or excluded.

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death. The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium. Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...

, as well as bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...

s (which have effect on calcium levels after one or two days).

See also

  • Calcium metabolism
    Calcium metabolism
    Calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health....

  • Dent's Disease
    Dent's disease
    Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, hypercalciuria, calcium nephrolithiasis, nephrocalcinosis and chronic renal failure."Dent's...

  • Hypocalcaemia
    Hypocalcaemia
    In medicine, hypocalcaemia is the presence of low serum calcium levels in the blood, usually taken as less than 2.1 mmol/L or 9 mg/dl or an ionized calcium level of less than 1.1 mmol/L or 4.5 mg/dL. It is a type of electrolyte disturbance...

  • Electrolyte disturbance
    Electrolyte disturbance
    Electrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Electrolyte imbalances can develop by the following mechanisms: excessive ingestion; diminished...

  • Disorders of calcium metabolism
    Disorders of calcium metabolism
    Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body....

  • ATC code V03#V03AG Drugs for treatment of hypercalcemia
  • CYP24A1
    CYP24A1
    1,25-dihydroxyvitamin D3 24-hydroxylase, mitochondrial is an enzyme that in humans is encoded by the CYP24A1 gene.This gene encodes a member of the cytochrome P450 superfamily of enzymes...

    could play a role in Severe Infantile Hypercalcemia.
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