Hypercalcaemia

Hypercalcemia, also spelled hypercalcaemia, is a high

A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/L).[9]

The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma.^[10] After recognition, primary hyperparathyroidism should be proved or excluded.^[10]

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death.^[10] The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium.^[10] Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have effect on calcium levels after one or two days).^[11]

Causes

Primary hyperparathyroidism and malignancy account for about 90% of cases of hypercalcaemia.^[12][13]

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

Parathyroid function

• Primary hyperparathyroidism
  • Solitary parathyroid adenoma^[14]
  • Primary parathyroid hyperplasia[15]
  • Parathyroid carcinoma^[16]
  • Multiple endocrine neoplasia (MEN1 & MEN2A)^[17]
  • Familial isolated hyperparathyroidism^[18]
• Lithium use
• Familial hypocalciuric hypercalcemia/familial benign hypercalcemia^[19][20][21]

Cancer

Hypercalcemia of malignancy (cancer) is due to a variety of mechanisms. The two most common are humoral hypercalcemia of malignancy and local osteolytic hypercalcemia due to bony metastasis. Humoral hypercalcemia of malignancy involves the tumor releasing a hormone which increases calcium mobilization (most commonly

Hypercalcemia of malignancy may also occur due to tumor production of Vitamin D or parathyroid hormone. These causes are rare and constitute about 1% of all causes of hypercalcemia of malignancy.^[22]

Hypercalcemia of malignancy usually portends a poor prognosis, and the medial survival is 25–52 days of its development.^[22] It has an incidence of 30% in those with cancer, and the prevalence is estimated to be about 2-3% in the United States.^[22]

Common cancer types that are associated with hypercalcemia of malignancy include:

• Solid tumor with metastasis via local osteolytic hypercalcemia: which can be due to any tumor that metastasizes to the bone. But common causes include
  myeloma or lymphoma of the bone^[22]
• Solid tumor with humoral mediation of hypercalcemia:
  urothelial cancers, and breast cancer.^[22]
• Hematologic cancers: including multiple myeloma, lymphoma, leukemia
• Ovarian small cell carcinoma of the hypercalcemic type

Vitamin-D disorders

• Hypervitaminosis D
  (vitamin D intoxication)
• Elevated
  1,25(OH)₂D (see calcitriol under Vitamin D) levels (e.g. sarcoidosis and other granulomatous diseases such as tuberculosis, berylliosis, histoplasmosis, Crohn's disease, and granulomatosis with polyangiitis
  )
• Idiopathic hypercalcaemia of infancy^[23]
• Rebound hypercalcaemia after rhabdomyolysis

High bone-turnover

• Hyperthyroidism
• Multiple myeloma
• Prolonged immobilization
• Paget's disease
• Thiazide use
• Vitamin A intoxication^[15]

Kidney failure

• Tertiary hyperparathyroidism
• Aluminium intoxication
• Milk-alkali syndrome^[15]

Other

• Acromegaly
• Adrenal insufficiency
• Zollinger–Ellison syndrome
• Williams Syndrome
• Excessive calcium consumption

Diagnosis

Diagnosis should generally include either a calculation of

Once calcium is confirmed to be elevated, a detailed history taken from the subject, including review of medications, any vitamin supplementations, herbal preparations, and previous calcium values. Chronic elevation of calcium with absent or mild symptoms often points to primary hyperparathyroidism or Familial hypocalciuric hypercalcemia. For those who has underlying malignancy, the cancers may be sufficiently severe to show up in history and examination to point towards the diagnosis with little laboratory investigations.^[15]

If detailed history and examination does not narrow down the differential diagnoses, further laboratory investigations are performed. Intact PTH (iPTH, biologically active parathyroid hormone molecules) is measured with immunoradiometric or immunochemoluminescent assay. Elevated (or high-normal) iPTH with high urine calcium/creatinine ratio (more than 0.03) is suggestive of primary hyperparathyroidism, usually accompanied by low serum phosphate. High iPTH with low urine calcium/creatinine ratio is suggestive of familial hypocalciuric hypercalcemia. Low iPTH should be followed up with Parathyroid hormone-related protein (PTHrP) measurements (though not available in all labs). Elevated PTHrP is suggestive of malignancy. Normal PTHrP is suggestive of multiple myeloma, vitamin A excess, milk-alkali syndrome, thyrotoxicosis, and immobilisation. Elevated Calcitriol is suggestive of lymphoma, sarcoidosis, granulomatous disorders, and excessive calcitriol intake. Elevated calcifediol is suggestive of vitamin D or excessive calcifediol intake.^[15]

The normal range is 2.1–2.6 

Abnormal

The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause. In those with a calcium level above 13 mg/dL, calcium level that is rising rapidly or those with altered mental status, urgent treatment is required.[22]

Fluids and diuretics

Initial therapy:^{[citation needed]}

• • IV fluids is the initial therapy.^[22] Hypercalcemia usually causes symptoms that lead to chronic dehydration, such as nausea, vomiting, anorexia, and nephrogenic diabetes insipidus (inability of the kidney to concentrate the urine). IV fluid rehydration allows the kidneys to excrete more calcium, and usually lowers the calcium level by 1–2 mg/dL.^[22]
  • increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion.
  • after rehydration, a
    loop diuretics
    tend to depress calcium reabsorption by the kidney thereby helping to lower blood calcium levels
  • caution must be taken to prevent
    magnesium
    depletion

Additional therapy:^[citation needed]

• bisphosphonates are pyrophosphate
  analogues with high affinity for bone, especially areas of high bone-turnover.
  • they are taken up by osteoclasts and inhibit osteoclastic bone resorption, therefore inhibiting calcium release from osteoclasts
  • current available drugs include: (1st generation)
    risedronate
  • Bisphosphonates are used as a first line therapy for those with hypercalcemia of malignancy. They are used as both an acute therapy and are usually continued long term to prevent hypercalcemia.^[22]
  • Bisphosphonates are not recommended in those with chronic kidney disease or those who are severely dehydrated as they may worsen or cause kidney disease.^[22]
  • Bisphosphonates caused normalization of calcium levels in 60-90% of patients who were treated for hypercalcemia of malignancy.^[22]
• Denosumab is a bone anti-resorptive agent that can be used to treat hypercalcemia in patients with a contraindication to bisphosphonates such as severe kidney failure or allergy.
  • Denosumab is a monoclonal antibody that inhibits osteoclasts. It acts by binding
    NFKB.^[22]
  • Denosumab caused normalization of calcium levels in 70% in those with hypercalcemia of malignancy.[22]
• Calcitonin blocks bone resorption by inhibiting osteoclasts and also increases urinary calcium excretion by the kidneys.^[22]
  • Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
  • Due to its limited duration of action (it works for 48–96 hours, then efficacy decreases as the calcitonin receptors are downregulated) its use is limited to acute hypercalcemia as a bridge therapy until more long-term treatments can be initiated.^[22]

Other therapies

• rarely used, or used in special circumstances:
  • plicamycin inhibits bone resorption (rarely used)
  • gallium nitrate inhibits bone resorption and changes structure of bone crystals (rarely used)
  • glucocorticoids
    increase urinary calcium excretion and decrease intestinal calcium absorption
    • no effect on calcium level in normal or primary hyperparathyroidism
    • effective in hypercalcemia due to malignancy with elevated vitamin D levels (many types of malignancies raise the vitamin D level).^[22]
    • also effective in
      hypervitaminosis D and sarcoidosis
  • dialysis usually used in severe hypercalcaemia complicated by kidney failure. Supplemental phosphate should be monitored and added if necessary
  • phosphate therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium, but this can further increase the risk for kidney stones and nephrocalcinosis

Other animals

Research has led to a better understanding of hypercalcemia in non-human animals. Often the causes of hypercalcemia have a correlation to the environment in which the organisms live. Hypercalcemia in house pets is typically due to disease, but other cases can be due to accidental ingestion of plants or chemicals in the home.

In certain outdoor environments, animals such as horses, pigs, cattle, and sheep experience hypercalcemia commonly. In southern

• Calcium metabolism
• Dent's disease
• Electrolyte disturbance
• Disorders of calcium metabolism

References