hypercalcemia

What is hypercalcemia

Hypercalcemia means you have too much calcium in your blood. Too much calcium in your blood can weaken your bones, create kidney stones, and interfere with how your heart and brain work.

Your blood calcium level may get too high due to:

  • Certain kinds of cancers
  • Problems with certain glands
  • Too much vitamin D in your system
  • Being on bed rest for a long time

The most common causes of hypercalcemia are primary hyper-parathyroidism (a result of overactive parathyroid glands) and malignancy. The parathyroid glands are four tiny glands are situated behind your thyroid gland. Other causes of hypercalcemia include cancer, certain other medical disorders, familial hypocalciuric hypercalcemia, some medications, and taking too much of calcium and vitamin D supplements 1).

Signs and symptoms of hypercalcemia range from nonexistent to severe. Hypercalcemia diagnosis often is made incidentally in asymptomatic patients when a high calcium level is detected in blood samples.

Hypercalcemia leads to hyperpolarization of cell membranes. Patients with levels of calcium between 10.5 and 12 mg per dL can be asymptomatic 2). When the serum calcium level rises above this stage, multi-system manifestations become apparent. This constellation of symptoms has led to the mnemonic “Stones, bones, abdominal moans, and psychic groans,” which is used to recall the signs and symptoms of hypercalcemia, particularly as a result of primary hyperparathyroidism.

Neuromuscular effects include impaired concentration, confusion, corneal calcification, fatigue, and muscle weakness 3). Nausea, abdominal pain, anorexia, constipation, and, rarely, peptic ulcer disease or pancreatitis are among the gastrointestinal manifestations. The most important renal effects are polydipsia and polyuria resulting from nephrogenic diabetes insipidus, and nephrolithiasis resulting from hypercalciuria. Other renal effects include dehydration and nephrocalcinosis. Cardiovascular effects include hypertension, vascular calcification, and a shortened QT interval on the electrocardiogram. Cardiac arrhythmias are rare. Bone pain can occur in patients with hyperparathyroidism or malignancy. Osteoporosis of cortical bone, such as the wrist, is mainly associated with primary hyperparathyroidism 4). Excess parathyroid hormone (PTH) also can result in subperiosteal resorption, leading to osteitis fibrosa cystica with bone cysts and brown tumors of the long bones.

Clinical manifestations of hypercalcemia

  • Renal “stones”
    • Nephrolithiasis
    • Nephrogenic diabetes insipidus
    • Dehydration
    • Nephrocalcinosis
  • Skeleton “bones”
    • Bone pain
    • Arthritis
    • Osteoporosis
    • Osteitis fibrosa cystica in hyperparathyroidism (subperiosteal resorption, bone cysts)
  • Gastrointestinal “abdominal moans”
    • Nausea, vomiting
    • Anorexia, weight loss
    • Constipation
    • Abdominal pain
    • Pancreatitis
    • Peptic ulcer disease
  • Neuromuscular “psychic groans”
    • Impaired concentration and memory
    • Confusion, stupor, coma
    • Lethargy and fatigue
    • Muscle weakness
    • Corneal calcification (band keratopathy)
  • Cardiovascular
    • Hypertension
    • Shortened QT interval on electrocardiogram
    • Cardiac arrhythmias
    • Vascular calcification
  • Other
    • Itching
    • Keratitis, conjunctivitis

Treatment depends on the underlying disorder. The principal challenges in the management of hypercalcemia are distinguishing primary hyperparathyroidism from conditions that will not respond to parathyroidectomy and knowing when it is appropriate to refer the patient for surgery.

Many patients with primary hyperparathyroidism have a benign course and do not need surgery. Hypercalcemic crisis is a life-threatening emergency. Aggressive intravenous rehydration is the mainstay of management in severe hypercalcemia, and antiresorptive agents, such as calcitonin and bisphosphonates, frequently can alleviate the clinical manifestations of hypercalcemic disorders.

Figure 1. Hypercalcemia

Hypercalcemia

Footnote: Spectrum of hypercalcemia indicated by serum total and ionized calcium levels

What is Calcium

Calcium is the most plentiful mineral found in the human body. Your skeleton contains 98 percent of total body calcium; the remaining 2 percent circulates throughout your body. Nerve cells, body tissues, blood, and other body fluids contain the rest of the calcium.

Calcium is one of the most important minerals for the human body. It helps form and maintain healthy teeth and bones. A proper level of calcium in the body over a lifetime can help prevent osteoporosis.

Calcium helps your body with:

  • Building strong bones and teeth
  • Clotting blood
  • Sending and receiving nerve signals
  • Squeezing and relaxing muscles
  • Releasing hormones and other chemicals
  • Keeping a normal heartbeat

One half of circulating calcium is free (ionized) calcium, the only form that has physiologic effects. The remainder is bound to albumin, globulin, and other inorganic molecules. Low albumin levels can affect the total serum calcium level. Each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL without affecting the ionized calcium concentration. Thus, directly measuring the free calcium level is more convenient and accurate, but the following formula can be used to calculate the corrected total serum calcium level:

  • Corrected calcium (mg/dL) = 0.8 x (4.0 g per dL –[plasma albumin]) + [serum calcium (mg/dL)]

Note that calcium correction based on the above calculation may be inaccurate, particularly in geriatric patients. Ionized calcium levels should be obtained if hypocalcemia is considered to be clinically significant.

Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (calcitriol), and calcitonin control calcium homeostasis in your body. Increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal excretion of calcium cause hypercalcemia. Normal serum calcium levels are 8 to 10 mg per dL (2.0 to 2.5 mmol per L), although the exact range can vary among laboratories. Normal ionized calcium levels are 4 to 5.6 mg per dL (1 to 1.4 mmol per L). Hypercalcemia is considered mild if the total serum calcium level is between 10.5 and 12 mg per dL (2.63 and 3 mmol per L).5 Levels higher than 14 mg per dL (3.5 mmol per L) can be life threatening.

Actions of the hormones involved in calcium homeostasis

  • Parathyroid hormone (PTH) causes ↑Calcium, ↓Phosphate (PO4) levels in your blood
    • Parathyroid hormone effect on bones: Supports osteoclast resorption
    • Parathyroid hormone effect on gut: Indirect effects via ↑calcitriol from 1-hydroxylation
    • Parathyroid hormone effect on kidneys: Supports calcium resorption and phosphate (PO4) excretion, activates 1-hydroxylation
  • Vitamin D (also referred to as “calciferol”) is a steroid hormone that is obtained through your diet or produced by the action of sunlight on vitamin D precursors in your skin. Calcitriol (vitamin D3 or 1,25-dihydroxyvitamin D [1,25(OH)2D]), the active form of vitamin D, is derived from successive hydroxylation of the precursor cholecalciferol, first in the liver (25-hydroxylation), then in the kidneys (1-hydroxylation). Adequate vitamin D is necessary for bone formation. However, the principal target for vitamin D is the gut, where it increases the absorption of calcium and phosphate. Thus, in vitamin D-mediated hypercalcemia, serum phosphate levels tend to be high.
    • Calcitriol (vitamin D3 or 1,25-dihydroxyvitamin D [1,25(OH)2D]) causes ↑Calcium and ↑Phosphate (PO4) levels in your blood
    • Calcitriol (vitamin D3 or 1,25-dihydroxyvitamin D [1,25(OH)2D]) effect on bones: No direct effects
    • Calcitriol (vitamin D3 or 1,25-dihydroxyvitamin D [1,25(OH)2D]) effect on gut: ↑Calcium and ↑Phosphate (PO4) absorption
    • Calcitriol (vitamin D3 or 1,25-dihydroxyvitamin D [1,25(OH)2D]) effect on kidneys: No direct effects
  • Calcitonin is a 32-amino acid hormone produced by the parafollicular C cells of the thyroid. Calcitonin is a weak inhibitor of osteoclast activation and opposes the effects of PTH on the kidneys, thereby promoting calcium and phosphate excretion. Calcitonin levels might be elevated in pregnant patients and in patients with medullary carcinoma of the thyroid. However, there are no direct clinical sequelae, and serum calcium levels usually are normal.
    • Calcitonin causes ↓Calcium and ↓Phosphate (PO4) levels in blood when hypercalcemia is present
    • Calcitonin effect on bones: Inhibits osteoclast resorption
    • Calcitonin effect on gut: No direct effects
    • Calcitonin effect on kidneys: Promotes calcium and phosphate (PO4) excretion
  • PTH-related peptide (PTHrP) is the principal mediator in hypercalcemia associated with solid tumors 5). PTHrP is homologous with PTH at the amino terminus, the region that comprises the receptor-binding domain. PTHrP binds the PTH receptor and mimics the biologic effects of PTH on bones and the kidneys.

Hypercalcemia outlook (prognosis)

How well you do depends on the cause of your high calcium level. The outlook is good for people with mild hyperparathyroidism or hypercalcemia that have a treatable cause. Most of the time, there are no complications.

People with hypercalcemia due to conditions such as cancer or sarcoidosis may not do well. This is most often due to the disease itself, rather than the high calcium level.

Hypercalcemia possible complications

Gastrointestinal

  • Pancreatitis
  • Peptic ulcer disease

Kidney

  • Calcium deposits in the kidney (nephrocalcinosis)
  • Dehydration
  • High blood pressure
  • Kidney failure. Severe hypercalcemia can damage your kidneys, limiting their ability to cleanse the blood and eliminate fluid.
  • Kidney stones. If your urine contains too much calcium, crystals may form in your kidneys. Over time, the crystals may combine to form kidney stones. Passing a stone can be extremely painful.

Psychological

  • Depression
  • Difficulty concentrating or thinking
  • Nervous system problems. Severe hypercalcemia can lead to confusion, dementia and coma, which can be fatal.

Skeletal

  • Bone cysts
  • Fractures
  • Osteoporosis. If your bones continue to release calcium into your blood, you can develop the bone-thinning disease osteoporosis, which could lead to bone fractures, spinal column curvature and loss of height.

Heart

  • Abnormal heart rhythm (arrhythmia). Hypercalcemia can affect the electrical impulses that regulate your heartbeat, causing your heart to beat irregularly.

These complications of long-term hypercalcemia are uncommon today.

Hypercalcemia causes

Besides building strong bones and teeth, calcium helps muscles contract and nerves transmit signals. Normally, if there isn’t enough calcium in your blood, your parathyroid glands secrete a parathyroid hormone (PTH) hormone that triggers:

  • Your bones to release calcium into your blood
  • Your digestive tract to absorb more calcium
  • Your kidneys to excrete less calcium and activate more vitamin D, which plays a vital role in calcium absorption

This delicate balance between too little calcium in your blood and hypercalcemia can be disrupted by a variety of factors.

PTH (parathyroid hormone) is an 84-amino acid hormone produced by the four pea-sized parathyroid glands posterior to the thyroid gland. In response to low serum calcium levels, PTH raises calcium levels by accelerating osteoclastic bone resorption and increasing renal tubular resorption of calcium. It also increases calcitriol, which indirectly raises serum calcium levels. PTH causes phosphate loss through the kidneys. Thus, in patients with PTH-mediated hypercalcemia, serum phosphate levels tend to be low.

What causes hypercalcemia?

Parathyroid hormone (PTH) and Vitamin D help manage calcium balance in the body.

  • Parathyroid hormone (PTH) is made by the parathyroid glands. These are four small glands located in the neck behind the thyroid gland.
  • Vitamin D is obtained when the skin is exposed to sunlight, and from dietary sources.

The most common cause of high calcium blood level is excess parathyroid hormone (PTH) released by the parathyroid glands. This excess occurs due to:

  • An enlargement of one or more of the parathyroid glands.
  • A growth on one of the glands. Most of the time, these growths are benign.

Men and women of all ages can have a high blood calcium level. However, it is most common in women over age 50 (after menopause). In most cases, this is due to an overactive parathyroid gland.

Hypercalcemia causes

  • Parathyroid hormone-related
    • Primary hyperparathyroidism*: Sporadic, familial, associated with multiple endocrine neoplasia 1 (MEN 1) or 2 (MEN 2)
    • Tertiary hyperparathyroidism: Associated with chronic kidney disease or kidney failure or vitamin D deficiency
  • Vitamin D-related
    • Vitamin D intoxication: Usually 25-hydroxyvitamin D2 (also known as “calcidiol”) in over-the-counter supplements. In suspected overdose of over-the-counter vitamin D, the level of 25-hydroxyvitamin D3 (“calcidiol”), not 1,25-dihydroxyvitamin D3 (“calcitriol” or 1,25-dihydroxyvitamin D [1,25(OH)2D]) should be measured. Macrophages can cause granuloma-forming (i.e., sarcoidosis, tuberculosis, Hodgkin’s lymphoma) increased extra-renal conversion of 25-hydroxyvitamin D3 to calcitriol. PTH levels are suppressed, and levels of 1,25-dihydroxyvitamin D3 are elevated. Hypercalcemia mediated by excessive vitamin D responds to a short course of glucocorticoids if the underlying disease is treated.
    • Granulomatous disease sarcoidosis, berylliosis, tuberculosis. Tuberculosis, Paget’s disease and sarcoidosis can raise blood levels of vitamin D, which stimulates your digestive tract to absorb more calcium.
    • Hodgkin’s lymphoma
  • Malignancy
    • Humoral hypercalcemia of malignancy* (mediated by PTH-related peptide [PTHrP]). Hypercalcemia of malignancy occurs in several settings 6). It is mediated most commonly by systemic PTH-related peptide (PTHrP) in patients with solid tumors. This is known as the humoral hypercalcemia of malignancy. PTHrP mimics the bone and renal effects of PTH. In contrast to primary hyperparathyroidism, the humoral hypercalcemia of malignancy is associated with suppressed PTH levels and normal calcitriol levels. Extensive bone lysis also can cause malignancy-associated hypercalcemia. Multiple myeloma and metastatic breast cancer can present in this way. In osteolytic hypercalcemia, the alkaline phosphatase level is usually markedly elevated. Hodgkin’s lymphoma causes hypercalcemia through increased production of calcitriol.
    • Solid tumors, especially lung, head, and neck squamous cancers, renal cell tumors
    • Local osteolysis* (mediated by cytokines) multiple myeloma, breast cancer
  • Medications
    • Thiazide diuretics (usually mild)*: Thiazide diuretics increase renal calcium resorption and cause mild hypercalcemia that should resolve when the medication is discontinued. Thiazide diuretic therapy can unmask many cases of primary hyperparathyroidism.
    • Lithium: Lithium use can cause hypercalcemia by increasing the set point of PTH, requiring a higher serum calcium level to switch off PTH secretion 7).
    • Milk-alkali syndrome (from calcium antacids). Consumption of large amounts of calcium carbonate via calcium-containing antacids can lead to hypercalcemia, alkalosis, and renal insufficiency—an uncommon disorder termed milk-alkali syndrome 8).
    • Vitamin A intoxication (including analogs used to treat acne). Large doses of vitamin A and its analogs can cause hypercalcemia, which appears to be mediated through increased bone resorption.
  • Other endocrine disorders
    • Hyperthyroidism (overactive thyroid gland): Thyrotoxicosis-induced bone resorption can result in mild hypercalcemia.
    • Adrenal insufficiency
    • Acromegaly
    • Pheochromocytoma: Pheochromocytoma is thought to cause hypercalcemia through the production of PTHrP. Pheochromocytoma may be associated with primary hyperparathyroidism as part of type 1 multiple endocrine neoplasia syndrome (MEN-1).
  • Genetic disorders
    • Familial hypocalciuric hypercalcemia: mutated calcium-sensing receptor
  • Other
    • Immobilization, with high bone turnover (e.g., Paget’s disease, bedridden child)
      • Being on bed rest for a long time.
      • Being bed-bound (or not being able to move) for a long period of time. People who have a condition that causes them to spend a lot of time sitting or lying down can develop hypercalcemia. Over time, bones that don’t bear weight release calcium into the blood.
    • Recovery phase of rhabdomyolysis. Hypercalcemia also can occur in the recovery phase of rhabdomyolysis-induced renal injury, when calcium deposited in soft tissue is mobilized.
    • Too much calcium in your diet. This is called milk-alkali syndrome. It most often occurs when a person is taking more than 2000 milligrams of calcium bicarbonate supplements a day.
    • An inherited condition that affects the body’s ability to manage calcium. A rare genetic disorder known as familial hypocalciuric hypercalcemia causes an increase of calcium in your blood because of faulty calcium receptors in your body. Familial hypocalciuric hypercalcemia doesn’t cause symptoms or complications of hypercalcemia.
    • Severe dehydration. Calcium blood level may also be high if your body is low on fluids or water. A common cause of mild or transient hypercalcemia is dehydration. Having less fluid in your blood causes a rise in calcium concentrations.

NOTE: * The most common causes of hypercalcemia.

Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia is an inherited disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with virtually 100 percent penetrance. Familial hypocalciuric hypercalcemia is characterized biochemically by lifelong modest elevation of the serum calcium concentration with a relatively mismatched hypocalciuria and normal or mildly elevated circulating parathyroid hormone (PTH) level that is not suppressed by the hypercalcemia 9). Individuals with familial hypocalciuric hypercalcemia are usually asymptomatic and the disorder is considered benign.

Patients have moderate hypercalcemia from an early age but relatively low urinary calcium excretion. PTH levels can be normal or only mildly elevated despite the hypercalcemia. This mild elevation can lead to an erroneous diagnosis of primary hyperparathyroidism. Familial hypocalciuric hypercalcemia can be differentiated by use of a 24-hour urinary collection for calcium; calcium levels will be high or normal in patients with hyperparathyroidism and low in patients with familial hypocalciuric hypercalcemia. Parathyroidectomy is not beneficial in patients with familial hypocalciuric hypercalcemia.

Familial hypocalciuric hypercalcemia is associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CaSR) gene 10). The calcium-sensing receptor (CaSR) protein is a G-protein-coupled receptor that belongs to family (or class) C, which includes seven exons and is mainly expressed in parathyroid and renal tubule cells, as well as in bones 11).

Calcium-sensing receptor (CaSR) helps maintain a nearly constant levels of extracellular calcium (Cao2+) in the blood and other extracellular fluids. By sensing even minute changes in the Cao2+ from its normal level, CaSR modulates the functions of key tissues, especially the parathyroid glands and the kidneys.5 In the parathyroid glands, CaSR senses perturbations in the Cao2+ level of only a few percent and then responds to the hypocalcemia by increasing PTH secretion, stabilizing mRNA and inducing the proliferation of parathyroid cells. In the kidneys, CaSR stimulates Ca2+ reabsorption in the cortical thick ascending limb in response to hypocalcemia, and 1-hydroxylation of 25-hydroxyvitamin D3 [25(OH)D3] in the proximal renal tubules 12).

Calcium-sensing receptor (CaSR) is also expressed in the skeleton, but the importance of CaSR in bone formation and resorption remains somewhat controversial. Studies in mice with a conditional knockout of the CaSR gene have indicated that CaSR has key roles in osteoblasts 13). The skeleton could mediate PTH independently with the homeostatical uptake or release of calcium during induced hypocalciuria, actions that may involve the CaSR gene. The calcium-sensing receptor is present in the skeleton, and the absence of exon 5 results in defective mineralization of cartilage and bone, which produces rickets as the predominant skeletal abnormality in mouse models 14). In case reports, human familial hypocalciuric hypercalcemia caused by inactive mutations of CaSR rarely manifested as rickets. A recent report described a patient who developed severe adolescent rickets due to vitamin D deficiency 15). Another report considered that vitamin D deficiency modulates the severity of familial hypocalciuric hypercalcemia 16).

Hypercalcemia prevention

Most causes of hypercalcemia cannot be prevented. Women over age 50 should see their health care provider regularly and have their blood calcium level checked if they have symptoms of hypercalcemia.

Talk to your health care provider about the correct dose if you are taking calcium and vitamin D supplements.

Hypercalcemia signs and symptoms

You might not have signs or symptoms if your hypercalcemia is mild. Hypercalcemia is most often diagnosed at an early stage using routine blood tests. More-severe cases produce signs and symptoms related to the parts of your body affected by the high calcium levels in your blood.

Hypercalcemia symptoms may include:

  • Kidneys. Excess calcium in your blood means your kidneys have to work harder to filter it. This can cause excessive thirst and frequent urination.
  • Digestive system. Hypercalcemia can cause stomach upset, nausea, vomiting, poor appetite and constipation.
  • Bones. In most cases, the excess calcium in your blood was leached from your bones, which weakens them. This can cause bone pain, muscle weakness and depression. Bone pain and long-term spine changes, if the bones have become thinner or weaker.
  • Muscle weakness or twitches
  • Brain. Hypercalcemia can interfere with the way your brain works, resulting in confusion, lethargy and fatigue. It can also cause depression.
  • Heart. Rarely, severe hypercalcemia can interfere with your heart function, causing palpitations and fainting, indications of cardiac arrhythmia, and other heart problems.

Most people have no symptoms.

Symptoms due to high calcium level may vary, depending on the cause and how long the problem has been present.

Clinical manifestations of hypercalcemia

  • Renal “stones”
    • Nephrolithiasis
    • Nephrogenic diabetes insipidus
    • Dehydration
    • Nephrocalcinosis
  • Skeleton “bones”
    • Bone pain
    • Arthritis
    • Osteoporosis
    • Osteitis fibrosa cystica in hyperparathyroidism (subperiosteal resorption, bone cysts)
  • Gastrointestinal “abdominal moans”
    • Nausea, vomiting
    • Anorexia, weight loss
    • Constipation
    • Abdominal pain
    • Pancreatitis
    • Peptic ulcer disease
  • Neuromuscular “psychic groans”
    • Impaired concentration and memory
    • Confusion, stupor, coma
    • Lethargy and fatigue
    • Muscle weakness
    • Corneal calcification (band keratopathy)
  • Cardiovascular
    • Hypertension
    • Shortened QT interval on electrocardiogram
    • Cardiac arrhythmias
    • Vascular calcification
  • Other
    • Itching
    • Keratitis, conjunctivitis

Hypercalcemia diagnosis

Because hypercalcemia can cause few, if any, signs or symptoms, you might not know you have the disorder until routine blood tests show a high level of blood calcium. Blood tests also can reveal whether your parathyroid hormone level is high, indicating that you have hyperparathyroidism.

To determine if your hypercalcemia is caused by an underlying problem, such as cancer or sarcoidosis, your doctor might recommend imaging tests of your bones or lungs.

Hypercalcemia workup

An accurate diagnosis is needed in hypercalcemia. Patients with kidney stones should have tests to evaluate for hypercalcemia.

  • Serum calcium
  • Serum parathyroid hormone (PTH)
  • Serum PTHrP (PTH-related protein)
  • Serum vitamin D level
  • Urine calcium

Figure 2. Hypercalcemia workup

Hypercalcemia workup

Footnotes: Diagnostic algorithm for the evaluation of hypercalcemia. Primary hyperparathyroidism and malignancy account for more than 90 percent of cases. Intact PTH will be suppressed in cases of malignancy-associated hypercalcemia, except for the extremely rare parathyroid carcinoma. The physician can conclude diagnostic testing and treat the causative disorder once a final diagnosis step has been reached.

Abbreviations: Ca++ = calcium; OTC = over-the-counter; PTH = parathyroid hormone; PTHrP = parathyroid hormone-related peptide; TSH = thyroid-stimulating hormone; T4 = free thyroxine; MRI = magnetic resonance imaging.

Figure 3. Interpreting serum Intact PTH levels

Interpreting serum Intact PTH levels

Footnote: Representative serum calcium and PTH (parathyroid hormone) levels in patients with calcium disorders. The four differently shaped panels depict where the serum calcium level will plot in relation to the PTH level in various conditions. In primary hyperparathyroidism, a high PTH level correlates with a high calcium level. In malignancy-associated hypercalcemia, PTH is suppressed.

Hypercalcemia treatment

Treatment is aimed at the cause of hypercalcemia whenever possible. People with primary hyperparathyroidism (PHPT) may need surgery to remove the abnormal parathyroid gland. This will cure the hypercalcemia.

People with mild hypercalcemia may be able to monitor the condition closely over time. Asymptomatic patients with mild hypercalcemia generally do not benefit from normalization of their serum calcium levels. Patients with calcium levels greater than 14 mg per dL or symptomatic patients with calcium levels greater than 12 mg per dL should be immediately and aggressively treated 17).

Extremely high calcium levels can be a medical emergency. You might need hospitalization for treatment with IV fluids and diuretics to promptly lower the calcium level to prevent heart rhythm problems or damage to the nervous system.

The safest and most effective treatment of hypercalcemic crisis is saline rehydration followed by furosemide (Lasix) diuresis, calcitonin, and bisphosphonates.

Severe hypercalcemia that causes symptoms and requires a hospital stay may be treated with the following:

  • Fluids through a vein: IV fluids is the most important therapy. Volume expansion and glucocorticoid replacement can correct the hypercalcemia that occasionally occurs in patients with adrenal insufficiency.
  • Calcitonin (Miacalcin). This hormone from salmon controls calcium levels in the blood. Mild nausea might be a side effect.
  • Calcimimetics. This type of drug can help control overactive parathyroid glands. Cinacalcet (Sensipar) has been approved for managing hypercalcemia.
  • Dialysis, if kidney damage is involved
  • Diuretic medicine, such as furosemide
  • Drugs that stop bone breakdown and absorption by the body (bisphosphonates). Intravenous osteoporosis drugs, which can quickly lower calcium levels, are often used to treat hypercalcemia due to cancer. Risks associated with this treatment include osteonecrosis of the jaw and certain types of thigh fractures.
  • Denosumab (Prolia, Xgeva). This drug is often used to treat people with cancer-caused hypercalcemia who don’t respond well to bisphosphonates.
  • Glucocorticoids (steroids). If your hypercalcemia is caused by high levels of vitamin D, short-term use of steroid pills such as prednisone are usually helpful.

When you were in the hospital, you were given fluids through an IV and drugs to help lower the calcium level in your blood. If you have cancer, you may have had treatment for that, as well. If your hypercalcemia is caused by a gland problem, you may have had surgery to remove that gland.

Table 1. Medications for the treatment of hypercalcemia

AgentMode of actionIndication in hypercalcemiaCautions
Normal saline 2 to 4 L IV daily for 1 to 3 daysEnhances filtration and excretion of Ca++Severe↑Ca++ > 14 mg per dL (3.5 mmol per L) Moderate↑Ca++ with symptomsMay exacerbate heart failure in elderly patients Lowers Ca++ by 1 to 3 mg per dL (0.25 to 0.75 mmol per L)
Furosemide (Lasix) 10 to 20 mg IV as necessaryInhibits calcium resorption in the distal renal tubuleFollowing aggressive rehydration↓K+, dehydration if used before intravascular volume is restored
Bisphosphonates Pamidronate (Aredia), 60 to 90 mg IV over 4 hours Zoledronic acid (Zometa), 4 mg IV over 15 minutesInhibits osteoclast action and bone resorptionHypercalcemia of malignancyNephrotoxicity, ↓Ca++, ↓PO4, rebound↑Ca++ in hyperparathyroidism Maximal effects at 72 hours
Calcitonin (Calcimar or Miacalcin) 4 to 8 IU per kg IM or SQ every 6 hours for 24 hoursInhibits bone resorption, augments Ca++ excretionInitial treatment (after rehydration) in severe/Ca++Rebound↑Ca++ after 24 hours, vomiting, cramps, flushing Rapid↑Ca++ within 2 to 6 hours
Glucocorticoids Hydrocortisone, 200 mg IV daily for 3 daysInhibits vitamin D conversion to calcitriolVitamin D intoxication, hematologic malignancies, granulomatous diseaseImmune suppression, myopathy
Plicamycin (Mithracin), 25 mcg per kg per day IV over 6 hours for 3 to 8 dosesCytotoxic to osteoclastsRarely used in severe↑Ca++Marrow, hepatic, renal toxicity
Gallium nitrate (Ganite) 100 to 200 mg per m2 IV over 24 hours for 5 daysInhibits osteoclast actionRarely used in severe↑Ca++Renal and marrow toxicity

Abbreviations: IV = intravenously; Ca++ = calcium;/ = increase; ¬ = decrease; K+ = potassium; PO4 = phosphate radical; IM = intramuscularly; SQ = subcutaneously.

Hydration and diuresis

In patients with mild hypercalcemia, adequate hydration should be encouraged and immobilization discouraged. In symptomatic patients, a loop diuretic (e.g., furosemide) can be prescribed. Recent evidence suggests that estrogen-replacement therapy might be beneficial in postmenopausal women with primary hyperparathyroidism 18). In patients with severe hypercalcemia, the mainstay of management is aggressive intravenous rehydration. Normal saline should be used to achieve a urine output of 200 mL per hour. Only when the intravascular volume has been restored should a loop diuretic be used in low dosages (e.g., furosemide, 10 to 20 mg) to further lower the serum calcium level if necessary.

Medications

In malignancy-associated hypercalcemia, intravenous pamidronate (Aredia), 60 to 90 mg, can be given by four-hour infusion 19). This agent often will normalize the serum calcium level, but peak effects do not occur until 48 to 72 hours after infusion. Caution must be used with bisphosphonates19 in patients with renal impairment. In severe hypercalcemia refractory to saline diuresis, calcitonin (Calcimar, Miacalcin) can be given every six hours. This treatment has a rapid onset but short duration of effect, and patients develop tolerance to the calcium-lowering effect. Other antiresorptive agents that are used occasionally include plicamycin (Mithracin) and gallium nitrate (Ganite). In hypercalcemia mediated by vitamin D and in hematologic malignancies (e.g., myeloma, lymphoma), glucocorticoids are the first line of therapy after fluids.

Hemodialysis

In cases of resistant, life-threatening hypercalcemia, hemodialysis against a low-calcium dialysate is more effective than peritoneal dialysis in lowering serum calcium levels. Therapy for the underlying condition should be instituted as soon as possible. Consultation with an endocrinologist is recommended.

Surgical and other procedures

Problems associated with overactive parathyroid glands often can be cured by surgery to remove the tissue that’s causing the problem. In cases of hypercalcemic crisis resulting from primary hyperparathyroidism, urgent parathyroidectomy is potentially curative 20). In many cases, only one of a person’s four parathyroid glands is affected. A special scanning test uses an injection of a small dose of radioactive material to pinpoint the gland or glands that aren’t working properly.

Criteria for surgery in Primary hyperparathyroidism 21):

  • Serum total calcium level > 12 mg per dL (3 mmol per L) at any time
  • Hyperparathyroid crisis (discrete episode of life-threatening hypercalcemia)
  • Marked hypercalciuria (urinary calcium excretion more than 400 mg per day)
  • Nephrolithiasis
  • Impaired renal function
  • Osteitis fibrosa cystica
  • Reduced cortical bone density (measure with dual x-ray absorptiometry or similar technique): Bone mass more than two standard deviations below age-matched controls (Z score less than 2)
  • Classic neuromuscular symptoms: Proximal muscle weakness and atrophy, hyperreflexia, and gait disturbance
  • Age younger than 50

Hypercalcemia Self-care

After you go home, follow your health care provider’s instructions about making sure your calcium level does not get high again.

You may need to drink a lot of liquids.

  • Make sure you drink as much water every day as your provider recommends.
  • Keep water next to your bed at night and drink some when you get up to use the bathroom.

DO NOT cut back on how much salt you eat.

Your provider may ask you to limit foods with a lot of calcium, or not to eat them at all for a while.

  • Eat fewer dairy foods (such as cheese, milk, yogurt, ice cream) or DO NOT eat them at all.
  • If your provider says you can eat dairy foods, DO NOT eat those that have extra calcium added. Read the labels carefully.

To further keep your calcium level from getting high again:

  • DO NOT use antacids that have a lot of calcium in them. Look for antacids that have magnesium. Ask your provider which ones are OK.
  • Ask your doctor what medicines and herbs are safe for you to take.
  • If your doctor prescribes medicines to help keep your calcium level from getting too high again, take them the way you’re told to. Call your doctor if you have any side effects.
  • Stay active when you get home. Your provider will tell you how much activity and exercise are OK.

You will probably need to get blood tests after you go home.

Keep any follow-up appointments you make with your provider.

References   [ + ]