1 What Is Hypercalcemia?

99% of calcium is stored in the skeleton and the remaining 1% in the blood. Calcium is important for the formation of bones and teeth, transmitting nerve impulses, heart contraction, and contraction of smooth and skeletal muscles. Calcium levels are regulated by the effects of the parathyroid gland and a vitamin in the gut, kidneys, and bones. The increase and decrease in the level of calcium can have a detrimental effect on bodily functions. Hypercalcemia is characterized by abnormally high levels of calcium in the blood. It is a disorder commonly encountered by primary care physicians.

Approximately one in five hundred patients who are treated in a general medicine clinic has undiagnosed primary hyperparathyroidism , the leading cause of hypercalcemia.

It is one of the most common life-threatening disorders and is associated with malignancy.  Almost 10%–20% of people with cancer get hypercalcemia, and 40% of those with myeloma. Hyperparathyroidism and malignancy disease is the common cause and accounts for nearly 90% of cases of hypercalcemia. Patients with breast cancer and multiple myeloma are more at risk, although it may occur in patients with squamous cell carcinoma of the lung, ovarian cancer, cancers of the head, neck, and prostate, and lymphoma.

Diagnosis of hypercalcemia most often is made incidentally when a high calcium level is detected in blood samples. The principal challenges in the management of hypercalcemia are distinguishing primary hyperparathyroidism from conditions that will not respond to a parathyroidectomy and knowing when it is appropriate to refer the patient for surgery.

It is essential that physicians know how to evaluate and optimally manage patients with hypercalcemia, because treatment and prognosis vary according to the underlying disorder.

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2 Symptoms

Symptoms of hypercalcemia are related to the severity and rate of change of calcium levels. More severe symptoms are noted in a sudden rise of calcium levels.

In chronic cases, the body adapts to a slow rise in calcium. Symptoms may also be dominated by the underlying clinical condition causing the disease.

The neuropsychiatric symptoms include:

There is also interference in the transmission of nerve impulses. Such symptoms are more pronounced in the elderly, and symptoms may last for many days even after calcium levels have gone back to normal.

Renal symptoms include:

  • Polyuria: Increased urine output. The kidneys are unable to concentrate urine. It may cause dehydration and decrease the flow of blood through the kidneys. This impairs the kidneys, and they are unable to excrete calcium.
  • Renal stones and renal failure
  • Flank pain
  • Polydipsia
  • Nocturia

Cardiovascular manifestations include:

  • Short QT interval
  • Hypertension
  • Cardiovascular calcifications
  • Increased cardiac muscle contractility and irritability
  • ECG changes
  • Decreased heart rate

The normal contractility of the skeletal, smooth, and cardiac muscles is interfered by these symptoms. Impaired cardiac muscles may cause abnormal heart rhythm or even cardiac arrest.

Gastrointestinal symptoms include:

Gastrointestinal effects are caused by a decrease in smooth muscle activity. This causes delayed gastric emptying and gastrointestinal motility.

Musculoskeletal include:

Patients with hypercalcemia experience bone pain with skeletal metastases. Patients without skeletal metastases may also experience bone pain due to the calcium acting as a neuro-sensitizer, which decreases the pain threshold. Prolonged rise in blood calcium levels may cause the calcium to precipitate within the kidney or the urinary tract, which may result in urinary stone formation. Untreated hypercalcemia may pose a risk for progressive mineralization of bone, hypercalciuria, nephrocalcinosis, and deterioration to renal failure. 

3 Causes

Common causes of hypercalcemia include:

Others include:

  • Sporadic
  • Familial
  • Osteolytic hypercalcemia
  • Humoral hypercalcemia of malignancy
  • Ectopic production of calcitriol (by lymphoma)
  • Hypercalcemia of granulomatous disease
  • Chronic renal failure with aplastic bone disease
  • Tertiary hyperparathyroidism
  • Acute renal failure
  • Familial hypercalcemic hypocalciuria
  • Lithium-associated hypercalcemia
  • Vitamin D intoxication
  • Hypercalcemia of malignancy:
    • Osteolytic hypercalcemia
    • Humoral hypercalcemia of malignancy
    • Ectopic production of calcitriol (by lymphoma)
    • Hypercalcemia of granulomatous disease
    • Chronic renal failure with aplastic bone disease
    • Tertiary hyperparathyroidism
    • Acute renal failure
    • Familial hypercalcemic hypocalciuria
    • Lithium-associated hypercalcemia
    • Vitamin D intoxication

Other causes:

  • Increased calcium intake
  • Pheochromocytoma
  • Congenital lactase deficiency
  • Hyperthyroidism
  • Vitamin A intoxication
  • Thiazides
  • Milk-alkali syndrome
  • Immobilization
  • Theophylline

Prognosis depends on the cause of the increased calcium levels. Hypercalcemia can have a good prognosis when the cause is treatable and the treatment is started promptly. If hypercalcemia is associated with malignancy, prognosis is poor and potentially fatal. Early diagnosis is important in order to avoid long-term complications. In some cases, symptoms have a slow onset, such as weakness, anorexia, nausea, and constipation. The symptoms may be non-specific, whereas other times they develop very quickly, such as dehydration, renal failure, and coma, which may give rise to life-threatening situations. Mild hypercalcemia can be asymptomatic, but as the level of calcium rises, the symptoms begin to appear in all systems. 

4 Making a Diagnosis

To diagnose hypercalcemia, your doctor will thoroughly examine blood test results.

Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:

  • Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)
  • Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 8-10 mg/dL (2-2.5 mmol/L)
  • Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)

Hypercalcemia from malignancy usually progresses quickly; thus, rapidly rising calcium levels should increase suspicion of malignancy.

Hypercalcemia from hyperparathyroidism is usually mild, asymptomatic, and sustained for years. Immunoreactive parathyroid hormone (PTH) and ionized calcium should be simultaneously measured.

Other causes of hypercalcemia can usually be distinguished, or at least considered, on the basis of medical history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, urinary calcium, and thyroid function may also be useful in some cases.

These investigations help find the cause of hypercalcemia and also give an indication of renal function. Other investigations, such as ECG and radiology examinations like X- ray or bone scans, can be done to show bone metastases. 

5 Treatment

The main goal of treatment for hypercalcemia is to normalize blood levels of calcium by increasing urinary excretion and decreasing bone resorption of calcium, and then treating the underlying disorder causing the trouble.

Certain drugs like thiazide diuretics that inhibit urinary calcium excretion should be ceased. Drugs which decrease renal blood flow, such as ranitidine, should also be avoided. Some dietary supplements have been found to cause abnormal increase in calcium levels, like vitamin A and D, so these supplements should be stopped. Dietary restrictions for patients with hypercalcemia and those at risk have not been found to be beneficial. There is no data to suggest that hypercalcemia is attributed to food.

The currently available treatment modalities are:

  • Fluid therapy and diuretics: This includes increased fluid intake, forced dieresis, and consuming plenty of salt.
  • Hydration is necessary to correct the volume deficits caused by recurrent vomiting and defects in renal concentration of urine.
  • Increased salt intake raises the osmotic pressure of body fluids and helps eliminate more salts from body.
  • Loop diuretics like furosemide are added with the intention of preventing volume overload and, consequently, pulmonary edema, as well as prevent further absorption of calcium. These can usually decrease serum calcium by 1–3 mg/dL within twenty-four hours.

Patients with chronic renal failure due to decreased urine production in combination with high calcium intake are at risk of developing hypercalcemia. In order to rehydrate the patient, intravenous fluid is administered. The fluid volume depends on the extent of dehydration and cardiovascular and renal functions. Four to six liters of saline on day one and three to four for many days after is usual. After treatment, repeated blood tests should be done for reassessment. Assessment of cardiac and urinary output should be performed as well.

Asymptomatic or mildly symptomatic forms do not require immediate treatment. A serum calcium level of 12 to 14 mg/dL also may not require immediate treatment. However, an acute rise will require aggressive measures. Patients whose serum concentration is more than 14mg/dL need immediate treatment regardless of symptoms.

The preferred approach depends on the severity of hypercalcemia:

  • Mild hypercalcemia: Factors that can aggravate hypercalcemia should be avoided, including thiazide diuretics, lithium carbonate therapy, volume depletion, prolonged inactivity or bed rest, and diets rich in calcium. Patients are recommended to have at least six to eight glasses of water per day for adequate hydration to minimize the risk of nephrolithiasis.
  • Moderate hypercalcemia: Patients should follow the above precautions. They are treated with saline hydration and bisphosphonates.
  • Severe hypercalcemia: Patients require aggressive therapy, which consists of a three–pronged approach viz. volume expansion with isotonic saline, administration of salmon calcitonin, and concurrent administration of zoledronic acid or pamidronate.

Role of bisphosphonates and calcitonin: Bisphosphonates have a high affinity for bone, especially in areas of high-born turnover.

  • They are taken up by osteoclasts and inhibit osteoclastic bone resorption.
  • Current available drugs include: Etidronate, tiludronate, IV pamidronate, alendronate, zoledronate, and risedronate. Pamidronate /Aredia (60-90mg IV over two hours) and Zoledronic acid /Zometa (4mg IV over fifteen minutes) are the two most common drugs that are well-tolerated with limited side effects.
  • All patients with cancer-associated hypercalcemia 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 hypercalcemia will recur in the patient with hypercalcemia of malignancy. Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative.
  • Patients with renal failure and hypercalcemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in renal failure.

Calcitonin has a dual mechanism of action: it inhibits bone resorption and also increases urinary calcium excretion.

  • It is used in life-threatening hypercalcemia.
  • It also prevents recurrences.
  • Dose is four units per kg via subcutaneous or intramuscular route every twelve hours and is not usually continued indefinitely.

Uncommon Therapies

These are rarely used or are used in special circumstances and include:

  • Plicamycin inhibits bone resorption.
  • Gallium nitrate inhibits bone resorption and changes the structure of bone crystals.
  • Glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption.

They have no effect on calcium levels in normal or primary hyperparathyroidism.

They are effective in hypercalcemia due to osteolytic malignancies (multiple myeloma, leukemia, Hodgkin's lymphoma, carcinoma of the breast) due to antitumor properties.

  • Also effective in hypervitaminosis D and sarcoidosis.
  • Dialysis is usually used in severe hypercalcemia complicated by renal failure. Supplemental phosphate should be monitored and added, if necessary.
  • Phosphate therapy can correct the hypophosphatemia in the face of hypercalcemia and lower serum calcium.

In some patients, surgeries like parathyroidectomy may be needed.

6 Prevention

There are no foolproof ways to prevent the condition, but being aware of your family history and getting regular checkups will help, as the doctor will be able to spot any body changes. The doctor may suggest a twenty-four-hour urine collection in order to measure the calcium levels in the kidney.

To prevent hypercalcemia, the following measures are suggested:

  • Drink the right amount of fluids—this will prevent dehydration and the formation of kidney stones.
  • Get enough salt in your diet.
  • Control nausea and vomiting.
  • Stay active by walking; exercise is important to help maintain bone density and thus prevent bones from breaking down.
  • Smoking has shown to increase bone loss as well as cause serious health problems.
  • Stop taking drugs that can cause hypercalcemia or affect its treatment, when possible. Check with the doctor before taking calcium and vitamin D supplements, as overdosing on these supplements may cause hypercalcemia.

Hypercalcemia causes the body to absorb less calcium from food. However, changing the diet to decrease calcium will not lower the amount of it in the blood.

7 Lifestyle and Coping

Lifestyle modifications are necessary in order to cope with hypercalcemia.

Supportive care can comfort patients who are terminally ill.

When cancer can no longer be treated, supportive care for hypercalcemia may include the following:

  • Prevent and manage side effects of therapy, such as getting too much fluid.
  • Protect from injury caused by confusion.
  • Prevent fractures by being gentle.
  • Help with walking and other weight-bearing exercises.
  • Control pain, nausea, vomiting, and constipation.

Supportive care can also comfort family members who may become upset by the changes hypercalcemia causes in their loved one's thinking and behavior.

Patients and caregivers should learn the signs of hypercalcemia. Hypercalcemia can affect your quality of life and be life-threatening if not treated right away. You and your caregiver should learn the symptoms and report them to your doctor as soon as they occur.

Staying active and drinking plenty of fluids will help prevent hypercalcemia.

8 Risks and Complications

The various complications of hypercalcemia include: