Hypercalcaemia

• Signs and Symptoms
• Prognosis
• Diagnosis
• Treatment

Hypercalcaemia is characterised by abnormally high levels of calcium in the blood. Calcium plays an important role in the functioning of the body. It is essential for the formation and maintenance of bones and teeth, the transmission of nerve impulses, the contraction of heart, smooth and skeletal muscles and the maintenance of normal clotting functions. Calcium balance in the body is tightly regulated by the effects of parathyroid hormone (PTH) and a vitamin on the gut, kidney and bone. 99% of the body’s calcium is stored in the skeleton and the remaining 1% of calcium is in the blood (serum). Both increased and decreased levels of serum calcium can have a serious effect on the way the body functions.
Hypercalcaemia is one of the most common life threatening disorders associated with malignancy. It occurs in 10 to 20% of people with cancer and in 40% of those with myeloma. Mild asymptomatic hypercalcaemia occurs in about 1 in 1000 of the population, especially elderly women and is usually the result of primary hyperparathyroidism. The causes of hypercalcaemia range from primary hyperparathyroidism and malignant disease to excess action of vitamin D, excessive calcium intake, endocrine disorders (thyrotoxicosis and Addison’s disease), drugs (thiazide diuretics, vitamin D analogues, chronic lithium use and vitamin A) and miscellaneous problems such as long-term immobility and familial hypocalciuric hypercalceamia. Primary hyperparathyroidism and malignant disease account for greater than 90% of the cases of hypercalcaemia. It most frequently occurs in patients with breast cancer and multiple myeloma, although other cancers also at risk include squamous cell carcinoma of the lung, ovarian cancer, prostate cancer lymphoma, leukaemia, renal cancer and cancers of the head and neck. As calcium plays a role in maintaining the passage of electrolytes through cell membranes (permeability), it impacts on the cellular activity of multiple body organs.

Signs and Symptoms

Signs and symptoms are directly related to the cellular activity of the involved body system. Mild elevations in calcium levels may be asymptomatic.
Gastrointestinal: anorexia, constipation, nausea, vomiting, excessive thirst (polydipsia), decreased gastrointestinal tract muscle contraction (peristalsis). These GI effects are caused by a decrease in smooth muscle activity which results in both delayed gastric emptying and GI motility. Dehydration caused by nausea and vomiting may also exacerbate the hypercalcaemia.
Neuromuscular: Mild to moderate hypercalcaemia: muscle weakness, fatigue, difficulty in concentrating, mild confusion, restlessness, irritability. Severe hypercalcaemia: lethargy, significant muscle weakness, severe confusion, coma. Neuromuscular symptoms reflect interference with nerve impulse transmission. Changes in personality and mental status of the patient may also be attributed to the cause of the hypercalcaemia, that is cancer or cancer medications such as opioids or sedatives. Neurological symptoms may be more pronounced in the elderly and may last for several days, even after calcium levels have returned to normal.
Cardiovascular: Increased cardiac muscle contractility and irritability, ECG changes, decreased heart rate, blockage of the conducting fibre network in the heart and high blood pressure (hypertension). Cardiac symptoms interfere with the normal contractility of the skeletal, smooth and cardiac muscles. These impaired cardiac muscles may result in abnormal heart rhythms or even a cardiac arrest.
Renal: increased urine output (polyuria), renal stones, flank pain, renal failure. Polyuria is caused by the kidneys inability to concentrate urine. Dehydration may also result and cause a decrease in the blood flow through the kidney which then impairs the kidneys ability to excrete calcium.
Musculoskeletal: bone pain, tenderness, fractures. Many patients with hypercalcaemia have skeletal metastases and experience bone pain. Bone pain can also present in patients without skeletal metastases due to the calcium acting as a neurosensitizer which decreases the pain threshold. The natural history of hypercalcaemia relates to the aetiology of the elevated calcium levels. The spectrum ranges from familial hypocalciuric hypercalcaemia which is asymptomatic, not progressive and not associated with any increased mortality, to hypercalcaemia present in the terminal stages of metastatic malignancy, which is an oncological emergency. With prolonged elevation of blood calcium levels, calcium may precipitate within the kidney (nephrocalcinosis) or within the urinary tract, resulting in urinary stone formation. Untreated hypercalcaemia therefore poses the risk of progressive mineralization of bone, hypercalciuria, nephrocalcinosis and deterioration to renal failure.

Prognosis

The prognosis of hypercalcaemia depends upon the cause of increased calcium levels. When the underlying cause is treatable and the treatment is initiated promptly, hypercalcaemia can have a good prognosis. However, when associated with malignancy that has progressed into development of hypercalcemia, prognosis is poor. Hypercalcaemia is potentially fatal. Early diagnosis is important, as the cause of high blood calcium is usually identified and treated to avoid long-term complications. Signs and symptoms may be confused with those of end stage disease in terminal patients. In some patients, symptoms may be non-specific and have a slow onset. Some examples of these are:

• Anorexia
• Weakness
• Nausea
• Vomiting
• Constipation

In other cases, symptoms such as dehydration, renal failure and coma may develop very quickly resulting from very rapidly rising calcium levels. This may result in a life threatening situation. Symptoms do not always correlate with serum calcium levels. These must be closely compared with an in-depth patient history, examination and laboratory report. Signs and symptoms of hypercalcaemia can be numerous and nonspecific. They depend on the underlying cause and how quickly the calcium level rises. Mild hypercalcaemia may be asymptomatic but as the calcium levels rise, the symptoms begin to appear in all body systems. Some non-specific findings associated with hypercalcaemia include: decreased heart rate, hypertension, proximal muscle weakness (chronic hypercalcaemia), bony tenderness, increased tendon reflexes, unwanted tongue movements, dehydration and even coma.

Diagnosis

Hypercalcaemia is diagnosed by laboratory tests including: serum calcium, albumin, phosphate, alkaline phosphate, BUN, creatinine, electrolytes and PTH level. These investigations assist in diagnosing the cause of hypercalcaemia and give a baseline indication of renal function. Urinary calcium should be measured as hypercalciuria may be detected. Other investigations may include an ECG and radiology examinations such as x-ray or bone scans which may show bone metastases.

Treatment

The treatment of hypercalcaemia is determined by the underlying disease, the degree of the hypercalcaemia and the patient’s clinical presentation. The aim of treatment is directed at decreasing serum calcium levels by increasing urinary excretion of calcium and decreasing bone resorption of calcium. Immobilization should be avoided as inactivity will cause an increase in bone resorption of calcium. The level of activity will be appropriate for the patient’s physical condition and other measures such as pain control may need to be considered prior to undertaking any physical activities. A review of the patient’s medications will need to be considered. Drugs that inhibit urinary calcium excretion, such as thiazide diuretics, should be ceased. NSAID and H2-receptor drugs, such as Ranitidine which decrease renal blood flow, should also be avoided if possible. Any calcium, Vitamin A and D supplements should also be ceased. Dietary restrictions of calcium have not been proven to be of any benefit to patients that are hypercalcaemic, or at risk of hypercalcaemia. Currently there is no data to suggest that hypercalcaemia has been attributed to food. However, some dietary supplements can cause abnormally hight levels of calcium in the blood. Patients with chronic renal failure are at risk of becoming hypercalacemic due to calcium intake.
This is due to decreased urine production, in combination with high calcium intake). Intravenous fluids (0.9% sodium chloride) will be administered to rehydrate the patient, the volume of fluid given will depend on the extent of the patients dehydration and cardiovascular and renal functions. At least 4-6 litres of saline on day 1, and 3-4 litres for several days thereafter is usual. Diuretics such as frusemide may also be given. Repeat blood tests should be taken several hours after treatment and reassessed. Cardiac status and urinary output should also be assessed, thus a strict fluid balance chart should be maintained on the patient. Oral phosphates, which inhibit bone resorption, may be administered. Diarrhoea is a common side effect and may lead to non-compliance. Bisphosphonates, which are given intravenously, inhibit osteoclast activity that contributes to bone resorption may also be administered. The two most common drugs used are Pamidronate/Aredia (60-90mg IV over 2 hours) and Zoledronic Acid/Zometa (4mg IV over 15 minutes). Both of these agents are generally well tolerated with limited side effects such as mild fever and irritation at the infusion site.

References

Kindly Supplied by Virtual Nursing Education. Additional references: [1] Kumar, P and Clark, M Eds (2002), Clinical Medicine 5th Edition, W.B. Saunders, London. [2] Longmore, M et al (2001), Oxford Handbook of Clinical Medicine 5th Edition, Oxford University Press, Oxford. [3] Hemphill, R (2005), Hypercalcaemia, eMedicine, Department of Emergency Medicine, Vanderbilt University.