Hypercalcaemia

Contributed by Dr Kate Scatchard, specialist registrar and Dr Stephen Falk, consultant clinical oncologist, Bristol Haematology and Oncology Centre

Section 1: Epidemiology & aetiology
In primary care hypercalcaemia is frequently an asymptomatic unexpected finding but it should always be investigated further.

Hypercalcaemia is more common than hypocalcaemia. A study of 100,000 hospital in-patients found 78 cases of hypercalcaemia, half of which were found incidentally.

Of these, 45 per cent had known malignancy and the next most common cause was primary hyperparathyroidism, affecting 16.5 per cent. In the general population the overall incidence of hypercalcaemia is lower and non-malignant causes account for over 90 per cent of cases.

Calcium plays a critical role in the structural integrity of bone, and 99 per cent of the body's calcium is sequestered within the skeleton. The remainder plays an equally vital role in neuromuscular activity and intracellular signalling pathways.

There is considerable exchange of calcium within the body. The constant turnover of skeletal calcium due to bone re-modelling requires a calcium intake of 1,000mg per day.

Plasma calcium levels are tightly regulated, maintaining a narrow range of 2.12-2.55mmol/l. In the plasma, 50 per cent of calcium is bound to plasma proteins, predominantly albumin, and is unavailable. The rest is present in the free ionised form.

Hormonal control
Calcium levels are normally under the control of three hormones: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol) and calcitonin.

PTH is secreted by the four parathyroid glands adjacent to the poles of the thyroid in response to falling extracellular calcium levels. It increases bone osteoclast activity releasing skeletal calcium and increasing reabsorption of calcium in the renal tubules. Vitamin D raises calcium levels by stimulating gut uptake of dietary calcium. When levels rise above normal, calcitonin is released from the C cells of the thyroid gland to inhibit bone degradation by osteoclasts, stimulate calcium incorporation into bone by osteoblasts and enhance calcium excretion by the renal tubules.

Hyperparathyroidism
Primary hyperparathyroidism is caused by excessive release of PTH. This is usually from a single benign adenoma within one of the glands although multiple adenomas, gland hyperplasia and frank malignancy can also occur. Excess PTH is also associated with multiple endocrine neoplasia syndromes.

Over 90 per cent of cases of hypercalcaemia are caused by primary hyperparathyroidism or malignancy. There are a number of much rarer causes that should also be considered if neither of these two is present (see box).

 

 Causes of hypercalcaemia
 Mechanism  Cause
Excess PTH Primary hyperparathyroidism, tertiary
hyperparathyroidism, ectopic PTH secretion
Excess osteoclast activity, due to malignancy
Bone metastases secreting osteoclastic factors, myeloma, PTH-rp release from tumour
Excess vitamin D Excess vitamin D ingestion, iatrogenic, granulomatous diseases - eg, sarcoidosis,
Wegner's disease, subcutaneous fat necrosis of newborn
DrugsThiazide diuretics, lithium, aluminium toxicity from long-term renal dialysis, total parenteral nutrition, tamoxifen, foscarnet, theophylline,
vitamin A intoxication, steroid withdrawal
Excess calcium intakeMilk alkali syndrome
Endocrine diseaseUncontrolled thyrotoxicosis, Addison's disease
Miscellaneous  Familial hypocalciuric hypercalcaemia

Section 2: Diagnosis
Mild hypercalcaemia (2.8-3.0mmol/l) is often asymptomatic. It leads to a diagnosis of hyperparathyroidism in 70- 80 per cent of cases.

Those affected tend to be men over 50 years of age. They are more likely than those with a normal calcium level to have additional co-morbidities such as hypertension.

As calcium levels rise to moderate (3.1-3.4mmol/l) or severe (above 3.5mmol/l) patients are more likely to exhibit symptoms that can be quite nebulous and have an insidious onset. The extent of the symptoms is often linked to the rapidity of onset. A calcium level of above 4mmol/l may lead to coma and death due to cardiac arrhythmias or acute renal failure.

Symptoms
Classically, primary hypercalcaemia is said to present as 'stones, bones, abdominal groans and psychiatric moans'. This is unusual today because abnormal calcium levels are more likely to be detected early as a result of multichannel autoanalysers introduced in biochemistry labs in the 1970s.

Patients may complain of weakness, fatigue, bone pain, constipation, abdominal pain due to pancreatitis or peptic ulcers, anorexia, nausea or vomiting, drowsiness, confusion, hallucinations, polyuria, dehydration and excessive thirst.

Symptomatic hypercalcaemia is more commonly associated with advanced malignancy as the changes in calcium tend to be more rapid and severe. The presence of renal stones or soft tissue calcification implies a longstanding problem.

Blood tests
Once elevated calcium has been identified, the measurement should be repeated on a fasting sample taken without a tourniquet at least two weeks after stopping any thiazide diuretics. A full history and examination should be undertaken, looking in particular for other signs of malignancy or sequelae of hypercalcaemia.

Further blood tests include FBC, renal function, LFTs including tests for alkaline phosphatase (ALP), serum protein and albumin, serum phosphate, TFTs and PTH.

Raised plasma protein levels can falsely elevate serum calcium readings by increasing overall serum calcium while levels of active free calcium remain unchanged. Conversely, low plasma protein or albumin levels can provide a falsely reassuring calcium reading. A formula should be used to calculate corrected calcium (see box below). This figure should be used to assess the degree of abnormality.

Signs of malignancy
Raised ALP may imply increased bone turnover as the source of excess calcium. More widely deranged LFTs may be an indicator of advanced malignancy. Prolonged polyuria can lead to severe dehydration precipitating acute renal failure.

PTH levels are usually suppressed in patients with calcium levels above the upper limit of normal. This demonstrates that the homeostatic mechanism controlling calcium is functioning normally, as occurs when hypercalcaemia is due to malignancy. A 'normal' PTH level in the presence of hypercalcaemia is therefore inappropriate and is a strong indicator of hyperparathyroidism.

Investigations include a chest X-ray, 24-hour urine collection for calcium and creatinine clearance and DEXA bone scanning. The parathyroid glands can be imaged using MRI, high-resolution CT or technetium 99m sestamibi scintigraphy.

Corrected calcium formula
Corrected calcium (mmol/l) = measured total Ca (mmol/l)) + 0.02(40 - serum albumin (g/l)) where 40 represents the average albumin level.

Section 3: Treatment of hyperparathyroidism
Hyperparathyroidism is treated by surgical resection. When performed by an experienced endocrine surgeon, this gives success rates of 95 per cent with a low risk of complications.

The 2002 National Institute of Health (NIH) consensus can be used to differentiate between patients requiring surgery and those with hyperparathyroidism mild enough to be managed by surveillance (see box).

Parathyroidectomy
Parathyroidectomy can be performed by a standard exploration to identify all four glands via a transverse neck incision. However, this approach is becoming increasingly replaced with minimally invasive techniques such as focused parathyroidectomy through a 2cm unilateral incision, or endoscopic parathyroidectomy. Where hyperparathyroidism is due to gland hyperplasia rather than an adenoma, three and a half of the four glands are removed.

Patients who have undergone a large incision can afterwards be at risk of acute airway compromise from an expanding haematoma within the wound that can lead to venous congestion and glottic closure.

Vomiting and retching can also disrupt the primary closure and should be avoided by the use of anti-emetics.

Hungry bone syndrome
Approximately 2 per cent of patients become transiently hypocalcaemic following parathyroidectomy due to 'hungry bone' syndrome where the skeleton avidly takes up calcium, magnesium and phosphate in order to replace previously lost bone mass.

Those with established bone damage, as indicated by an elevated ALP before surgery, are most at risk. They should be given information on the symptoms of hypocalcaemia, have their serum calcium checked one to two weeks after surgery, and be given calcium supplementation if necessary.

Calcium levels should then be re-checked after six months. PTH levels can be used to monitor residual parathyroid gland function, although these can remain elevated for several months following surgery while bone health is restored. In the first six months after parathyroidectomy, a raised PTH in the presence of a normal calcium should not be a cause for concern.

Surveillance
Patients managed by surveillance should undergo serum calcium measurement at six month intervals. They should also have annual assessment of renal function and bone densitometry every one to two years.

Patients should be warned to avoid factors that might exacerbate their hypercalcaemia, such as a high dietary intake of calcium or vitamin D. Approximately 25 per cent of the patients managed by surveillance will subsequently require surgery.

NIH parathyroid surgery guidelines

  • Symptomatic primary hyperparathyroidism.
  • Asymptomatic primary hyperparathyroidism if Ca>2.8mmol/l.
  • Urinary calcium >400mg/24hrs.
  • Creatinine clearance <70 per cent of expected.
  • Bone density T score >-2.5.
  • Patient <50 years old.
  • Medical surveillance not desirable/possible.
  • Patient preference.

Section 4: Managing hypercalcaemia in malignancy
Hypercalcaemia is one of the commonest complications of malignancy, occurring in between 10-20 per cent of cancer patients. It is most often seen in those with a diagnosis of advanced lung, breast, or squamous cell cancer, or myeloma.

The diagnosis of hypercalcaemia may be delayed because symptoms can be non-specific and easily attributable to the malignancy or to side-effects of treatment. It is usually a poor sign, as 75 per cent of cancer patients who develop hypercalcaemia are likely to die within the next three months.

Although prompt diagnosis, rehydration and treatment can improve symptoms and be life-saving in the short term, where a patient has refractory widespread disease for which no active treatment is being pursued it may be appropriate to consider withholding treatment. This should be discussed in advance with the patient.

Bisphosphonate treatment
If treatment is to be undertaken the patient should be rehydrated with normal saline. This improves renal function and allows the kidneys to increase calcium excretion.

A bisphosphonate such as pamidronate or zoledronate is then given to stabilise bone turnover by inhibiting osteoclast activity. Side effects can include pyrexia, hypophosphataemia, hypomagnesia, renal impairment, GI disturbance and transient asymptomatic hypocalcaemia.

Pamidronate normalises calcium in 70-80 per cent of patients within four days. Serum calcium should be rechecked on the fifth day and a further 90mg given if it remains elevated. The effect generally lasts for three weeks and therefore maintenance doses can be given monthly or bimonthly.

Zolendronate has a marginally higher response rate and longer duration of action. Oral bisphosphonates such as ibandronate may also be used for maintenance. In addition to their effect on calcium, regular bisphosphonate use has also been shown to reduce the morbidity of bone metastases, by reducing fracture rates and reducing the need for radiotherapy for bone pain.

Other treatments
If the patient is resistant to bisphosphonate treatment alternative strategies include further aggressive hydration in conjunction with a regular loop diuretic such as furosemide to maximise renal calcium excretion.

However, this can be problematic in frail patients because it causes potentially large shifts in fluid volumes.

Other agents such as calcitonin or plicamycin are now rarely used, even though calcium tends to fall faster with these treatments than with a bisphosphonate. The duration of response is lower, tachyphylaxis frequently occurs and there is a higher incidence of side-effects.

When hypercalcaemia is due to haematological malignancy such as myeloma, a glucocorticoid equivalent to 40-60mg of prednisolone daily can help by reducing tumour synthesis of the locally active cytokines stimulating bone turnover.

If there is no response after 10 days then steroids should be stopped.

Active treatment of the underlying cancer with chemotherapy or hormonal manipulation is also likely to improve calcium control. Palliative radiotherapy has no effect on calcium levels.

Follow-up
Patients with advanced malignancy undergoing therapies will generally be under the care of an oncologist and a community palliative care team. Serum calcium and renal function are checked at least monthly and IV maintenance bisphosphonate therapy is prescribed.

Patients on oral bisphosphonates will be seen by their oncologist less frequently and may therefore require monitoring by their GP in collaboration with a palliative care nurse. Treatment is continued until the patient has deteriorated to the point where further treatment of their calcium is inappropriate.

References

  • Clines G, Guise T. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005; 12: 549-83.
  • Dent D, Miller J, Klaff L et al. The incidence and causes of hypercalcaemia. Postgrad Med J 1987; 63: 745-50.
  • Jacobs T, Bilezikian J. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90: 6,316-22.
  • Kearney T, Dang C. Diabetic and endocrine emergencies. Postgrad Med J 2007; 83: 79-86.
  • Ross J, Saunders Y, Edmonds P et al. A Systematic review of the role of bisphosphonates in metastatic disease Health Technol Assess 2004; 8(4): 1-176.
  • Suliburk J, Perrier N. Primary hyperparathyroidism. Oncologist 2007; 12: 644-53.
  • Taniegra E. Hyperparathyroidism. Am Fam Physician 2004; 69: 333-9.

 

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