Hypercalcaemia in Malignancy

Normal Serum Calcium ranges between 2.20 and 2.6 mmol. Hypercalcemia is defined as serum calcium above 2.6.

Hypercalcemia occurs in 20-30% of individuals with malignancy. ¹

Calcium Metabolism

Calcium is the most abundant mineral in the body. It is essential for neurotransmission in muscles and nerves, muscle contraction, cardiac function and blood coagulation. There are 25,000 mmol or approximately 1 kg of calcium in the body. More than 90% of the calcium stores in the body are in the skeleton.

Approximately 40-50% of the calcium in the serum is bound to proteins, primarily albumin, and the remaining calcium is unbound. The unbound portion of calcium in blood is described as free calcium or ionised calcium. Total serum calcium assays measure both the unbound and bound portions of calcium. Ionised calcium is responsible for the calcium effects seen clinically in hypercalcaemia. Therefore, ionised calcium is the best measured indicator of active calcium.

Plasma calcium is maintained within the reference range by a complex interplay of three major hormones: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol) and calcitonin. The three hormones act primarily at bone, kidney and small intestine sites to maintain appropriate calcium levels.

Calcium enters the body through the small intestine and eventually is excreted via the kidney. Bone can act as a storage depot. This entire system is controlled through a feedback loop; individual hormones increase or decrease the serum calcium concentration.

Learning bite

For hypercalcaemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.

Pathophysiology: UV Light

When calcium levels increase in a person with normal regulatory mechanisms, the hypercalcaemia suppresses the secretion of PTH. Normally, PTH stimulates release of calcium from bone by direct osteolytic action and via osteoclast upregulation. Therefore, a decline in serum PTH concentration decreases the flux of calcium from bone to extracellular fluid. PTH also acts to reabsorb calcium in the loop of Henle and distal tubule in the kidney. When PTH levels decrease, much of the filtered calcium is excreted in the urine. Finally, PTH stimulates enzymatic conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D.

Ultraviolet light

Ultraviolet (UV) light converts 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3). Alternatively, previtamin D is directly ingested and transported by proteins to the liver, where it is converted to 25-hydroxyvitamin D. In the kidney, 25-hydroxyvitamin D (calcidiol) is converted to the active metabolite 1,25-dihydroxyvitamin D by a PTH-stimulated process. 1,25-dihydroxyvitamin D (calcitriol) serves to promote intestinal absorption of calcium. When PTH is suppressed because of hypercalcaemia, levels of 1,25-dihydroxyvitamin D decline, and thus intestinal calcium absorption declines.

Learning bite

Bone resorption, local bone destruction and enhanced intestinal absorption of calcium are believed to be responsible for hypercalcaemia associated with malignancy.

Pathophysiology: PTH-rp

Many carcinomas are believed to cause hypercalcaemia by producing parathyroid hormone-related protein (PTH-rp) or by synthesising and releasing soluble factors that stimulate osteoclastic bone resorption.

Parathyroid hormone-related protein and cytokines appear to stimulate bone resorption [6] by increasing osteoclast formation and inhibiting bone formation. Osteoclasts are specialised bone cells that are responsible for bony destruction that generally results in calcium release from the bone into the blood stream. Thus increased stimulation of osteoclast function may lead to increased serum calcium concentrations. In addition to increasing osteoclast activity, PTH-rp increases calcium concentrations by enhancing renal tubular calcium reabsorption. It has been suggested that 1,25-dihydroxyvitamin D3 contributes to hypercalcaemia by increasing intestinal absorption of calcium.

Hypercalcemia also occurs due to ectopic production of PTH and PTH produced by Parathyroid carcinoma and due to Paraprotein binding.²

Signs and Symptoms of Hypercalcaemia

The severity of symptoms is not always related to the degree of hypercalcaemia, but often reflects the rapidity of onset. Patients do not always exhibit all of the clinical features. The onset of hypercalcaemia may be insidious.

Neurological

Fatigue, lethargy, confusion, myopathy, hyporeflexia, seizures, psychosis and coma. The most frequent effect of hypercalcaemia is delirium.

General

Dehydration, polydipsia, polyuria, pruritis. Weakness and bone pain may also be present.

Gastrointestinal

Anorexia, nausea and vomiting, weight loss, constipation, ileus and abdominal pain.

Cardiac

Shortened QT, prolonged PR, Wide and flattened T waves, J waves, Ventricular and Atrial Arrhythmias and Bradycardia which can be fatal

Renal

Polyuria, polydipsia, dehydration and development of kidney stones.

Early

Polyuria, nocturia, polydipsia, dehydration, anorexia, easy fatigability, weakness, hyporeflexia, pain may be precipitated or exacerbated by hypercalcaemia.

Late

Apathy, irritability, depression, decreased ability to concentrate, obtundation, coma, profound muscle weakness, nausea and vomiting, constipation, increased gastric acid secretion, acute pancreatitis, pruritus, visual disturbances, sudden death from cardiac dysrhythmias may occur if calcium rises quickly, especially in patients taking digoxin.

Learning bite

In unexplained vomiting, thirst, polyuria or confusion, it is prudent to check serum calcium.

Physical Examination

Hypercalcaemia has few physical examination findings specific to its diagnosis. Often it is the symptoms or signs of underlying malignancy that bring the patient with hypercalcaemia to seek medical attention.

The primary malignancy may be suggested by lung findings, skin changes, lymphadenopathy, or liver or spleen enlargement.

Hypercalcaemia can produce a number of non-specific findings, as follows:

• Hypertension and bradycardia may be noted in patients with hypercalcaemia
• Abdominal examination may suggest pancreatitis or the possibility of an ulcer
• Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more prominent in the lower extremities and may have bony tenderness to palpation
• Hyporeflexia and tongue fasciculations may be present
• Anorexia or nausea may occur
• Polyuria and dehydration are common
• Lethargy, stupor or even coma may be observed
• Long-standing hypercalcaemia may cause band keratopathy, but this is rarely recognised in the emergency department

If hypercalcaemia is as a result of sarcoidosis, vitamin D intoxication or hyperthyroidism, patients may have physical examination findings suggestive of those diseases.

Causes

Hypercalcaemia is divided into PTH-mediated hypercalcaemia (primary hyperparathyroidism) and nonPTH-mediated hypercalcaemia. Malignancy-associated hypercalcaemia is the commonest cause of hypercalcaemia in hospitalised patients.

Hypercalcemia affects 20-30 % of cancer patients, more common in Breast cancer, Lung cancer and multiple myeloma.

Hypercalcaemia in the setting of malignancy usually indicates disseminated disease.

• PTH-mediated hypercalcaemia is related to increased calcium absorption from the intestine
• NonPTH-mediated hypercalcaemia includes the following:

Hypercalcaemia associated with malignancy

Unlike PTH-mediated hypercalcaemia, the elevation of calcium that results from malignancy generally worsens until therapy is provided. Hypercalcaemia caused by malignancy is the result of increased osteoclastic activity within the bone.

Granulomatous disorders

High levels of calcitriol may be found in patients with sarcoidosis and other granulomatous diseases. In these disorders, the increased level of calcitriol results from production within the macrophages, which constitute a large portion of some granulomas.

Iatrogenic

In some cases, elevation of calcium is a known adverse effect of the patients medications. A complete review of current medications for patients presenting with hypercalcaemia is important.

Learning bite

In patients with myeloma, carcinoma of the lung and breast, suspect the possibility of hypercalcaemia. Hypercalcaemia of malignancy usually indicates disseminated disease and a poor prognosis.

Differential Diagnosis of Hypercalcaemia

Non malignant causes of hypercalcaemia include:

• Chronic renal failure
• Endocrine disorders (hyperthyroidism, phaeochromocytoma, Addisons disease)
• Familial hypocalciuric hypercalcaemia
• Immobilisation
• Laboratory artifact due to altered albumin concentration or serum pH
• Medications (vitamin A toxicity [dietary fads, isotretinoin overdose, multivitamin overdose], oestrogens, antioestrogens, thiazides, lithium)
• Milk-alkali syndrome
• Primary hyperparathyroidism
• Vitamin D toxicity
• Granulomatous disease (sarcoidosis, tuberculosis)

Malignancies causing hypercalcaemia

Calcium Level

Always relate serum calcium levels to serum albumin levels [5].

Method for calculating correction of calcium level to reflect albumin level:

• If serum albumin is less than 40 g/L, increase measured calcium by 0.20 mmol/L for every 10 g of albumin below 40 g/L
• If serum albumin is greater than 40 g/L, reduce measured calcium by 0.20 mmol/L for every 10 g of albumin over 40 g/L

Alternatively:

• Corrected calcium (mmol/L) = Measured calcium (mmol/L) + [0.02 x (40 measured albumin g/L)]

Determining the Cause

After a diagnosis of hypercalcaemia is established, the next step is to determine the cause. Initial testing is directed at malignancy, hyperparathyroidism and hyperthyroidism, the most common causes of hypercalcaemia.

Measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid function. A reference range is 10-60 p/ml. A non-suppressed PTH level in the presence of hypercalcaemia suggests a diagnosis of primary hyperparathyroidism. If the PTH level is suppressed in the face of an elevated calcium level, hyperparathyroidism is unlikely.

Parathyroid hormone-related peptide (PTH-rP) is thought to mediate the hypercalcaemia that develops with many malignancies. Assays to measure this peptide are available.

Other electrolytes also may be disturbed in hypercalcaemia. Serum phosphate levels tend to be low or normal in primary hyperparathyroidism and hypercalcaemia of malignancy. Phosphate levels are elevated in hypercalcaemia secondary to vitamin Drelated disorders or thyrotoxicosis. Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcaemia.

If laboratory evidence of primary hyperparathyroidism is present, CT scan of the head, MRI, ultrasound or nuclear parathyroid scans may be helpful.

Plain x-rays may reveal demineralisation, pathologic fractures, bone cysts and bone metastases. Renal imaging, ultrasound or IVP may show evidence of calcification or stones.

Introduction

The most effective management of cancer-associated hypercalcaemia is successful treatment of the underlying malignancy.

Until this is achieved, three primary treatment goals include:

1. Correcting intravascular volume contraction
2. Enhancing renal excretion of calcium
3. Inhibiting accelerated bone resorption

Important general supportive measures include the removal of calcium from parenteral feeding solutions, discontinuation of the use of oral calcium supplements and discontinuation of medications that may independently lead to hypercalcaemia e.g. lithium, calcitriol, vitamin D and thiazides. Further measures can include, if possible, an increase in the weight-bearing mobility of the patient and discontinuation of the use of sedative drugs, including analgesic drugs to enhance the patient’s mental clarity and promote weight-bearing ambulation.

Many agents are available to treat acute hypercalcaemia including normal saline, furosemide, calcitonin, glucocorticoids, bisphoshonates and gallium nitrate.

Hydration with intravenous normal saline (NaCl 0.9%) is the first step in the acute management of hypercalcaemia. Since most patients suffering from acute hypercalcaemia are volume contracted, the administration of normal saline is important because it expands intracellular volume in addition to increasing renal calcium clearance. The optimal administration rate of normal saline is determined by the severity of hypercalcaemia, the degree of volume contraction, the ability of the patient to tolerate fluid, and the overall clinical status of the patient. Although there are no randomised clinical trials to guide this therapy, in general practice, normal saline is administered at a rate of 200-500 ml/h [11].

Mobilisation

Mobilisation of the patient is important, as it slows down the loss of skeletal calcium associated with immobility.

Older Treatments

Older treatments like mithramycin and calcitonin have recently been replaced with newer management strategies, mostly involving bisphosphonates. Emerging therapeutic approaches include monoclonal antibodies to parathyroid hormone related peptide (PTH-rP), inhibition of RANK ligand through the use of a soluble form of its receptor osteoprotegerin, analogues of vitamin D and selective inhibition of the Ras-Raf-MAPK-ERK signalling pathway [15].

Calcitonin

The value is questionable because the reductions are small (approximately 1.0 mg/dl [0.25 mmol/L]) and transient [10].

Mithramycin

This was the mainstay of therapy for hypercalcaemia associated with cancer before the bisphosphonates became available. It remains effective, but its use is limited by potential adverse effects [10].

Gallium nitrate

Use is now limited as administration must be continuous and is laborious and less effective than previously thought. Furosemide has been used in a fluid overloaded patient but not recommended due to potential complications and availability of drugs which inhibit bone resorption.³

Bisphosphonates

Bisphosphonates include zoledronic acid, etidronate disodium and pamidronate disodium. Bisphosphonates are toxic to osteoclasts and inhibit osteoclast precursors, thereby decreasing osteoclast function. Currently, etidronate is commercially available in both oral and intravenous dosage forms and pamidronate is only available in the intravenous dosage form. Pamidronate can be given in day case units and community hospital settings quite easily.

Bisphosphonates have replaced older methods used to treat hypercalcaemia. They are the best studied, safest and most effective agents for use in hypercalcaemia associated with malignancy. They take up to 3 days to start working and 5-7 days to exert maximum effect. Approximately 60-90% of patients have normal serum calcium levels within 4-7 days, and responses last for 1-3 weeks. RCTs of pamidronate have shown it to be effective in reduction of hypercalcaemia associated with malignancy [13,17] (Level 1C). Although a direct comparison of the two drugs in a randomised clinical trial showed a statistically significant increase in the efficacy of zoledronate, the difference in control of calcium was small [17].

In a 2005 Cochrane database systematic review of the use of bisphosphonates in multiple myeloma, there was no effect on hypercalcaemia associated with multiple myeloma [15] (Level 1A). However, with the rarity of this complication in myeloma and the large confidence intervals seen in the trials, they commented that such an effect is still possible. As compared with pamidronate, zoledronate has the advantage of rapid and simpler administration (15 min vs. 2 h for infusion), whereas pamidronate is less expensive [16] (Level 1B).

Pamidronate and zoledronate have been reported to cause or exacerbate renal failure, but this effect has generally occurred in patients receiving multiple doses.

Other bisphosphonates include clodronate, etidronate and ibandronate, which are first generation Bisphosphonates and are weak inhibitors of bone resorption.

Learning bite

The mainstay of treatment in addition to rehydration has become bisphosphonates.

Glucocorticoids

Glucocorticoid combat hypercalcemia by increasing urinary calcium excretion and decreasing intestinal absorption of calcium by decreasing calcitriol production by activated mononuclear cells in lung and lymph nodes.⁴

Dialysis and other Treatments

In patients who have cancers that are likely to respond to therapy, but in whom acute or chronic renal failure is present, aggressive saline infusion is not possible. Further, other therapies such as bisphosphonates should be used with caution, if at all. In these circumstances, dialysis against a dialysate containing little or no calcium is a reasonable and highly effective option for selected patients [10]. There are no randomised control trials (RCTs) and only case reports [10] (Level 3).

The receptor activator of nuclear factor-KB ligand (RANKL) system is the molecular pathway that leads to osteoclast recruitment and differentiation and bone resorption in hypercalcaemia associated with cancer. Agents that interfere with the system, such as recombinant osteoprotegerin (a decoy receptor for RANKL) or monoclonal antibodies directed against RANKL, have been proposed as novel treatments for hypercalcaemia associated with malignant disease, as have monoclonal antibodies, which neutralise PTH-rP [10].

A number of randomised clinical trials comparing bisphosphonates to saline and diuretics alone and to other antiresorptive agents such as calcitonin have confirmed the superiority of bisphosphonates [16,17] (Level 1B).

Key Points

• Hypercalcaemia is often found during routine laboratory work ordered on chronically ill patients who are still asymptomatic
• Familiarity with the causes of hypercalcaemia is essential because certain types can be easily treated
• Severe hypercalcaemia is a medical emergency requiring immediate treatment
• If left untreated, hypercalcaemia can adversely affect multiple organ systems, including the bones and kidneys
• Hypercalcaemia in the setting of malignancy usually indicates disseminated disease
• Hypercalcaemia usually indicates a very poor prognosis – 4/5 of patients die within a year

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