Hypercalcaemia

Hypercalcaemia is defined as a serum corrected calcium concentration >2.6 mmol/L.

Hypercalcaemia is a common electrolyte abnormality. It occurs when the serum calcium concentration exceeds the amount by which calcium can be deposited in bone or excreted by the kidneys.

Normal serum calcium levels range from 2.2-2.6 mmol/L.

Corrected calcium levels > 2.6 mmol/L are defined as hypercalcaemia. Depending on the level of serum calcium, hypercalcaemia can be graded:

• Mild: 2.6-3.0 mmol/L
• Moderate: 3.0-3.5 mmol/L
• Severe: > 3.5 mmol/L

The most common causes of hypercalcaemia are malignancy and primary hyperparathyroidism. For more information see our notes on malignant hypercalcaemia.

Calcium binds to albumin in the serum.

Due to calcium binding to albumin, a corrected calcium level needs to be determined taking into account the albumin level. With modern laboratories, a corrected calcium result is normally automated. 

It is estimated that the serum calcium concentration rises by 0.25 mmol/L (0.8 mg/dL) for every 10 g/L (1 g/L) increase in serum albumin concentration. The can be calculated manually using the following formula:

Corrected calcium (mg/dL) = serum calcium (mg/dL) + 0.8 x (4.0 - serum albumin [g/dL])

In the context of hyperalbuminaemia, which may occur due to dehydration, the total calcium concentration is a not a reflection of ionised calcium. Ionised calcium refers to the ‘free’ pool of calcium. Normal free ionised calcium in the context of hypercalcaemia is known as pseudohypercalcaemia. 

NOTE: attention must be paid to patients with normal calcium concentrations due to low albumin who have raised ionised calcium levels. This is consistent with hypercalcaemia.

Calcium is distribuited between bone and the intra- and extra-cellular compartments.

The majority of body calcium, 99%, is stored in bone.

1% of total body calcium is found within the intracellular compartment. Here it plays a key role in intracellular signalling. 

0.1% of total body calcium is found within the extracellular pool, this is divided into:

• Ionised (50%) - metabolically active, or ‘ionised’, free pool of calcium.
• Bound (41%) - bound to albumin (90%) and globulin (10%).
• Complexed (9%) - forms complexes with phosphate and citrate.

The balance between stored calcium and the extracellular pool of calcium is a closely regulated process. It is controlled by the interaction of three hormones; parathyroid hormone (PTH), vitamin D and calcitonin.

Decreased extracellular calcium is detected by the calcium-sensing receptor (CaSR) on the parathyroid gland. The parathyroid glands respond to the fall in serum calcium by releasing PTH. PTH stimulates the resorption of calcium from bone, activation of vitamin D (leads to calcium absorption from enterocytes) and increased renal tubular reabsorption of calcium. 

Conversely, a rise in extracellular calcium detected by the CaSR has the opposite effect. It leads to a reduction in the release of PTH and stimulates the release of calcitonin. This combined effect helps decrease bone resorption and promotes calcium excretion in the kidneys. 

Malignancy and primary hyperparathyroidism collectively account for >90% of the causes of hypercalcaemia.

Hypercalcaemia may occur by a variety of mechanisms:

• Malignancy: hypercalcaemia is commonly due to release of parathyroid related peptide (PTHrP), which mimics the action of PTH. Other mechanism include osteolytic damage to bone or activation of vitamin D.
• Hyperparathyroidism: elevated levels of PTH seen secondary to an adenoma or hyperplasia.
• Vitamin D: hypercalcaemia develops due to excess ingestion of vitamin D or granulomatous disease that increases vitamin D activation.
• Miscellaneous mechanisms: several conditions have unique mechanisms leading to hypercalcaemia.

Malignancy

Up to 30% of cancers develop hypercalcaemia as part of the natural disease course. Development of malignant hypercalcaemia is associated with a poor prognosis. 

For more information, see our notes on malignant hypercalcaemia. 

Primary hyperparathyroidism

Primary hyperparathyroidism is commonly implicated in hypercalcaemia. It is due to excess release of PTH, which leads to bone resorption and excess calcium release. It commonly occurs secondary to a parathyroid adenoma.

Other mechanisms include generalised parathyroid hyperplasia. Primary hyperparathyroidism may be part of a more systemic inherited condition known as multiple endocrine neoplasia. For more information, see our notes on MEN syndromes.

Secondary and tertiary hyperparathyroidism

Secondary hyperparathyroidism is a cause of hypocalcaemia. It is seen in renal impairment due to failed activation of vitamin D, reduced calcium reabsorption and reduced secretion of phosphate. Collectively this causes hypocalcaemia. 

However, overtime the overactivation of the parathyroid glands can lead to autonomous overproduction of PTH, which does not respond to a rise in calcium concentration. The net result is hypercalcaemia and high PTH levels. This is known as tertiary hyperparathyroidism

Thyrotoxicosis

Elevated thyroid hormones can lead to thyroid hormone-mediated bone resorption. Mild hypercalcaemia can be seen in up to 20%.

Hypervitaminosis D

High concentrations of vitamin D lead to hypercalcaemia by increasing calcium absorption and bone resorption. This usually occurs due to inadvertent ingestion of excess amounts of vitamin D or continuing a high loading dose for too long.

Some conditions lead to excess endogenous production of activated vitamin D, which include:

• Granulomatous disorders (e.g. sarcoidosis)
• Cancers (e.g. lymphoma)

Milk alkali syndrome

Milk alkali syndrome is due to the excess ingestion of milk or calcium containing compounds (e.g. calcium carbonate).

The full syndrome is characterised by:

• Hypercalcaemia
• Metabolic alkalosis
• Acute kidney injury

Hypercalcaemia is compounded by metabolic alkalosis, which affects calcium excretion in the distal convoluted tubule of the nephron. In addition, the high calcium levels cause renal vessel vasoconstriction that causes renal impairment and further compounds calcium excretion. Stopping the excess ingestion will lead to improvement in alkalosis and renal function as long as irreversible damage has not occurred. 

Other causes

• Chronic lithium use: enhances PTH release
• Thiazide diuretics: lowers urinary calcium excretion
• Adrenal insufficiency: multiple proposed mechanisms

FHH is a rare autosomal dominant disorder that causes mild hypercalcaemia.

FHH is due to a mutation in the calcium-sensing receptor (CaSR) of parathyroid cells. This essentially results in a ‘resetting’ of the sensing mechanism to a higher level of calcium.

FHH is characterised by mild hypercalcemia and hypocalciuria.. The inappropriately low urine calcium helps differentiate it from primary hyperparathyroidism.

Hypercalcaemia is characterised by renal stones, bone pain, polyuria, abdominal pain and psychiatric features.

The classic features of hypercalcaemia are usually remembered using the phrase:

'Stones, bones, thrones, abdominal groans and psychiatric moans’

Mild hypercalcaemia

• Polyuria: due to an element of nephrogenic diabetes insipidus 
• Polydipsia
• Mild cognitive impairment
• Dyspepsia

Moderate hypercalcaemia

• All mild features
• Constipation
• Weakness
• Fatigue
• Dehydration
• Nausea

Severe hypercalcaemia

• All mild and moderate features
• Confusion
• Abdominal pain: may develop due to renal stones
• Vomiting
• Oliguria/anuria: due to AKI (usually reversible if corrected)
• Cardiac dysrhythmias: shortens the QT interval. Long-standing hypercalcemia can lead to calcium deposition on cardiac structure.
• Pancreatitis
• Coma

It is important to look for signs of the underlying diagnosis. Usually a diagnosis of cancer is previously known but this may be the first presentations. A lump in the neck may be suggestive of a thyroid adenoma.

The diagnosis of hypercalcaemia is based on a serum corrected calcium > 2.6 mmol/L.

Confirm hypercalcaemia

First confirm hypercalcaemia with a bone profile. The level and duration of hypercalcaemia may indicate the underlying diagnosis. 

• Long-standing, asymptomatic, mild hypercalcaemia may be seen in FHH
• Sudden, symptomatic, moderate-to-severe hypercalcaemia is suggestive of malignancy (e.g. Calcium >2.75 mmol/L
• Primary hyperparathyroidism is usually seen with mild, chronic elevations in calcium (e.g. calcium < 2.75 mmol/L)

Parathyroid hormone

PTH is essential in the work up of hypercalcaemia. It is useful at differentiating between primary hyperparathyroidism and hypercalcaemia of malignancy.

• Elevated PTH (i.e. PTH-mediated): suggestive of primary hyperparathyroidism or tertiary hyperparathyroidism
• Mid-to-upper normal PTH (suspected PTH-mediated): in the context of hypercalcaemia this is considered ‘inappropriately high’ and suggestive of hyperparathyroidism
• Low or low-normal PTH (i.e. non-PTH mediated): suggestive of malignancy, which needs to be excluded. Hypervitaminosis D also possible.

Other investigations

In suspected malignant cases, PTHrP can be requested but it is an expensive test and not routinely completed in clinical practice. Other common investigations include:

• Routine bloods: FBC, U&E, LFT, CRP/ESR
• Thyroid function test
• Vitamin D levels
• ACE (if sarcoid suspected)
• Malignancy screen: protein electrophoresis, serum free light chains, tumour markers
• Urine calcium levels (if FHH suspected)
• General imaging: routine chest x-ray, consider CT chest abdomen pelvis if malignancy suspected
• Parathyroid imaging: used if primary hyperparathyroidism suspected. Neck ultrasound, parathyroid uptake scans (e.g. 99mTc MIBI) and MRI can all be used.

The management of hypercalcaemia depends on the severity and underlying cause.

The principle treatment of symptomatic hypercalcaemia in fluid resuscitation. Those with mild hypercalcaemia may be advised to increase oral intake, whereas those with more severe hypercalcaemia will need admission to hospital for intravenous therapy. 

Treatment recommendations

• Mild (< 3 mmol/L) and asymptomatic/mild symptoms: no specific treatment. Increase oral fluids (6-8 glasses of water) and avoid precipitants (e.g. thiazide diuretics, lithium, dehydration).
• Moderate (3-3.5 mmol/L): acute rise requires inpatient admission for intravenous fluids. Chronically raised elevations may not require acute management depending on the aetiology and symptomatology.
• Severe (>3.5 mmol/L): all patients require urgent admission to hospital and treatment. Treatment involves aggressive intravenous fluids and consideration of bisphosphonates, particularly if malignancy is suspected. 

Intravenous fluids

The management of severe hypercalcaemia initially involves the use of intravenous fluids given at 200-300 ml/hour (i.e. 4-6 hourly bags) then decreased to maintain urine output at 100-150 ml/hour (usually 8 hour bag enough). This is one of the classic situations when the addition of a loop diuretic (e.g. furosemide) to fluids can be used to enhance urinary calcium excretion.

Bisphosphonates

Bisphosphonates can be considered in severe hypercalcaemia, particularly if malignancy is suspected. They are analogues of inorganic pyrophosphate, which are absorbed onto the surface of the boney network and work by inhibiting the action of osteoclasts. 

Unfortunately, they can take several days (2-4) before their action is noticed but they provide calcium-lowering effects over a prolonged period (2-4 weeks). Pamidronate or zoledronic acid are typically used. They are potentially nephrotoxic and contraindicated in severe renal impairment.

An alternative to bisphosphonates is denosumab, which is a monoclonal antibody that binds to RANK ligand and inhibits the action of osteoclasts. 

Additional therapies

Other treatment options depend on the suspected underlying cause:

• Corticosteroids: may be used in hypervitaminosis D. 
• Surgery: able to provide a cure in primary hyperparathyroidism. Potential option in tertiary hyperparathyroidism
• Cinacalcet: calcimimetic that mimics the action of calcium on calcium-sensing receptors. May be utilised in primary hyperparathyroidism if surgery has failed or not an option. Also used in secondary/tertiary hyperparathyroidism.
• Dialysis: may be reserved for severe, refractory hypercalcaemia.