Hypercalcaemia

Question 1

Hypercalcaemia mnemonic

Answer 1

“stones, bones, abdominal groans and psychiatric moans”

Question 2

Causes of hypercalcaemia - CHIMPANZEES

Answer 2

Question 3

It is worth remembering the “renal stones, painful bones, abdominal groans and psychiatric moans” mnemonic for the symptoms of hypercalcaemia:

… stones
… bones
Abdominal … refers to symptoms of constipation, nausea and vomiting
… moans refers to symptoms of fatigue, depression and psychosis

Answer 3

It is worth remembering the “renal stones, painful bones, abdominal groans and psychiatric moans” mnemonic for the symptoms of hypercalcaemia:

Renal stones
Painful bones
Abdominal groans refers to symptoms of constipation, nausea and vomiting
Psychiatric moans refers to symptoms of fatigue, depression and psychosis

Question 4

Primary Hyperparathyroidism

Answer 4

Primary hyperparathyroidism is caused by uncontrolled parathyroid hormone produced directly by a tumour of the parathyroid glands. This leads hypercalcaemia: an abnormally high level of calcium in the blood. This is treated by surgically removing the tumour.

Question 5

Secondary Hyperparathyroidism

Answer 5

This is where insufficient vitamin D or chronic renal failure leads to low absorption of calcium from the intestines, kidneys and bones. This causes hypocalcaemia: a low level of calcium in the blood.

The parathyroid glands reacts to the low serum calcium by excreting more parathyroid hormone. Over time the total number of cells in the parathyroid glands increase as they respond to the increased need to produce parathyroid hormone. This is called hyperplasia. The glands become more bulky. The serum calcium level will be low or normal but the parathyroid hormone will be high. This is treated by correcting the vitamin D deficiency or performing a renal transplant to treat renal failure.

Question 6

Tertiary Hyperparathyroidism

Answer 6

This happen when secondary hyperparathyroidism continues for a long period of time. It leads to hyperplasia of the glands. The baseline level of parathyroid hormone increases dramatically. Then when the cause of the secondary hyperparathyroidism is treated the parathyroid hormone level remains inappropriately high. This high level of parathyroid hormone in the absence of the previous pathology leads to high absorption of calcium in the intestines, kidneys and bones and causes hypercalcaemia. This is treated by surgically removing part of the parathyroid tissue to return the parathyroid hormone to an appropriate level.

Question 7

Summary - Hyperparathyroidism

Answer 7

Question 8

If a person has unexplained mild or moderate hypercalcaemia and has no or minimal symptoms, assess the person to determine the underlying cause, depending on clinical judgement.

Ask about:

Answer 8

Any clinical features of hypercalcaemia, their severity and duration.
Note: in cases of malignancy-associated hypercalcaemia, it may be difficult to determine if symptoms are due to hypercalcaemia itself or the underlying malignancy.
Any symptoms suggesting underlying malignancy, such as fever, weight loss, night sweats, decreased appetite, cough, general malaise.
Any known medical conditions or co-morbidities, such as osteoporosis, fragility fractures, renal stones, or malignancy.
Any past history of radiotherapy to the head and neck.
Any family history of hypercalaemia (for example due to genetic forms of primary hyperparathyroidism, or familial hypocalciuric hypercalcaemia).
Any drug treatments, supplements, or over-the-counter preparations that may be causative or contributory.

Question 9

Examine the person

If a person has unexplained mild or moderate hypercalcaemia and has no or minimal symptoms, assess the person to determine the underlying cause, depending on clinical judgement.

Answer 9

Examine the person:
Assess hydration status — people with hypercalcaemia are often dehydrated due to nephrogenic diabetes insipidus due to reduced oral intake resulting from anorexia, nausea and vomiting due to the hypercalaemia itself.
Assess for cognitive impairment. See the CKS topics on Delirium and Dementia for more information.
Assess for signs of an underlying cause, including head and neck, respiratory, abdomen, breast, and lymph node examination. Note: parathyroid adenomas or carcinomas are rarely palpable.

Question 10

In … hyperparathyroidism, the increase in serum calcium is usually asymptomatic, mild and stable, or slowly progressive over years.

Answer 10

In primary hyperparathyroidism, the increase in serum calcium is usually asymptomatic, mild and stable, or slowly progressive over years.

Question 11

In …-associated hypercalcaemia, there is often rapid-onset, severe hypercalcaemia, and associated systemic symptoms.

Answer 11

asymptomatic, mild and stable, or slowly progressive over years.
In malignancy-associated hypercalcaemia, there is often rapid-onset, severe hypercalcaemia, and associated systemic symptoms.

Question 12

Consider arranging additional investigations to determine the underlying cause, depending on clinical judgement, and manage appropriately - Hypercalcaemia

Answer 12

Full blood count — to diagnose or exclude anaemia of chronic disease or haematologic malignancy.
Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) — may be increased in malignancy or other inflammatory or granulomatous conditions.
Estimated glomerular filtration rate (eGFR) and creatinine — to assess hydration status, for acute kidney injury (AKI) and chronic kidney disease (CKD).
Serum and urine protein electrophoresis, including testing for urine Bence-Jones protein — to exclude myeloma.
Liver function tests — to exclude liver metastases or chronic liver failure; alkaline phosphatase may be increased in primary hyperparathyroidism, Paget’s disease with immobilization, myeloma, or bone metastases.
Thyroid function tests — to exclude thyrotoxicosis.
Parathyroid hormone (PTH) — typically raised in primary (and tertiary) hyperparathyroidism, and suppressed or undetectable in malignancy-related hypercalcaemia or other non PTH-dependent causes.
Arrange for a random PTH sample and check a serum adjusted calcium level at the same time. Primary hyperparathyroidism may be suggested if the result is above the midpoint of the reference range, or below the midpoint of the reference range with a concurrent adjusted serum calcium level of 2.6 mmol/L or above.
Vitamin D — if vitamin D toxicity is suspected (rare).
Serum cortisol (morning sample at 8–9 am) — if Addison’s disease is suspected.
Early morning urine sample to measure the urinary albumin:creatinine ratio (ACR) — if CKD is suspected
Chest X-ray — to exclude lung cancer or metastases, lymphoma, sarcoidosis, or tuberculosis.

Question 13

Hypercalcaemia is defined as a serum calcium concentration of … mmol/L or higher, on two occasions, following adjustment (correction) for the serum albumin concentration.

Answer 13

Hypercalcaemia is defined as a serum calcium concentration of 2.6 mmol/L or higher, on two occasions, following adjustment (correction) for the serum albumin concentration.

Question 14

Ranges of serum calcium concentration are used to classify the severity of hypercalcaemia:

Answer 14

Mild hypercalcaemia is an adjusted serum calcium concentration of 2.6–3.00 mmol/L.
Moderate hypercalcaemia is an adjusted serum calcium concentration of 3.01–3.40 mmol/L.
Severe hypercalcaemia is an adjusted serum calcium concentration of greater than 3.40 mmol/L.

Question 15

There are multiple possible underlying causes of hypercalcaemia, the two most common being …

Answer 15

There are multiple possible underlying causes of hypercalcaemia, the two most common being primary hyperparathyroidism and malignancy.

Question 16

If the person has severe hypercalcaemia or severe symptoms:

Answer 16

Arrange emergency admission to hospital for further specialist assessment and management such as intravenous fluids and intravenous bisphosphonate therapy (pamidronate or zoledronate).

Question 17

Assessing for complications of hypercalcaemia by arranging additional tests.

Bone mineral density by dual-energy X-ray absorptiometry (DEXA) to assess for …. There is typically greatest reduction in bone density seen at the distal third of the radius, followed by the hip and lumbar spine.

Answer 17

Bone mineral density by dual-energy X-ray absorptiometry (DEXA) to assess for osteoporosis. There is typically greatest reduction in bone density seen at the distal third of the radius, followed by the hip and lumbar spine.

Question 18

… is the only curative treatment for primary hyperparathyroidism, with cure rates of more than 98% reported in specialist centres.

Answer 18

Parathyroidectomy is the only curative treatment for primary hyperparathyroidism, with cure rates of more than 98% reported in specialist centres.

Question 19

Clinical indications for parathyroidectomy include a person with primary hyperparathyroidism with:

Answer 19

Symptomatic disease.
Age under 50 years.
Adjusted serum calcium concentration that is 0.25 mmol/L or more above the upper limit of normal. Note: the National Institute for Health and Care Excellence (NICE) recommends an adjusted serum calcium level of 2.85 mmol/L or above.
Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2.
Renal stones or presence of nephrocalcinosis on renal imaging; increased renal stone risk on 24-hour urine or biochemical urine analysis.
Presence of osteoporosis or vertebral or other fragility fracture.

Question 20

Clinical indications for possible conservative management of primary hyperparathyroidism include a person with:

Answer 20

Asymptomatic disease.
Age 50 years or over.
Adjusted serum calcium concentration that is less than 0.25 mmol/L above the upper limit of normal.
No end-organ damage (renal stones, fragility fractures, or osteoporosis) or other co-morbidities making them unfit for surgery.

Question 21

If parathyroid surgery is not indicated, declined, contraindicated, or has failed, specialist management of hypercalcaemia may include:

Answer 21

Cautious correction of vitamin D deficiency if appropriate.
Calcium-lowering therapy with calcitonin which can have a rapid calcium-lowering effect by inhibiting bone resorption and renal calcium reabsorption.
Calcium-lowering therapy with the calcimimetic drug cinacalcet which may reduce serum calcium concentration. It does not have an effect on bone density or hypercalciuria.
Calcium-lowering therapy with the anti-resorptive agent desunomab, which may have a role in the emergency management of severe refractory hypercalaemia and bisphosphonate-refractory hypercalaemia of malignancy.
Bisphosphonate therapy to improve bone mineral density.
Glucocorticoid therapy for vitamin D-mediated hypercalcaemia, for example caused by some granulomatous diseases or lymphoma.

Question 22

High PTH +ca?

Answer 22

Primary hyperparathyroidsm

Question 23

Management of acute hypercalcaemia

Answer 23

Aggressive saline infusion (5L in 24hours)
Loop diuretics if heart/renal failure

Bisphosphonates - most effective (zoledronic acid/pamidronate)
Inhibit osteoclast activity
Lower calcium levels in 50% of patients in 4 days

Calcitonin or denosumab in refractory hypercalcaemia

Question 24

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

Answer 24

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

Question 25

Normal serum calcium levels range from … -. … mmol/L.

Answer 25

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

Question 26

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

Answer 26

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

Question 27

The most common causes of hypercalcaemia are …

Answer 27

The most common causes of hypercalcaemia are Malignant hypercalcaemia and Primary hyperparathyroidism.

Question 28

Malignant hypercalcaemia

Answer 28

Malignancy is the most common cause of hypercalcaemia in the inpatient population. Up to 30% of cancers develop hypercalcaemia as part of the natural disease course, a development that is associated with a poor prognosis.

Hypercalcaemia commonly occurs due to release of parathyroid related peptide (PTHrP), which mimics the action of PTH. Other mechanisms include osteolytic damage to bone or activation of vitamin D.

Question 29

Primary hyperparathyroidism

Answer 29

Primary hyperparathyroidism is the most common cause of hypercalcaemia in the general population. It occurs 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 parathyroid hyperplasia and rarely parathyroid cancer. Primary hyperparathyroidism may be part of a genetic syndrome known as Multiple endocrine neoplasia.

Question 30

Tertiary hyperparathyroidism

Answer 30

Secondary hyperparathyroidism is characterised by excess PTH production secondary to low serum calcium, typically due to chronic kidney disease or vitamin D deficiency.

Tertiary hyperparathyroidism is characterised by autonomous PTH excess due to parathyroid hyperplasia in response to longstanding secondary hyperparathyroidism - seen in patients with chronic kidney disease. Like primary hyperparathyroidism and unlike secondary hyperparathyroidism this is associated with hypercalcaemia.

Question 31

Thyrotoxicosis

Answer 31

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

Question 32

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:

Answer 32

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

Question 33

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:

Answer 33

The full syndrome is characterised by:

Hypercalcaemia
Metabolic alkalosis
Acute kidney injury

Question 34

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.

Answer 34

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.

Question 35

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

Answer 35

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

Question 36

FHH

Answer 36

Familial hypocalciuric hypercalcaemia is a rare autosomal dominant disorder that causes mild hypercalcaemia.

Question 37

FHH is an autosomal dominant condition caused by a mutation to calcium-sensing receptors (CaSR). CaSRs play an important role in calcium regulation:

Answer 37

Parathyroid gland: CaSRs enable the parathyroid gland to sense changes to calcium levels and respond appropriately.
Kidneys: CaSRs have a number of complex functions that appear to increase calcium excretion in the urine when serum levels are raised.
FHH normally causes a mildly elevated calcium with a PTH that is either mildly elevated or at the upper limit of normal. As such it is excellent at biochemically mimicking primary hyperparathyroidism. It can be distinguished by looking for the hypocalciuria that is present in FHH but absent in PHPT.

Question 38

Hypercalcaemia is characterised by …

Answer 38

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

Question 39

Many individuals will be asymptomatic (particularly with primary hyperparathyroidism) and the abnormality is picked up incidentally on routine blood tests. Clinical features, when present, may reflect both the hypercalcaemia and the raised PTH (in cases where this is elevated). In those who are symptomatic the classic phrase ‘bones, stones, thrones, abdominal groans, and psychic moans’ can act as an aide-mémoire.

Answer 39

Bones - fragility fractures, bone pain
Stones - renal calculi
Thrones - polyuria, constipation
Abdominal groans - abdominal pain, N&V, pancreatitis
Psychic moans - mood disturbance, depression, fatigue, psychosis

Question 40

Symptoms - hypercalcaemia

Answer 40

Symptoms

Fatigue
Myalgia
Mood changes
Depression
Insomnia
Polydipsia
Polyuria
Constipation
Fragility fracture
Renal colic

Question 41

Signs - hypercalcaemia

Answer 41

Signs

Dehydration (skin turgor, dry mucous membranes)
Hypertension
Cardiac arrhythmia (severe disease)
Confusion (severe disease)

Question 42

Confirm hypercalcaemia HOW?

Answer 42

First confirm hypercalcaemia with a bone profile. Most laboratories will automatically give a corrected calcium result.

Question 43

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

Answer 43

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.

Question 44

In suspected malignant cases, PTHrP may be requested. Other common investigations include:

Answer 44

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.

Question 45

Treatment recommendations for hypercalcaemia (mild,moderate and severe)

Answer 45

Mild (< 3 mmol/L) and asymptomatic/mild symptoms: increase oral fluids 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.

Question 46

The management of severe hypercalcaemia initially involves the use of intravenous fluids. 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.

Answer 46

The management of severe hypercalcaemia initially involves the use of intravenous fluids. 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.

Question 47

Bisphosphonates - hypercalcaemia

Answer 47

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.

Question 48

Pamidronate or zoledronic acid are typically used in hypercalcaemia, but they are potentially .. and contraindicated in severe .. impairment.

Answer 48

nephrotoxic and contraindicated in severe renal impairment.

Question 49

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

Answer 49

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

Question 50

Other treatment options depend on the suspected underlying cause: (hypercalcaemia)

Answer 50

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.