Hypercalcaemia
Hypercalcaemia - Summary
Hypercalcaemia can be defined as a serum calcium concentration of 2.65 mmol/L (or higher) on two occasions, following adjustment (correction) for the serum albumin concentration.
Mild hypercalcaemia: adjusted serum calcium concentration of 2.65–3.00 mmol/L.
Moderate hypercalcaemia: adjusted serum calcium concentration of 3.01–3.40 mmol/L.
Severe hypercalcaemia: adjusted serum calcium concentration of greater than 3.40 mmol/L.
More common causes (accounting for 90% of people with hypercalcaemia) are:
Primary hyperparathyroidism.
Cancer.
Less common causes include:
Drugs including thiazide diuretics, lithium, calcium plus antacids, or calcium-containing antacids ('milk-alkali syndrome').
Granulomatous diseases including sarcoidosis, tuberculosis.
Renal failure/transplantation.
Immobilization (Paget's disease only).
Dehydration.
Chronic liver disease.
Hypercalcaemia is potentially life-threatening, particularly when it is severe, due to the effects of hypercalcaemia on the kidneys, heart, and brain.
Many people with chronic hypercalcaemia are asymptomatic, particularly when hypercalcaemia is mild.
When symptoms of hypercalcaemia are present, they are often non-specific. The extent of symptoms is related to both the severity of the hypercalcaemia and its rate of onset.
Clinical features of hypercalcaemia include (the mnemonic 'bones, moans, groans, and stones' may be helpful):
Skeletal ('bones')
Bone pain.
Pathological fractures.
Neuromuscular ('moans')
Fatigue, muscle weakness.
Increased pain (in people with cancer).
Impaired concentration and memory.
Depression.
Drowsiness (common), delirium, seizures, coma.
Neurological signs (for example upper motor neurone deficits and ataxia).
Gastrointestinal (abdominal 'groans')
Nausea, vomiting, anorexia, weight loss.
Constipation, abdominal pain.
Peptic ulcer, pancreatitis (both rare).
Renal ('stones')
Renal colic.
Polyuria, polydipsia, and dehydration (due to nephrogenic diabetes insipidus).
Renal impairment (due to nephrocalcinosis).
A blood sample is required to measure serum calcium and serum albumin concentrations. Prolonged application of a tourniquet should be avoided.
The test should be repeated to confirm the result, unless the person has hypercalcaemia that is severe (adjusted serum calcium concentration greater than 3.40 mmol/L) or is symptomatic, when they should be admitted immediately to hospital.
A blood sample should be taken to test parathyroid hormone (PTH) levels, or referral arranged to an endocrinologist for investigation.
In the context of hypercalcaemia, if the PTH level is high, the most likely diagnosis is primary hyperparathyroidism.
If the PTH level is within the reference range, primary hyperparathyroidism remains a likely diagnosis, but other causes (including cancer) must be excluded.
If the PTH level is low or undetectable, the most likely diagnosis is cancer.
It should be noted that primary hyperparathyroidism may coexist with cancer, resulting in PTH levels that are normal or elevated despite cancer being present.
For people with unexplained hypercalcaemia that is mild or moderate and asymptomatic, the underlying cause should be identified. There may be more than one cause. Referral is recommended to the appropriate specialist, depending on the suspected cause.
Following specialist endocrine assessment, monitoring of people with asymptomatic primary hyperparathyroidism who have no indications for parathyroidectomy or who decline parathyroidectomy may be done in primary care.
Have I got the right topic?
This CKS topic covers the diagnosis of hypercalcaemia, how to determine the underlying cause, and its management in primary care, and briefly covers the secondary care management of hypercalcaemia.
There are separate CKS topics on Chronic kidney disease - not diabetic and Palliative cancer care - nausea & vomiting.
The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.
How up-to-date is this topic?
How up-to-date is this topic?
Changes
April to August 2010 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.
Update
New evidence
Evidence-based guidelines
No new evidence-based guidelines since 1 May 2010.
HTAs (Health Technology Assessments)
No new HTAs since 1 May 2010.
Economic appraisals
No new economic appraisals relevant to England since 1 May 2010.
Systematic reviews and meta-analyses
No new systematic review or meta-analysis since 1 May 2010.
Primary evidence
No new randomized controlled trials published in the major journals since 1 May 2010.
New policies
No new national policies or guidelines since 1 May 2010.
New safety alerts
No new safety alerts since 1 May 2010.
Changes in product availability
No changes in product availability since 1 May 2010.
Goals and outcome measures
Goals
To support primary health care professionals to:
Detect and diagnose hypercalcaemia
Determine the likely underlying cause, if possible and appropriate
Offer appropriate management to people with hypercalcaemia depending on the likely underlying cause
Admit the person to hospital or hospice for immediate treatment and investigation when appropriate
Refer the person to a specialist for further investigation and management depending on the likely underlying cause
Be aware of the requirements for monitoring in people with asymptomatic primary hyperparathyroidism who have not undergone parathyroidectomy
Background information
Definition
What is it?
Hypercalcaemia can be defined as a serum calcium concentration of 2.65 mmol/L (or higher) on two occasions, following adjustment (correction) for the serum albumin concentration [Davies et al, 2002; Smellie et al, 2008].
Hypercalcaemia can be classified as mild, moderate, or severe based on adjusted serum calcium concentration. However, this does not necessarily reflect the severity of symptoms which are also dependent on the rate of onset of hypercalcaemia [Smellie et al, 2008].
Mild hypercalcaemia is an adjusted serum calcium concentration of 2.65–3.00 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.
Causes
What causes it?
More common causes (accounting for 90% of people with hypercalcaemia):
Less common causes:
Drugs (prescribed or over-the-counter).
Thiazide diuretics.
Lithium.
Vitamin D intoxication.
Vitamin A intoxication.
Calcium plus antacids, or calcium-containing antacids ('milk-alkali syndrome').
Sarcoidosis.
Tuberculosis.
Other rarer granulomatous diseases.
Renal failure/transplantation.
Familial hypocalciuric hypercalcaemia.
Immobilization in people with Paget's disease (and children).
Non-parathyroid endocrine diseases:
Thyrotoxicosis.
Addison's disease.
Phaeochromocytoma.
Vasoactive intestinal polypeptide hormone-producing tumour (VIPoma; a type of islet cell tumour).
Other causes:
Dehydration.
Recovery phase of rhabdomyolysis.
Chronic liver disease.
[Bilezikian, 1993; Chan et al, 1997; Carroll and Schade, 2003; Ralston et al, 2004]
Primary hyperparathyroidism
Primary hyperparathyroidism
Primary hyperparathyroidism is the excessive and inappropriate secretion of parathyroid hormone (PTH), usually from a single parathyroid adenoma. This is the cause in 80% of people with primary hyperparathyroidism [Chan et al, 1997; Kumar and Clark, 2005].
Less commonly, such secretion is from diffuse hyperplasia of all the parathyroid glands, multiple parathyroid adenomas, or (rarely) parathyroid cancer (about 0.5%) [Chan et al, 1997; Kumar and Clark, 2005].
Primary hyperparathyroidism is a common feature of the rare multiple endocrine neoplasia (MEN) syndromes types 1 and 2A [Chan et al, 1997; Brandi et al, 2001].
Excess PTH causes hypercalcaemia by increasing renal calcium reabsorption and mobilizing calcium from bone. It also indirectly increases intestinal calcium absorption, by increasing synthesis of serum 1,25-dihydroxyvitamin D3 (calcitriol, the active form of vitamin D3) [Chan et al, 1997; Bushinsky and Monk, 1998].
Primary hyperparathyroidism is occasionally familial [Chan et al, 1997].
Cancer
Cancer
For most people with cancer who present with hypercalcaemia, the cancer is already known [Bushinsky and Monk, 1998].
The cancers most commonly associated with hypercalcaemia include squamous cell lung cancer, breast cancer, and multiple myeloma.
Other cancers in which hypercalcaemia occurs include: lymphomas; leukaemias; cancers of the kidney, bladder, ovary, oesophagus, or head and neck; and colorectal, prostatic, pancreatic, cervical, primary liver, thyroid, and non-squamous cell lung cancers [Kovacs et al, 1995; Chisholm et al, 1996; Chan et al, 1997; Bushinsky and Monk, 1998].
Hypercalcaemia can occur in cancers with or without skeletal metastases.
The mechanism for hypercalcaemia in almost all people with cancer is secretion (by cancer cells) of parathyroid hormone-related peptide (PTHrP) and other circulating factors.
PTHrP is not detected on standard assays for parathyroid hormone, but specific assays for PTHrP are sometimes available [Bushinsky and Monk, 1998; Twycross et al, 2009].
Cancer is usually advanced if hypercalcaemia occurs. When the underlying cancer cannot be treated, median survival for people with hypercalcaemia is 2–3 months [Chan et al, 1997; Regnard and Dean, 2010].
Drugs
Drugs
Thiazide diuretics
Thiazide diuretics can cause hypercalcaemia by increasing the renal tubular reabsorption of calcium, but other mechanisms are postulated. Hypercalcaemia is usually mild.
Often, the underlying cause is found to be primary hyperparathyroidism, with hypercalcaemia only worsened by the thiazide.
Lithium
Lithium causes hypercalcaemia by altering the parathyroid feedback threshold, stimulating parathyroid hypertrophy (with long-term use), and reducing renal calcium clearance.
Most people taking lithium have a slight increase in serum calcium concentration within 4 weeks of starting treatment, but the level is usually within the normal range and returns to baseline when treatment is discontinued.
Vitamin D intoxication
Hypercalcaemia may be caused by excessive oral intake of vitamin D, its metabolites, or vitamin D analogues. It may also be caused by excessive topical application of potent vitamin D analogues.
The smallest dose that produces toxicity is not known; there is considerable variation in individual responsiveness to vitamin D.
Vitamin A intoxication
Hypercalcaemia can be caused by taking excessive amounts of oral vitamin A (more than 50,000 IU/day) for weeks or months.
Other manifestations of vitamin A toxicity include dermatitis, alopecia, and hepatic dysfunction.
Calcium plus antacids, or calcium-containing antacids ('milk-alkali syndrome')
This syndrome is characterized by headache, nausea, neuromuscular irritability, lethargy, hypocalciuria, metabolic alkalosis, and hypercalcaemia.
It is caused by ingestion of large amounts of calcium and bicarbonate.
Risk factors include renal impairment, thiazide diuretic use, and pre-existing alkalosis.
[Chan et al, 1997; Wermers et al, 2007; Jones and Twomey, 2009]
Granulomatous diseases
Granulomatous diseases
Granulomatous diseases in which hypercalcaemia may occur include sarcoidosis, tuberculosis, leprosy, histoplasmosis, berylliosis, eosinophilic granuloma, and silicone-induced granuloma.
Hypercalcaemia continues during anti-tuberculous chemotherapy.
The cause is ectopic production of 1,25-dihydroxyvitamin D3 (calcitriol), which causes vitamin D toxicity.
Treatment is typically directed at the underlying disorder (for example anti-tuberculous chemotherapy), and corticosteroids are often used.
Renal failure/transplantation
Renal failure/transplantation
Hypercalcaemia can occur:
In chronic renal failure, due to tertiary hyperparathyroidism.
In secondary hyperparathyroidism, parathyroid glands are hypertrophied because of hypocalcaemia that can occur during chronic renal failure. Tertiary hyperparathyroidism occurs when the hypertrophied parathyroid glands start to release excess parathyroid hormone autonomously, which becomes unregulated.
Following renal transplantation, because of tertiary hyperparathyroidism and the restoration of 1,25-dihydroxyvitamin D3 produced by the transplanted kidney.
During the recovery phase of acute renal failure, due to rebound increases in levels of parathyroid hormone and 1,25-dihydroxyvitamin D3.
Familial hypocalciuric hypercalcaemia
Familial hypocalciuric hypercalcaemia
Familial hypocalciuric hypercalcaemia is a rare, autosomal dominant disorder caused by a mutation in the calcium sensing receptor.
It is characterized by hypocalciuria, asymptomatic hypercalcaemia, and a normal (or occasionally high) parathyroid hormone level.
Hypercalcaemia is present from birth, but the condition is often not detected until well into adulthood.
Treatment is not necessary.
Immobilization
Immobilization
Immobilization can lead to hypercalcaemia in people with accelerated bone turnover, due to enhanced osteoclast activity and diminished osteoblast activity ('uncoupling' of bone cell activity).
People with Paget's disease, cancer, or primary or secondary hyperparathyroidism are at risk. Secondary hyperparathyroidism can occur in people with chronic renal failure owing to parathyroid hypertrophy. Children who are immobilized (for example because of fractures) can also become hypercalcaemic.
Non-parathyroid endocrine diseases
Non-parathyroid endocrine diseases
Thyrotoxicosis
Hypercalcaemia in thyrotoxicosis is usually mild and returns to normal with correction of thyroid function.
The cause is excessive osteoclast activity.
Phaeochromocytoma
This can cause hypercalcaemia by the production of parathyroid hormone-related peptide.
Hypercalcaemia may also occur due to co-existing primary hyperparathyroidism in multiple endocrine neoplasia (MEN) type 2A.
Addison's disease
This is a rare cause of hypercalcaemia, which results from the loss of the antagonistic effects of glucocorticoids on calcium absorption and bone mobilization, together with dehydration.
Vasoactive intestinal polypeptide hormone-producing tumour (VIPoma; a type of islet cell tumour)
When hypercalcaemia is present, it can be severe.
VIPomas can coexist with primary hyperparathyroidism in MEN type 1.
Features include large-volume diarrhoea and hypokalaemia.
Prevalence and incidence
How common is it?
Accurate estimates of the prevalence of hypercalcaemia in the general (non-hospitalized) population in England are lacking. The prevalence of hypercalcaemia depends on the value used as the upper limit of normal, the reliability of the analytical method, and the population being tested [Klee et al, 1988].
A predominantly hospital-based study in England, and a community-based survey in Sweden, found the prevalence of hypercalcaemia to be about 1%, with women being affected more commonly than men [Harrop et al, 1982; Palmér et al, 1988].
The English study was a retrospective evaluation of 24,500 people undergoing biochemical profiling at a laboratory in Derby, at the request of a clinician (75% of the participants were hospitalized) [Harrop et al, 1982]. About 1% had a plasma calcium concentration greater than 2.60 mmol/L on two occasions. (This reference range upper limit is lower than the level of 2.65 mmol/L used in this CKS topic.)
In the survey in Sweden, of 16,401 people attending for health screening [Palmér et al, 1988], 1.1% had a serum calcium concentration greater than 2.60 mmol/L on two occasions. Hypercalcaemia occurred in 1.7% of women and 0.4% of men. This difference between the sexes is probably due to the higher prevalence of primary hyperparathyroidism in women.
Primary hyperparathyroidism is the most common cause of hypercalcaemia, accounting for over half of all people with hypercalcaemia [Bushinsky and Monk, 1998].
In Tayside (Scotland) between 1997 and 2006, the prevalence was 1.82–6.72 per 1000 population. The annual incidence varied from 4.13–11.30 per 10,000 person-years [Yu et al, 2009].
Peak incidence is in the fifth and sixth decades of life, but primary hyperparathyroidism occurs in people of all ages. However, it is rare in children younger than 15 years of age [Chan et al, 1997].
There is a female to male ratio of 2.5–3.5:1 [Chan et al, 1997; Yu et al, 2009].
Cancer is the second most common cause of hypercalcaemia [Bushinsky and Monk, 1998].
Hypercalcaemia occurs in 10–20% of people with cancer at some point during the course of their illness [Chisholm et al, 1996; Heys et al, 1998; Saunders et al, 2004].
The prevalence of hypercalcaemia in people taking long-term lithium is reported, in cross-sectional studies, to be 15–60% [Jones and Twomey, 2009].
Hypercalcaemia occurs in 10–20% of people with sarcoidosis.
It occurs in a smaller proportion of people with tuberculosis [Chan et al, 1997].
Complications
What are the complications?
Hypercalcaemia is potentially life-threatening, particularly when it is severe, due to the effects of hypercalcaemia on the kidneys, heart, and brain [Ziegler, 2001; Carroll and Schade, 2003].
For the clinical features of hypercalcaemia, see When to suspect.
Diagnosis and assessment
Diagnosis and assessment of hypercalcaemia
When to suspect
When should I suspect hypercalcaemia?
Many people with chronic hypercalcaemia are asymptomatic, particularly when hypercalcaemia is mild.
When symptoms of hypercalcaemia are present, they are often non-specific.
The extent of symptoms is related to both the severity of the hypercalcaemia and its rate of onset.
Clinical features of hypercalcaemia include (the mnemonic 'bones, moans, groans, and stones' may be helpful):
Skeletal ('bones')
Bone pain (may be seen in people with primary hyperparathyroidism or cancer).
Pathological fractures (due to osteoporosis in primary hyperparathyroidism).
Neuromuscular ('moans')
Fatigue, muscle weakness.
Increased pain (in people with cancer).
Impaired concentration and memory.
Depression.
Drowsiness (common), delirium, seizures, coma.
Neurological signs (for example upper motor neurone deficits and ataxia).
Gastrointestinal (abdominal 'groans')
Nausea, vomiting, anorexia, weight loss.
Constipation, abdominal pain.
Peptic ulcer, pancreatitis (both rare).
Renal ('stones')
Renal colic due to kidney stones (nephrolithiasis). This is rare when hypercalcaemia is due to cancer, but is seen in some people with primary hyperparathyroidism.
Polyuria, polydipsia, and dehydration (due to nephrogenic diabetes insipidus).
Renal impairment (due to nephrocalcinosis).
Cardiovascular
Hypertension.
Shortened QT interval on electrocardiogram (ECG).
Potentiation of digitalis action or toxicity.
Cardiac arrhythmias (rare).
Other
Itching.
Keratitis, conjunctivitis, and corneal calcification.
Basis for recommendation
Basis for recommendation
Many people are asymptomatic
The information that many people with hypercalcaemia are asymptomatic, particularly when hypercalcaemia is mild, with the diagnosis being made incidentally, is derived from narrative reviews [Ralston, 1992; Bushinsky and Monk, 1998; Carroll and Schade, 2003].
Symptoms are often non-specific
This information is derived from narrative reviews [Ralston, 1992; Smellie et al, 2008].
Extent of symptoms is related to severity and rate of onset
This information is derived from narrative reviews [Ralston, 1992; Bushinsky and Monk, 1998; Weiss-Guillet et al, 2003].
Clinical features
The clinical features of hypercalcaemia are derived from several narrative reviews [Ralston, 1992; Chan et al, 1997; Bushinsky and Monk, 1998; Carroll and Schade, 2003; Weiss-Guillet et al, 2003; Ralston et al, 2004; Smellie et al, 2008; Waters, 2009] and a textbook [Twycross et al, 2009]. Each clinical feature was stated in at least two articles or texts.
The information that renal colic is rare when hypercalcaemia is due to cancer is derived from a narrative review [Ralston, 1992]. Another narrative review states that up to 6% of people with calcium-containing kidney stones have (primary) hyperparathyroidism [Bushinsky and Monk, 1998].
The information that both peptic ulcer and pancreatitis are rare in people with hypercalcaemia is derived from a narrative review [Chan et al, 1997].
Diagnosis
How should I make a diagnosis of hypercalcaemia?
Take blood to measure serum calcium and serum albumin concentrations.
Avoid prolonged application of a tourniquet when taking blood to test serum calcium concentration.
Ensure that the calcium concentration is adjusted (corrected) for the serum albumin concentration. If the laboratory has not already done so (or measured the ionized calcium concentration), use the following calculation:
Adjusted Ca (mmol/L) = measured Ca (mmol/L) + (0.02 x [40 – Alb (g/L)]), where Ca is serum calcium concentration and Alb is serum albumin concentration.
This calculation may be inaccurate at extreme albumin concentrations, if the person has paraproteinaemia, or if the person is acidotic. In these circumstances, an ionized calcium concentration should be requested.
Repeat the test to confirm, unless the person has hypercalcaemia that is severe (adjusted serum calcium concentration greater than 3.40 mmol/L) or symptomatic, when they should be admitted immediately to hospital.
Diagnose:
Mild hypercalcaemia — when the adjusted calcium concentration is 2.65–3.00 mmol/L.
Moderate hypercalcaemia — when the adjusted calcium concentration is 3.01–3.40 mmol/L.
Severe hypercalcaemia — when the adjusted calcium concentration is greater than 3.40 mmol/L.
Basis for recommendation
Basis for recommendation
Take blood to measure serum calcium and serum albumin concentrations
This recommendation is based on a narrative review, Best practice in primary care pathology [Smellie et al, 2008].
Avoid prolonged application of a tourniquet
Historically, it was thought that the apparent serum calcium concentration increased if a tourniquet was applied to distend the vein for venepuncture [McMullan et al, 1990].
Although one regional Canadian guideline recommends that a tourniquet should be avoided when taking blood to measure serum calcium concentration [Alberta Medical Association, 2008], one small study found no important effect of tourniquet use on adjusted calcium concentrations [McMullan et al, 1990]. Two narrative reviews recommend avoiding prolonged application of a tourniquet [Smellie et al, 2008; Waters, 2009] presumably because of the uncertainty regarding this issue.
Ensure that the calcium concentration is adjusted for serum albumin
The formula used to adjust the serum calcium concentration is based on narrative reviews [Rizzoli and Bonjour, 1992; Murphy et al, 2006; Waters, 2009].
The reason for adjusting for serum albumin concentration is that a large proportion of circulating calcium is bound to albumin, and low albumin levels can affect the total serum calcium level [Carroll and Schade, 2003].
The statement that the calculation may be inaccurate at extreme albumin concentrations, if the person has paraproteinaemia (for example in multiple myeloma) or if the person is acidotic, is derived from narrative reviews [Ralston, 1992; Bushinsky and Monk, 1998; Inzucchi, 2004; Smellie et al, 2008].
Repeat to confirm
The recommendation to repeat the test (provided there are no indications for immediate management) is based on two narrative reviews [Klee et al, 1988; Smellie et al, 2008] and a study of 24,500 people who underwent testing of plasma calcium concentrations at a biochemistry department in Derby at the request of their physician [Harrop et al, 1982]. Three-quarters of samples were from hospital inpatients. Of 738 people whose initial plasma calcium concentration was greater than 2.60 mmol/L, 404 people had repeat tests. Of the people who had repeat tests, only 201 (50%) had a second plasma calcium concentration greater than 2.60 mmol/L. The higher the initial plasma calcium concentration, the more likely was the repeat test to confirm hypercalcaemia. The confirmation rate was 37% for the range 2.61–2.70 mmol/L, 72% for the range 2.71–2.80 mmol/L, 93% for 2.81–2.90 mmol/L, and 98% for greater than 2.90 mmol/L.
The recommendation to admit people with severe or symptomatic hypercalcaemia is based on a narrative review [Smellie et al, 2008].
When to diagnose mild, moderate, and severe hypercalcaemia
These recommendations are derived from a narrative review [Smellie et al, 2008]. The concentration of serum calcium affects management.
Determining the underlying cause
How do I determine the underlying cause?
Do not routinely investigate people with hypercalcaemia that is severe (adjusted serum calcium concentration greater than 3.40 mmol/L) or symptomatic. These people should be admitted to hospital for urgent treatment and investigation.
Hypercalcaemia may develop in the context of known disease (for example cancer) where the cause is apparent.
For people with unexplained hypercalcaemia that is mild or moderate (adjusted serum calcium concentration 3.40 mmol/L or less) and asymptomatic, look for the underlying cause. There may be more than one cause.
Review the medical history and look for clinical features of:
Cancer (especially breast, lung, and haematological cancers).
Renal failure, dialysis, or transplantation.
Renal impairment or kidney stones (suggesting primary hyperparathyroidism).
Osteoporotic fracture (this can occur in people with primary hyperparathyroidism that has been present for many years).
Sarcoidosis or tuberculosis.
Paget's disease of bone (only causes hypercalcaemia if the person is immobilized).
Thyrotoxicosis or other endocrine diseases.
Dehydration (may be a cause of transient hypercalcaemia, or a symptom).
Determine if the person is taking any drugs or vitamin supplements that can cause hypercalcaemia. These include calcium supplements, thiazide diuretics, vitamin D or vitamin D analogues (oral or topical), vitamin A, lithium, or calcium-containing antacids (or calcium supplements co-prescribed with antacids) which can cause milk-alkali syndrome.
Ask about any family history of primary hyperparathyroidism, familial hypocalciuric hypercalcaemia, or other endocrine tumours (that is, pituitary, adrenal, pancreatic, or thyroid tumours suggesting multiple endocrine neoplasia).
Check for any previous increased or high-normal serum calcium concentrations. In primary hyperparathyroidism, the increase in serum calcium level is usually mild and stable, or is slowly progressive over a period of years.
Take a blood sample to test parathyroid hormone (PTH) levels or refer the person to an endocrinologist for investigation.
Testing for PTH is not always available in primary care. If this is the case, refer the person to an endocrinologist (urgently if necessary).
Check with the local biochemistry laboratory regarding whether PTH testing is available, any specific collection tube is needed, or the sample needs to be transported rapidly or taken close to the laboratory.
Consider doing the following additional investigations, but do not delay urgently referring the person to secondary care if cancer is suspected:
Chest X-ray (for lung cancer or metastases, sarcoidosis, or tuberculosis).
Renal function and serum electrolytes (for renal failure, milk-alkali syndrome, or renal impairment in primary hyperparathyroidism or myeloma).
Full blood count (for anaemia of chronic disease).
Erythrocyte sedimentation rate or C-reactive protein (may be increased in cancer).
Serum and urine protein electrophoresis, including testing for urine Bence–Jones protein (for myeloma).
Serum alkaline phosphatase (may be increased in primary hyperparathyroidism, Paget's disease with immobilization, myeloma, or bone metastases) and other liver function tests (for liver metastases; chronic liver failure is also a rare cause of hypercalcaemia).
Serum phosphate (may be low in primary hyperparathyroidism) and chloride (may be increased in primary hyperparathyroidism). These tests are often done automatically when serum calcium is requested; there is little value in requesting them if they are not.
Thyroid function tests (for thyrotoxicosis).
Serum cortisol (morning sample, at 8–9 a.m. — Addison's disease is a rare cause).
Urinalysis for urine protein (for renal disease).
Basis for recommendation
Basis for recommendation
When to evaluate
The recommendation to not investigate routinely people with severe or symptomatic hypercalcaemia in primary care, and that these people should be admitted to hospital for urgent treatment and investigation, is based on expert opinion from a narrative review [Smellie et al, 2008]. Hence, it is only recommended to look for the underlying cause if hypercalcaemia is mild or moderate and asymptomatic.
The recommendation to look for the underlying cause is also based on expert opinion from a narrative review that the main role of the GP in the management of hypercalcaemia is to distinguish between malignant and hyperparathyroid causes, in order to make the appropriate specialist referral [Murphy et al, 2006].
The information that hypercalcaemia may develop in the context of known disease is also based on expert opinion from a narrative review [Smellie et al, 2008].
Reviewing medical history and looking for clinical features
This list is based on possible causes of hypercalcaemia, and their symptoms.
Drugs or vitamin supplements
This list is based on drugs that are known to cause hypercalcaemia.
Family history
The recommendation to ask about any family history of primary hyperparathyroidism, familial hypocalciuric hypercalcaemia, or other endocrine tumours (that is, pituitary, adrenal, pancreatic, or thyroid tumours suggesting multiple endocrine neoplasia [MEN]) is based on a narrative review [Inzucchi, 2004]. Primary hyperparathyroidism can be familial [Chan et al, 1997], and primary hyperparathyroidism is a common feature of the rare MEN syndromes, which are partly inherited [Kumar and Clark, 2005].
Previous calcium concentrations
The recommendation to check for any previous serum calcium concentrations in the person's notes is based on expert opinion (in a narrative review) that, in primary hyperparathyroidism, the increase in serum calcium level is usually mild and stable, or is slowly progressive over a period of years [Inzucchi, 2004].
Measuring parathyroid hormone (PTH) levels or referring to an endocrinologist
The recommendation to measure PTH is based on consistent expert opinion in narrative reviews [Klee et al, 1988; Ralston, 1992; Carroll and Schade, 2003; Selby, 2003; Murphy et al, 2006; Smellie et al, 2008].
The recommendation that referring the person to an endocrinologist for investigation is an alternative management option (instead of investigation) is based on feedback from CKS expert reviewers.
The information that PTH testing is not always available in primary care is based on feedback from CKS expert reviewers. Referral to an endocrinologist is likely to be the only management option if PTH testing is not available.
The recommendation to check with the local biochemistry laboratory whether a specific collection tube is needed, and whether the sample needs to be transported rapidly to the laboratory or taken close to the laboratory is based on expert opinion from a narrative review [Smellie et al, 2008].
The recommendation to measure PTH before attempting to treat the hypercalcaemia is based on expert opinion (from a narrative review) that a decrease in calcium concentration can trigger PTH release, leading to the mistaken conclusion that the hypercalcaemia is PTH-dependent [Klee et al, 1988].
Additional investigations
This list is derived from several narrative reviews [Klee et al, 1988; Davies et al, 2002; Carroll and Schade, 2003; Inzucchi, 2004; Murphy et al, 2006; Smellie et al, 2008; Waters, 2009].
Interpreting PTH levels
How should I interpret parathyroid hormone levels?
Check with the local biochemistry laboratory for the reference range of normal values for parathyroid hormone (PTH), as it depends on the analytical method used.
In the context of hypercalcaemia:
If the PTH level is high, the most likely diagnosis is primary hyperparathyroidism. Other possible diagnoses are familial hypocalciuric hypercalcaemia and tertiary hyperparathyroidism.
If the PTH level is within the reference range, primary hyperparathyroidism remains a likely diagnosis, but other causes (including cancer) must be excluded.
If the PTH level is low or undetectable, the most likely diagnosis is cancer. Other possible causes include drugs, granulomatous disease (for example sarcoidosis or tuberculosis), immobilization (in people with Paget's disease), or non-parathyroid endocrine disease.
Be aware that primary hyperparathyroidism may coexist with cancer, resulting in PTH levels that are normal or elevated despite cancer being present.
Basis for recommendation
Basis for recommendation
Check with the local biochemistry laboratory for reference range
The recommendation to check with the local biochemistry laboratory for the reference range of normal values for parathyroid hormone (PTH) is made on the basis that several different methods are available for measuring PTH [Klee et al, 1988; Pagana and Pagana, 2010]. Published reference ranges vary considerably.
High PTH level
The recommendations in relation to a high PTH level are derived from consistent expert opinion from narrative reviews [Ralston, 1992; Carroll and Schade, 2003; Murphy et al, 2006] and a textbook [Pagana and Pagana, 2010].
PTH levels within the reference range
The recommendations in relation to PTH levels within the reference range take into account inconsistency in the published literature, and are a safe compromise given the uncertainty.
Four narrative reviews state that normal, high-normal, or 'inappropriately detectable' PTH levels indicate primary hyperparathyroidism, or (less commonly) tertiary hyperparathyroidism or familial hypocalciuric hypercalcaemia [Ralston, 1992; Carroll and Schade, 2003; Selby, 2003; DTB, 2010].
One narrative review states that, if PTH levels are normal, cancer should be excluded [Murphy et al, 2006].
Low PTH level
The recommendations in relation to a low or undetectable PTH level are derived from consistent expert opinion in narrative reviews [Ralston, 1992; Carroll and Schade, 2003; Smellie et al, 2008].
Be aware that hyperparathyroidism may coexist with cancer
This recommendation is based on expert opinion from a narrative review [Ralston, 1992].
Management
Management
Scenario : Unconfirmed cause: covers the management of people with hypercalcaemia for whom the cause has not been confirmed. This includes the management of people with suspected cancer, but does not include people with suspected hyperparathyroidism.
Scenario : Suspected/confirmed primary hyperparathyroidism: covers the management of people with suspected or confirmed primary hyperparathyroidism.
Scenario : Known cancer: covers the management of people with hypercalcaemia who already have a confirmed diagnosis of cancer.
Scenario : Unconfirmed cause
Scenario : Hypercalcaemia - unconfirmed cause
Management
How should I manage a person with hypercalcaemia without a confirmed cause?
If the person has severe hypercalcaemia (adjusted serum calcium concentration greater than 3.40 mmol/L) or symptomatic hypercalcaemia, admit immediately to hospital.
If the person has asymptomatic, mild or moderate hypercalcaemia (adjusted serum calcium concentration 3.40 mmol/L or less):
Repeat the serum calcium concentration after 1 week to exclude rapidly evolving hypercalcaemia that is suggestive of cancer and requires admission to hospital.
If cancer is suspected, refer urgently (to be seen within 2 weeks) to the appropriate specialist. See the CKS topics in the clinical speciality on Cancer - suspected (NICE referral advice).
If primary hyperparathyroidism is suspected, see Primary hyperparathyroidism.
If familial hypocalciuric hypercalcaemia is suspected, refer the person to an endocrinologist.
If the person has known renal failure (stage 5 chronic kidney disease), refer them to their renal specialist. See the CKS topic on Chronic kidney disease - not diabetic.
If renal failure is detected which was not previously known (not a typical presentation of hypercalcaemia), consider admitting the person to hospital or referring them urgently to a renal specialist (depending on the symptoms and likely speed of onset).
If the person is taking any drugs that may be contributing to the hypercalcaemia, stop them if appropriate and recheck the serum calcium.
If milk-alkali syndrome is suspected, consider admitting the person to hospital for correction of fluid and electrolyte abnormalities.
If the person is taking lithium, contact their mental health specialist to discuss whether to stop the lithium, monitor the serum calcium, or refer to an endocrinologist.
If hypercalcaemia is due to vitamin D ingestion, it may take many weeks for the serum calcium concentration to return to normal after discontinuing vitamin D.
If the adjusted serum calcium remains high after discontinuation of the drug, look for another underlying cause or refer to an endocrinologist or other appropriate specialist.
If non-parathyroid endocrine disease is suspected as the cause of hypercalcaemia, refer the person to an endocrinologist. Admission to hospital or urgent referral may be required (for example if Addison's disease or thyrotoxicosis are suspected).
If immobilization in Paget's disease is suspected:
Address the immobilization, if possible, and monitor the person's serum calcium concentration.
If mobilization is not possible, or the person's serum calcium concentration remains increased, refer the person to an endocrinologist, rheumatologist, or specialist in bone disease.
If sarcoidosis is suspected, refer the person to a respiratory specialist (or other specialist depending on disease manifestation).
If tuberculosis is suspected, see the CKS topic on Tuberculosis.
If a cause is not clear (for example, because the parathyroid hormone level is normal), refer the person to an endocrinologist.
Basis for recommendation
Basis for recommendation
Admit the person if they are symptomatic or have severe hypercalcaemia
This recommendation is based on expert opinion from a narrative review [Smellie et al, 2008].
Repeat the serum calcium concentration after 1 week
This recommendation is based on the opinion of a CKS expert reviewer.
Urgently refer if cancer is suspected
This is based on Referral guidelines for suspected cancer from the National Institute for Health and Clinical Excellence (NICE) [NICE, 2005] (see the CKS topics in the clinical speciality on Cancer - suspected (NICE referral advice)), as well as narrative reviews [Ralston et al, 2004; Murphy et al, 2006].
Refer to an endocrinologist if familial hypocalciuric hypercalcaemia is suspected
This recommendation is based on international guidelines on the management of primary hyperparathyroidism [Bilezikian et al, 2009]. Primary hyperparathyroidism must be excluded, and familial hypocalciuric hypercalcaemia needs to be confirmed by 24-hour urinary calcium levels.
Refer people with known renal failure to their renal specialist
This is based on a NICE guideline on the management of chronic kidney disease in adults in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2008]. See the CKS topic on Chronic kidney disease - not diabetic.
Consider admitting to hospital or referring urgently to a renal specialist those people with renal failure that was not previously known
This recommendation is based on what CKS considers to be good clinical practice and comments from a CKS expert reviewer.
Stop any drugs contributing to hypercalcaemia if appropriate and recheck the serum calcium
This recommendation is based on expert opinion from a narrative review [Bushinsky and Monk, 1998].
The recommendation to consider admitting people with suspected milk-alkali syndrome is based on expert opinion from a narrative review, that correction of fluid and electrolyte abnormalities may be needed [Chan et al, 1997].
The recommendation to contact the person's mental health specialist if they are taking lithium, in order to discuss whether to stop the lithium, monitor the serum calcium, or refer to an endocrinologist, is based on expert opinion from a narrative review [Jones and Twomey, 2009]. The authors state that management options for lithium-induced hypercalcaemia include:
Discontinuing lithium, after which hypercalcaemia generally resolves.
Continuing lithium, with regular monitoring, if hypercalcaemia is mild and asymptomatic.
Surgical parathyroid exploration when lithium cannot be discontinued or calcium levels do not decrease after it has been discontinued for an appropriate time.
Hypercalcaemia due to vitamin D ingestion may take many weeks to correct because of the long elimination half-life (10–20 days) of 25-hydroxyvitamin D [Barth et al, 2008].
The recommendation to look for another underlying cause or refer the person to an endocrinologist or other appropriate specialist if the adjusted serum calcium level remains high after discontinuation of the drug, is based on what CKS considers to be good clinical practice. It is also based on evidence from narrative reviews that primary hyperparathyroidism is the most common cause of hypercalcaemia in the community [Chan et al, 1997; Bushinsky and Monk, 1998], particularly when hypercalcaemia is mild [Bilezikian, 1993].
Refer to an endocrinologist if non-parathyroid endocrine disease is suspected
Non-parathyroid endocrine diseases that can cause hypercalcaemia usually need specialist investigation and management.
Immobilization in Paget's disease
In the absence of trial-based evidence, the recommendation to address the immobilization, if possible, and monitor the person's serum calcium concentration is based on what CKS considers to be good practice.
The recommendation to refer the person to a specialist if mobilization is not possible or the person's serum calcium concentration remains high is based on evidence that oral or intravenous bisphosphonates are effective and should be prescribed. This evidence is from an observational study and expert opinion in a UK guideline on the management of Paget's disease of bone (from the Bone and Tooth Society of Great Britain and the National Association for the Relief of Paget's Disease) [Selby et al, 2002] and narrative reviews [Siris et al, 2006; Ralston et al, 2008]. Referral as opposed to treatment in primary care is recommended on the basis of expert opinion in a published letter (responding to the guideline) that hypercalcaemia in Paget's disease is more likely to be due to coexisting primary hyperparathyroidism, that bisphosphonates increase parathyroid hormone levels, and therefore primary hyperparathyroidism should be excluded prior to starting a bisphosphonate [Gutteridge, 2006].
Refer the person to a respiratory specialist (or other specialist, depending on disease manifestation) if sarcoidosis is suspected
This recommendation is based on what CKS considers to be appropriate referral pathways and on expert opinion from a narrative review on the primary care management of sarcoidosis [Wu and Schiff, 2004].
Refer to an endocrinologist if a cause is not clear
This recommendation is made on the basis that an endocrinologist is most likely to have the expertise to determine the cause.
Scenario : Suspected/confirmed primary hyperparathyroidism
Scenario : Hypercalcaemia - suspected/confirmed primary hyperparathyroidism
Management
How should I manage a person with suspected primary hyperparathyroidism?
For information on when to suspect primary hyperparathyroidism, see Determining the underlying cause and Interpreting PTH levels.
If the person has hypercalcaemia that is severe (adjusted serum calcium concentration greater than 3.40 mmol/L) or symptomatic, admit immediately to hospital.
If the person has asymptomatic, mild or moderate hypercalcaemia (adjusted serum calcium concentration 3.40 mmol/L or less), refer to an endocrinologist.
See Secondary care.
Basis for recommendation
Basis for recommendation
Admit if the person has hypercalcaemia that is severe or symptomatic
This recommendation is based on expert opinion from a narrative review [Smellie et al, 2008].
Referral to an endocrinologist if primary hyperparathyroidism or familial hypocalciuric hypercalcaemia (FHH) are suspected
When primary hyperparathyroidism or FHH are suspected, because of increased parathyroid hormone levels in the context of hypercalcaemia, referral to an endocrinologist is required (for confirmation of the diagnosis, assessment for the need for parathyroidectomy, and referral to a parathyroid surgeon or, if appropriate, conservative management) [Bilezikian et al, 2009; Eastell et al, 2009; Khan et al, 2009; Silverberg et al, 2009; Udelsman et al, 2009]. This requires experience and expertise in the management of people with primary hyperparathyroidism or FHH. For more information, see Secondary care.
Secondary care
How is primary hyperparathyroidism managed in secondary care?
In secondary care, the endocrinologist may:
Confirm the diagnosis, by:
Excluding other causes of hypercalcaemia.
Measuring the 25-hydroxyvitamin D level, as this affects the interpretation of parathyroid hormone levels.
Measuring 24-hour urinary calcium. Low levels indicate familial hypocalciuric hypercalcaemia.
Assess the need for parathyroidectomy and referral to a parathyroid surgeon. Indications for parathyroidectomy include:
Symptomatic disease.
People younger than 50 years of age.
Kidney stones.
Adjusted serum calcium concentration that is 0.25 mmol/L or more above the upper end of the reference range.
Estimated glomerular filtration rate less than 60 mL/min (although this threshold depends on other factors, such as age).
Reduced bone mineral density at the lumbar spine, femoral neck, total hip, or distal radius (T-score –2.5 or less for peri-menopausal or postmenopausal women, and men 50 years of age or older; Z-score –2.5 or less for premenopausal women and men younger than 50 years of age).
Manage people who do not undergo parathyroidectomy. This includes:
Vitamin D supplements, if necessary.
Advice on a normal dietary intake of calcium.
If appropriate, treatment with a bisphosphonate. Other options for treatment (if required) include hormone replacement therapy, raloxifene, and the calcimimetic drug cinacalcet.
Basis for recommendation
Basis for recommendation
This information is derived from international guidelines on the management of asymptomatic primary hyperparathyroidism [Bilezikian et al, 2009; Eastell et al, 2009; Khan et al, 2009; Silverberg et al, 2009; Udelsman et al, 2009].
Monitoring
What monitoring is required for a person with asymptomatic, confirmed primary hyperparathyroidism who has not undergone parathyroidectomy?
Following specialist endocrine assessment, monitoring of people with asymptomatic primary hyperparathyroidism who have no indications for parathyroidectomy or who decline parathyroidectomy may be done in primary care, if this is agreed locally.
Monitor:
Serum calcium and renal function — every 12 months.
Blood pressure — every 6 months; manage as for essential hypertension. See the CKS topic on Hypertension - not diabetic.
Bone mineral density (at the lumbar spine, femoral neck, total hip, and distal radius) — every 1–2 years, depending on local guidance.
For symptoms of hypercalcaemia — opportunistically.
Refer the person back to the endocrinologist if:
Symptoms of hypercalcaemia develop.
Adjusted serum calcium concentration increases to 0.25 mmol/L or more above the upper end of the normal range (for example greater than 2.90 mmol/L).
Estimated glomerular filtration rate is less than 60 mL/min.
At any site on bone mineral density measurement, the T-score is –2.5 or less (for peri-menopausal or postmenopausal women, and men 50 years of age or older) or the Z-score is –2.5 or less (for premenopausal women and men younger than 50 years of age).
Basis for recommendation
Basis for recommendation
These recommendations are based mainly on international guidelines on the management of asymptomatic primary hyperparathyroidism [Bilezikian et al, 2009; Eastell et al, 2009; Khan et al, 2009; Silverberg et al, 2009; Udelsman et al, 2009]. In addition:
The information that, following specialist endocrine assessment, monitoring of people with asymptomatic primary hyperparathyroidism (who have no indications for parathyroidectomy or decline parathyroidectomy) may be done in primary care, if this is agreed locally, is based on what CKS considers to be acceptable practice.
The recommendation to monitor blood pressure every 6 months is based on expert opinion from a narrative review [Davies et al, 2002]. Hypertension is more common in people with primary hyperparathyroidism compared with the general population [Chan et al, 1997]. The cardiovascular risks are not known [Bilezikian et al, 2009] and hypertension does not improve following parathyroidectomy [Chan et al, 1997].
In the absence of evidence or published opinion, the recommendation to monitor for symptoms of hypercalcaemia opportunistically is based on what CKS considers to be good clinical practice.
Scenario : Known cancer
Scenario : Hypercalcaemia - known cancer
Management
How should I manage a person with hypercalcaemia who has known cancer?
Consider whether it is appropriate to treat the hypercalcaemia.
Treatment may not be appropriate if the person was deteriorating rapidly (day-by-day) before they developed hypercalcaemia.
If the person has symptomatic hypercalcaemia, or moderate or severe hypercalcaemia (adjusted serum calcium concentration greater than 3.0 mmol/L) — if appropriate, admit immediately to hospital or a hospice (preferably involving the person's specialist).
Intravenous fluids and bisphosphonates (with or without other treatment) are required. See Secondary care.
If the person has asymptomatic, mild hypercalcaemia (adjusted serum calcium concentration 3.0 mmol/L or less), seek immediate specialist advice. The specialist may advise immediate admission or planned admission over the next few days.
If immediate admission is not necessary:
Provided there are no contraindications (such as severe renal impairment or heart failure), advise the person to maintain good hydration by drinking 3–4 L of fluid per day.
Reassure the person that it is not necessary to adopt a low calcium diet.
Advise the person to immediately report any symptoms of hypercalcaemia.
Encourage mobilization, if possible.
Advise the person to avoid any medications or vitamin supplements that could worsen hypercalcaemia.
Basis for recommendation
Basis for recommendation
Consider whether it is appropriate to treat the hypercalcaemia
There may be situations when treatment is not considered appropriate, for example when the person has advanced cancer and is not suffering distressing or unpleasant symptoms as a result of hypercalcaemia [Kovacs et al, 1995]. There is no evidence that treatment of hypercalcaemia affects overall mortality, unless the primary cancer is treatable [Kovacs et al, 1995].
However, treatment can alleviate distressing symptoms and improve quality of life [Kovacs et al, 1995; Heys et al, 1998; Ralston et al, 2004], returning the person to their pre-hypercalcaemic state within 3–4 days. Hypercalcaemia may reduce the pain threshold in people with cancer [Heys et al, 1998]. Furthermore, bisphosphonates reduce bone pain and the risk of pathological fractures, and calcitonin may have similar beneficial effects [Kovacs et al, 1995]. Because median survival is 2 months, treatment may be considered worthwhile [Regnard and Dean, 2010].
The information that treatment may not be appropriate if the person was deteriorating rapidly (day-by-day) before they developed hypercalcaemia is based on the opinion of a CKS expert reviewer.
Management of symptomatic, or moderate or severe hypercalcaemia
These recommendations are based on expert opinion from narrative reviews.
For people with symptomatic hypercalcaemia or severe hypercalcaemia (adjusted serum calcium concentration greater than 3.4 mmol/L), there is consistent expert opinion from narrative reviews [Kovacs et al, 1995; Bushinsky and Monk, 1998; Heys et al, 1998; Carroll and Schade, 2003; Weiss-Guillet et al, 2003; Ralston et al, 2004; Smellie et al, 2008] and a textbook [Regnard and Dean, 2010] that immediate intravenous fluids and bisphosphonates are required, although definitions of 'severe' hypercalcaemia and the thresholds for admission vary slightly.
For people with asymptomatic, moderate hypercalcaemia (adjusted serum calcium concentration 3.0–3.4 mmol/L), there is no consensus in the published literature on the appropriate management.
Narrative reviews on the management of hypercalcaemia from any cause recommend oral rehydration (if possible) and non-urgent administration of intravenous bisphosphonates for this group [Bilezikian, 1993; Bushinsky and Monk, 1998; Carroll and Schade, 2003; Smellie et al, 2008].
However, a textbook and narrative reviews specifically about the management of cancer-associated hypercalcaemia recommend immediate treatment with intravenous fluids and bisphosphonates [DTB, 1990; Weiss-Guillet et al, 2003; Ralston et al, 2004; Regnard and Dean, 2010].
Admission (if appropriate) is recommended on the basis of expert opinion from a narrative review that calcium levels tend to increase faster in people with cancer-associated hypercalcaemia than in people with other causes of hypercalcaemia (for example primary hyperparathyroidism) [Ralston, 1994]. Because the likelihood of symptoms is related to the rate of onset of hypercalcaemia [Ralston, 1992; Bushinsky and Monk, 1998; Weiss-Guillet et al, 2003; Stewart, 2005], people with cancer are more likely to become symptomatic at lower levels of serum calcium. Furthermore, the serum calcium level is more likely to increase further, and lead to greater risk of harm, if it is not treated urgently.
Management of asymptomatic, mild hypercalcaemia
There is also no clear consensus in the literature on the appropriate management of people with cancer-associated, asymptomatic, mild hypercalcaemia.
Most authors recommend non-urgent treatment with intravenous bisphosphonates and oral fluids only for people without symptoms who have an adjusted serum calcium concentration 3.0 mmol/L or less [DTB, 1990; Bilezikian, 1993; Bushinsky and Monk, 1998; Heys et al, 1998; Carroll and Schade, 2003; Smellie et al, 2008]. However, lower thresholds for urgent treatment, at adjusted serum calcium concentrations of 2.7–2.9 mmol/L, are recommended in a guideline on the management of multiple myeloma [Smith, 2005], a narrative review [Ralston et al, 2004], and a textbook [Regnard and Dean, 2010].
Because of the lack of a clear consensus, CKS recommends seeking immediate specialist advice.
Management if immediate admission is not necessary
The recommendation to maintain good hydration by drinking 3–4 L of fluid per day (provided there are no contraindications) is based on expert opinion from a narrative review [DTB, 1990].
The recommendation to reassure the person that it is not necessary to adopt a low calcium diet is based on expert opinion from narrative review [DTB, 1990; Kovacs et al, 1995]. This is because intestinal absorption of calcium is usually reduced.
In the absence of any published evidence or opinion, the recommendation to advise the person to immediately report any symptoms of hypercalcaemia is based on what CKS considers to be good clinical practice.
The recommendation to encourage mobilization is based on expert opinion from a narrative review that mobilization will help to prevent the generalized bone resorptive state (and so exacerbation of hypercalcaemia) that results from inactivity and bed rest [Kovacs et al, 1995].
The recommendation to advise the person to avoid any medications or vitamin supplements that could worsen hypercalcaemia is based on expert opinion from a narrative review [Kovacs et al, 1995].
Secondary care
What treatments are given in secondary care for people with cancer-associated hypercalcaemia?
Management of cancer-associated hypercalcaemia in secondary care usually involves:
Intravenous fluids (saline) — this is important, particularly if renal function affected, but is rarely sufficient in isolation to control the hypercalcaemia.
Intravenous bisphosphonates — intravenous pamidronate or zoledronic acid are preferred.
Management of the underlying cancer (for example chemotherapy or radiotherapy).
Other treatments that may be used include:
Subcutaneous calcitonin — occasionally this is given if (repeated) intravenous bisphosphonates are ineffective.
Corticosteroids — are only effective for myeloma and lymphoma.
Furosemide — this is occasionally used in conjunction with intravenous fluids, although there are concerns about its safety and the lack of evidence of efficacy.
Dialysis — occasionally dialysis is necessary.
Oral bisphosphonates — are occasionally used for maintenance therapy, once the calcium level has normalized. However, they are not as effective as, and delay rather than prevent the need for, intravenous bisphosphonates.
Subcutaneous fluids and bisphosphonates — are occasionally used.
Basis for recommendation
Basis for recommendation
This information is based on evidence from a systematic review of bisphosphonates for hypercalcaemia due to cancer [Saunders et al, 2004], a guideline on the management of multiple myeloma [Smith et al, 2005], narrative reviews [DTB, 1990; Ralston, 1994; Kovacs et al, 1995; Heys et al, 1998; Deftos, 2002; LeGrand et al, 2008], a textbook [Regnard and Dean, 2010], and two case reports [Walker et al, 1996]. In addition, several CKS expert reviewers stated that management of the underlying cancer is a key treatment for hypercalcaemia.
Evidence
Evidence
Supporting evidence
There is no supporting evidence section on interventions for hypercalcaemia or its underlying causes because treatments are usually delivered in secondary care.
Search strategy
Scope of search
A literature search was conducted for guidelines and systematic reviews on the primary care management of Hypercalcaemia with additional searches in the following areas:
Diagnosis of hypercalcaemia
Diagnosis of the cause of hypercalcaemia
Management of acute severe hypercalcaemia
Management of hyperparathyroidism
Search dates
Medline and Embase
January 2000 – May 2010
Key search terms
Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.
exp Hypercalcemia/, Hypercalcemia.tw, Hypercalcaemia.tw
exp Hyperparathyroidism, Primary/, exp Hyperparathyroidism/
exp Bone Neoplasms/, exp Lymphoma/, exp Hematologic Neoplasms/, exp Thyroid Neoplasms/, exp Breast Neoplasms/
exp Osteitis Deformans/
Table 1. Key to search terms.| Search commands | Explanation |
|---|---|
| / | indicates a MeSh subject heading with all subheadings selected |
| .tw | indicates a search for a term in the title or abstract |
| exp | indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree |
| $ | indicates that the search term was truncated (e.g. wart$ searches for wart and warts) |
Sources of guidelines
National Institute for Health and Clinical Excellence (NICE)
Scottish Intercollegiate Guidelines Network (SIGN)
National Guidelines Clearinghouse
British Columbia Medical Association
Institute for Clinical Systems Improvement
Guidelines International Network
National Library of Guidelines
National Health and Medical Research Council (Australia)
University of Michigan Medical School
Michigan Quality Improvement Consortium
National Resource for Infection Control
NHS Scotland National Patient Pathways
Agency for Healthcare Research and Quality
UK Ambulance Service Clinical Practice Guidelines
RefHELP NHS Lothian Referral Guidelines
Medline (with guideline filter)
Driver and Vehicle Licensing Agency
NHS Plus (occupational health practice)
Sources of systematic reviews and meta-analyses
Systematic reviews
Protocols
Database of Abstracts of Reviews of Effects
Medline (with systematic review filter)
EMBASE (with systematic review filter)
Sources of health technology assessments and economic appraisals
NIHR Health Technology Assessment programme
NHS Economic Evaluations
Health Technology Assessments
Canadian Agency for Drugs and Technologies in Health
International Network of Agencies for Health Technology Assessment
Sources of randomized controlled trials
Central Register of Controlled Trials
Medline (with randomized controlled trial filter)
EMBASE (with randomized controlled trial filter)
Sources of evidence based reviews and evidence summaries
DynaMed
Central Services Agency COMPASS Therapeutic Notes
Sources of national policy
Health Management Information Consortium (HMIC)
Sources of medicines information
The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.
British National Formulary (BNF)
electronic Medicines Compendium (eMC)
European Medicines Agency (EMEA)
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