• 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.

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].

• 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.

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.

• 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.
• See Interpreting PTH levels.
• 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).

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].

• 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 levels is within the reference range, primary hyperparathyroidism remains a likely diagnosis, but other causes (including cancer) must be excluded.
• If PTH levels 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.

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].