Changes

June 2026 — minor update. A minor typographical error was corrected.

Update

Goals

To support primary healthcare professionals to:

• Detect and diagnose hypercalcaemia and determine the underlying cause, where possible and appropriate.
• Arrange emergency hospital admission (or hospice) for specialist assessment and management, if appropriate.
• Offer initial management in primary care, depending on the severity of hypercalcaemia and likely underlying cause.
• Arrange referral to a specialist for further investigation and management depending on the likely underlying cause.
• Monitor people with asymptomatic primary hyperparathyroidism or those for whom parathyroid surgery is inappropriate.
• Monitor people with treated hypercalcaemia of malignancy at risk of recurrence, if appropriate.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

What is it?

• 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 [Smellie et al, 2008; NICE, 2019a].
  • Reference ranges may vary according to local laboratories.
• The ranges of serum calcium concentration used to classify the severity of hypercalcaemia vary in the literature. In general [Smellie et al, 2008; Walsh, 2016; Turner, 2017; BMJ Best Practice, 2023; Mc Donald, 2023]:
  • Mild hypercalcaemia is an adjusted serum calcium concentration of greater than 2.6 but less than 3 mmol/L.
  • Moderate hypercalcaemia is an adjusted serum calcium concentration of 3 to 3.5 mmol/L.
  • Severe hypercalcaemia is an adjusted serum calcium concentration of greater than 3.5 mmol/L.

What causes it?

There are multiple possible underlying causes of hypercalcaemia, the two most common being primary hyperparathyroidism and malignancy (which together account for 90% of cases) [Minisola, 2015; Walsh, 2016; Motlaghzadeh, 2021; BMJ Best Practice, 2022].  Be aware that more than one underlying condition may co-exist [Turner, 2017; BMJ Best Practice, 2023].

• Primary hyperparathyroidism
  • This is the commonest cause of hypercalcaemia and usually presents as mild asymptomatic hypercalcaemia, due to excessive and inappropriate secretion of parathyroid hormone (PTH) secreted by the parathyroid glands [Minisola, 2015; BMJ Best Practice, 2022; Sadiq, 2024].
  • Increased secretion of PTH alters the regulation of serum calcium by increasing bone resorption and renal calcium reabsorption, and indirectly by increasing intestinal calcium absorption [Minisola, 2015].
  • There are different possible sources of excess PTH:
    • A solitary parathyroid adenoma is the cause in about 85% of cases [Pallan et al, 2012; Turner, 2017; BMJ Best Practice, 2022].
    • Less commonly, secretion is from multiglandular parathyroid hyperplasia, ectopic parathyroid adenomas, or parathyroid cancer (very rare - 1% of cases of primary hyperparathyroidism) [Pallan et al, 2012; Turner, 2017; BMJ Best Practice, 2022].
  • Primary hyperparathyroidism has a genetic basis identifiable in about 10% of cases [Minisola, 2022]. It may be associated with rare inherited endocrinopathies including multiple endocrine neoplasia (MEN) syndromes and hyperparathyroidism jaw tumour syndrome, or as an isolated condition such as familial isolated hyperparathyroidism [Pallan et al, 2012; Turner, 2017; Minisola, 2022].
• Malignancy
  • Malignancy is the second most common cause of hypercalcaemia, but the most common cause in an in-patient setting [Pallan et al, 2012; Zagzag, 2018; BMJ Best Practice, 2023]. It is often a late finding in advanced malignancy, and the underlying disease is often known when hypercalcaemia is identified [Pallan et al, 2012; Minisola, 2015; Turner, 2017].
    • Malignancy-related hypercalcaemia should be suspected if there is rapid-onset hypercalcaemia, severe hypercalcaemia, and/or symptoms. Typically serum PTH levels are suppressed or undetectable [Minisola, 2015].
  • Hypercalcaemia can occur in malignancy with or without skeletal metastases. There are two main mechanisms of hypercalcaemia in malignancy [Minisola, 2015; Zagzag, 2018; Asonitis, 2019; BMJ Best Practice, 2022; Tonon, 2022]:
    • In around 80% the mechanism is secretion of parathyroid hormone-related protein and other circulating factors by the tumour (a paraneoplastic syndrome). The malignancies most commonly associated with this type of hypercalcaemia include squamous cell carcinomas of lung, oesophagus, head and neck, skin, cervix; and breast, kidney, prostate, and bladder cancer.
    • In approximately 20% of bone metastases cause osteolysis and release of skeletal calcium, for example, in breast cancer and multiple myeloma.
    • Uncommon mechanisms for hypercalcaemia due to malignancy include increased ectopic extra-renal production of the active metabolite of Vitamin D (usually by lymphomas) and ectopic PTH secretion.
  • The malignancies most commonly associated with hypercalcaemia include leukaemia, multiple myeloma, lung cancer, and breast cancer [BMJ Best Practice, 2022].  
• Drugs
  • Thiazide diuretics 
    • Hypercalcaemia is usually mild and caused by increased renal reabsorption and reduced urinary calcium excretion [Minisola, 2015; BMJ Best Practice, 2022].
    • Calcium levels usually return to normal after discontinuation of the thiazide unless there is an underlying primary hyperparathyroidism [Pallan et al, 2012; Minisola, 2015; BMJ Best Practice, 2022].
  • Lithium
    • Lithium may directly stimulate PTH secretion and increase renal calcium reabsorption. The effects are typically reversed on drug withdrawal [Minisola, 2015; BMJ Best Practice, 2022].
    • Lithium decreases the sensitivity of the calcium-sensing receptor to calcium, and it may also unmask pre-existing primary hyperparathyroidism [Pallan et al, 2012].
  • Vitamin D 
    • Hypercalcaemia may be caused by excessive oral intake of vitamin D, its metabolites and analogues, or excessive topical application of potent vitamin D analogues [Minisola, 2015; BMJ Best Practice, 2022].
  • Vitamin A
    • Hypercalcaemia can be caused by taking excessive amounts of oral vitamin A for weeks or months, thought to be due to stimulation of bone resorption and inhibition of bone formation [Borgan, 2022].
  • Calcium
    • Excessive calcium supplement use or excess calcium intake may lead to hypercalcaemia [BMJ Best Practice, 2022].
    • Milk-alkali syndrome is defined by hypercalcaemia, metabolic alkalosis and acute kidney injury, and is caused by ingestion of large amounts of calcium and absorbable alkalis (such as antacids, particularly products with calcium carbonate) [Motlaghzadeh, 2021; Sadiq, 2024].
• Granulomatous diseases
  • These include sarcoidosis, tuberculosis, leprosy, histoplasmosis, candidiasis, coccidiomycosis, berylliosis, eosinophilic granuloma, inflammatory bowel disease, and silicone-induced granuloma [Minisola, 2015].
  • The mechanism is thought to be ectopic production of calcitriol (the active form of Vitamin D) by cells in the lungs and lymph nodes [Zagzag, 2018].
• Renal
  • In chronic renal failure, low calcium levels cause parathyroid gland hypertrophy (secondary hyperparathyroidism). Tertiary hyperparathyroidism occurs when the hypertrophied glands start to produce excess unregulated PTH autonomously, causing calcium levels to rise inappropriately [Turner, 2017; Sadiq, 2024].
  • In end-stage renal disease and/or people receiving renal replacement therapy, treatment with calcium and calcitriol or vitamin D analogues may precipitate hypercalcaemia [Minisola, 2015].
  • Following renal transplantation, hypercalcaemia may occur due to pre-existing parathyroid hyperplasia and the restoration of 1,25-dihydroxyvitamin D₃ production by the transplanted kidney [Minisola, 2015].
  • During the recovery phase of acute kidney injury (AKI), hypercalcaemia may result from rebound increases in levels of PTH and 1,25-dihydroxyvitamin D₃. If the AKI was due to rhabdomyolysis, hypercalcaemia also results from subsequent mobilization of calcium deposited in muscle and soft tissue [Minisola, 2015].
• Familial hypocalciuric hypercalcaemia
  • This is a rare, benign, autosomal dominant disorder of calcium metabolism caused by a mutation in the calcium-sensing receptor leading to a general calcium insensitivity [Turner, 2017; Zagzag, 2018].
  • It is characterized by mild, lifelong asymptomatic hypercalcaemia, hypophosphataemia, reduced renal calcium excretion, and a normal or slightly elevated PTH level [Turner, 2017; BMJ Best Practice, 2022].
  • Hypercalcaemia is present from birth, but the condition may not be detected until adulthood [Pallan et al, 2012; Minisola, 2015].
• Non-parathyroid endocrine diseases
  • Thyrotoxicosis
    • The cause is excessive osteoclast activity with associated excess bone resorption relative to bone mineralization [Tonon, 2022; Sadiq, 2024].
    • Hypercalcaemia is usually mild and asymptomatic and returns to normal with correction of thyroid function [Tonon, 2022].
  • Addison's disease
    • This is a rare cause of hypercalcaemia resulting from increased calcium resorption from bone and dehydration which can occur in untreated adrenal insufficiency [Sadiq, 2024].
  • Phaeochromocytoma
    • This can cause hypercalcaemia due to the production of parathyroid hormone-related peptide (PTHrP) or co-existing primary hyperparathyroidism in MEN type 2A syndrome  [Minisola, 2015; Sadiq, 2024].
• Immobility
  • Imbalance of increased osteoblast activity and decreased osteoblast activity may lead to increased bone resorption and hypercalcaemia uncommonly in people with limited mobility [Sadiq, 2024].
    • This is more common when there is high bone turnover, for example in younger people or people with Paget's disease [Singer, 2014; Minisola, 2015]. In some cases, hypercalcaemia of another cause is worsened by immobility.

How common is it?

Hypercalcaemia is a common disorder, and its prevalence varies depending on the study definitions used, the population studied, and the underlying cause [Jick, 2015; Minisola, 2015; Turner, 2017].

• In the general population the reported prevalence of hypercalcaemia varies between 0.1% and 2% [Turner, 2017; Sadiq, 2024].
• Primary hyperparathyroidism is the most common cause of hypercalcaemia [Minisola, 2015; BMJ Best Practice, 2022].
  • Globally, the reported prevalence of primary hyperparathyroidism varies between 0.2 and 1.3% and has been increasing over time, although it is not clear if this reflects an increase in true incidence [Soto-Pedre, 2023]. 
  • A population-based study in Tayside, Scotland, from 2007 to 2018 found an annual incidence of 4 to 6 per 10,000 person-years and an overall prevalence over this time of 0.84% [Soto-Pedre, 2023]. 
  • It is more common in older adults, with prevalence increasing with age, and is 2–3 times more common in women than men [Soto-Pedre, 2023].
  • Parathyroid cancer as a cause of primary hyperparathyroidism is very rare, with an incidence of about 4 per 10 million person-years in a US population-based study [Lee, 2007].
• The prevalence of malignancy-associated hypercalcaemia varies in the literature.
  • A UK population-based analysis of a primary care database of adults with malignancy (n = 37,442) found the overall annual prevalence of hypercalcaemia was 0.67%. Prevalence estimates varied with cancer type and stage [Jick, 2015].
  • A retrospective study of 569,000 patients treated at 565 oncology outpatient sites between 2009 and 2013 in the USA found that hypercalcaemia of malignancy affected 2 to 2.8% of all cancer patients, and that rates were highest for multiple myeloma patients (7.5 - 10.2% annual prevalence) and lowest for those with prostate cancer (1.4 - 2.1%) [Gastanaga, 2016].
  • Expert review articles suggest that around 20% of people with malignancy will be affected by hypercalcaemia at some point in the course of their illness [Turner, 2017; Vakiti, 2023].
  • Rates may be gradually decreasing due to new treatment choices [El-Hajj Fuleihan, 2023; Vakiti, 2023].
  • Incidence increases with advanced stage cancer; one review article states that the prevalence is 20–30% in people with advanced cancer, with a yearly incidence of 1–2% across all cancer types [Zagzag, 2018].
  • One literature review found that multiple myeloma has the highest prevalence of hypercalcaemia, followed by breast, renal, and squamous carcinomas of any origin [Asonitis, 2019].
• Up to 8% of people develop hypercalcaemia while taking thiazide diuretics [Minisola, 2015].
• Up to 25% of people treated with lithium develop hypercalcaemia, and monitoring is advised during treatment [Meehan, 2018; Kovacs, 2022].
• Milk-alkali syndrome was historically associated with antacid treatment, but is becoming more common due to increased prescribing and over-the-counter use of calcium and vitamin D preparations in the management of osteoporosis, and has become the third most common cause of hypercalcaemia [Motlaghzadeh, 2021; Rout, 2024].
• Hypercalcaemia occurs in:
  • 6-18% of people with sarcoidosis [Sève, 2021].
  • About 20% of hospitalized patients with tuberculosis [John, 2020]. Reported overall incidence rates vary between 2.3 to 28%, and most are asymptomatic.
  • Up to 20% of people with hyperthyroidism [Chen, 2017; Tonon, 2022]. Usually hypercalcaemia in this context is mild and asymptomatic, and cases of severe hypercalcaemia are rare.

What is the prognosis?

The prognosis of hypercalcaemia is variable depending on the underlying cause. Where causative processes are benign and have treatment options, the prognosis is good, whereas when it is due to malignancy or granulomatous disorders, the overall prognosis may be very poor [Sadiq, 2024]. Pharmacological treatment and associated strategies such as rehydration can provide normalisation of calcium levels, although how sustained this response is will depend on the underlying pathology [BMJ Best Practice, 2023].

• Surgical treatment for most cases of symptomatic primary hyperparathyroidism is curative [Pokhrel, 2024; Bilezikian, 2022]. Cure rates for people who have a single adenoma are over 95% and recurrence rates are under 2% [Ishii, 2018].
• In a retrospective, population-based observational study in Scotland (n = 904), 15% of people with conservatively managed asymptomatic primary hyperparathyroidism showed evidence of disease progression over an average of 4.7 years, and 2.9% underwent surgical treatment [Yu, 2011].
• In a US prospective observational study (n = 116) of people with asymptomatic primary hyperparathyroidism, 37% showed signs of disease progression (such as worsening hypercalcaemia, renal stones, and reduced bone mineral density) and met criteria for surgery over 15 years of follow-up [Rubin, 2008].
• Hypercalcaemia is a negative prognostic factor in people with cancer [Minisola, 2015; Zagzag, 2018; El-Hajj Fuleihan, 2023].
  • Hypercalcaemia associated with malignancy tends to present with severe hypercalcaemia and significant symptoms and signs, often presenting as an emergency [Zagzag, 2018]. An analysis of cancer patients admitted with hypercalcaemia as a primary diagnosis in the USA between 2006 and 2012 found an in-hospital mortality rate of 6.8% [Wright, 2015].
  • A review article notes that people with malignancy-associated hypercalcaemia have a mean survival of 2–3 months [Zagzag, 2018]. Another quotes 50% mortality at 1 month and up to 75% at 3 months after diagnosis [Tonon, 2022].
  • The poor prognosis is not necessarily due to hypercalcaemia directly, but the fact that it usually correlates with an advanced cancer stage. Nonetheless, hypercalcaemia may not indicate advanced malignancy, and primary hyperparathyroidism or other underlying causes of hypercalcaemia may co-exist with malignancy [Turner, 2017].
  • However, the high mortality associated with hypercalcaemia of malignancy has declined significantly over the past few decades due to the development of increasingly effective chemotherapeutic drugs [El-Hajj Fuleihan, 2023].
• If hypercalcaemia is drug-associated, calcium levels may normalize after a few weeks following drug withdrawal [Minisola, 2015].

When should I suspect hypercalcaemia?

Hypercalcaemia is most commonly detected on the basis of blood test results in the UK, and mild chronic hypercalcaemia is usually asymptomatic. Consider a diagnosis of hypercalcaemia if:

• There is an incidental finding of a corrected serum calcium concentration of 2.6 mmol/L or higher on blood testing.
• A patient with advanced cancer deteriorates suddenly.
• There are suggestive clinical features (which are often non-specific and relate to the severity and rate of onset of hypercalcaemia):
  • Skeletal
    • Bone pain and skeletal deformities.
    • Osteoporosis and fractures associated with underlying bone disorders (fragility fractures in hyperparathyroidism, or pathological fractures in malignancy). See the CKS topic on Osteoporosis - prevention of fragility fractures for more information.
  • Neuromuscular and neuropsychiatric
    • Drowsiness, delirium, and coma. See the CKS topic on Delirium for more information.
    • Fatigue, lethargy, muscle weakness, and insomnia. See the CKS topics on Tiredness/fatigue in adults and Insomnia for more information.
    • Impaired concentration and memory and confusion. See the CKS topic on Dementia for more information.
    • Depression, anxiety, irritability, and psychosis. See the CKS topics on Depression, Generalized anxiety disorder, and Psychosis and schizophrenia for more information.
    • Neurological signs (for example upper motor neurone deficits, hypotonia, hyporeflexia, and ataxia).
  • Gastrointestinal
    • Nausea, vomiting, anorexia, and weight loss.
    • Constipation and abdominal pain. See the CKS topic on Constipation for more information.
    • Peptic ulcer and pancreatitis (both rare). See the CKS topics on Dyspepsia - proven peptic ulcer and Pancreatitis - acute for more information.
  • Renal
    • Renal colic due to renal stones (nephrolithiasis). See the CKS topic on Renal or ureteric colic - acute for more information.
    • Thirst, polyuria, polydipsia, nocturia, and dehydration (due to nephrogenic diabetes insipidus).
    • Renal impairment (due to nephrocalcinosis and/or obstructive uropathy). See the CKS topic on Chronic kidney disease for more information.
  • Cardiovascular
    • Hypertension. See the CKS topic on Hypertension for more information.
    • Shortened QT interval; prolonged PR interval on electrocardiogram (ECG).
    • Cardiac arrhythmias such as ventricular fibrillation (rare).
  • Other
    • Flushing, itching, and band keratopathy (calcium deposits in the cornea - rare). See the CKS topic on Itch - widespread for more information.

How should I confirm a diagnosis of hypercalcaemia?

If a diagnosis of hypercalcaemia is suspected:

• Arrange a serum calcium blood test and interpret the result.
  • Avoid prolonged application of a tourniquet during venepuncture.
  • Ensure the laboratory result shows the calcium concentration is adjusted (corrected) for the serum albumin concentration. Note: the calculation of a corrected calcium value is usually completed by the laboratory, but may be inaccurate at extreme albumin concentrations, or if there is paraproteinaemia or acidosis.
  • Do not measure ionised calcium when testing for primary hyperparathyroidism.
• Classify the severity of hypercalcaemia, and manage appropriately.
  • Mild — adjusted calcium concentration is 2.6–2.99 mmol/L.
  • Moderate — adjusted calcium concentration is 3.0–3.5 mmol/L.
  • Severe — adjusted calcium concentration is greater than 3.5 mmol/L.
• A raised calcium test should be repeated to confirm a diagnosis of hypercalcaemia, however, it may be appropriate to arrange this repeat test in a secondary care setting, depending on the severity of the hypercalcaemia and the urgency of the clinical presentation.
  • If the person has mild hypercalcaemia and is asymptomatic or has mild symptoms, repeat the serum calcium level after one week to confirm the diagnosis.
  • If the person has severe hypercalcaemia or has severe symptoms, arrange emergency hospital admission for further assessment and management. See the section on Management for more information. 
  • If the person has moderate hypercalcaemia and symptoms, or if they have moderate hypercalcaemia and known malignancy, arrange the repeat test in an urgent timeframe rather than delaying referral to confirm the diagnosis. See the section on Management for more information. If the person is asymptomatic and does not have a known or suspected malignancy, repeat the calcium level within a week, depending on clinical judgement, liaising with the on-call specialist team if uncertain.
• If a diagnosis of hypercalcaemia is confirmed on repeat testing, assess the severity of hypercalcaemia and manage accordingly. See the sections on Assessment and  Management for more information.

How should I assess unexplained hypercalcaemia?

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:
  • 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, or 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 hypercalcaemia (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.
• Examine the person:
  • Assess hydration status — people with hypercalcaemia are often dehydrated due to nephrogenic diabetes insipidus resulting from renal resistance to vasopressin induced by the hypercalcaemia. Dehydration then leads to a further increase in serum calcium concentration. There may also be reduced oral intake resulting from anorexia, nausea and vomiting due to the hypercalcaemia 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.
• Review the duration and pattern of hypercalcaemia:
  • Check for any previous serum calcium concentrations in the medical records to assess the chronicity of hypercalcaemia.
    • In primary hyperparathyroidism, the increase in serum calcium is usually asymptomatic, mild and stable, or slowly progressive over years.
    • In malignancy-associated hypercalcaemia, there is often rapid-onset, severe hypercalcaemia, and associated systemic symptoms.
• Consider arranging additional investigations to determine the underlying cause, depending on clinical judgement, and manage appropriately. See the Scenario on Hypercalcaemia - unconfirmed cause for more information on ongoing management. Note that the decision about which tests are performed, and whether they are more appropriately done in primary or secondary care, will depend on the clinical situation (for example, the severity of the hypercalcaemia, the presence or absence of symptoms, the speed of onset, and the likely diagnosis where this can be established from clinical assessment).
  • 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.
    • Check with the local biochemistry laboratory regarding PTH testing collection requirements, such as recording the sample collection time, and sample transport arrangements.
    • Note: if PTH testing is not available in primary care, refer the person to an endocrinologist unless a non-endocrine underlying cause is suspected, the urgency depending on clinical judgement.
  • Full blood count — to diagnose or exclude anaemia of chronic disease or haematologic malignancy. See the CKS topic on Haematological cancers - recognition and referral for more information.
  • 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). See the CKS topics on Acute kidney injury and Chronic kidney disease for more information.
  • Serum and urine protein electrophoresis, including testing for urine Bence-Jones protein — to exclude myeloma. See the CKS topic on Multiple myeloma for more information.
  • 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. See the CKS topic on Jaundice in adults for more information on chronic liver failure.
  • Thyroid function tests — to exclude thyrotoxicosis. See the CKS topic on Hyperthyroidism for more information.
  • Vitamin D — if vitamin D toxicity is suspected (rare).
    • Note: vitamin D levels may be low in cases of primary hyperparathyroidism, however assessment for vitamin D insufficiency or deficiency is not needed prior to specialist referral.
  • Serum cortisol (morning sample at 8–9 am) — if Addison's disease is suspected. See the CKS topic on Addison's disease for more information.
  • Early morning urine sample to measure the urinary albumin:creatinine ratio (ACR) — if CKD is suspected. See the CKS topic on Chronic kidney disease for more information.
  • Chest X-ray — to exclude lung cancer or metastases, lymphoma, sarcoidosis, or tuberculosis. See the CKS topics on Lung and pleural cancers - recognition and referral, Haematological cancers - recognition and referral, and Tuberculosis for more information.

Scenario: Hypercalcaemia - unconfirmed cause

From age 18 years onwards.

Scenario: Hypercalcaemia - known malignancy

From age 18 years onwards.

Scenario: Follow-up in primary care

From age 18 years onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on the primary care management of hypercalcaemia.

Search dates

June 2019 - July 2024

Key search terms

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 24th June 2019). These were combined with filters to identify guidelines, systematic reviews and primary care relevant literature in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases. 

S6    S1 OR S2 OR S3 OR S4 OR S5 
S5    AB hyperparathyroidism OR TI hyperparathyroidism 
S4    (MH "Hyperparathyroidism+") 
S3    AB ( ((milk-alkali or (milk alkali)) N2 syndrome*) ) OR TI ( ((milk-alkali or (milk alkali)) N2 syndrome*) ) 
S2    AB ( (hypercalcaemia* or hypercalcemia*) ) OR TI ( (hypercalcaemia* or hypercalcemia*) ) 
S1    (MH "Hypercalcemia") 

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • 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
• The Cochrane Library:
  • 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

• The Cochrane Library:
  • 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

• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

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)
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.