Changes

December 2024 — new topic. A literature search was conducted in August 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

Goals

To support primary health care professionals to:

• Suspect a diagnosis of Cushing's syndrome based on clinical signs and symptoms.
• Differentiate between exogenous and endogenous Cushing's syndrome.
• Manage exogenous Cushing's syndrome in primary care.
• Arrange screening investigations for suspected endogenous Cushing's syndrome, where appropriate.
• Arrange referral to endocrinology for confirmation of diagnosis, identification of underlying cause, and initiation of treatment of endogenous Cushing's syndrome.
• Provide patient information and support.
• Arrange long-term follow up to monitor and manage any complications of Cushing's syndrome.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

QIPP — Options for local implementation

No QIPP indicators were found during the review of this topic.

What is it?

• Cushing’s syndrome is a chronic multi-system condition that occurs as a result of prolonged exposure to excess exogenous or endogenous glucocorticoids. 
  • It encompasses a wide range of clinical signs and symptoms (such as weight gain, central obesity, violaceous striae, and facial plethora) and multiple metabolic, cardiovascular, and neuropsychological complications.
• Exogenous (or iatrogenic) Cushing’s syndrome develops as a result of therapeutic use of corticosteroids through any route of administration.
  • It is the most common cause of Cushing's syndrome. 
• Endogenous Cushing’s syndrome occurs as a result of overproduction of glucocorticoids, which can be:
  • Adrenocorticotrophic hormone (ACTH) dependent — caused by conditions which produce high or inappropriately normal levels of ACTH leading to overproduction of cortisol by the adrenal glands (for example ACTH-secreting pituitary tumours) or less commonly an ectopic source (for example a neuroendocrine tumour).
  • ACTH independent — caused by conditions that result in excessive adrenal cortisol production despite suppressed ACTH levels, for example, adrenal adenoma, carcinoma (rare), or autonomous adrenal hyperplasia (very rare).
• Cushing’s disease refers specifically to Cushing’s syndrome caused by an ACTH-secreting pituitary tumour.
• Cyclical Cushing’s syndrome refers to intermittent increases in cortisol levels that lead to recurrent episodes of clinical symptoms.
• Pseudo-Cushing’s syndrome/non-neoplastic hypercortisolism are terms used to describe the development of cushingoid features due to relatively mild increases in cortisol levels associated with conditions such as obesity, alcohol misuse, psychiatric disease, or as a result of prolonged physical stress (for example severe illness or excessive exercise).

[Sharma, 2015; Nieman, 2018; Nishioka, 2019; Fleseriu, 2021; Cai , 2022; Savas, 2022; Gadelha, 2023; Nowak, 2023; Reincke, 2023; BMJ Best Practice, 2024; BNF, 2024; Maness, 2024]

What causes it?

Cushing’s syndrome is caused by prolonged exposure of body tissues to excess glucocorticoids from an exogenous or endogenous source.

• Exogenous causes of Cushing’s syndrome
  • Exogenous or iatrogenic Cushing’s syndrome develops as a result of therapeutic use of corticosteroids — it is the most common cause of Cushing’s syndrome.
  • Exposure can occur through any route of delivery including oral, injected, inhaled, or topical.
  • The risk of developing Cushing’s syndrome increases with higher dosages and longer duration of corticosteroid use. 
• Endogenous causes of Cushing’s syndrome
  • Endogenous causes of Cushing’s syndrome are rare and are usually categorised as:
    • Adrenocorticotrophic hormone (ACTH) dependent (80–85% of cases). 
    • ACTH-independent (15–20% of cases).
• ACTH-dependent causes of Cushing’s syndrome include:
  • ACTH-secreting pituitary adenomas (Cushing’s disease)
    • Cushing’s disease is the most common cause of endogenous Cushing’s syndrome occurring in around 80% of cases.
    • Excessive adrenal secretion of cortisol occurs as a result of overproduction of ACTH by the pituitary adenoma (which is relatively resistant to negative feedback from the hypothalamic-pituitary-adrenal [HPA] axis). 
    • Most ACTH-secreting pituitary tumours arise sporadically; however, in rare cases, they may occur as part of a genetic syndrome such as Carney complex or multiple endocrine neoplasia type 1.
  • Ectopic ACTH secreting tumours
    • Ectopic ACTH secreting tumours account for 10–20% of cases of ACTH-dependent Cushing’s syndrome — most are of lung or other neuroendocrine tumour origin.
    • The location of the neuroendocrine tumour is not known at presentation in up to 20% of cases, but may reveal itself over time.
    • Around 40% of cases of ectopic ACTH secreting tumours have metastatic disease at presentation. 
  • Corticotropin-releasing hormone (CRH)-secreting tumours
    • CRH-secreting tumours are extremely rare and occur in less than 1% of people with Cushing’s syndrome.
• ACTH-independent causes of Cushing’s syndrome include:
  • Adrenal adenoma
    • Adrenal adenomas are the most common cause of ACTH-independent Cushing’s syndrome (up to 90% of cases) and overproduce cortisol despite suppressed ACTH levels.
  • Adrenal carcinoma
    • Adrenal carcinoma is very rare (accounting for around 1% of all cases of Cushing’s syndrome) and typically presents as a large, rapidly growing adrenal mass.
    • Adrenal carcinoma can occur at any age but is most common in adults aged 40–60 years and children younger than 5 years. 
  • Rarer causes of ACTH-independent Cushing’s syndrome include:
    • Primary bilateral macronodular adrenal hyperplasia (usually in adults).
    • Primary pigmented nodular adrenal disease (isolated or as part of Carney complex, often in young adults).
    • McCune-Albright syndrome (may occur in the very young, including during the first year of life).
• Cyclical Cushing’s syndrome
  • Cyclical Cushing’s syndrome is thought to occur in 8–19% of people with Cushing’s syndrome. It usually manifests with fluctuating levels of cortisol between excess and normal, but rarely there may be periods where cortisol secretion is below normal.
  • Any cause of Cushing’s syndrome can produce a cyclical pattern — Cushing’s disease is the most commonly identified underlying cause (in over 50%), followed by ectopic ACTH secretion and adrenal tumours.
  • Cyclical Cushing’s syndrome is more common in females and people aged 50–60 years.
• Cushing’s syndrome in children
  • Cushing’s syndrome in children is extremely rare.
  • As with adults, use of exogenous corticosteroids is the most common cause in children and adolescents.
  • Cushing’s disease is the most common endogenous cause in children over the age of 6–7 years, and shows a male-predominance pre-pubertally. Adrenal causes are more common in younger children.
  • Cushing’s syndrome in infancy and early childhood can be associated with McCune–Albright syndrome.
• Cushing’s syndrome in pregnancy
  • Cushing’s syndrome in pregnancy is rare with most cases occurring as a result of adrenal adenoma.

[Sharma, 2015; Lonser, 2017; Nishioka, 2019; Barbot, 2020; Fleseriu, 2021; Hakami, 2021; Cai , 2022; Savas, 2022; Scoffings, 2022; Gadelha, 2023; Nowak, 2023; Reincke, 2023; BMJ Best Practice, 2024; Maness, 2024]

What are the risk factors?

Risk factors for Cushing’s syndrome include:

• Exogenous use of corticosteroids.
  • Use of supraphysiological doses of glucocorticoids (through any route including oral, intra-articular, inhaled, and topical) increases the risk of Cushing’s syndrome.
• Pituitary adenoma
  • Up to 80% of people with endogenous Cushing’s syndrome have an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma (Cushing’s disease).
  • Most ACTH-secreting pituitary adenomas occur sporadically. In rare cases, they can occur as part of a genetic syndrome such as multiple endocrine neoplasia type 1.
• Adrenal adenoma
  • Around 10–15% of people with Cushing’s syndrome have adrenal adenomas which overproduce cortisol.
  • Adrenal adenomas are often discovered incidentally during abdominal imaging for other reasons.
  • In most cases, following investigation, these ‘adrenal incidentalomas’ are found to be benign and non-functioning and do not require treatment.
• Adrenal carcinoma
  • Adrenal carcinoma is very rare and occurs in around 1% of people with endogenous Cushing's syndrome — overproduction of other steroid hormones (such as androgens) may occur in addition to cortisol.
• Neuroendocrine tumours
  • Cushing’s syndrome develops as a result of ectopic ACTH secretion from neuroendocrine tumours in a small number of people.
  • The most commonly identified sites are the lungs (small cell lung cancer and bronchial carcinoids), pancreas, thymus, and thyroid. 

[Sharma, 2015; Nishioka, 2019; Ceccato, 2021; Savas, 2022; Gadelha, 2023]  [Reincke, 2023; BMJ Best Practice, 2024]

How common is it?

• Exogenous (or iatrogenic) Cushing’s syndrome
  • The most common cause of Cushing's syndrome is prolonged use of corticosteroids (through any route of administration).
  • Data on the prevalence of exogenous Cushing's syndrome is lacking — current epidemiological studies relate only to endogenous disease.
• Endogenous Cushing’s syndrome
  • Endogenous Cushing’s syndrome is uncommon. 
    • Estimates of annual incidence in the general population range from 1.8–3.2 cases per million people [Hakami, 2021].
    • Estimated prevalence ranges from 57–79 cases per million people [Hakami, 2021]. 
    • Available data is likely to be an underestimate as many people with mild or atypical symptoms or cyclical Cushing’s syndrome may remain undiagnosed.
  • Cushing’s syndrome is rare in children and adolescents, but can occur at any age — most people are diagnosed between 20–50 years of age.
    • One Danish population-based registry of Cushing’s syndrome in young people aged 0–20 years (n=40) reported [Holst, 2017]:
      • An annual incidence of 0.89 cases per million people (95% CI 0.63–1.16).
      • A prevalence of 26 cases per million people (95% CI 18.9–35.8).
      • Median age at diagnosis 13.8 years (Interquartile range 10.5–18.2 years).
  • Females are 3–4 times more commonly affected than males post-pubertally.
• ACTH-dependent causes of Cushing’s syndrome (70–80% of endogenous cases):
  • Cushing's disease (ACTH-secreting pituitary tumour) is the most common cause of endogenous Cushing’s syndrome.
    • The estimated annual incidence of Cushing's disease ranges from 1.2–2.4 per million people with a prevalence of around 40 cases per million people [Nishioka, 2019].
    • Cushing’s disease is 3–4 times more common in females than males. Peak incidence occurs between the third and sixth decades of life.
  • Ectopic ACTH secreting tumours and more rarely corticotrophin-releasing hormone (CRH)-secreting tumours are less common, accounting for around 5–10% of cases [Limumpornpetch, 2022].
• ACTH independent causes of Cushing’s syndrome (20–25% of endogenous cases):
  • Around 15% of people with Cushing’s syndrome have adrenal adenoma — estimated annual incidence is 0.6 per million people [Barbot, 2020].
  • Adrenal carcinoma is rare — the estimated annual incidence is 0.2 per million people [Barbot, 2020].

[Nishioka, 2019; Barbot, 2020; Hamblin, 2022; Limumpornpetch, 2022; Gadelha, 2023; Reincke, 2023; BMJ Best Practice, 2024; Maness, 2024]

What is the prognosis?

• Cushing’s syndrome is associated with a marked increase in morbidity and mortality.
  • Without treatment, persistent hypercortisolism leads to the progression of clinical features and complications (metabolic, cardiovascular, and psychiatric).
• Mortality associated with Cushing’s syndrome.
  • One meta-analysis [Limumpornpetch, 2022] of all-cause and cause-specific mortality in people with non-malignant endogenous Cushing’s syndrome (n= 3691) found that:
    • The number of deaths reported was three times higher than expected for an age and sex-matched population (standardised mortality rate = 3.0; 95% CI, 2.3–3.9).
    • Age, male sex, diabetes, and ectopic ACTH secretion were predictive of higher mortality rates.
  • The most common causes of death associated with Cushing’s syndrome are cardiovascular disease, infection, thromboembolism, and malignancy.
• Morbidity associated with Cushing's syndrome.
  • Treatment to normalise cortisol levels can reverse but may not always resolve the clinical features and complications associated with Cushing’s syndrome. 
  • Increased morbidity related to cardiovascular and metabolic risk factors and decreased quality of life may persist in the long term, despite successful treatment. 
    • One retrospective cross-sectional study [Schernthaner-Reiter, 2019] of people in remission following treatment for Cushing’s syndrome (n=118; 52 with pituitary, 58 with adrenal and 8 with ectopic underlying causes) found that:
      • Diabetes resolved in 56%, depression in 52%, hypertension in 36%, and hyperlipidaemia in 23% of people.
      • Age, BMI, fasting glucose, and number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities.
  • Weight gain/obesity is a common clinical feature at diagnosis of Cushing’s syndrome — despite successful treatment 75% of patients will still be overweight or obese 5 years after remission.
  • Early diagnosis, prompt treatment to normalise cortisol levels, and strict control of cardiovascular and metabolic risk factors are essential in improving long-term prognosis.
• Pituitary causes of Cushing’s syndrome.
  • Surgical treatment for pituitary adenoma is usually followed by remission; however, recurrence rates are high (between 9.6 and 18%) with around half occurring within 5 years of surgery.
• Adrenal causes of Cushing’s syndrome.
  • Surgical treatment (adrenalectomy) for unilateral adrenal adenoma usually results in cure — recurrence in the contralateral adrenal gland is rare.
  • The prognosis for adrenal carcinoma varies according to stage at diagnosis.
• Ectopic ACTH secreting causes of Cushing’s syndrome.
  • The prognosis for ectopic Cushing's syndrome depends on the aetiology of the tumour but is often poor as these tumours tend to be aggressive and are often metastatic at diagnosis.

[Nishioka, 2019; Ferriere, 2020; Hakami, 2021; Braun, 2022; Savas, 2022; Scoffings, 2022; Gadelha, 2023; Reincke, 2023; BMJ Best Practice, 2024]

What are the complications?

Cushing’s syndrome is associated with a wide variety of systemic complications, which affect quality of life and reduce survival.

• Cardiovascular and cerebrovascular disorders
  • Cardiovascular complications (including hypertension, atherosclerosis, and cardiac remodelling) combined with increased thrombotic risk are a major cause of increased mortality in people with Cushing’s syndrome. 
• Metabolic disorders
  • Weight excess and visceral obesity are among the most common clinical features of Cushing’s syndrome occurring in 57–100% of people.
  • Impaired glucose tolerance and diabetes mellitus are common in Cushing's syndrome — diabetes occurs in 20–60% of cases.
  • Dyslipidaemia is a common complication occurring in 50–80% of people with Cushing’s syndrome.
• Hypercoagulability
  • Cushing’s disease is associated with a 10-fold increased risk of developing venous thromboembolism and can present with deep vein thrombosis or pulmonary embolism.
• Immunosuppression
  • Hypercortisolism has an immunosuppressive effect resulting in increased susceptibility to infections (in particular opportunistic infections) and sepsis.
• Musculoskeletal disorders
  • Premature osteoporosis and fracture occur in around half of people with Cushing’s syndrome.
  • Proximal myopathy is commonly described in Cushing’s syndrome and has a reported prevalence of 42–83%.
• Neuropsychiatric disorders
  • Mood disorders such as depression, anxiety and emotional lability, and cognitive deficits are common in Cushing’s syndrome both in the active disease and remission phases.
• Other complications include:
  • Decreased libido (in 25–90%), hypogonadism in men (50–75%) and oligomenorrhoea or amenorrhoea in women (70–80%).
  • Hirsutism, acne, and alopecia.
  • Hypokalaemia.
  • Renal stones.
• Complications in pregnancy include:
  • For the fetus: increased rates of miscarriage, intrauterine growth retardation, pre-term delivery, and peri-natal mortality.
  • For the mother: hypertension, pre-eclampsia, poor wound healing, diabetes, fractures, and infection.

[Lonser, 2017; Nishioka, 2019; Barbot, 2020; Ferriere, 2020; Fleseriu, 2021; Hamblin, 2022]  [Savas, 2022; Scoffings, 2022; Gadelha, 2023; Reincke, 2023; BMJ Best Practice, 2024]

When should I suspect Cushing’s syndrome?

• No single sign or symptom is pathognomonic for Cushing’s syndrome.
  • Diagnosis can be challenging and often delayed due to non-specific clinical features that overlap with many more common conditions and vary from person to person.  
  • Cushing’s syndrome can present insidiously (with symptoms and signs developing gradually over time) or evolve rapidly depending on the underlying cause, severity of hypercortisolism, and duration of exposure to excess cortisol.
• Clinical features that are thought to be most specific for Cushing’s syndrome (but may not always be present) include:
  • Proximal muscle wasting and weakness. 
  • Facial plethora. 
  • Violaceous striae. 
  • Thin friable skin.
  • Easy bruising. 
  • Recurrent infection
  • Poor wound healing. 
  • Premature osteoporosis or unexplained fractures.
• Other clinical features which are commonly associated with Cushing’s syndrome include:
  • Weight gain with central obesity.
  • Facial rounding.
  • Hypertension.
  • Impaired glucose tolerance/diabetes mellitus.
  • Hyperlipidaemia.
  • Supraclavicular and/or dorsocervical fat pads.
  • Hypokalaemia (uncommon — occurs in around 10% with Cushing's disease and more commonly with ectopic ACTH secretion).
  • Venous thromboembolism.
  • Neuropsychiatric disorders including depression, emotional lability, anxiety, insomnia, and cognitive impairment — psychiatric changes are common with Cushing’s syndrome occurring in 70–85% of cases.
  • Renal stones.
  • Menstrual disturbance such as oligomenorrhoea or amenorrhoea.
  • Hirsutism — be aware that rapid onset of virilisation in females may be a sign of adrenal carcinoma.
  • Hair thinning.
  • Acne.
  • Fatigue.
  • Hepatic steatosis.
• Cushing’s syndrome is rare in children but can present at any age and should be considered in children presenting with either:
  • Linear growth deceleration (combination of increased weight with decreasing height percentile).
  • Atypical pubertal development.
• Cushing’s syndrome is rare in pregnancy but should be considered in pregnant women presenting with:
  • Violaceous striae (especially if located at sites other than the abdomen), skin thinning, easy bruising, acne, hirsutism, proximal muscle weakness, or unexplained fractures.
• Suspect Cushing’s syndrome in people presenting with:
  • Clinical features associated with Cushing’s syndrome that are unusual for age for example:
    • Hypertension in people younger than 40 years of age.
    • Osteoporosis in premenopausal women and men younger than 65 years.
  • Multiple and progressive clinical features of Cushing’s syndrome.
  • Adrenal incidentaloma identified through abdominal imaging for other reasons.

How should I assess a person with suspected Cushing’s syndrome?

• Take a history asking about:
  • Signs and symptoms suggestive of Cushing’s syndrome.
    • Be alert for any clinical features that are unusual for age such as osteoporosis and hypertension in young people.
  • Onset and progression of symptoms.
  • Prescribed and over-the-counter medication including:
    • Use of local and systemic corticosteroids (including oral, intra-articular, inhaled, and topical) to exclude exogenous glucocorticoid exposure.
    • Oral contraception or hormone replacement therapy — oestrogens increase hepatic production of cortisol-binding globulin, and therefore increase serum cortisol levels artefactually.
  • Conditions other than Cushing’s syndrome that can be associated with clinical and biochemical signs suggestive of hypercortisolism such as:
    • Pregnancy.
    • Obesity.
    • Alcohol use disorder.
    • Polycystic ovary syndrome.
    • Neuropsychiatric conditions (such as depression and eating disorders).
    • Chronic kidney or liver disease.
    • Malnutrition.
    • Physical stress such as intense chronic exercise or recent surgery. 
• Examine the person, looking for:
  • Key signs of Cushing’s syndrome including:
    • Bruising without obvious trauma.
    • Thin friable skin.
    • Facial plethora or rounding.
    • Violaceous striae.
    • Supraclavicular and/or dorsocervical fat pads.
    • Proximal muscle weakness.
  • Less specific signs of Cushing’s disease such as:
    • Hypertension, weight gain and central obesity, acne, and hirsutism.
      • Be aware that signs of virilization in females (such as rapid-onset or increased hirsutism, voice deepening, and clitoral enlargement) may indicate underlying adrenal carcinoma.
  • Signs of linear growth deceleration in children.
    • Measure weight and height and plot on growth chart.
• If signs and symptoms of Cushing's syndrome are identified Consider screening investigations.

What else might it be?

• Non-neoplastic hypercortisolism (previously known as pseudo-Cushing’s syndrome).
  • Several conditions other than Cushing’s syndrome can cause a functional activation of the hypothalamic-pituitary-adrenal (HPA) axis leading to biochemical and sometimes clinical features of endogenous cortisol excess. These include:
    • Obesity.
    • Alcohol use disorder.
    • Polycystic ovary syndrome.
    • Neuropsychiatric conditions such as depression and eating disorders.
    • Chronic kidney disease.
    • Malnutrition.
    • Physical stress such as intense chronic exercise. 
    • Pregnancy.

How should I investigate suspected Cushing's syndrome in primary care?

• If exogenous Cushing's syndrome is suspected:
  • Investigations for hypercortisolism are not routinely required — gradual reduction of exogenous glucocorticoids and careful monitoring of symptoms are indicated.
    • Seek specialist advice if symptoms do not respond to a gradual reduction of glucocorticoids as expected or the need for further investigation is considered.
    • For more information, see the section on Management of exogenous Cushing's syndrome.
• If endogenous Cushing’s syndrome is suspected:
  • Seek specialist advice urgently if Cushing’s disease is suspected in pregnancy or childhood.
  • For non-pregnant adults, depending on local protocol, discuss with endocrinology or arrange screening investigations in primary care to confirm elevation of cortisol levels.
  • First-line screening tests for suspected endogenous Cushing’s syndrome include: 
    • Overnight dexamethasone suppression test.
    • 24-hour urinary free cortisol.
    • Late night salivary cortisol — may not be available in all areas.
  • Perform more than one screening test in people with a positive initial screening test to increase diagnostic accuracy:
    • Repeat the initial test or carry out a different second screening test.
    • There is no particular recommended order of screening. All of the screening tests can produce false-positive and false-negative results — the choice of test depends on the specific clinical situation. Seek advice from endocrinology if unsure.
  • Be aware that:
    • Random, untimed cortisol levels are rarely useful unless grossly elevated — cortisol levels fluctuate and are influenced by many factors including circadian rhythm, feedback control, stress, and levels of cortisol binding globulin.
    • Interpretation of results can be difficult due to wide variation in cortisol levels in different clinical situations.
• Consider additional tests such as:
  • Pregnancy testing in women of childbearing age to exclude pregnancy.
  • HbA1c as Cushing’s syndrome is associated with impaired glucose tolerance and diabetes.
• Refer to endocrinology for further investigation and management if:
  • Any screening test is found to be outside the normal reference range.
  • Initial screening tests are negative, but signs or symptoms are progressive or there is a high suspicion of Cushing’s syndrome.
  • Cyclical Cushing’s syndrome is suspected — fluctuant levels are common and in some cases of cyclical Cushing's syndrome all tests may remain in the normal range.
• Further investigations in secondary care may include:
  • Plasma adrenocorticotrophic hormone (ACTH) to differentiate between ACTH-dependent and ACTH-independent causes of Cushing’s syndrome:
  • If ACTH is suppressed:
    • Diagnostic testing may include imaging (CT or MRI) of the adrenal glands to identify underlying causes such as adrenal adenoma.
  • If ACTH is not suppressed:
    • Diagnostic testing may include pituitary MRI, inferior petrosal sinus sampling, and stimulation with corticotropin releasing hormone or desmopressin to identify a pituitary underlying cause.
    • If ectopic ACTH secretion is suspected, neck-to-pelvis thin slice CT scan may be performed, followed by specific PET scans if no tumour is identified on CT.

How should I manage a person with exogenous Cushing's syndrome in primary care?

From age 1 month onwards.

How should I manage a person with endogenous Cushing's syndrome in primary care?

From age 1 month onwards.

How should I follow up a person with Cushing's syndrome?

From age 1 month onwards.

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• (MH "Cushing's syndrome+") 
• AB Cushings* disease OR TI Cushing's* disease
• AB Cushing's syndrome OR TI Cushing's syndrome

• 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
• Health Protection Agency
• World Health Organization
• National Guidelines Clearinghouse
• Guidelines International Network
• TRIP database
• GAIN
• NHS Scotland National Patient Pathways
• New Zealand Guidelines Group
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• University of Michigan Medical School
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• UK Ambulance Service Clinical Practice Guidelines
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work(occupational health practice)

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

• 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

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

• Bandolier
• Drug & amp; Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

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

• Healthtalkonline
• BMJ - Patient Journeys

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

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.

• 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.

• 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.

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.

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.

• Animal studies
• Original research is not written in English

• 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

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.

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.

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.

None.