Cushing’s syndromeBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f945 (Published 27 March 2013) Cite this as: BMJ 2013;346:f945
- Julia Kate Prague, specialty registrar 1,
- Stephanie May, general practitioner2,
- Benjamin Cameron Whitelaw, consultant physician1
- 1Endocrinology, King’s College Hospital, London SE5 9RS, UK
- 2Stockwell Group Practice, London SW9, UK
- Correspondence to: B C Whitelaw
- Accepted 1 January 2013
A 45 year old woman was being regularly reviewed in primary and secondary care because of a five year history of type 2 diabetes that had required early insulin treatment; refractory hypertension; and subsequent chronic kidney disease. She had previously described other symptoms, including weight gain, bruising, flushes, and low mood, all of which had been attributed to obesity and menopause. She was not taking any glucocorticoids. After presenting to her local emergency department with a Colles’ fracture after a low impact fall, she was referred to the endocrinology department for suspected Cushing’s syndrome; subsequent investigation confirmed the diagnosis.
What is Cushing’s syndrome?
Cushing’s syndrome describes the clinical consequences of chronic exposure to excess glucocorticoid irrespective of the underlying cause. Endogenous causes of Cushing’s syndrome are rare and include a cortisol-producing adrenal tumour, which may be benign or malignant; excess secretion of adrenocorticotrophic hormone (ACTH) from a pituitary tumour (Cushing’s disease); or an ectopic ACTH-producing tumour (ectopic Cushing’s syndrome). More commonly, prolonged administration of supraphysiological glucocorticoid treatment (including tablets, inhalers, nasal sprays, and skin creams) can also cause the same clinical condition1 2 (also known as exogenous or iatrogenic Cushing’s).
How common is Cushing’s syndrome?
Conversely, endogenous Cushing’s is rare. Analysis of a national register in Denmark reported an annual incidence of two cases per million people4
However, screening studies of high risk populations show a higher prevalence of endogenous Cushing’s syndrome: in patients referred to secondary care for poorly controlled diabetes, prevalence was 0.6% in one prospective multicentre study5 and 0.5% in those referred for resistant hypertension in a single centre retrospective review of 4429 consecutive referrals6
Endogenous Cushing’s is usually (in 70% of cases) a result of a pituitary tumour7
Why is Cushing’s syndrome missed?
A small single centre case series (n=33) found that the mean time to diagnosis after the first presenting symptom of Cushing’s syndrome was 6.0 years,8 during which time the diagnosis had been missed in several consultations.
The often slowly progressive, non-specific set of symptoms typical of Cushing’s syndrome may not be noticed as a developing disease history in the context of many brief encounters with primary care services, or may be attributed to other common conditions, including depression and menopause.9 Furthermore, Cushing’s syndrome may mimic common conditions such as obesity, poorly controlled diabetes, and hypertension, which progress over time and often coexist in patients with metabolic syndrome or in those poorly compliant with treatment or advice.5
Topical glucocorticoids are commonly prescribed for eczema, asthma, and allergic rhinitis, and some formulations are available without prescription. Awareness is lacking that prolonged treatment with topical glucocorticoids, in all administered forms at moderate doses, can cause Cushing’s syndrome.2
Why does this matter?
Untreated Cushing’s syndrome is associated with 50% mortality at five years, predominantly from cardiovascular events (congestive cardiac failure or myocardial infarction) or infection.10 A UK cohort study found that after treatment patients in remission had a standardised mortality ratio of 3.3, which rose to 16 for patients who had persistent disease despite treatment.11
Cushing’s syndrome causes substantial morbidity: it can affect the musculature, causing myopathy and congestive cardiac failure; bone integrity, causing early osteoporosis; reproductive function, causing menstrual irregularity and infertility; and mood disturbance.
Delayed diagnosis can result in irreversible organ damage and in some cases can prevent the early opportunity to diagnose malignancy (for example, adrenocortical carcinoma or ACTH secretion from a small cell lung cancer).
How is Cushing’s syndrome diagnosed?
Clinical features (box)
Ask about progressive symptoms of multisystem disease. A retrospective single centre case series (n=70) and analysis of other combined series (n=711) showed that the following symptoms are potentially relevant9: weight gain (in 97% of cases of Cushing’s syndrome), depression (62%), subjective muscle weakness (29%), headache (47%), and osteoporosis (50%). A history of diabetes (50%) and/or hypertension (74%) is probably important,9 especially if these have been refractory to treatment and associated with end organ complications.
Assess for any possible use of exogenous glucocorticoids, especially inhalers and skin creams.
Ask to see serial photographs of the patient to assess for a change in appearance.
Typical features of Cushing’s syndrome9
Features that best discriminate Cushing’s syndrome from other common conditions
Skin—Easy bruising, facial plethora, purple striae
Musculoskeletal system—Proximal muscle weakness and/or myopathy; early osteoporosis with or without vertebral fractures or osteonecrosis of femoral or humeral head
Skin and hair—Thin skin, poor wound healing, hirsutism, or scalp thinning
Body habitus—Weight gain and central obesity; dorsocervical fat pad (“buffalo hump” ), supraclavicular fat pads, facial fullness (“moon face”)
Reproductive system—Menstrual irregularity, infertility
Psychiatric effects—Depression, psychosis, irritability, insomnia, fatigue
Cardiovascular effects—Congestive cardiac failure, hypertension, thrombosis (including deep vein thrombosis and myocardial infarction)
Immune system—Immunosuppression causing recurrent and atypical infection, including tuberculosis
Look for features of the classic Cushingoid phenotype (box). The discriminant index for Cushing’s syndrome is a ratio: the proportion of people in whom a clinical sign of the disease is found compared with the proportion of people in whom the disease is suspected but who, after investigation, are confirmed to have simple obesity. The higher the index, the higher the likelihood of a diagnosis of Cushing’s syndrome being correct. On the basis of a study of 159 people, signs that have the best discriminatory value are easy bruising (62% of cases, discriminant index 10.3), objective muscle weakness (56%, 8.0), plethora (94%, 3.0), and purple striae (56%, 2.5).9 Absence of these signs, however, does not exclude the diagnosis.
Investigating for endogenous causes of Cushing’s syndrome can be difficult. If clinical suspicion is high, it would be appropriate to refer to an endocrinologist for further evaluation or perform a screening test in primary care first after prior arrangement with the local laboratory or phlebotomy service. The table⇓ outlines the possible screening tests performed by specialists; these are necessary because routine blood tests—for example, random serum cortisol, liver function, cholesterol, or glucose—are not normally useful for confirming or excluding the diagnosis.12
If the clinical suspicion of endogenous Cushing’s syndrome is high then perform a confirmatory test: either a 24 hour urine collection for urinary free cortisol (if the patient’s renal function is normal) or a late night salivary cortisol if available. If, however, the clinical suspicion is low and the aim is primarily to exclude endogenous Cushing’s syndrome, then late night salivary cortisol or an overnight dexamethasone suppression test would be more appropriate because of the higher sensitivities of the tests (table⇑).
If screening tests are negative, reassure the patient but consider repeating the evaluation at six months, particularly if signs or symptoms progress.
If screening tests are positive, refer the patient to an endocrinologist for further investigation. Plasma ACTH would be measured and, if this is suppressed, imaging would focus on the adrenals (with computed tomography). If plasma ACTH is in the normal range or raised, magnetic resonance imaging of the pituitary and sometimes computed tomography of the chest and abdomen would follow, depending on the origin of the suspected tumour.
If a patient is taking exogenous glucocorticoids it is generally not possible to confirm or refute the diagnosis of Cushing’s syndrome by means of biochemical tests. The clinical history and examination is therefore extremely important, and if suspicion of Cushing’s syndrome is high then review the dose and duration of treatment needed.
Patients who have severe depression or who drink alcohol to excess may have pseudo-Cushing’s syndrome, a condition that clinically and biochemically resembles Cushing’s syndrome but resolves if the depression or alcoholism ends. The mechanisms responsible are poorly understood but are thought to involve inappropriate regulation of the hypothalamic-pituitary-adrenal axis at the level of the hypothalamus.17 This represents a pitfall in accurately diagnosing Cushing’s syndrome, and specialist advice is needed.
How is Cushing’s syndrome managed?
Management depends on the underlying cause. Surgical resection of the pituitary, adrenal, or ACTH-producing tumour is the primary treatment of choice and is often curative.
If the disease is secondary to exogenous glucocorticoid treatment then titration of the steroid dose as soon as clinically possible is indicated. Discontinuing treatment abruptly may risk precipitating adrenal crisis because prolonged treatment may have caused suppression of the hypothalamic-pituitary-adrenal axis, so reducing the steroids to a low or maintenance dose is the safest initial intervention.
Consider the diagnosis of Cushing’s syndrome in patients who have discriminating signs (such as early osteoporosis, myopathy, or easy bruising) or multiple features, especially if becoming progressively more severe (such as refractory diabetes and hypertension associated with end organ complications)
Delayed diagnosis can cause life threatening illness and irreversible organ damage and may compromise the management options of any underlying tumour
If endogenous Cushing’s syndrome is suspected, refer to an endocrinologist; possible screening tests include urinary free cortisol, salivary cortisol, and an overnight dexamethasone test
Surgical resection can cure endogenous causes of Cushing’s syndrome
Cite this as: BMJ 2013;346:f945
This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Health Care, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at.
Contributors: JKP wrote the first draft, and all authors revised subsequent drafts and agreed the final version before submission. BCW is the guarantor.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).
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