Abstract
Endogenous pathologic hypercortisolism, or Cushing's syndrome, is associated with poor quality of life, morbidity, and increased mortality. Early diagnosis may mitigate against this natural history of the disorder. The clinical presentation of Cushing's syndrome varies, in part related to the extent and duration of cortisol excess. When hypercortisolism is severe, its signs and symptoms are unmistakable. However, most of the signs and symptoms of Cushing's syndrome are common in the general population (e.g., hypertension and weight gain) and not all are present in every patient. In addition to classical features of glucocorticoid excess, such as proximal muscle weakness and wide purple striae, patients may present with the associated comorbidities that are caused by hypercortisolism. These include cardiovascular disease, thromboembolic disease, psychiatric and cognitive deficits, and infections. As a result, internists and generalists must consider Cushing's syndrome as a cause, and endocrinologists should search for and treat these comorbidities. Recommended tests to screen for Cushing's syndrome include 1 mg dexamethasone suppression, urine free cortisol, and late night salivary cortisol. These may be slightly elevated in patients with physiologic hypercortisolism, which should be excluded, along with exogenous glucocorticoid use. Each screening test has caveats and the choice of tests should be individualized based on each patient's characteristics and lifestyle. The objective of this review is to update the readership on the clinical and biochemical features of Cushing's syndrome that are useful when evaluating patients for this diagnosis.
Invited Author's profile
Dr L K Nieman is a Senior Investigator at the National Institutes of Health (NIH) Clinical Research Center and head of the Endocrine Consult service. She also directs the Office of Human Subjects Research Protections for intramural NIH. From 1991 to 2001 she served as the clinical director of intramural National Institute of Child Health and Human Development (NICHD), overseeing the clinical care of the institute's patients and ensuring compliance with human subjects' research regulations. Dr L K Nieman is an active clinical investigator, with special expertise in the disorders of hypercortisolism.
Signs and symptoms of Cushing's syndrome
Cushing's syndrome is caused by chronic exposure to excess cortisol. Its associated comorbidities contribute to a decreased quality of life (1) and an increased standardized mortality rate compared to the general population (2, 3, 4, 5). Although some studies show an increased mortality regardless of remission status (4), most studies indicate that an early diagnosis is important to reduce mortality and morbidity (6, 7). Detection relies first on clinical suspicion and then on biochemical confirmation.
The clinical presentation of Cushing's syndrome varies, in part related to the extent and duration of cortisol excess. When hypercortisolism is severe, its signs and symptoms are unmistakable. In particular, proximal muscle weakness, wasting of the extremities with increased fat in the abdomen, torso and face, and wide purple striae, suggest marked hypercortisolism. However, most of the signs and symptoms of Cushing's syndrome are common in the general population (Table 1), and not all are present in every patient. As a result, patients with mild or cyclic disease may not present in the more classical way. (A discussion of so-called subclinical Cushing's syndrome is beyond the scope of this article.)
Signs and symptoms of Cushing's syndrome.
| More common | Less common |
|---|---|
| Decreased libido | EKG abnormalities or atherosclerosis |
| Obesity/weight gain | Striae |
| Plethora | Edema |
| Round face | Proximal muscle weakness |
| Menstrual changes | Osteopenia or fracture |
| Hirsutism | Headache |
| Hypertension | Backache |
| Ecchymoses | Recurrent infections |
| Lethargy, depression | Abdominal pain |
| Dorsal fat pad | Acne |
| Anormal glucose tolerance | Female balding |
Because of the variety in presentation, patients are often referred to subspecialists for complaints that are gynecologic (oligomenorrhea, hirsutism, infertility), dermatologic (red facial skin, poor wound healing, striae, acne), orthopedic/rheumatologic (fractures, low bone mineral density), metabolic (hypertension, diabetes, dyslipidemia), infectious (community acquired and infections seen with immunosuppression (8)), cardiovascular (stroke, myocardial infarction, pulmonary embolism (9)), neurologic (decreased strength, headaches, decreased memory and cognition), psychiatric (depression, anxiety, mood change), and nonspecific (fatigue, backache, and weight gain). Because of this, early detection may not occur unless the specialist considers other features not related to the referral question. It is important to screen for the associated comorbidities in patients with the disorder. Newer tests such as cardiac MRI (to study structure/function) and CT (to evaluate atherosclerosis) may be useful in the future but have not yet been validated fully (10, 11). It is essential to treat comorbidities, both while trying to establish the diagnosis and beyond.
One might not suspect the diagnosis in milder cases based on a single visit without consideration of a complete history. However, Cushing's syndrome tends to progress over time so that an accumulation of relevant features over time often leads to the diagnosis; previous photographs may help identify this progression. One recent study showed that face classification software correctly classified nearly all of the patients (85%) and controls (95%) using facial photographs. Further prospective research in patients suspected of having Cushing's syndrome is needed to validate this tool (12).
A few recent studies compared the prevalence of various features in patients with established Cushing's syndrome and those suspected to have the condition in whom it was excluded. The latter group is often referred to as having ‘pseudo-Cushing's syndrome’ because they may have clinical features compatible with the syndrome, and sometimes biochemical features, but do not have endogenous pathologic hypercortisolism. In the first study, 32 patients with Cushing's syndrome were compared to 23 with pseudo-Cushing's syndrome (13). Easy bruising and osteoporosis were more common in patients with Cushing's syndrome but polycystic ovary syndrome was more common in those with pseudo-Cushing's syndrome. By contrast, the frequency of many features of Cushing's syndrome were similar in both groups, including diabetes, hypertension, acne, hirsutism, and menstrual disorders, probably reflecting the features that prompted evaluation.
In a second study, 53 of 73 patients were ultimately found to have Cushing's disease, while the remaining 20 were classified as having pseudo-Cushing's syndrome, despite having elevated urine free cortisol (UFC) and/or an abnormal response to dexamethasone, 1 mg (14). Among the latter group, more than half had a BMI>30 kg/m2 and moon facies or increased dorsocervical fat. Myopathy, hirsutism, acne, and osteoporosis were present in <20%.
Mood and cognitive changes have long been recognized as important clues to the presence of Cushing's syndrome (15). Chief among these is the development of a more labile mood, with irritability and expressions of anger that may seem relatively unprovoked. Classically, short-term memory is impaired, as is mental calculation – these can and should be evaluated at the bedside by history and recall of three objects and serial seven subtractions. Problems with sleep-onset and sleep-maintaining insomnia, as well as early morning awakening are common. General psychiatric functioning may deteriorate – often along the lines of the pre-morbid personality – e.g., the patient with occasional depression may develop severe chronic depression when hypercortisolemic.
Biochemical diagnosis of Cushing's syndrome
While biochemical features of hypercortisolism may firmly establish the diagnosis, a variety of conditions are associated with mild physiologic hypercortisolism in the absence of Cushing's syndrome, as shown in Table 2. Cushing's syndrome may be suspected in these patients because of the presence of features that are common in the absence of Cushing's syndrome, such as weight gain, hypertension, and mood changes. As noted above, such patients are often referred to as having pseudo-Cushing's syndrome because they do not have the condition despite having mild hypercortisolism and compatible features. One approach to these patients is to wait to test until the condition has resolved (acute illness), is adequately treated (depression), or is abandoned (daily strenuous exercise), in which case the mild hypercortisolism may resolve as well.
Physiologic hypercortisolism.
| Some clinical features of CS may be present |
| Pregnancy |
| Depression and other psychiatric conditions (36, 37) |
| Alcohol dependence |
| Glucocorticoid resistance |
| Morbid obesity |
| Poorly controlled diabetes mellitus |
| Unlikely to have any clinical features of CS |
| Physical stress (hospitalization, surgery, pain) (38) |
| Malnutrition, anorexia nervosa |
| Intense chronic exercise |
| Hypothalamic amenorrhea |
| CBG excess (increased serum but not UFC) |
The Endocrine Society's Clinical Practice Guideline for the diagnosis of Cushing's syndrome recommends that exogenous administration/ingestion of glucocorticoids be considered and excluded before performing screening tests. The guideline recommends using two of three screening tests to establish the diagnosis: UFC, late night salivary cortisol, or 1 mg dexamethasone suppression test (16). It is important to individualize the choice of the test(s) and to perform more than one of the cortisol tests, if they are chosen, to minimize the effect of day-to-day variations.
A number of factors influence the outcome of screening tests for Cushing's syndrome. Common among them are the need for laboratory testing and the requirement for accuracy and precision at low quantifiable hormone levels. These issues will be discussed in conjunction with each test.
Dexamethasone suppression test
The 1 mg overnight dexamethasone suppression test interrogates whether glucocorticoid negative feedback is normal. This outpatient test involves administration of dexamethasone, 1 mg by mouth, between 2300 and 00 h, and the measurement of serum cortisol between 0800 and 0900 h the following morning. The results are normal if the cortisol is <1.8 μg/dl (50 nmol/l). (Higher values are associated with a lack of appropriate negative feedback in Cushing's syndrome patients.) This value is very close to the functional detection limit of some assays, so that inherent assay variability might account for an ‘abnormal’ result close to the cutoff point.
Falsely abnormal results occur in a variety of settings. Women taking oral estrogens may have an increase in corticosteroid-binding globulin (CBG), which in turn increases total cortisol, potentially leading to abnormal results (17). The measurement of salivary cortisol was not found to be helpful in one study of 19 women on oral contraceptives; another study of 21 such women found improved specificity compared to the use of serum cortisol as an endpoint (91% vs 62%). However, each of these was worse than the corresponding specificity of healthy control individuals not taking oral contraceptives (98% for each) (18). Thus, salivary cortisol after dexamethasone may be a better outcome measure than serum cortisol. However, its performance has not been compared to that of other screening tests in women taking oral estrogens.
Medications may accelerate or impair dexamethasone metabolism (http://medicine.iupui.edu/flockhart/table.htm) potentially causing falsely abnormal or normal results respectively (19). Dexamethasone is metabolized by the CYP3A4 complex, which is stimulated or inhibited by many commonly used drugs. Valassi et al. (20) studied whether medication use altered the results of the test. They found that those patients who did not have Cushing's syndrome but were taking medications were more likely to have an abnormal test result that those who were medication free (specificity 70% vs 96% respectively, P=0.014). Conversely, in another study, up to 8% of patients with Cushing's disease had a normal response (i.e., suppression) to the low-dose dexamethasone suppression test (21). Measurement of dexamethasone levels can help identify potential abnormal clearance of dexamethasone but has not come into general practice (22).
Urine free cortisol
UFC reflects the integrated tissue exposure to free cortisol over 24 h and so provides a unique perspective on glucocorticoid physiology that is different from the other two tests. The choice of the assay technique appears to affect whether a patient with mild Cushing's syndrome will have a normal or abnormal UFC (23, 24). This is explained by cross-reactivity with cortisol precursors and metabolites in immunoassays, which is not present in the structurally based assays such as high performance liquid chromatography or tandem mass spectrometry (25). As a result, a patient may have a normal result in the structurally based assay but an abnormal result in the immunoassay. The pre-test probability (26) may influence the decision to use UFC, with a low pre-test probability suggesting this choice.
As mentioned earlier, the pseudo-Cushing states are associated with a physiologic increase in UFC; for such individuals, other screening tests may be preferable. Caveats to the test include its inconvenience, with the attendant possibility of under- or over-collection. For this reason, the measurement of both creatinine and volume are helpful to assess completeness, and patients must be able to comply with the correct collection procedures. UFC is falsely raised when the volume is >5 l (27) and falsely low when glomerular filtration rate falls (28).
More than one UFC measurement is needed to avoid false negative results, detect cyclic hypercortisolism, and validate the diagnosis, as patients with Cushing's disease may have quite variable UFCs (29), ranging from normal to severely elevated values in the same patient.
Salivary cortisol
Serum and salivary cortisol reach a nadir just after sleep initiation (30); this entrained circadian phenomenon is disrupted when sleep occurs at different times of the day such as with shift work or travel to a new time zone. Patients with Cushing's syndrome lose this diurnal nadir and have increased serum and salivary cortisol values at bedtime compared with obese and pseudo-Cushing's patients (23, 31). Salivary cortisol has the advantage of allowing for in-home collection using a salivette (a cotton pledget in a plastic tube); because cortisol is thermally stable at room temperature, the collection can be mailed to a laboratory for analysis. One caveat for salivary cortisol is that it increases with age, hypertension, and diabetes (32), so that its use in such patients may give a falsely positive result. Additionally, immunoassays may increase the false positive rate (33), potentially because of cross-reactivity with cortisone, which salivary glands convert from cortisol via 11β-hydroxysteroid dehydrogenase type 2 (34). A major advantage of salivary cortisol is that it tends to be abnormal when UFC (measured by structural assays) is normal or only mildly elevated in patients with proven Cushing's syndrome (8, 19).
A Cushing's syndrome index
Nugent et al. (35) advanced this idea in 1964, stating ‘In the differential diagnosis … [of Cushing's syndrome], the physician uses clinical signs and simple laboratory data in addition to information … from past experiences to make a decision concerning the probability of the diagnosis’. The authors developed a Bayesian equation using the incidence of signs and symptoms of Cushing's syndrome in 211 patients. They then used the equation to calculate the probability of Cushing's syndrome in 111 patients. The clinical features included osteoporosis, central/generalized obesity, weakness, bruising/acne, plethora, colored striae, edema, hirsutism, oligomenorrhea, headache, abnormal glucose tolerance, age <35 years, diastolic blood pressure >105 mmHg, red blood cell volume >49 fl, and serum potassium <3.6 mEq/l. This approach returned a ‘confident’ diagnosis of Cushing's syndrome in nine out of 38 patients with the disorder, and the exclusion of the syndrome in 45 out of 93 without the disorder.
Unfortunately, the results of this Bayesian analysis do not give high positive (16%) and negative (61%) predictive values. However, the concept of an ‘index’ deserves to be reevaluated with current data.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA.
Acknowledgements
This paper forms part of a special issue of European Journal of Endocrinology on Cushing's syndrome. This article is adapted from work presented at the IMPROCUSH-1: Improving Outcome of Cushing's Syndrome symposium, 12–14 October 2014. The meeting was supported by the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft für Endokrinologie. The opinions or views expressed in this special issue are those of the authors, and do not necessarily reflect the opinions or recommendations of the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft fur Endokrinologie.
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This article is adapted from work presented at IMPROCUSH-1, 12–14 October 2014. The meeting was supported by the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft für Endokrinologie. The opinions or views expressed in this article are those of the authors, and do not necessarily reflect the opinions or recommendations of the supporters of the symposium.
