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Try out PMC Labs and tell us what you think. Learn More. Objective: The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. At each stage the Task Force incorporated needed changes in response to written comments. Conclusions: After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma.
We recommend initial use of one test with high diagnostic accuracy urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg h dexamethasone suppression test. We recommend that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test. Patients with concordant abnormal should undergo testing for the cause of Cushing's syndrome. Patients with concordant normal should not undergo further evaluation. We recommend additional testing in patients with discordantnormal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.
Patients with unusual features for age e. Algorithm for testing patients suspected of having Cushing's syndrome CS. All statements are recommendations except for those prefaced by suggest. Diagnostic criteria that suggest Cushing's syndrome are UFC greater than the normal range for the assay, serum cortisol greater than 1. Tests deed to determine the cause of Cushing's syndrome e.
Conditions associated with hypercortisolism in the absence of Cushing's syndrome a. The Clinical Guidelines Subcommittee of The Endocrine Society deemed detection and diagnosis of patients with Cushing's syndrome a priority area in need of practice guidelines and appointed a six-member Task Force to formulate evidence-based recommendations. The Task Force followed the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group, an international group with expertise in development and implementation of evidence-based guidelines 1.
The Task Force used the best available research evidence that members identified and systematic reviews and metaanalyses of test accuracy to inform the recommendations 2. The Task Force also used consistent language and graphical descriptions of both the strength of a recommendation and the quality of evidence. A detailed description of this grading scheme has been published elsewhere 3.
The Task Force has confidence that patients who receive care according to the strong recommendations will derive, on average, more good than harm. Low- or very low-quality evidence usually le to weak recommendations because of uncertainty about the balance between risks and benefits; strong recommendations based on low-quality evidence usually indicate the panel's strong preference against the alternative course of action but are subject to change with new research.
Given a weak recommendation, careful consideration of the patient's circumstances, values, and preferences is appropriate to determine the best course of action. Linked to each recommendation is a description of the evidencevalues that panelists considered in making the recommendation when making these explicit was necessaryand remarksa section in which panelists offer technical suggestions for testing conditions, dosing, and monitoring.
These technical comments reflect the best available evidence applied to a typical patient. Often this evidence comes from the unsystematic observations of the panelists and should therefore be considered suggestions. Whereas the most common cause is iatrogenic from medically prescribed corticosteroids, endogenous Cushing's syndrome is an uncommon disorder.
European population-based studies reported an incidence of two to three cases per 1 million inhabitants per year 45. Excess cortisol production, the biochemical hallmark of endogenous Cushing's syndrome, may be caused by either excess ACTH secretion from a pituitary or other ectopic tumor or independent adrenal overproduction of cortisol. Although Cushing's syndrome is clinically unmistakable when full blown, the spectrum of clinical presentation is broad, and the diagnosis can be challenging in mild cases.
Few, if any, features of Cushing's syndrome are unique, but some are more discriminatory than others, including reddish purple striae, plethora, proximal muscle weakness, bruising with no obvious trauma, and unexplained osteoporosis 678. More often patients have a of features that are caused by cortisol excess but that are also common in the general population, such as obesity, depression, diabetes, hypertension, or menstrual irregularity.
We encourage caregivers to consider Cushing's syndrome as a secondary cause of these conditions, particularly if additional features of the disorder are present. If Cushing's syndrome is not considered, the diagnosis is all too often delayed.
Thus, certain psychiatric disorders depression, anxiety disorder, obsessive-compulsive disorderpoorly controlled diabetes mellitus, and alcoholism can be associated with mild hypercortisolism and may produce test suggestive of Cushing's syndrome, including abnormal dexamethasone suppressibility and mildly elevated UFC 9. Circulating cortisol concentrations are usually normal or slightly reduced in obesity, but severe obesity can raise UFC. It is thought that higher brain centers stimulate CRH release in these conditions, with subsequent activation of the entire HPA axis As a result, the overlap in UFC excretion is limited to values up to about 4-fold normal.
The earliest reports of mortality in Cushing's syndrome likely described individuals with severe hypercortisolism, representing one end of the clinical spectrum. These reports documented a median survival of 4. However, with modern-day treatments the standard mortality ratio SMR after successful normalization of cortisol was similar to that of an age-matched population during 1—20 yr of follow-up evaluation in one study Because markers of cardiovascular risk remain abnormal for up to 5 yr after surgery, further studies are needed to assess long-term SMR In patients who have persistent moderate hypercortisolism despite treatment, SMR is increased 3.
These data are consistent with the increased cardiovascular mortality and morbidity reported in patients with iatrogenic Cushing's syndrome secondary to the chronic use of synthetic corticosteroids Successful treatment of hypercortisolism reverses, but may not normalize, features of Cushing's syndrome. Bone mineral density and cognitive dysfunction improve after successful surgical treatment of Cushing's syndrome but do not normalize in all patients 16 Additionally, quality of life improves after surgical treatment but remains below that of age- and gender-matched subjects for up to 15 yr Indirect evidence supporting the need for intervention includes the finding that the risk of infection is lower in patients with mild to moderate, compared with severe, hypercortisolism There are limited and conflicting data regarding whether surgical treatment of patients with mild hypercortisolism in the setting of an adrenal incidentaloma is superior to medical treatment of comorbidities alone 202122 Although there are no formal controlled studies of consequences of cure in pediatric Cushing's syndrome, improvements in growth and body composition after treatment are reported in both patients with adrenal and those with pituitary causes 24 Final stature in patients with endogenous Cushing's syndrome was reported to be disappointing 26but more recent data showed that most patients reach a final height within their predicted parental target range Treatment of patients with moderate to severe Cushing's syndrome clearly reduces mortality and morbidity.
Because Cushing's syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would reduce the risk of residual morbidity. However, no data addressing this assumption have been reported. Our recommendations for testing for Cushing's syndrome are based on direct evidence from observational studies indicating a large treatment effect which we have rated as low to moderate quality evidence on morbidity and mortality in patients diagnosed with the condition.
The next section of this document focuses on evidence that bears indirectly on these recommendations. The research in this area yields data on the likelihood of Cushing's syndrome in certain populations and on the accuracy of currently available tests in these populations. As a result, the majority of our recommendations are based on very low- to low-quality evidence. Higher-quality evidence to support testing should come from studies directly comparing the effect of testing strategies on patient-important outcomes.
To date such evidence is not available in this field. These guidelines focus on the more common clinical scenarios, with brief mention of conditions and situations that are rare or more complicated than space limitations allow; we hope that the reader will investigate these further. Features of Cushing's syndrome may occur as a result of exogenous glucocorticoid use.
The severity of the Cushingoid features depends on the potency of the preparation used, its dose, the route and duration of its administration, and whether concomitant medications prolong its half-life A thorough drug history noting current or recent use of these medications, oral, rectal, inhaled, topical, or injected, should be obtained before embarking on any biochemical testing Megestrol acetate medroxyprogesterone acetate is a synthetic progesterone derivative that has glucocorticoid activity and in high doses may cause Cushing's syndrome Our recommendation is based on high-quality evidence because it derives from the common observation that pursuing the alternative, testing to establish the diagnosis of Cushing's syndrome without first excluding exogenous glucocorticoid use, is associated with a very large risk of undesirable effects including unnecessary testing and the associated consequences without expectation of benefit.
Cushing's syndrome is more likely to be present when a large of s and symptoms, especially those with high discriminatory index e. However, there is a wide spectrum of clinical manifestations at any given level of hypercortisolism. Because Cushing's syndrome tends to progress, accumulation of new features increases the probability that the syndrome is present. A review of old photographs of the patient may help the clinician better appreciate whether physical changes have occurred over time.
In children, the sensitivity of combined reduced linear growth and increased weight is quite high. Although the probability of Cushing's syndrome has not been evaluated in a large of children, clinical experience suggests that the specificity of these clinical features for the diagnosis is also very high As a result, tests for Cushing's syndrome are not indicated in obese children unless their statural growth rate has slowed.
Clinicians often evaluate patients with an incidentally found adrenal nodule for autonomous adrenal cortisol excess. Bulow et al. Testing for Cushing's syndrome in certain high-risk populations has shown an unexpectedly high incidence of unrecognized Cushing's syndrome as compared with the general population.
Although there are limited data on the prevalence of the syndrome in these disorders, the diagnosis should be considered. In one study, 2—3. Most of these patients had unilateral adrenal adenomas In another recent report, one of 99 patients with newly diagnosed diabetes mellitus had surgically proven Cushing's disease Screening studies of patients with hypertension reported a 0.
Unsuspected Cushing's syndrome also was found in as many as Unfortunately, there is little information on additional comorbidities and risk factors in these studies. The few data on the outcome, after surgical remission of hypercortisolism, in patients with unsuspected Cushing's syndrome are mixed; hypertension and diabetes did not improve in all individuals 202122 Patients with familial disease that puts them at risk of Cushing's syndrome e.
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