Abstract
Cushing's syndrome (CS) is a classical rare disease: it is often suspected in patients who do not have the disease; at the same time, it takes a mean of 3 years to diagnose CS in affected individuals. The main reason is the extreme rarity (1–3/million/year) in combination with the lack of a single lead symptom. CS has to be suspected when a combination of signs and symptoms is present, which together make up the characteristic phenotype of cortisol excess. Unusual fat distribution affecting the face, neck, and trunk; skin changes including plethora, acne, hirsutism, livid striae, and easy bruising; and signs of protein catabolism such as thinned and vulnerable skin, osteoporotic fractures, and proximal myopathy indicate the need for biochemical screening for CS. In contrast, common symptoms like hypertension, weight gain, or diabetes also occur quite frequently in the general population and per se do not justify biochemical testing. First-line screening tests include urinary free cortisol excretion, dexamethasone suppression testing, and late-night salivary cortisol measurements. All three tests have overall reasonable sensitivity and specificity, and first-line testing should be selected on the basis of the physiologic conditions of the patient, drug intake, and available laboratory quality control measures. Two normal test results usually exclude the presence of CS. Other tests and laboratory parameters like the high-dose dexamethasone suppression test, plasma ACTH, the CRH test, and the bilateral inferior petrosal sinus sampling are not part of the initial biochemical screening. As a general rule, biochemical screening should only be performed if the pre-test probability for CS is reasonably high. This article provides an overview about the current standard in the diagnosis of CS starting with clinical scores and screenings, the clinical signs, relevant differential diagnoses, the first-line biochemical screening, and ending with a few exceptional cases.
Highlights
CLINICAL REASONING PROBLEMSSolving clinical cases correctly [11]—and efficiently [12]— is one of the great challenges in daily clinical practice
We demonstrated that the 15-plasma-steroid panel was able to discriminate 35 patients with subclinical CS from 21 with overt clinical CS and normal controls
If clinically a CS is likely, a single negative test should not lead to the exclusion of an endogenous hypercortisolism
Summary
Solving clinical cases correctly [11]—and efficiently [12]— is one of the great challenges in daily clinical practice. As Clinical Reasoning is mainly based on pattern recognition and illness script formation [16, 17], it is quite clear that diagnosing CS correctly is even more challenging than many other diseases: statistically, a family practitioner diagnoses between 0 and 1 patient with CS in his work-life. As physicians will only evaluate a small number of true Cushing patients, it is difficult for them to develop the corresponding illness scripts to diagnose the disease in time. To foster the clinical reasoning process, different attempts have been made
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