5 EVALUATION OF CUSHING'S SYNDROME John Newell-Price, M.D. and Mike Besser, M.D. Northern General Hospital, Sheffield, UK and St Bartholomew's Hospital, London, UK. OVERVIEW The protean clinical manifestations of Cushing's syndrome (CS) are really only the starting point for biochemical evaluation. When florid clinical features are present diagnosis may be straightforward. In contrast, when physical symptoms and signs are subtle diagnosis may be far more taxing. The principal biochemical features of Cushing's syndrome are an excess endogenous integrated secretion of cortisol, loss of the normal feed-back of the hypothalamo-pituitary-adrenal axis (HPA) and disturbance of the normal circadian rhythm of cortisol secretion. The biochemical tests that are used in the diagnosis of Cushing's syndrome rely upon these disturbances of normal physiology. In the investigation of Cushing's syndrome initial biochemical tests of high sensitivity should be employed to avoid missing mild disease, although the diagnosis may latter be refuted by tests of higher specificity. Differential diagnosis can only be embarked upon once the diagnosis of Cushing's syndrome is firmly established. In this chapter we will review the biochemical tests used for diagnosis and differential diagnosis. Imaging tests are discussed in the relevant chapters. ASSESSMENT OF CIRCADIAN RHYTHM The loss of the normal circadian rhythm of cortisol secretion seen in patients with Cushing's syndrome was first reported by Doe et al in 1960 (1). The overlap in serum cortisol values in patients with Cushing's syndrome and normal subjects diminishes with clock time and this forms the hasis of the midnight cortisol test. In our own series a single sleeping serum cortisol was greater than 50 nmollL (1.8Ilg/dL) in 150 patients with subsequently confmned Cushing's syndrome (three of whom had suppressed circulating cortisol levels on a 2mg/day 48-hour low-dose dexamethasone-suppression test), whilst in control subjects the sleeping midnight serum cortisol was less L. S. Blevins Jr. (ed.), Cushing’s Syndrome © Kluwer Academic Publishers 2002