Cushing’s syndrome

Abstract

Cushing’s syndrome (CS) results from prolonged exposure to elevated endogenous cortisol. The increased cortisol production is due to adrenal lesions (ACTH independent CS) or driven by ACTH excess from pituitary or ectopic sources (ACTH dependent CS). The clinical presentation has some variations depending on the etiology. The most common findings are central obesity, hypertension, irregular periods in women and decreased libido in men, hyperlipidemia, impaired glucose tolerance and diabetes, hypercoagulability, muscle weakness, depression, thin skin and violaceous striae, poor wound healing and predisposition to infections. ACTH independent CS, in the vast majority is due to a unilateral tumor, adenoma or carcinoma (ACC). ACC may have a mixed androgen-cortisol secretion and women may present with virilization. The bilateral disease consists of primary pigmented nodular adrenocortical disease (PPNAD), primary nonpigmented micronodular hyperplasia and ACTH independent macronodular hyperplasia (AIMAH). When the source of excess ACTH is the pituitary, the disorder is called Cushing disease (CD) and it accounts for about 70% of cases of CS. The cause is usually a benign corticotroph microadenoma and rarely a pituitary carcinoma or corticotroph hyperplasia due to excess CRH stimulation. Cushing disease is more common in the young adults, especially women. The clinical signs appear insidiously over months to years. Central obesity, glucose intolerance, menstrual irregularities and depression are the most common features. Ectopic ACTH secretion accounts for about 8-18% of all cases of CS. It is usually caused by neuroendocrine tumors with small cell lung cancer being the most common. The clinical features are similar to that of CD. However the onset and progression of clinical features are usually overt and rapid with weight loss, hyperkalemia and hyperpigmentation as main features. The prevalence of ectopic ACTH appears to be equal in both genders. CS due to isolated ectopic CRH secretion is extremely rare. Commonly recommended initial testing is urinary free cortisol, late-night salivary cortisol or 1 mg overnight dexamethasone suppression test (DST), followed by an ACTH level. Imaging is key to delineate etiology, complemented by Dexamethasone-CRH test and IPSS (inferior petrosal sinus sampling) if the ACTH source is in doubt or pseudo Cushing is suspected. When amenable, the first line in treatment is surgical removal of the causative lesion. The pharmacological treatment is aimed at decreasing the adrenal steroid secretion or blocking its action at the receptor level. Radiotherapy and chemotherapy are adjunctive therapies depending on the etiology. CS has always been a diagnostic and therapeutic challenge. Persistence and recurrence are real concerns and lifelong follow-up is warranted.