Cushing Syndrome

Overview
  • Cushing Syndrome is a clinical syndrome associated with excessive levels of glucocorticoids. The source of excessive glucocorticoids may be from endogenous overproduction of cortisol by the adrenal cortex or from exogenous pharacological administration of synthetic glucocorticoids such as dexamethasone or prednisone. Whatever the etiology of glucocorticoid excess, a common clinical syndrome arises which is referred to as Cushing Syndrome.
Etiologies
  • Endogenous Overproduction
    • Over-production of the endogenous glucocorticoid cortisol may occur due to a variety of functional neoplasms which either directly secrete cortisol itself or secrete proteins which normally regulate adrenocortical cortisol secretion. For example, functional adrenocortical adenomas may directly secrete cortisol independent of regulation by ACTH. Alternatively, corticotroph pituitary adenomas of the anterior pituitary may secrete ACTH in an unregulated manner thus stimulating oversecretion of cortisol by an otherwise normal adrenal cortex. Traditionally, this specific etiology has been known as Cushing Disease and represents the most common etiology of endogenous glucocorticoid overproduction. In some cases non-pituitary neoplasms, referred to as Ectopic Neoplasms, secrete ACTH in an unregulated manner resulting in over-secretion of cortisol by an otherwise normal adrenal cortex. Such a paraneoplastic syndrome occurs frequently due to the SCLC subtype of bronchogenic carcinomas and carcinoids.
  • Exogenous Administration
    • Large dosages of synthetic glucocorticoids with far more potency than cortisol, such as dexamethasone or prednisone, are commonly administered for long periods in an attempt to suppress immune functions. Sadly, a common adverse effect of such dosage schemes is Cushing Syndrome and this iatrogenic source is by far the most common etiology of the disorder today.
Clinical Consequences
  • Overview
    • The symptomology associated with glucocorticoid excess, regardless of its particular etiology, is known as Cushing Syndrome and is described below. Many of the syndrome's features are predictable exaggerations the physiological actions of glucocorticoids described in glucocorticoid physiology.
  • Metabolic Derangements
    • Glucocorticoid excess results in excessive hepatic gluconeogenesis which manifests as hyperglycemia and glucosuria due to elevation of glood glucose. For unknown reasons chronic excess of glucocorticoids causes wide-ranging derangements of adiposity. This not only results in weight gain and obesity but also body-wide redistribution of adipose tissue manifesting as a centrifugal centrifugal distribution of fat, along with Moon Facies and a Buffalo Hump. Long-term excess of glucocorticoids also results in wasting of multiple tissues, likely in an attempt to liberate amino acids for excess hepatic gluconeogenesis. This includes muscle wasting along with thinning and weakening of the skin which results in characteristic striae, especially around centrifugally expanding belly.
  • Immune Derangements
    • Long-term glucocorticoid excess significantly reduces inflammatory responses which can result in infection susceptibility and poor wound healing due to immune suppression.
  • Bone Derangements
    • Excess glucocortoid levels reduce formation of bone, over time resulting in osteoporosis and increased risk of bone fractures.
  • Endocrine Leak
    • At extremely high levels cortisol can begin inappropriately activating nuclear receptors specific for other cortisteroid hormones. Activation of aldosterone receptor can result in hypertension while activation of androgen receptor can result in hirsuitism and amenorrhea.
Laboratory Diagnosis
  • Overview
    • Given our understanding of cortisol release described in glucocorticoid physiology the basic source of any non-iatrogenic cause of Cushing Syndrome can be determined using several laboratory assays. These include determination of urinary cortisol and plasma ACTH levels measured over a 24hr time periods at baseline and following low and high dose administration of the synthetic glucocorticoid dexamethasone.
  • Pituitary Corticotroph Adenomas
    • Although these adenomas secrete ACTH in an unregulated manner, because they are neoplasms of cells which normally secrete ACTH some residual regulatory response remains. Consequently although plasma ACTH levels will remain elevated even after low-dose dexamethasone administration, high-dose administration of dexamethasone administration activates sufficient negative feedback that ACTH levels typically decline.
  • Cortisol-secreting Adrenocortical Adenomas
    • Because the anterior pituitary is normal in this disease context plasma ACTH levels will be very low as adenoma-derived cortisol feedback-inhibits pituitary ACTH secretion.
  • ACTH-secreting Ectopic Neoplasm
    • Because ectopic neoplasms are not related to cells of the anterior pituitary, they are completely unresponsive to normal regulatory mechanisms of ACTH secretion. Consequently, ACTH levels are not repressed by low or even high-dose dexamethasone administraiton.
Morphology
  • The pathological changes observed in the adrenal cotex depends on the etiological source of Cushing Syndrome. Etiologies associated with ACTH overproduction, whether pituitary or ectopic neoplasms, are associated with bilateral hypertrophy of the adrenal cortices consistent with the role of ACTH as a trophic factor for adrenocortical tissue. Cortisol-secreting adrenocortical adenomas are typically unilateral yellowish, encapsulated tumors within the adrenal cortex. Given the reduced levels of endogenous ACTH in this context, surrounding non-neoplastic adrenocortical tissue is atrophied. Finally, Cushing Syndrome associated with excess iatrogenic glucocorticoid administration manfests as bilateral atrophy of adrenal cortices due to suppression of endogenous ACTH production.