What is Cushing's syndrome?

What is Cushing's Syndrome?

Cushing's syndrome is a rare endocrine disorder caused by chronic excessive exposure to glucocorticoid hormones, either from exogenous steroid use or endogenous overproduction of cortisol, with an estimated incidence of 2 to 8 per million people annually for endogenous causes. 1, 2

Definition and Core Pathophysiology

Cushing's syndrome represents a constellation of clinical manifestations resulting from prolonged hypercortisolism that is not due to normal physiological stress responses. 1, 3 The syndrome can arise from:

• Exogenous sources: Chronic glucocorticoid medication use (most common overall cause) 1, 2
• Endogenous sources: Autonomous cortisol overproduction from tumors or hyperplastic tissue 3, 2

Etiologic Classification

ACTH-Dependent Causes (60-80% of endogenous cases)

• Cushing's disease: Pituitary corticotroph adenomas secreting ACTH, accounting for 60-70% of endogenous cases 1, 4
• Ectopic ACTH syndrome: Non-pituitary tumors producing ACTH or CRH, with thymic sources representing up to 2% of cases 4, 5
• Elevated ACTH levels indicate the cortisol excess originates from pituitary or ectopic sources rather than the adrenal gland itself 4, 5

ACTH-Independent Causes

• Benign adrenal adenomas: Unilateral cortisol-secreting tumors that suppress ACTH production 4
• Adrenal carcinomas: Suspected when tumors exceed 5 cm with irregular margins, inhomogeneity, or local invasion 4
• Bilateral adrenal disease: Including primary pigmented nodular adrenal dysplasia or ACTH-independent macronodular hyperplasia 3
• Suppressed ACTH levels indicate autonomous adrenal cortisol production 3

Clinical Manifestations

Classic Physical Features

The syndrome presents with characteristic signs including:

• Dermatologic: Facial plethora, easy bruising, purple abdominal striae, fragile skin, hirsutism, and acne 6, 4, 1
• Body habitus: Central weight gain, moon facies, dorsal and supraclavicular fat accumulation (buffalo hump) 6, 4, 1
• Musculoskeletal: Proximal muscle weakness and protein catabolism 6, 5, 1

Metabolic and Cardiovascular Complications

• Hypertension: Occurs in 70-90% of patients, driven by mineralocorticoid receptor activation from excess cortisol overwhelming protective enzymes, increased renal sodium absorption, renin-angiotensin system activation, and vascular sensitization to catecholamines 6, 4, 7
• Glucose abnormalities: Exceed 80% prevalence, mimicking severe metabolic syndrome 6, 4
• Dyslipidemia and cardiovascular disease: Contributing to increased mortality from myocardial infarction and cerebrovascular accidents 2, 8

Neuropsychiatric Manifestations

• Mood disorders, depression, anxiety, and neurocognitive changes are common 6, 4, 1
• These symptoms overlap significantly with other conditions, complicating diagnosis 4

Diagnostic Delay and Clinical Significance

The average diagnostic delay is 3 years from symptom onset, resulting in severe multisystem morbidity and increased mortality from cardiovascular events, pulmonary emboli, and infections. 4, 2, 8 This delay occurs because many features (weight gain, hypertension, mood changes) are common in the general population and may be attributed to other conditions like metabolic syndrome. 6, 4

Prevalence in Specific Populations

While Cushing's syndrome is rare in the general population, it may have higher prevalence in certain clinical contexts:

• Up to 4% in patients with resistant hypertension 6
• However, systematic screening of 423 resistant hypertension patients found no overt cases, suggesting it remains uncommon even in this high-risk group 6
• Subclinical Cushing syndrome (abnormal dexamethasone suppression without overt symptoms) is the most common hormonal dysfunction in adrenal incidentalomas 6

Key Clinical Pitfall

The most critical pitfall is failing to exclude exogenous glucocorticoid use before pursuing extensive endogenous Cushing's syndrome workup, as iatrogenic causes are far more common than endogenous overproduction. 5, 1