Cushing syndrome

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Cushing Syndrome

Definition

Cushing syndrome is the clinical state resulting from prolonged, pathological exposure to excess glucocorticoids (hypercortisolism), regardless of the source. When hypercortisolism is specifically caused by an ACTH-secreting pituitary adenoma, the condition is called Cushing disease - a subset of Cushing syndrome.

Campbell-Walsh-Wein Urology, p. 3134
Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 501

Etiology and Classification

The causes fall into three broad categories:

1. Exogenous (Iatrogenic) - Most Common Overall

Administration of synthetic glucocorticoids (oral, topical, inhaled, intranasal) is the most common cause in the Western world. Even low doses can produce the syndrome. A careful history is essential - patients may be unaware of steroid content in herbal preparations or nasal sprays.

2. Endogenous - ACTH-Dependent (80-85% of endogenous cases)

Cause	Proportion	Notes
Cushing disease (pituitary ACTH adenoma)	~70% of endogenous	Usually a microadenoma; F > M 2:1
Ectopic ACTH syndrome	~10-15%	Nearly always malignant tumors (small cell lung, carcinoid, etc.); higher ACTH → bilateral adrenal hyperplasia + hyperpigmentation
Ectopic CRH syndrome	<1%	Extremely rare

3. Endogenous - ACTH-Independent (~10-20% of endogenous cases)

Adrenal adenoma or adrenal carcinoma - autonomous cortisol secretion suppresses the HPA axis; serum ACTH is low
Primary Pigmented Nodular Adrenocortical Disease (PPNAD) - occurs in 30% of patients with Carney complex; shows a paradoxical rise in UFC after dexamethasone
AIMAH (ACTH-independent macronodular adrenal hyperplasia)
Campbell-Walsh-Wein Urology, p. 3135-3137

Pathophysiology

The zona fasciculata of the adrenal cortex normally secretes up to 20 mg cortisol/day under control of the HPA axis:

Hypothalamus releases CRH (under circadian control by the suprachiasmatic nucleus) → stimulates anterior pituitary corticotrophs
Anterior pituitary releases ACTH (from POMC cleavage) → stimulates adrenal cortex
Cortisol feeds back negatively to suppress both CRH and ACTH

Normal cortisol peaks in the early morning (~7-8 AM) and reaches a nadir at ~11 PM. In Cushing syndrome, this circadian rhythm is lost - the inability to suppress late-night cortisol is the earliest detectable abnormality.

Campbell-Walsh-Wein Urology, p. 3134

Clinical Features

Classic Physical Findings

System	Features
Fat redistribution	Central obesity, moon facies (round face), buffalo hump (dorso-cervical fat), supraclavicular fat pads; limbs spared
Skin	Purple/violaceous striae (abdomen, thighs, buttocks, arms); skin thinning and fragility; easy bruising; Liddle sign (skin peeling with tape removal); facial plethora
Hair/acne	Hypertrichosis (facial lanugo in women); scalp thinning; acne
Infections	Susceptibility to dermatophytes, Pityrosporum; opportunistic fungal infections
Musculoskeletal	Proximal muscle weakness; osteoporosis; vertebral fractures; kyphosis
Metabolic	Hypertension; hyperglycemia/diabetes mellitus (20% of patients); dyslipidemia
Reproductive	Loss of libido; menstrual irregularities in women
Neuro/psych	Depression, anxiety, cognitive impairment

Women are affected 4x more frequently than men in non-iatrogenic cases. Peak onset is in the 20s-30s.

Ectopic ACTH syndrome presents differently: rapid onset, severe hypokalaemic alkalosis, hyperpigmentation (from high ACTH/MSH), and less classic cushingoid features because the disease course is often shorter.

Andrews' Diseases of the Skin, p. 578
Campbell-Walsh-Wein Urology, p. 3136

Diagnosis

Step 1: Screening (confirm hypercortisolism)

Three first-line screening tests - at least two abnormal tests are required:

Test	Method	Notes
24-hour urinary free cortisol (UFC)	Reflects unbound circulating cortisol; unaffected by CBG level	Upper normal: 110-138 nmol/24h; values >4x ULN are diagnostic; falsely low if GFR <30 mL/min
Overnight 1mg dexamethasone suppression test (DST)	1 mg dexamethasone at 11 PM → check 8 AM cortisol	Cortisol <50 nmol/L (1.8 mcg/dL) rules out Cushing syndrome; preferred in renal impairment
Late-night salivary cortisol (MSC/LNSC)	11 PM salivary cortisol (2 measurements)	Reflects loss of circadian nadir; convenient outpatient test

Pseudo-Cushing syndrome (HPA hyperactivity without true Cushing syndrome) occurs in depression, alcoholism, anxiety, poorly controlled DM, and morbid obesity - causing false positives.

Henry's Clinical Diagnosis, p. 501
Lippincott Illustrated Reviews: Pharmacology, p. 875-876

Step 2: Confirm and Localize the Cause

Measure plasma ACTH:

Low/suppressed ACTH → ACTH-independent (adrenal source) → CT/MRI adrenals
Normal/elevated ACTH → ACTH-dependent → distinguish pituitary vs. ectopic

For ACTH-dependent disease:

Pituitary MRI (note: ~50% of Cushing disease patients have no visible adenoma on MRI; 10% of normal people have incidental pituitary abnormalities)
High-dose DST (8 mg overnight): suppression suggests pituitary source (Cushing disease); no suppression suggests ectopic - but limited reliability
Inferior petrosal sinus sampling (IPSS) after CRH stimulation = gold standard for distinguishing Cushing disease from ectopic ACTH. Central:peripheral ACTH ratio >2 (basal) or >3 (post-CRH) = pituitary source
Chest CT/octreotide scan to find ectopic source
Campbell-Walsh-Wein Urology, p. 3137-3139

Laboratory Findings Summary

Elevated serum cortisol, UFC, or late-night salivary cortisol
Loss of circadian rhythm of ACTH and cortisol
Failure to suppress cortisol with dexamethasone

Treatment

Treatment depends on the underlying cause, and requires a multidisciplinary team.

Exogenous Cushing Syndrome

Gradual tapering of exogenous glucocorticoids (never abrupt cessation - risk of adrenal insufficiency and steroid withdrawal syndrome)
Allow HPA axis recovery over weeks to months

Cushing Disease (Pituitary Adenoma)

Trans-sphenoidal surgical resection is the first-line treatment; cure rate ~60-80%
~25% relapse on long-term follow-up
Post-op: expect transient adrenal insufficiency requiring glucocorticoid replacement for up to 1 year
Failed surgery: options include reoperation, stereotactic radiation (risk: delayed response, hypopituitarism), or bilateral adrenalectomy
Bilateral adrenalectomy: rapid definitive cure, but requires lifelong steroid replacement; risk of Nelson syndrome (progressive ACTH-secreting pituitary tumor growth post-adrenalectomy due to loss of cortisol feedback)

Ectopic ACTH Syndrome

Resect the primary tumor when possible
If unresectable: medical adrenal blockade with ketoconazole, metyrapone, mitotane, or etomidate (for acute crisis); bilateral adrenalectomy as last resort

Adrenal Cushing Syndrome (Adenoma/Carcinoma)

Unilateral or bilateral laparoscopic adrenalectomy
Adrenal carcinoma: adrenalectomy + mitotane (adjuvant); poor prognosis

Medical Therapy (adjunctive/bridging)

Drug	Mechanism
Ketoconazole	Inhibits 11β-hydroxylase and cholesterol side-chain cleavage
Metyrapone	Blocks 11β-hydroxylase
Mitotane	Adrenolytic; used in adrenal carcinoma
Pasireotide	Somatostatin analogue; reduces ACTH in Cushing disease
Mifepristone	Glucocorticoid receptor antagonist; useful when surgery is not possible

Campbell-Walsh-Wein Urology, p. 3139-3141

Pseudo-Cushing Syndrome

Mimics Cushing syndrome clinically and biochemically but is not due to a primary HPA axis pathology. Causes: alcoholism (increased cortisol secretion + reduced cortisol metabolism by hepatic damage), severe depression, anxiety disorders, poorly controlled DM, morbid obesity.

The CRH stimulation test (with low-dose DST) helps distinguish: in true Cushing syndrome, CRH raises cortisol despite prior dexamethasone; in pseudo-Cushing, it does not.

Comprehensive Clinical Nephrology, p. 1504

Key Points Summary

Feature	Detail
Most common cause	Iatrogenic (exogenous steroids)
Most common endogenous cause	Cushing disease (pituitary ACTH microadenoma, ~70%)
Gold standard to distinguish pituitary vs. ectopic ACTH	Inferior petrosal sinus sampling (IPSS)
First-line screening tests	24h UFC, overnight DST, late-night salivary cortisol
Earliest abnormality	Loss of late-night cortisol suppression
Most specific skin finding	Wide purple striae + easy bruising + skin thinning
Treatment of Cushing disease	Trans-sphenoidal surgery (60-80% cure)
Risk after bilateral adrenalectomy for Cushing disease	Nelson syndrome

Recent evidence note: A 2024 systematic review and meta-analysis (PMID 38888685) highlights that distinguishing true Cushing syndrome from non-neoplastic hypercortisolism (pseudo-Cushing) remains challenging with standard tests - consistent with the textbook guidance above that multiple tests and clinical context are needed.

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