Sindrom Cushing

01Pathophysiology

Cushing's syndrome is the clinical state produced by chronic exposure to excess glucocorticoid. The phenotype is the same regardless of source, but the source determines workup and treatment. Cortisol normally rises in the morning and falls at night under tight pulsatile regulation by hypothalamic CRH and pituitary ACTH. In disease, this circadian rhythm is lost first, which is why late-night salivary cortisol is one of the earliest abnormalities and a screening anchor.

Excess cortisol drives gluconeogenesis and insulin resistance, producing hyperglycemia and frank diabetes. It causes protein catabolism, which thins the skin, fragments collagen (giving the wide violaceous striae), and selectively wastes type II muscle fibers, hence the proximal myopathy. Cortisol promotes lipolysis peripherally but redistributes fat centrally through differential lipoprotein lipase activity, producing central obesity, supraclavicular pads, dorsocervical hump, and rounded face with thin extremities, a near-pathognomonic body habitus.

At supraphysiologic levels, cortisol occupies the mineralocorticoid receptor (overwhelming the protective enzyme 11-beta-hydroxysteroid dehydrogenase type 2 in the kidney), causing sodium retention, hypertension, and hypokalemic metabolic alkalosis. This finding is most pronounced in ectopic ACTH syndromes where cortisol levels are extreme. Cortisol also suppresses osteoblasts and impairs calcium absorption, producing osteoporosis with vertebral compression fractures in young patients, a high-yield clue.

Immunosuppressive effects (impaired neutrophil chemotaxis, lymphocyte apoptosis) explain recurrent skin infections, oral thrush, and reactivation of latent infections. Catecholamine potentiation and direct CNS effects yield mood lability, depression, insomnia, and overt psychosis. In children, the most reliable early sign is growth arrest with continued weight gain, which separates Cushing's syndrome from simple obesity (where height velocity is preserved or accelerated).

When the cause is ACTH-dependent, persistently elevated ACTH stimulates bilateral adrenal hyperplasia and may produce hyperpigmentation through MSH activity (most evident in ectopic ACTH due to magnitude). When the cause is ACTH-independent (adrenal adenoma, carcinoma, or bilateral macronodular hyperplasia), autonomous cortisol secretion suppresses pituitary ACTH, so the contralateral adrenal atrophies and hyperpigmentation is absent.

02Classification and Clinical Manifestation

03Diagnostic Workup

The diagnostic logic flows in two clear phases. Phase one is biochemical confirmation that hypercortisolism actually exists. The first-line tests are 24-hour urinary free cortisol, late-night salivary cortisol, and the 1 mg overnight dexamethasone suppression test. Two abnormal results from two different first-line tests are required before moving forward, because each test alone has imperfect sensitivity and specificity. The screening test of choice in pregnancy is 24-hour urinary free cortisol, because dexamethasone suppression is unreliable due to elevated cortisol-binding globulin.

Phase two is anatomical localization, and this is where students stumble. The very first step of phase two is a plasma ACTH level, not imaging. ACTH below 5 pg/mL points to an adrenal source, and the next test is an adrenal CT. ACTH above 20 pg/mL points to a pituitary or ectopic source, and the next test is a pituitary MRI. If the MRI shows a clear adenoma at least 6 mm in size and the high-dose dexamethasone test suppresses cortisol, no further testing is needed. If the MRI is negative, equivocal, or shows an incidentaloma (which is common, since 10 percent of the population has pituitary incidentalomas), the gold standard is bilateral inferior petrosal sinus sampling, which directly measures ACTH gradient between the pituitary venous drainage and the periphery.

The high-dose dexamethasone suppression test exploits the fact that pituitary corticotroph adenomas retain partial negative feedback at supraphysiologic cortisol levels, while ectopic tumors do not respond to glucocorticoid feedback at all. Cortisol suppression of more than 50 percent points to a pituitary source. This test has been largely supplanted by petrosal sinus sampling because ectopic carcinoid tumors can mimic pituitary suppression patterns, but the principle remains testable.

04Management and Treatment

The therapeutic approach hinges on identifying and removing the cortisol source. For iatrogenic Cushing's syndrome, the cornerstone is a gradual glucocorticoid taper. The hypothalamic-pituitary-adrenal axis takes 6 to 12 months to recover after prolonged suppression, so abrupt withdrawal precipitates adrenal crisis. Common taper strategies reduce the dose by 10 to 20 percent every 1 to 2 weeks once below physiologic equivalent (about 5 mg prednisone daily), with morning dosing and stress-dose coverage during illness or surgery (typically hydrocortisone 50 to 100 mg IV every 8 hours).

For Cushing's disease, the first-line treatment is transsphenoidal selective adenomectomy by an experienced neurosurgeon, with remission rates of 70 to 90 percent for microadenomas and 50 to 65 percent for macroadenomas. Postoperatively, transient secondary adrenal insufficiency is expected and is actually a marker of surgical success; patients require hydrocortisone replacement (usually 15 to 25 mg per day in divided doses) for 6 to 12 months until the suppressed normal corticotrophs recover. If surgery fails or is incomplete, options include stereotactic radiosurgery (effects take months to years), pasireotide (a somatostatin analogue), cabergoline (a dopamine agonist), and steroidogenesis inhibitors. Bilateral adrenalectomy is curative but reserved as last resort because it produces lifelong adrenal insufficiency and risks Nelson's syndrome, in which the pituitary adenoma enlarges aggressively due to loss of cortisol feedback, producing visual field defects and hyperpigmentation.

For adrenal adenoma, unilateral laparoscopic adrenalectomy is curative. Because the contralateral adrenal has been suppressed by autonomous cortisol secretion, postoperative glucocorticoid replacement is required for 6 to 12 months. Adrenal carcinoma requires open en bloc resection with regional lymphadenectomy, followed by adjuvant mitotane, an adrenolytic agent that also inhibits steroidogenesis. Prognosis is poor, with 5-year survival under 40 percent.

For ectopic ACTH syndrome, the priority is locating and resecting the primary tumor. When the source cannot be found or is unresectable, steroidogenesis inhibitors control hypercortisolism. Ketoconazole (200 to 400 mg orally twice or three times daily, with hepatic monitoring) inhibits multiple steroidogenic enzymes. Metyrapone (500 mg to 6 g daily in divided doses) inhibits 11-beta-hydroxylase. Osilodrostat (2 to 30 mg twice daily) is a newer 11-beta-hydroxylase inhibitor approved when surgery is not curative. Etomidate is reserved for ICU-level emergencies given as a continuous infusion. Mifepristone is a glucocorticoid receptor antagonist used when hyperglycemia is the dominant problem; it does not lower cortisol levels (which complicates monitoring) and is contraindicated in pregnancy.

The "next best step" logic is consistent: confirm hypercortisolism biochemically before any imaging; obtain ACTH before localizing imaging; perform petrosal sinus sampling when pituitary MRI and biochemistry conflict; and always cover patients with stress-dose steroids in the perioperative period after curative surgery.

Contraindications to standard therapies include ketoconazole in liver disease and in patients on QT-prolonging drugs, mifepristone in pregnancy and endometrial cancer, and mitotane in pregnancy (it is teratogenic and persists in adipose tissue for years).

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common errors on this topic cluster around three themes. First, students conflate Cushing's syndrome (any cause of hypercortisolism) with Cushing's disease (pituitary corticotroph adenoma only). Use the umbrella term unless ACTH localization has confirmed a pituitary source. Second, students reach for imaging before biochemistry. The correct sequence is always confirm hypercortisolism first, then measure ACTH, then image. Ordering a pituitary MRI in a patient with central obesity but normal cortisol screening tests is a classic distractor, because pituitary incidentalomas are present in roughly 10 percent of the population and a positive scan in a patient without biochemical disease leads to unnecessary surgery. Third, students forget that the most common cause of Cushing's syndrome is iatrogenic. A vignette describing a patient with rheumatoid arthritis, asthma, lupus, or a transplant who develops moon facies and central obesity is asking you to recognize exogenous steroid exposure, where the laboratory findings are paradoxical: low ACTH, low endogenous cortisol, but florid Cushingoid phenotype.

Subtle traps include the rapid-onset Cushing's syndrome with weight loss, hypokalemia, hyperpigmentation, and edema in a smoker, which is ectopic ACTH from small cell lung carcinoma, not Cushing's disease. Another trap is the patient with psychiatric symptoms, alcoholism, or uncontrolled diabetes producing pseudo-Cushing's biochemistry; the dexamethasone-CRH test or repeated late-night salivary cortisol after stabilization disambiguates this. A young patient with osteoporotic vertebral fracture, hypertension, and diabetes should trigger thinking about Cushing's syndrome even without obvious habitus changes. In children, the hallmark is growth failure with weight gain, and a child with normal or accelerated linear growth almost certainly does not have Cushing's syndrome regardless of body habitus.

The core competency being tested is diagnostic sequencing: knowing that hypercortisolism must be confirmed biochemically before any anatomical workup, that ACTH determines the next imaging study, and that petrosal sinus sampling resolves ambiguity between pituitary and ectopic sources. The secondary competency is recognizing the catabolic phenotype (thin skin, easy bruising, wide violaceous striae, proximal myopathy, osteoporosis) that distinguishes true Cushing's syndrome from common obesity, because this distinction is what the question writer is hiding inside the vignette.