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Cushing syndrome [may 2008]


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INFORMATION

Causes:

a) ACTH-DEPENDENT

Cushing’s Disease: Pituitary hypersecretion of ACTH. 70% (microadenoma 80-90%, macroadenoma 10-20%)
Ectopic secretion of ACTH by non-pituitary tumors 15-20% (50% microcytic tumours of the lung).
Ectopic secretion of CRH by non-hypothalamic tumors.

b) ACTH-INDEPENDENT

Iatrogenic Cushing’s by exogenous administration of glucocorticoids.
Adrenocortical adenomas or carcinomas.
Bilateral micronodular dysplasia.
Bilateral macronodular ACTH-independent hyperplasia.

Clínical:

The symptoms and signs of Cushing’s syndrome are the result of chronic exposure to excess glucocorticoids. There is a wide spectrum of manifestations from the subclinical form to the clinical syndrome, depending on the intensity and duration of the hypercortisolaemia.

The most frequent are: central obesity with moon face, buffalo hump, skin atrophy, ecchymoses, haemorrhagic diathesis, purpura. Thromboembolic events, red-wine-colored striae. Proximal muscle weakness. Osteoporosis. Glucose intolerance. Hypertension. Menstrual irregularities. Emotional lability, depression, irritability, paranoia, anxiety. Increase in the frequency of infections. Hyperpigmentation in cases of increased ACTH. Hirsutism, acne, virilization in women with the increase of adrenal androgens.

Diagnosis:

The diagnosis of Cushing’s Syndrome involves:

Suspicion based on signs or symptoms of the patient.
Quantifying hypercortisolaemia.
Determining the cause

Exclude in:

Clinical demonstrations of Cushing’s syndrome: Central obesity, cutaneous striae, hirsutism…
Illnesses caused or aggravated by hypercortisolism:. Diabetes mellitus, polycystic ovaries, osteoporosis...
Study of adrenal incidentalomas.

Diagnosing on suspicion. Screening:

Suppression with 1 mg dexamethasone: cortisol<1.8 µg/dl excludes Cushing’s syndrome (Sens 90-95%, spec 87.5%). False negatives occur in renal and liver insufficiency. False positives with inhibitors of enzyme P450 (barbiturates, phenytoin, carbamazapine …), estrogens, pregnancy
24 hour Urinary Cortisol: Normal: 80-120 µg/24 h. If > 300 µg/24 h highly suggestive of Cushing’s (Sens 95%)
Nocturnal Cortisol at 23 & 24 hrs: 2-3 samples on different days; if in a single sample the cortisol is < 1.8 µg/dl, Cushing’s syndrome is excluded with Sens 100%. If cortisol > 7.5 in at least 2 samples it is diagnostic of Cushing’s syndrome.

Diagnosing the syndrome. Confirming the diagnosis of Cushing’s syndrome

Suppression average with dexamethasone (0.5 mg/6H/2 days): a value of cortisol <1.8 µg/dl excludes Cushing’s syndrome with a Sens 98%. False positives occur with treatment of anti-convulsants or contraception.

Differential Diagnosis: Etiology. Confirming the diagnosis of Cushing’s syndrome

Basal ACTH: one can assume it is ACTH-independent if the concentration of ACTH is <5 pg/ml with a serum cortisol of > 15µg/dl. It is ACTH-dependent if ACTH > 15 pg/ml. If the concentration of ACTH is between 5-15 it is suggestive of ACTH-dependent Cushing’s although it is recommended a test of stimulus with CRH/DDAVP be carried out.
Ectopic Co-secretion: up to 70%, one or various CRH, calcitonin, gastrin, somatostatin, PP, VIP, HCG, glucagon, subunit _, GHRH, CEA
Strong suppression with dexamethasone (2mg/6H/2 days): useful in the differential diagnosis of ACTH-dependent Cushing’s syndrome. Cushing’s syndrome is centrally caused if the cortisol is <6.9 µg/dl and urinary cortisol is reduced by 90% (Sens 83%, Spec 100%)
Stimulus with CRH: distinguishes between central and ectopic secretion of ACTH. If the plasma cortisol increases by more than 20% of the basal level one can proceed to the diagnosis of central Cushing’s (Sens 91%, Spec 95%)
Other tests:
- Stimulation with desmopressin DDAVP
- Stimulation with CRH + DDAVP
- Stimulation test with metopirone

Diagnosing the location