CUSHING SYNDROM

Fig. 22.3A and B: Cushing syndrome: (A) Moon face with Hirsutism; (B) Purple striae over thighs.

Clinical features are similar irrespective of etiology and include:

• Truncal obesity with buffalo hump and thin extremities due to centripetal fat distribution. Purple striae may be present on protuberant abdomen and thighs, due to skin stretching.

• Short stature with normal or advanced bone age (due to androgen excess).

• Moon-like facies, with cheek flushing, double chin and hypertrichosis (Fig. 22.3)

• Masculinizing features due to androgen excess, e.g. hypertrichosis, acne, pubic hair, deepening of voice and clitoromegaly.

• Hypertension is common and may lead to heart failure.

• Otherfeatures include easy bruising and susceptibility to infections as well as osteoporosis, psychological disturbances and proximal myopathy in long-stand­ing cases.

Laboratory diagnosis aims to demonstrate hyper- cortisolism and its etiology.

• Indirect evidences of hypercortisolism include presence of polycythemia, lymphopenia, eosinopenia, hyperlipidemia, hypercalciuria, hyperinsulinemia and hyperglycemia.

• Endocrinal evaluation requires multiple tests as follows, since no single test is confirmatory.

- Elevated mid-night cortisol levels (gt;4.4 #956;g#8725;dl) strongly indicate possibility of Cushing syndrome. Midnight sample is necessary to account for diurnal variation in cortisol levels, which are highest in morning and lowest at midnight. Late-night salivary cortisol levels may be used for outdoor evaluation.

- Elevated 24-hr urinary free cortisol (UFC) levels (gt;75 #956;g#8725;m²) is a useful screening test.

- Dexamethasone suppression test: Single dose of dexamethasone (PO 25-30 #956;g#8725;kg) at 11 pm normally suppresses plasma cortisol levels lt; 5 #956;g/ dl at 8 AM next morning.

D/D between Cushing syndrome (adrenal) and Cushing disease (pituitary) involves:

• Low Plasma ACTH levels (lt;5 pg/ml) in adrenal tumors, which do not rise after CRH challenge (IV 1 #956;g#8725;kg), unlike normal or high values in ACTH-secreting pituitary or ectopic adenomas (gt;15 pg/ml). Ectopic ACTH secretion must be suspected in presence of very high ACTH levels gt; 100 pg/ml.

• Two-step Dexamethasone suppression test with PO Dexamethasone for 2 consecutive days in different doses (30 #956;g#8725;kg#8725; day q6hr on day 1 and 120 #956;g#8725;kg#8725; d q6hr on day 2). Children with ACTH-independent Cushing syndrome do not show cortisol suppression. However in Cushing disease due to microadenoma of pituitary, cortisol levels are suppressed with higher doses.

In brief, Cushing syndrome due to:

• Adrenal lesions have low ACTH, high UFC and negative high-dose DST (No suppression).

• Pituitary lesions have high ACTH, high UFC and variable results on high-dose DST

• Ectopic ACTH have high ACTH, high UFC and negative high-dose DST

• Exogenous causes have low ACTH, high UFC and negative high-dose DST

Radio-imaging studies (CT/MRI) may be necessary to detect adrenal and pituitary tumors, while other X-rays may be used to detect osteoporosis and advanced bone age.

Management depends on the etiology:

• Adrenal tumors require unilateral or subtotal adre­nalectomy, along with pre-/post-operative hydro­cortisone supplementation.

• Pituitary tumors with adrenal hyperplasia (Cushing disease) is best treated with trans-sphenoidal microsurgery.

• Medical therapy with inhibitors of steroidogenesis, e.g. cyproheptadine, bromocriptine, ketoconazole, etc. is rarely effective, with frequent side effects.

Diagnosis is supported by typical biochemical abnor­malities (hypokalemia, hypernatremia, alkalosis) and confirmed by high aldosterone levels and suppressed plasma renin activity. CT/MRI helps to localize the tumor.

Treatment is mainly surgical with excision of tumor or adrenalectomy, though nodular hyperplasia may be managed with mineralocorticoid antagonists, e.g. spironolactone.

Secondary hyperaldosteronism is generally transient, caused by high renin secretion, either as: (a) compensatory mechanism to restore glomerular filtration rate, e.g. in CCF, nephrotic syndrome, renal artery stenosis, etc. or (b) due to a Renin-secreting Wilms' tumor. These cases predominantly present with features of primary disease. Hypokalemia and hypertension are absent in secondary hyperaldosteronism.

22.5.6