Cushing’s syndrome

It results from chronic exposure to excessive levels of circulating glucocorticoids. Cushing’s syndrome may be ACTH dependent or ACTH independent characterized by high or low levels of ACTH respectively.

Causes of Cushing’s syndrome

ACTH dependent

• Cushing’s disease (CNS causes)
• Ectopic ACTH syndrome e.g. in small cell carcinoma of the lung, bronchial carcinoids
• Ectopic CRH syndrome
• Exogenous ACTH administration

ACTH independent

• Adrenal adenoma
• Adrenal carcinoma
• Adrenal hyperplasia
• McCune Albright syndrome
• Exogenous glucocorticoid syndrome

Cushing’s disease results from pituitary adenoma, and may be associated with MEN1 and 2 syndromes. It is the most common cause of endogenous Cushing’s syndrome. Overall, exogenous administration of steroids is the most common cause of Cushing’s syndrome.

Cushing’s syndrome presents with abdominal obesity, wasting of the limbs, round face, “buffalo hump”, hirsutism, frontal balding, muscle weakness, easy bruising, lethargy, depression, menstrual irregularities, proximal myopathy, vertebral stress fractures, osteoporosis, purplish abdominal striae, hyperpigmentation, hypertension and glucose intolerance. Adrenal adenomas generally secrete glucocorticoids, but in case of an ACTH-dependent disease, androgens are also elevated. Hypokalemic metabolic alkalosis may be seen due to excess aldosterone. Rapid onset is seen in carcinoma associated with Cushing’s syndrome. Glucocorticoids inhibit GnRH pulsatility with decreased secretion of FSH and LH causing menstrual irregularities and decreased libido. There is greater frequency of infections because of inhibition of immune function by glucocorticoids which decrease the number of CD4 cells, NK cells, inhibit the transmigration of WBCs across the endothelium and inhibit cytokine synthesis.

Physiologically, cortisol levels are highest in the morning with lowest levels at midnight. In Cushing’s syndrome, the circadian rhythm is lost. Initial testing is for free cortisol levels and low dose dexamethasone suppression. Late night salivary cortisol, serum and urinary free cortisol will be elevated. All cases of Cushing’s syndrome will show lack of suppression of cortisol levels to low dose (2 mg) dexamethasone while all healthy adults will show suppression.

ACTH levels, high dose (8 mg) dexamethasone suppression test (DST) and CRH stimulation test can be used to differentiate between causes of Cushing’s syndrome. ACTH levels will differentiate between ACTH dependent (high ACTH) and ACTH independent (low ACTH) types. High dose DST differentiates pituitary causes (suppresses) from adrenal tumor or adenoma, ectopic and exogenous steroid use (does not suppress). CRH stimulation physiologically causes a rise in serum ACTH and cortisol levels. Pituitary tumors respond to CRH with rise in ACTH and cortisol above baseline . In adrenal Cushing’s, the low ACTH and high cortisol levels at baseline are not affected by CRH injection. In ectopic Cushing’s, the high ACTH and high cortisol levels at baseline are usually not altered by the CRH administration.

The bilateral inferior petrosal sinus sampling (BIPSS) test samples blood surrounding the pituitary, allowing for accurate diagnosis of pituitary origin of high ACTH. Adrenal or lung lesions can be visualized by CT or MRI while pituitary MRI is recommended for evaluating Cushing’s disease.

Treatment depends on underlying conditions like adrenalectomy in adrenal adenomas, treating ectopic tumors with resection, chemotherapy etc. Cushing’s disease is treated with transsphenoidal surgery. Cortisol levels are decreased by ketoconazole, metyrapone, mitotane and etomidate. ACTH modulators include dopamine agonists like bromocriptine, octreotide and retinoic acid. Glucocorticoid receptor blockers like mifepristone are also used.

v) Hyperaldosteronism: It may be primary or secondary. Primary hyperaldosteronism results from aldosterone excess due to adrenal tumor secreting aldosterone, adrenal hyperplasia or autonomous aldosterone production. If primary hyperaldosteronism is caused by an adenoma, it is known as Conn’s syndrome. Primary hyperaldosteronism is associated with low renin levels and is called hyporeninemic hyperaldosteronism. Secondary hyperaldosteronism results from pathological activation of the renin-angiotensin-aldosterone system (RAS) seen in renal artery stenosis, coarctation of the aorta, renin secreting tumors, diuretics, Gittleman’s syndrome and Bartter’s syndrome. It is a hyperreninemic hyperaldosteronism.

Mutations in cell membrane potassium channels resulting in increased sodium permeability have been associated with primary hyperaldosteronism. Hyperaldosteronism is associated with hypertension, hypokalemia, hypernatremia, metabolic alkalosis, muscle weakness, cramps, insulin resistance, cardiac fibrosis etc. Hypervolemia occurs without peripheral edema due to effects of ANP (atrial natriuretic peptide). Secondary hyperaldosteronism may be normotensive or hypertensive and present with clinical features of the underlying condition like heart failure.

Diagnosis is by serum aldosterone and renin levels. Titers of angiotensin II type I receptor autoantibodies are elevated in primary hyperaldosteronism. Primary hyperaldosteronism (PA) is confirmed by captopril challenge test, intravenous saline infusion test, fludrocortisone suppression test or oral salt suppression test. They show elevated aldosterone levels in spite of salt and fluid loading in PA. Captopril challenge test shows high serum aldosterone and renin suppression in PA. Adrenal vein sampling or AVS involves sampling from the right and left adrenal veins, as well as from the inferior vena cava for measurement of aldosterone and cortisol concentrations. In unilateral adenoma or hyperplasia, aldosterone concentration in the same sided vein will be high while the contralateral side will be suppressed. CT or MRI can be used to detect adrenal masses

Treatment is by unilateral adrenalectomy in adrenal adenoma and unilateral adrenal hyperplasia. Radiofrequency ablation is an alternative. Medical therapy is preferred in bilateral adrenal hyperplasia with mineralocorticoid receptor antagonists such as spironolactone or eplerenone (does not have anti-androgen effects like gynecomastia). Some cases respond to low dose glucocorticoids as they decrease ACTH by negative feedback. Secondary hyperaldosteronism is treated by management of the underlying condition.