Etiology, Pathogenesis, and Epidemiology

Hypertension is present in 80% of patients with Cushing syndrome (less often when caused by exogenous synthetic corticosteroid administration) and results from an increase in both cardiac output and total peripheral resistance. The mechanisms underlying these hemodynamic changes are complex.²

In some patients, Cushing syndrome may be caused by concurrent overproduction of mineralocorticoids such as aldosterone, 11-deoxycorticosterone, and corticosterone. Although cortisol is capable of binding the mineralocorticoid receptor (MR), usually it does not because of the renal enzyme 11β-hydroxysteroid dehydrogenase type 2 (β-HSD2), which inactivates cortisol to corticosterone, thereby preventing its binding to the MR. However, in the patient with low β-HSD2 activity or extremely high cortisol levels (e.g., ectopic ACTH syndrome), there may be sufficient excess cortisol that MR binding occurs. Furthermore, alterations in oxidation-reduction (redox) status, potentially triggered by metabolic disturbance and cytokine activation, may alter the effects of corticosteroids at the MR function, converting cortisol from its receptor antagonist role seen in health to an agonist in inflammatory states.³

Subsequent cardiac and vascular MR activation may foster adverse cardiovascular inflammatory, hypertrophic, and fibrotic changes. Inhibition of the vasodilator nitric oxide (NO) by cortisol may also contribute to the hypertension, along with enhanced pressor responsiveness to catecholamines and angiotensin II (Ang II), heightened cardiac inotropic sensitivity to β-adrenergic stimulation, and increased plasma volume.² If affected, the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) are suppressed, even though circulating levels of renin substrate are increased. Some have proposed that elevated levels of vasoconstrictor hormones (vasopressin, endothelin-1, thromboxane, insulin) or subnormal concentrations of vasodilator systems (kallikrein-kinins, prostaglandins) contribute to the hypertension of Cushing syndrome, but the evidence is weak.² The vasodilator atrial natriuretic peptide (ANP) is elevated in Cushing syndrome, although biologic responses to ANP are impaired; in theory, ANP resistance could also contribute to the hypertension.⁴ Adipokines, including leptin and resistin, plus release of proinflammatory cytokines (tumor necrosis factor α, interleukin-6) may also contribute to the increased cardiovascular risk observed in Cushing syndrome.⁵

Successful treatment of Cushing disease or removal of an underlying adrenal adenoma usually results in BP reduction and partial return of the previously impaired nocturnal fall in arterial pressure, although hypertension persists in a sizable minority of patients.

Clinical Manifestations

Clinical features in Cushing disease result from elevated circulating levels of pro-opiomelanocortin hormones, including ACTH (increased pigmentation) and cortisol (central adiposity, insulin resistance or diabetes, muscle wasting/weakness, plethoric facies, purple striae [Fig. 41-2], easy bruising, osteoporosis, psychological problems). In some patients, androgen effects are observed (hirsutism, acne, virilization) and may be striking in those with adrenal adenoma or carcinoma. Ectopic ACTH syndrome caused by small cell bronchial carcinoma or other tumors (e.g., bronchial or thymic carcinoid) presents typically as a wasting disease, often with hyperpigmentation and hypokalemia. Hypertension is often associated with left ventricular hypertrophy, which can be disproportionate to BP, and frank cardiac failure is occasionally the presenting feature.⁶

Pseudo–Cushing syndrome can occur with a sustained high intake of alcohol by inducing augmented cortisol secretion and reduced cortisol metabolism caused by hepatic damage. Routine diagnostic tests are unable to distinguish alcoholic pseudo–Cushing syndrome from true Cushing syndrome, and reassessment after alcohol withdrawal may be required.⁷

Depression is associated with increased cortisol level. In obesity, the plasma clearance rate of cortisol is increased, leading to a slightly elevated production rate of cortisol, although plasma levels are normal. Careful psychological and physical screening will usually differentiate these patients from those with Cushing syndrome.

Diagnosis

An elevated urinary free cortisol excretion (or early-morning cortisol-creatinine ratio) and absence of suppression of 8 am plasma cortisol after a low dose of dexamethasone (1 mg at midnight) are the usual initial tests. Screening may also incorporate checks for elevated late-night salivary cortisol.

Further key investigations include computed tomography (CT) and magnetic resonance imaging (MRI) of the pituitary and adrenal glands and plasma ACTH (suppressed in cortisol-secreting adrenal tumors but elevated in ectopic ACTH syndrome). Further tests will depend on findings at this point. A high-dose dexamethasone suppression test partially suppresses ACTH in patients with pituitary tumors but not with ectopic ACTH. The response of plasma ACTH to a dose of corticotropin-releasing hormone may also help distinguish pituitary from adrenal or ectopic tumors. Simultaneous bilateral inferior petrosal sinus sampling for ACTH measurements is useful in differentiating Cushing disease from ectopic ACTH syndrome, when the previous tests give equivocal results. Imaging of the thorax, abdomen, and pelvis is indicated when ACTH-producing carcinoid tumors are suspected.

Treatment and Prognosis

Untreated, patients with Cushing syndrome have 50% 5-year mortality because of cardiovascular risk from hypertension, along with glucose intolerance and insulin resistance, hyperlipidemia, obesity, and elevated fibrinogen levels.⁸

Cure rates in treatment of Cushing disease are 80% to 90% by selective removal of a pituitary microadenoma and 50% for pituitary macroadenomas. Cushing syndrome caused by adrenal adenoma is almost always cured by unilateral adrenalectomy. However, in adrenal carcinoma, median survival is less than 2 years. The prognosis is also poor when Cushing syndrome results from ectopic ACTH syndrome caused by small cell bronchial carcinoma. If the ACTH-producing tumor is benign and can be located, however, removal usually leads to cure. After cure of Cushing syndrome, approximately 30% of patients have persistent hypertension.⁹

In managing the hypertension from Cushing syndrome, no evidence supports the use of any antihypertensive class over another. Potassium-losing diuretics can exacerbate both hypokalemia and glucose intolerance, whereas potassium-sparing diuretics, usually in combination with other antihypertensive agents, may correct hypokalemia and reduce edema while lowering BP.

The prevalence of pheochromocytoma in patients with hypertension in general medical outpatient clinics is 0.1% to 0.6%.¹¹ As with a firm diagnosis, however, the prevalence may be considerably higher because many people die with unsuspected pheochromocytoma.¹²

Pheochromocytomas can be sporadic or familial. Whereas sporadic cases are usually unicentric and unilateral, familial pheochromocytomas are often multicentric and bilateral. Familial pheochromocytomas are the result of a germ-line mutation in one of five genes: the RET gene leading to multiple endocrine neoplasia type 2; the von Hippel–Lindau (VHL) gene, which causes the von Hippel–Lindau syndrome; the neurofibromatosis type 1 (NF1) gene resulting in von Recklinghausen disease; and the genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB and SDHD), which are associated with familial paragangliomas and pheochromocytomas. More recently, mutations in KIF1Bβ, TMEM127, and MAX genes have also been associated with pheochromocytoma.¹³

Table 41-1 outlines clinical features of syndromes associated with pheochromocytoma. For patients with apparently sporadic pheochromocytomas, an underlying germ-line mutation of the genes mentioned may be present in about 20% of cases and should be considered in younger patients (<50 years) and those with multifocal or extra-adrenal tumors.^10,14 Patients found to harbor a germ-line mutation need to be identified for appropriate guidance of medical management for them and their families.

Clinical Manifestations

Clinical features of pheochromocytoma reflect episodic or continuous overproduction of catecholamines and depend in part on which catecholamine dominates. Symptoms include headache, sweating, palpitations, anxiety, and pallor (Fig. 41-4).¹⁵

Related posts:

Management of Refractory Heart Failure Membranous Nephropathy Plasma Exchange Recurrent Disease in Kidney Transplantation Immunologic Principles in Kidney Transplantation Gastroenterology and Nutrition in Chronic Kidney Disease

Stay updated, free articles. Join our Telegram channel

Join