Diagnosis of Cushing syndrome
Clinical presentation of Cushing syndrome is varied. In fact, in addition to hypertension, classic features such as central obesity, moon faces, buffalo hump, muscle wasting, and truncal striae can be subtle or entirely abscent.1,16
Furthermore, presentation can often mimic classic signs of the ever-prevalent metabolic syndrome.13,23 Nevertheless, urologists should appreciate that hypogonadal hypogonadism is not uncommon in patients with Cushing,13,16 while both urologists and nephrologists must be aware that nearly half of patients with Cushing syndrome develop urolithiasis.24
While diagnosis of hypercortisolemia is relatively straightforward, identification of its etiology can be one of the most complex tasks faced by modern endocrinologists. Briefly, an overnight low-dose dexamethasone suppression test, late night salivary cortisol, or 24-hour urinary free cortisol can serve as screening modalities to identify pathologic glucocorticoid elevations.25
The former strategy involves administration of 1 mg of dexamethasone at 11pm prior to a morning lab draw, and assessing if am cortisol is suppressed below a generally agreed upon cutoff of 5 mcg/dL.16 It is important to note that urinary free cortisol levels may not be sufficiently sensitive to screen patients with adrenal incidentalomas, 25 while late night salivary cortisol is a newer test with acceptable test characteristics that is gaining clinical traction.16, 26
Once hypercortisolemia is identified, its etiology must be established. Because of the complexity of this undertaking, some experts believe that endocrinologists at tertiary centers should be charged with the task.19
In short, ACTH levels are determined to separate patients with ACTH-dependent from those with ACTH-independent causes. In the latter group, adrenal imaging is obtained. The greatest diagnostic challenge lies in differentiating patients with Cushing disease from those with ectopic ACTH syndrome, since non-functional microadenomas of the pituitary are common and up to 50% of functional microadenomas are difficult to identify on imaging.17, 27 As such, petrosal sinus sampling for measurement of ACTH concentrations following CRH stimulation has largely become the test of choice.17, 28.
Treatment of Cushing syndrome
Cushing disease is treated with surgical resection or radiation of the pituitary lesion.17, 29 Bilateral adrenalectomy is usually reserved for when at least one attempt to treat pituitary pathology has failed.30-32
In these instances, the patient must be counseled regarding life-long mineralocorticoid/glucocorticoid supplementation and Nelson-Salassa syndrome (occurring in 8-30% of patients), where bilateral adrenalectomy results in accelerated growth of the pituitary lesion, producing complications such as compression of the ocular chiasm and elevation in intracranial pressure.17, 33
For patients with ectopic ACTH syndrome, identification and resection of the primary malignancy is often therapeutic. Nevertheless, bilateral adrenalectomy remains an option for those with unresectable disease and acceptable life-expectancy.17, 34 ACTH independent disease stemming from an adrenal mass is treated with total or partial adrenalectomy.35
Primary hyperaldosteronism, described by Jerome Conn in mid-20th century, nearly always results from disregulated production of aldosterone by the adrenal gland(s) outside of control of the renin-angiotensin-aldosterone system (RAAS) (Figure 1).
As such, diagnosis is made by documenting an elevated serum aldosterone level in the setting of a reduced renin level. 36-38 An aldosterone (ng/dL) to renin (ng/mL/hr) ratio of ≥20 (some suggest ≥30) in the setting of an aldosterone concentrations above ≥15 ng/mL are strongly suggestive of Conn syndrome, and confirmatory testing is initiated at this point.39-42
Hyperaldosteronism nearly uniformly results in hypertension, and the condition is present in 5% of hypertensive patients.40, 43 Hypokalemia, albeit classically associated with Conn syndrome, is present in only a minority of contemporary patients and, thus, normal potassium levels should not rule out diagnosis of hyperaldosteronism.36
Due to a rise of blood pressure with elevated aldosterone levels in nearly all patients, normotensive individuals with adrenal adenomas who are not taking antihypertensive medications do not require an evaluation for primary aldosteronism. In fact, only 1% of adrenal adenomas exhibit excess aldosterone production.44
Once the diagnosis of hyperaldosteronism is made, identification of its exact etiology is critical in those patients who are surgical candidates (Figure 1). By far the most common causes of Conn syndrome are bilateral adrenal hyperplasia (also known as idiopathic hyperplasia) and aldosterone-secreting adrenal adenoma, accounting for 60% and 35% of the condition, respectively.36 Because adrenalectomy is therapeutic only when unilateral adrenal hypersecretion is established, bilateral adrenal hypersecretion must be ruled out even if adrenal imaging documents a unilateral adrenal mass.
As such, findings on CT or MRI cannot completely dictate management for the following reasons: (1) some 20% of aldosterone-producing adenomas measure <1cm and may not be detectable on imaging (2) non-functional adrenal incidentalomas may be present in patients with bilateral adrenal hyperplasia in some 25% of cases.45
Thus, many experts recommend routine adrenal vein sampling for all patients with Conn Syndrome who are otherwise appropriate candidates for adrenalectomy. Through femoral vein access, blood from the vena cava, right adrenal vein, and left adrenal vein are tested for cortisol and aldosterone concentrations. Cortisol concentrations serve as a quality metric of appropriate adrenal vein canulation, since cortisol levels in the adrenal vein are higher than that in the inferior vena cava. Also, cortisol concentrations are used for normalization of aldosterone levels.
As such, lateralization of aldosterone is determined by the following formula: (Aldosteronedominant/Cortisoldominant)/(Aldosteronenon-dominant/Cortisolnon-dominant).1, 46 If normalized aldosterone levels are >2x higher from one adrenal vein than from its contralateral counterpart, adrenalectomy of the hypersecreting adrenal gland should be considered.45
In patients in whom aldosterone hypersecretion does not lateralize or those who are not surgical candidates, aldosterone receptor blockers such as spironolactone and eplerenone are employed.38 Some rare forms of familial hyperaldosteronism can be corrected with glucocorticoid supplementation, as in these patients mineralocorticoid secretion is modulated by ACTH.47