A 66-year-old woman is brought to the emergency department due to agitation, restlessness, and poor sleep. Over the past 3 months, she has had headaches and generalized weakness. She has gained 6.3 kg (13.9 lb) without a change in diet. The patient's medical history is unremarkable, and she takes no medications. She has smoked a pack of cigarettes daily for the past 50 years but does not use recreational drugs or alcohol. Blood pressure is 160/110 mm Hg and pulse is 90/min. Laboratory results are as follows:
| Sodium | 140 mEq/L |
| Potassium | 3.2 mEq/L |
| Chloride | 102 mEq/L |
| Bicarbonate | 28 mEq/L |
| Blood urea nitrogen | 12 mg/dL |
| Creatinine | 0.9 mg/dL |
| Glucose | 205 mg/dL |
| Calcium | 9.4 mg/dL |
Which of the following is the most likely cause of this patient's hypertension?
Secondary causes of hypertension | |
Condition | Clinical clues/features |
Renal parenchymal disease |
|
Renovascular disease |
|
Primary hyperaldosteronism |
|
Obstructive sleep apnea |
|
Pheochromocytoma |
|
Cushing syndrome |
|
Thyroid disease |
|
Primary hyperparathyroidism |
|
Coarctation of the aorta |
|
This patient's hypertension, neuropsychiatric disturbances (eg, agitation, restlessness), hyperglycemia, and weight gain suggest hypercortisolism (Cushing syndrome). Other potential manifestations include proximal muscle weakness, central adiposity with enlargement of the supraclavicular and dorsal neck fat pads, abdominal striae, facial rounding, and ecchymosis. Most cases of Cushing syndrome are due to exogenous glucocorticoid intake, ectopic ACTH production (eg, small cell lung cancer), or ACTH-producing pituitary adenomas (Cushing disease). Primary adrenal hypercortisolism (eg, adrenal adenoma) is less common. Associated hypokalemia, most often seen with ectopic ACTH-producing tumors, suggests severe hypercortisolism because very high levels of cortisol, a glucocorticoid, can overwhelm enzymatic inactivation and activate mineralocorticoid receptors, leading to hypokalemic metabolic alkalosis.
Initial testing for suspected hypercortisolism can include a 24-hour assay for urine free cortisol, a late-night salivary cortisol measurement, or a low-dose dexamethasone suppression test. Once hypercortisolism is established, an ACTH level can determine whether it is ACTH-dependent (Cushing disease, ectopic ACTH production) or ACTH-independent (adrenal disease, exogenous glucocorticoid intake). Patients with an elevated ACTH should have a high-dose dexamethasone suppression test to determine whether ACTH production is pituitary (dexamethasone suppresses cortisol) or ectopic (dexamethasone does not suppress cortisol).
(Choices B and F) Renovascular hypertension—which can be due to fibromuscular dysplasia (younger patients) or renal artery stenosis (older patients, particularly smokers)—is a common cause of secondary hypertension. Associated findings may include flash pulmonary edema and elevated creatinine, but weight gain and hyperglycemia are not seen.
(Choice C) Hypothyroidism can cause hypertension associated with weight gain and hyperglycemia. However, typical neuropsychiatric symptoms include fatigue and depression rather than agitation and restlessness; hypokalemia is not a common effect.
(Choice D) Pheochromocytoma is a catecholamine-producing adrenal medullary tumor that causes hypertension, headaches, neuropsychiatric symptoms (eg, anxiety, restlessness), and hyperglycemia. However, diaphoresis is typically present, and weight gain and hypokalemic metabolic alkalosis are not typical.
(Choice E) Aldosterone activates mineralocorticoid receptors but not glucocorticoid receptors (even at high levels). Therefore, primary hyperaldosteronism (ie, Conn syndrome) would cause hypertension and hypokalemia (mineralocorticoid activity), but features of hypercortisolism (eg, hyperglycemia, restlessness, significant weight gain) would not be expected.
Educational objective:
Cushing syndrome (ie, hypercortisolism) is characterized by hypertension, neuropsychiatric disturbances, hyperglycemia, and weight gain. Very high cortisol levels can activate mineralocorticoid receptors, leading to hypokalemic metabolic alkalosis.