How is potassium affected in Cushing's syndrome?

Potassium in Cushing's Syndrome

Hypokalemia occurs in approximately 25-57% of patients with Cushing's syndrome, with severity directly correlated to cortisol levels rather than ACTH levels, and is most pronounced in ectopic ACTH syndrome where it can be severe enough to cause life-threatening cardiac arrhythmias. 1, 2

Pathophysiology of Hypokalemia in Cushing's Syndrome

The mechanism of potassium depletion in Cushing's syndrome involves cortisol acting as a mineralocorticoid when present in excess. 1, 3 This occurs through:

• Saturation of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme that normally inactivates cortisol at the renal tubule, allowing cortisol to inappropriately access mineralocorticoid receptors 1, 3
• The ratio of tetrahydrocortisol metabolites to tetrahydrocortisone is significantly elevated in Cushing's syndrome (1.81 vs 0.81 in controls), indicating defective 11β-HSD2 activity 3
• This ratio is even higher in ectopic ACTH syndrome (4.12) compared to pituitary-dependent Cushing's (1.49), and inversely correlates with serum potassium levels (r = -0.57) 3

Clinical Prevalence and Severity

Hypokalemia is significantly more common in ectopic ACTH syndrome (57% of patients) compared to other causes of Cushing's syndrome. 1 Key findings include:

• In Cushing's disease (pituitary-dependent), hypokalemia affects approximately 25.64% of patients 2
• Eight of nine patients with 24-hour urinary cortisol >6000 mcg/24 hr had hypokalemia 1
• There is a significant relationship between 24-hour urinary cortisol excretion and presence of hypokalemia (P = 0.003) 1
• Cortisol levels are negatively correlated with plasma potassium: 08:00 cortisol (r = -0.344), midnight cortisol (r = -0.435), and 24-hour urinary free cortisol (r = -0.281) 2

ACTH vs. Cortisol Relationship

Plasma ACTH levels do not correlate with hypokalemia severity, while cortisol levels show strong inverse correlation with potassium. 1, 2 This indicates:

• High cortisol level is the principal cause of hypokalemia in Cushing's syndrome, not ACTH level 1, 2
• No significant correlation exists between plasma ACTH and potassium levels (08:00: r = -0.093, midnight: r = -0.184) 2
• Plasma ACTH levels were similar between patients with hypokalemia and normokalemia 2

Associated Hypertension

Hypertension occurs in 70-90% of patients with Cushing's syndrome, with the main mechanism being overstimulation of mineralocorticoid receptors by cortisol. 4 Clinical characteristics include:

• Hypertension was present in 78% of ectopic ACTH patients, with 45% requiring 3 or more antihypertensive drugs 1
• The pathogenesis involves activation of mineralocorticoid receptors, making standard antihypertensive agents (renin-angiotensin system blockers, calcium channel antagonists, adrenergic blockers, diuretics) often ineffective 4
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are the most effective antihypertensive agents in Cushing's syndrome 4, 5

Screening Considerations

When evaluating for Cushing's syndrome as a cause of secondary hypertension, the 2024 ESC guidelines recommend: 4

• 24-hour urinary free cortisol as a screening test
• Low-dose dexamethasone suppression test as an alternative
• Reviewing prior potassium levels, as hypokalaemia increases the likelihood of coexistent endocrine hypertension 4

Management Implications

Target potassium levels should be 4.0-5.0 mEq/L to prevent cardiac complications, as both hypokalemia and hyperkalemia adversely affect cardiac excitability and conduction. 4, 6 Management considerations include:

• Correction of potassium deficits may require supplementation of both magnesium and potassium 4
• In patients with severe hypokalemia and Cushing's syndrome, definitive treatment requires addressing the underlying hypercortisolism through surgical resection or medical therapy with steroidogenesis inhibitors 5
• Mineralocorticoid receptor antagonists serve dual purposes: treating hypertension and preventing hypokalemia 4, 5

Common Pitfall

Failing to recognize that hypokalemia in Cushing's syndrome is cortisol-mediated rather than ACTH-mediated can lead to inadequate treatment strategies. The focus should be on controlling hypercortisolism rather than simply replacing potassium, as potassium supplementation alone will be ineffective without addressing the underlying cortisol excess. 1, 2