Why is metabolic alkalosis common in patients with Cushing's syndrome?

From the Guidelines

Metabolic alkalosis is a common finding in patients with Cushing's syndrome due to the mineralocorticoid effects of excess cortisol, which leads to increased sodium reabsorption, potassium excretion, and subsequent hypokalemia, all contributing to an alkalotic state. The pathogenesis of hypertension in Cushing's syndrome, as described in the study by 1, involves activation of mineralocorticoid receptors by cortisol, which plays a crucial role in the development of metabolic alkalosis. Key factors contributing to this condition include:

• Excessive cortisol levels activating mineralocorticoid receptors
• Increased sodium reabsorption and potassium excretion in the distal tubules of the kidneys
• Hypokalemia stimulating hydrogen ion secretion to maintain electrical neutrality, leading to alkalosis
• Cortisol promoting bicarbonate reabsorption in the kidneys and increasing acid excretion, further contributing to the alkalotic state
• Volume expansion and hypertension often seen in Cushing's syndrome, increasing bicarbonate reabsorption

Management of metabolic alkalosis in Cushing's syndrome involves treating the underlying cause, whether it's a pituitary adenoma, adrenal tumor, or exogenous glucocorticoid use, while monitoring and correcting electrolyte imbalances, particularly potassium levels, as noted in the context of resistant hypertension in Cushing's syndrome 1. Potassium supplementation may be necessary to prevent gastrointestinal irritation, with doses typically ranging from 40-100 mEq daily, divided into multiple doses. Understanding this pathophysiology helps clinicians anticipate and address the metabolic alkalosis that frequently accompanies Cushing's syndrome.

From the Research

Metabolic Alkalosis in Cushing's Syndrome

Metabolic alkalosis is a common finding in patients with Cushing's syndrome, particularly those with ectopic ACTH secretion. Several studies have investigated the relationship between Cushing's syndrome and metabolic alkalosis:

• A case report published in 2015 2 described a patient with ectopic Cushing's syndrome who developed severe metabolic alkalosis, which was successfully treated with acetazolamide.
• A study published in 2002 3 found that hypokalemia was more prevalent in patients with ectopic Cushing's syndrome than in those with other causes of Cushing's syndrome, and that there was a significant relationship between 24-hour urine cortisol excretion and the presence of hypokalemia.
• Another study published in 2022 4 found that ketoconazole, a medication used to treat Cushing's disease, was effective in controlling hypercortisolism in 66% of patients, but that hypokalemia was a frequent metabolic effect, occurring in 30% of patients.

Pathophysiology of Metabolic Alkalosis in Cushing's Syndrome

The pathophysiology of metabolic alkalosis in Cushing's syndrome is complex and involves several factors:

• Excess cortisol can act as a mineralocorticoid, leading to sodium retention and potassium excretion, which can contribute to metabolic alkalosis 3.
• The kidney plays a crucial role in maintaining acid-base balance, and factors such as effective arterial blood volume, glomerular filtration rate, chloride, and potassium can affect bicarbonate reabsorption and regeneration 5.
• Metabolic alkalosis can be maintained by factors such as volume contraction, hypokalemia, hypochloremia, and aldosterone excess 5.

Clinical Implications

Metabolic alkalosis can have significant clinical implications, including:

• Severe hypokalemia, which can lead to muscle weakness, fatigue, and cardiac arrhythmias 2, 3, 4, 6.
• Respiratory complications, such as shortness of breath and respiratory failure 6.
• Diagnostic dilemmas, as metabolic alkalosis can be a presenting feature of Cushing's syndrome 6.