The Cortisol-to-Cortisone Shunt
We will briefly review a vital pathophysiology concept called the cortisol-to-cortisone shunt.
The two isoforms of 11beta-hydroxysteroid dehydrogenase play essential roles in the cortisol-to-cortisone shunt. 11beta-hydroxysteroid dehydrogenase type 1 converts inactive cortisone to active cortisol in the liver, which subsequently binds to its hepatic glucocorticoid receptor 11beta-hydroxysteroid dehydrogenase type 2 converts active cortisol to inactive cortisone at the level of the kidney. This protects the renal mineralocorticoid receptor from direct activation by cortisol, under normal physiologic conditions.
Next, let us talk about the concept of physiologic cortisol resistance.
Cortisol can bind both hepatic glucocorticoid and renal mineralocorticoid receptors, and indeed under normal physiological conditions, plasma levels of cortisol are up to 1,000-fold higher than that of aldosterone. 11beta-hydroxysteroid dehydrogenase type 2 inactivates physiological concentrations of cortisol and thus protects the renal mineralocorticoid receptor from direct activation by cortisol.
Next, we will compare the two major isoforms of 11BHSD2
This table compares the various isoforms of 11beta-hydroxysteroid dehydrogenase. It is essential to bear in mind that 11beta-hydroxysteroid dehydrogenase type 1, which is predominantly in the liver, bone and adipose, primarily increases circulating levels of active cortisol. On the other hand, 11beta-hydroxysteroid dehydrogenase type 2, which is predominantly in the kidney, sweat and salivary glands, promotes physiologic cortisol resistance at the renal mineralocorticoid receptor, by inactivating cortisol into cortisone
Now we will review some essential clinical pearls
Patients in Addisonian crises do not require concomitant mineralocorticoid administration if their total daily dose of glucocorticoid is greater than or equal to 50mg of hydrocortisone, or steroid equivalent. Supraphysiologic doses of hydrocortisone, given during an emergency, will activate the renal mineralocorticoid receptor and provide additional “mineralocorticoid coverage.” There is an important caveat to bear in mind, patients managed with dexamethasone will require additional mineralocorticoid coverage irrespective of the dose of dexamethasone used. This is because there is limited binding of dexamethasone to renal mineralocorticoid receptors.
For this reason, if a patient with acute Addisonian crises is managed with dexamethasone, irrespective of the steroid equivalent dose of dexamethasone given, mineralocorticoids will need to be administered.
In Apparent mineralocorticoid excess or licorice ingestion, there is an impaired activity of 11beta-hydroxysteroid dehydrogenase type 2, the enzyme responsible for converting active cortisol to inactive cortisone at the level of the kidney. This will be covered in a separate presentation on endocrine causes of resistant hypertension.
In both ACTH-dependent and ACTH-independent Cushing’s, 11beta-hydroxysteroid dehydrogenase type 2 is overwhelmed by an abundance of circulating cortisol, leading to reduced deactivation of cortisol to cortisone in the kidney. This defect results in a state of cortisol excess, which is again similar to what is seen in apparent mineralocorticoid excess (AME) or even licorice ingestion.
The excess cortisol, therefore, stimulates the mineralocorticoid receptor in the kidney. This increased mineralocorticoid action leads to renal potassium wasting and sodium retention. This explains the reason why patients with Cushing’s syndrome may develop significant hypokalemia and hypertension.
This is the end of the presentation on the cortisol-to-cortisone shunt