This article is part of a series on USMLE Step 1 Study.
I haven’t seen too much about this on USMLE forums, so I thought I would write a quick post on it.
Black licorice contains the active ingredient glycyrrhizin, which is metabolically active.
Glycyrrhizin INHIBITS the activity of 11-Beta hydroxysteroid dehydrogenase. 11-BHSD, meanwhile, catalyzes the conversion of cortisol to cortisone.
Finally, it’s important to know that cortisone is an inactive metabolite of cortisol. So, the effect of licorice ingestion resembles that which would result simply from having more cortisol on board.
Why does more cortisol cause hypertension? Well, cortisol is active not just at the glucocorticoid receptor, but also at the mineralocorticoid receptor, which is classically reserved for aldosterone. Consequently, 11-BHSD blockade substantially increases mineralocorticoid activity, and thus increases blood pressure. Excess licorice consumption may then be said to cause the syndrome of apparent mineralocorticoid excess, also known as pseudohyperaldosteronism.
How does aldosterone increase blood pressure? Binding at the mineralocorticoid receptor in kidney epithelial cells drives the expression of the basolateral Na/K ATPase, as well as expression of the epithelial sodium channel (ENaC). So, more sodium is reabsorbed in the principal cells of the late distal convoluted tubule and collecting duct. Water follows sodium, and so blood pressure is supported.
Another important consequence of sodium reabsorption is potassium wasting. As sodium enters the bloodstream, potassium is excreted by the Na/K ATPase. This leads me to what might be the most important consequence of glycerrhizin ingestion: electrolyte balance. Hypokalemia can cause generalized muscle weakness as well as lethal arrhythmias. So, look for these complications in a USMLE question involving a patient who eats too much licorice.
Saline-resistant metabolic alkalosis
Hyperaldosteronism, whether true or false, causes metabolic alkalosis. This is because aldosterone stimulates activity at the H+/K+ exchanger in the alpha-intercalated cells of the late distal convoluted tubule and collecting duct. Aldosterone also directly stimulates the H+ ATPase of these cells. The result of both activities is to encourage H+ excretion, which will complex ammonia in the collecting duct. So, alkalosis results.
In the case of apparent mineralocorticoid excess, the alkalosis is deemed “chloride-resistant”. I always thought the terms chloride-resistant and chloride-responsive were extremely confusing. The terms saline-resistant and saline-responsive are often used instead, and I think these terms are much better.
In any case, the alkalosis caused by AME, and by any other scenario with constitutive mineralocorticoid activity (Conn syndrome, Liddle syndrome, Cushing’s disease) is saline-unresponsive, simply because administration of saline would not address the underlying cause of the alkalosis. Consider on the other hand saline-responsive alkalosis:
Saline-responsive alkalosis simply refers to an alkalosis that can be successfully-treated by volume expansion. The most basic example would be contraction alkalosis. Contraction alkalosis is an alkalosis that results from plain-water loss. This might be seen in a burn victim, for example. Why does plain water loss cause alkalosis?
For one, as water is removed, bicarbonate simply becomes more concentrated. This is a bit of a fudgy explanation, and if you want me to go into it further and explain what’s really happening there, please leave a comment and ask. A second reason is that contraction activates the RAAS system, and angiotensin II drives the Na+/H+ transporter at the early proximal tubule. More Na+ is taken in, to support blood pressure; meanwhile, though, H+ is sent into the lumen; this H+ then complexes with HCO3- and allows bicarbonate reabsorption. More bloodstream bicarbonate leads to alkalosis. Finally, aldosterone is hyperactive in plain water loss, leading to distal sodium uptake at the expense of H+.
Administration of saline in this situation would address the problem. More volume would dilute the bicarb, diminishing the alkalosis (again fudgy). Further, volume expansion would decrease RAAS activity and decrease angiotensin II, thus allowing more bicarb excretion in the early proximal tubule. Finally, aldosterone secretion would slow down.
If you’re asking yourself whether or not an alkalosis is saline-responsive, simply examine the underlying pathophysiology. Knowledge of the mechanisms at hand make it clear that the alkalosis caused by pseudohyperaldosteronism would not be saline-responsive. Addition of saline wouldn’t reduce the mineralocorticoid activity. Only switching to a healthier snack would solve the issue.
Glycyrrhizin in pharmacology
Knowledge of this system might be useful in situations beyond treatment of candy addicts. Carbenoxolone, a medication for peptic ulcer disease, is derived from glycyrrhetinic acid, a compound related to glycyrrhizin. Carbenoxolone therapy could produce side effects similar to those seen in licorice ingestion.
Why does carbenoxolone treat peptic ulcer disease? I’m pretty sure the benefit has nothing to do with 11-BHSD inhibition (in fact, increasing cortisol levels might actually be damaging, since glucocorticoids are known to cause, rather than treat, peptic ulcer disease).
Rather, carbenoxolone directly inhibits the enzymes that degrade prostaglandins PGE-2 and PGF-2α. So, carbenoxolone treatment causes increased levels of these prostaglandins. And, recall that prostaglandins are protective to the gut. NSAIDs cause GI damage by reducing prostaglandin levels, and misoprostol, a synthetic prostaglandin mimetic, is used to treat peptic ulcer disease.
So, getting really imaginative, we could look out for mineralocorticoid excess in someone receiving treatment for peptic ulcer disease. Now, I certainly don’t think you’ll be held responsible for carbenoloxone on the USMLE exam. But I like looking for connections like these, because this style of connection-oriented thinking certainly is tested on the USMLE.