Licorice and Hypokalemia

I’ve been asked about licorice and hypokalemia. So here’s the short answer. The adrenal cortex make two classes of steroids – glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Steroid hormones initiate their effect by activating an intracellular receptor. I’ll limit my discussion to the effect of aldosterone on the principal cell of the cortical collecting tubule. There aldosterone stimulates the Na-K-ATPase (directly or indirectly). This results in sodium reabsorption and potassium secretion. Excess of aldosterone leads to hypertension (because of the sodium retention) and hypokalemia because of excess potassium secretion and consequent urinary loss. It also causes increased acid excretion and thus metabolic alkalosis via a mechanism I have omitted.

The kidney could distinguish cortisol from aldosterone by having mineralocorticoid specific receptors which it has; but most of the steroid receptors are nonspecific responding to either cortisol or aldosterone. In a failure of Occam’s razor God decided to deal with this problem using a more complicated scheme. This is not the only time God forsook Occam when designing the kidney – bicarbonate reabsorption is another example.

To ensure that every time you get a surge of cortisol you don’t get a mineralocorticoid response God (you can substitute evolution if it makes you happier) created 11-beta-hydroxysteroid dehydrogenase. This enzyme metabolizes cortisol to cortisone which does not activate the renal steroid receptors preventing an inappropriate mineralocorticoid response.

Licorice contains glycyrrhizic acid which inhibits 11-beta-hydroxysteroid dehydrogenase thus allowing cortisol to exert an aldosterone like effect; ie cortisol is not metabolized to cortisone and thus stimulates sodium retention, potassium wastage, and acid excretion. A licorice glutton presents with high blood pressure and hypokalemic metabolic alkalosis. He looks just like a patient with primary hyperaldosteronism, but when aldosterone levels in the blood are measured they are zero. A history of large consumption of licorice makes the diagnosis.

Only natural licorice has this effect because only it contains glycyrrhizic acid. Most of the licorice sold has artificial flavoring and thus does not convey risk. An interesting example of organic being worse than artificial. How much natural licorice consumption will cause this syndrome is not known, but it’s a lot. So if you like natural licorice and you take it in moderate amounts there’s nothing to worry about.

Since biology operates under the rule that anything that can go wrong will go wrong, patients have been described with a genetic defect in 11-beta-hydroxysteroid dehydrogenase. Thus they present with a syndrome identical to that caused by licorice gluttony only they haven’t taken licorice. With all the perils nature hurls at us it’s remarkable that life exists on Earth.

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