Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

Abstract

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

Keywords: Japanese Kampo medicine; hypokalemia; licorice; pharmacokinetics; pseudoaldosteronism.

Figure 1

Molecular mechanism of licorice-induced pseudoaldosteronism. At the distal nephron, especially in the principal cells of the cortical collecting duct, type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) is inhibited by glycyrrhetinic acid-3-O-sulphate (GA3S) and possibly other metabolites, resulting in increased levels of cortisol (F), with similar affinity to the mineralocorticoid receptor as that of for aldosterone. Mineralocorticoid receptors (MR) induce stabilization of epithelial sodium channels (ENaC) on the apical side, which increases sodium reabsorption. This results in peripheral edema, hypertension, and lower plasma renin activity, whereas potassium is excreted as a cationic ion via the renal outer medullary potassium channel. The unbound fraction of metabolites under hypoalbuminemia enables them to efficiently reach 11β-HSD2. Older age is related to lower function of 11β-HSD2, and diuretics affect their phenotype. E, cortisone; AQP, aquaporin; ROMK, renal outer medullary potassium channel; GA, glycyrrhetinic acid; OAT, organic anion transporter.

Figure 2

Pharmacokinetics of glycyrrhizin-metabolites. Licorice, the root or stolon of Glycyrrhiza glabra or G. ularensis, contains glycyrrhizin (GL), a glycoside of glycyrrhetinic acid (GA) with two molecules of glucuronic acid. When GL is administered orally, it is hydrolyzed to GA by the intestinal bacteria and then absorbed into blood circulation. GA in blood circulation is not excreted into the urine but is transferred into the liver, sulfated to GA-3-O-sulphate (GA3S) by sulfotransferase (SULT) 2A1, and excreted into bile via multidrug resistance-associated protein (MRP) 2. In humans, GA3S is detected at a higher concentration than GA. In the intestine, GA3S is hydrolyzed to GA by the intestinal bacteria and is partially absorbed from the intestine into blood circulation to exhibits enterohepatic circulation, whereas the unabsorbed portion of GA3S is excreted in the feces. Orally taken GL is effectively hydrolyzed to GA by intestinal bacteria in constipated patients, which enhances its bioavailability. Hyper direct-bilirubin could thus be a surrogate marker of multidrug resistance-associated protein 2 dysfunction.