Liquorice Toxicity: A Comprehensive Narrative Review

Abstract

Background: Renowned since ancient times for its medical properties, liquorice is nowadays mainly used for flavoring candies or soft drinks. Continuous intake of large amounts of liquorice is a widely known cause of pseudo-hyperaldosteronism leading to hypertension and hypokalemia. These manifestations are usually mild, although in some cases may generate life-threatening complications, i.e., arrhythmias, muscle paralysis, rhabdomyolysis, and coma. In addition, liquorice has an important estrogenic-like activity.

Methods: We summarized the current knowledge about liquorice and reviewed 104 case reports in both the English and Italian languages from inception to June 2023 concerning complications due to an excess of liquorice intake.

Results: In contrast to most published data, female sex and old age do not appear to be risk factors. However, hypertension and electrolyte imbalance (mainly hypokalemia) are prevalent features. The detection of glycyrrhetinic acid in blood is very uncommon, and the diagnosis is essentially based on an accurate history taking.

Conclusions: Although there is not a significant mortality rate, liquorice toxicity often requires hospitalization and therefore represents a significant health concern. Major pharmaceutical drug regulatory authorities should solicit public awareness about the potentially dangerous effects caused by excessive use of liquorice.

Keywords: glycyrrhetinic acid; glycyrrhizin; liquorice; mortality; pseudo-hyperaldosteronism; toxicity.

Figure 1

Chemical structure of GL and GA [119]. The wavy line expresses the bond which may vary in 3D-orientation among the two epimers.

Figure 2

Schematic representation of metabolism pathway and toxicity mechanisms of liquorice and its derivatives. After oral intake, liquorice is converted to GL in the gut and this is hydrolyzed to GA by the β-glucuronidases of gut microbiota. GA is later absorbed in the blood stream and carried by serum albumin. In the liver, GA is converted to GA3S by SULT2A1. GA3S is excreted with the bile and enter the enterohepatic circulation. In tissues, GA and its metabolites inhibit 11β-HSD2 thus blocking the constitutive degradation of cortisol to cortisone. Available cortisol binds and activates MR cascade and their downstream effectors. In the kidneys, this event causes a potent increase in Na and H2O absorption combined with K excretion, via ROMKs, ENaCs and AQP2s channels. In blood vessels, GL metabolites boost contractile responses to pressor hormones and reduce endothelial NO production, concurring to AH. GL: Glycyrrhizin; GA: Glycyrrhetinic acid; GA3S: 18β-glycyrrhetyl-3-O-sulfate; SULT2A1: sulfotransferase 2A1; 11β-HSD2: 11-β-hydroxysteroid-dehydrogenase type II; CL: cortisol; CE: cortisone; MR: mineralocorticoid receptor; K: potassium; Na: sodium; H2O: water; ROMK: renal outer medullary potassium channel; ENaC: epithelial Na-channels; AQP2: acquaporine-2; OAT: organic anion transporter; NO: nitric oxide; AH: arterial hypertension.