INTRODUCTION
Licorice is the root of Glycyrrhiza glabra, an herbaceous perennial plant native of southern Europe and Asia, nowadays the main producing countries are Iran, Afghanistan, Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan and Turkey .
Licorice extract is made by boiling the roots and evaporating most of the water, obtaining a syrup. Licorice extract is widely used in food industry as a flavoring agent thanks to its sweetener property (about 50 times higher than sucrose).
The sources of licorice are numerous, and many of them are common used products like snacks, candies, cakes, chewing gums, drinks (some Belgian beers and Pastis), so an accidental over assumption is not so hard.
The active principle contained in the root is Glycyrrhizin (or glycyrrhizic acid), which is responsible of the high sweetening/flavoring properties, thirst quencher action and the side-effect of hypertension and hypokaliemia resulting from inhibition of 11-beta-hydroxisteroid dehydrogenase.
Licorice, Wikipedia.org
PHARMOKINETICS AND MECHANISM OF ACTION
Glycyrrhizin has low oral bioavailability and a single assumption is not sufficient to provoke the side-effect mentioned before.
After ingestion glycyrrhizin is metabolized to glycyrrhetic acid (hydrolysis reaction) by intestinal flora possessing a specific beta-glucuronidase. Glycyrrhetic acid inhibits 11-beta-hydroxisteroid dehydrogenase 200-1000 times more efficiently than glycyrrhizin, and its plasma permanence is prolonged by entero-hepatic circulation. So the conversion to glycyrrhetic acid prolonged and intesify the side-effect of licorice.
FDA suggest that glycyrrhizin intake should not exceed 100mg/day (corresponding at about 60-70g of licorice) to avoid the mineralcorticoid-like effect.
Duration of over-ingestion is also important, at least a 2 weeks licorice binge is necessary to cause a significant blood pressure rise.
Licorice abuse: time to send a warning message, 2012
Liquorice-induced rise in blood pressure: a linear dose-response relationship, 2001
11-beta-hydroxisteroid dehydrogenase
This enzyme catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa.
11β-hydroxysteroid + NADP+ 
an 11-oxosteroid + NADPH + H+
Cortisol has an intrinsic mineralcorticoid action and its plasma concentration is widely higher than aldosterone. This enzyme prevents cortisol binding to the mineralcorticoid receptor converting it to cortisone, so the receptor is not over stimulated.
Inhibition of 11-beta-hydroxisteroid dehydrogenase by licorice leads to a major quantity of cortisol available for binding the mineralcorticoid receptor and the consequent reabsorption of Na+ and excretion of K+.
So a “licorice intoxication” shows electrolyte imbalance (high Na+ / low K+ ) suggesting hyperaldosteronism, but plasma aldosterone is normal because there is no alteration at the adrenal gland, thus this condition is defined pseudo-hyperaldosteronism.
Toxicity of licorice can be increased in patients with low 11-beta-HSD activity (eg. due to genetic polymorphism), in old people, in women and in hypertensive. In addition factors that predispose to hypokalemia like diarrhea, diuretic therapy intensify the action of licorice.
11-Beta hydroxysteroid dehydrogenase, Wikipedia.org
Licorice abuse: time to send a warning message, 2012
PSEUDO-HYPERALDOSTERONISM and HEALTH CONSEQUENCES
This condition mimics hyperaldosteronism with suppression of plasma renin activity and aldosterone levels. The causes can be dietary, genetics and endocrinal.
Clinical signs, as seen before, in patient with licorice overdose are mainly hypertension and hypokalemia.
Hypertension can be severe: there are reports of patients with blood pressure of 200/110mmHg and 180/90mmHg, so a quick intervention is needed.
Hypokalemia can range from moderate to severe (3mEq/l – <2mEq/l). Low K+ levels can lead to arrhythmia with prolonged QT interval and presence of U wave, muscle weakness, myalgia, muscle cramps and constipation (from disturbed function of smooth muscle). In case of severe hypokalemia are reported flaccid paralysis and hyporeflexia, and in the most acute form rhabdomyolysis.
Licorice abuse: time to send a warning message, 2012
Hypokalemia, Wikipedia.org
Pseudohyperaldosteronism, liquorice, and hypertension, 2008
THERAPY and PROGNOSIS
The therapy first of all consist in immediate interruption of licorice intake, then patients that developed hypertension usually have a good response and prognosis if treated with antihypertensive.
Hypokalemia and its consequences can be treated with adequate potassium replacement and spironolactone therapy.
The general mineralcorticoid imbalance usually need a notable period to fully recover (up to 6 months in the worst case scenario), this is attributed to the long half life of glycyrrhetic acid and the long time required for the renin-angiotensin-aldosterone axis to stabilize.
Licorice abuse: time to send a warning message, 2012
