Background
Natural licorice is an extract from the root of Glycyrrhiza glabra, a 4- to 5-foot woody shrub that contains glycyrrhizic acid (GZA) and grows in subtropical climates in Europe, the Middle East, and Western Asia.
Licorice poisoning is rare. Although regular licorice ingestion can result in hypokalemia, hypernatremia, and water retention, the Joint Food and Agricultural Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) states that it is unlikely that adult consumption of 100 mg/day of GZA would produce ill effects. However, the committee suggested that highly susceptible persons could suffer effects at lower doses. [1]
Licorice extract and its principal component, GZA, have wide use in foods, tobacco products, and snuff. Licorice is also employed in cosmetics and has been extensively used in traditional and herbal medicine, including for indigestion and constipation. [2]
Indeed, licorice has been described as an "essential herbal medicine" in traditional Chinese medicine. [3] Topical licorice may be an effective treatment of aphthous ulcers, [4] and licorice may prevent dental caries in children. [5] Research indicates that licorice, topically applied prior to surgery, has significantly greater efficacy in the prevention of postoperative sore throat (as possibly caused by intubation) than do nonanalgesic methods. [6]
As a result of licorice's extensive applications, estimated consumption of licorice and GZA in the United States is high: 0.027-3.6 mg GZA per kilogram per day. [7] However, many candies marketed as licorice (eg, red licorice) have artificial licorice flavoring and do not contain GZA. Licorice root that is sold as a dietary supplement can be found with the GZA removed, resulting in a product known as deglycyrrhizinated licorice, or DGL. [8]
Licorice (or liquorice) is a plant of ancient origin and steeped in history. Licorice has been used as a medicinal agent in a number of cultures, [9] dating back to ancient Egypt and China. Medicinal uses have included the following:
Licorice flavor is found in a wide variety of licorice candies. Licorice is also found in some soft drinks (eg, root beer) and is in some herbal teas, where it provides a sweet aftertaste. [17]
Licorice extract (block, powder, or liquid) may be applied to cigarette tobacco at levels of about 1-4% to enhance and harmonize the flavor characteristics of smoke, improve the moisture-holding characteristics of tobacco, and act as a surface-active agent for ingredient application. [18]
Pathophysiology
Natural licorice possesses both mineralocorticoid properties and glucocorticoid properties.
Consumption of large doses of GZA in licorice extract can lead to a syndrome known as hypermineralocorticoidism, characterized by hypokalemia and serious hypertension. [19, 20] (Most licorice-flavored foods available in the United States do not contain GZA, and they do not produce this syndrome, which is observed with the long-term consumption of moderate-to-significant amounts of natural licorice.)
Biochemical studies indicate that glycyrrhizinates inhibit 11-beta-hydroxysteroid dehydrogenase (type 2), the enzyme responsible for inactivating cortisol through conversion to cortisone. As a result, a continuous, high-level exposure to GZA compounds can produce hypermineralocorticoid-like effects in animals and humans. These effects are reversible upon withdrawal of licorice or GZA. [7]
In the kidney, cortisol activation of mineralocorticoid receptors alters renal tubular exchange of sodium (retained), potassium (excreted), and hydrogen ions (excreted), producing an increased extracellular volume (hypertension, [21] edema), hypokalemia (weakness, muscle spasm), [22] and metabolic alkalosis. [23]
Pseudoprimary aldosteronism from chronic licorice ingestion is characterized by low serum and urinary aldosterone levels and decreased serum renin activity. This differs from true primary hyperaldosteronism caused by aldosterone-producing adenomas or primary adrenal hyperplasia, which is characterized by elevated urine and serum aldosterone levels.
Licorice can reduce the serum testosterone level, probably by blocking 17-hydroxysteroid dehydrogenase and 17,20 lyase. [24] Licorice has therefore been considered an adjuvant therapy for hirsutism and polycystic ovary syndrome. [25]
The exact amount of ingested GZA that produces mineralocorticoid toxicity is unclear. A meta-analysis to assess the effect of chronic ingestion of licorice found that the mean daily dose of GZA across 18 studies was 377.9 mg, which is approximately 189 g of black licorice a day, assuming 2.0 mg/g (0.2% w/w) GZA in black licorice.
However, the concentration of GZA changes significantly depending on the product. Licorice findings range between 0.26 and 7.9 mg/g, with the range in health products found to be 0.30-7.9 mg/g. A typical pack of Liquorice Allsorts was found to contain 91.0 mg, a serving of licorice tea contained 20.0 mg, and a single licorice pipe contained 4.6 mg. With only limited and sporadic consumption of licorice, it would be difficult to ingest more than 500 mg of GZA per day. Assuming an average concentration of 2.0 mg/g for black licorice confectionery, it would require consumption of 250 g per day to reach 500 mg of GZA daily. This quantity is relatively high, but as evidenced by numerous case reports a small portion of the population does consume licorice at these levels. [2]
A study by Af Geijerstam et al reported finding a significant rise in blood pressure in healthy persons who consumed 100 g of GZA per day for 14 days, suggesting that licorice has a higher potency than previously recognized. Moreover, the subjects’ renin and aldosterone levels were suppressed, outcomes consistent with the development of pseudohyperaldosteronism. The investigators suggested that JECFA’s aforementioned indication that 100 mg/day of GZA in most adults would not likely have adverse effects may need to be reconsidered. [26]
Prognosis
Patients generally fully recover with discontinuation of exposure. After licorice exposure is discontinued, spontaneous correction of hypertension and hypokalemia generally occur within several weeks; however, months may pass before the renin-aldosterone system becomes active again. [27] Muscle weakness/paralysis may resolve within days of potassium replacement.
Severe, and sometimes fatal, complications following ingestion of licorice can occur. In these cases, significant quantities of licorice have typically been consumed in the short- to medium-term. Reported complications include rhabdomyolysis, hypertensive encephalopathy, and cardiac arrest and death. [2] In one case, long-term licorice use led to pseudoaldosteronism with intractable hypokalemia, the result being lethal polymorphic ventricular arrhythmias. [28]
