Liquorice Toxicity: History
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Contributor:
Giovanna Ceccuzzi
,
Alessandro Rapino
,
Benedetta Perna
,
Anna Costanzini
,
Andrea Farinelli
,
Ilaria Fiorica
,
Beatrice Marziani
,
Antonella Cianci
,
Federica Rossin
,
Alice Eleonora Cesaro
,
Michele Domenico Spampinato
,
Roberto De Giorgio
,
Matteo Guarino

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. 

  • glycyrrhetinic acid
  • glycyrrhizin
  • liquorice
  • mortality

1. Historical Background, Source and Use of Liquorice

The genus name of Glycyrrhiza comes from the union of the ancient Greek words glykos (sweet) and rhiza (root). There are about 30 different naturally occurring species of Glycyrrhiza [1]. Most of the commercial liquorice is extracted from Glycyrrhiza glabra, a member of Leguminosae, growing especially in Southern Europe (varietas typica), the Middle East (varietas violacea), and Russia (varietas glandulifera). Other popular species are Glycyrrhiza uralensis, Glycyrrhiza pallidiflora (Chinese liquorice), and Glycyrrhiza lepidota (American liquorice) [2].
The first medical use of liquorice is witnessed in Assyrian and Egyptian prescriptions for treating bruises or swelling [3] and in Chinese culture, where it remains one of the most used medical herbs [4]. According to traditional Chinese medicine, liquorice is primarily used to intensify the properties of the other drugs and to better flavor herbal preparations. Moreover, it has been known to relieve or improve fatigue, debilitation, asthma, and phlegm [4]. In Europe, liquorice was fist mentioned by the Greek botanist Teophrastus (IV-III century B.C.) as “the Scinthian root” [5]. Its therapeutic properties were better described in the Roman period: Plinius suggested this plant as a remedy against infertility [6]. During the Middle Ages, the School of Salerno (VIII-IX century) fused Greco-Roman medical studies with Arabic knowledge and proposed liquorice to treat lung abnormalities (such as asthma and cough), gastrointestinal (GI) disorders (burning sensation, mouth ulceration and liver disorders), cardiovascular diseases (heart palpitations and draining), and skin and mucosae lesions [6].
Nowadays, liquorice is commonly used in several areas. Recognized as safe by the Food and Drug Administration, it is largely used for flavoring tobacco, food, and pharmaceutical drugs [7]. A broad range of biological activities have been described in literature, including anti-obesity, anti-diabetic [7][8][9], anti-inflammatory, and antioxidant properties [10]. Moreover, liquorice seems to exert a role in ameliorating allergic/inflammatory diseases of the skin [9], evoking ulcer healing, exerting a laxative effect [11][12][13], and providing hepatoprotective activity [12][14]. Furthermore, liquorice has been shown to have anticarcinogenic, antimicrobial, and antiviral activities, although the exact underlying mechanisms are not fully understood yet [9][13].
According to the Food and Drug Administration, approximately 90% of the consumption is related to smoking, while the dietary intake of Glycyrrhetinic acid (GA) is unremarkable [7]. However, the possibility of exceeding the safety threshold and developing signs/symptoms of toxicity can be linked to a daily overconsumption of readily available products (e.g., flavored candies or beverages). In this line, de-glycyrrhizinated liquorice has been recently produced in order to avoid LT as a possible side effect [1].

2. Chemical Composition

Commonly used liquorice products contain rhizomes and root extracts, as these parts of the plant are qualitatively and quantitatively richer in bioactive molecules than leaves, which are usually discarded by manufacturers [15][16]. As for most of the plant extract-based products, the phytochemical composition of liquorice extracts varies due to several factors, such as the genetic background of the plant variety, the environmental growing conditions, and the methods of liquorice processing [14][15]. Different extraction techniques and analytical methods have been developed and compared in order to determine the chemical composition of liquorice extracts and to improve the yield of the constituents of interest [17]. It has been estimated that about 40 to 50% of the dry weight of Glycyrrhiza glabra root extract consists of a bioactive mixture of water-soluble compounds [17].
Above 400 distinct molecules have been extracted by Glycyrrhiza species, with triterpene saponins, flavonoids, and free phenols being the most abundant ones [17]. While liquiritin and isoliquiritin flavonoids confer the yellow color to liquorice roots, the saponins GL, GA, and their triterpenoid derivatives have been identified as the most bioactive compounds of liquorice in vivo [12][18]. GL (also referred to as GA) consists of an 18β-GA molecule linked to a disaccharide formed by two β-D-glucuronic acid molecules [12][19]. Glucuronidase enzyme expressed by the plant or animal/human gut microbiota catalyzes the hydrolysis of GL to two GA pentacyclic triterpenoids, the epimers 18α-GA and 18β-GA [20], differing from each other due to their C18-H-, trans-, and cis-configuration. Evidence suggests that GA epimers have different activities in humans and animals [20][21].

3. Pharmacokinetics

The general population is usually exposed to liquorice derivatives after ingestion (i.e., foods, sweets, and supplements) and, to a much lower extent, to intravenous injection of GL, as reported in clinical studies investigating GL efficacy for chronic hepatitis treatment [18][22]. GL has a limited oral bioavailability, resulting in negligible blood levels after a single dose up to 1600 mg/kg [12]. After ingestion, GL undergoes pre-systemic hydrolysis to GA via specialized β-glucuronidase enzymes expressed by the intestinal microbiota. In particular, Eubacterium spp. (strain GHL), Ruminococcus spp. PO1-3, and Clostridium innocum ES2406 evoke GL hydrolysis, whereas common β-glucuronidases expressed by Escherichia coli do not catalyze the GA production [23][24]. While in the plasma of rats, a small amount (4%) of GL was detectable only after a high oral dosage (i.e., 200 mg/kg), GL resulted undetectable in humans even after 100 to 800 mg of oral administration [22]. However, the identification of a minimal amount of GL (1.1–2.5% of the dose) in human urine suggests a minimal absorption of this molecule in the GI tract [25]. In parallel, after oral GL intake (10–480 mg/kg), GA has been reported to reach the highest plasma levels (Cmax) after 12 to 16 h (Tmax) in rats. A similar dynamic was described in humans (Tmax = 8–12 h) [22]. Thus, GL is fully metabolized and absorbed in the GA form.
The essential role of gut bacteria on the bioavailability of liquorice-active derivates was highlighted by the evidence that GA was absent in the plasma of germ-free rats treated with oral liquorice [22]. Moreover, the matrix of GL delivery (i.e., aqueous or pure extracts of liquorice roots) is proven to affect GA bioavailability [22]. After its release, GA is rapidly absorbed and conveyed to the liver almost completely combined (>99.9%) with serum albumin, occupying both specific and nonspecific bindings sites of this carrier protein. In the liver, the dehydroepiandrosterone sulfotransferase (also identified as sulfotransferase 2A1) transforms GA in 18β-glycyrrhetyl-3-O-sulfate (GA3S) subsequently expelled in the bile [22]. The canalicular multi-specific organic anion transporter (cMOAT) promotes the biliary excretion of GA derivatives [26]. Biliary metabolites of GA are then released into the GI tract and partially reconverted by enterobacteria into GA molecules that subsequently re-enter the blood circulatory system. Indeed, multiple absorption peaks in the GA plasma concentration–time curve were reported by pharmacokinetic studies on liquorice, showing a second maximal absorption peak approximately 20 h post-administration. Carrier proteins with restricted saturation capacity mediate the enterohepatic cycling of GL derivatives [22][26]. In conclusion, GA shows a biphasic pattern of elimination, in which the distribution in the central compartment is followed by a slow, dose-dependent phase of elimination. The enterohepatic cycling is a major determinant to understand the delay in the plasma clearance of GA [26]. However, conflicting data about the absorption rate have been reported by both preclinical and clinical studies [22]. These discrepancies in the quantitative analysis of GL active compound absorption are attributable to the inter-individual differences in GA blood levels after equal amount of liquorice intake and related GL hydrolyzation (by gut microbiota variety), permanence in the gut lumen (dependent on different GI transit), carrier protein expression, and liver function [12][22][26].

4. Biochemical Mechanism of Toxicity

LT mechanisms are mainly triggered by the imbalance of cortisol and aldosterone pathways, leading to PsA. In physiological conditions, aldosterone and cortisol act as competitive ligands and activators of the mineralocorticoid receptors (MR) in the cortical collecting duct cells of the kidney because of their similar molecular structures and receptor affinity. However, cortisol activity on MR is limited by its degradation via 1β-hydroxysteroid-dehydrogenase type 2 (11β-HSD2), resulting in the production of cortisone, which is almost inactive due to the negligible affinity to MR [12][27][28]. Conversely, the aldosterone released by the adrenal glands exerts its functions in the kidney by mediating sodium (Na) and water reuptake along with potassium (K) elimination, thus preserving the acid-base equilibrium [29]. In particular, aldosterone controls the transcriptional modulation of Na-K exchangers, epithelial Na-channels, renal outer medullary K channels, aquaporins, and bicarbonate-chloride antiporters via MR activation.
Liquorice derivatives inhibit 11β-HSD2, thus blocking cortisol conversion and eliciting MR activation by this hormone. In the renal glomeruli, this event induces an outsized aldosterone-like effect leading to an increase of Na reabsorption and K excretion, underlying the distinctive features of PsA (i.e., hypokalemia, AH, oedema, and MA) [12][27][28]. In adults, the 11β-HSD2 is also expressed in the heart, brain, and vasculature [28]. Liquorice metabolites evoke AH even by increasing arterial tone, improving contractile reaction to pressor hormones (via activation of the endothelin system) and decreasing the synthesis of endothelial nitric oxide [28]. Moreover, in vivo experiments suggest that liquorice retains a central hypertensive effect independent from the 11β-HSD2 inhibition. Indeed, the injection of GA into the rat brain boosted blood pressure (BP), with no changes in renal functions [28].
In vitro studies highlighted that both GL and GA inhibit 11β-HSD2, although the GA potency of inhibition is roughly 200 times greater than GL ones. In patients with liquorice-induced PsA, GA3S is the metabolite detected at the highest blood concentration, suggesting its pivotal role in LT onset [27].
The development of PsA activates the negative feedback control of the aldosterone release leading to BP increase and K level decrease. However, preclinical evidence suggests that aldosterone hepatic degradation might be restricted by GL or GA via the inhibition of the 5β-reductase and 3β-hydroxysteroid dehydrogenase, thus preserving the systemic levels of this hormone [30].

Other Liquorice-Induced Side Effects

Further to PsA, GA was observed to affect sexual activity and reproduction in male rats, whereas it evoked a mild inhibition of androgenic hormones in humans [31][32]. In female rats, GA evoked estrogenic activity, as reflected by uterine response and vaginal opening [32].
In addition to GA, liquorice seems to have an estrogenic effect due to flavonoids and isoflavonoids. Liquiritigenin, a flavonoid component, exhibits good binding affinity for the bovine uterine estrogen receptor [32], while glabridin and glabrene mimic estrogen activity, maintaining calcium balance [31]. Moreover, GA is proved to induce miscarriages and should be avoided in subjects taking oral contraceptives, hydrocortisone, and prednisone. Finally, GA can have a contributory effect in the treatment of polycystic ovary syndrome [12][31].
In terms of GI function, isoliquitigenin, a flavonoid component of liquorice, may decrease bowel mobility, independent of cholinergic inhibition or adrenergic and/or nitrergic exacerbation [32].

5. Clinical Risk Factors for LT

The following paragraphs will detail the risk factors for developing LT.

5.1. Daily Dosage

The Scientific Committee on Food declared a GL consumption of 100 mg/day to be safe, based on studies involving human volunteers [33]. However, even lower doses may provoke critical manifestations according to different individual susceptibility to GA, as is widely reported in the literature [7][27][31][34][35][36][37][38]. Apart from one paper by Sigurjònsdòttir et al. [36], most studies showed no clear correlation between GA levels and severity of manifestations, such as, for example, degree of AH.

5.2. Age

Old age (over 65 years) may affect several processes of GL metabolism and there is an age-dependent decrease in 11-BHSD2 levels [1][27][37]. In addition, a reduction of glucocorticoid receptor concentration may cause a decrease in negative feedback in the hippocampus, with a resulting elevation in serum cortisol concentrations. This phenomenon may contribute to the inhibition of 11β-HSD2 [1][22][27][37]. Furthermore, the elderly are often affected by several comorbidities (and in particular delayed GI transit), which might increase the risk of LT.

5.3. Sex

Female sex is more susceptible to LT [27]. Two main factors may play a role in LT: (i) a higher frequency of constipation, which affects the process of hydrolyzation of GL, and (ii) the estrogenic and antiandrogenic effects of liquorice, which influence calcium homeostasis, testosterone levels, and vaginal/uterine response (in animal studies) [32]. No sex differences were found in the development of AH, although an intrinsic difference in the renin angiotensin aldosterone system between females and males was demonstrated [38]. In particular, Sigurjònsdòttir et al. highlighted that serum aldosterone concentrations were markedly decreased in men vs. women after the administration of the same dose of liquorice [38].

5.4. Metabolism

Wide inter-individual variations in GA blood levels occur even at the same dose of liquorice intake, and this may be explained by differences in terms of gut microbiota-related GL hydrolyzation [12][22], actual content of GL in the intestinal lumen [12][22], and liver function [18].
As for the primary metabolism, the hydrolyzation ratio is also determined by the GL intestinal transit time: the slower it is, the more GL is hydrolyzed, thus resulting in a higher GA concentration [17]. This may explain why constipated patients experience LT more frequently than subjects with a normal bowel habit.
Although GA cannot be eliminated by urine excretion, it can be absorbed by renal proximal tubular epithelial cells, becoming a substrate of organic anion transporters 1 and 3. Hypoalbuminemia related to altered liver function can increase the unbound fraction of GA and its availability to tubular epithelial cells, where 11β-HSD2 is expressed [39]. In addition, a significant inter-individual difference of liver enzymes and canalicular transport of glucuronides, which affect secondary metabolism of GA and its time of excretion, can be demonstrated [8]. In support of this concept, patients with chronic hepatitis and liver cirrhosis demonstrated 0.7 and 0.23 times lower plasma clearance, respectively, compared to healthy subjects [39].

5.5. Comorbidities and Concomitant Use of Other Medications

Since LT is related to the development of PsA, patients with AH, kidney disease, and hydro-electrolyte imbalance (i.e., hypokalemia, hypernatremia, and MA) are more prone to develop this toxicity [27][37]. In particular, patients with pre-existing cardiovascular disease are at higher risk of MACEs [37]. GI disorders with diarrhea and/or vomiting as well as renal losses could predispose to electrolyte imbalance [1]. Moreover, patients with polycystic ovary syndrome have a greater susceptibility to AH [28]; however, the mineralocorticoid and the mild antiandrogenic activity may mitigate the spironolactone side-effects in these patients [32].
The concomitant use of other medications can reduce or amplify the clinical feature of LT. Indeed, antihypertensive drugs may mask AH, while thiazide and loop diuretics increase the risk of severe hypokalemia. Finally, steroids increase the inhibition of 11β-HSD2, thereby promoting AH and other LT-related features. Conversely, K-sparing drugs (e.g., aldosterone blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers) may prevent liquorice-induced hypokalemia [27].

6. Clinical Manifestations

The most described clinical picture of LT is linked to the aldosterone-like activity of liquorice, including hydro-electrolyte disorder with related ECG alterations, MA, skeletal muscle disorders, and AH.

6.1. Cardiovascular Disorders

Mild to severe AH with secondary organ impairment (i.e., hypertensive encephalopathy [34][40][41][42][43][44], hypertensive retinopathy [45][46], acute kidney injury [47][48][49][50], MACEs [51][52][53][54][55][56][57][58][59][60][61][62], pulmonary edema [63][64]) were commonly described. Sigurjònsdottir et al. showed a linear dose-response relationship between liquorice intake and BP increase [36]. Nevertheless, a pre-existent chronic antihypertensive therapy might hide AH. Only one paper described a patient with hypotension associated with supraventricular tachycardia secondary to liquorice-induced hypokalemia [65]. Severe K depletion is associated with typical ECG features (i.e., QT interval prolongation, U waves, and ST segment slight elevation in V1–V3). Few cases described hypokalemia-induced fatal arrhythmias leading to cardiac arrest in the absence of other established causes [53][54][56][58][59][60][61][62][66][67]. Liquorice was lethal in only two cases [59][60]. Hasegawa et al. reported a patient developing heart failure resembling dilated cardiomyopathy [52]. Acute heart failure with pulmonary edema has been described [63][64].

6.2. Muscle and Neurological Manifestations

In almost half of patients reported in the table (50 out of 104), muscle symptoms (i.e., fasciculation, myoclonus, fatigue) were the first complaint with mild to severe rhabdomyolysis.
Among papers describing patients with altered mental status [40][42][68][69], Francini-Pesenti et al. and Ceccuzzi et al. reported an unconscious young woman with LT and daily oral contraceptive, confirming that this pharmacological combination is contraindicated, as previously described. In the other cases the unconsciousness was related to major adverse events, i.e., torsade de point [58][60][67], cardiac arrest [54][59][66], Brugada-like pattern [56], and ventricular tachycardia [61][62]. Neurological manifestations were quite frequently (27 out of 104) reported, such as flaccid paresis [56][69][70][71][72][73][74][75][76] and hypertensive encephalopathy microhemorrhages [41][44].

6.3. Others

GI symptoms are rare in LT and include abdominal pain, nausea, vomiting, and diarrhea [68][75][77][78][79].
Beyond hypertensive retinopathy, Dobbins et al. described five cases of retinal and occipital vasospasm, manifesting with a transient visual loss [80]. As described by Deutch et al., GA enhances the contractile response of smooth muscle, giving rise to an ocular migraine-like clinical phenotype, without headache [28].
Finally, Omar et al. reported a possible role of GA in thromboembolic events, but, only one case has been described [1][81].
Though liquorice is not acknowledged to affect the blood cell count in humans, Celik et al. described a patient with liquorice-induced thrombocytopenia [82]. Indeed, GL has been shown to cause platelet suppression in animal models [12][82].

7. Diagnosis

Hyperaldosteronism/PsA induced by LT should be distinguished according to the various etiologies [27][60]. Hyperaldosteronism is an endocrine disorder occurring when the adrenal glands produce an excess of aldosterone and can be etiologically classified into primary and secondary forms [83][84]. Primary hyperaldosteronism is commonly due to Conn syndrome (i.e., a primary tumor of the adrenal gland) or bilateral (less frequently monolateral) adrenal hyperplasia, ectopic aldosterone-secreting tumors, aldosterone-producing adrenocortical carcinomas, and familiar hyperaldosteronism type 1 [83][84]. Secondary hyperaldosteronism results from an excessive activation of the renin-angiotensin-aldosterone system, related to renin-producing tumors, renal artery stenosis, or overload conditions with relative hypovolemia (e.g., left ventricular heart failure, cirrhosis with ascites, and pregnancy) [85]. PsA is characterized by hypokalemia, MA, and reduced renin level without an increase in aldosterone level. Primary causes include either gene abnormalities (i.e., MR mutations, Liddle’s syndrome, apparent mineralocorticoid excess syndrome, and congenital adrenal hyperplasia) or acquired mechanisms (i.e., hypercortisolism and LT) [86].
Although the clinical history is essential for LT diagnosis, liquorice overuse is often underreported or even overlooked. Indeed, the use of GL as sweetener for foods and drugs is widespread; therefore its unintentional intake may occur regardless the conscious consumption of candies [78][87]. Moreover, physicians should be aware of over-the-counter herbal mixtures commonly consumed to treat digestive symptoms or quit smoking [88], lose weight [77], or treat infertility [47]. To date, most of the herbal compounds are unlicensed by pharmaceutical drug regulatory authorities and the actual amount of active ingredients are neither listed nor standardized.

8. Treatment and Prognosis

In almost all the reported cases, clinical manifestations improved with quitting liquorice consumption and intravenous hydro-electrolyte support. In 84 out of 104 cases, hospital admission was necessary. The LT prognosis is generally good, with complete symptom resolution in 30 days [66]. Since no direct antidote is available, the therapy only consists in correcting the hydro-electrolyte imbalance, reducing AH, and avoiding severe complications. The persistence of symptoms, such as AH, can be explained by large volume of GA distribution, its long half-life (12 h), and prolonged enterohepatic circulation. In addition, LT mechanisms generate a hormonal disorder through the amplification of gene transcription, which may need time to be completely restored [26][27][28][38]. Only two papers described cases of LT leading to death for MACEs [59][60].

This entry is adapted from the peer-reviewed paper 10.3390/nu15183866

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