Licorice induced hypokalemia,edema,and thrombocytopenia

Abstract

Licorice originates from the root of Glycyrrhiza glabra, which has a herbal ingredient, glycyrrhizic acid, and has a mineralocorticoid-like effect. Chronic intake of licorice induces a syndrome similar to that found in primary hyperaldosteronism. Excessive intake of licorice may cause a hypermineralocorticoidism-like syndrome characterized by sodium and water retention, hypertension, hypokalemia, metabolic alkalosis, low-renin activity, and hypoaldosteronism. In this case report, an association of hypokalemia, edema, and thrombocytopenia that is developed due to the excessive intake of licorice is presented. There are case reports in the literature, which suggest that toxicity findings may emerge with hyperaldosteronism-like manifestations such as hypokalemia, edema, and hypertension. However, any knowledge of thrombocytopenia as a resultant was not encountered among these reported toxic effects. Our case is important because it shows that the excessive intake of licorice may cause a toxic effect in the form of thrombocytopenia. This report is the first presented case to show thrombocytopenia due to licorice syrup consumption.

Introduction

Licorice originates from the root of Glycyrrhiza glabra. Licorice has been shown to have a mineralocorticoid-like effect. ¹ Excessive intake of licorice induces a syndrome with findings similar to those in primary hyperaldosteronism. Licorice-induced hypokalemia is a rare disorder first described by Revers in 1946. ² This syndrome is characterized by sodium and water retention, edema, hypokalemia, hypertension, and suppression of renin aldosterone. ³

The active ingredient in licorice, glycyrrhizin (glycyrrhizic acid and glycyrrhizinate), induces pseudohyperaldosteronism by inhibiting the 11-β-hydroxysteroid dehydrogenase type 2 (11-β-HSD2), which converts active glucocorticoid cortisol to locally inactive cortisone. ⁴ This inhibition results in the activation of renal mineralocorticoid receptors by cortisol. The net effect of renal mineralocorticoid receptor activation is sodium reabsorption and potassium excretion with transient hypernatremia, persistent hypokalemia, hypertension, and metabolic alkalosis, leading to a phenotype similar to that of the syndrome of apparent mineralocorticoid excess. ⁵ Herein, a case with hypokalemia, edema, and thrombocytopenia that is developed due to the intake of licorice syrup is presented.

The importance of this case is that it shows that excessive consumption of licorice may cause thrombocytopenia. Although cases of licorice-induced hypokalemia and edema have been previously reported in several studies, this is the first case of a licorice-induced thrombocytopenia condition presented in the literature.

Case report

A 45-year-old male patient was admitted to the emergency department with the complaints of edema and weakness. He had no history of chronic disease, vomiting, diarrhea, sweating, or the use of drugs, including diuretics, laxatives, herbal medications, and alcohol abuse. A detailed personal history revealed that he drank 1 L licorice syrup as a regional beverage per day over the past 4 days and 2.5 L of licorice syrup on the day 5 (1 L of syrup includes 100 g of licorice root containing approximately 200 mg glycyrrhizic acid).

On physical examination, his blood pressure was 110/70 mmHg; he appeared tired and weak and had increased pitting edema of both the lower limbs. The laboratory data were normal except for the fact that there were hypokalemia (3.0 mmol/L), mild metabolic alkalosis (pH = 7.50, pco₂ = 32 mmHg, HCO₃ = 30 mmol/L), and thrombocytopenia (96,000 platelets per mm³). A peripheral blood smear was normal except for a slight decrease in platelets. Further investigations revealed that he had low plasma aldosterone concentration (0.07 nmol/L; (normal; 0.08–0.69)) with low plasma renin (upright) (4.5 mE/L; (normal; 5–75)) and a normal cortisol concentration (388 nmol/L; (normal; 160–690)). Thyroid function tests and plasma ACTH levels were within the normal range. The abdominal ultrasonography, the lower extremities, and a renal artery doppler ultrasonography were normal.

The clinical findings were thought to be due to the intake of excess licorice root syrup. Therefore, other causes of edema, hypokalemia, and thrombocytopenia were excluded. Thus, no medication was recommended for the patient, but he was advised to stop drinking licorice syrup. Three days later, a follow-up physical examination showed that the findings returned to normal. The results of the complete blood count and peripheral blood smear were evaluated as normal, and there was no sign of thrombocytopenia. Hypokalemia and the other biochemical parameters returned to normal. The patient’s clinical control was performed weekly for a month. Edema was not observed again. The level of potassium was 4.8 mmol/L, and the platelet count was 360,000 per mm³. This follow-up showed that he had made a full recovery. Since the clinical findings returned to normal, after he stopped drinking licorice syrup, this diagnosis was confirmed. This report presents the first case of thrombocytopenia due to licorice syrup consumption in the literature.

Discussion

In this case report, the association of hypokalemia, edema, and thrombocytopenia induced by the excessive intake of licorice was presented. There are case reports in the literature suggesting that toxicity findings may emerge with hyperaldosteronism-like manifestations, such as hypokalemia, edema, and hypertension. However, any knowledge of thrombocytopenia as a resultant was not encountered among these toxic effects. Our case is important because it shows that an excessive intake of licorice may cause a toxic effect in the form of thrombocytopenia.

Hypokalemia, hypertension, and hypoaldosteronism should alert the physician who diagnoses licorice-induced pseudohyperaldosteronism. ⁶ This is a mechanism by which licorice’s active ingredient, glycyrrhizic acid, has a mineralocorticoid-like side effect. It causes hypokalemia through the inhibition of the renal enzyme 11-β-HSD, which is responsible for renal conversion of cortisol to local receptors by cortisol, resulting in a state of apparent mineralocorticoid excess. The inhibitory effect on 11-β-HSD is reversible.^7–11 Excessive intake of licorice may cause a hypermineralocorticoidism-like syndrome characterized by sodium and water retention, hypertension, hypokalemia, metabolic alkalosis, low-renin activity, and hypoaldosteronism.^5,12–14

Endocrinopathies, which include Cushing syndrome, ectopic corticotrophin syndrome, Liddle syndrome, and mineralocorticoid excess, and which can lead to pseudohyperaldosteronism, should be excluded through a differential diagnosis. ¹⁵ Plasma renin and aldosteron levels were low in our case, and this was dependent on the pseudohyperaldosteronism due to licorice intake. However, the clinical findings and results of biochemical analyses did not support endocrinopathies. The blood pressure was also normal, and there were normal cortisol and ACTH levels as well. Edema and hypokalemia disappeared after he stopped the licorice intake, and he needed no medications. The levels of renin and aldosterone were initially suppressed and then returned to normal, so endocrinopathies were excluded from the differential diagnosis.

Other risk factors for developing a licorice-induced mineralocorticoid effect include old age and chronic inflammatory conditions.^6,16 Our case was in the middle age group and had no chronic disease. Generally, onset and severity of the symptoms are considered to be related to the duration of licorice usage, the dose, and individual susceptibility. ¹⁷ Even doses as low as 50 g of licorice consumed daily are mentioned as revealing significant clinical effects. ¹⁸ There are several studies in the literature that report cases with hypermineralocorticoidism findings developed following the use of gum known to contain glycyrrhizic acid in very low amounts. ¹⁹ The reason why some people are so susceptible to low amounts of glycyrrhizic acid remains to be clarified.^3,20 The World Health Organization suggested that consumption of 100 mg/day would be unlikely to cause adverse effects. ²¹ However, there is apparently a great individual variation in the susceptibility to glycyrrhizic acid. In the most susceptible individuals, a regular daily intake of no more than about 100 mg glycyrrhizic acid, which corresponds to 50 g licorice sweets (assuming a content of 0.2% glycyrrhizic acid), seems to be enough to produce adverse effects. ⁷ Our patient had consumed about 1 L of licorice syrup a day (about 200 mg glycyrrhizic acid) for 4 days and 2.5 L of syrup (about 500 mg glycyrrhizic acid) on day 5.

Although water and sodium retention, edema, and hypokalemia had developed in our case due to excessive licorice intake, interestingly no rise was observed in his blood pressure. Also, hypokalemia and edema developed in the case we presented, while no hypertension was defined. This indicates that licorice may cause hypokalemia, water retention, and edema without hypertension. In addition, a decrease in platelets in our patient was due to the intake of licorice. In a literature review, researchers reported that in an animal study, glycyrrhizin caused a platelet suppression response to glycyrrhizin. ²² Use of licorice in the form of syrup or tea has increased as a laxative or flavoring, in chewing gum, breath fresheners, or in food products and herbal medicines.

Considering the increasing use of licorice and its potential effects, it should be emphasized that hypokalemia, edema, and thrombocytopenia may be related to licorice usage and that practitioners should take detailed medicine intake histories into account. The importance of this case relates to showing that excessive consumption of licorice may cause thrombocytopenia.