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Lozenge‐Induced Hypermineralcorticoid State––A Unique Case of Licorice Lozenges Resulting in Hypertension and Hypokalemia

Licorice consumption resulting in metabolic abnormalities including hypokalemia and metabolic alkalosis along with hypertension has been described in the literature as far back as the 1950s. Licorice extract has been used widely for thousands of years for its medicinal properties and in food preparation. Toxicity has resulted from its ingestion in products such as herbal supplements, candy, laxatives, and tea. However, there are no published reports of toxicity from the ingestion of lozenges. We report a case of licorice lozenge–induced hypermineralcorticoid state, with hypokalemia, metabolic alkalosis, and hypertension, highlighting the importance of taking a detailed dietary history in the evaluation of hypermineralcorticoid state. A 66-year-old man with a medical history of peripheral neuropathy and newly diagnosed hypertension was noted to have hypokalemia on routine laboratory tests for 4 months. His blood pressure was 152/80 mm Hg, and recent laboratory tests showed a serum potassium level of 2.5 mmol/L (normal range, 3.5–5.3) and a metabolic alkalosis with serum bicarbonate level of 34.6 mmol/L (normal range, 24–31). Findings from the rest of his metabolic panel were within normal limits. Workup was initiated to evaluate the unexplained hypokalemia. Urine studies were consistent with renal potassium wasting based on a urine potassium of 92 mEq/L and a transtubular potassium gradient (TTKG) of 16.9 (UK >15 mEq/L, TTKG >7). Serum renin activity was low at 0.11 ng/dL/h (0.25–5.82) and serum aldosterone was low at 1 ng/dL (≤28). The possibility of Cushing syndrome was investigated. His early morning cortisol level was normal at 9.4 mg/dL (4–22), while 24-hour urine cortisol level was elevated at 128 mg (4–50) with a normal urine creatinine level of 0.9 g/24 h. Cortisol at 8 AM after a 1 mg dexamethasone suppression test was 1.58 mg/dL (<2.0), which excludes Cushing syndrome. He was referred to the endocrinology department for further evaluation. There was no history to suggest the intake of medications that cause renal or gastrointestinal loss of potassium, including laxatives, diuretics, corticosteroids, or antibiotics such as aminoglycosides, amphotericin, and penicillins. Additional history revealed that he had been taking an unusually large amount of cough lozenges for the past 3 to 4 months in order to distract his attention from neuropathic pain. Interestingly, the ingestion of the lozenges coincided with his hypokalemia. He had been consuming approximately 160 tablets per day of a licorice-containing lozenge, “Fisherman’s Friend––Extra Strong,” amounting to approximately 240 g of cough drops per day containing 288 mg of glycyrrhizin. For reference, the European Commission Scientific Committee on Food has proposed an upper limit of 100 mg/d of glycyrrhizin, which is found in approximately 60 g to 70 g of licorice candy. The patient was advised to discontinue the consumption of these licorice-containing lozenges and to follow up with repeat tests in 6 weeks. At follow-up, the serum potassium level was low-normal (3.6 mmol/L), but the patient was again noted to be hypertensive and the 24-hour urinary free cortisol level continued to be high at 133 mg. He admitted to have cut down but had not stopped the lozenge intake (80 per day), which still contained higher-than-recommended levels of glycyrrhizin. Follow-up tests 7 weeks after cessation of the lozenges demonstrated complete resolution of the hypokalemia (serum K 4.1 mmol/L), metabolic alkalosis (serum bicarbonate 26 mmol/L), and hypertension, as well as normalization of the 24-hour urinary free cortisol (25.3 mg). Excessive consumption of licorice leading to a hypermineralocorticoid state has been well-described in the literature. The mechanism was initially thought to be secondary to the binding of the active metabolites of licorice, namely glycyrrhizic acid and glycyrrhetinic acid, to mineralocorticoid receptors. However, it was later demonstrated that this is unlikely as glycyrrhetinic acid has a particularly weak affinity for the mineralcorticoid receptor. The currently accepted model is that glycyrrhetinic acid inhibits the enzyme 11b-hydroxysteroid dehydrogenase, preventing the metabolism of cortisol to inactive cortisone. The excess cortisol binds to renal mineralocorticosteroid receptors, leading to a syndrome of mineralocorticoid excess, hypokalemia, metabolic alkalosis, and hypertension. Interestingly, although the urinary cortisol is elevated in licorice-induced toxicity, the serum cortisol tends to be normal. The mechanism for this involves two isoforms of 11b-hydroxysteroid dehydrogenase. The type 1 isoform of 11b-hydroxysteroid dehydrogenase functions mainly as a reductase. It is expressed widely in the body and appears to be co-localized to sites of Address for correspondence: Ishita Singh, MD, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare Systems, Endocrinology 111D, West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073 E-mail: isingh@mednet.ucla.edu