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.1, 2 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.3, 4 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,3 which is found in approximately 60 g to 70 g of licorice candy.5
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.1, 2 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.6 The currently accepted model is that glycyrrhetinic acid inhibits the enzyme 11β‐hydroxysteroid dehydrogenase, preventing the metabolism of cortisol to inactive cortisone.7, 8 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 11β‐hydroxysteroid dehydrogenase. The type 1 isoform of 11β‐hydroxysteroid dehydrogenase functions mainly as a reductase. It is expressed widely in the body and appears to be co‐localized to sites of glucocorticoid receptor expression. The type 2 isoform on the other hand acts as an oxidizing or inactivating enzyme and is predominantly found in the collecting tubules of the kidney, colon, and salivary glands, tissues that express mineralocorticoid receptors.9, 10, 11 Metabolites of licorice selectively inhibit the type 2 isoform of 11β‐hydroxysteroid dehydrogenase, thus explaining the high urinary cortisol levels in patients with licorice toxicity, as was seen in our patient. In addition, the ingestion of glycyrrhetinic acid also results in prolongation of the half‐life of plasma cortisol levels and a corresponding increase in the serum cortisol to cortisone ratio.12 An appreciable mineralocorticoid effect in response to licorice administration in patients with Addison disease is only seen when it is taken with oral cortisone (cortisone acetate) or if there is some residual functional adrenal tissue.12, 13
The differential diagnosis to be considered includes causes of hyperaldosteronism and psuedohyperaldosteronism. In primary and secondary hyperaldosteronism there is an increase in serum aldosterone levels along with low plasma renin activity. In contrast, pseudohyperaldosteronism presents with normal or low serum levels of aldosterone and renin. Rare causes of apparent mineralocorticoid excess include genetic deficiency of 11β‐hydroxysteroid dehydrogenase type 2, which can sometimes present in adulthood. Liddle syndrome, a form of pseudohyperaldosteronism, is an autosomal dominant disorder of the epithelial sodium channels present in the collecting ducts of the kidney, which manifests with hypertension, metabolic alkalosis, and hypokalemia. While it usually presents in childhood, it is often asymptomatic and may remain undiagnosed until adulthood. Congenital adrenal hyperplasia secondary to 17‐α hydroxylase and 11‐hydroxylase deficiency may present similarly as a result of 11‐deoxcorticosterone accumulation, which has aldosterone‐like action; this commonly presents in childhood. Other causes of pseudohyperaldosternism include Cushing syndrome and glucocorticoid resistance syndrome.
Management of licorice‐induced hypermineralocorticoid requires removal of the offending agent and supportive treatment, most commonly potassium supplementation for hypokalemia. Normalization of clinical features and laboratory findings occurs within 2 to 4 months.8 Although the licorice‐induced hypermineralcorticoid state is a well‐described condition, it is uncommon and can be difficult to diagnose. As a result of the ubiquity of licorice additives in common food items, this entity should be considered even if the patient does not report an obvious source of excess licorice ingestion. Eliciting a detailed dietary and medication history can be crucial for making the diagnosis of licorice toxicity, as was seen in this case.
Disclosure
The authors have no conflicts of interest to disclose.
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