A rare case of apparent mineralocorticoid excess induced by chronic liquorice ingestion

Abstract

Summary

Apparent mineralocorticoid excess (AME) syndrome is a rare condition caused by the inhibition of the renal enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The most common acquired cause is chronic liquorice ingestion. We report the case of a 61-year-old woman who developed profound hypokalaemia, metabolic alkalosis, and QT prolongation due to excessive liquorice tea consumption. This case underscores the importance of detailed dietary history in patients with unexplained electrolyte disturbances and demonstrates the potentially fatal cardiovascular consequences of a widely available herbal remedy.

Learning points

• Hypokalaemia may present subtly but can carry life-threatening risks.

• Apparent mineralocorticoid excess should be considered in patients with resistant hypokalaemia and unexplained hypertension.

• A thorough dietary and over-the-counter medication history is essential in the evaluation of electrolyte disorders.

• Liquorice, although natural, can exert potent physiological effects with severe clinical consequences.

Background

Liquorice, derived from Glycyrrhiza glabra, has been used for centuries in traditional medicine and remains popular today in herbal teas and over-the-counter preparations for gastrointestinal symptoms (1). Its principal active compound, glycyrrhizin, is metabolised to glycyrrhetinic acid, which inhibits 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the distal nephron. This enzyme normally converts cortisol to its inactive metabolite cortisone, preventing inappropriate activation of the mineralocorticoid receptor. Inhibition of 11β-HSD2 leads to cortisol-mediated mineralocorticoid receptor activation, resulting in sodium retention, potassium wasting, hypertension, and metabolic alkalosis – collectively known as apparent mineralocorticoid excess (AME) (2).

Recent narrative reviews have emphasised that liquorice toxicity remains under-recognised, despite well-documented reports of severe hypertension, rhabdomyolysis, arrhythmias, and sudden cardiac death associated with excessive glycyrrhizin ingestion (3). Failure to identify the culprit exposure may lead to unnecessary investigations, including adrenal imaging, genetic testing, or invasive procedures. While regulatory assessments regard 100 mg of glycyrrhizin per day as safe, cases of liquorice-induced hypertension and electrolyte disturbance have been reported at much lower doses, highlighting marked inter-individual variability in glycyrrhetinic acid sensitivity (3). If unrecognised, liquorice-induced AME can precipitate life-threatening electrolyte abnormalities and malignant arrhythmias.

Case presentation

A 61-year-old Caucasian woman was referred for persistent hypokalaemia over the previous 4 months that was unresponsive to oral potassium replacement. She reported light-headedness and intermittent palpitations. Her medical history included hypothyroidism, Barrett’s oesophagus, iron deficiency anaemia, and gastritis. Medications included levothyroxine 25 μg once daily, amitriptyline 10 mg once at night, omeprazole 20 mg twice daily, and famotidine 40 mg once at night. She was otherwise well, with a diet rich in fruits and vegetables. Her general practitioner had initiated oral potassium, 24 mmol three times daily, with no improvement.

Vital signs on admission were as follows: heart rate: 88 bpm, blood pressure: 165/90 mmHg, SpO₂: 100% on room air, temperature: 36.8°C, and respiratory rate: 14/min. Physical examination was unremarkable.

Investigation

ECG revealed sinus rhythm, frequent premature ventricular complexes, and a prolonged corrected QT interval (QTc: 581 Ms). See Table 1 for initial laboratory investigations. Arterial blood gas analysis revelaed pH: 7.48, HCO₃⁻: 38.7 mmol/L, and base excess: +15.2 mmol/L.

Table 1.

Initial laboratory investigations on admission.

Parameter	Value	Reference range
Serum potassium, mmol/L	2.8	3.5–5.1
Serum sodium, mmol/L	143	135–145
Serum magnesium, mmol/L	1.0	0.7–1.0
Serum phosphate, mmol/L	0.82	0.8–1.5
Serum adjusted calcium, mmol/L	2.29	2.2–2.6
Serum creatinine, μmol/L	79	60–110
ALT, U/L	22	<40
ALP, U/L	62	40–129
Bilirubin (total), μmol/L	8	<21
Morning cortisol, nmol/L	432	160–550

The patient’s historical potassium values from her medical records over the 4-month period ranged from 2.7 to 3.2 mmol/L. Despite aggressive intravenous potassium replacement (40 mmol), her levels remained static. A detailed history revealed the consumption of more than five cups of liquorice tea daily over the previous 4 years. The diagnosis of AME was made.

Treatment

All liquorice products were discontinued. Spironolactone 25 mg once daily was initiated.

Outcome and follow-up

Three days later, metabolic alkalosis improved (HCO₃⁻: 34.3 mmol/L; base excess: +10.0), but potassium remained low. By day 10, potassium had risen to 5.3 mmol/L, pH was 7.34, HCO₃⁻ was 29.2 mmol/L, and base excess was +3.5. Blood pressure stabilised at 120/60 mmHg, and the QTc interval returned to normal.

Discussion

This case represents a severe manifestation of acquired AME caused by chronic liquorice ingestion, characterised by refractory hypokalaemia, marked metabolic alkalosis, hypertension, and significant QT prolongation. These features align with the known biochemical effects of glycyrrhizin-mediated 11β-HSD2 inhibition, which permits cortisol to inappropriately activate mineralocorticoid receptors and produce a phenotype indistinguishable from aldosterone excess (1, 2). Persistent hypokalaemia, despite aggressive replacement, suggested ongoing mineralocorticoid excess, and the rapid improvement following liquorice cessation further supported the diagnosis. The diagnostic process was limited by the absence of renin and aldosterone measurements, which are typically suppressed in liquorice-induced AME. However, the compelling history of heavy liquorice intake, the classic biochemical profile, and complete recovery following withdrawal and spironolactone provided strong causal evidence and prevented unnecessary endocrine investigations. The differential diagnosis of hypertension with hypokalaemia and metabolic alkalosis includes primary hyperaldosteronism, Liddle’s syndrome, congenital AME, acquired AME, renal artery stenosis, and renin-secreting tumours. These are compared in Table 2. Excessive liquorice ingestion can produce a syndrome closely resembling congenital AME (via 11β-HSD2 inhibition), but, unlike the inherited genetic disorder, the liquorice-induced form is acquired and, in most cases, reversible upon withdrawal of the offending agent (2). Recent literature highlights liquorice toxicity as an increasingly recognised clinical and public health issue. Severe hypertension, rhabdomyolysis, arrhythmias, and sudden cardiac death have been reported with excessive glycyrrhizin intake (3). The broad review by Wahab et al. confirms the potent biological activity of Glycyrrhiza glabra even in ‘natural’ preparations (1). Pharmacovigilance reports, including those from the FDA Adverse Event Reporting System, further emphasise the frequency of liquorice-associated hypertension and electrolyte disturbances, underscoring the need for regulatory attention. Toxicological assessments have proposed a tentative acceptable daily intake (ADI) of glycyrrhizin of ∼0.2 mg/kg/day, yet ingestion via common herbal teas or confectionery may easily exceed this threshold (3, 4). More recent studies have provided further mechanistic and clinical insights. A narrative review identified older age, low albumin, constipation, and concomitant diuretics as major risk factors that enhance glycyrrhizin-metabolite bioavailability and predispose to pseudo-hyperaldosteronism (5). A randomized crossover trial demonstrated that even low-dose liquorice (100 mg glycyrrhizin/day) significantly raised blood pressure and suppressed renin and aldosterone in healthy adults (6). These findings underscore that clinically relevant mineralocorticoid-like effects may occur at much lower exposure levels than previously recognized, especially in susceptible individuals. This case reinforces key clinical lessons: resistant hypokalaemia should always prompt evaluation for mineralocorticoid excess, ECG monitoring is crucial due to arrhythmic risk, and comprehensive dietary histories are essential, as herbal products are often overlooked. The dramatic clinical improvement following cessation of liquorice consumption underscores the importance and reversibility of this condition when promptly diagnosed. Improved patient education, clearer food labelling, and heightened clinical awareness are essential to prevent liquorice-induced AME.

Table 2.

Differential diagnoses of hypertension with hypokalaemia and metabolic alkalosis. Comparison of biochemical profiles, clinical features, aetiology, and management of major causes, including primary hyperaldosteronism, Liddle’s syndrome, congenital and liquorice-induced apparent mineralocorticoid excess, renal artery stenosis, and renin-secreting tumours.

Condition	Renin (expected)	Aldosterone (expected)	Key features	Aetiology	Typical treatment
Primary hyperaldosteronism	Low	High	Hypertension, hypokalaemia, metabolic alkalosis	Adrenal adenoma or hyperplasia	MR antagonists; adrenalectomy, if unilateral
Liddle’s syndrome	Low	Low	Early-onset HTN, hypokalaemia, metabolic alkalosis	ENaC gain-of-function mutation	Amiloride/triamterene
Congenital AME	Low	Low	Severe childhood HTN, failure to thrive	11β-HSD2 mutation	MR antagonists; low-salt diet
Liquorice-induced AME (this case)	Low*	Low*	Resistant hypokalaemia, hypertension, QTc prolongation	Glycyrrhizin inhibition of 11β-HSD2 (acquired)	Withdrawal of liquorice; MR antagonists
Renal artery stenosis	High	High	Hypertension (often resistant), hypokalaemia, renal bruit, impaired kidney function	Reduced renal perfusion → secondary hyperaldosteronism	Revascularisation; ACE inhibitors/ARBs
Renin-secreting tumour (reninoma)	High	High	Severe hypertension, hypokalaemia, metabolic alkalosis; usually young patients	Juxtaglomerular cell tumour	Surgical excision

^*Expected pattern from published cases, not measured here.

HTN, hypertension; AME, apparent mineralocorticoid excess; MR, mineralocorticoid receptor; ENaC, epithelial sodium channel; QTc, corrected QT interval; ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for the publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

Both authors contributed equally to patient management, data collection, manuscript drafting, and critical revision. Both authors approved the final version for submission.