Potassium chloride mixture may maintain hypokalaemia and hypertension

Abstract

Hypokalaemia can be treated with potassium chloride mixture. Some mixtures contain liquorice extract (glycyrrhizin) as a supplement to improve taste. Glycyrrhizin can cause pseudohyperaldosteronism and thereby result in hypertension and hypokalaemia. We here present a case where treatment with potassium chloride mixture causes hypertension and hypokalaemia in a 50-year-old woman. After unravelling differential diagnosis, the potassium chloride mixture was stopped. After the discontinuation, the patient’s blood pressure was well managed and the potassium levels normalised.

Background

Patients with hypokalaemia can be treated with oral potassium chloride supplements as tablets or mixture. There are two potassium mixture products used clinically in Denmark. To improve the taste, both contain extract of liquorice in the form of glycyrrhizin.

The glycyrrhizin taste is used in the Scandinavian countries, whereas flavours like cherry and orange are used elsewhere in Europe (Pharma-Skan, Skanderborg, Denmark).

Worldwide, liquorice is frequently used in tea and herbal medicine.

Case presentation

A 50-year-old, normal-weight, formerly healthy woman was referred by her general practitioner to the nephrology outpatient clinic due to hypertension (during 6 years) and hypokalaemia (during 2 years). Due to chest discomfort, the patient was initially investigated with normal coronary arteriography, echocardiography and gastroscopy.

Both office ambulatory blood pressure and 24 hours measurement of blood pressure showed hypertension; 145–150/90–95 mm Hg during treatment with verapamil slow release (Isoptin SR) 120 mg two times daily. Plasma potassium level was 3.2 mmol/L—despite treatment with 25 mL potassium chloride mixture two times daily (50 mmol daily).

The reason the potassium chloride subsidy had been initiated in the first place remains unclear but was thought as a supplement to previous diuretic treatment (as antihypertensive purpose) which in the meantime had been discontinued.

The patient had no excess intake of liquorice extract apart from that contained in the potassium chloride mixture.

Investigations

The initial investigation showed normal ultrasound of kidneys and urinary tract, normal captopril renography with equal distribution between right and left kidney, normal renal function and no proteinuria.

Plasma renin was immeasurably low (<2 mIU/L), plasma aldosterone was low in the normal range (80 pmol/L). Bicarbonate was high in the normal range (26 mmol/L), the pH was not measured. Plasma free cortisol was normal (221 nmol/L). Unfortunately, free cortisone was not measured. Plasma magnesium was normal (0.95 mmol/L). The urinary excretion of potassium was high (45 mmol/L) indicating a renal loss of potassium. Additional biochemistry was found unremarkable.

Treatment

As the patient had noticed the taste of liquorice in the potassium chloride mixture, it was recognised that the mixture did indeed contain extract of liquorice, and the patient discontinued this supplement.

Outcome and follow-up

In subsequent controls, the patient’s plasma potassium was normal (3.9 mmol/L) and blood pressure was now well controlled on the calcium antagonist treatment alone (128/81 mm Hg).

After a further 1-year observation without potassium chloride supplements, the patient continued to have stable normal blood pressure (125/80 mm Hg) on medical treatment with verapamil slow release and normal plasma potassium (3.6 mmol/L).

Discussion

Glycyrrhizin is known to inhibit type 2 isoenzyme for 11-β-hydroxysteroid dehydrogenase type 2 (11-β-HSD2). 11-ß-HSD2 converts cortisol to cortisone.¹ Glycyrrhizin, therefore, causes increased plasma cortisol/cortisone ratio (figure 1). Cortisol has a greater effect on the mineralocorticoid receptor than cortisone, thus resulting in increased mineralocorticoid activity, so-called pseudohyperaldosteronism.² Furthermore, glycyrrhizin seems to have a minor direct stimulating effect on the mineralocorticoid receptors in the kidney, and inhibits the metabolism of aldosterone (figure 1).³

Figure 1.

It shows the mechanism of action of liquorice (glycyrrhizin) in pseudohyperaldosteronism. 11-β-HSD2, 11-β-hydroxysteroid dehydrogenase; MCR, mineralocorticoid receptor.

Patients with pseudohyperaldosteronism present with symptoms that imitate hyperaldosteronism such as sodium retention, oedema, hypokalaemia, metabolic alkalosis, but low plasma aldosterone.⁴

In this case, potassium chloride mixture containing glycyrrhizin is expected to maintain hypertension and hypokalaemia in a middle-aged woman already getting antihypertensive treatment.

When suspected as a maintenance or contributory cause, it was discontinued, after which the blood pressure decreased and the potassium level normalised.

Studies have suggested that an intake of as little as 100 mg glycyrrhizin daily may cause pseudohyperaldosteronism and hence hypertension and hypokalaemia.^{5 6} The patient in this case administered 50 mL daily of potassium chloride solution, corresponding to a total of 111 mg glycyrrhizin (stated by the manufacturer) or approximately 72 g of liquorice (keeping in mind that glycyrrhizin content in liquorice may vary from 0.27 to 7.9 mg/g⁷) (figure 2).

Figure 2.

It shows the amount of liquorice the patient’s daily intake of potassium chloride may equal. The amount of glycyrrhizin in liquorice may vary from 0.27 to 7.9 mg/g.⁷

Several differential diagnoses were considered in the investigation process. Unilateral renal artery stenosis was excluded by captopril renography, primary and secondary hyperaldosteronism was excluded by low levels of renin and aldosterone, and the fact that the condition was reversible invalidates genetic causes (such as the rare biallelic loss-of-function mutations in the enzyme βHSD2; apparent mineralocorticoid excess or congenital adrenal hyperplasia).

The treatment with potassium chloride mixture as a maintenance cause was therefore a likely cause. The effect of the discontinuation supports this theory.

Learning points.

• Liquorice contains glycyrrhizin which can lead to pseudohyperaldosteronism.

• Pseudohyperaldosteronism is characterised by hypertension, hypokalaemia and metabolic alkalosis.

• Potassium chloride mixture contains liquorice (glycyrrhizin) and may lead to pseudohyperaldosteronism and thereby maintains low plasma potassium concentration.