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Basic Clin Pharmacol Toxicol. 2019 May;124(5):607-614. doi: 10.1111/bcpt.13178. Epub 2018 Dec 18.

Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study.

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Division of Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, Tokyo, Japan.
Center for Kampo Medicine, Keio University School of Medicine, Tokyo, Japan.
Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Faculty of Environment and Information Studies, Keio University, Kanagawa, Japan.


Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.


chronic hepatitis; glycyrrhetinic acid; glycyrrhizin; hypokalaemia; multidrug resistance-associated protein 2; pseudoaldosteronism


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