Elevated direct bilirubin: Possible predictors for pseudoaldosteronism: Case–control study

Abstract

Aim: Pseudoaldosteronism is a known side-effect of licorice, and Japanese traditional Kampo medicine is one of the major areas of use of licorice in Japan. Multidrug resistance protein 2 (Mrp2) dysfunction is important for pseudoaldosteronism. Congenital deficiency of Mrp2 causes constitutional jaundice with elevated direct bilirubin. Hence, elevated direct bilirubin can be a biomarker of Mrp2 dysfunction. The relationship between pseudoaldosteronism and elevated direct bilirubin, however, has not been studied as yet. The aim of the present study was therefore to evaluate the relationship between elevated direct bilirubin and hypokalemia, an important characteristic of pseudoaldosteronism. Methods: This retrospective observational study included patients who first visited the Kampo Clinic at Keio University Hospital between May 2008 and March 2015. Inclusion criteria were Kampo formulas including licorice prescribed for >2 weeks, and availability of laboratory data on direct bilirubin and change in serum potassium. Results: Data from 243 patients (57 men, 186 women) were used in the analysis. Mean age was 52.0 AE 16.2 years. Hypokalemia was noted in three patients (1.3%), among whom elevated direct bilirubin was noted in two (0.9%). The remaining patient with hypokalemia was diagnosed with pseudo-Bartter's syndrome because of loop diuretic use. The remaining 240 patients had neither hypokalemia nor elevated direct bilirubin (P = 0.0001, Fisher's exact test). Conclusion: Elevated direct bilirubin is an important predictor of pseudoaldosteronism.

Liquorice-induced hypokalaemia in patients treated with Yokukansan preparations: identification of the risk factors in a retrospective cohort study

“…Since 99.9% of circulating GA are bound to albumin, 29 hypoalbuminaemia may increase the unbound fraction of GA through pharmacokinetic alteration, resulting in an enhancement of the pharmacological actions of GA. Yoshino and colleagues have suggested that hypoalbuminaemia was a risk factor for pseudoaldosteronism in three other Kampo-medicines. 30 The present results are the first to report that hypoalbuminaemia is a possible risk factor for liquorice-induced hypokalaemia due to YK preparations.…”

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

“…We used the cut‐off values applied by the Department of Laboratory Medicine at Keio University Hospital. We also applied additional conditions for each definition according to our previous report . An elevated D‐Bil level was defined as the presence of ≥2 readings of ≥0.3 mg/dL during the study period.…”

“…Dubin‐Johnson syndrome involves congenital dysfunction of Mrp2 and is characterized by elevated D‐Bil levels . We published a small retrospective cohort study that described patients with probable pseudoaldosteronism who also had elevated D‐Bil levels …”

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

“…Therefore, hypoalbuminemia may be an important risk factor for PsA. Indeed, hypoalbuminemia has been identified as a risk factor in patients receiving yokukansan, which contains 1.5 g of licorice daily (49), as well as in other case series (50,51).…”

“…When bile excretion of GA3S is suppressed due to Mrp2 dysfunction (Figure 2), GA3S is transferred into the blood circulation. We have previously highlighted the involvement of Mrp2 in the biliary excretion of GL metabolites in rats (27,34,35) and possibly in humans (50,51). GL metabolites significantly accumulate in the EHBR (27,34,35).…”