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• Re: Liquorice-induced hypokalaemia in patients treated with Yokukansan preparations: identification of the risk factors in a retrospective cohort study
  Tetsuhiro Yoshino
  Published on: 23 March 2018

• Published on: 23 March 2018

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

  • Tetsuhiro Yoshino, Instructor Center of Kampo Medicine, Keio University School of Medicine

  We read, with great interest, the retrospective cohort study by Shimada et al. on liquorice-induced hypokalaemia in patients treated with Yokukansan (YK) preparations (1). Their findings suggest that monitoring of serum potassium should be performed at least monthly in patients with the following risk factors: YK administration, co-administration of potassium-lowering drugs, hypoalbuminaemia, and administration of a full dose of YK preparation. These recommendations can be easily applied in a daily clinical setting, and might reduce future pseudoaldosteronism cases. However, we would like to highlight two points that we believe should be considered when interpreting the results of the study.

  Our first concern is the uncertainty of the criteria for selecting variables in the Cox proportional hazard model.

  Table 3, “Demographic data of the subjects”, shows the P value of each item.
  The authors included items with P value < 0.05 in the Cox proportional hazard model, namely YK administration, co-administration of potassium-lowering drugs, hypoalbuminaemia, administration of a full dose of YK preparation, and baseline serum potassium. At the same time, sex and age were included in the model shown in table 4 even though they had P values > 0.05.

  As been pointed out by one reviewer, Eiseki Usami, authors should clarify a relationship between table 3 and 4. If authors have analyzed all items in table 3, it should be mentioned and shown in table 4 a...

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  We read, with great interest, the retrospective cohort study by Shimada et al. on liquorice-induced hypokalaemia in patients treated with Yokukansan (YK) preparations (1). Their findings suggest that monitoring of serum potassium should be performed at least monthly in patients with the following risk factors: YK administration, co-administration of potassium-lowering drugs, hypoalbuminaemia, and administration of a full dose of YK preparation. These recommendations can be easily applied in a daily clinical setting, and might reduce future pseudoaldosteronism cases. However, we would like to highlight two points that we believe should be considered when interpreting the results of the study.

  Our first concern is the uncertainty of the criteria for selecting variables in the Cox proportional hazard model.

  Table 3, “Demographic data of the subjects”, shows the P value of each item.
  The authors included items with P value < 0.05 in the Cox proportional hazard model, namely YK administration, co-administration of potassium-lowering drugs, hypoalbuminaemia, administration of a full dose of YK preparation, and baseline serum potassium. At the same time, sex and age were included in the model shown in table 4 even though they had P values > 0.05.

  As been pointed out by one reviewer, Eiseki Usami, authors should clarify a relationship between table 3 and 4. If authors have analyzed all items in table 3, it should be mentioned and shown in table 4 at least as results of univariate analyses. It looks like two laboratory test parameters with P values < 0.05 have been removed from the model; alanine aminotransferase (ALT) and blood urea nitrogen. Makino et al. reported that liver fibrosis affected the pathogenesis of pseudoaldosteronism via decreased function of multidrug resistance-associated protein 2 (2), and some clinical scores show that ALT is a good marker of liver fibrosis (3,4). Therefore, including these items in the model is both statistically and physiologically reasonable.

  Another concern is the handling of continuous variables, baseline serum potassium level and age, in the Cox proportional hazard model.
  The authors considered baseline serum potassium level as a binary variable in the analysis, although it was originally a continuous variable, and the threshold value (≧4.1 mEq/L) was established by additional analysis. Conversely, age was considered a continuous variable and the authors did not perform the same additional analysis. The authors could avoid such discrepancy by handling continuous variables in the same manner.

  In addition, the range of age in their data is roughly 50-90 years, and the variable has approximately 40 units. It is vital to check the proportionality of age with the Schoenfield residual plot. If outliers exist, especially in the younger age, this variable could have many more units. The Cox proportional hazard model is very prone to being distorted by even a few outliers. Furthermore, it is difficult to compare the hazard ratio of age with that of the other binary variables, which only have one unit (0 or 1), even if there was a significant effect of age.

  Two more minor points are the lack of the number at risk in the bottom of Kaplan-Mayer curve and information of observation period in the method section.

  Overall, we congratulate the authors on their interesting and clinical-oriented research. The spread of alternative and complementary medicine opens up a new problem, one of safety. Humans now have greater longevity than humans did in the ancient era when many traditional herbal formulas were developed. Healthcare providers should be cautious about side effects of alternative and complementary medicines, especially elderly patients with slower drug metabolism and excretion. More studies should be conducted regarding the pharmacokinetics of compounds made from liquorice, and the clinical risk factors of pseudoaldosteronism in other populations.

  References
  1. Shimada S, Arai T, Tamaoka A, et al. Liquorice- induced hypokalaemia
  in patients treated with Yokukansan preparations: identi cation of the risk factors in a retrospective cohort study. BMJ Open 2017;7:e014218. doi:10.1136/ bmjopen-2016-014218

  2. Makino T, Ohtake N, Watanabe A, et al. Down-Regulation of a Hepatic Transporter Multidrug Resistance-Associated Protein 2 Is Involved in Alteration of Pharmacokinetics of Glycyrrhizin and Its Metabolites in a Rat Model of Chronic Liver Injury. Drug Metab Dispos 2008;36:1438-43. doi:10.1124/dmd.108.021089

  3. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M, APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun; 43(6):1317-25. doi:10.1002/hep.21178

  4. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069-1075. doi:10.1016/S0140-6736(00)04258-6

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  Conflict of Interest:
  None declared.

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