Benzodiazepine-Associated Hepatic Encephalopathy Significantly Increased Healthcare Utilization and Medical Costs of Chinese Cirrhotic Patients: 7-Year Experience
Background and Objectives
In cirrhosis, hypersensitivity to benzodiazepines (BZD) and precipitating hepatic encephalopathy (HE) have been reported. The aim of this study was to evaluate the safety, economic impact and modifiable factors that are associated with the excess risk of BZD-associated HE in cirrhotic patients.
Between July 2005 and March 2012, 1,612 Chinese cirrhotic patients with and without using long-t 1/2-BZD or short-t 1/2-BZD were enrolled and followed up for 6 months.
Among BZD users, the per-person HE-related healthcare utilization and medical costs were found to have progressively increased from 2005 to 2012. Cirrhotic BZD users had a higher percentage of smoking, alcohol drinking, simultaneous consumption of non-BZD drugs, and had a higher incidence of non-cirrhotic chronic illness than non-BZD users. Multivariate analysis indicated that hypoalbuminemia (<3 g/dL), long-acting (t 1/2 > 12-h), high-dosage (>1.5 defined daily dose equivalents) and long-duration (>2-months) BZD use, carrier of variant genotypes (AG + GG) of GABRA 1 (rs2290732) and having the wild genotype (TT) of GABRG 2 (rs211037) were significant predictors of the development of BZD-associated HE in cirrhotic patients. Additionally, synergistic effects of the above significant predictors on BZD-associated HE risk could be identified.
Our study confirms the clinical and economic impact of BZD-associated HE in cirrhotic BZD-users. Accordingly, extra caution is needed when treating cirrhotic BZD users with the above risk factors in order to avoid the BZD-associated HE in cirrhotic patients.
KeywordsBenzodiazepines Hepatic encephalopathy Cirrhotic patients GABRA genotype
This work was funded by research grants NSC100-2314-B-010-059-MY3 and NSC 101-2314-B-075-011-MY3 from the National Science Council, and V102C-014 and V102C-016 by the Taipei Veterans General Hospital. The authors thank members of the Division of Taiwan’s National Health Insurance (NHI) medical costs statistic center, Taipei Veterans General Hospital; Lin Yu-Zhen, Huang Jing-Han, Wei Xiu-Mei and Peng Chi-Yi for their excellent technical assistances.
Conflict of interest
- 7.Barakdi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine receptor in hepatic encephalopathy due to fuliminat hepatic failure in the rat: reversal by a benzodiazepine antagonist. Clin Sci. 1984;67:167–175.Google Scholar
- 11.Schafer DF, Fowler JM, Munson PJ, Thakur AK, Waggoner JG, Jones EA. Gamma-aminobutyric acid and benzodiazepine receptors in an animal model of fulminant hepatic failure. J Lab Clin. 1983;102:870–880.Google Scholar
- 17.Yang YY, Lin HC, Lee WP, et al. Association of the G-protein and alpha-2 adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of effects of diuretics in cirrhotic patients with refractory ascites: a randomized clinical trial. Gut. 2010;59:1545–1553.PubMedCrossRefGoogle Scholar
- 20.Guidelines for ATC Classification and DDD Assignment. Oslo, Norway, World Health Organization, Collaborating Centre for Drug Statistic Methodology; 2009.Google Scholar
- 38.Conn HO, Lieberthal MM. The hepatic coma syndromes and lactulose. Baltimore, MD: Williams and Wilkins; 1979:214.Google Scholar