Effects of Sodium Valproate Monotherapy on Blood Liver Enzyme Levels in Patients with Epilepsy: A Meta-Analysis

Abstract

We conducted this meta-analysis to assess the effects of sodium valproate (VPA) monotherapy on blood liver enzymes in patients with epilepsy. PubMed, Web of Science, EBSCO, Cochrane Library, Wanfang, China national knowledge infrastructure databases were searched. Nine studies were included. Results showed: (1) The overall SMD for blood AST, ALT, and GGT levels of VPA monotherapy group versus control group were 0.70 (95% CI=0.31 to 1.09, Z=3.52, p=0.0004), 0.47 (95% CI=− 0.01 to 0.95, Z=1.91, p=0.06), 0.44 (95% CI=0.29 to 0.60, Z=5.55, p<0.00001), respectively. (2) In subgroup meta-analysis, increased blood AST and GGT levels were observed in epileptic minors (AST: total SMD=0.85, 95% CI=0.40 to 1.30, Z=3.69, p=0.0002; GGT: total SMD=0.46, 95% CI=0.29 to 0.63, Z=5.25, p<0.00001). Elevated blood ALT level was observed in Asian patients receiving VPA monotherapy (total SMD=0.70, 95% CI=0.51 to 0.90, Z=7.01, p<0.00001), and the early stage of VPA monotherapy (total SMD=0.93, 95% CI=0.57 to 1.29, Z=5.09, p<0.00001). Overall, our results indicated that blood AST and GGT were significantly increased in epileptic minors receiving VPA monotherapy. The elevation of blood ALT was observed in Asian patients and the early stage of VPA monotherapy. However, due to the small number of included studies, our results should be considered with caution.

Key words

sodium valproate - epilepsy - therapy - liver enzymes

Publication History

Received: 03 October 2020

Accepted after revision: 20 May 2021

Article published online:
19 July 2021

• References

• 1 Thijs RD, Surges R, O’Brien TJ. et al. Epilepsy in adults. Lancet 2019; 393: 689-701
• 2 Pearson Smith JN, Patel M. Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci 2017; 18: E2365
• 3 Luoni C, Bisulli F, Canevini MP. et al. Determinants of health-related quality of life in pharmacoresistant epilepsy: Results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia 2011; 52: 2181-2191
• 4 Fadare JO, Sunmonu TA, Bankole IA. et al. Medication adherence and adverse effect profile of antiepileptic drugs in Nigerian patients with epilepsy. Neurodegener Dis Manag 2018; 8: 25-36
• 5 Mullan KA, Anderson A, Illing PT. et al. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA 2019; 93: 417-435
• 6 Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem 2013; 46: 1323-1338
• 7 Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695-714
• 8 Schulpis KH, Karikas GA, Tjamouranis J. et al. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia 2001; 42: 1359-1362
• 9 Li ZY, Liu Y, Wang DZ. et al. Clinical Significance of the Changes of Amino Acid in Children with Epilepsy on Valproate Monotherapy. J Mod Lab Med 2017; 32: 24-31
• 10 Haznedar P, Doğan Ö, Albayrak P. et al. Effects of levetiracetam and valproic acid treatment on liver function tests, plasma free carnitine and lipid peroxidation in childhood epilepsies. Epilepsy Res 2019; 153: 7-13
• 11 Luef G, Rauchenzauner M, Waldmann M. et al. Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res 2009; 86: 42-47
• 12 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097
• 13 Ming Liu. Systematic Review, Design And Implementation of Meta-analysis. Beijing: People’s Medical Publishing House; 2011: 90
• 14 Wells G, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Health Research Institute. 2010
• 15 Callaghan N, Majeed T, O'Connell A. et al. A comparative study of serum F protein and other liver function tests as an index of hepatocellular damage in epileptic patients. Acta Neurol Scand 1994; 89: 237-241
• 16 Čepelak I, Žanić Grubišić T, Mandušić A. et al. Valproate and carbamazepine comedication changes hepatic enzyme activities in sera of epileptic children. Clin Chim Acta 1998; 276: 121-127
• 17 Lv SP, Tan L. Effects of carbamazepine and valproate on thyroid hormone levels in male patients with epilepsy. Med Journal Qilu 2005; 20: 42-45
• 18 Ugras M, Yakinci C. Protein C, protein S and other pro- and anticoagulant activities among epileptic children using sodium valproate. Brain Dev 2006; 28: 549-553
• 19 Dewan P, Aggarwal A, Faridi MM. Effect of phenytoin and valproic acid therapy on serum lipid levels and liver function tests. Indian Pediatr 2008; 45: 855-858
• 20 Saleh DA, Ismail MA, Ibrahim AM. Non alcoholic fatty liver disease, insulin resistance, dyslipidemia and atherogenic ratios in epileptic children and adolescents on long term antiepileptic drug therapy. Pak J Biol Sci 2012; 15: 68-77
• 21 Xu X, Guo C, Liang X. et al. Potential biomarker of fibroblast growth factor 21 in valproic acid-treated livers. Biofactors 2019; 45: 740-749
• 22 Banerjea MC, Diener W, Kutschke G. et al. Pro- and anticoagulatory factors under sodium valproate-therapy in children. Neuropediatrics 2002; 33: 215-220
• 23 Societas Neurologica Japonica In: Guideline for Epilepsy Diagnose and Treatment in Japan. Igaku-Shoin Ltd; Tokyo: 2010
• 24 Guo HL, Jing X, Sun JY. et al. Valproic Acid and the Liver Injury in Patients With Epilepsy: An Update. Curr Pharm Des 2019; 25: 343-351
• 25 Surendradoss J, Chang TKH, Abbott FS. Assessment of the Role of in Situ Generated (E)-2,4-diene-valproic Acid in the Toxicity of Valproic Acid and (E)-2-ene-valproic Acid in Sandwich-Cultured Rat Hepatocytes. Toxicol Appl Pharmacol 2012; 264: 413-422
• 26 Jafarian I, Eskandari MR, Mashayekhi V. et al. Toxicity of Valproic Acid in Isolated Rat Liver Mitochondria. Toxicol Mech Methods 2013; 23: 617-623
• 27 Jin J, Xiong T, Hou X. et al. Role of Nrf2 activation and NF-kB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice. Food Chem Toxicol 2014; 73: 95-104
• 28 Yagi M, Nakamura T, Okizuka Y. et al. Effect of CPS14217C>A genotype on valproic-acid-induced hyperammonemia. Pediatr Int 2010; 52: 744-748
• 29 Fukushima Y, Seo T, Hashimoto N. et al. Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gamma-glutamyltransferase in valproic acid-treated patients. Clin Chim Acta 2008; 389: 98-102
• 30 Saruwatari J, Deguchi M, Yoshimori Y. et al. Superoxide dismutase 2 Val16Ala polymorphism is a risk factor for the valproic acid-related elevation of serum aminotransferases. Epilepsy Res 2012; 99: 183-186
• 31 Star K, Edwards IR, Choonara I. Valproic acid and fatalities in children: A review of individual case safety reports in VigiBase. PLoS One 2014; 9: e108970
• 32 Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia 2002; 43: 53-59
• 33 Wang L, Ren G, Li J. et al. Genetic polymorphism analysis of cytochrome P4502E1 (CYP2E1) in a Chinese Tibetan population. Medicine (Baltimore) 2017; 96: e8855
• 34 Mu G, Xiang Q, Zhou S. et al. Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis. Pharmacogenomics 2019; 20: 189-212
• 35 Physicians Desk Reference. Sodium Valproate 53rd ed.. Montvale, NJ: Medical Economics; 1999: 417-419