Download PDF
Horm Metab Res 2021; 53(07): 425-434
DOI: 10.1055/a-1517-6550
Review

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

Jie Fu
1   Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
,
Tao Tao
1   Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, China
,
Zuoxiao Li
1   Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, China
,
Yangmei Chen
2   Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
,
Xiu Chen
1   Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, China
,
Jinglun Li
1   Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, China
,
Lilei Peng
3   Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, China
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

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

Supplementary Material



Publication History

Received: 03 October 2020

Accepted after revision: 20 May 2021

Article published online:
19 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Thijs RD, Surges R, O’Brien TJ. et al. Epilepsy in adults. Lancet 2019; 393: 689-701
    CrossrefPubMedGoogle Scholar
  • 2 Pearson Smith JN, Patel M. Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci 2017; 18: E2365
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 5 Mullan KA, Anderson A, Illing PT. et al. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA 2019; 93: 417-435
    CrossrefPubMedGoogle Scholar
  • 6 Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem 2013; 46: 1323-1338
    CrossrefPubMedGoogle Scholar
  • 7 Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695-714
    CrossrefPubMedGoogle Scholar
  • 8 Schulpis KH, Karikas GA, Tjamouranis J. et al. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia 2001; 42: 1359-1362
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 13 Ming Liu. Systematic Review, Design And Implementation of Meta-analysis. Beijing: People’s Medical Publishing House; 2011: 90
    Google Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 22 Banerjea MC, Diener W, Kutschke G. et al. Pro- and anticoagulatory factors under sodium valproate-therapy in children. Neuropediatrics 2002; 33: 215-220
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Societas Neurologica Japonica In: Guideline for Epilepsy Diagnose and Treatment in Japan. Igaku-Shoin Ltd; Tokyo: 2010
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 32 Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia 2002; 43: 53-59
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 35 Physicians Desk Reference. Sodium Valproate 53rd ed.. Montvale, NJ: Medical Economics; 1999: 417-419
    Google Scholar