T60 - Investigating The Role Of One-Carbon Metabolism Pathway In Complicated Alcohol Withdrawal States

Abstract

Background Complicated withdrawal states in alcohol dependence syndrome (ADS) include alcohol withdrawal seizures (AWS) and delirium tremens (DT) and are associated with significant medical and psychiatric morbidity. Existing evidence suggests that in patients with chronic ADS, the associated deficiency of vitamin B12 and folic acid could lead to hyperhomocysteinemia through the inhibition of methionine synthase (MS) and methylene tetrahydrofolate reductase (MTHFR) enzymes of the one-carbon metabolism pathway. Hyperhomocysteinemia has been found to be associated with complicated alcohol withdrawal especially withdrawal seizures (AWS). The common variant of the MS A2756G gene has been found to be associated with lower plasma homocysteine levels. The homozygote variant of the MTHFR A1298C gene results in partial loss of enzyme activity. Thus, it may be worthwhile to study the above SNPs in patients with complicated alcohol withdrawal states and correlate the findings with plasma homocysteine, vitamin B12 and folate levels. Methods In our study, we aimed to investigate the association of MTR A2756G (responsible for the MS enzyme) and MTHFR A1298C polymorphisms with complicated withdrawal states i.e. AWS and delirium tremens (DT). We also measured levels of plasma homocysteine, vitamin B12 and folate in these patients. The sample consisted of a total of 150 male patients with ADS of which 84 patients had simple withdrawal state (SWS), 30 patients had DT and 36 patients had AWS. Assessments included a general physical examination, biochemistry panel, a complete blood count, assays of plasma homocysteine, vitamin B12 and folate along with genotyping for the MTR A2756G and MTHFR A1298C polymorphisms. Results There was no difference in the mean age at onset of dependence (SWS - 28.2 ± 5.7; DT - 28.2 ± 4.6; AWS - 27.9 ± 5, F = 0.03, p = 0.9). However, there was a significant association between the mean daily units of alcohol consumed and complicated alcohol withdrawal states. (SWS - 13.6 ± 3.7; DT - 19.8 ± 3.9; AWS - 17.1 ± 4.9, F = 27.8, p The study also found no differences in the serum homocysteine levels (SWS – 0.91; DT – 0.91; AWS – 0.88 nmol/ml, t = 0.9, p = 0.6), vitamin B12 levels (SWS – 274; DT – 265; AWS – 230 pg/ml, t = 1.2, p = 0.5), and folate levels (SWS – 99.3; DT – 99.1; AWS – 98.2 pg/ml, t = 2.4, p = 0.1). Although vitamin B12 and folic acid levels fell in the lower end of the normal range, no deficiency states were observed. No association was found between levels of plasma homocysteine, vitamin B12 & folic acid levels and complicated alcohol withdrawal states. No significant differences were found between the groups with respect to haematological and biochemical parameters examined. The two groups did not differ significantly with respect to genotype frequency of the SNPs examined (MTHFR A1298C and MTR A2756G). Discussion Our study finds that it is the quantity of alcohol consumed in a day that is associated with complicated withdrawal states with frequent heavy drinkers more likely to have severe withdrawal. It would be worthwhile to explore this further as no clear genetic risk factors emerged. The study was limited by its sample size, the use of cross-sectional sampling method and the exclusion of female patients from the study. However, it is one of the first studies to examine these SNPs in a south Indian population. The role of the one-carbon metabolism pathway in these states remains an important area of research with numerous possible treatment implications.