The effect of magnesium administration on erythrocyte transketolase activity in alcoholic patients treated with thiamine

Abstract

Background and aims

Chronic alcoholic patients are at increased risk of developing deficiencies of thiamine and magnesium. Thiamine is an essential co-factor for a number of enzymes involved in carbohydrate metabolism and requires optimal levels of magnesium for biological function. However, whilst thiamine supplementation is well established for the treatment of alcoholic patients, the importance of magnesium is often overlooked. We describe the effect of concurrent thiamine and magnesium administration on the activity of the thiamine-dependent enzyme erythrocyte transketolase in a cohort of chronic alcoholic patients.

Methods

Baseline erythrocyte transketolase activities were measured on blood samples collected from 36 chronic alcoholic patients presenting acutely to the Accident and Emergency department. Patients received either intravenous Pabrinex (thiamine) supplemented with magnesium sulphate (n = 18) or Pabrinex only (n = 18). Post-treatment bloods were collected for re-assessment of erythrocyte transketolase activity. The change in transketolase activities (pre-vs. post-treatment) between the two patient groups were compared by Mann-Whitney U test.

Results

The increase in transketolase activity following treatment in the cohort receiving Pabrinex supplemented with magnesium sulphate was significantly greater (p = 0.018) than that produced in the cohort receiving Pabrinex alone.

Conclusion

In the acute management of a sample of chronic alcoholic patients, those receiving magnesium sulphate with Pabrinex have higher increases in erythrocyte transketolase activity compared with those receiving Pabrinex alone. We conclude that concurrent magnesium administration with Pabrinex may be required for enabling full efficacy of Pabrinex treatment, as demonstrated by its positive effect on erythrocyte transketolase activity.

Keywords

Pabrinex Wernicke’s encephalopathy Korsakoff’s psychosis co-factor magnesium sulphate

Introduction

Scotland has the highest rate of alcohol-related deaths in the UK.¹ Amongst the various disease states induced by excessive alcohol consumption are the development of alcohol-related brain damage. Wernicke’s encephalopathy (WE), a disorder of the central nervous system classically characterised by loss of brain function, is caused in chronic alcoholic patients as a result of a deficiency of thiamine (Vitamin B₁).

Multiple doses of thiamine are usually required to replenish stores and prevent progression to irreversible Korsakoff’s psychosis. Chronic alcoholics have a 30–80% incidence of clinical or biochemical signs of thiamine deficiency. WE is not a rare disorder. Autopsy studies have revealed a prevalence of 1–2% in western society among the general population. The full triad of symptoms (confusion, ataxia and ophthalmoplegia) is present in only 12% of WE patients.² WE is prevented and treated by administering intravenous Pabrinex, a mixture of B vitamins that includes thiamine (B₁), riboflavin (B₂) and pyridoximine (B₆), in addition to nicotinamide and vitamin C. In spite of this, the incidence of Korsakoff’s psychosis has been noted to be steadily increasing in the East End of Glasgow since 1990.³

It has long been recognised that chronic alcoholics are also at increased risk of magnesium depletion. The magnesium-depleting effect of ethanol in these patients is thought to arise as a result of a direct magnesuric effect on the nephron, malnutrition and gastrointestinal losses.⁴ Although parenteral thiamine replacement is standard practice in the treatment of alcoholic patients presenting to the Emergency Department, routine co-supplementation with magnesium sulphate is not common practice in the treatment of these patients. Magnesium is an essential co-factor in the conversion of thiamine to its active form, thiamine pyrophosphate (TPP). The TPP complex is an essential coenzyme in several metabolic processes in the brain. Without correction of concomitant magnesium deficiency there may be impaired utilisation of thiamine.⁵

Erythrocyte transketolase (TK) is a thiamine-dependent enzyme in the pentose-phosphate pathway. The role of TPP enables a functional assessment of status in the form of TK activity measurement. As thiamine deficiency becomes more severe the cellular thiamine stores and hence coenzyme levels become depleted and TK activity (TKA) decreases. Since thiamine activation of TK is dependent on magnesium, we propose that treatment of acutely presenting chronic alcoholic patients with Pabrinex supplemented with magnesium sulphate will increase the absolute activity of transketolase.

The aim of this study is to clarify the effect of concurrent magnesium supplementation with thiamine administration on TKA in a cohort of alcoholic patients admitted through the Emergency Department.

Methods

All participants (n = 36, 23 men and 13 women, median age 50 years, age range 18–60 years) were recruited to the pilot study following admission through the Accident and Emergency department from January to December 2007. Patients were recruited between the ages of 18 and 65 years and those with heart failure, renal impairment including previous renal transplant and dialysis therapy were excluded. All recruits were Caucasian and written consent was obtained prior to venesection.

Thiamine in its commercial form, Pabrinex, was parenterally administered to patients with or without magnesium sulphate (MgSO₄) supplementation. Patients were randomised to receive either standard treatment (Pabrinex multivitamin vials 1 + 2 in 1 L of saline or 5% dextrose over one hour) or standard treatment plus 2 g MgSO₄ (infused in the same bag of crystalloid) over one hour. Repeat samples were then drawn after two hours post administration of Pabrinex ± MgSO₄. Haemolysate fractions were prepared according to the method of Bayoumi and Rosalki and analysed for TKA using the modified method employed by Smeets et al. on a Roche Cobas FARA centrifugal analyser (Roche diagnostics).^6,7 Haemoglobin concentrations were determined using the Siemens ADVIA 120 (Siemens Healthcare Diagnostics, Deerfield, IL, USA) and TKA expressed as activity units per gram haemoglobin (U/g Hb). Ethical and Research and Development approval was obtained from the Lanarkshire Research Ethics Committee.

The significance of any changes in TKA between pre- and post-treatment values within each patient cohort was analysed by the Wilcoxon signed rank test. Any differences between the two patient cohorts regarding the change in TKA in response to treatment was analysed by Mann-Whitney U test.

Results

The first patient cohort (n = 18) received intravenous Pabrinex supplemented with MgSO₄. The second group (n = 18) received Pabrinex alone as part of their routine treatment. Bloods were analysed for baseline TKA pre- and post-treatment in the respective patient groups. The TKA increased following infusion of Pabrinex in all patients regardless of the addition of MgSO₄ (Figure 1). The median TKA for the control group receiving Pabrinex significantly increased from 0.62 (interquartile range (IQR): 0.48–0.78) U/g Hb at baseline to 0.82 (IQR: 0.67–1.00) U/g Hb post-treatment (p = 0.013). Similar results were observed for the group receiving Pabrinex + MgSO₄ with baseline median TKA 0.75 (IQR: 0.55–1.21) U/g Hb increasing to 1.07 (IQR: 0.96–1.12) U/g Hb (p = 0.004).

Figure 1.

Comparison of pre- and post-treatment TKA.

The increase in TKA baseline levels in patients treated with Pabrinex supplemented with MgSO₄ was compared to those treated with Pabrinex alone (Figure 2). The change in TKA for the group receiving Pabrinex + MgSO₄ was significantly greater than that observed in the patient group receiving Pabrinex alone (p = 0.018).

Figure 2.

Comparison of the change in TKA from baseline between treatment cohorts.

These results suggest that, in a small sample of chronic alcoholic patients receiving intravenous Pabrinex, those receiving MgSO₄ with Pabrinex have higher increases in TKA following administration of treatment compared with those receiving Pabrinex alone.

Discussion

The results from this study demonstrate that TKA increased following infusion of Pabrinex in all patients regardless of the addition of MgSO₄. However, the increase in TKA in patients following treatment with Pabrinex supplemented with MgSO₄ was significantly greater than that observed in the patient group receiving Pabrinex alone as part of their routine treatment. These results suggest that the use of intravenous magnesium concomitantly with Pabrinex may enhance TKA in chronic alcoholic patients.

It is recognised that large doses of intravenous thiamine are rapidly required for the prevention of WE in treating alcoholic patients. In the absence of treatment, alcohol withdrawal syndrome carries approximately 30% mortality. However, with appropriate management, mortality rates as low as 4% have been reported.⁸ It is also evident that the role of magnesium in the acute treatment of chronic alcoholic patients has been largely overlooked. The Royal College of Physicians advocate the administration of intravenous magnesium to alcoholic patients at risk of developing WE only if hypomagnesaemia has been confirmed.⁹ However, the administration of thiamine treatment to patients experiencing alcohol withdrawal may also be influenced by magnesium depletion.⁵

The results from this study indicate that magnesium may be required for enabling full efficacy of Pabrinex treatment, as demonstrated by its positive effect on erythrocyte TKA. The Cochrane review states that there is insufficient evidence as to the duration of treatment and dosages of thiamine required for the treatment of WE, while acknowledging that thiamine utilisation in patients experiencing alcohol withdrawal is probably influenced by magnesium status.²

The empiric administration of magnesium sulphate in conjunction with thiamine is not supported by the clinical evidence available at present. However, this study has highlighted a positive biochemical effect of this practice. We support the view that magnesium may be an absolute requirement in achieving biochemical efficacy of the current treatment regimens of chronic alcoholics acutely admitted to Accident and Emergency departments.

Footnotes

Declaration of conflicting interests

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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