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Why Alcoholics Should Receive Vitamin B1 (Thiamine) by IV Before any Glucose Infusions

Summary:

  • It is well known that chronic alcoholics are at high risk for being deficient in vitamin B1 (thiamine), which is known to put the patient at an increased risk for Wernicke-Korsakoff Syndrome, cerebellar degeneration, and cardiovascular dysfunction.
  • The current standard of treatment for such patients is to give them thiamine 100 mg intravenously (IV) before administering glucose containing IV fluids and then to continue this dose for several days.
  • The inability of pyruvate to enter the TCA cycle causes the cell to convert the pyruvate to lactate (or lactic acid) in order to be able to maintain glycolysis at a minimum rate.  Therefore, if you feed the cell more glucose without giving the needed thiamine to allow for the forward movement of cellular reactions for complete ATP generation, you only increase the amount of lactic acid produced.
  • This development of acidosis, the inability of the pentose phosphate pathway to protect the cell from reactive oxygen species that damage cellular structures and the mounting stress on the cell overall, results in either cell death or activation of apoptosis.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed:
October 2015

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Explanation

  • It is well known that chronic alcoholics are at high risk for being deficient in vitamin B1 (thiamine).1,2  This is clinically relevant, as thiamine deficiency in this patient population is known to put the patient at an increased risk for Wernicke-Korsakoff Syndrome, cerebellar degeneration, and cardiovascular dysfunction.3-5  In fact, reports have shown that approximately 13-42% of alcoholics had evidence of Wernicke-Korsakoff Syndrome and cerebellar degeneration on autopsy.6,7   If the thiamine deficiency is left untreated, these complications can result in irreversible damage to several parts of the central nervous system (CNS). 

    How should alcoholic patients with Wernicke-Korsakoff Syndrome receive thiamine replacement?
    The current standard of treatment for such patients is to give them thiamine 100 mg intravenously (IV) before administering glucose containing IV fluids and then to continue this dose for several days.  The focus of this publication is explain why the thiamine should be given be prior to administering glucose.  Failing to do so has been known to worsen the Wernicke-Korsakoff Syndrome and result in irreversible damage to the brain.  Oral replacement in the setting of acute alcohol intoxication is not appropriate for a number of reasons (see past newsletter 2010 volume 3 issue 8 for more information). 

    What type of brain damage is seen in thiamine deficient alcoholic patients?
    The brain damage is known to vary but typically involves the formation of hemorrhagic and necrotic lesions in the mammillary bodies of the brain, hypothalamus, thalamus, the periaqueductal region, and floor of the fourth ventricle, and cerebellar vermis.7  The damage to these areas of the brain is, in part, likely due to the direct toxic effects of alcohol (and its metabolites) on the tissue.  In addition, these regions are likely to be more sensitive to the availability of thiamine for cellular function.  These regions require adequate availability of ATP for energy and NADPH for reductive biosynthesis reactions of fatty acid synthesis and protection of the cell from the damages of reactive oxygen species so that the cell can maintain its tissue integrity and function.3  Furthermore, in a state of thiamine deficiency or states of stress, the metabolic requirements can be greater, thus up regulating other cellular reactions to compensate for the current situation.7  This is particularly problematic for patients given glucose containing fluids without first increasing the availability of thiamine. 

    What does thiamine contribute that allows the cells in the brain to respond to this metabolic demand?
    Upon absorption into the body, thiamine is used to form thiamine pyrophosphate, which is an essential co-factor used by several cellular enzymes.3  The pyrophosphate portion added to thiamine is important since this group is used to bind to magnesium and then further bind to amino acid side chains on the cellular enzyme.3  This allows the thiamin pyrophosphate to function as a co-factor to that enzyme so that it can facilitate the forward movement of its assigned biochemical reactions.  One of the most important sets of biochemical reactions requiring the availability of thiamine includes the reactions involved in glycolysis and the tricarboxylic acid (TCA) cycle.  There are three enzymes that facilitate several reactions involved in these processes that require the presence of thiamine pyrophosphate.  These enzymes are a-ketoglutarate dehydrogenase, branched chain amino acid dehydrogenase, and pyruvate dehydrogenase.3,7  The forward movement of glycolysis and the TCA cycle are essential for the cell's ability to generate the ATP needed to maintain other cellular activity. 

    Several problems exist when these enzymes are nonfunctional because of deficiency in thiamine.  The first, and most obvious, is that enough ATP cannot be generated in order for the cell to maintain its other cellular reactions and biologic functions.  The second is a known accumulation of a-keto acids and lactic acid within the cell.3,7,8  These two adverse effects only add to the mounting stress on the cell.  The other set of reactions that depend on the availability of thiamine are in the pentose phosphate pathway.  The enzyme transketolase, in particular, is an enzyme that requires thiamine pyrophosphate as a co-factor in order for the pentose phosphate pathway to: 1) generate NADPH used for reductive biosynthesis reactions inside the cell (such as fatty acid biosynthesis, detoxification of drugs by monooxygenases, and glutathione reactions to protect the cell from reactive oxygen species); 2) generate ribose-5-phophate used in nucleotide biosynthesis; 3) metabolize pentose sugars from our diet into intermediates for glycolysis.  This pathway is of relevance since it helps to protect the cell from stressors that occur during metabolism and cellular activities.  Failure of the pentose phosphate pathway can result in damage to many of the intracellular structures. 

    The culmination of all these stressors as a result of thiamine deficiency can activate intracellular pathways of apoptosis (or programmed cell death).7  This is likely why on autopsy these patients have areas of hemorrhage and necrosis. 

    What happens if you do not give the thiamine first before starting an intravenous glucose infusion?
    As stated above, many of these cells and biochemical pathways may be upregulated in times of stress or with nutritional deficiencies.  Therefore, if they are given the precursors for ATP production (such as glucose), then these cells will begin to rapidly utilize them.  The problem comes in the inability of the previously described enzymes of glycolysis and the TCA cycle to move the reactions forward so that the precursor (i.e., glucose) can be utilized to generate the amount of ATP that it can normally produce.  As a result, intermediate products within the pathways begin to accumulate and the system will eventually back up.  So, not only is ATP failing to be adequately generated, but pyruvate is accumulating as a result of continued glycolysis.  The inability of pyruvate to enter the TCA cycle causes the cell to convert the pyruvate to lactate (or lactic acid) in order to be able to maintain glycolysis.3,7  The reason the cell converts pyruvate to lactate is to regenerate the NAD+ required for the process of glycolysis to continue and to generate a net balance of at least 2 ATP.3  Therefore, as you feed the cell more glucose without giving the needed thiamine to allow for the forward movement of cellular reactions for complete ATP generation, you only increase the amount of lactic acid produced.   This development of acidosis, the inability of the pentose phosphate pathway to protect the cell from reactive oxygen species that damage cellular structures and the mounting stress on the cell overall, results in either cell death or activation of apoptosis. 

    Therefore, thiamine should be given first so that when the glucose is given, the glucose will more likely be utilized to form ATP and prevent the acceleration of cell damage/death to structures in the brain.  The degree of damage that may have already occurred from the patient's chronic alcoholism, as well as the deficiency of thiamine, can manifest in varying degrees of cognitive impairment and musculoskeletal coordination.  If severe enough, the risk of death is great.  Lastly, it is important that while the initial administration of thiamine is important to prevent the worsening of Wernicke-Korsakoff Syndrome, it will likely take several months to correct some of effects of thiamine deficiency.

    References:

    1. Gastaldi G, Casirola D, Ferrari G et al. Effect of chronic ethanol administration on thiamin transport in microvillous vesicles of rat small intestine.  Alcohol 1989;24:83-89.
    2. Hoyumpa AM, Jr. Mechanisms of thiamin deficiency in chronic alcoholism.  Am J Clin Nutr  1980;33:2750-2761.
    3. Lieberman M, Marks AD.  Chapter 20: Tricarboxylic acid. In: Mark's Basic Medical Biochemistry A Clinical Approach. 3rd Ed.  Lieberman M, Marks AD eds. Wolters Kluwer/Lippincott Williams & Wilkins. Philadelphia, PA. 2009.
    4. Medline Plus. Beriberi. U.S. National Library of Medicine/National Institutes of Health.  Accessed December 2010.  
    5. National Institutes of Health.  National Institute of Neurological Disorders and Stroke.  NINDS Wernicke-Korsakoff Syndrome Information Page.  Accessed last December 2010. 
    6. Harper C, Rodriguez M, Gold J et al.  The Wernicke-Korsakoff syndrome in Sydney--a prospective necropsy study.  Med J Aust  1988;149:718-720. 
    7. Singleton CK, Martin PR.  Molecular mechanisms of thiamin utilization.  Curr Mol Med  2001;1:197-207.  
    8. Holowach J, Kauffman F, Ikossi MG et al.  The effects of a thiamin antagonist, pyrithiamin, on levels of selected metabolic intermediates and on activities of thiamin-dependent enzymes in brain and liver.  J Neurochem 1968;15:621-631.

MESH Terms & Keywords

  • Vitamin B1, Thiamine, Alcoholics, Wernicke-Korsakoff Syndrome