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).
should alcoholic patients with Wernicke-Korsakoff Syndrome receive thiamine
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).
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.
does thiamine contribute that allows the cells in the brain to respond to this
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.
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
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
happens if you do not give the thiamine first before starting an intravenous
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.
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
- 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.
- Hoyumpa AM, Jr. Mechanisms of thiamin deficiency in chronic alcoholism. Am J Clin Nutr 1980;33:2750-2761.
- 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.
- Medline Plus. Beriberi. U.S. National Library of Medicine/National Institutes of Health. Accessed December 2010.
- National Institutes of Health. National Institute of
Neurological Disorders and Stroke. NINDS Wernicke-Korsakoff Syndrome
Information Page. Accessed last December 2010.
- Harper C, Rodriguez M, Gold J et al. The Wernicke-Korsakoff
syndrome in Sydney--a prospective necropsy study. Med J Aust
- Singleton CK, Martin PR. Molecular mechanisms of thiamin utilization. Curr Mol Med 2001;1:197-207.
- 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.