Ordinarily I would not includ the entirety of such a long post in my
reply, but this is such a fine example of a knowledgeable and reasoned
response, it deserves repetition--besides repetition for the value of
the specific facts you enumerate.
In my own private reply, I had alluded to the dangers of a glucose
infusion in an alcoholic unless adequate thamine was provided, as
supporting the idea of a sudden, rather than gradual, catastrophic
reaction.
However, I also cited a paper at the recent Society for Neuroscience
meeting relating mast cell proliferation in the thalamus, preceding
focal lesions in thiamine-deficient rats. I read this as an argument
for a gradual process, but it occurs to me now that although perhaps
contributing to prodromal symptoms they could be activated in the rapid
lesioning processes precipitated by a sudden demannd (e.g. glucose
infusion). What is your thinking on this?
Authors were M. Terry-Ferguson, R.C McRee, and P.J. Langlais (PJL the
corresponding author), Psychologogy Dept, San Diego State University.
(SFN abstradct #576.1, the 1998 meeting; see www.sfn.org)
I found especially interesting your section on (genetically based?)
vulnerability of specirfic organs... Cf. my meandering response to
another post re--what--borna virus and depression or PD and
neurotrophins? something like that. (Not sure why he inisists on
pegging it to neurotrophins, however).
F. Frank LeFever, Ph.D.
New York Neuropsychology Group
In <73u4ld$33p$1 at nnrp1.dejanews.com> pelorus at coastalnet.com writes:
>>In article <365026CB.99A507D5 at mail.rz.uni-duesseldorf.de>,
>kalensch at uni-duesseldorf.de wrote:
>> Can anybody give me useful information about the onset of the cell
death
>> in Korsakoff patients. Precisely, my question is if the neurons die
in a
>> short period after the critical level of thiamin deficiency or if
their
>> death is progressive in terms of long-term atrophy until the first
>> functional symptoms are measurable. Is the amount of atrophy
correlated
>> with the functional deficits?
>>>> Thanks,
>> Tobi
>>>Dear Tobi,
>>I will try to give you some "useful" information re the
Wernicke-Korsakoff
>Syndrome and cell death. My insights into your question are both
biochemical
>and medical in nature.
>>Any time you hear that someone "drank themselves to death" (if it is
true)
>their death is due either to a cirrhosis related problem or to a
specifically
>thiamin related syndrome. Far more common is death by "Holiday Heart"
(heavy
>drinking over a weekend or holiday, followed by a sudden
cardiac/arrythmogenic
>death on Monday morning while returning to work). Probably 95% or
more of
>these arrythmogenic deaths could be prevented by supplementing one's
alcohol
>with thiamin.
>>In the Wernicke-Korsakoff Syndrome, I can tell you very definitely
that
>people can feel entirely "normal" right up to an acute point in time
and die
>within four to five hours of acute thiamin deficiency. Similarly,
when
>recognized for what it is, an IV squirt of 100mg of thiamin will very
rapidly
>transform these individuals back to their "normal" states of health in
about
>two hours.
>>Most physicians do not even know when this occurs or has happened.
There are
>three principal reasons for this:
>>(A) Few MD's are familiar (on a daily basis) with thiamin-related
illnesses;
>(B) All alcohol-related admissions to hospitals are treated via
protocols that
>include thiamin, magnesium, and other nutrients, so docs don't even
have to
>think about thiamin per se; and
>(C) In the USA, thiamin is the most commonly prescribed chemical
parenterally
>administered by medics and EMS personnel for individuals with an
altered state
>of consciousness (the protocol consists of thiamin, glucose, and
Narcan).
>Narcan and glucose generally produce their results within a few
seconds while
>thiamin responsiveness at the neural level requires an hour or more.
>>These medicines are used to treat the ONLY three conditions that
share the
>following features and characteristics:
>>(1) The treatment is safely and easily administered and the disease is
rapidly
>fatal if not specifically and quickly treated (thiamin reverses the
WKS,
>glucose eliminates hypoglycemia, and Narcan reverses a narcotic OD).
>(2) The conditions cause stupor and coma and are quickly reversed by
specific
>replacement therapy.
>>Wernicke-Korsakoff affects the brain. Wet beriberi affects the
heart. Dry
>beriberi affects the peripheral nerves of the extremities. How do
these
>conditions differ? At the biochemical level, there are a handful of
>extremely important biochemical pathways that require thiamin or
thiamin
>diphosphate as a catalytic cofactor. These are:
>>(1) The pyruvate dehydrogenase multienzyme complex (PDH). (2)
>Alpha-ketoglutarate dehydrogenase (AKD). (3) Transketolase (TK). (4) A
>"cascade" of integral membrane proteins that nominally regulate the
>"phosphate potential" of thiamin's phosphate esters (membrane-bound
thiamin
>is present as thiamin, thiamin monophosphate (TMP), thiamin diphsphate
(TDP),
>and thiamin triphosphate (TTP). The thiamin polyphosphates are
depleted
>during energy-coupled reactions accompanying cell membrane
depolarizations
>(via thiamin specific phosphatases) and are built back up simultaneous
with
>repolarization (thiamin/ATP kinases). Each transition, say from TMP
to TDP,
>or from TMP to TTP, is catalyzed by a unique enzyme and in general the
enzyme
>catalyzing the energetically uphill reaction is different from the one
that
>catalyzes the reverse chemical reaction in vivo.
>>Enzymes one through three (above) occur in well hydrated environments
(inner
>mitochondrial matrix or cell cytoplasm), require only TDP (and not its
other
>forms), and occur in organic-specific isoenzyme versions. The
proteins named
>in four (above, the membrane-linked proteins) are the same in cardiac
fibers
>as they are in nerve cells and also have great sequence homology
across
>species. Thiamin's membrane functions are the "last to go" in thiamin
>depleted organisms and cells. Thiamin's integral membrane proteins
are
>anisotropically organized on and in cell membranes such that they
physically
>"shuttle" thiamin molecules back and forth during energy-linked
ATP-coupled
>processes.
>>When thiamin crosses a membrane's innermost substance (between the two
lamina
>of a bilayer membrane) it undergoes a spontaneous and reversible
>anisotropically-oriented hydro-dehydration reaction that generates two
naked
>protons in the forward direction and that consumes two base
equivalents in
>the reverse direction. These are coupled to ATP hydrolysis and
ADP's
>phosphorykation, respectively. Because thiamin's forward and reverse
>phosphorylation reactions are mechanistically coupled to its motions
back and
>forth across the membrane, the "thiamin shuttle" can be seen to be a
>biochemical pathway that generates and consumes transmembrane
electrochemical
>gradients of protons and hydroxyl ions, e.g. reactions otherwise known
as
>"chemiosmotic processes". Chemiosmotic energy transducing reactions
are
>characteristically coupled to electron transport systems in membranes
and
>mechanistically link thiamin to oxidative phosphorylation,
photosynthesis,
>and solute transport reactions of a fundamental nature (sugar and
amino acid
>transport, particularly) in cells of every type. Again, these
reactions
>appear to have a very ancient biological origin and are fundamental to
the
>metabolism of every known form of life.
>>The PDH also performs critical functions in cellular metabolis,. It
stands as
>the interface between all of intermediary metabolism and the citric
acid
>cycle. The PDH-complex, which consists of literally hundreds of
subunits with
>multiple [Magnesium ion-thiamin diphosphate] binding sites, uses TDP
to
>oxidatively decarboxylate pyruvate. The remaining two carbon
aldehyde, which
>is transiently bound to thiamin at its C2-thiazolium position,
condenses with
>citrate as the priming reaction for the citric acid cycle. Two
reducing
>equivalents (in the form of hydrogen ions) are passed to the
respiratory chain
>by the reaction.
>>Anaerobic cells also contain a TDP-dependent enzyme that
decarboxylates
>pyruvate, but these cells are distinguished from aerobic cells by
virtue of
>their inability to perform the reaction in an oxidative manner at this
>specific site. As such, it is the way cells use thiamin that
determines
>whether they can utilize oxidative, anaerobic, or both/either pathways
to
>generate energy in the form of ATP. Indeed, it is the binding of ATP
to the
>PDH in aerobic cells that blocks the binding of TDP to its catalytic
sites on
>the multienzyme complex. It is felt that the competitive binding of
ATP and
>TDP to these sites functions in vivo as the principal site of
hysteretic
>control over all of metabolism. An enzyme cannot be more fundamental
than
>the one that accomplishes this task.
>>Under steady state circumstances it is thiamin's binding to the PDH
complex
>that regulates the cell's ATP potential. When stressed by thiamin
>deficiency, however, it is the Transketolase that appears to cause the
most
>trouble first. This probably happens because the PDH is
intramitochondrial
>whereas the TK resides in the cytoplasmic portions of the cell where
the
>availability of thiamin may be more labile during thiamin depletion
>circumstances. This may occur because mitochondria have a high
lipid-water
>coefficient, containing both inner and outer membranes and TDP's
strong
>non-specific binding to membranes generally. At steady state
metabolism, all
>TDP dependent enzymes in any particular cell have different binding
>affinities for the thiamin moiety and, similarly, different organs
have
>unique partition coefficients for thiamin, particularly in the
stressed
>state. The point here is that thiamin deficiency manifests in
different
>cells, in different individuals, and in different genetic lineages
within
>populations according to the binding affinities for thiamin
(TDP)present in
>specific organs and in specific regions and cell populations in any
>particular organ.
>>This is of particular importance in the Wernicke-Korsakoff Syndrome,
which is
>the only thiamin deficiency syndrome that has been shown to have a
known
>genetic defect at its foundation. There is a very rare condition that
>results in death in the first one to three years of life that is
>characterized by multiple, difficult to control seizures. These
children
>have been said to show a deficiency of thiamin triphosphate in their
brains,
>and by inference a missing or malfunctioning [TDP->TTP]-ATP kinase or
>phosphotransferase. Some have doubted the true existence of a genetic
defect
>in these patients, noting that individuals who die of cortical
convulsions
>will very naturally deplete their TTP reserves because they have
seized
>without repolarizing: e.g. the membranes themselves are "DEAD" (can no
longer
>perform their biological functions).
>>Studies of beriberi in Asian populations and also of prisoners of war
who
>have been starved do not frequently reveal clinical syndromes like the
WKS,
>which apparently requires a European lineage. The ancient Chinese
texts
>describing beriberi only discuss wet beriberi, dry beriberi, and
infantile
>beriberi, and one must recognize that beriberi in all its forms was
the
>LEADING atraumatic cause of death in the rice eating populations of
Asia for
>most of the past 1,000 years. It is thought that a subsegment of the
>population with the European lineage has a defective transketolase
whose
>ability to bind TDP is much lower than normal. The defect is not so
severe
>as to cause problems in states of thiamin reserve but to manifest
quickly
>when thiamin is deprived from the diet. Thiamin deficiency, BTW, is
thought
>to be the single most common deficiency in teenaged mothers in the
United
>States, so it is not just alcoholics who confront the risk of
developing
>acute Wernicke-Korsakoff Syndrome.
>>>Now, what is the difference between the Wernicke Syndrome and the
Korsakoff
>"state"? The Wernicke patient is the one in the midst of a thiamin
>deficiency crisis in the periaqueductal grey portions of the brain.
The
>aqueduct is a narrow channel that connects the capacious ventricles of
the
>upper brain to the spinal cord and through which cerebrospinal fluid
passes.
>The cells lining the aqueduct perform multiple solute transport
reactions
>between the CSF and the neural tissues. At the clinical level these
people
>have bolt-forward eyes from their opthalmoplegia, wide pupils from an
>adrenaline rush that accompanies the terror they experience, profound
ataxia,
>and a "nearly" speechless form of confusion. These patients look, act,
and
>are truly "mad" (not angry, though!).
>>If these patients are not treated within an hour or so of the onset of
the
>opthalmoplegia, they will die. If they are rescued at the last
moment, they
>go on to become Korsakoff "Psychosis" patients. Korsakoff patients
are
>friendly and cheerful, fluently communicative, and entirely demented,
being
>unable to form any "new" memories in real time.
>>Is there a "dose-response" curve for this unique disease also known as
>"alcoholic dementia". Yes, there are clearly degrees of impairment.
Does
>the level of impairment correlate with levels of atrophy found in
>peri-aqueductal tissues: Yes it does. Can focal deficits of cellular
>viability create symptoms or manifestations disproportionate to their
>absolute number of neural radiations: Yes, very much so in neural
circuits.
>Does cell death occur acutely in otherwise "healthy" tissues suddenly
>experiencing an acute thiamin deficiency: Yes, absolutely this is the
case.
>>Finally, you asked (above): "...or if their death is progressive in
terms of
>long-term atrophy until the first functional symptoms are measurable.
Is the
>amount of atrophy correlated with the functional deficits?". To this
I can
>only say that repeated bouts of thiamin deficiency are common in
marginally
>sufficient individuals. These individuals appear dull witted in their
youths
>and get duller with time.
>>>Robert D. Brown, MD
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