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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