welcome to another MedCram comm board vitals question this one's from us Emily
step one and comlex level one Bank a 35 year old female was being evaluated for
diabetes she visited a Diagnostic Center to get a glucose tolerance test done the
attending staff at the center accidentally administered ten times the
dose of oral glucose which was supposed to be given after some time she showed
neurological disturbances and they sent her to the IDI by ambulance at the IDI
she was found to have lactic acidosis the physicians strongly suspect an
inborn defect of carbohydrate metabolism which of the following enzymes is
probably deficient in the patient which led to lactic acidosis and your five
choices are a glycogen synthase B liver phosphorylase C pyruvate dehydrogenase D
phosphofructokinase one and E muscle phosphorylase okay so the thing you've
got to realize is what is the metabolism of glucose so glucose is take it into
the body and it undergoes something called glycolysis and that's a
multi-step process that we don't want to necessarily go through completely but
the byproduct of this is something called pyruvate and as a result of this
going from glucose to pyruvate you actually get some ATP now ATP is kind of
the currency of energy in the body so ATP is energy without this energy your
body will not work however this is not the majority way of getting energy from
the body what the body does is it takes pyruvate and goes through an enzyme
called pyruvate dehydrogenase which I'll abbreviate PD and that leads us to an
intermediate called acetyl co a an acid sealed Co a then goes into Krebs cycle
which goes around and around and around and the result of that is in fact ATP
via mitochondria so this involves nadh fadh2
and we don't want to get into that specific so this is kind of the overall
thing glucose will go to pyruvate via something called glycolysis and then
pyruvate is converted into acetyl co a by pyruvate dehydrogenase and then
acetyl co a then goes into Krebs cycle which is right here it's complicated and
all the way around the cycle over and over again and you make nadh and fadh2
and even a GTP it all ends up being ATP after you go through the electron
transport chain which is in the matrix and inter membrane space of the
mitochondria that makes ATP okay so this is the major way that ATP is made now if
there is a problem for instance right here with pyruvate dehydrogenase in
other words if there is a shutdown of this enzyme then what will happen is
they'll have to be a switch somewhere so pyruvate will then have to go somewhere
else and be metabolized elsewhere now the thing I haven't shown you here is
that glycolysis also takes something called nad Plus which is very important
nad plus and converts nad plus into n a d H ok so that's a reducing agent and
it's this NADH can actually also go to the electron transport chain and create
ATP here's the problem if you have glucose which is going to pyruvate and
this is the only thing that's occurring eventually what could happen is you
could use up all of your nad plus okay so what the body does is if you're
unable to replenish your nad plus here in the electron transport chain
pyruvate will then be converted and shuttled over to a different pathway so
in other words if this pyruvate dehydrogenase is shutting down pyruvate
has to be metabolized in a way that will regenerate NAD+ so that you can contain
you would glycolysis and make ATP in this way because if this is shut down
you can't make it this way so again if pyruvate dehydrogenase is
not working you're not going to get ATP here you're going to have to get ATP
from here and to be able to do that you have to make sure you have enough nad
plus to do that the NADH has to be converted back into nad plus and the way
they do that is to convert pyruvate into lactic acid and so therefore when you
see a problem with pyruvate dehydrogenase you see a shuttling of
pyruvate instead of going to acetate Kawai you see it going to this thing
called lactic acid so that's key to understand so if we go back to the
question stem you'll notice that our patient here in the emergency room had a
large amount of lactic acidosis and that was after the patient was accidentally
administered ten times the dose of oral glucose which was supposed to be given
so basically what we're seeing is that in this situation there's so much
glucose that's being made that it's flooding this pathway and if this is the
rate limiting step or if there's some sort of problem here at pyruvate
dehydrogenase you're going to get an increase in this pyruvate and the
pyruvate is going to be shuttled over to this lactic acid and the reason is is
because you have to regenerate this nad plus so you can get a TP so based on
these answer choices what do you think the right answer is and of course the
answer is pyruvate dehydrogenase the problem with it being glycogen synthase
is because in glycogen synthase you actually have a problem making glycogen
and you have problems with hypoglycemia and you have to metabolize in a
different way so you get ketoacidosis etc the problem with liver phosphorylase
is that you get only mild hypoglycemia and you get actually infiltration of the
liver with glycogen so that can't be it we've already said that C is the right
choice look at D with phosphofructokinase 1 the
thing that you've got to remember is that the issue is further up here in
glycolysis because remember phosphofructokinase 1 is the rate
limiting step for the pathway of glycolysis so what you actually see is a
buildup of glycogen you see actually very low levels of pyruvate and
therefore lactic acid with exercise and actually exercise tolerance is impaired
finally muscle phosphorylase is also known as McArdle syndrome and it looks
very similar to phosphofructokinase 1 there's poor exercise tolerance and
issues with levels of glycogen glucose etc and so not consistent with lactic
acidosis which is actually low in McArdle syndrome so again knowledge of
the pathway specifically that pyruvate has two fates one is lactic acid that
regenerates the NAD+ and the other is SE TOA which is the main way that it's
metabolized in the Krebs cycle which forms ATP via the electron transport
chain thanks for joining us