Alicia Caver says; "your energy metabolism class is amazing." Thank you, Alicia. "And now I'm
trying to understand my Genova Organix test. Could this be less than optimal thiamine? I'm so puzzled
as to whether something funky is going on with my alpha-ketoglutarate, succinate, and fumarate.
Citrate is in the lower third quintile, cis aconitate is in the upper fourth quintile near
the yellow, isocitrate is in the upper third quintile, alpha-ketoglutarate is in the upper
fourth quintile near the yellow range. Succinate is in the upper first quintile, fumarate's in the
lower fifth quintile in the yellow and malate is in the upper third quartile, pyruvate is in the
upper fourth quartile near the yellow, lactate is in the lower fifth quartile in the yellow."
I apologize to anyone who's not looking at this. It would be great to have like the
graphic presentation on the screen, I'm sure for people to follow this. And so I'll come back to
that and summarize it, but she goes on to say; "Other random thought, could it be possible
for metabolic acidosis to impact the Krebs cycle redox couples?
Looking at past blood work I've had high anion gap and low CO2 for a long time, but my doctors never
said anything and I haven't been able to figure out what's causing it yet. Any ideas you have for
me to check out would be much appreciated." Okay, a lot to unpack here. So
I guess I'm going to rephrase all these things as low and high relative to the middle quintile,
because I think it's much easier to understand in that way, because we're not really talking
about anything being out of the reference range here. We're talking about things being
in different positions within the normal range relative to each other.
So if we take the reference benchmark as the middle of the fifth quintile, we could say that
lactate is at the top, lactate is quite high, pyruvate is high
and citrate is in the middle. So I guess if we break apart that,
it sounds like pyruvate is disproportionately going into lactate instead of going into citrate,
which means that anaerobic glycolysis is kind of elevated. And the citric acid cycle
is kind of depressed relative to one another. And so that's sounding like low oxygen delivery
relative to demand, at least at that point. And then from citrate, we are going through the cycle
and we say citrate's in the middle, cis aconitate is quite high,
isocitrate is in the middle. So it does sound like the citrate synthase enzyme could be
slightly blocked. And that is the most sensitive enzyme to oxidative stress, so that's interesting.
The alpha-ketoglutarate is in the upper fourth quartile,
whereas succinate is in the upper first quartile so alpha-ketoglutarate is high and succinate is
low. So that suggests that alpha-ketoglutarate dehydrogenase is impaired. I would say,
given that the precursor is high and the end product is low, I would say that that enzyme
is the one that has the clearest evidence for being impaired. They both use NADH and they both
are sensitive to oxidative stress, but I see, this is why you're asking about thiamine...
... because alpha-ketoglutarate is the first one out of the two to use thiamine, so converting
citric acid to citrate doesn't require thiamine, converting alpha-ketoglutarate to succinate does.
And then fumarate is very high, malate is kind of high.
So the fumarate being high, clearly that's not from succinate feeding into it. Well,
I don't think that's from succinate feeding into it. I think the succinate is in low supply
and citrate is spilling backwards into fumarate and that's probably driven by...
And so that sort of puts the citrate synthase reaction into further perspective because it
sounds like oxidative stress is inhibiting that and making the citrate go backwards into fumarate.
Wait a second... So it's going to go into oxaloacetate. Fumarate, malate, oxaloacetate. The
citrate's going backwards into oxaloacetate. The oxaloacetate is going to be very, very rapidly...
Oxaloacetate doesn't hang around, so it's going to be very rapidly converted.
Yeah, I think that makes sense. So the fumarate could be coming from somewhere else,
so... It intersects with the urea cycle and a couple other things, but I think probably the
citrate synthase reaction is more blocked than it looks from just looking at the citrate to
cis-aconitate... or citrate to isocitrate ratio. I think the cis-aconitate being high
suggests a block there that's probably funneling the citrate backwards and winding up, accumulating
as fumarate. So in that case then, I'm not so sure about the thiamine because oxidative stress and
low NAD+ are both involved there. And then, as to why the pyruvate's disproportionately
going to lactate versus citrate, then the low NAD+ kind of really supports that. I think
thiamine deficiency could be involved here, but I think this is looking more like
a block of the respiratory chain leading to
lower oxidation of NADH to NAD+, which you're compensating for partially by converting the
pyruvate to lactate, which helps generate more NAD+ to help keep the citric acid cycle going.
But nevertheless, the NAD+ sensitive steps of the citric acid cycle
are being inhibited. So that could be hypoxia, it could be high-intensity exercise,
it could be taking metformin or berberine, it could be having a complex 1 disorder,
and of course, I would sort of measure this against symptoms. So if you feel great, I wouldn't
overinterpret this. But if you have something that feels like messed up energy metabolism,
then I think it's best correlated with a deficiency in the respiratory chain, whether
that's driven by oxygen, by increased demand, through high-intensity exercise, through taking
complex 1 inhibitors like metformin or berberine, or through having a genetic complex 1 disorder.
Thiamine is possible but if it's thiamine deficiency, then you should also see elevations in
alanine as well. So I would get a plasma amino acids test, and then you could also look at the
thiamine level in the blood and you could look at... HDRI has an
erythrocyte transketolase activity test, and it's listed as ETKA
on their requisition form. All right. Hope that helps, Alicia. Thank you for your question.