Since the issue of anaerobic metabolism came up at my last appointment, I've been doing some mad cranial stretching again. Trying to figure out: is it an oxygen issue? a C02 issue? Am I getting through the Krebs cycle but just not the final step of oxidative phosphorylation? Or am I not even getting through Krebs? I know I'm getting through glycolysis & pyruvate fermentation...otherwise I wouldn't be alive.
In fact, I'm so utterly reliant on anaerobic metabolism (glycolysis + pyruvate fermentation to lactate) that my most recent zyto scan showed my pancreas was stressed in addition to gallbladder, heart, & spleen. The others made sense, but the pancrease? I don't even eat sugar!! But that's the thing... because I'm reliant on glycosis, the pancrease needs to produce abundant glucagon to convert glycogen stored in the liver to glucose in the bloodstream, and because glycosis is being relied on to produce ATP, the pancreas needs to produce abundant insulin to constantly bring glucose into the cells. That's why at Dr. B's office this week, I tested for sensitivities to glycogen & glucagon.
This is a multisystem problem. The adrenals also become stressed in an effort to raise blood sugar. The liver becomes stressed because it needs to speed up gluconeogenesis, glycogeolysis, and glycogeolysis (glucose, glycogen-> glucose, glucose -> glycogen.) It's a vicious cycle of draining the endocrine & detoxification system.
I recall doing a lot of research on this.. in fact, this has been the only area of CFS research that I've really paid any attention to the last few months. However the research was in its nascence and I couldn't derive any practical input toward treatment, so I decided to focus on infections instead. Now that infections are coming down and I realize my remaining issues are all classical CFS symptoms, I know it's happening at the cellular level. You can never kill enough infections to restore cellular metabolism because infections become pathological from pH disturbance (anaerobic metabolism creates an acidic environment). That much I know now.
The rest of this post might be the wheels in my head typing while withholding any type of flow whatsoever, but I hope you'll bear with me this one time. Because this is the holy grail of chronic fatigue. When we can figure out the mitochondrial problem, we figure out our energy problem.
I'll start with a theory on acidosis. Dr. Paul Cheney said the blood pH actually stays alkaline because 2,3-dpg is low, which means oxygen isn't being utilized by the cells. Hemoglobin don't deliver oxygen, cells go into anaerobic metabolism, tissues become acidic, and kidney reabsorb bicarbonate to make up for it. This leads to what we often see as a disconnect in blood pH and urine pH. The blood is alkaline but the urine is acidic.
What always interested me about his theory was 2,3-dpg, which he says is due to low glutathione.
The catch-22, according to David Gregg, PhD, is that with anaerobic metabolism, there is not only low utilization of o2 but there is low c02 production!! Remember c02 is also produced by the krebs cycle. So oxygen isn't being displaced by c02 in hemoglobin & hemoglobin aren't being signaled to deliver their oxygen to cells. The c02 problem further reinforces anaerobic metabolism.
This explains why I was tested for being sensitive to c02 by Dr. B on Thursday. I always thought it was an oxygen problem, but my oxygen saturation is fine. I'm sure all of our oxygen saturations are fine. But we're not producing enough c02 to spark the utilization of oxygen, so it becomes a c02 problem too (that's why Cheney wanted us to "rebreathe" c02 using a brown bag--simple but logical)
I remember when I did an exercise stress test at UCLA pulmonary lab, my post-exercise ammonia & lactate skyrocketed. The chief of pulmonology attributed it to "deconditioning." (Can you believe how far we've come? I did this test back in April of 2008) . True, even when the best athletes in the world exercise to anaerobic threshhold they show high levels of lactic acid, but not nearly that high, and certainly not ammonia.
Well now we know that's because lactate is the end product of the ATP-generating mechanism we rely on when we're not utilizing oxygen. But what about ammonia? Now we get to the fun part..Bear with me, it's all leading to the breaking news I posted yesterday.
Many of us may not have problems with ammonia, but if you have the CBS+ mutation in the methylation cycle, you will have faster flow down your transsulfuration pathway and create excess sulfites & ammonia. I definitely have excess ammonia. In fact, Dr. B tested it as the main culprit to my insomnia, esp. during the nights after doing resistance exercise. I used to think it was just the lactate, but if we're relying on anaerobic metabolism for energy, that means we're relying on protein catabolism for muscle energy!!! Well, protein digestion leads to ammonia! Of course, everyone has ammonia production in their bodies, but healthy people have a working urea cycle in their livers to remove 80-90% of the ammonia as urea through the kidneys. Many CFS patients have overworked livers, so their urea cycle isn't working effectively. This leads to excess endogenous ammonia!
*Inhale*--like it maters though!
So let's go back to the breaking news yesterday. CFS/ME patients have excess hydrogen sulfide. Back in Sept 2008,
Marian Dix Lemle already published a hypothesis for H2S as a causative mechanism for CFS/ME."Specifically, H2S binds to the mitochondrial enzyme
cytochrome c oxidase, which is part of Complex IV of the electron transport chain, and attenuates oxidative phosphorylation and ATP production." Basically, she hypothesizes that H2S disturbs the process after krebs responsible for the vast majority of our ATP production, resulting in anaerobic metabolism.
Both she and Dr. Meirleir say bacteria produce h2s. She says signalling molecule, he says survival defense mechanism in the presence of heavy metals. I think it's likely heavy metal or toxins are involved, but there are also theories that pathogens and metals have a symbiotic relationship so who knows. It doesn't really matter for now.
The real question is: is the h2s production originating from the gut or from the cellular level? Both of the two above researchers say gut, but Rich Van Kroyenburg, who hypothesized a methylation cycle block as the cause of CFS, gives a convincing argument for the latter.
He says that oxidative stress causing the equilibrium between cysteine & cystine to shift toward cystine (the oxidized state). Rich: "C ystine is the substrate for an alternative reaction catalyzed by the enzyme cystathionine gamma lyase, which is at the beginning of a pathway that produces hydrogen sulfide..."
Ok, so he is saying oxidative stress (which CFS patients have been measured to have) creates a substrate for the reaction leading to h2s. But how does this tie to the CBS+ mutation I mentioned earlier? Does excess sulfite production lead to h2s excess?
Rich: "Both enzymes in the transsulfuration pathway, i.e. cystathionine beta synthase and cystathionine gamma lyase, are capable of catalyzing reactions that will produce hydrogen sulfide from cysteine or homocysteine."
Ok, so now we know there is a possible cellular metabolism element & a possible gut element to the h2s production that can lead to anaerobic metabolism. My goal for the next few weeks is to study the krebs cycle & oxidative phosphorlyation cycle in detail. I want to know exactly where it breaks down after anaerobic metabolism, and with the vials for the Krebs intermediates I should be able to get a much better picture.
I know I bash western medicine a lot, but I'm bashing the institution, not the scientists & doctors dedicated to the hippocratic oath. We wouldn't have gotten this far without you.
My friends, I know this is a freakin crusade, but we're gonna get to the bottom of this.
In fact, I'm so utterly reliant on anaerobic metabolism (glycolysis + pyruvate fermentation to lactate) that my most recent zyto scan showed my pancreas was stressed in addition to gallbladder, heart, & spleen. The others made sense, but the pancrease? I don't even eat sugar!! But that's the thing... because I'm reliant on glycosis, the pancrease needs to produce abundant glucagon to convert glycogen stored in the liver to glucose in the bloodstream, and because glycosis is being relied on to produce ATP, the pancreas needs to produce abundant insulin to constantly bring glucose into the cells. That's why at Dr. B's office this week, I tested for sensitivities to glycogen & glucagon.
This is a multisystem problem. The adrenals also become stressed in an effort to raise blood sugar. The liver becomes stressed because it needs to speed up gluconeogenesis, glycogeolysis, and glycogeolysis (glucose, glycogen-> glucose, glucose -> glycogen.) It's a vicious cycle of draining the endocrine & detoxification system.
I recall doing a lot of research on this.. in fact, this has been the only area of CFS research that I've really paid any attention to the last few months. However the research was in its nascence and I couldn't derive any practical input toward treatment, so I decided to focus on infections instead. Now that infections are coming down and I realize my remaining issues are all classical CFS symptoms, I know it's happening at the cellular level. You can never kill enough infections to restore cellular metabolism because infections become pathological from pH disturbance (anaerobic metabolism creates an acidic environment). That much I know now.
The rest of this post might be the wheels in my head typing while withholding any type of flow whatsoever, but I hope you'll bear with me this one time. Because this is the holy grail of chronic fatigue. When we can figure out the mitochondrial problem, we figure out our energy problem.
I'll start with a theory on acidosis. Dr. Paul Cheney said the blood pH actually stays alkaline because 2,3-dpg is low, which means oxygen isn't being utilized by the cells. Hemoglobin don't deliver oxygen, cells go into anaerobic metabolism, tissues become acidic, and kidney reabsorb bicarbonate to make up for it. This leads to what we often see as a disconnect in blood pH and urine pH. The blood is alkaline but the urine is acidic.
What always interested me about his theory was 2,3-dpg, which he says is due to low glutathione.
The catch-22, according to David Gregg, PhD, is that with anaerobic metabolism, there is not only low utilization of o2 but there is low c02 production!! Remember c02 is also produced by the krebs cycle. So oxygen isn't being displaced by c02 in hemoglobin & hemoglobin aren't being signaled to deliver their oxygen to cells. The c02 problem further reinforces anaerobic metabolism.
This explains why I was tested for being sensitive to c02 by Dr. B on Thursday. I always thought it was an oxygen problem, but my oxygen saturation is fine. I'm sure all of our oxygen saturations are fine. But we're not producing enough c02 to spark the utilization of oxygen, so it becomes a c02 problem too (that's why Cheney wanted us to "rebreathe" c02 using a brown bag--simple but logical)
I remember when I did an exercise stress test at UCLA pulmonary lab, my post-exercise ammonia & lactate skyrocketed. The chief of pulmonology attributed it to "deconditioning." (Can you believe how far we've come? I did this test back in April of 2008) . True, even when the best athletes in the world exercise to anaerobic threshhold they show high levels of lactic acid, but not nearly that high, and certainly not ammonia.
Well now we know that's because lactate is the end product of the ATP-generating mechanism we rely on when we're not utilizing oxygen. But what about ammonia? Now we get to the fun part..Bear with me, it's all leading to the breaking news I posted yesterday.
Many of us may not have problems with ammonia, but if you have the CBS+ mutation in the methylation cycle, you will have faster flow down your transsulfuration pathway and create excess sulfites & ammonia. I definitely have excess ammonia. In fact, Dr. B tested it as the main culprit to my insomnia, esp. during the nights after doing resistance exercise. I used to think it was just the lactate, but if we're relying on anaerobic metabolism for energy, that means we're relying on protein catabolism for muscle energy!!! Well, protein digestion leads to ammonia! Of course, everyone has ammonia production in their bodies, but healthy people have a working urea cycle in their livers to remove 80-90% of the ammonia as urea through the kidneys. Many CFS patients have overworked livers, so their urea cycle isn't working effectively. This leads to excess endogenous ammonia!
*Inhale*--like it maters though!
So let's go back to the breaking news yesterday. CFS/ME patients have excess hydrogen sulfide. Back in Sept 2008, Marian Dix Lemle already published a hypothesis for H2S as a causative mechanism for CFS/ME."Specifically, H2S binds to the mitochondrial enzyme
cytochrome c oxidase, which is part of Complex IV of the electron transport chain, and attenuates oxidative phosphorylation and ATP production." Basically, she hypothesizes that H2S disturbs the process after krebs responsible for the vast majority of our ATP production, resulting in anaerobic metabolism.
Both she and Dr. Meirleir say bacteria produce h2s. She says signalling molecule, he says survival defense mechanism in the presence of heavy metals. I think it's likely heavy metal or toxins are involved, but there are also theories that pathogens and metals have a symbiotic relationship so who knows. It doesn't really matter for now.
The real question is: is the h2s production originating from the gut or from the cellular level? Both of the two above researchers say gut, but Rich Van Kroyenburg, who hypothesized a methylation cycle block as the cause of CFS, gives a convincing argument for the latter.
He says that oxidative stress causing the equilibrium between cysteine & cystine to shift toward cystine (the oxidized state). Rich: "C ystine is the substrate for an alternative reaction catalyzed by the enzyme cystathionine gamma lyase, which is at the beginning of a pathway that produces hydrogen sulfide..."
Ok, so he is saying oxidative stress (which CFS patients have been measured to have) creates a substrate for the reaction leading to h2s. But how does this tie to the CBS+ mutation I mentioned earlier? Does excess sulfite production lead to h2s excess?
Rich: "Both enzymes in the transsulfuration pathway, i.e. cystathionine beta synthase and cystathionine gamma lyase, are capable of catalyzing reactions that will produce hydrogen sulfide from cysteine or homocysteine."
Ok, so now we know there is a possible cellular metabolism element & a possible gut element to the h2s production that can lead to anaerobic metabolism. My goal for the next few weeks is to study the krebs cycle & oxidative phosphorlyation cycle in detail. I want to know exactly where it breaks down after anaerobic metabolism, and with the vials for the Krebs intermediates I should be able to get a much better picture.
I know I bash western medicine a lot, but I'm bashing the institution, not the scientists & doctors dedicated to the hippocratic oath. We wouldn't have gotten this far without you.
My friends, I know this is a freakin crusade, but we're gonna get to the bottom of this.