@rodgergrummidge Can you point me to a resource / webpage that explains the tests you refer to, so I can talk to my doc about it?
Hi
@XenForo , some basic info below.
A brief background on pyruvate metabolism, energy production and CFS: When energy demands are high (eg exercise) in a normal non-CFS person, carbohydrates are converted to pyruvate via glycolysis. The pyruvate then passes into the mitochondria where the pyruvate dehydrogenase enzyme converts it to acetyl-coenzyme A (acetyl CoA). Acetyl-CoA then enters the TCA cycle which is used to fuel energy production. A deficiency in any of these steps could result in reduced energy production and CFS-type symptoms. In fact, a number of studies have suggested that PDH activity is reduced in some CFS patients. Because impaired PDH activity results in the reduced conversion of pyruvate to Acetyl-CoA, pyruvate tends to 'pile up' in cells, particularly when energy demands are high (eg. during exercise). Under these conditions, pyruvate is converted to lactate. Excessive pyruvate accumulation and lactate production can lead to lactic acidosis, a condition that can lead to CFS-type symptoms.
How can PDH deficiency be determined? PDH enzymatic activity can be measured directly in the test tube from a tissue/blood biopsy, but not many labs are able to perform such tests accurately. Initial investigations usually examine the blood/serum/plasma levels of both pyruvate and lactate. If both are elevated, PDH activity may be impaired (note however, that there are other conditions that can lead to lactic acidosis and so pyruvate/lactate measurements alone dont provide a definite diagnosis). Note that in some CFS patients, blood lactate and pyruvate can be normal, and increased levels are only found i) in the cerebral spinal fluid and/or ii) after exercise challenge. So an exercise challenge could be an important step in determining if a PDH deficiency exists.
Lactate and pyruvate pathology tests: Lactic acidosis can be indirectly analysed by an increase in the anion gap (blood concentration of sodium minus those of chloride plus bicarbonate). Lactate can also be directly measured in the blood in most pathology labs. Blood pyruvate can also be directly measured in many path labs . Note that blood pyruvate levels are plagued by errors in collection and handling; furthermore, pyruvate is a very unstable compound. Pyruvate and lactate are often assessed by the Lactate
yruvate ratio where ratios <10 or >20 would be considered abnormal and further testing would be required to determine if the cause is a PDH deficiency.
DCA, a drug used for treating PDH deficiencies: Dichloroacetate (DCA) is a potent lactate-lowering drug that
activates PDH activity. PDH activity is controlled by 2 enzyme 'switches': i) Pyruvate dehydrogenase phosphatase (PDP) that switches PDH
on and ii) pyruvate dehydrogenase kinase (PDK) that switches PDH
off. DCA works by 'jamming' the PDK 'off-switch', thus leaving PDH in the '
on-position'. Thus, some patients who i) have a PDH deficiency (which may include some CFS patients), ii) have decreased conversion of pyruvate to Acetyl-CoA and so decreased mitochondrial energy production and iii) lactic acidosis may benefit from the ability of DCA to activate PDH.
DCA treatment and monitoring: At least one diagnostic criteria where DCA treatment could be considered would be in patients diagnosed with a PDH functional deficiency that also have increased levels of both pyruvate and lactate. Some CFS patients may fit this criteria with elevated pyruvate and lactate in the blood and/or cerebal spinal fluid. Daily treatment with DCA would normally commence with a 'low dose' and progress with a dose-escalation while monitoring symptoms. Response to DCA treatment (efficacy) would monitored by regular analysis of both pyruvate and lactate in the blood. A therapeutic effect would be measured as a return to normal levels of pyruvate and lactate in the blood or cerebral spinal fluid.
Monitoring toxicities: Neuropathy is a potential toxicity described in a number of trials. I'm not sure how it would be tested, but your doctor should make sure to follow up with appropriate tests. Liver toxicities can be measured by examining liver enzymes in your blood tests. Similarly, kidney toxicities can be analysed by examining kidney enzymes/functions using standard pathology tests that your doctor will know. I would also monitor glucose levels as DCA may affect carbohydrate usage through the glycolytic pathway.
That is a 'brief' overview, but there is probably much that I have either forgotten to include or just skimmed (getting tired), so please dont take my word as any ultimate authority.
I'll try and find some info/webpages to post sometime later to point you in the right direction (starting to crash now). I'm sure others may also have some good suggestions/ideas. I hope it helps with some of your decisions in terms of diagnostics and treatments.
best of luck
Rodger
