Using organic acids to resolve chief complaints and improve quality of life in chronically ill patients Part V Jeffrey Moss, DDS, CNS, DACBN jeffmoss@mossnutrition.com 413-530-08580858 (cell) 1 Summer of work exposes medical students to system s ills, The New York Times, September 9, 2009 a tidal wave of chronic illness 2 Baracos VE. Overview on metabolic adaptation to stress, pp. 1-13. An understanding of the nature of stress is fundamental to the rational design of nutrient mixtures to feed patients whose homeostasis has been altered by one or more stressors. All stresses may be presumed to be associated with characteristic modifications in the metabolism of lipids, carbohydrates, amino acids, and micronutrients. 3 1
Bengmark S. Acute and chronic phase reaction a mother of disease, Clin Nutr, Vol. 23, pp. 1256-66, 2004 4 5 Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a mind-body interface? Neurosignals,, Vol. 17, pp. 144-152, 2009 6 2
7 Organic Acids Central Energy Pathway Markers 8 9 3
Morris MC & Tangney CC. A potential design flaw of randomized trials of vitamin supplements, JAMA, Vol. 305, No. 13, pp. 1348-1349, April 6, 2011 Nutrient levels are rarely considered in trial inclusion criteria. Further, trial volunteers are typically healthy behavior-seeking individuals and are unlikely to have low nutrient intake. More probably, intake levels are already at the level for optimal functioning and further supplementation provides no additional benefit. Three RCTs examining the effect of vitamin E supplementation on cognition have been published and all have null results. Of note, none of these trials targeted individuals who had low dietary intake. 10 11 12 4
13 14 Interconversion of Metabolic Fuels Interconversion of metabolic fuels, Coffee CJ. Metabolism, Fence Creek Publ., Madision, CT, 1998, p. 102 15 5
Lord RS & Bralley JA. Eds., Laboratory Evaluations for Integrative and Functional Medicine, 2 nd Edition, Metametrix Institute, Duluth GA, 2008 16 The big picture 17 The citric acid cycle (CAC) is not only the final common pathway of energy release from food components, but is also the source of basic structural or anabolic molecules that are drawn away from the cycle to support organ maintenance and neurological function. Therefore, the CAC serves both anabolic and catabolic functions of the body, representing a crossroads of food conversion and utilization. 18 6
Conversions of the CAC intermediates are under the control of enzymes, many of which require vitamin derived cofactors and essential elements for their function. Abnormal spilling of CAC intermediates in urine can indicate mitochondrial inefficiencies in energy production. Detection of such abnormalities can explain the biochemical basis of excessive fatigue and weakness and guide ways to improve energy production by supplying specific B- complex vitamins. 19 Citrate Isocitrate cis-aconitate 20 Citrate is frequently the most abundant organic acid in urine. 21 7
Ammonia, a common metabolic byproduct, is toxic and must be neutralized via the urea cycle or excreted. The anionic properties of citrate, cisaconitate and isocitrate are used to counterbalance the cationic ammonium ion excretion. Abnormally high levels of these three organic acids in urine can indicate that this renal ammonia removal mechanism is being used. A caveat about such a conclusion, however, is that elevation of the entire CAC intermediate group is a sign of functional coenzyme Q10 insufficiency. 22 Low levels of citrate, isocitrate, and cisaconitate may occur due to the multiple pathways that draw CAC intermediates away for biosynthesis Low urinary citrate is related to urolithiasis. A pattern of high cis-aconitate with low isocitrate is consistent with a defective aconitase enzyme. Aconitase, which requires cysteine and iron as cofactors, is one of the mitochondrial matrix enzymes most sensitive to oxidative damage. 23 α-ketoglutarate 24 8
The oxidation of isocitrate produces α- ketoglutarate (αkg), also known as 2- ketoglutarate or 2-oxoglutarate. In the next reaction of the CAC, α-kg is oxidized in an energy-releasing step that requires a dehydrogenase enzyme complex, called α-ketoglutarate dehydrogenase complex (KGDC), which is similar to pyruvate dehydrogenase complex Low activity of this enzyme has been shown to produce elevated excretion of α-kg. The same five B vitamins are necessary for the action of KGDC 25 Levels of α-kg can also serve to mark an aspect of the carbohydrate and fat metabolic relationship. When metabolic conditions, such as insulin intolerance, act stimulate fatty acid (especially palmitate) synthesis, the rising levels of palmitoyl-coa cause an effective inhibition of glutamate t dehydrogenase. d low urinary α-kg is a marker for the upregulated fatty acid synthesis, increased palmitic acid in plasma and cell membranes, and increased serum triglycerides. 26 Succinate 27 9
Succinate cannot play its role in cellular energy production when CoQ10 is inadequate because the electrons must be passed directly to bound CoQ10. Elevated succinate excretion is a marker for increased requirement for both CoQ10 and riboflavin. When succinate levels drop below normal, leucine and isoleucine are effective precursors that are converted into succinate to assure functioning of the CAC. Since the conversion requires adequacy of vitamin B12, functional adequacy of B12 should be assured when amino acids are used to raise succinate. 28 Fumarate Malate 29 The removal of electrons from succinate generates fumarate. Fumarate is then converted to malate. Because of the sequential nature of these reactions in the mitochondrial matrix, fumarate and malate elevations serve as additional markers to substantiate the extent of metabolic interference from CoQ10 deficiency or cytochrome oxidase defects. 30 10
Methylmalonate inhibits the malate transporter, suggesting that elevated malate may also appear as part of the pattern vitamin B12 deficiency. Elevated malate also could result from fatty acid synthesis stimulation. Low fumarate and malate concentrations in urine are a sign that the refilling reactions for the CAC are not keeping up with losses of intermediates to other pathways. 31 Amino acid catabolism supplies a major portion of compounds that resupply the CAC. 32 Hydroxymethylgluatate 33 11
β-hydroxy-β-methylglutaryl-coa, commonly referred to as hydroxymethylglutarate (HMG) is the metabolic precursor of both cholesterol and CoQ10. Low levels of HMG may reflect inadequate synthesis and possible deficiency of CoQ10. Statin pharmaceuticals used to lower serum cholesterol do so by inhibiting the HMG-CoA reductase; however, they also simultaneously inhibit the endogenous synthesis of CoQ10 and cause accumulation of HMG. 34 Leucine is metabolized to HMG, which can then either be split into acetate groups by HMG-CoA lyase or enter the steroid biosynthesis pathway via HMG- CoA reductase. 35 Thank you!! 36 12