Study Guide Organix

Reading Assignments
1. Textbook Chapter 6-Organic Acids, Pages 324 - 396

(pp 341 – 350 are redundant from Week 2)

2. Paths to Health: Organic Acids

1.    Laboratory report design that allows easy identification of extremely elevated or depressed levels.

2.    Hypometabolic compensatory states identified by patterns of low organic acids.

3.    Interpretation of 𝛼-ketoglutarate as biomarker of systemic pH

4.    Low hippurate and other phenyl bacterial biomarkers as biomarkers of insufficient dietary polyphenol intake

3. Handbook of Nutrient Assessments, Chapter 6

Questions for Critical Thinking

PAGES IN LABORATORY EVALUATIONS FOR INTEGRATIVE AND FUNCTIONAL MEDICINE

(pp 327-329) Name the primary organic acid abnormalities that occur in carnitine deficiency.

1. Elevated adipate
2. Elevated suberate
3. Elavated ethylmalonate

(pp 336-337) What patterns of abnormalities discriminate mitochondrial inefficiency from ammonia challenge as a cause of citric acid elevation?

• Ascribe high levels of citrate, aconitate and isocitrate to ammonia when 
• (a) Only citrate, aconitate and isocitrate are found high or 
• (b) orotate is concurrently elevated.

(pp 355-359) What does NMDA stand for? Why is this nomenclature important for interpretations of organic acid elevations?

• NMDA is the abbreviation for the N-methyl-D-aspartic acid class of ionotropic glutamatergic neuron receptors. 
• It is those receptors that are agonized by quinolinic acid and potentiated by picolinic acid resulting in potential glutamate toxicity in neurons.

(pp 360-361) What urinary organic acid elevation may justify specifically aggressive vitamin C supplementation?

• Aggressive vitamin C therapy may help to reduce elevated p-hydroxy-phenyl-lactic acid and the concomitant elevated cell division rate stimulation that tends to produce systemic oxidative stress.

(p 361) Explain the relationship of Figure 4.20 to 8-OHdG.

• Failure of the reciprocal regulation shown in Figure 4.20 can impair up-regulation of hepatic glutathione synthesis as the major response to oxidative stress, leading to exacerbated and prolonged cellular (esp. mitochondrial) damage from oxidant effects.

(pp 364-365) Why is supplementation with glucarate salts NOT indicated by abnormalities in urinary glucarate?

• Urinary glucarate is a marker of increased hepatic detoxification system activity. It is a by-product of pathways leading to glucuronic acid formation. 
• Oral glucarate is not helpful for assisting hepatic detoxification or for relieving potential elevated rates of intestinal bacterial glucuronide hydrolysis.

(p 366) What is the implication of LOW homocysteine for the likelihood of finding elevated alpha-hydroxybutyrate?

• Elevated AHB signals up-regulated hepatic glutathione synthesis, and that process demands flow of HCys into L-Cys formation to form gamma glutamyl-cystinyl-glycine (glutathione). 
• Thus, low plasma HCys can signal a late-stage of chronic glutathione depletion where total body sulfur amino acid availability is failing to keep up with the demand.

(p 375) Explain how elevated benzoate can be a marker of either impaired detoxification or intestinal bacterial overgrowth. What other biomarker can help to differentiate the two scenarios?

•  Benzoate can become elevated due to 
• (a) failure of hepatic clearance by hippurate formation (impaired detoxification) or 
• (b) elevated levels of benzoate release from dietary polyphenols by intestinal bacteria overgrowth where the hepatic clearance system capacity is exceeded. 

• If hippurate is concurrently elevated, then scenario (b) is likely. 
• If hippurate is normal or low, then scenario (a) is confirmed.

(pp 387 - 388) What is the difference between arabinitol and arabinose. Which one is a well-documented marker of intestinal yeast overgrowth?

• Arabinose is a five carbon sugar found in grapes and other fruits and vegetables. 
• It is a substrate for growth of some bacteria. 

• Arabinitol is the corresponding sugar alcohol that is formed by conversion of dietary carbohydrates by intestinal Candida species, and it serves as a biomarker of overgrowth, including severe, invasive candidiasis. Urinary arabinose does not reflect such conditions.

SECTIONS IN PATHS TO HEALTH: ORGANIC ACIDS

Chapter 4: Examples of low metabolite levels signaling sub-normal activity

Chapter 5: Glutathione capacity erosion patterns

Chapter 6: Mitochondrial retraction as compensation to prevent cell death

Questions from Figures

(Table 6.3) Which organic acids become elevated in maple syrup urine disease? Why? High doses of what essential nutrient are helpful in certain forms? Why don’t all forms respond to the nutrient supplementation?

•  Genetic abnormalities in maple syrup urine disease generally reduce the activity of branched chain keto dehydrogenase, resulting in elevated levels of a-keto-iso-caproate, a-keto-iso-valerate, and a-keto-b-methyl-iso-valerate. 
• Raising cellular levels of thiamin, riboflavin, niacin, pantothenic acid and lipoic acid may restore the enzyme activity. 
• If the genetic polymorphism causes severe alteration in enzyme binding sites for the cofactors, the raising their concentrations may have no effect.

(Table 6.7) Which organic acids are used to discriminate potential vitamin deficiencies causing homocysteine elevation?

• Homocysteine elevation can result from deficiencies of folate or vitamin B12 that are revealed by elevations of FIGLU and methylmalonate, respectively.

(Figure 6.14 & 6.15) Explain how products of the kynurenin pathway can provide evidence of micronutrient status and central nervous system perturbations.

• Vitamin B6 deficiency causes impairment of the hepatic kynurenin pathway that is used to convert tryptophan into nicotinic acid. 
• The pathway steps that are affected result in accumulation of xanthurenic acid and, secondarily, kynurenic acid. 
• In the vitamin B6 sufficient state, however, inflammation produces increased activity of the kynurenin pathway in the brain where the products that accumulate most often are quinolinate and Picolinate because brain tissue does not express the enzyme required to complete the conversion to nicotinic acid.

(Figure 6.21) Explain how glycine insufficiency cause elevated pyroglutamate.

• Glycine is required in the kidney to sustain reformation of glutathione from the constituent amino acids. 
• Lack of sufficient glycine to perform this function is one reason that the critical gamma-glutamyl pathway is truncated prior to executing the GSH reconstruction, causing release of the glutamic acid moiety as pyroglutamate.

Case Illustration (CI) Questions

(CI 6.3) How might the bold-arrow cycle in Figure 6.1 lead to confusion about the pattern of high and low results found in this case? How do the further details of Figure 6.2 offer explanation?

• An uninformed interpretation of the bold arrow that forms the central circular pattern in the figure might be that interruption at any single step would always cause low levels of the product for that step and high levels of the substrate and all preceding intermediates. 
• Figure 6.2 draws attention to the selective permeability of the mitochondrial membranes that are regulated by transport proteins. Those actions allow specific citric acid cycle intermediates to easily leave so that their levels do not become elevated.

 (CI 6.7) What facts in the patients’ history might explain the elevated glucarate finding?

 Cigarette smoking and therapeutic drugs cause increased activity in hepatic detoxification pathways, producing elevated glucarate.

(CI 6.8) What does a 6-month progressive lowering of urinary sulfate with persistent elevation of pyroglutamate imply about a patients’ prognosis? What specific nutrient interventions are indicated?

• One may presume that a patient displaying progressive lowering of urinary sulfate is in a state of chronic toxicant challenge or oxidative stress, and a concurrent, persistently elevated pyroglutamate indicates that renal losses of glutathione may be a contributing factor. 
• Glutathione support via preformed GSH or its precursor amino acids Cys, Met, Gly and related amino acids, Tau, Ser, Thr may be helpful for restoring GSH status.

Paths to Health: Organic Acids Questions

(Chapter 4) Why should biomarkers of disease like elevated cholesterol or pyruvate be considered as biomarkers of other kinds of pathology when they are abnormally low?

• Any biomarker that is an intermediate in normal cell processes such as cholesterol and pyruvate may produce metabolic disturbances when it is present at very low levels because its absence is likely to adversely impact one or more systems needed for maintaining healthy responses.

(Chapter 5) What pattern of results for urinary sulfate and 8-OHdG, and plasma methionine for the strongest indication of poor glutathione response capacity? Why?

• A pattern of low urinary sulfate with elevated 8-OHdG and low plasma methionine spells a deep erosion of a patients capacity to meet glutathione demands because an uncorrected oxidative stress is present in the face of already low total body glutathione turnover indicated by the low sulfate, and drawing of the major dietary essential sulfur-containing amino acid methionine into the attempts to meet the demands.

(Chapter 6) Why don’t cells die under conditions of chronic lack of magnesium, CoQ10, or iron for meeting requirements to complete the electron transfer from food energy substrates to form water, CO2 and ATP?

• If the depletion of critical factors for the final stage of mitochondrial activity is too sudden or severe, many cells do die, releasing their contents to allow others to survive. 
• In less severe depletions, however, most critical cell functions can continue at the expense of less critical ones and with the cost of lower reserves of mitochondria to meet demands. 
• So, a patient with chronic fatigue syndrome, may stay alive with loss of function for even simple daily-tasks and loss of cognition for work-related functions.