oat part 1 - welcome to your future! the school of applied ... · the power of organic acids...

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Welcome!

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Tracy’s health counseling certification is from Columbia University for the Institute of Integrative Nutrition in New York.

She has completed ongoing training and is working on a certification in understanding the root causes of chronic illness with the Institute of Functional Medicine and on an additional Masters degree in Human Nutrition at Bridgeport University.

She holds a Masters degree in Engineering from MIT and a Masters degree in Management from The Sloan School at MIT.

WS Deep Dive Clinical Courses

Online Q&A bulletin board access within this course is available to you for follow-up at any time. Please make use of this tool to expand your (and others’) learning.

Take lots of notes! The more often you see these connections, the more readily you will be able to recall them. Repetition breeds Retention.

If you ever have any technical trouble with your WSHC membership or site access, please don't hesitate to contact our team at [email protected]

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The Power of Organic Acids Testing (OAT)

Part 1 (of 3)

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Today’s Agenda

Making it Simple – But Accurate

Maximize, Minimize, Prioritize

Labwork: the Diamonds and the Devils in the Detail

Organic Acids Testing: An Overview Data Formats

Test Panel Options

Access & Preparation

OAT Markers

Fat Metabolism

Carbohydrate Metabolism

Citric Acid Cycle

Webinar 2 & 3 Outlook

Additional Resources

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Mayhem in the Media

Over 14,000 unique disease, syndromes,

and illness in the ICD-10 Guidebook

No wonder our clients can feel overwhelmed, scared, and dis-empowered.

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Making It Simple,

“There is no ‘disease’ in the body, only dis-ease. The origin is always unique – always.” - Dr. Jeffrey Bland

GENES

ILL-NESS

WELL-NESS

BIOCHEMISTRYENVIRONMENT

Choices Choices

But Accurate

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Functional Medicine: The Big Picture

G E N E S ILL-NESS

ENVIRONMENT:

What we Maximize, Minimize, and

Prioritize

WELL-NESS

InteractiveBiochemistry

Endocrine (Hormones)

Immune (Inflammation)

Nervous (Neurotransmitters)

Digestion(Nutrients)

Metabolism(Energy)

Detoxification(Clearance)

?

Choices

Choices

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All Things are Interconnected

Oxygen Intake and Spiritual Mindset

Stress and Stress Management

Toxins and Detoxification Ability

Sensitivities and Allergies and Immune Health

Energy Generation and Circulation

Nourishment and Absorption Ability

Genetic Predispositions and Infections

Cardiovascular Disease

Elevated Homocysteine

Low Cellular B12

High MethymalonicAcid (MMA)

Low Stomach Acid

Low Cellular Energy Production

Fatigue

Lack of Exercise

High Lactate

Sleep apnea

Sympathetic Dominance (COMT)

High Malate,Fumarate, HMG

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Optimal Health is Not Complicated

Maximize Put in what’s needed for this unique personRaw materials your body needs to function and heal Oxygen, Water, Vitamins, Minerals, Antioxidants, Protein, Healthy Fats

MinimizeTake out what’s harmful for this unique personToxins, Infections, Allergens, Stress, Trauma

PrioritizeCreate an environment for healing for this unique personSleep, Rest, Laughter, Stress ReductionExercise, Stretching, BreathingMeaningful Relationships

And then the body will heal itself – will naturally seek wellness.

Simplifying the face of

health can be very calming and inspiring

to your clients.

Of course, we are not very good at doing these three things consistently. The result: Chronic Dis-ease in the body. This is Why Your Clients Need You!

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Over 14,000 unique disease, syndromes,

and illness in the ICD-10 Guidebook

Our clients often feel anything from dis-empowered, to overwhelmed, to fearful.

The ONLY thing that can “go wrong” andprevent our clients fromliving their optimal life is

the failure to Maximize, Minimize, & Prioritize

for their unique body.

Our clients can become Empowered, Organized, and Confident.

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●Eating: Chewing, Rushed, Late night●Digestive enzymes, stomach acid, bile●Gut microbial balance●Constipation/Diarrhea/Bloating/Belching●Antibiotics, NSAID, OCP, Antidepressants●Intestinal inflammation, permeability

●No gallbladder or appendix or tonsils●Celiac disease, gastric bypass, fractures●Root canals, cardiac ablation, surgeries●Hysterectomy, intestinal permeability

●Allergy, Asthma, Eczema, Autoimmune Dx●Inflammatory symptoms e.g arthritis●Steroids, chemotherapy●Food allergy/sensitivity/reaction●Frequent/severe/chronic infection, WBCs●Intestinal permeability

Throughout all Map areas●Key family health history●Relevant medications●Labwork findings

●Relationships●Work, Purpose●Spiritual practice, Connection●Hobby, play, rejuvenation●Exercise, movement, rest, sleep

●Oxygen, sleep apnea, asthma●RBC size, number, health; MTHFR●Varicose veins, swollen ankles●Blood pressure, cardiac inflammation

What will be helpful for further understanding this person's unique status

What your client is currently taking (prescription drugs, over-the-counter medication, supplements)

Specific steps you believe will be helpful to this client (given what you know now; of course you will keep this updated)

●Fatigue, cellular energy generation●Estrogen dominance, low T●Thyroid, metabolism, weight●Insulin resistance, T2D●Stress, adrenal fatigue

●Liver function, health●Phase 1 & 2 balance●Constipation, no GB, MTHFR +●Heavy metals, pesticides, fillings●Unique toxic exposure (paint)●Chlorine/Fluroide/Bromine

●SAD, Paleo, Vegan, Pescatarian●Needs e.g. O3, Mg, Zn, protein●Eating disorders, dysfunction●Dairy-free, heavy grains, organic●Diet Coke, Cool Whip, Wesson oil

●Nerve, brain issues●Anxiety, depression●ADD/ADHD, focus●Anger, volatility●Quick to cry, moody

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Labwork: The Diamonds and the Devils in the Detail

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Labwork: Diamonds & Devils

• Objective data is a blessing and powerful tool for assessment.• Data can inspire your clients to see their body objectively – and make change!

• However…• Lab data is ONE important piece of information.• Typically lab markers are assessed at a single point in time.• Labs can and do make errors.• There is always more than one reason a marker can be elevated/suppressed. ALWAYS.

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Labwork: Misconceptions & Myths

As long as a lab value is within the reference range, it's “okay” and doesn't merit treatment, investigation or attention. RR = 95% of the population!

MCV 98 and Fasting Glucose 98 are both likely BIG issues and opportunities!

Watching markers “trend” up or down can create empowerment to avoid disease.

Average = Normal. Or “fine”. The ideal place for every patient to be – all the time - is in the middle of the reference range.

CRP (C-reactive protein) TRR is 1.0-3.0mg/L, yet ideal is less than 1.0

Devil in the detail. Timing and circumstances can influence greatly the interpretation and the reliability of the data measured.

First morning vs. later afternoon cortisol or Progesterone on Day 8 vs. Day 21 of a menstrual cycle. Both examples will (and should!) differ significantly.

Don’t worry! As long as a lab value is within the reference range, the patient doesn't have a need-to-know the details.

Encourage your clients always to ask for actual copies of their lab data. Ask to see copies of the past 2 years of data as part of your initial health history review.

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Labwork: Misconceptions & Myths - More

It's IN there! Using only serum measurements to assess sufficiency in vitamins and minerals. Many physicians will unfortunately try to convince their patients that any other assessment is unnecessary or “over-the-top”.

Highly influenced by dietary intake over past few days.

RBC levels of minerals are more helpful (e~3 mos. Level).

Functional markers for vitamins (e.g. organic acids data!) can distinguish between gut absorption vs. cellular absorption or sufficiency.

Assessing and making decisions based on only a single marker vs. the whole picture where symptoms seem inconsistent with initial test results.

Cultivate Beginner’s Mind. Question everything repeatedly.

See the Forest AND the Trees. Avoid relying on a single marker to make any conclusions.

Lab data is ONE point of perspective. Defer to the patient’s unique experience and intuition as first priorities!

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Common Labwork Gotchas

Genetics. Our need for certain nutrients may be significantly higher or lower than the “average” person. Our whole genetic make-up matters (e.g. just because someone doesn’t have MTHFR SNPs doesn’t mean that their Homocysteine won’t be high.)

Lifestyle. Think about themes to target your Labwork recommendations. Professional athletes almost universally struggle with oxidative stress. MDs almost universally have low adrenal function. Assess and support each individual as unique.

Explain Clearly and then Double-Check. Be crystal clear with patients about the state in which lab samples need to be collected. Then confirm; they may or may not have followed the recommended prep. Ask them exactly what they did in the lead-up to lab sample collection. To some, “first morning fasting” means 10:15am and after a couple cups of coffee.

Check the Reference Ranges. They can and do vary by lab and by location (esp. by country) and by age/sex (for some markers).

Normal for an individual is personal. Wherever possible, compare current labs to prior values. Someone has to normally (and perhaps quite healthily) be in the tail ends of the reference ranges. Is it their healthy baseline or a long-time, unrecognized issue?

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Organic Acids Testing:An Overview

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Organic Acids Introduction

Functional markers of metabolic effects of a situation in the body

Today’s comprehensive test panels typically assess OA via urine and include the effects of inadequate nutrients, toxic exposure/overload, cellular energy production, neurotransmitter activity, and microbial activity.

OAs are intermediate metabolites of normal physiological functioning which build up preceding a blockage in a biochemical process.

Abnormally high or low levels can point to opportunities to improve functioning e.g. key nutrient needs, dietary changes, antioxidant protection, microbial modulation, or detoxification. OA data shows what’s missing.

Blockage is usually due to a missing cofactor or enzyme (that requires a certain nutrient) that is impairing normal functioning.

Yields customized data on what is happeningin a unique individual at a unique point in time.Reflects diet, lifestyle, genetics, current supplement intake, and genetics.

B

Blockage

CA

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Organic Acids Introduction

Genetics affect cofactor binding or nutrient availability. Of the more than 3500 metabolic enzymes in the body,over 20% require nutrient cofactors.*

For example, Maple Syrup Urine Disease (very high levels of branched-chain keto acids in urine are due to an acute lack of enzymes to break them down, which requires thiamine, Vitamin B1).

Traditionally OAT is used to diagnose neonatal inborn errors of metabolism.**Testing technology was developed in the 1960s to allow this assessment. These severe effects are rare, often result in encephalopathy, and may cause early death or major growth retardation.

Hundreds of labs worldwide check for the small subset of inborn errors of metabolism. These are typically indicated by extremely high levels of organic acids and manifest asacute dysfunction early in life.

Tracy’s client said her doctor scoffed when she request OA testing,“Now, why would I run that? After all, I’m pretty sure she’s not a child?!”

In a functional medicine context, organic acids testing is looking for more mild or moderate elevations to indicate subtle imbalances in biochemistry.

* http://ajcn.nutrition.org/content/75/4/616.full.pdf+html** https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210240/

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The Ups and Downs of Organic Acids

A perfect example of focusing on the upstream drivers of dis-ease and how to correct imbalances vs. the downstream “naming, blaming, and taming” of a diagnosis.

Some OAs are exception metabolites. That is, generally found only in small levels in urine of individuals with healthy metabolic processing (e.g. methylmalonic acid).*

Other OAs are normal byproducts in moderate levels and are expected in urine (e.g. kreb’s cycle metabolites of cellular metabolism, neurotransmitter metabolites). These OAT results are of note when levels are significantly suppressed or elevated. *

• http://clinchem.aaccjnls.org/content/clinchem/26/13/1847.full.pdf

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Genova Data Display – Organix et al.

For undesired organic acids (that would typically be low/absent), the conventional “normal” range for undesired metabolites is below the 95% reference interval.

Typically the full upper fifth (top quintile) will be flagged as “red” and of concern. You will want to look for borderline cases in the 4th quintile, especially where multiple markers are suggestive of an issue. Optimal levels have not been researched but are likely very low.

Be sure to assess the numerical results and not just the placement of the visual marker.

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Genova Data Display – NutrEval et al.

For undesired organic acids (that would typically be low/absent), the conventional “normal” range for undesired metabolites is below the 95% reference interval – which is noted in the right-hand column.

The green zone represents one standard deviation from normal. The yellow zone captures between the 1st and 2nd standard deviation. The red zone is beyond 2 standard deviations (that is above the95% reference interval).

Be sure to assess the numerical results and not just the placement of the visual marker.

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GPL Data Display

All data is displayed as a box plot.*

The box captures one standard deviation from mean (~65% of the data).

The lines with endpoints capture the reference range (95% of the data).

Points outside the lines are outliers (outside the 95% norm).

When the reference range is bounded by zero, the range is stated simply as lessthan the upper 95%ile end. There will be no visual low end range marker.

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GPL Data Display - Nutrients

GPL’s nutrient section is a mixture of urinary nutrient excretion and organic acid levels.

The asterisked markers are organic acids, with a high level indicating a need for more. The other markers are urinary nutrients with an isolated high level likely indicating surplus and a low level indicating a need for more.

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Comprehensive OAT Options & Availability

For comprehensive OAT testing, in the US, there are two primary providers: Genova Diagnostics & Great Plains Laboratory.

Genova measures in ug/mg creatinine; GPL measures in mmol/mol creatinine. Thus, the results are not comparable. The creatinine ratio adjusts for varying levels of dilution.

I have found that some conventional physicians are aware of the value of and open to checking just a few markers contained in these panels. Most often, I have found these are available:

Cellular nutrient markers for B12 (methylmalonic acid - MMA) and Folate(formiminoglutamic acid - FIGlu), typically in blood instead of urine.*

Oxidative stress markers (8-hydroxy-2-deoxyguanosine (8-OHdG), lipid peroxides)

For GPL, organic acid markers are included within

OAT – organic acids only, includes wider array of microbial markers than Genova products and also oxalate markers

OAT+ - can be combined with one of the following in combination kit orders: Amino Acids Urine Test, IgG Food Allergy panel, or a SNP1000 panel of common SNPs.

Microbial-only OAT – “MOAT” – also available with mini stool test just for yeast

* “Organic Acids in Man” by R. Chalmers, 2012 p.176. Many fewer OAs are measurable in blood vs. urine.

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Comprehensive OAT Options

For Genova, organic acid markers are included within

Organix: organic acids only (a few more detoxification markers than in NutrEval). Includes a wider array of vitamin markers than GPL.

Organix also available in Microbial-markers-only component

ONE: organic acids, urinary amino acids, lipid peroxides, 8-OHdG

TRIAD : a combination of Organix, amino acids, and IgG4 food sensitivity (available in blood-spot version for short-list of IgG4 foods or longer panel with a blood draw- no NY)

ION : very extensive panel similar to NutrEval that includes Organix, amino acids, fatty acids, RBC nutrient and toxic elements, Vit D, coQ10,

NutrEval : very extensive panel similar to ION

Let’s take a look at some of these!

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Organic Acids Test Access

Patient hesitate to pursue? Online resources that expand on the value can be helpful e.g. https://chriskresser.com/which-lab-tests-are-essential/

First-morning urine preference generally dictates that these will be submitted via at-home sample collections

In the US, insurance can provide partial payment coverage when test is acquired via a licensed practitioner with a contractual relationship with the national lab, depending on the type of insurance. Currently not reimbursable by Medicare.

Both GPL and Genova test kits can be acquired via several online outlets (in the US, notallowed in some states, at the moment including NY, NJ, RI, MA or MD). For example,

www.MyMedLab.com . At present, GPL is $325; Organix is $345.

www.DirectLabs.com. At present, Organix is $399.

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Organic Acids Test Preparation

Recommended instructions to proactively give your patients

We encourage you to choose to make the collection process easy. Be sure to thoroughly read the testkit instructions several days in advance – not the evening prior to collection – so you feel comfortable and well prepared.

Shipment pick-ups should not be scheduled a Thursday, Friday, or just prior to a holiday. We recommend you collect your sample Monday – Wednesday.

For 3 days prior to the test, be sure you avoid all of the following: fruit of any kind (dried, frozen, fresh, etc.) foods with mold or fungus (e.g. gorgonzola cheese) processed food of any kind (e.g. any preservatives, colorings, MSG) any non-critical, OTC, or intermittent medications

Make sure you get ample protein the day before you do the morning urine collection (at least 50 grams) and eat a typical diet and normal meals (for you). Avoid alcohol the day before.

Fast overnight - water only - (at least 8 hours) prior to collection. Collect your sample very first thing in the morning (prior to any exertion).

Make sure you have a FedEx pick up time scheduled for your sample. (For Genova), there is a yellow or orange instruction sheet in your kit which gives detailed shipment instructions.

Test results typically take about a month from when they are received by the lab.

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Organic Acids Testing:Cellular Energy Production

• Throughout these pages, recommended, confirming and interconnected organic acid markers will be displayed in blue for easy review.

• Clinical study references are included via footer links which can be easily accessed in the webinar PDF file.

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The Car - and the Gas

Tens of trillions of cells in the human body.

The cell membrane as the cellular “brain”, making choices about what is allowed in and out

Nucleus as the cellular “control center”

Endoplasmic reticulum as the cellular “kitchen”

Golgi complex as the cellular “shipping depot”

Lysosomes as the cell's “garbage disposal”

Cytosol is the cellular liquid “space” to move around in

Mitochondria are cellular “energy factories”

ATP (human cellular fuel) production happenswithin the cell, primarily within mitochondriain a multi-step process that requires oxygenand a variety of specific micronutrients as well as food (macronutrients).

* http://people.eku.edu/ritchisong/301notes1.htm

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Feeding Your Cells

Proteins Carbohydrates FatsFats

Amino Acids Monosaccharides Fatty AcidsGlycerol

Eat the Food

Digest the Food

Absorb the Nutrients into Blood

Nutrients into Cells

Make ATP

Acetyl CoA

Glycolysis

The Citric Acid Cycle

Electron Transport Chain


Beta Oxidation

ATP: Energy to do Work!

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Cellular Respiration

* "Cell Respiration" by RegisFrey. Licensed under CC BY-SA 3.0 via Wikimedia Commons

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Assessing Blockages

* Sample test results from portion of Genova Diagnostics “NutrEval FMV” test, the urinary organic acids portion

Urinary organic acids can show where blockages exist in energy production.

Metabolic intermediates tend to build up in the biochemical step prior to a blockage.

The root cause might be a lack of cofactors (green circles),toxic inhibitors (red circles), oxidative stress or low levels of enablingnutrients (e.g. CoQ10)or a combination of these factors.

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Mitochondrial Function OAT

Organix

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GPL

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Fatty Acid Oxidation - 1

In all tissues except the brain, most ATP production in the human body is derived from fatty acid oxidation.

Primarily beta oxidation in the mitochondria.Peroxisomes can do so (though less so) as a back-up.

Typical fatty acid oxidation requires carnitine (can be synthesized from dietary lysine) for the “shuttle” transport of fatty acids into the mitochondria.

Adipate and Suberate are byproducts of the alternative fatty acid oxidation pathway in peroxisomes that is utilized when mitochondrial oxidation is limited. * May be elevated in those with uncontrolled T2D or ketogenic diet (in both cases where body is seeking strong reliance on this metabolic pathway). Nutritionally, these elevations can be evidence of

Insufficient carnitine (less fatty acid transport into mitochondria)

Insufficient riboflavin, Vitamin B2 (required for coenzymes in fatty acid oxidation, including FAD which is key at the succinate stage of kreb’s cycle – look also for possible, concurrent elevated succinate and/or glutarate)

Insufficient magnesium, which also enables enzymes for fatty acid oxidation. It is also particularly important for insulin sensitivity (note if T2D is involved).

Store-bought gelatin (or similar products) may have adipic acid as an additive; check labels.

Sebacic Acid and Methylsuccinic Acid are markers of this same pathway (GPL panel)

http://jn.nutrition.org/content/118/5/541.extract and https://www.ncbi.nlm.nih.gov/pubmed/1945558 and https://www.ncbi.nlm.nih.gov/pubmed/8930414 .

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Fatty Acid Oxidation - 2

Ethylmalonate is formed from butyrate (an important short-chain fatty acid from bacterial fermentation). When insufficient carnitine or riboflavin impairs the oxidation of butyrate and makes it available for other reactions, excessive levels of ethylmalonate can form.

This pathway is different from suberate/adipate! Ethylmalonate may be low/normal in those with low SCFA or butyrate production** (consider this data from stool test results or soon after taking antibiotics). May be elevated in those with high SCFA level (e.g. SIBO, dramatic dysbiosis).

High levels correlate with obesity in animals. *** Address blockage in this pathway before increasing dietary fats.

Inborn enzyme limit (“SCAD”) would result in extremely high levels (well above 95%ile) and is rare, genetically-driven, and non-responsive to B2 or carnitine.*****

Aspirin and Influenza virus both inhibit fatty acid oxidation and cause reversible elevation in these markers. Both situations were responsive to support with Vitamin B2 and Carnitine in animals. ****

Elevations in these markers might affect any body system, especially in those with insulin resistance (e.g. poor muscle stamina, fatigue (esp. early morning), obesity, hypoglycemia elevated body fat, triglycerides).

** https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718213/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433427/*** https://www.ncbi.nlm.nih.gov/pubmed/2215249 **** https://www.ncbi.nlm.nih.gov/pubmed/3340286***** http://www.nature.com/pr/journal/v39/n6/full/pr19962569a.html

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Carbohydrate Metabolism - 1

Glucose catabolism (glycolysis) produces a large amount of pyruvate and some lactate.

When anaerobic conditions are present, more L-lactate is produced.

When lactate is high and pyruvate is low, there is likely impairment in overall ATP production which typically responds well to supplementation with CoQ10 (statin drugs?). **

Assess oxygen deprivation scenarios e.g. asthma, COPD, sleep apnea, anemias, high elevation.

Check for possible concurrent elevation in one or more of the last three steps of citric acid cycle as confirmation of a need for more CoQ10 (high succinate, fumarate, malate; also hydroxymethylgutarate (HMG)).

Zinc is necessary to activate Lactate Dehydrogenase (LDH) which converts lactate. Low zinc may contribute to lactate elevation.

Patients with high lactate may report higher muscle fatigue/ache,lack of stamina, and overall fatigue. Perhaps headache, foggy brain.

The drug metformin impairs lactate oxidation and thus urinary excretion may be higher, if there’s good kidney clearance;otherwise, lactate may build up in blood. *

There are no known concerns with isolated low lactate (except maybe being a couch potato?).

* https://www.ncbi.nlm.nih.gov/pubmed/24283301**https://www.ncbi.nlm.nih.gov/pubmed/26177139 and https://www.ncbi.nlm.nih.gov/pubmed/9208260and https://www.ncbi.nlm.nih.gov/pubmed/8827783

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Normally, high pyruvate levels are prevented via ongoing conversion to Acetyl-CoA, whose enzymes require B vitamins (B1, B2, B3, B5) and alpha lipoic acid as cofactors, with a special emphasis on thiamine which activates the first of 3 sequential enzymes.

When Pyruvate is high (or also both Lactate and Pyruvate are elevated), a block in one or more of these enzyme steps is likely at play. One or more nutrients may be helpful, especially thiamine (B1) and pantothenic acid (B5).

Look for concurrent elevations in other vitamin markers (e.g. high levels of α-keto acids which will confirm a need for more thiamine, alpha lipoic acid, and perhaps other of the above Bs as well)

Both markers are typically elevated in those with untreated T2D, in which case Alpha lipoic acid is an ideal choice (improves insulin sensitivity and reduces elevations in both lactate and pyruvate, 300-600mg twice daily, ramp slowly)**

Consider possible toxicity (e.g. mercury, arsenic, antimony, cadmium).Animal study shows ample zinc to counter effects of mercury in this vein. ***

Pantothenic acid (B5) is necessary for the formation of Acetyl-CoA.

Low pyruvate is commonly due to hyperglycemia (insufficient insulin), insufficient magnesium (required for glycolysis to form pyruvate), fluoride toxicity (also affects thyroid function!), low adrenaline (check for lower vanilmandelate), or obviousprolonged fasting or anorexia. Short-term alanine can help to raise (3-4g/day).

* https://www.ncbi.nlm.nih.gov/pubmed/9727848** https://www.ncbi.nlm.nih.gov/labs/articles/10333946/ and https://www.ncbi.nlm.nih.gov/pubmed/10468203 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756298/*** https://www.ncbi.nlm.nih.gov/pubmed/22413763 and http://www.sciencedirect.com/science/article/pii/S0147651310003830

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B-hydroyxbutyrate (BHB) is a ketone produced in response to the body choosing to use fatty acid oxidation for fuel in the absence of fuel from carbohydrates. Especially first morning in urine, this may be elevated as a result of fasting or perhaps impaired glucose control.

For most people, elevation of this marker will be an expected confirmation of a low-carb diet or intermittent fasting* (it’s a separate discussion whether they are thriving on that choice) or perhaps an unexpected confirmation of burgeoning T2D diabetes. Summary possibilities:

Low overnight cortisol

Dietary carbohydrate restriction or extended fasting

Unaddressed Type 2 diabetes with insufficient insulin (also in unmanaged Type 1)

Highly aggressive exercise the day prior

Other ketoacidosis (e.g. severely elevated methylmalonic acid (MMA), indicating B12 deficiency)

Typically, acetyl-CoA combines with oxaloacetic acid to form Citric Acid (to start the cycle). If there is little glycolysis at play in the cycle to replenish oxaloacetic acid, the acetyl-CoA build up and forms acetoacetyl-CoA (in GPL panel) that can become ketones.

For insulin resistance, this can be addressed via known nutrient solutions e.g. biotin (check for high β-hydroxyisovalerate), chromium, alpha lipoic acid (check for high pyruvate and/or lactate and α-keto acids ), magnesium. Also stress reduction!

In extreme cases, impaired electron transport chain can affect cellular energy production this far upstream as well if there are cytochrome oxidase impairments (genetic – or requires iron). Requires significant CoQ10 support. ** Look for confirming elevation in CAC intermediates, esp. latter half: Suc, Fum, Mal.

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1191213/** https://www.ncbi.nlm.nih.gov/pubmed/2823522

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Carbohydrate Metabolism Connections

SAD Diet, insulin resistance, moderate ketone elevation, biotin deficiency

High Acetoacetic acid precursors for ketones.

Very high ketones. Very low-carb diet.No blood sugar issues or associated symptoms.

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Feeding Your Cells

Proteins Carbohydrates FatsFats

Amino Acids Monosaccharides Fatty AcidsGlycerol

Eat the Food

Digest the Food

Absorb the Nutrients into Blood

Nutrients into Cells

Make ATP

Acetyl CoA

Glycolysis


Electron Transport Chain


Beta Oxidation

ATP: Energy to do Work!

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Citric Acid Cycle - 1

* http://clinchem.aaccjnls.org/content/48/5/708

Controlled by enzymes (every arrow), all of which have element and vitamin cofactors. Enzymes may also be deactivated at various points by toxic elements, including fluoride. Abnormal spilling of intermediates in urine can indicate a block at that point – and likely upstream.

Intermediates can also be derived from amino acids. Thus sufficient protein intake, digestion, and absorption are necessary for ongoing, balanced CAC activity. Overall levels will tend to be higher at an earlier age.

Impairment in electron transport chain downstream will often cause two or more of the final CAC stages to build up – indicating a need for more CoQ10 (consider drugs user here too e.g. statins, beta blockers, tricyclic antidepressants (TCAs), many diabetesdrugs (e.g. glyburide, Sulfonylureas).

In genetic impairment of cytochrome oxidase, NADH is not utilized well, and all latter markers will likely be elevated (succinate, fumarate, malate, perhaps alpha ketoglutarate – or even all stages!).*

Acetyl-CoA

The function of the CAC is the harvesting of high-energy electrons from carbon fuels.

Final common pathway of energy release from breakdown of fats, carbs, and protein

Intermediates used throughoutthe body to support organs

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Low citrate is most often caused by upstream limiters or insufficient Acetyl-CoA. Adequate B6 is required to replenish Oxa(oxaloacetic acid) to make Cit. via amino acid. Adequate B5 is key to make Acetyl-CoA.

Kidney stones have common coincidence with low urinary citrate excretion.*

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419133/ ** https://www.ncbi.nlm.nih.gov/pubmed/3981272 and ** https://www.ncbi.nlm.nih.gov/pubmed/1115248 and https://www.ncbi.nlm.nih.gov/pubmed/9475502*** http://pubs.acs.org/doi/abs/10.1021/pr050377%2B and https://www.ncbi.nlm.nih.gov/pubmed/15560797 and https://www.ncbi.nlm.nih.gov/pubmed/16841252 # https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268370/

Isolated high citrate may be due to high carbohydrate intake, citrate form supplement use (e.g. mag citrate), low glutathione (may need cysteine, selenium, Vit. B6; check for low pyroglutamate), or low iron (the latter two needed for make enzyme for next two steps of the CAC).

Isolated High Cit, Cis, and Iso together may be indicative of pancreatic dysfunction (citrate is key for making bicarbonate buffer to help maintain pH throughout the body; urine likely more acidic), or ammonia toxicity – which can be confirmed for endogenous ammonia production (urea cycle capacity exceeded) via orotate 0r via bacterial dysbiosis via microbial markers. **

Insufficient arginine is often the culprit here. Protein availability? Maybe supplement citrulline.#

Isolated Low Cit, Cis, and Iso together is likely due to a failure to refill intermediates via amino acids. Increasing protein intake, digestion, and/or absorption is key. Short-term use of citrate-based supplements may also bring relief (e.g. magnesium, calcium).

High Cis and low Iso is an impaired enzyme. Again, requires glutathione and Iron – not too low or too high. Particularly vulnerable to oxidative damage. High 8-Ohdg bloodwork might confirm. Among many other potential sources, high xanthurenate build-up (from insufficient Vit. B6) can create significant oxidative stress. ***

Acetyl-CoA

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α-ketoglutarate (Akg, also 2-oxoglutarate) is created from isocitric acid. Enzyme requires Vitamin B3, magnesium, and manganese and is particularly inhibited by aluminum.

Good news is that AKG can be refilled via several different amino acids (e.g. glutamic acid) along with B6. AKG also scavenges ammonia and may be low with high ammonia (see prior Cit, Cis, Iso notes).

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467174/ ** http://www.jbc.org/content/251/5/1406.long*** https://www.ncbi.nlm.nih.gov/pubmed/23322652 and https://www.ncbi.nlm.nih.gov/pubmed/9153450 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097389/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776615/

Fatty acid synthesis (as via increased triglycerides) may also inhibit Akg and drive depletion. **

Fatigue and lower exercise stamina associated with low AKG levels may be helped with α-ketoglutaric acid supplement (~500-1000 mg twice daily)*

Akg is converted to Succinate (Suc) via an enzyme that requires the same four B vitamins and ALA as Pyruvate Dehydrogenase and also CoA (which you will remember requires pantothenic acid, B5). So high Akg may corroborate earlier findings re: weakness in this area. Check for high Pyruvate, alone or along with Lactate, other α-keto acids, pantothenic acid (GPL). As with all enzymes, it’s vulnerable to toxicity too.

Succinate starts the back half of the CAC where electrons are transferred to the Electron Transport Chain –which must be transferred directly to bound CoQ10. Elevated succinate is a marker for increased need for both CoQ10 and Riboflavin (B2).*** Suc conversion to Fumarate (Fum) requires B2 and iron (anemia?). For B2, check also for elevated glutarate. Suc may also be produced by gut or vaginal microbes. Bacterial degradation of excess, non-absorbed glutamine can produce high levels of succinic acid.

Succinate is refilled via branched chain amino acids (protein availability?); low levels are likely due to insufficient B12 - or Folate (B9). Check for high Formiminoglutamatic acid and/or methylmalonic acid.

Acetyl-CoA

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Succinate is converted to fumarate (Fum),then malate (Mal). All three are excellentmarkers of the need for more CoQ10when elevated (due to deficiency or cytochrome oxidase impairment).

Malate is actively pumped outside themitochondria to help with electron movement.

High levels of methylmalonate (MMA) interfere with this transport. * Thus high Mal combined with higher MMA might also indicate issues with Vitamin B12 (esp. if Mal elevation is isolated). The enzyme that converts Mal to Oxaloacetic acid (final stage of the CAC) also also requires Vitamin B3.

As with other CAC stages, Low Mal and/or Fum are likely due to a failure to refill CAC intermediates via amino acids. Phenylalanine or tyrosine can help as triage while root causes are being addressed.

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292169/

Acetyl-CoA

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Not part of the CAC, Hydroxymethylglutarate (HMG) is the precursor to Coenzyme Q10 and cholesterol and includes three Acetyl-CoA molecules. When HMG is elevated, the body is likely trying to increase its production of CoQ10 and is blocked. CoQ10 supplementation is recommended.

Statin drugs will drive this marker up relative to their impact in blocking this pathway. Impact varies based on mitochondria health and bio-individual drug metabolism. *

HMG may also be elevated in ketogenic or fasting states (check for high BHB). Interesting theory too of mild elevation being caused by an intestinal yeast overgrowth producing high compactin which acts just like a statin, inhibiting HMG reductase (perhaps check for high fungal dysbiosis markers).

Low HMG may be due to low levels of Acetyl-CoA (check for low Pyruvate and/or Adipic/Subericupstream). Synthesis requires Vitamin B5, magnesium, and glutathione as well. Low HMG is paradoxically also indicative of a need for more CoQ10 (due to a slow rate of synthesis). Consider checking serum cholesterol and CoQ10 as well as steroid hormones.

As an aside, high insulin can hyper-stimulate HMG reductase to make excess cholesterol. This mechanism, however, has not been shown to deplete HMG when glycolysis & beta oxidation arehealthy.

* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55074/ and https://www.ncbi.nlm.nih.gov/pubmed/12137559 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833493/

Exhausted statin drug user with myopathy

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Citric Acid Cycle Connections

Consistent elevations in latter stages; indicative of high need for CoQ10. No statin use.

Enzyme impairment at the Cis stage, likely in part due to oxidative stress from high xanthurenate (need for Vitamin B6).

Rock-bottom succinate (also exception within CAC) coincident with high methylmalonic acid. Clear need for Vitamin B12.

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Looking Ahead

Webinar #2: OAT Markers, Physiology, and Patterns Vitamins and Amino Acids

Microbes and Dysbiosis

Detoxification

Neurotransmitters

The special case of Oxalates

Webinar #3: Case Studies Putting the Puzzle Pieces Together

NutrEval

GPL

Organix

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More Resources

The functional labs’ interpretive guides are surprisingly helpful and detailed. I definitely recommend you review them as part of this course experience. They are posted in the course Documents section as well as a few links in the Comments area at the bottom of the course page.

By far, the most useful booklet for quick-and-dirty interpretation I have everencountered for functional Labwork interpretation: The Metametrix Handbook. Yes, an oldy but a very goody made by Metametrix before they merged with Genova. Unfortunately only available now in e-book format on I-Tunes (~$20).

If you are committed to becoming fluent in working with functional labs, it’s probably timeto take the plunge into a textbook. To build some deep understanding and expand your insight into what markers fully mean. I highly recommend Laboratory Evaluations for Integrative and Functional Medicine by Richard Lord and J. Alexander Bralley, 2008. Very expensive on a variety of sites but best price at Genova (~$200).

For the true geek, wanting a deep dive intothe biochemistry of nutrients, considerAdvanced Nutrition & Human Metabolismby Sareen Gropper.

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Thank you!

The Power of Organic Acids TestingPart 1