The Organic Acids Test - Evaluation and Treatment For Candida & Metabolic Toxicity

Copyright of Kurt N. Woeller, D.O., Tracy Tranchitella, N.D. and Educational Research Association. This material may not be reprinted, distributed or

used without permission.

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• Why is Candida such a complex problem?

• Examples of Candida toxicity:• Colonization of the digestive system, and Candida’s

unique pathogenicity.

• Arabinose toxicity

• Gliotoxin, Pentosidines, and Acetylaldehyde

• Testing options for Candida detection

• Treatment options for Candida

Lecture Overview

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Support Documents for Module #3

• Constipation Remedies:• Dosing suggestions

• Patient handout

• Die-Off Reaction Management - patient handout

• Antifungal Dosing – At a Glance

• Mild, Moderate, and Severe Candida Protocols + patient yeast program (blank sample)

• Fungal Hypersensitivity Food List (pdf) – patient handout

• Lecture slides (pdf)

• Lecture slides - note taking (pdf)

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Arabinose

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Why Is Candida So Complex?

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Fungi – Biological Group Of Organisms

•Yeasts – ex: Candida, Saccharomyces

•Molds – ex: Aspergillus, Penicillium

•Mushrooms

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Candida Overview• Is considered a ‘commensal’ organism that is a normal

part of the human flora, i.e. mouth, gastrointestinal tract.

• Estimates are that Candida exists in approximately 80% of the human population without causing harm. • Is this really true?

• Common issues linked to Candida overgrowth are thrush (oral candida), vaginal infections, skin and nail plate infections.

• HIV, cancer and other immunocompromised diseases have greater risk of Candida pathogenicity.

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Unicellular Candida

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Unicellular Yeast to Hypha Formation

Highly invasive at this point.

Invades the mucosal lining

of the

intestinal tract.

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François L. Mayer, et. Al. Candida albicanspathogenicity mechanisms. Virulence. Feb

15, 2013; 4(2): 119–128.

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Candida Transformation• To infect host tissue, the unicellular form of Candida

switches to a more invasive multicellular form based on environmental changes (i.e. pH, food supply, temperature, CO2) at the tissue level – much of which it can control!

• Changes can include:• pH – low pH (less than 6), Candida predominately grows in

the yeast form (unicellular), whereas at a higher pH (greater than 7) more hyphal forms are induced. Neutral (pH of 7) to alkaline (pH greater than 7) can cause stress to Candida.

• Candida is able to alter extracellular pH by uptake of various amino acids and produce ammonia (raising pH).

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Candida Transformation

• Food supply – under nutrient starvation Candida can alter its environmental pH and induce hyphal formation too. • Its preferred food source is glucose, but amongst other

normal flora in the digestive system it lives in a state of competition which controls its population growth.

• Dissemination to the blood stream Candida seeks higher levels of glucose without much competition.

• Candida can alter its metabolism for lipids and amino acids upon encountering and engulfment by macrophages.

• Phagocytized Candida can even pierce through immune cells and escape gaining access to all organ tissue throughout the body.

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Other Factors in Candida Transformation and Pathogenicity

• Heat shock proteins (HSP) – these specialized proteins are designed to prevent against protein unfolding and aggregation, caused by environmental stress, which normally induces cell death. HSPs are involved in Biofilm formation, morphogenesis, virulence, and drug resistance too.

• Metal accumulation – Candida acquires iron, zinc, manganese and copper for metabolic survival, with iron and zinc as primary minerals.

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Adhesins and Invasins

• Candida has specialized proteins which allow it to adhere to other microorganisms, abiotic surfaces, and host cells. These adhesion proteins are also involved in Biofilm formation.

• Invasin proteins allow for two different ways for Candida to penetrate host cells:• Active penetration – hyphal driven process with

various protease secretions allowing cell penetration.

• Induced endocytosis – expressed proteins on the cell surface induce engulfment of the Candida cell.

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IL-6 can induce HPA activity for the release of ACTH production

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Leaky Gut

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Candida invasion into tissue

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How Do Common Antifungal Medications Work?Diflucan versus Nystatin

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Nystatin (similar in oral absorption of Amphotericin B)

• Binds to ergosterol which serves the same function as cholesterol in mammal cell membranes.

• Forms holes in the membrane that allow potassium (K+) leakage causing cell death.

• Both can be toxic when given I.V. However, given orally have very good safety record because of poor intestinal absorption.

Nystatin

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Dosing strength is variable:• 100,000s for oral thrush, but may need to

be in the millions for digestive chronic candidiasis. • 100,000 units/ml (standard)• 100,000 units to 250,000+ units/ml

(compounded from special pharmacy).• 5ml = 1 teaspoon• ¼ teaspoon to 1 teaspoon 3 to 4x/day

Nystatin (continued)

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•Nystatin can be taken for long periods of time, i.e. many months, even years without concern for liver stress (personal experience).

•Needs to be dosed multiple times throughout the day to continue its antifungal effectiveness.

Nystatin (continued)

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Diflucan (Nizoral, Sporanox and Lamisil have similar activity against ergosterol):

• Inhibits a cytochrome P450 enzyme 14α-demethylase.

• P450 is common enzyme in plants, molds, and bacteria.

• 14α-demethylase is necessary to produce ergosterol – part of the cell membrane.

Diflucan

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• Absorption is rapid in approximately 2 hours

• Caution regarding liver stress, as well as prolonged QT interval.

• Contraindicated with SSRIs and certain acid blockers, i.e. Propulsid.

• Ideally, should be checking liver enzymes every 4 to 8 weeks with continued use.

Pediatric Dosing: 3mg to 6mg/kg (some literature indicates as high as 6 to 12 mg/kg).

On average = 5mg/kg/day

Diflucan (continued)

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Drug Therapy For Virulence Factors

•Targeting virulence factors is an area of evolving research. For example:• Blocking adhesion and invasin proteins.• Altering heat shock protein function• Altering Candida cell nutrient and

mineral utilization.

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Additional Examples of Candida Toxicity

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Candida

Human macrophage

Myeloperoxidase-WBC enzyme

response to Candida infectionClO-

Hypochlorite ion - powerful oxidizing agent-tissue damage

Active ingredient of Clorox®

N-acetyl

Glucosamine,

Glucuronic acid

Arabinose,

Tartaric acid

Hyaluronic acid

Intercellular cement

References1. Jahn M, et al. Carbohydr Res. 1999, 321:228-34.

2. Shimizu MT et al. J Med Vet Mycol. 1995, 33:27-31

hyaluronidase

Production of arabinose, tartaric acids as indirect markers of invasive Candidiasis

Kills Candida

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Following Information On Pentosidine Toxicity, Gliotoxin, etc.

www.greatplainslaboratory.com

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Arabinose & Arabitol

D-Arabinose D-Arabitol

Arabinose is a type of yeast sugar that is not known to be produced by humans.

A compound , aka. arabinatol which can normally be found in humans, and is a byproduct of

yeast. Can be also be converted by intestinal bacteria into Arabinose.

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• May be found in some food in small quantities – apple juice or apple sauce.

• Worsening of autistic behavior after eating apples – likely do to arabinose has been seen clinically.

• Arabinose has been found high in schizophrenics and other conditions too.

Additional Sources of Arabinose

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Aldehyde Group of Arabinose

Aldehyde (CH

Epsilon Amino Group (NH3)

Aldehyde

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Function of Lysine

• Essential amino acid not synthesized in animals

• Metabolism is towards Acetyl-CoA production

• Aides with calcium absorption, muscle protein and hormone production, various enzymes and antibodies.

• Clinical uses of Lysine (suspected effects):• Anxiolytic effects via overactive serotonin (5-HT4)

receptors in the gut – anxiety-induced diarrhea.

• Anxiety reduction via benzodiazepine receptors

• Food sources – eggs, meat, fish, cereal grains, beans, soy.

• Recommended Daily Intake = 12mg/kg/day

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Lillard, S. Candida Albicans. Published online in Mold-Help 411 (2004)

•Biotin suppresses yeasts ability to form hypha, preventing it from entering its invasive state.

•1,000 mcg taken three to four times a day is recommended (Lillard, 2004).

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Arginine

Arginine is involved in blood pressure control, immune function, ammonia detoxification, growth hormone

release, insulin regulation and more.

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Pentosidine

Arabinose-Lysine Complex + Arginine = Pentosidine

Arabinose from candida can complexwith Lysine which then interacts with the amino acid Arginine to form the toxic byproduct called Pentosidine.

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• Cross-linked proteins – decrease flexibility of structural proteins of collagen and muscle.

• Decrease enzyme activity

• Possible damage to myelin

• Autoimmune reactions to dysfunctional proteins.

• Decrease ability to clear neurofibrillary tangles

Problems Linked to Pentosidines

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Neurofibrillary Tangles

Amyloid plagues stimulate microglial which can leadto brain inflammation.

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Serotonin

Quinolinic acid

Gamma

Interferon

from immune

system due to

infection

Kills cells containing bacteria, viruses, parasites. May also damage infectious organisms themselves. IDO causes drastic reduction in

tryptophan for protein synthesis needed by infected cells and infectious organisms.

Beta

amyloid

peptide-

Alzheimer’s

Excess tryptophan

Causes failure to

Kill infectious agents

Cortisol

Stress

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Quinolinic AcidProduction

Serotonin

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Nicotinamide adenine dinucleotide

Oxidized Reduced

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Redox Reactions

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Mitochondrial Function Being Affected By Yeast

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Analogs

Malic Acid (MA) Tartaric Acid – analog to MA

Citramalic Acid – analog to MA

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• Malic acid is needed as a back-up source for blood sugar conversion when the body runs low.

• Blood sugar is one of the main fuel sources for brain function.

Malic Acid

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• Toxic substance in high amounts damaging muscles and kidney.

• Found to be elevated in those with fibromyalgia, joint pain, depression, chronic fatigue.

• FDA lists as Generally Recognized As Safe (GRAS) – used as an additive in processed foods.

• Baking powder, cream of tartar, grape and lime flavored beverages, grape and grape products, and poultry.

Tartaric Acid

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• Inhibits an enzyme called Fumerase.

• Inhibiting fumerase shuts down the ability to make adequate amounts of malic acid.

• Malic acid is needed to supply ongoing substrate for normal Kreb Cycle function.

Tartaric Acid (continued)

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• Like tartaric acid, citramalic acid is an analog of malic acid.

• It contains an extra methyl (CH3) group.

• Acts like tartaric acid by inhibiting the production of malic acid.

Citramalic Acid

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Inhibited by Tartaric Acid & Citramalic Acid

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Fig. 1. The tricarboxylic acid cycle during typical metabolism. Carbohydrates and fatty acids enter the cycle as acetyl-CoA and through a series of enzymatic steps produce energy utilizing two electron carriers, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2). NADH and FADH2 are metabolized by complex I and complex II, respectively, of the

electron transport chain (ETC). Complex V of the ETC produces adenosine triphosphate (ATP), the energy carrier of the cell.

From: Gastrointestinal dysfunction in autism spectrum disorders: the role of the mitochondria and the enteric microbiome (2015), Frye, et.al.

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Krebs Cycle & Mitochondrial Metabolites

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Additional Documents Section of ‘Resource Center’

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• L-Carnitine – 50mg to 100mg/kg per day

• Ubiquinol (active CoQ1O) – 5mg to 10 mg/kg (approx. 100 to 200+mg daily).

• NADH – 5 mg+ daily

• Malic Acid – 500mg to 1000mg daily. NOTE: usually no more than 2000mg of L-carnitine or 400mg of CoQ10 are used daily for individuals with adult weights.

Mitochondrial ‘Cocktail’ Example

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Additional Document Section of ‘Resource’ Center

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www.nbnus.com

See handout “Mitochondrial Cocktail Options” for dosing recommendations in Module 2

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• Gliotoxin – can fragment the DNA of lymphocytes (T-cells), white blood cells, and macrophages.

• Gliotoxin can directly lead to immune suppression, i.e. lower Secretory IgA.

• Gliotoxin generate free radicals depleting glutathione.

Gliotoxin – immunotoxic substance produced by yeast and molds

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#2, #4, #5 – often associate with mold exposure, i.e. Aspergillus, Penicillum

#9 - A chemical byproduct released from fumonisins during passage through the gastrointestinal tract. Fumonisins are fungal toxins produced primarily by F. verticillioides. Elevated levels can be caused by the intake of corn or corn-based food contaminated with fumonisins.

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• Amphotericin B - 125mg to 250mg three times daily for 4 to 8+ weeks• Biocidin – 1 to 2+ capsules two to three times daily for 4 to 8+ weeks, and/or• Olive Leaf Extract (Olivirex from BioBotanical Research) – shown to be

effective against Aspergillus – 1+ capsule two to three times daily for 4 to 8+ weeks

BioBotanical Research – www.BioBotanicalResearch.com

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Aspergillus Mold - Corn Silo

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Course Document

“Fungal Hypersensitivity Food List”

Found in Module #3

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Plants, yeast and bacteria – can ferment glucose into Acetylaldehyde and finally into alcohol.

Alcohol symptoms have been observed

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Various issues related to excess Acetylaldehyde:

1. Interferes with vitamin B6 - B6 necessary for many neurochemical reactions, oxalate metabolism, blocking Pentosidine formation.

2. Altering neurotransmitter function

3. Disrupts tubulin formation in nerve cells

4. Leads to muscle pain and irritation

Acetylaldehyde Toxicity

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• Alcohol dehydrogenase converts ethanol into Acetylaldehyde.

• Acetylaldehyde is then converted into acetic acid by Acetylaldehyde Dehydrogenase.

Acetylaldehyde Conversion

Acetaldehyde + NAD+ + H2O → acetate + NADH + 2H+

Body naturally gets rid of acetic acid or converts into Acetyl-CoA

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• Conversion of acetylaldehyde to acetic acid to acetyl-CoA requires:

• NADH

• Riboflavin (B2)

• Iron

• Molybdenum – 50mcg to 100mcg daily

Acetylaldehyde Detoxification

Acetaldehyde + NAD+ + H2O → acetate + NADH + 2H+

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Testing Options for Candida

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Candida Antibodies

Blood Test:

• Candida IgA – lower levels in blood versus gut. Primary immunoglobulin in digestive system and mucosal surfaces, i.e. sinuses, eyes, vagina, bladder.

• Candida IgM – 1st produced against invading organism

• Candida IgG - 2nd produced, but most abundant, gives long-term immunity. Does indicate systemic recognition of candida.

• What about PCR?

Saliva testing another option - primary antibody is Secretory IgA which can indicate

overgrowth in the digestive system.

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STRUCTURE&

FORMATIONOF

sIgA

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Yeast Culture

Candida can be difficult to culture in the lab which is why it sometimes doesn’t show up on a stool test, but evidence of its existence is found

via the Organic Acids Test.

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Sensitivity Testing

• Tablets of medications and/or botanicals are placed in culture dish.

• The larger the ‘zone’ the greater the killing or inhibition efficiency of the remedy.

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Treatment Options for Candida

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www.nbnus.com

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General Support Supplements

• Foundational nutrients – should include a wide variety of B-vitamins, vitamin C, D, and E, as well as minerals, calcium and magnesium, etc.

• Essential fatty acids, i.e. Cod Liver Oil, fish oil

• Multi-Strain Probiotic – TherBiotic Complete, VSL#3, ProBio Premium, etc.

• Additional supplements to consider:• Biotin - 1000mcg (1mg) two to three times daily

• Molybdenum - 50mcg to 100mcg daily

• Mitochondria Support, i.e. L-Carnitine, Ubiquinol

• L-Lysine – 500mg to 1000mg+ daily

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Molybdenum & Biotin

10 drops = 100mcg 1 tablet = 1000mcg

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High Dose Probiotics

2 capsules = 225 billion organisms 1 packet = 225 billion organisms

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Lower Dose Probiotics

1 capsule = 20 billion+ organisms (approximately)

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1 capsule = 180mg of Allicin 1 drop = 40 mcg of Allicin

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Yeast Control Packet

• Black Walnut• Goldenseal• Allimax (Garlic)• Uva Ursi• 5 to 15+ drops of

each remedy 3X daily. • Rotate one remedy

every 5 to 7 days.

New Beginnings Nutritionals

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Grapefruit Seed Extract

Multiple Options:Grapefruit Seed Extract(Nutribiotic) – 5 to 15+ drops 3 times daily –strong taste, usually needs to be given in

dilute citrus juice.

10 drops = 100mg of GSE

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USP Effectiveness

Testing of Biocidin®

Demonstrates inhibitory activity of

against both gram positive and

gram negative bacteria, yeast and

fungus.

Bilberry extract, Grape Seed extract, Milk

Thistle, Echinacea, Goldenseal, Shiitake,

White Willow, Garlic, Black Walnut (hull

and leaf), Raspberry, Fumitory, Gentian,

Noni, Tea Tree oil, Galbanum oil,

Lavender oil, Oregano oil

TextText

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6 weeks of Biocidin (8 drops TID) + Culturelle (4 capsule daily)

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Nystatin:• Tablet (500,000 units) - 1/2 to 3 tablets

3x/day.• Oral Suspension (100,000 units/ml) – ¼

teaspoon to 3+ teaspoons 3x/day.5ml = 1 teaspoonNOTE: can use for prolonged periods of time, i.e. multiple months. In some cases have had to use for 1

to 2+ years.

Prescription Medications

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Diflucan (Fluconazole):• Tablet = 100mg, 150mg, 200mg – used once daily

• Oral suspension – 10mg/ml or 40mg/ml

• Average daily dose = 5mg/kg/day

• Length (variable) – 15 to 30 days+

• Can rotate with other antifungals, i.e. Nystatin.

• MUST monitor liver function every to 6 to 8 weeks.

Other medications such as Sporanox and Lamisil can be used similarly (note: Nizoral – no longer use)

Prescription Medication

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Mild Overgrowth or Sensitive Individual

See ‘Mild Candida Protocol’ – Module 3

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Moderate Overgrowth

See ‘Moderate Candida Protocol’ – Module 3

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Severe Overgrowth

See ‘Severe Candida Protocol – Module 3

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• Candida cell wall is made up of various forms of fiber – Candex can help to digest these fiber components.

• No threat of resistance

• 1 to 2 capsules once to twice daily between meals – 30 minutes before or 90 minutes after food.

• Useful for sensitive individuals or as an additional remedy either with botanicals or medication antifungals.

Candex

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Typical “Die-Off” symptoms

• Headache

• Nausea

• Fatigue

• Irritability

• Moodiness

• Digestive bloating and gas

• Fever

• Diarrhea or mixed bowel, i.e. constipation and loose stools

• Rashes

• Body itching

• Hyperactivity and increased self-stimulatory behavior

• Sleep disturbance

See “Die-Off Reaction Management” document in Module #3 for supplement and dosing suggestions

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Steps To Take Prior To Antifungal Therapy

•Dietary Intervention:• GFCF & Antifungal Diet (see individual

documents).

• Foundational supplements + Biotin, etc.

•Constipation remedies (see document in Module 4).

• Ideally, have these steps in place 2 to 4 weeks prior to starting.

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Julie Matthews, CNC –www.nourishinghope.com

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Constipation

Remedy Examples:

• Magnesium Citrate or Oxide – 250mg to 400mg (preferably at bedtime)

• Oxypowder (www.oxypowder.com) – 1 to 4 capsules daily

• Magnesium + Slippery Elm (capsules or powder) – 3 to 6 capsules or 1 to 2 teaspoons powder daily.

• Aloe Vera Juice – 1 to 2 tablespoons with juice 1 to 3 times daily

• TruFiber (www.nbnus.com) – 1 to 2 tablespoons daily

• Ground Flax Seeds or some other non-gluten fiber – 1 to 2 teaspoons daily.

• Fleet’s Enema – 1 daily for 3 to 5 days

• MiraLax – taken once daily – ¼ to 1 capful

• High dose probiotics – increasing amounts of probiotics can lead to relief of constipation.

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Credit to Sydney Baker, M.D:

• The goal of the antifungal parade is to rotate amongst various antifungal remedies.

• Helps to differentiate what antifungal works the best (based on clinical response of individual).

• Helps to diminish potential resistance against one particular antifungal remedy.

• Helps to diminish the potential liver toxicity that might occur with systemic antifungal medications.

• Can use for extended periods of time, i.e. months.

• The parade can be set up weekly, biweekly, etc.

The Antifungal Parade

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• Nystatin – dose three times daily for 7 to 14 days

• Diflucan – dose once daily for 7 to 14 days

• Amphotericin B (oral) – dose three times daily for 7 to 14 days.

• Sporanox – dose once daily for 7 to 14 days

• Nystatin – dose three times daily for 7 to 14 days

• Lamisil – dose once daily for 7 to 14 days

• Back to Nystatin or Amphotericin B, etc.

Another option is to double the dose of

antifungals after 7 days.

Antifungal Parade (example)

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Topic

• “Chronic Candida – The Role of Biofilms in Candida Pathogenicity and Treatment Options”• What are Biofilms?

• How and why are they created?

• The role of Biofilms in Candida pathogenicity

• Expanded treatment options

• The role of Biofilms in bacteria infections

Module #4

Thank YouKurt N. Woeller, D.O. & Tracy Tranchitella, N.D.

www.AutismMasteryCourse.com

AutismMastery@gmail.com