Transcript Dr. Woody McGinnis Presentation

Toxins in Autism:
Mercury to PCB’s
Woody R. McGinnis M.D.
Anaheim, June 28, 2003
Irene (Vicky) Colquhoun
1920-2000
Parent Pioneers
Bernard Rimland
Ellen Bolte
Brenda O’Reilly
Victoria Beck
Rik Rollens
The Mercury Team
Autism and ADHD are
Symptoms
Multiple underlying problems
Variation and commonality
Gut and nutrition paramount
Cornerstones
Suboptimal Nutrition
Food Intolerances
Microbial Overgrowths
Toxins
Gut Disease
Predominates
Esophagitis
Gastritis
Duodenitis
Colitis
69%
42%
67%
88%
Autistic Gut Symptoms
•
Abdominal pain
Chronic diarrhea
Constipation
Night-awakening
69%
58%
35%
42%
Gut Status
Poor digestion and absorption
Leaky gut: proteins out, toxins
and antigens in
Microbial overgrowths
Poor enzyme production
Altered signaling to CNS
Gut Dysfunction
Microbes
Overgrow
Nutrients
Low
Peps, Ags,
Toxins In
Laboratory Indices of Vitamin and
Mineral Deficiency in Autism
Defeat Autism Now
27 October 2002
San Diego
Tapan Audhya Ph.D.
Emar Vogelaar Ph.D.
Low Nutrient Levels in Autism
% Children < Normal Level
(187 Autistic, 11-16 y.o vs. 10-17 y.o. controls)
70
60
50
40
30
20
10
0
Vit A
Carotene
Before supplements
Vit C
Vit D
After supplements
Vit E
Low Nutrient Levels in Autism
% Children < Normal Level
187 Autistics (11-16 y.o.) v. Controls (10-17 y.o.)
70
60
50
40
30
20
10
0
B1
B2
Before supplements
B3
After supplements
B5
% Children < Normal Level
Low Nutrient Levels in Autism
60
50
40
30
20
10
0
B6
B12
Folate
Before supplements
Biotin
After supplements
Inositol
Substrate Requirement for Maximal
Activity of P5P Dependent Enzymes
KM
Controls (n=16) v. Autistics (n=8-17)
70
60
50
40
30
20
10
0
Pyridoxal kinase
Glutamate
transaminase
Controls
Autistics
Glutamate
decarboxylase
Substrate Requirement for Maximal
Activity of P5P Dependent Enzymes
1000
900
800
700
600
500
400
300
200
100
0
DOPA
decarboxylase
Histidine
decarboxylase
Controls
Autistics
5-HTP
decarboxylase
Low Minerals in Autism
% Children< Normal Level
(132 Autistics, 42 Controls)
70
60
50
40
30
20
10
0
RBC Zinc
RBC Magnesium
RBC Selenium
Membrane Fatty Acids
90
80
70
60
50
40
30
20
10
0
Low EPA
Low GLA
High AA
High Tran
Nutrient Blockade
Absorption
Transport
Breakdown
Excretion
Inhibition
Blocked Absorption
Heavy metals: direct mucosal injury
Oral contraceptives block managnese
Insecticides: lipase inhibition
Poor acid production from microbial
toxins and peptides means poor absorption
of magnesium, zinc, B6 and amino acids
Blocked Transport
PCB’s block RBP, so low stored
and circulating Vitamin A
Cadmium displaces Zinc
Toxin-lowered [Magnesium]: poor P5P entry
Caramel coloring blocks P5P entry
Increased Breakdown
Ubiquitous toxins, including
polyhalogenated hydrocarbons
(PCB’s, PCDD’s, PCDF’s) cause:
Vitamin A destruction
Increased Excretion
ETOH and Gentamycin: Vitamin B
Theophylline: Magnesium
Mercury: Magnesium and Calcium
Sulfa and Indocin: Folate
Tartrazine: Zinc
Nutrient Inhibition
Insecticides and theophylline bind B6dependent enzymes
Sulfa drugs antagonize Folate
Lead competes for Calcium binding sites
Benzene binds Pyridoxine (B6)
Hydrazines (jets, corrosion inhibiter) and
Hydrazides (“Alar” on fruits, cigarettes and
especially potato chips): B6 look-a-likes
Environmental Toxins in Autism?
Some Clues:
D-glucaric acid increased in 78%
Plasma glutathione low in 46%
Lower glutathione peroxidase (GSHPx)
Organic Toxins in Autism
Elevated Plasma Levels
% Children>Normal
Levels
70
60
50
40
30
20
10
0
Benzene
Iso Acetone
Pentane
Hexane
Organic Toxins in Autism
% Children>Normal Level
Elevated Plasma Levels
35
30
25
20
15
10
5
0
Aroclors(PCB)
Perchlorethylene
Xylene
Elevated Toxins in Autism
(41 autistics, 24 controls)
Red Blood Cell Levels
% Children>Normal
Levels
35
30
25
20
15
10
5
0
Aluminum
Arsenic
Cadmium
Lead
Toxins in Autism
% Children>Normal Level
Elevated Red Blood Cell Levels
30
25
20
15
10
5
0
Total mercury
Organic mercury Inorganic mercury
Metals in autism?
• Clinical Pediatrics, 1988; 23(1):41-44
Temporal association lead and autism
• Am J Dis Chld, 1976;130:47-48
Higher blood lead levels and response
to EDTA chelation.
• DAN 2001 case report: normal 4 y.o.
regresses severely to ASD post-amalgams
HEAVY METALS
AC / DC
DANGER DANGER
EROTIC LIQUID CULTURE
JEREMY & THE SUICIDES
MEGA DEATH
METALLICA
MOTORHEAD
NEAR LIFE EXPERIENCE
NEUROTICA
NEW AMERICAN SHAME
PSYCHOTICA
VITAMIN F
Toxic Metals
Mercury
Lead
Cadmium
Arsenic
Nickel
Tin
Free Copper
Free Iron
Metals: Toxic Mechanisms
Membrane damage
Protein distortion
Calcium channel block
Nutrient depletion
Immune suppression
Detoxifier depletion
Oxidative stress
Sensitivity to Metals
Chemical form
Amount and duration
Age, gender, genetics
Nutrition and immunity
Other toxins
Autism / Mercury Clues
Acidosis
Cholinergic block
Low sulphate
Autoimmunity
TH2 shift
Demyelination
Seizures
Visual
Depressed NK Purkinje / granule
Se depletion
B6 depletion
Pink Disease
From 1890, often lethal
Often pink cheeks, nose and painful hands
(‘acrodynia’)
Calomel teething powder
Typically latent onset
Only 1 in 500 exposed
Pink Disease
Apathy
Lost play
Sound / light
Touch averse
Head-banging
Repetitive rocking
Repetitive hands
Poor muscle tone
Seizures
Infections, insomnia
Autism / Mercury Traits
Social deficit
Speech loss
Echolalia
Repetitive
Lateral gaze
Flapping
Circling
Abnormal G.I.
Toe-walking
Head-banging
Touch-averse
Sound sensitive
Poor eye-hand
Rashes
Poor sleep
ADHD
Case study – C.M.
EPA maximum is 0.1 mcg Hg / kg / day
First Hep-B 12.5 mcg, so X 30 that day
[Presumed] 25 mcg in each DPT and
H-flu. By 6 mos, total Hg 187.5 mcg,
or X 2 EPA (total exposure)
CASE STUDY - C.M.
90
80
70
60
50
40
30
20
10
0
FIRST
SECOND
THIRD
FOURTH
Thimerosal Aliases
Ethyl mercury
Elcide
Ethylmercurithiosalicylate
Mercurothiolate
Merfamin
Merthiolate
Ethylmercuric thiosalicylate
Timerasol, Thimerosal, Thiomerosal..
Mercury Injections
No safety studies
Organic forms of Hg most toxic
Faroes Islands bolus lesson
Infants poor excretors
Vaccines open BBB
Thimerosal and Autism
• CDC: initial suggestion of association,
prior to revision of study results
• IOM: thimerosal / autism link “plausible”
• First published epidemiological report:
incidence of autism X 6 if received DPT
with Hg [Geier M and Geier D, 2003]
Metals-Detox Nutrients
Vitamin C 250-2000 mg b.i.d ups GSH
Vitamin E 150-400 IU daily helps Se
combat Hg and Cd
Selenium 1-4 mg/kg/day
Melatonin up to 0.1 mg/kg
Lipoic Acid 1-10 mg/kg
Support MET pathway
Taurine 200-1000mg/d
Glutathione
Calcium and Heavy Metals
Mercury increases calcium loss
Calcium aids lead excretion
Cadmium decreases calcium
absorption
DMSA Perspectives
Thousands of autistics
No irreversible side effects
Nutritional and gut prep first
Stay up on the zinc
Many excellent responses
Some talk only on DMSA days
Heavy Metals and the Gut
Mercury and cadmium avidly bind
intestine and are highly caustic
Mercury blocks vitamin B6 and DPPIV
in the gut
Antibiotic-altered flora may recirculate
mercury
DMSA Mechanisms?
Reduction of Hg and other heavy metals
Reduction of Cu burdens
Clear sensitive muscarinic cerebraldilating receptors.
Definition
Free-radicals are highly-reactive molecules
which damage cells by oxidizing lipids,
proteins and nucleic acids.
Some free-radicals are a natural by-product
of energy metabolism. Environmental
toxins are either free-radicals themselves,
or lead to the generation of free-radicals in
the body (as do infections and allergies).
Increase Free-Radicals
Smoking, pollution, ozone, metals
Inflammatory cytokines
Infections, allergies
Oxidized foods, food additives
Dirty foods (insecticide, herbicide)
Unbound Copper and Iron
Depleted anti-oxidant defense
Protect from Free-Radicals
Vitamin C
Vitamin E
Vitamin A
Vitamin B6
Zinc
Carnosine
Niacinamide
Folate
Urate
Glutathione (GSH)
Metallothionein (MT)
GSHPx
Vanilla
Catalase
Phenothiazines
SOD
Estrogen
Melatonin EPA
CoQ10
Definition
Oxidative Stress is cellular impairment
resulting from free-radicals in excess of
available anti-oxidant defense.
The interplay of genes, nutrients and
toxins determines the level of oxidative
stress.
Metals Increase Oxidative Stress
• Metals with high-affinity for SH-groups
(Hg,Pb,Cd,As,) deplete GSH and MT
• Metals with fluctuating valency (Cu, Fe,
Mn) generate free radicals directly
• Metals which mimic calcium (Pb,Sn) overexcite the cell via increased intracellular
calcium, which generates free radicals.
Especially Sensitive to
Oxidative Stress
Gut: extreme sensitivity of
mucosa to free-radicals
Brain: high lipid, low GSH,
low metallothionein levels
Oxidative Stress in Autism?
Extensive GI inflammation
Opiod binding blocked by GSH
DPPIV active in reducing conditions
Muscarinic targets
Stim-relieving effect of GSH
DMSO a hydroxyl scavenger
Increased PLA2
Response to DMSA
Autoimmunity
Oxidative Stress in Autism?
Poor anti-oxidant nutrient status
Lower GSH and GSHPx
Extreme copper intolerance
Phenolic intolerance
Breathe ethane in ADHD
ApoE4 genotypes
Vitamin C / carnosine trials
B6 blockade in autism
50% high-Mauve
PHF LEVELS
6
5
4
AVERAGE
MEDIAN
3
2
1
0
ADD
ADHD
AUT
High-PHF Rats
Exceedingly high biomarkers for
oxidative stress in these SHR.
Oxidative stress and symptoms in
these animals relieved by
vitamin C or MET.
Zinc is Free-Radical Protection
Blocks lipid peroxidation
Protects protein structure by coordination
with SH-groups, blocking Cu and Fe.
Essential for maintenance of Vit A level
Supplementation increases GSH
Co-factor for MET pathway
Key constituent for SOD
Deficiency increases SO4 loss
Glutathione (GSH)
Ubiquitous FR-quencher, lst-line gut defense
Protects receptor and enzyme function
Key partner to MT
Substrate for GSHPx and Phospholipid
Hydroperoxide GSHPx
Excellent responses to I.V. GSH
Significant oral absorption, intact
Excellent responses to oral 10-50mg/kg/d
Oxidative Stress
Measurement (“Biomarkers”)
Anti-oxidant nutrient levels
Endogenous anti-oxidant compounds
Oxidized lipids, including breathe
Oxidized proteins
Oxidized nucleic acids
Isoprostanes, Isolevuglandin adducts
Apoptosis
The Mauve Factor
Excellent response to anti-oxidants
across multiple diagnoses
Zinc and B6 deficits, which vary
individually and which fluctuate
Putative metric for oxidative stress
“Mauve Factor” Means Pyrroles
• Measurable as
“Kryptopyrrole”
• A core test in the
the management
of all behavioral
disorders
• 1-800-494-7785
Urinary Pyrrole:
The Mauve Factor
Useful, economical, may be pivotal.
Elevation makes zinc,Vitamin B6
and anti-oxidants top priorities
Careful handling: highly labile
Autistic Urinary Pyrrole Levels and B6
(10mg/kg/day) + Zn (25mg) + Mg (400mg)
micromoles/100ml
120
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Months of Treatment
Mauve Factor Inhibits Heme
Heme Inhibition associated with
decreased Zn, increased Fe.
Heme-dependent anti-oxidant
enzymes include: catalase,
peroxidase, cystathionine synthase,
heme-hemopexin for MT synthesis,
p450, cytochromes for energy
production.
Diketone Neurofilament Injury
Conclusion
Oxidative stress may be the primary,
shared pathological mechanism for
diverse factors contributing to autism,
and its reversal may significantly
affect the course of the disease.
Biomarker studies underway.
Potential for objective criteria to guide
therapy, enhance focus for gene and
tissue studies.
Goal: Lessen Oxidative Stress
Minimize toxins, infections, allergens
Give plenty of anti-oxidants
Support detoxification metabolism:
Vitamins B6, B12, (Folate)
Magnesium, Zn, Selenium (folic acid)
(Methionine)
METHIONINE
ATP, Mg
HC
B6 (Mg, Zn)
GSH
MT
CYS
TAU
SO4
SO4
DETOX
BILE
Detoxification
Organic foods, pure water
Clean living environment
No additives or flavor enhancers
Regular bowel movements: fiber, magcitrate, vitamin C, bethanecol
Plug nutritional holes and suppress
overgrowths
DMSA / Lipoic Acid metals protocol
Basic Lab List
Stool studies
Mauve Factor
RBC minerals
Organic acids
Serum IgG / IgE
food allergy
Vitamins (esp A)
RBC fatty acids
Peptides
PCR for mycopl.
and chlamydia
Immune profile
Toxins
Amino acids
Treatment
Supplements
Food avoidance
Suppress overgrowths
Detoxify
Really Key Nutrients
Zinc
Magnesium
Calcium
Vitamin B6
Fatty Acids
Vitamin A
Vitamin C
Vitamin E
Vitamin B12
Biotin
GSH
Supplementation
History, physical, lab, empirical
Don’t be deceived: use sensitive
measurements
Keep re-checking to confirm
Changing needs and variability
General Approach
Introduce interventions individually
Smaller doses may be necessary at first
Continue interventions unless reason to stop
If combination nutritional formulations are not
well-tolerated, add one-at-a-time
Adding Nutrients Individually
Build sequentially
Zinc, then P5P/Magnesium Glycinate,
Calcium, Selenium, C, E, Multi-Vit
without Copper, Biotin, B12, Cod liver oil
(for Vitamin A)
Really assure zinc
Away from food, minerals and P5P
Zinc/Manganese about 3:1
Fatty-Acid Basics
Pre-treat with anti-oxidants
Treat low-normal GLA, DGLA
and EPA lab values
Dry hair or skin, allergy: usually
need fish oil EPA
Infections, leaky gut: usually
need evening primrose GLA