Oxidative Stress & Autism A Paradigm for Effective Treatment
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Oxidative Stress & Autism
A Paradigm for Effective Treatment
Allen T. Lewis, MD, FAAP
Medical Director, Pfeiffer Treatment Center Warrenville, Illinois
Bringing Balance to the World – One Person at a Time
Health Research Institute
© HRI/PTC 2008 – All Rights Reserved
Health Research Institute
Questions
• What is autism? • How did it happen?
© HRI/PTC 2008 – All Rights Reserved
• What can be done?
Bringing Balance to the World – One Person
Health Research Institute
An Axial Approach
• Axis I • Axis II • Axis III • Axis IV • Axis V Clinical Disorders Personality Disorders & Mental Retardation General Medical Conditions Psychosocial & Environmental Problems Global Assessment of Functioning
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
A Preponderance of Autisms
Social interaction:
• poor eye contact • inability to regulate social interaction • inability to develop age appropriate relationships • delay or lack of spoken language • abnormal or absence of imitative play • rituals • repetitive mannerisms (aka “stims”) • restricted areas of interest
Language:
© HRI/PTC 2008 – All Rights Reserved
Symbolic or imaginative play:
Bringing Balance to the World – One Person
Health Research Institute
Three Strikes
Drs. Hornig and Lipkin describe in animal model studies a 3 strike concept of potential cause for neurodevelopmental disorders. It is a triad of (1) genetic susceptibility in light of (2) critically timed environmental insults of (3) sufficient severity and quantity that trigger the disease process that manifests as a neurodevelopmental disorder (i.e. PDD, ASD, etc.).
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Understanding a Disease Process
What does it look like?
• Diagnostic criteria • Level of functioning • Clinical manifestations
© HRI/PTC 2008 – All Rights Reserved
What is broken?
• Genetic & Epigenetic influences • Physiology/ Biochemistry • Review of systems
Bringing Balance to the World – One Person
Health Research Institute
Manifestations of an Illness
© HRI/PTC 2008 – All Rights Reserved
• Physical • Behavioral • Developmental • Neuropsychiatric
Bringing Balance to the World – One Person
Health Research Institute
Mechanisms of an Illness
• Organ Systems
• brain, bowel, etc.
• General metabolic processes
• Oxidative stress & inflammation
© HRI/PTC 2008 – All Rights Reserved
• Individual Biochemical Pathways
• trace metals, methylation, pyrrole chemistry
• Systemic, regional or local
• global brain effects or specific regions.
Bringing Balance to the World – One Person
Health Research Institute
A Biologically Impaired Brain
Primary Brain Dysfunction
– Abnormalities in structure and/or maturation – Genetic predisposition for Axis 1 symptoms
Acquired Brain Dysfunction
© HRI/PTC 2008 – All Rights Reserved
– Metabolic, biochemical and nutritional imbalances – Oxidative stress and Metallothionein dysfunction
=> Resulting in Sensory Integration Dysfunction
Disorganized processing of sensory, biochemical, or neuropsychiatric signals leading to abnormal behavior, learning and development.
Bringing Balance to the World – One Person
Health Research Institute
More than the Brain
• • • • • • Gastrointestinal Neurologic Immune Autoimmune Metabolic Biochemical
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Paradigm of Autism
ASD is a medical illness
- with a biologically impaired brain, - commonly associated with multiple medical problems and organ systems, - with genetic and acquired factors - leading to abnormal behavior, learning, and development - that is treatable.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Why Oxidative Stress?
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
What is Oxidative Stress?
• An excess of chemical free-radicals that can damage proteins and essential fats, as well as disrupt normal cellular processes. • Oxygen free radicals are one of many free radicals that lead to oxidative damage. Nitrogen species and ionized metals are also important free radicals.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Consequences of Ox Stress
• Inflammation • Poor immune function • Neurodegeneration • Impaired methylation and other cellular processes • Increased sensitivity to toxic influences • Depletion of glutathione and metallothionein
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Severity of Oxidative Injury
Both genetic susceptibility and the severity of the environmental insult likely determines the degree to which the injury is manifest: (1) Mild injury results in PDD or speech delay. (2) Severe injury results in lower functioning ASD or mutism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Timing of Oxidative Injury
• Early injury => ASD
Delayed or impaired maturation resulting in immature brain cells and developmental delay
© HRI/PTC 2008 – All Rights Reserved
• Late or cumulative injury => Alzheimer’s Disease
Degeneration of mature cells and thereby loss of previously established normal brain function.
Bringing Balance to the World – One Person
Health Research Institute
Evidence of Oxidative Stress
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Vascular Damage in the Kidney
Study of treatment-naive patients with autism vs. age matched controls:
• Evidence of increased oxidative markers in the urine. • Evidence of oxidative damage to vascular tissues.
Yao Y et al. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006 Aug;63(8):1161-4.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of Vascular Study
• Increased oxidative damage of fats, vascular tissues, and other molecules may be present in many tissues and organs of the body, i.e. brain, bowel.
© HRI/PTC 2008 – All Rights Reserved
• Antioxidant therapy may be helpful for patients with ASD.
Bringing Balance to the World – One Person
Health Research Institute
WBC/Leukocyte Study
Study of treatment-naive patients with autism vs. age matched control:
• Increased oxidative stress in the white blood cell (WBC). • Increased inflammation. • Decreased immune function. • Significant disturbance in methylation.
Suh J et al. Altered Sulfur Amino Acid Metabolism in Immune Cells of Children Diagnosed with Autism. Am J Biochem Biotechnol. 2008 4(2); 105-113.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of WBC Study
• Similar disturbances in cellular function extend beyond the kidney to another tissue. • Oxidative stress plays an important role in the disruption of normal cellular processes. • Biochemical abnormalities exist in autism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Neuroinflammation
Study of autism and control brain tissue for evidence of immune-mediated differences.
• Evidence of active neuroinflammation of the cerebral cortex, white matter and cerebellum of autism brain tissue. • Evidence of a proinflammatory response in the cerebrospinal fluid of patients with autism.
Vargas D et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 57 (1); 67-81.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Oxidative Injured Brain
Study of autism brain samples for evidence of oxidative injury in comparison to control brain samples.
• Direct evidence of oxidative damage was found in all samples of autism brain and in no control sample.
Evans T el at. The Autistic Phenotype Exhibits a remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation. Am J Biochem Biotechnol 2008. 4(2); 61-72.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of Ox Brain Injury
• Oxidative injury of proteins in the brain would likely be associated with neurologic abnormalities. • Oxidative injury of brain tissue likely plays a role in autism. • A better understanding of oxidative injury in the brain and other tissues is needed and would likely lead to improvements in the treatment of autism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
What can be done?
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Goals of Treatment
• • • • Identification of broken systems. Restoration of normal function. Protection from re-injury. Promotion of normal physical, emotional, and mental health. • Thereby, establish more normal learning and development.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pieces of the Autism Puzzle
• • • • • Neurologic Psychiatric Gastrointestinal Immunologic Biochemical
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Nutrients and Neurotransmission
The Brain is a Chemical Factory
• Zinc is required for GABA synthesis • Vitamin B6 is required for Serotonin (5-HT) synthesis • Copper (Cu++) is a cofactor in the conversion of Dopamine (DA) to Norepinephrine (NE) • The Methyl:Folate ratio impacts the levels of Dopamine, Norepinephrine and Serotonin
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Biochemical Individuality Matters
Due to genetics and epigenetic influences individuals may be - deficient in several nutrients, as well as - overloaded in others.
© HRI/PTC 2008 – All Rights Reserved
Multiple vitamins are rarely effective, as they may - contribute to nutrient excess for those with pre-existing overload (i.e. copper, folate) and/or - induce another nutrient imbalance.
Bringing Balance to the World – One Person
Health Research Institute
Targeted Treatment with Nutrients
•
Genetic nutrient deficiency may require many times the RDA to achieve normalization/optimization.
© HRI/PTC 2008 – All Rights Reserved
• Genetic overloads may require biochemical therapy to eliminate the nutrient excess. • Treatment focuses on correcting specific imbalances that manifest with specific clinical symptoms.
Bringing Balance to the World – One Person
Health Research Institute
Differential Diagnosis of Biochemistry
• Pyrrole Disorder • Disordered Metal Metabolism - Copper Excess - Zinc Deficiency • Folic Acid-responsive Methylation
(aka Low Histamine)
© HRI/PTC 2008 – All Rights Reserved
• Methionine-responsive Methylation
(aka High Histamine)
• Metallothionein dysfunction
Bringing Balance to the World – One Person
Health Research Institute
Pyrrole Disorder
Clinical Features: • • • • Anxiety Fear Mood Swings Stress Intolerance:
Emotional, biochemical, & physical
Metabolic Consequences: • • • • • • Increased oxidative stress Vitamin B-6 Deficiency Impaired serotonin synthesis Zinc deficiency Low blood arachindonic acid levels Physiologic stress
© HRI/PTC 2008 – All Rights Reserved
• Misperceptions • Sensory issues:
Light, sound, and tactile
• Increased risk of PTSD related triggers
Bringing Balance to the World – One Person
Health Research Institute
Copper Excess
Clinical Features: • • • • • • Hyperactivity Temper Tantrums Learning problems Agitation Tinnitus Depression
(dysthymic or refractory)
Metabolic Consequences: • • • Increased oxidative stress Increased inflammatory responses and stresses Increased Norepinephrine effects due to increased conversion from Dopamine Increased strain on zinc requirements
© HRI/PTC 2008 – All Rights Reserved
•
• Post-partum Depression
Bringing Balance to the World – One Person
Health Research Institute
Zinc Deficiency
Clinical Features: • Explosive temper • Poor memory and mental lethargy • Poor and delayed growth • Frequent infections • Poor wound healing • Acne • Diarrhea • Hypogeusia • White spots on finger nails Metabolic Consequences: • • • • • Reduced defense against oxidative stress Decreased GABA formation Altered copper homeostasis Impaired cell-mediated immunity Poor energy
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Low Blood Histamine
Clinical Features: • • • • • • • Generalized anxiety Depression Panic Agitation & paranoia Racing thoughts Underachievement Good response to benzodiazepine medication • History of significant side effects with SSRI or antihistaminic medications Metabolic Consequences: • • • Folate deficiency Over-methylation Tendency to high dopamine, serotonin and norepinephrine
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Elevated Blood Histamine
Clinical Features: • • • • • • • • ADHD OCD, perfectionism Blank mind Rumination Addictive behavior Seasonal allergies Migraine headaches A history of good response to SSRI medication. Metabolic Consequences: • • • • Methyl Deficiency Under-methylation Low levels of dopamine and serotonin. Intolerance to higher doses of folic acid.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Metallothionein
Short, linear, cysteine-rich proteins present in all tissues of the body that are required for trace metal metabolism and other functions: • MT I & II are present in all tissues and regulate zinc and copper; thereby cell transcription, immune function and more. Furthermore, MT I & II are in high concentrations in the intestinal and blood-brain barriers protecting the body and brain from penetration of toxic metals.
© HRI/PTC 2008 – All Rights Reserved
• MT III is present mainly in the brain and acts as a neuronalgrowth-inhibitory factor in the development, organization, and apoptosis of brain cells. • MT IV is present primarily in the GI tract and regulates stomach acid pH, and taste/texture discrimination by the tongue.
Bringing Balance to the World – One Person
Health Research Institute
Metallothionein Dysfunction
Disturbances in zinc and copper are directly related to MT dysfunction. Quantitative depletion: Zinc is one of the primary inducers of MT; therefore, zinc depletion leads to lower levels of MT, decreased zinc transport and zinc delivery to target tissues.
© HRI/PTC 2008 – All Rights Reserved
Functional Impairment: Excess copper displaces zinc from MT and thereby reduces zinc availability to tissues.
Bringing Balance to the World – One Person
Health Research Institute
MT Dysfunction in Autism
Brain Structure and Function
• impaired pruning during development • impaired functioning in tissues with high MT concentrations - Purkinjie cells, hippocampus, amygdala, pineal body and inferior olives.
© HRI/PTC 2008 – All Rights Reserved
Impaired immune modulation and T cell function Impaired digestive enzyme function Impaired functioning of the Blood Brain Barrier and the barrier function of the bowel wall Impaired or crippled protection from oxidative stress
Bringing Balance to the World – One Person
Health Research Institute
Increased Oxidative Stress
Pro-oxidant Influences: • • • • • Elevated Copper Emotional Stress Environmental toxins Immune abnormalities Physical injury Overwhelmed Defenses: • • • • • Glutathione Deficiency Zinc deficiency Impaired metallothionein function Selenium deficiency Malnutrition
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pfeiffer Research on ASD
The Pfeiffer Treatment Center has evaluated approximately 20,000 patients, 5,500 with ASD, since 1989. Analysis of this data has shown:
– – – – – Undermethylation in Autism, 1999. Elevated copper/zinc in autism, 2000 Elevated unbound copper in autism, 2001 Metallothionein deficiency in autism, 2001 & 2003 Confirmation of these biochemical imbalances in treatmentnaïve patients with autism, 2003 – Oxidative Stress in Autism, 2006 & 2008
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pfeiffer Assessment
• Comprehensive medical evaluation focusing on the differential diagnosis of biochemistry and associated medical conditions. • Thorough laboratory assessment of biochemistry and other conditions if needed. • Development of individualized nutrient program to address biochemical needs. • Monitoring of response to treatment and reassessment every 6-12 months.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Contact Information
Allen T. Lewis, MD, FAAP Medical Director Pfeiffer Treatment Center 4575 Weaver Parkway 630-505-0300 630-836-0667 (fax) info@hriptc.org
© HRI/PTC 2008 – All Rights Reserved
Warrenville, IL 60555
Bringing Balance to the World – One Person
Health Research Institute
PTC Locations
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Oxidative Stress & Autism
A Paradigm for Effective Treatment
Allen T. Lewis, MD, FAAP
Medical Director, Pfeiffer Treatment Center Warrenville, Illinois
Bringing Balance to the World – One Person at a Time
Health Research Institute
© HRI/PTC 2008 – All Rights Reserved
Health Research Institute
Questions
• What is autism? • How did it happen?
© HRI/PTC 2008 – All Rights Reserved
• What can be done?
Bringing Balance to the World – One Person
Health Research Institute
An Axial Approach
• Axis I • Axis II • Axis III • Axis IV • Axis V Clinical Disorders Personality Disorders & Mental Retardation General Medical Conditions Psychosocial & Environmental Problems Global Assessment of Functioning
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
A Preponderance of Autisms
Social interaction:
• poor eye contact • inability to regulate social interaction • inability to develop age appropriate relationships • delay or lack of spoken language • abnormal or absence of imitative play • rituals • repetitive mannerisms (aka “stims”) • restricted areas of interest
Language:
© HRI/PTC 2008 – All Rights Reserved
Symbolic or imaginative play:
Bringing Balance to the World – One Person
Health Research Institute
Three Strikes
Drs. Hornig and Lipkin describe in animal model studies a 3 strike concept of potential cause for neurodevelopmental disorders. It is a triad of (1) genetic susceptibility in light of (2) critically timed environmental insults of (3) sufficient severity and quantity that trigger the disease process that manifests as a neurodevelopmental disorder (i.e. PDD, ASD, etc.).
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Understanding a Disease Process
What does it look like?
• Diagnostic criteria • Level of functioning • Clinical manifestations
© HRI/PTC 2008 – All Rights Reserved
What is broken?
• Genetic & Epigenetic influences • Physiology/ Biochemistry • Review of systems
Bringing Balance to the World – One Person
Health Research Institute
Manifestations of an Illness
© HRI/PTC 2008 – All Rights Reserved
• Physical • Behavioral • Developmental • Neuropsychiatric
Bringing Balance to the World – One Person
Health Research Institute
Mechanisms of an Illness
• Organ Systems
• brain, bowel, etc.
• General metabolic processes
• Oxidative stress & inflammation
© HRI/PTC 2008 – All Rights Reserved
• Individual Biochemical Pathways
• trace metals, methylation, pyrrole chemistry
• Systemic, regional or local
• global brain effects or specific regions.
Bringing Balance to the World – One Person
Health Research Institute
A Biologically Impaired Brain
Primary Brain Dysfunction
– Abnormalities in structure and/or maturation – Genetic predisposition for Axis 1 symptoms
Acquired Brain Dysfunction
© HRI/PTC 2008 – All Rights Reserved
– Metabolic, biochemical and nutritional imbalances – Oxidative stress and Metallothionein dysfunction
=> Resulting in Sensory Integration Dysfunction
Disorganized processing of sensory, biochemical, or neuropsychiatric signals leading to abnormal behavior, learning and development.
Bringing Balance to the World – One Person
Health Research Institute
More than the Brain
• • • • • • Gastrointestinal Neurologic Immune Autoimmune Metabolic Biochemical
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Paradigm of Autism
ASD is a medical illness
- with a biologically impaired brain, - commonly associated with multiple medical problems and organ systems, - with genetic and acquired factors - leading to abnormal behavior, learning, and development - that is treatable.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Why Oxidative Stress?
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
What is Oxidative Stress?
• An excess of chemical free-radicals that can damage proteins and essential fats, as well as disrupt normal cellular processes. • Oxygen free radicals are one of many free radicals that lead to oxidative damage. Nitrogen species and ionized metals are also important free radicals.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Consequences of Ox Stress
• Inflammation • Poor immune function • Neurodegeneration • Impaired methylation and other cellular processes • Increased sensitivity to toxic influences • Depletion of glutathione and metallothionein
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Severity of Oxidative Injury
Both genetic susceptibility and the severity of the environmental insult likely determines the degree to which the injury is manifest: (1) Mild injury results in PDD or speech delay. (2) Severe injury results in lower functioning ASD or mutism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Timing of Oxidative Injury
• Early injury => ASD
Delayed or impaired maturation resulting in immature brain cells and developmental delay
© HRI/PTC 2008 – All Rights Reserved
• Late or cumulative injury => Alzheimer’s Disease
Degeneration of mature cells and thereby loss of previously established normal brain function.
Bringing Balance to the World – One Person
Health Research Institute
Evidence of Oxidative Stress
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Vascular Damage in the Kidney
Study of treatment-naive patients with autism vs. age matched controls:
• Evidence of increased oxidative markers in the urine. • Evidence of oxidative damage to vascular tissues.
Yao Y et al. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006 Aug;63(8):1161-4.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of Vascular Study
• Increased oxidative damage of fats, vascular tissues, and other molecules may be present in many tissues and organs of the body, i.e. brain, bowel.
© HRI/PTC 2008 – All Rights Reserved
• Antioxidant therapy may be helpful for patients with ASD.
Bringing Balance to the World – One Person
Health Research Institute
WBC/Leukocyte Study
Study of treatment-naive patients with autism vs. age matched control:
• Increased oxidative stress in the white blood cell (WBC). • Increased inflammation. • Decreased immune function. • Significant disturbance in methylation.
Suh J et al. Altered Sulfur Amino Acid Metabolism in Immune Cells of Children Diagnosed with Autism. Am J Biochem Biotechnol. 2008 4(2); 105-113.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of WBC Study
• Similar disturbances in cellular function extend beyond the kidney to another tissue. • Oxidative stress plays an important role in the disruption of normal cellular processes. • Biochemical abnormalities exist in autism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Neuroinflammation
Study of autism and control brain tissue for evidence of immune-mediated differences.
• Evidence of active neuroinflammation of the cerebral cortex, white matter and cerebellum of autism brain tissue. • Evidence of a proinflammatory response in the cerebrospinal fluid of patients with autism.
Vargas D et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 57 (1); 67-81.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Oxidative Injured Brain
Study of autism brain samples for evidence of oxidative injury in comparison to control brain samples.
• Direct evidence of oxidative damage was found in all samples of autism brain and in no control sample.
Evans T el at. The Autistic Phenotype Exhibits a remarkably Localized Modification of Brain Protein by Products of Free Radical-Induced Lipid Oxidation. Am J Biochem Biotechnol 2008. 4(2); 61-72.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Implications of Ox Brain Injury
• Oxidative injury of proteins in the brain would likely be associated with neurologic abnormalities. • Oxidative injury of brain tissue likely plays a role in autism. • A better understanding of oxidative injury in the brain and other tissues is needed and would likely lead to improvements in the treatment of autism.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
What can be done?
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Goals of Treatment
• • • • Identification of broken systems. Restoration of normal function. Protection from re-injury. Promotion of normal physical, emotional, and mental health. • Thereby, establish more normal learning and development.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pieces of the Autism Puzzle
• • • • • Neurologic Psychiatric Gastrointestinal Immunologic Biochemical
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Nutrients and Neurotransmission
The Brain is a Chemical Factory
• Zinc is required for GABA synthesis • Vitamin B6 is required for Serotonin (5-HT) synthesis • Copper (Cu++) is a cofactor in the conversion of Dopamine (DA) to Norepinephrine (NE) • The Methyl:Folate ratio impacts the levels of Dopamine, Norepinephrine and Serotonin
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Biochemical Individuality Matters
Due to genetics and epigenetic influences individuals may be - deficient in several nutrients, as well as - overloaded in others.
© HRI/PTC 2008 – All Rights Reserved
Multiple vitamins are rarely effective, as they may - contribute to nutrient excess for those with pre-existing overload (i.e. copper, folate) and/or - induce another nutrient imbalance.
Bringing Balance to the World – One Person
Health Research Institute
Targeted Treatment with Nutrients
•
Genetic nutrient deficiency may require many times the RDA to achieve normalization/optimization.
© HRI/PTC 2008 – All Rights Reserved
• Genetic overloads may require biochemical therapy to eliminate the nutrient excess. • Treatment focuses on correcting specific imbalances that manifest with specific clinical symptoms.
Bringing Balance to the World – One Person
Health Research Institute
Differential Diagnosis of Biochemistry
• Pyrrole Disorder • Disordered Metal Metabolism - Copper Excess - Zinc Deficiency • Folic Acid-responsive Methylation
(aka Low Histamine)
© HRI/PTC 2008 – All Rights Reserved
• Methionine-responsive Methylation
(aka High Histamine)
• Metallothionein dysfunction
Bringing Balance to the World – One Person
Health Research Institute
Pyrrole Disorder
Clinical Features: • • • • Anxiety Fear Mood Swings Stress Intolerance:
Emotional, biochemical, & physical
Metabolic Consequences: • • • • • • Increased oxidative stress Vitamin B-6 Deficiency Impaired serotonin synthesis Zinc deficiency Low blood arachindonic acid levels Physiologic stress
© HRI/PTC 2008 – All Rights Reserved
• Misperceptions • Sensory issues:
Light, sound, and tactile
• Increased risk of PTSD related triggers
Bringing Balance to the World – One Person
Health Research Institute
Copper Excess
Clinical Features: • • • • • • Hyperactivity Temper Tantrums Learning problems Agitation Tinnitus Depression
(dysthymic or refractory)
Metabolic Consequences: • • • Increased oxidative stress Increased inflammatory responses and stresses Increased Norepinephrine effects due to increased conversion from Dopamine Increased strain on zinc requirements
© HRI/PTC 2008 – All Rights Reserved
•
• Post-partum Depression
Bringing Balance to the World – One Person
Health Research Institute
Zinc Deficiency
Clinical Features: • Explosive temper • Poor memory and mental lethargy • Poor and delayed growth • Frequent infections • Poor wound healing • Acne • Diarrhea • Hypogeusia • White spots on finger nails Metabolic Consequences: • • • • • Reduced defense against oxidative stress Decreased GABA formation Altered copper homeostasis Impaired cell-mediated immunity Poor energy
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Low Blood Histamine
Clinical Features: • • • • • • • Generalized anxiety Depression Panic Agitation & paranoia Racing thoughts Underachievement Good response to benzodiazepine medication • History of significant side effects with SSRI or antihistaminic medications Metabolic Consequences: • • • Folate deficiency Over-methylation Tendency to high dopamine, serotonin and norepinephrine
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Elevated Blood Histamine
Clinical Features: • • • • • • • • ADHD OCD, perfectionism Blank mind Rumination Addictive behavior Seasonal allergies Migraine headaches A history of good response to SSRI medication. Metabolic Consequences: • • • • Methyl Deficiency Under-methylation Low levels of dopamine and serotonin. Intolerance to higher doses of folic acid.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Metallothionein
Short, linear, cysteine-rich proteins present in all tissues of the body that are required for trace metal metabolism and other functions: • MT I & II are present in all tissues and regulate zinc and copper; thereby cell transcription, immune function and more. Furthermore, MT I & II are in high concentrations in the intestinal and blood-brain barriers protecting the body and brain from penetration of toxic metals.
© HRI/PTC 2008 – All Rights Reserved
• MT III is present mainly in the brain and acts as a neuronalgrowth-inhibitory factor in the development, organization, and apoptosis of brain cells. • MT IV is present primarily in the GI tract and regulates stomach acid pH, and taste/texture discrimination by the tongue.
Bringing Balance to the World – One Person
Health Research Institute
Metallothionein Dysfunction
Disturbances in zinc and copper are directly related to MT dysfunction. Quantitative depletion: Zinc is one of the primary inducers of MT; therefore, zinc depletion leads to lower levels of MT, decreased zinc transport and zinc delivery to target tissues.
© HRI/PTC 2008 – All Rights Reserved
Functional Impairment: Excess copper displaces zinc from MT and thereby reduces zinc availability to tissues.
Bringing Balance to the World – One Person
Health Research Institute
MT Dysfunction in Autism
Brain Structure and Function
• impaired pruning during development • impaired functioning in tissues with high MT concentrations - Purkinjie cells, hippocampus, amygdala, pineal body and inferior olives.
© HRI/PTC 2008 – All Rights Reserved
Impaired immune modulation and T cell function Impaired digestive enzyme function Impaired functioning of the Blood Brain Barrier and the barrier function of the bowel wall Impaired or crippled protection from oxidative stress
Bringing Balance to the World – One Person
Health Research Institute
Increased Oxidative Stress
Pro-oxidant Influences: • • • • • Elevated Copper Emotional Stress Environmental toxins Immune abnormalities Physical injury Overwhelmed Defenses: • • • • • Glutathione Deficiency Zinc deficiency Impaired metallothionein function Selenium deficiency Malnutrition
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pfeiffer Research on ASD
The Pfeiffer Treatment Center has evaluated approximately 20,000 patients, 5,500 with ASD, since 1989. Analysis of this data has shown:
– – – – – Undermethylation in Autism, 1999. Elevated copper/zinc in autism, 2000 Elevated unbound copper in autism, 2001 Metallothionein deficiency in autism, 2001 & 2003 Confirmation of these biochemical imbalances in treatmentnaïve patients with autism, 2003 – Oxidative Stress in Autism, 2006 & 2008
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Pfeiffer Assessment
• Comprehensive medical evaluation focusing on the differential diagnosis of biochemistry and associated medical conditions. • Thorough laboratory assessment of biochemistry and other conditions if needed. • Development of individualized nutrient program to address biochemical needs. • Monitoring of response to treatment and reassessment every 6-12 months.
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
Health Research Institute
Contact Information
Allen T. Lewis, MD, FAAP Medical Director Pfeiffer Treatment Center 4575 Weaver Parkway 630-505-0300 630-836-0667 (fax) info@hriptc.org
© HRI/PTC 2008 – All Rights Reserved
Warrenville, IL 60555
Bringing Balance to the World – One Person
Health Research Institute
PTC Locations
© HRI/PTC 2008 – All Rights Reserved
Bringing Balance to the World – One Person
