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The Underlying Pathology of Chronic Disease DEBBY HAMILTON, M.D., MPH AARM SEPTEMBER 2018 FINANCIAL DISCLOSURE: MEDICAL DIRECTOR OF RESEARCHED NUTRITIONALS 1
The Underlying Pathology of Chronic Disease
DEBBY HAMILTON, M.D., MPH
AARM SEPTEMBER 2018
FINANCIAL DISCLOSURE: MEDICAL
DIRECTOR OF RESEARCHED NUTRITIONALS
1
2
Lyme Disease 3
4
5
How we
learned
to
practice
medicine
6
Symptoms
Diagnosis
Prescription
7
Treatment by cause of
symptoms
Symptoms
Biologic
Cause
Treatment
Plan
8
Common Symptoms in
Chronic Disease
9
Fatigue
10
Poor recovery from exercise
Poor endurance11
Fatigue in children
12
13
14
Mitochondrial
Function
1. ATP production-produce
energy for the cell
2. Initiating and performing
apoptosis and cell death
3. Calcium homeostasis
4. Iron homeostasis
15
“”
Children with autism were more likely
to have mitochondrial dysfunction,
mtDNA over replication, and mtDNA
deletions than typically developing
children.
MITOCHONDRIAL DYSFUNCTION IN AUTISM
Giolivi C. et al. Mitochondrial dysfunction in autism
JAMA. 2010 December 1; 304(21): 2389–2396.
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17
Oxidative Stress 18
Definition
Imbalance between the
production of free
radicals and the ability
of the body to
counteract or detoxify
their harmful effects
through neutralization by
antioxidants
Causes of
Mitochondrial Dysfunction
and Oxidative Stress
Mitochondrial
Dysfunction
Medicines
Poor Nutrition
Stress
Pesticides
(Glyphosate)
Heavy Metals
Environmental toxins
Oxidative Stress
Medicines
Poor Nutrition
Stress
Pesticides
(Glyphosate)
Heavy Metals
Environmental Toxins
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Oxidative Stress in Autism
Research comparing anti-oxidant markers and
markers of lipid peroxidation to assess oxidative
stress
Study population: 20 children with ASD
25 matched healthy controls
Results: Positive in ASD children younger than 6
yrs
Decreased anti-oxidant markers with SOD and
GSH-PX
Increase in lipid peroxidation marker MDA
Meguid, N.A., Dardir, A.A., Abdel-Raouf, E.R. et al. Biol Trace Elem Res (2011) 143: 58.
doi:10.1007/s12011-010-8840-9
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Increasedoxidative
stress
Then:
21
Increased
need for
glutathione
What are the functions of Glutathione?
1. Master Antioxidant
2. Reduces Free Radicals
3. Detoxifies Chemicals
4. Chelates Heavy Metals
5. Protects Mitochondrial DNA
6. Cellular Anti-inflammatory compound
7. Storage and transport of cysteine
8. Enhances immune function
and transport of cysteine
22
Environmental Chemicals:
Depletion of glutathione
Tylenol
Acetone/solvents
Fuel/gasoline
Heavy Metals
Pesticides/Herbicides
Nitrates: Food
preservatives
Artificial sweeteners
Synthetic food dyes
Benzopyrenes: tobacco
Industrial pollutants
Ethanol
Household chemicals:
detergents, cleaners,
bleach
Plastics
Non-stick cookware
Chlorine treated water
Formaldehydes
X-rays
EMF’s
UV radiation
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Brain Glutathione Levels – A Novel Biomarker for Mild
Cognitive Impairment and Alzheimer’s Disease. Mandal,
Pravat K. et al. Biological Psychiatry , Volume 78 , Issue 10 , 702
- 710
Alzheimer’s disease dependent reduction of GSH
was observed in both Hippocampus and Frontal
C (p < 0.001).
GSH reduction in these regions correlated with
decline in cognitive functions.
Hippocampal GSH discriminates between mild
cognitive impairment and healthy controls
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Chronic Pain 25
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Acute Inflammation
Normal immune response to injury or infection
Chronic Inflammation
Prolonged abnormal immune response
Oxidative Stress
Normal part of metabolism and immune
response
Chronic Oxidative Stress
Destructive process that damages DNA and
cell membranes
29Inflammation
Lyme
Cardiovascular [1] [2]
Osteoarthritis
Obesity
Autism
Depression
Autoimmune Disorders
rheumatoid arthritis
lupus
asthma
inflammatory bowel diseases (ulcerative colitis, Crohn’s)
1 Anker SD et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heartfailure. Eur Heart J. 1999; 20: 683–693
2Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol.1996; 27: 1201–1206
30Inflammation
Cytokines
Proinflammatory
Il-1
Il-6
IL-8
TNF-alpha
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32
33
34
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Neuroinflammation:
The Brain on Fire36
Pathology of Depression
37
Vargas DL. Et al. Neuroglial activation and
neuroinflammation in the brain of patients with
autism. Annals of Neurology. 2005. 57,67-81.
A: normal cerebellum in
control patient
B-C: atrophic
cerebellum in a patient
with autism with loss of
purkinje and granular
cells
D-K: activated microglial
and inflammatory cells
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Digestive
Symptoms
39
40
Disrupted
Gut-Brain-
Microbiome:
Leads to
Leaky Gut
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42
Disrupted Gut-Brain-Microbiome in
Autism Spectrum Disorder
40 autistic subjects (36 out of 40 autistic subjects were classified as severe ASDs, Childhood Autism Rating Scale (CARS) value >37) and 40 neurotypical controls
Analysis of gut microbiota
Results:
Candida was more than double in the autistic than neurotypical subjects
Significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance
Strati F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017. 5:24.
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Effect of Probiotics on
Alzheimer’s disease
60 Patients with Alzheimer’s disease randomized to 30 patients taking probiotics versus 30 patients on placebo for 12 weeks
Results: Patients on probiotics
Significant improvement in Mini-mental state exam (p<0.0001)
Decreased plasma malondialdehyde levels
Decreased CRP
Decreased TG’s
Akbari E. et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind controlled trial. Frontiers in Aging NeuroScience. 2016. Volume 8(256).
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Depression Depression
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Genetic Influences 46
47Chronic Pathology
Chronic Disease
Oxidative stress, mitochondrial dysfunction and, inflammationcommon events in skin of patients with Fibromyalgia. Sanchez-Dominguez B. Mitochondrion. 2015 Mar;21:69-75.
Recent studies have shown some evidence demonstrating that oxidative stress, mitochondrial dysfunction andinflammation may have a role in the pathophysiology of fibromyalgia.
Skin biopsies from patients showed a significant mitochondrial dysfunctionwith reduced mitochondrial chain activities and bioenergetics levels and increased levels of oxidative stress.
OS, mitochondrial dysfunction andinflammation as interdependent events in the pathophysiology of FM
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Neurodegeneration49
Peacock BN, Gherezghiher TB, Hilario JD, Kellermann GH. New insights into
Lyme disease. Redox Biology. 2015;5:66-70.
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Diabetes
and
Cardiac
Disease
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Treatment for chronic disease
Repair and support mitochondria
•Membrane repair
•Support nutrients in ATP production from breakdown of macronutrients to Krebs cycle to oxidative phosphorylation
1
Decrease causes of oxidative stress and inflammation
2Increase anti-oxidants to counteract oxidative stress including activating Nrf2
3Decrease inflammation through down regulating inflammatory mediators and improving microbiome
4
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Diagnosis of Mitochondrial
Dysfunction
Urine organic acids (OAT)
Blood Lactate and pyruvate
Plasma Acyl-carnitine profile
CoQ10 levels
Liver enzymes and ammonia
Quantitative amino acids
Creatinine kinase
Mitochondrial Disease: additional testing
muscle biopsy, genetic profiles, echocardiogram, analysis of cerebral spinal fluid
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Mitochondrial Dysfunction
Repair mitochondrial membrane
Phospholipids
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Repair mitochondrial membranePhospholipids
Support mitochondrial functionCoQ10/UbiquinolCarnitineNADHAlpha-lipoic acidB vitaminsVitamin E
MITOCHONDRIAL DYSFUNCTION
Support
for
oxidative
stress
Anti-oxidants to combat oxidative stress
Glutathione
Molecular Hydrogen (H2 : Hydrogen gas)
Vitamin E: mixed tocopherols and tocotrienols
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
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Diagnosis:Oxidative Stress
Test for DNA/RNA damage: 8-hydroxydeoxyguanosine (8-OHdG)
Urine and blood
Test for lipid peroxidation: 8-isoprostane
Urine and blood
Anti-oxidant Reserves and enzyme function: Total antioxidant capacity, glutathione peroxidase, superoxide dismutase (SOD) Blood tests
Glutathione blood level (Need to draw and put on ice immediately to be accurate)
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Molecular Hydrogen: H2
Hydrogen gas is very stable molecule
Neutralizes harmful free radicals, including the hydroxyl radical1
Hydrogen electron donation turns hydroxyl into water
Diffuses across membranes, including mitochondria, due to its small size2
Most antioxidant supplements are limited in their cellular distributions and are poorly taken up by organelles like mitochondria 3
Hydrogen has the ability to effectively penetrate biomembranes and infiltrate into organelles, such as mitochondria and the nucleus 3
In contrast to many antioxidants, H2 also has the advantage of being able to penetrate the blood-brain barrier 3
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Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Ikuroh Ohsawa, et al. Nature Medicine Vol 13, No. 6, June 20072 Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine, Ohta S., Pharmacology & Therapeutics, Volume 144, Issue 1, October 2014, Pages 1–113Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine, Nicolson G. et al., International Journal of Clinical Medicine, 2016, 7, 32-76
Molecular Hydrogen: H2
Summary
Anti-oxidant for dangerous hydroxyl radical without destroying free radicals needed for metabolism
Activates Nrf2 anti-oxidant cascade including glutathione peroxidase, catalase, and superoxide dismutase (SOD)
Decreases pro-inflammatory cytokines through cell signaling
Promotes mitochondrial ATP energy function
1Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine, Ohta S., Pharmacology & Therapeutics, Volume 144, Issue 1, October 2014, Pages 1–11
2Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine, Nicolson G. et al., International Journal of Clinical Medicine, 2016, 7, 32-76
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Neuroinflammation: Molecular Hydrogen
Research: animal study with hydrogen rich saline
3 groups: control, induced amyloid-beta neural inflammation, and induced amyloid inflammation plus hydrogen saline
Results:
Hydrogen-saline prevented amyloid-beta induced neuroinflammation and oxidative stress
Wang C et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibition of JNK and NF-KB activation in a rat model of amyloid-beta induced Alzheimer’s disease. Neuroscience Letters. 2011. 491(2):127-132.
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Molecular Hydrogen:Parkinson’s Disease
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Randomized placebo controlled trial
48 weeks consuming either 1000 ml of molecular hydrogen water or placebo
Results
Statistically significant improvement in the molecular hydrogen group: Unified Parkinson’s Disease Rating Scale (UDPRS)
Worsening disease rating in the placebo group
Yoritaka, A., et al., Pilot study of H(2) therapy in Parkinson’s disease: A randomized double-blind placebo-controlled trial. Movement Disorders, 2013.
Support for Inflammation and Abnormal Cytokines
Glutathione
Molecular Hydrogen (H2 : Hydrogen gas)
Vitamin E: mixed tocopherols and tocotrienols
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
Probiotics
Omega 3 fatty acids
Boswellia
White willow bark
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Goal: Activate Nrf2:
Nuclear Factor 2
Master regulator of the
antioxidant system
Mechanism: A Nrf2
activator releases protein
into the cell nucleus where
it binds to DNA and
activates anti-oxidant
enzymes such as catalase,
glutathione peroxidase,
and superoxide dismutase
and these enzymes can
neutralize up to 1 million
free radicals
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Goal:
Block
NFKB
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References for Glutathione
Cooke RW. Et al Reduction of oxidative stress marker in lung fluid of preterm infants after
administration of intra-tracheal liposomal glutathione. Bio Neonate. 2005;87(3):178-80.
Hauser AR. Et al. Randomized, double-blind, pilot evaluation of intravenous glutathione in
Parkinson's disease. Mov Disord. 2009 May 15;24(7):979-83. doi: 10.1002/mds.22401.
James J. Et al. Am J Clin Nutr 2004;80:1611-161
Kern JK. Et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med
Sci Monit. 2011; 17(12): CR677–CR682
Madrigal JL. Et al. glutathione depletion, lipid peroxidation and mitochondrial dysfunction are
induced by chronic stress in rat brain. Neuropsychopharm. 2001. 24(4).
Marí M. et al. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxidants & Redox
Signaling. 2009;11(11):2685-2700.
Morris G. et al. The glutathione system: a new drug target in neuroimmune disorders. Mol
Neurobiol. 2014 Dec;50(3):1059-84.
Sechi G. Et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease
Prog Neurospychopharm Biol Psych. 1996 Oct;20(7):1159-70.
Sinha R. Et al. Oral supplementation with liposomal glutathione elevates body stores of
glutathione and markers of immune function. European Journal of Clinical Nutrition advance
online publication, 30 August 2017; doi:10.1038/ejcn.2017.132. (Tri-Fortify™ study)
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References for Molecular Hydrogen
Ichihara, M., et al., Beneficial biological effects and the underlying mechanisms of molecular
hydrogen - comprehensive review of 321 original articles. Med Gas Res, 2015. 5: p. 12.
Ohta, S., Molecular hydrogen as a preventive and therapeutic medical gas: initiation,
development and potential of hydrogen medicine. Pharmacol Ther. 2014.
Molecular hydrogen foundation: www.molecularhydrogenfoundation.com
Yu, J., et al., Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic
cholangiocytes by activating Nrf2 expression. Toxicol Lett. 2015. 238(3): p. 11-19.
Ohno, K., M. Ito, and M. Ichihara, Molecular hydrogen as an emerging therapeutic medical
gas for neurodegenerative and other diseases. Oxidative Medicine and Cellular Longevity.
2012. 2012: p. 353152.
Dixon, B.J., J. Tang, and J.H. Zhang, The evolution of molecular hydrogen: a noteworthy
potential therapy with clinical significance. Med Gas Res. 2013. 3(1): p. 10.
Dohi, K., et al., Molecular Hydrogen in Drinking Water Protects against Neurodegenerative
Changes Induced by Traumatic Brain Injury. PLoS One. 2014. 9(9): p. e108034.
Saitoh Y, et al. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon
mutagenicity, genotoxicity, and subchronic oral toxicity. Toxicology and Industrial Health.
2010. 26(4):203-216.
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