Concepts and Tools for Helping our Tough Nuts NAA Conference Nov 2014 St. Petersburg, FL Anju Usman, MD, FAAFP, ABIHM, Hom-‐C Disclaimer •  Information provided here is for educational purposes only •  Not to be taken as specific medical advice •  Clinical trials for interventions have not been done. •  Nutraceuticals are not FDA approved •  Dr. Usman is owner and medical director of True Health Medical Center and Pure Compounding Pharmacy IntegraKve and HolisKc Approach •  Treat the whole body not the diagnosis •  Symptoms give us clues •  Look for the cause of symptoms •  Avoid what harms •  Give what helps •  Treat the underlying metabolic abnormaliKes •  Chronic disorders associated with chronic inﬂammaKon •  Every paKent is an individual Why is my child not responding? •  •  •  •  •  •  ConKnued exposure to toxin, mycotoxin Chronic infecKons, Bioﬁlm MulKple medical problems, complex case Undiagnosed geneKc abnormality Autoimmunity Incomplete workup and inconsistent treatment, are we missing something? –  –  –  –  –  GI Immune Endocrine Neurologic Metabolic •  EMF sensiKvity •  Fear driven, belief system •  IntenKon is more important than technique What works, what doesn’t work? •  Start one protocol/intervenKon at a Kme •  List symptoms before and aYer, check ATEC before and aYer •  ConKnue what works •  Stop what doesn’t work •  Response gives us clues –  PosiKve –  NegaKve –  No Change •  RevisiKng old protocols Most Effective Integrative Interventions in My Practice •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  Gluten Free/Casein Free /Sugar Free Diet Diets in General, must be individualized Organic Diet Good Fats- omega 3, cholesterol, Vit D, Phospholipids (PC, PS) Zinc Probiotics/Prebiotics Methyl B12 and/or OH B12 subcutaneous injections Methylation/Sulfation Support using genomics to guide choices High Dose Leucovorin for CFD Mitochondrial Cocktails/ Carnitine Natural Detoxification, Natural Binding Agents Heavy Metal Detoxification Strategies Redox Signaling, Oxidative Therapies Adrenal and Thyroid Support Hyperbaric Oxygen Therapy Addressing Underlying Infections, don’t forget Parasites MOST IMPORTANT – TREATING THE GUT!!!, Biofilm Protocols Homotoxicolgy Essential Oils Don’t Forget the Basics •  •  •  •  History Physical Examination Laboratory Testing Clean Up –  Environmental Controls –  Dietary Interventions –  Address Gastrointestinal Health •  Foundational Nutrients –  Vit C (antioxidant) –  Vit B6/P5P –  Magnesium –  Zinc, Se, Mb –  Omega 3 Clean up the Child’s Environment •  Use natural, biodegradable and perfume free detergents and cleaning agents, do not dry clean clothes. •  Avoid chlorine: use water ﬁlters, limit pool and hot tubs. •  Wear 100% co]on clothes, avoid ﬂame retardant materials (anKmony). •  Use ﬂuoride-‐free toothpaste (Kn, Ktanium). •  Avoid playing on pressure treated wood (arsenic). •  Use stainless steel, ceramic, glass or cast iron cookware, avoid aluminum and non sKck. •  Use an air puriﬁer, especially in the bedroom. •  Avoid prolonged exposure to ba]eries (light up shoes). •  No plasKc furniture (polyvinyl chloride). •  Use aluminum-‐free baking powder, deodorant. Do not cook in aluminum foil or drink from aluminum cans. •  Avoid use of herbicides or pesKcides, on lawns, garden, home or on pets. •  Use natural shampoos, soaps, loKons, make-‐up, lipsKck.. 9 Clean up the Diet •  •  •  •  •  •  •  •  •  •  •  Casein-free/Gluten-free/Diet Trial for 3-6 months. Avoid sugar and refined starch, replace with whole grains Maximize antioxidants and phytonutrients. Avoid excitotoxic foods and high phenolic foods Limit processed and preserved foods; organic is best. Drink plenty of filtered water. Never microwave in plastics or Styrofoam, do not store food in plastic or foil, or cook on Teflon coated pans. Eliminate seafood. Add good fats (olive, coconut, flax). Avoid hydrogenated and trans fats and esterified fats. Cook with saturated(hard) fats. Buy hormone-free, antibiotic-free, organic meat and eggs. Add fermented foods (coconut kefir, kombucha,…). Careful if allergic or sensitive to yeast, candida, sacchyromyces, or amines. Avoid Excitotoxins •  •  •  •  •  •  •  •  •  •  Caffeine MSG NutraSweet Red/yellow food dyes Nitrites Sulfites * some patients are sulfur sensitive as well Glutamates Propionates Benzoates Limit intake of phenolics (apples, grapes, bananas, strawberries,…) Low Oxalate Diet (LOD) Susan Owen BS •  Oxalates are abundant in many plant foods •  When the gut is inflamed or becomes permeable excess oxalate from foods can be absorbed •  When present in high amounts can lead to oxidative damage, depletion of glutathione, and inflammation •  Excess oxalates form crystals after binding with calcium •  Symptoms include: Pain, Burning, Frequent Urination, Penis pain, Eye Poking, Family history of Kidney Stones, Vulvodynia •  Avoid High Oxalate Foods, consider Low Oxalate Diet •  Spinach, Greens, Nuts, Soy, Beets… •  Avoid Calcium and High Doses of Vitamin C, give Mg citrate, Vit B6. Promote sulfation, using B1, Biotin, Molybdenum •  Many herbs are high in oxalates Phenol Sulfotransferase (PST) Enzyme •  PST Enzyme helps to detox Phenols •  Phenols •  Hormones •  Salicylates and Phenolic foods •  Neurotransmi]ers •  Biologic Agents (yeast) •  PesKcides, Herbicides, Perfumes •  PST Enzyme weakness oYen manifests as hyperacKvity, accompanied by red cheeks and red ears. •  Pyridoxal 5’ Phosphate is a co-‐factor •  Epsom Salts Baths may help, Vit B1, Molybdenum, BioKn upregulate producKon of sulﬁte to sulfate (SUOX enzyme) Clean up the Child’s Gut •  Daily bowel movements are a goal. •  Add digestive enzymes with meals. •  Start high potency probiotics (acidophilus and bifidus). •  Start treatment for dysbiosis depending on symptoms and lab findings. –  –  –  –  –  –  Clostridia Yeast Strep Lyme, coinfections Viruses Parasites •  Address food allergies and sensitivities •  If persistent symptoms: –  Eliminate sugars from diet for 3-6 months •  Specific Carbohydrate Diet, GAPs, Paleo •  Careful with high protein diets if kidney issues, or sensitive to glutamate or ammonia •  Careful with ketogenic and high fat diets if fatty acid metabolism is abnormal –  Consider referral to knowledgeable GI specialist –  Check for oxalates in urine 15 Nature Reviews Neuroscience 2012 Microbial Flora •  Bacteria major component of colonic material •  Metabolism   Digestion, Energy Production   Production of B vitamins   Destruction of toxins and mutagens •  Immunity and Inflammation   Repression of pathogenic microbial growth   Prevent allergy   Prevent inflammatory bowel disease and inflammation •  The Colon has an obligate need for bacterial fermentation products or SCFA, short chain fatty acids “Composition and Metabolic Activities of Bacterial Biofilms Colonizing Food Residues in the Human Gut” (Macfarlane Sept 2006) Mice exhibiKng auKsm-‐like behaviors enjoyed a reducKon in their symptoms when treated with a human gut microbe, according to a study published recently in Cell. The microbe also eased the mice’s gastrointesKnal problems, which had previously linked to auKsm in humans. Pa]erson and colleagues devised an auKsm mouse model in which intesKnal walls break down allowing substances to leak out of the gut. Pa]erson found that the “auKsKc” mice harbored lower levels of Bacteroides fragilis in their guts. And when B. fragilis was added to the animals’ diets, they seemed to get be]er—both in terms of their behavior and their gastrointesKnal health. Ingestion of Lactobacillus Strain Regulates Emotional Behavior and Central GABA Receptor Expression in Mouse Via the Vagus Nerve Bravo. Aug 2011 •  Chronic treatment with L. rhamnosus (JB-1) induced regiondependent alterations in GABA(B1b) mRNA in the brain •  L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. •  L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. •  The neurochemical and behavioral effects were not found in vagotomized mice. 2013, 15, 1416-‐1463; Re-‐establish the microbiome Diet is key Fermented foods Exercise Avoid GMOs, pesKcides, anKbioKcs, hormones PROBIOTICs!!!! Varied types, rotate, plenty Bioﬁlm Protocols Fecal Transplants Detox the GUT!-‐ inﬂamed intesKnes are leaky and toxic •  Bind toxins in the gut •  •  •  •  •  •  •  •  It's ironic that I'm the most afraid when I'm being brave. Vulnerability = Courage. -‐ Brene Brown Detox •  Phase 1 -‐ acKvaKon •  Phase 2 -‐ conjugaKon •  Phase 3 – transportaKon –  cMOAT, OAT, MRP1, MRP2, GS-‐X •  Organic Anion Transporters •  Use Mg and ATP Found in IntesKnes, kidney tubules, liver hepatocytes Gut InﬂammaKon decreases MRP2 When Phase 3 blocked, turns oﬀ Phase 2 Hepatocytes-‐Liver-‐GB detox turned oﬀ when system is backed up –  MRP 3 sKll open so toxins go thru the kidneys instead (pee tox!) –  –  –  –  Oxidative Activation Phase I Phase II Glutathione Conjugation Sulfation Glucuronidation Blood Cellular MRP1 Phase III OATP LIVER Chris Shade, PhD MRP 2 Normal Small Intestine Kidney MRP2 Oxidative Activation Phase I Phase II Glutathione Conjugation Sulfation Blood Cellular MRP1 Phase III Chris Shade, PhD Inflammation causes Downregulation of MRP2 OATP LIVER MRP 2 Inflamed Small Intestine Glucuronidation Negative Feedback – Inhibition of Phase II Pathways Out – Gut Blocked Intestinal Load/LPS Goes to Kidneys Gut Inflames, Blocking Exit Chris Shade, PhD = Even More Retention Then Kidneys Weaken from Constant Infl and Can’t Filter Hg Kidney Load Increases Excretion Rates Decrease Toxin Retention and High Stress on Kidneys System Breakdown •  •  •  •  •  •  •  •  •  Toxin Overload/Inﬂamed Gut GSH depleKon (geneKc, epigeneKc, environmental load) AnKoxidants enzymes stressed, AnKoxidant depleKon Neurons become oxidized, release glutamate causing increase in peroxynitrite free radicals, rapid aging and NMDA receptor sKmulaKon (sKms!!!) IntesKnal inﬂammaKon downregulates Phase 2, kidneys now become stressed TransgeneraKonal dysfuncKon may cause suscepKbility Pre-‐birth exposure eﬀects aﬀects epigeneKcs In Utero exposure – depleted defense system Mitochondria become uncoupled (bad) Mitochondria have their own anKoxidant supersystem Have their own GSH Pool Create a lot of ROS Inside mito system is very reduced SuscepKble to oxidaKon by Hg, Cd, and As Good Mito -‐ drive nutrients and O2 into OxPhos •  Bad Mito (poorly coupled)-‐ damaged membrane create a lot of free radicals leak and produce very li]le ATP. Can not make enough CoQ10. •  •  •  •  •  OxidaKve Stress and Free Radicals •  Free radicals are unstable oxygen atoms that cause oxidaKon in our bodies, which damages cells. •  An increase in free radicals can be caused by such things as polluKon, pesKcides, and contaminated food and water. Lowered Redox Defense in AuKsm: (GSH:GSSG) Whole Cell 62% Mitochondria 43% ASD more susceptible to oxidative damage, especially at mitochondrial level! Impaired transsulfuraKon and oxidaKve stress in auKsKc children: Improvement with targeted nutriKonal intervenKons. S. Jill James, PhD. Am J Clin Nutr. 2004 Dec;80(6):1611-‐7. Methionine Transsulfuration to Cysteine and Glutathione Methionine THF 5,10CH2THF MTHFR Methylation Potential SAM 1 MS B12 2 BHMT 5CH3THF Betaine Choline 3 Transsulfuration Pathway MTase Cell Methylation SAH SAHH Adenosine Homocysteine 1 Folate Cycle 2 Methionine Cycle (SAM/SAH) B6 B6 3 CBS Cystathionine B6 Cysteine GSH GSSG Antioxidant Potential (GSH/GSSG) Amy Yasko Diagram (2005) 34 Methylenetetrahydrofolate Reductase (MTHFr 677 and 1298) •  MTHFr converts MethyleneTHF to MethylTHF •  If enzyme is weak, methyl groups are trapped and unable to provide methyl B12 for the methylaKon cycle •  MTHFr SNPs in Moms associated with increased risk of having a child with auKsm •  Enzyme is dependent on Vitamin B3 and B2 •  May lead to elevated homocysteine (>10) •  Associated with coagulaKon defects, poor detoxiﬁcaKon of nitrous oxide (anestheKc) Methionine Synthase (MTR, MTRR)   Enzyme converts Homocysteine to Methionine   Enzyme involved in Dopamine methylaKon   Dopamine Receptor (DRD4) methylaKon necessary for a]enKon and focus   Enzyme inhibited by Cu, Pb, Al, and Hg   Enzyme is dependent on the methylaKon of vitamin B12   Giving Methyl B12 is a promising treatment   PaKents with SNPs seem to have a BIG need for B12   Researched extensively by Dr. Richard Deth Catecholamine -‐O-‐ Methyl Transferase (COMT)   Enzyme transfers methyl groups to catecholamines, (dopamine, NE, and Epi)   Enzyme involved in neurotransmi]er breakdown   Cofactors include Magnesium, B3, and SAMe   If enzyme is weak (COMT +/+), methyl groups are not used eﬀecKvely may accumulate   If enzyme is eﬃcient (COMT -‐/-‐), methyl groups are used up rapidly and SAMe is depleted   In both cases, methylaKon and neurotransmission is impaired Cystathione Beta Synthase (CBS) -‐Enzyme defect cause an upregulaKon of this enzyme CBS converts HCY to cystathionine in a vitamin B6-‐ dependent reacKon -‐CBS acKvity is increased by SAMe, oxidaKve stress and TNF-‐alpha -‐Vitamin D was recently shown to increase the level of CBS -‐Testosterone decreases CBS acKvity -‐CBS also converts cysteine to hydrogen sulﬁde “CBS acKvity in DS limits methylaKon by removing HCY from the methionine cycle. The criKcal balance between methylaKon and transsulfuraKon is therefore altered. “ Deth, 2013 During oxidative stress multiple adaptive mechanisms shift the flux of sulfur resources toward GSH synthesis, including reduced activity of methionine synthase, increased activity of cystathionine-b-synthase (CBS) and decreased activity of cysteine dioxygenase (CDO). Lower methionine synthase activity reduces methylation, including dopamine-stimulated phospholipid methylation and its role in attention. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Richard Deth 2007 ContrasKng Roles for Nitric Oxide and Peroxynitrite in the PeroxidaKon of Myelin Lipids Peroxynitrite is formed by the reacKon of nitric oxide (NO) and superoxide. R. van der Veen Journal of Neuroimmunology, 2009 vol. 95 •  •  Neither NO nor superoxide alone induced signiﬁcant MDA (malondialdehyde) formaKon in myelin, indicaKng that peroxynitrite formaKon is required for myelin-‐lipid peroxidaKon. •  InteresKngly, NO actually inhibited lipid peroxidaKon in myelin, as demonstrated using simple NO donors. •  Peroxynitrite-‐induced peroxidaKon of myelin resulted in isoprostane formaKon. Isoprostanes are products of lipid peroxidaKon. •  Furthermore, increased levels of F2-‐isoprostanes and neuroprostanes were observed in spinal cords of mice during early progressive stages of autoimmune encephalomyeliKs. Genomics associated with OxidaKve Stress (re-‐dox) •  •  •  •  NOS-‐ nitrous oxide synthase SOD-‐ superoxide dismutase (SOD2-‐mito) GST-‐ glutathione sulfur transferase GPX-‐ glutathione peroxidase Syndrome of Allergy, Apraxia, and MalabsorpKon: CharacterizaKon of a Neurodevelopmental Phenotype that Responds to Omega 3 and Vitamin E SupplementaKon Morris, C. AlternaKve Therapies July/Aug 2009 •  Vitamin E deﬁciency symptoms overlap with apraxia. •  Polyunsaturated fa]y acids in the cell membrane are vulnerable to lipid peroxidaKon if Vitamin E is deﬁcient. •  InﬂammaKon of the gastrointesKnal (GI) tract and malabsorpKon of nutrients such as vitamin E and carniKne cause neurologic abnormaliKes. •  Total of 187 children with verbal apraxia received vitamin E, vitamin K and polyunsaturated fa]y acid supplementaKon. •  Common phenotype sensory issues, low muscle tone, coordinaKon diﬃculKes, food allergy, and GI symptoms emerged. •  97% reported dramaKc improvements, ASD was comorbid in 65% •  Speech, imitaKon, coordinaKon, eye contact, behavior, sensory issues improved Work up for MalabsorpKon/Apraxia –  Alpha tocopherol, Gamma tocopherol –  Vit A (retinol) –  Vit D25 OH –  Food Allergy Panel –  Antigliadin Ab/Celiac Panel –  Carnitine, free and total –  Acyl carnitine panel –  Stool for Fecal Fat –  Lipid Panel (cholesterol and triglycerides) –  Plasma Zinc/Serum Cu –  Blood Pb (lead), Aluminum –  Mito work up Nrf2 and NeuroprotecKon SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity. Toxicol Sci. 2010 Dec;118(2):613-24. Vanduyn N. Settivari, Wong, Nass •  MeHg poisonings in adults may result in severe psychological and neurological deficits, and in utero exposures can confer embryonic defects and developmental delays. •  Recent epidemiological and vertebrate studies suggest that MeHg exposure may also contribute to dopamine (DA) neuron vulnerability and the propensity to develop Parkinson's disease (PD). •  In this study, we describe a Caenorhabditis elegans model of MeHg toxicity that shows that low, chronic exposure confers embryonic defects, developmental delays, decreases in brood size and animal viability, and DA neuron degeneration •  We also demonstrate that the expression of SKN-1, is also expressed in the DA neurons, and a reduction in SKN-1 gene expression increases MeHginduced animal vulnerability and DA neuron degeneration. ChemoprevenKon by Keap1-‐Nrf2 Signaling pathway by Phase II Inducers •  Phytochemicals (and their Radicals!) •  ROS •  RNS •  RSS •  And even now data on DMPS and DMSA Slide courtesy Chris Shade, PhD Kwak et al., 2004, Mutation Research, 555:133-148 Mild OxidaKve Stress and Phytochemicals Upregulate AnKoxidants but Severe OxidaKve Stress Upregulates InﬂammaKon Mild ox stress turns on nrf2 Severe ox stress turns on nzb creaKng run away inﬂammaKon Right kind of oxidaKon versus wrong kind of oxidaKon Oxygen Based AnKoxidants NRF2 InducKon •  Enzyme inducers –  Phytochemicals, Polyphenols –  Sulfur compounds –  Prooxidants (ROS, RNS, RSS), –  Oxone, OxidaKve Therapies –  DMSA, DMPS •  Tags Keap 1 and 2 •  Triggers transcripKon of genes and makes AnKoxidant response element (ARE) in the nucleus •  Releases Phase 2 enzymes, anKoxidants, •  NrF2 and neuroprotecKon (parkinson’s mouse model) Phytochemicals Harataki, gotu kola, bacopa, pine bark Hartaki – Terminalia Chebula Polyphenolic compounds EGCG (green tea) Pomegranate Curcumin Ellagic Acid 53 Sulfur Compounds Sulforaphane – from cruciferous veggies, broccoli sprout extract Erucin – from crucifers; not as strong as SF Allyl-isothiocyanate “Oil of mustard”, horseradish Allicin – from garlic Cruciferous Compounds •  •  •  •  •  •  •  •  Stronger Free radical generators Stronger Inducer of Nrf2 Kill Bugs (anKviral, anKfungal, anKbacterial) Most toxic people can not tolerate these sulfur compounds Sulfur processing issues -‐ CBS mutaKons or funcKonal expression issues Molybdenum deﬁciency More cytotoxic than polyphenols Upregulate house keeping proteins (GPx, thioreductase) What if mechanism is dysregulated (not turned on, doesn’t turn oﬀ) •  •  •  •  •  •  •  •  •  •  •  Ochratoxin blocks Nrf2 Nrf2 increases survival in hyperoxia Mold toxic pts may not do well with 02 therapy Nrf2 is epigenKcally turned oﬀ in prostate Cancer, restored with DIM (nitrogen component of broccoli) Need threshold dose Time limited hormesis response System might get overworked Pulse dosing!!! Five on, two oﬀ Ten on, four oﬀ (parasite detox) HORMETIC SWITCH Detox the Gut with Binders, to re-‐establish Phase 3 and 2 •  IntesKnal Metal Detox (silica,sul{ydryl,carbon), binds 200mg of Hg/gm •  Clay does not bind metals but good for epithelium •  Zeolites do not bind metals, good for ammonia, a caKon exchange, may be contaminated with arsenic •  Charcoal/Carbon not great for metals, but bind pre]y much everything else •  Alginates are immunomodulatory •  PecKn helps to restore eﬀecKve detox by helping inﬂammaKon •  Chlorella (anionic exchange, caKonic exchange, thiol) •  Cholestyramine an anionic binder absorbs toxins, bile salts and fats, causes consKpaKon. Bile salts cause reabsorpKon of fat soluble biotoxins •  Chitosan an anionic binder also binds bile salts prevents absorpKon of fat •  Beta sitosterol (rice protein) helps lipidemia, does not bind bile salts •  Galactose prevents ammonia formaKon in brain •  Yucca binds ammonia Thank You!!