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This presentation tackles the growing problem of chronic toxicity and its effects on living systems, including the living system that is you. It describes toxin types, detoxification pathways, and a systems medicine model for supporting your body's detox capacity, and for thinking about what's really needed to reduce the pollution we're spewing into the world.

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  1. 1. DetoxificationA Systems Medicine Approach Keith Berndtson, MD
  2. 2. Definitions• Toxin: a substance with harmful effects on living systems. Includes heavy metals, biotoxins, and many industrial chemicals.• Detoxification: to remove or neutralize the toxic quality of toxins.• Xenobiotic: a chemical substance present within, but not made within a living thing - a substance that is “a stranger to life.”• Persistent Organic Pollutants (POPs): hazardous xenobiotics that resist degradation within living systems.• Toxic load: the sum total of toxins within a given living system.
  3. 3. How Toxicity Challenges Our Natural Detoxification Systems Truth Ubiquitous Too many to countComplex interactions ConsequencesAltered brain function Gut disturbances Reproductive effects Hormone disruption Nutrient depletion Inflammation Cancer Diabetes Autoimmune disease Degenerative diseaseCardiovascular disease and more...
  4. 4. Lipophilic ToxinsLow molecular weight, non-polar, fat-soluble toxins easily move intoor through phospholipid membranes and into cells. They distributewidely and can accumulate to hazardous levels. High molecularweight lipophilic toxins are especially difficult to eliminate. Common, Hazardous Lipophilic Toxins volatile organics polyaromatic hydrocarbons mold toxins polyvinyl chlorides industrial solvents ciguatera toxin pesticides combustion products microcystin phlalates perfluoro-octanoic acid dioxins bisphenols tetrachloroethylene PCBs flame retardants dinoflagellate toxins organohalides
  5. 5. Attention Please!Doctors Needed to Engage this ProblemGrowing awareness of the connection between toxicity and chronic disease.
  6. 6. Glutathione (GSH) A molecule of primordial importance Free radical and Phase 1 anions areanion binding sites: stabilized and COOH = carboxyl polarized, made NH = amino ready for active SH = sulfhydryl membrane transport 1. GSH maintains intracellular redox balance by mopping up oxidative stress. 2. Glutathione-S-transferases conjugate GSH to phase 1 drugs, toxins, and xenobiotics, preparing them for transport out. 3. GSH-dependent membrane transporters and efflux pumps play key roles in toxin elimination.
  7. 7. The Biotransformation of Lipophilic Toxins Phase 1 reactions add a functional group to a fat soluble toxin so the new structure can be conjugated (joined to) a phase 2 substrate. Phase 2 reactions continue the biotransformation process to create a water soluble compound suitable for elimination into bile or blood for transport and elimination by the bowel or kidneys. Phase 1 Phase 2 Fat soluble Water soluble Oxidation Sulfate conjugation Reduction Glucuronide conjugation Hydrolysis Glutathione conjugation Acetylation Amino acid conjugation
  8. 8. Key Phase 1 and 2 Pathway Sites The liver handles 70% of the biotransformation work in the body. Other active sites for these pathways include: 1. kidneys 2. lungs 3. skin 4. intestinal cells 5. endothelial cells of the blood- brain barrier What these locations have in common: 1. organs of detoxification 2. key tissue barriers
  9. 9. Phase 3: Membrane Transporters antigens from inflamed gut and hepatic artery are processed by Kupffer cells membrane transporters pump phase 2-processed toxins from liver cells into the biliary collection system toxins from inflamed gut enter liver from the membrane transporters pump portal vein phase 2-processed toxins into sinusoids for lymph and blood transport to kidneys
  10. 10. Membrane Transporters and Efflux Pumps ATP binding cassette (ABC) transporters modulate the absorption, distribution, metabolism, secretion, and toxicity of xenobiotics. Emerging evidence is defining their role in tissue defense, especially in the GI tract. P-glycoprotein is an ATP-dependent efflux pump whose role is to detoxify cells. It actively pumps toxins out of intestinal epithelial cells and helps resist invasion by enteric pathogens. MRP2 is an organic anion transporter found in liver, intestinal, and kidney cells. Mercado-Lubo R, McCormick BA. Gut Microbes 2010;1(5):301. It’s expression increases in the presence of intestinal inflammation, decreases in the presence of chronic toxicity.
  11. 11. Mercury Species as Transporter DisruptersAnimal evidence shows that conjugates of methyl-mercury and inorganic mercury are transportable substrates of MRP2. Bridges CC, Joshee L, Zalups RK. MRP2 and the handling of mercuric ions in rats exposed acutely to inorganic and organic species of mercury. Toxicol Appl Pharmacol 2011:251(1):50. Mercury anions interact with MRP1 and MRP2 either alone or as a mercury- glutathione complex. Wortelboer HM, et al. Glutathione-dependent interaction of heavy metal compounds with multidrug resistance proteins MRP1 and MRP2. Environ Toxicol Pharmacol 2008:26(1):102. HYPOTHESIS 1: MRP2 concentrates in the duodenum and upper jejunum. Inorganic mercury leaching from amalgams into swallowed saliva, and methylmercury produced within the gut microbiome, can interfere with transporter binding, slowing phase 3 and phase 2, creating a phase 1/2 mismatch. HYPOTHESIS 2: Un-conjugated methylmercury and inorganic mercury anions interact with transporters, causing malfunctions that would predict upper intestinal inflammation and slowed detoxification pathways.
  12. 12. Mercury DynamicsSpecies, Routes of Passage, and Analysis Mercury Speciation Testing Used to gauge methylmercury and inorganic mercury dynamics by comparing hair and urine levels to blood levels.
  13. 13. Mercury SourcesMethyl-mercury: seafood and gut-space conversionsInorganic mercury: dental amalgams and industry Methylmercury distribution in seafood
  14. 14. Mercury Toxicity Effects on the Brain and Nervous System Mechanisms Carvalho CM, et al. Inhibition of the human thioredoxin system: a molecular mechanism of mercury toxicity. J Biological Chemistry 2008;283(18):11913-23.Type of Brain Pathology Witnessed Mercury Autism Microtubule degeneration Yes Yes Overall, mercury inhibition Neuroinflammation Yes Yes was selective toward the thioredoxin system. InOxidative stress and lipid peroxidation Yes Yes particular, the remarkable Microglial/astrocytic activation Yes Yes potency of the mercury Reduced glutathione level Yes Yes compounds to bind the selenol-thiol group in the Mitochondrial dysfunction Yes Yes active site of the TrxR* Vascular endothelial cell dysfunction Yes Yes should be a major molecular Increased amyloid precursor protein Yes Yes mechanism of mercury toxicity. Impaired methylation Yes YesHigher pro-inflammatory cytokine levels Yes Yes *TrxR = thiodoxin reductase
  15. 15. Natural Detoxification Pathways Slide courtesy of Chris Shade, PhD, of Quicksilver Scientific
  16. 16. Disrupting the Detoxification Chain With compromise of small intestinal barrier integrity...1. Small intestinal inflammation overworks phase 3 transporters.2. Phase 3 slowing down-regulates phase 2 conjugation.3. Phase 2 slowing results in a backlog of un-conjugated toxins.4. Free radical damage rises due to the phase 1/phase 2 mismatch. ...comes systemic damage caused by chronic toxicity.
  17. 17. Leaky Gut Precursor to Chronic Toxicity, Autoimmune Disease“This new paradigm subverts traditional theories underlying the development of thesediseases and suggests that these processes can be arrested if the interplay between genesand environmental triggers is prevented by re-establishing the zonulin-dependentintestinal barrier function.” Fasano A. Leaky gut and autoimmune disease. Clin Rev Allergy Immunol 2012;42(1):71-8.
  18. 18. Leaky GutLoss of Tight Junction Functional Integrity Cascade Effects •Maldigestion Fasano A. Physiol Rev 2011;91:151 •Gluten sensitivity •Delayed food sensitivities •Dysbiosis •Nutrient malabsorption •Bacterial overgrowth •Yeast overgrowth •Bacterial translocation •Metabolic endotoxemia •Systemic inflammation •Neuro-inflammation •Autoimmune disorders •Chronic toxicity
  19. 19. Leaky GutCeliac Permissive and Non-Celiac Gluten Sensitivity Type 1: Celiac Permissive •3 celiac permissive genes: DQ 2.5, DQ 2.2, DQ8. •Celiac panel predicts likelihood of celiac disease, not gluten sensitivity. •Both malabsorption and leaky gut can appear with this form. •Gluten-free trial warranted. Type 2: Non-Celiac •No HLA genotype predictors thus far. •No testing helpful at present. •Malabsorption only with this form? •Gluten-free trial warranted.
  20. 20. Leaky Gut Bacterial Lipopolysaccharide (LPS) Translocation as a cause of Metabolic Syndrome Recurrent LPS translocation causes metabolic endotoxemia.LPS is an inflammatory component of the cell-wall of gram negative bacteria. Intestinal immune cells arelargely responsible for the maintenance of intestinal homeostasis and must elicit robust responses topathogens yet still tolerate the commensal microbiota. Leaky gut invites metabolic endotoxemia - anLPS-driven immune cascade that leads to obesity, diabetes, cancer, and cardiovascular disease.Burcelin R, Garidou L, Pomie C. Immuno-microbiota crosstalk: the new paradigm for metabolic diseases. Seminars in Immunology 2012;24:67-74.
  21. 21. Systemic Inflammation Pathways Involved in Neuroinflammation Gut- and peripherally-derived neuroimmune processes produce neuropsychiatric and neurocognitive consequences.Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacologicalimplications. Pharmacology and Therapeutics 2011;130(2):226-238.Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervoussystem in normal gastrointestinal function and disease. Gastroneterology 2009;136(6):2003-14.
  22. 22. The Sluggish Bowel Traffic jams in the gut space invite trouble.
  23. 23. Biotoxin IllnessChronic Inflammatory Response Syndrome High cytokine levels in the capillaries attract white The Biotoxin Pathway Capillaries blood cells, leading to restricted blood flow, and lower oxygen levels. HIF stimulates VEGF and TGF B-1. In genetically susceptible people, biotoxins bind to pattern receptors, HIF Reduced VEGF leads to fatigue, muscle cramps, and causing continuing, unregulated production of cytokines. shortness of breath (may be over-ridden by replacement with erythropoietin). TGF B-1 changes Surface cell type and interacts with Treg cells. Receptors Dendritic Biotoxin (Toll; Cells Immune System Symptoms tible) C-type Increased Cytokines (HLA suscep lectin; Patients with certain HLA genotypes HLA-DR (immune response genes) may develop mannose inappropriate immunity. Most common & others) are antibodies to: Fat cells then -Gliadin (affects digestion) produce more -Cardiolipins (affects blood clotting) leptin, leading to Treg cells: Pathogenic T cells obesity (which doesn’t respond to Split Products of exercise and diet). Complement Activation Excessive cytokine Leptin C4a: capillary hypoperfusion levels can damage receptor Bioto C3a: bacterial membranes leptin receptors in Damaged leptin the hypothalamus. Inflammation-related receptors lead to xin Nerve cell/ Hypothalamus symptoms reduced production axon by the hypothalamus High levels of cytokines produce flu-like VIP AVP of MSH, a hormone MSH symptoms: Headaches, muscle aches, fatigue, with many functions. unstable temperature, difficulty concentrating Biotoxins have direct and more. High levels of cytokines also result in !"#$%&(( effects, including increased levels of several other immune- )*$#(+,"( impairment of nerve response related substances, including TGF -$./( cell function. Reduced B-1, MMP-9, IL-1B, and PAI-1. MMP-9 delivers MSH inflammatory elements from blood to brain, In most people, Sleep Disturbance nerve, muscle, lungs, and joints. It combines biotoxins are Production of melatonin with PAI-1 in increasing clot formation and either removed is reduced, leading to arterial blockage. from the blood by the liver or chronic, non-restorative Resistant Coag-negative attached by the sleep. Staph Bacteria immune system, Chronic Pain broken down, Colonies of MARCoNS with resistance to multiple and excreted Endorphin production is antibiotics may develop in biofilm or mucus membranes. harmlessly. In suppressed. This can lead The bacteria produce substances that aggravate both people who to chronic, sometimes the high cytokine levels and low MSH levels. don’t have the unusual, pain. Reduced ADH right immune Gastrointestinal response genes, Changes in Cortisol Reduced MSH can cause the pituitary to Problems Prolonged Illness however, and ACTH levels produce lower levels of anti-diuretic biotoxins can Lack of MSH can cause White blood cells lose The pituitary may produce hormone (ADH), leading to thirst, frequent remain in the regulation of cytokine urination, and susceptibility to shocks from malabsorption in the gut, elevated levels of cortisol and body indefinitely. response, so that recovery ACTH in early stages of illness, static electricity. resulting in diarrhea. This is sometimes called “leaky from other illnesses, then drop to excessively low including infections levels later. (Patients should Reduced Androgens gut” and resembles (but is diseases, may be slowed. avoid steroids such as Reduced MSH can cause the pituitary to lower its not) celiac disease. IBS is prednisone, which can lowerc R. Shoemaker, 2011 often present. production of sex hormones. levels of ACTH) Find this chart @
  24. 24. Stealth Infections Tick-borne and various other bacteria, viruses, and parasites can stress detoxification systemsAnaplasmosis Babesiosis Bartonella Ehrlichiosis Borreliosis Mycoplasma Chlamydia Epstein-Barr HHV-6 Cytomegalovirus Entamoeba Blastocystis
  25. 25. The main problem is notexposure level, but toxicity retention caused by slowed detoxification pathways.• Sluggish and/or leaky bowel = slowed elimination, overworked transporters. Chronic toxicity is• Slowed phase 3 activity = retained a detox traffic jam toxicity as elimination doors close.• Slowed phase 2 activity = phase 1/2 mismatch, more oxidative stress.• Poor nutrition = added systemic pathway malfunctions.• Weak genes = susceptibilities to slowed detox function at various systemic pathway points.• Higher environmental exposure = greater risk of detox traffic jams.
  26. 26. Review: Basic Necessities forHigh-Performance Detoxification Functional glutathione-dependent pathwaysFunctional phase 1 and 2 detoxification pathways Functional phase 3 transporter pathways A non-inflamed, non-toxic gut.
  27. 27. Team Detox needs a PR campaign! Insert tag line here.
  28. 28. Glutathione Mammalian biology’s best friend. Phase 1 PathwaysThe ninjas warriors of biotransformation. Phase 2 Pathways The US Marshalls of cellular biology. Phase 3 Pathways The fast and reliable way to ship.
  29. 29. Toxicity creep: it gets worse• 10 billion pounds of toxic waste produced annually in US alone.• 47 million pounds of mercury dumped into US environment each year.• Xenobiotics and POPs a growing problem: bisphenols, PCBs, flame retardants, pesticides, combustion products, acrylamides, and more.• Toxins disrupt bodily systems: reproductive, developmental, circulatory, mental, neurological, hormonal, immune, digestive, metabolic, and most ironically - detoxification systems.
  30. 30. Ruzzin J. BMC Public Health 2012;12:298 The time for action is now!“The general population is exposedto sufficient POPs, in terms ofconcentration and diversity, toinduce metabolic disorders. Thesituation should attract the greatest What’s theattention from the public health andgovernmental authorities.” hangup?
  31. 31. Moral Man and Immoral Society Reinhold Niebuhr (1892–1971) is credited with coining the first circulated version of what’s now known as the Serenity Prayer. He was, and remains, widely admired for his theological, moral, and political insights, including the idea that humankind would always struggle to make the world a better place if left to its own authority.
  32. 32. Moral Hazard Niebuhr observed that groups condone immorality more than individuals because the moral responsibility for harms caused gets diffused within the group, making it easier to deflect accountability. Corporations and bureaucracies provide ample cover for greed, corruption, and the temptation to play God.We depend on social cooperation to achieve things we cannot accomplish on our own.That corporate needs conflict with social needs defines the moral hazard of our time.Niebuhr concluded that we cannot trust ourselves to find the path that leads to humanflourishing and that we must defer to a higher source of wisdom if we are to find aroad to health and sustainability. - excerpted from Seek Wisdom: The Modern Quest for Health and Sustainability
  33. 33. And Where is Our Medical Profession on the Issue of Chronic Toxicity? The Prayer of Maimonides (excerpted) Almighty God, you have created the human body with infinite wisdom. You have blessed the earth, the rivers and the mountains with healing substances that enable your creatures to alleviate their sufferings and heal their illnesses. You have endowed man with the wisdom to relieve suffering and to recognize disorders, to extract the healing substances, to discover their powers, and to apply them to suit every ill. Inspire me with love for my art, and let me be content with everything except the great science of my profession. Never let the thought arise that I have attained sufficient knowledge, for the art of medicine is great and the mind of man is ever expanding. 1135 -1204
  34. 34. Do we have a medical model to handle the complexity of chronic toxicity?•Medical toxicologists address the more straightforward problem of acute toxicity.•The chronic toxicity issue paralyzes doctors who lack the time and tools needed to deal with this level of complexity.•A systems medicine model can handle the clinical complexity of chronic toxicity.•What is this model and why is outside the mainstream?
  35. 35. The Systems Medicine ModelEnvironmental Systems: World System: Merge ecological science Coordinated effortswith corporate stewardship. to reduce toxicity. Most moral hazards Cultural Systems: Encourage health found here and sustainability. Political and Economic Systems: Develop policies that The Human Bodymind: reward progress toward Maintain and restore healthy and sustainable functional integrity living systems. through wise self-care and clinical methods that reduce chronic toxicity. Copyright Keith Berndtson, MD
  36. 36. Living Systems as Overlapping Networks A modern systems medicine model Text Diagram from: De Keulenaer GW, Brutsaert DL. Circulation 2011;123:1996-2005
  37. 37. Living Systems as Overlapping Networks An ancient systems medicine model
  38. 38. Factors underlying our different responses to toxic exposures: Species A• Genetic susceptibilities• Levels of exposure• Quality of nutrition• Organ reserves Pollution A• Hormone balance Species B• Tissue barrier integrity• Detoxification strength• Restorative strength• Emotional/spiritual balance Pollution B How are the As and Bs different? How are they the same?
  39. 39. How to Repair and Amplify Your Body’s Detoxification Systems• Get professional help. Find a good source of detoxification expertise.• Repair the gut. Restrict reactive foods and restore a healthy gut microbiome.• Mercury speciation testing. Assess the need for mercury detox support.• Test for biotoxin susceptibility. As warranted based on history.• Test for stealth infection. As warranted based on history.• Get nutrition counseling. For help with dietary changes, detox support.• Try acupuncture. And other methods for balancing energy flow.• Healthy lifestyle change. Find the structure and support you need. Warrior One Pose
  40. 40. Conclusions1. Hordes of toxins are infiltrating the living systems of the world.2. Natural detoxification pathways are overworked and undernourished.3. Healthy barriers support healthy detoxification (including moral barriers).4. The prognosis for any chronic disease relates to detoxification capacity.5. To reduce the costs of chronic disease, reduce chronic toxicity.6. Chronic toxicity is best addressed using the systems medicine model.7. Up with the systems medicine model!
  41. 41. Your source for professional detox support.For advanced detoxification expertise and a chance at feeling better no matter what your chronic health condition, call to schedule: 847-232-9800 or register online: www.parkridgemultimed.com15 N. Prospect Avenue, Park Ridge, IL 60068
  42. 42. Patient-centeredsystems medicine.