amending and maintaining a novel phase of detoxification ... · definition of detoxification...
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Amending and Maintaining a Novel Phase of
Detoxification in the Vaccinated and Unvaccinated
Detox Phase 2.5
Dr. Kelly Halderman, MD, NMD, CCN
Disclaimer
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This material is provided for educational and informational purposes only to licensed health care professionals. This information is obtained from sources believed to be reliable, but its accuracy cannot be guaranteed. Herbs and other natural substances are very powerful and can occasionally cause dangerous allergic reactions in a small percentage of the population. Licensed health care professionals should rely on sound professional judgment when recommending herbs and natural medicines to specific individuals. Individual use of herbs and natural medicines should be supervised by an appropriate health care professional. The use of any specific product should always be in accordance with the manufacturer's directions.
Objectives
•Phases 0, 1, 2 & 3 Detox•Bile Physiology •Phase 2.5 Detox •Factors that shut down Phase 2.5 Detox
•Strategies to fix
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Dr. Neil Nathan, MD“Toxic”
“I encourage you to listen to Scott Forsgren’s podcast with Dr. Kelly Halderman, MD, in which Dr. Halderman does a brilliant job of describing this process and suggesting supplements to help the body make and secrete bile more effectively.”
Phases 0,1, 2, 3 Detox
Definition of Detoxification
•Noun = The physiological removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver.
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30,000 ft view
• Phase 0 - import into the liver (or kidney)• Phase 1 - transformation enzymes
• oxidize, reduce & hydrolyze toxins/drugs• Phase 2 - conjugation enzymes
• these enzymes conjugate Phase I products• Phase 3 - final conjugated toxins from the bile to excretion.
What needs to be “Detoxified”?
Categories
• Exobiotics or “xenobiotics” = drugs, chemical carcinogens, environmental pollutants & dietary substances.
• Endobiotics = bilirubin, steroid hormones, thyroid hormones, bile acids, cholesterol, histamine & fat-soluble vitamins.
•Byproducts of neurotransmitter metabolism - dopamine, epi, NE, etc.
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What is needed?
• Several raw materials to help build enzymes• Cofactors make enzymes/transporters work• Manage inhibitors• Do not attempt to push detoxification without
first addressing the status of the host/patient• Minimize substrate competition
The Allostatic Load
• Vitamin & mineral deficiency, some diseases, tobacco smoke, alcohol, drugs & xenobiotics/endobiotics can overwhelm the system.
• The current count of environment “chemicals” is now approaching 100 million, and humans and other species are exposed to a great number of them.
Phase 0 DetoxTransport into the Liver Cell
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Canalicular membrane
Basolateral membrane
Phase 0 Detox
• Transport systems at the basolateral, sinusoidal domain of the hepatocyte
• Facilitate the selective uptake of various albumin-bound organic anions, cations, drugs, toxins and neutral compounds that are excreted into bile.
Phase 0 DetoxNTCP
•Sodium-Taurocholate Cotransporter (NTCP) SLC10A1•Primary carrier for conjugated bile-salt uptake from portal blood•+ statin transport
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Phase 0 DetoxOATP
•Organic-anion-transporting polypeptides (OATPs) SLCO1B1 &1B3•Bile salts, thyroid hormones, conjugated steroid hormones, prostaglandins, and bilirubin, xenobiotics & environmental toxins
GENETICS Review
What is a SNP?•S = Single•N = Nucleotide (A,C,T,G)•P = Polymorphism
•SNPs occur in:•Coding regions•Non-coding regions•Between genes
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Enzymes. Transporters.
•A person with a heterozygous or homozygousSNP, may have a decreased ability to convert (substrate A) to product (B).
• …or decreased ability to transport substances.
A B
Phase 0 Detox – genetics“The science”Polymorphisms (SNPs) in:
• OATP1B1 account for differences in clearance of drugs, and mutations in this OATP have been described in patients with pravastatin induced rhabdomyolysis.
• OATP1A2 have been associated with severe reactions to methotrexate
• OATP1B3 transports unconjugated bilirubin from the blood to the liver and variants have been described in patients with neonatal jaundice.
Competing for OATP• NSAIDs
• anti- hypertensives
• anti-viral therapeutics
• anti-neoplastic drugs
• cholesterol-lowering drugs
• diuretics
• antibiotics
• endogenous compounds: steroid hormones, neurotransmitters metabolites, uremic toxins
• exogenous compounds: nutraceuticals (e.g. phenolic acids & flavonoids), environmental contaminants & toxins (e.g. herbicide/pesticide components and mycotoxins)
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Phase 0 DetoxInhibitors • NTCP
• estrogens, endotoxin & pregnancy
• OATP
• caffeine
• flavonoids (e.g. apigenin, catechin, epicatechin)
• phenolic compounds (e.g. berries, chocolate)
• stilbene derivatives (e.g. resveratrol, 4-stilbenol, pterostilbene & mulberroside)
• lycopene, soy isoflavones, stevia, citrus, diesel exhaust.
Phase 0 DetoxStimulators
•NTCP - up-regulated by retinoids & prolactin
Phase 1 DetoxEnzymatic Transformation
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Phase 1 Detox
•OXIDATION •HYDROLYSIS•REDUCTION•HYDRATION•DEHALOGENATION
Phase 1 Detox
• Reactions break them into smaller, electrically-charged substances
• This process generates free radicals
• Excessive exposure to toxic chemicals induces phase 1 detox, causing it to become overactive
• --> overloading the body’s antioxidant systems & phase 2
• This gives rise to inflammation and liver disease
Raw Materials
• Riboflavin (B2)
• Niacin (B3)
• Pyridoxin (B6)
• Folic acid (non-synthetic = MTHF)
• Vitamin B12
• GSH
• Branched-chained amino acids
• Flavonoids
• Phospholipids
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Phase I Detox
Enzymatic Transformation by:
OXIDATION•Cytochrome P450 monooxygenase system•Flavin-containing monooxygenase system•Monoamine oxidase•Alcohol dehydrogenase & aldehyde dehydrogenase•Co-oxidation by peroxidases
Phase I Detox
Enzymatic Transformation by:
REDUCTION•NADPH-cytochrome P450 reductase•Reduced (ferrous) cytochrome P450
Phase I Detox
Enzymatic Transformation by:
HYDROLYSIS •Epoxide hydrolase•Esterases & amidases
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Inducers of CYP1 enzymes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/pdf/JNME2015-760689.pdf
Inhibitors of CYP1 enzymes
Phase 2 DetoxificationEnzymatic Conjugation
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Phase 2 Detox
•Glucuronidation•Sulfation•GSH conjugation•Methylation•Acetylation•Amino Acid conjugation
Phase II Detoxification
•Phase II enzymes increase the solubility & reduce the toxicity of phase I products.•Toxic-overwhelm, gene polymorphisms and/or a lack of these enzymes play a role in several forms of disease.
Phase 2 - Raw Materials
•Methionine•Cysteine•Magnesium•Glutathione•Vitamin B5, B12•Vitamin C
• Glycine
• Taurine
• Glutamine
• Folate
• Choline
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Clinical Evaluation for Phases 1 & 2 of Detoxification
Genetic Report: Phase 1 Detox
DUTCH: Phase 1 Detox
CYP19A1 = aromatase
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Phase 2 Detox• Genetics = possible predispositions
• Blood work - Liver injury - AST, ALT, GGT (bile ducts), Alkaline phosphatase
• DUTCH test - phase 2
•Sulfation - decrease in DHEA-S (DUTCH)
•COMT – for methylation
• Glucoronidation - High beta glucoronidase (GI MAP)
• GSH-conjugation - GGT, RBC glutathione (blood)
• Methylation - Doctor’s Data lab testing & DUTCH
• OAT
• Cyrex testing
Genetic Report: Phase 2 Detox
•SULTs•UGTs•GSH•GSTs•MTHFR, COMT, etc.
Methylation Panel - Doctor’s Data
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DUTCH test
Sulfation
Methylation
Cyrex 14
Phase 3 Detoxification Excretion
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Phase 3 Detox
Excretion • Bile → gut
•Kidney• Skin • Lungs - breathing
Bile Synthesis & Metabolism
Bile Functions• Emulsify & digest fat
• Regulates glucose metabolism
• Cholesterol metabolism
• Thyroid hormone
• GI microbes & motility (SIBO, leaky gut, constipation).
• Bile + phospholipids + toxins
out of liver intestines toilet
*can be reabsorbed via enterohepatic circulation.
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What is Bile?
•Bile consists of 85-95% water
•Endogenous solid constituents bile salts, bilirubin, phospholipids, cholesterol, amino acids, steroids, enzymes, porphyrins, vitamins, heavy metals, exogenous drugs, xenobiotics, environmental toxins, Immunoglobulin A, and mucus
•Hydration
Functions of Bile
Excretory Function
Digestive Function
Endocrine Signaling
Antimicrobial
Bile Flow
•Produced in liver, released into biliary tree, enters common bile duct
•Common bile duct joins with the pancreatic duct at the Ampulla Vater
•Sphincter of Oddi prevents Bile from entering intestines b/t meals
http://www.taseerlabs.com/Hepatitis/gallstones.html
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Bile Flow
•Bile produced b/t meals fills the bile duct and excess backs up into the gallbladder
•Bile is concentrated 5 -10x in the gallbladder
•Meal – Chyme (acid and partially digested fats) stimulates Secretin and CCK
•Secretin stimulates biliary duct cells to secrete bicarbonate and water to expand the volume of bile.
http://www.taseerlabs.com/Hepatitis/gallstones.html
Bile Flow•CCK stimulates contractions of the gallbladder and the common bile duct
•Gallbladder contracts, the sphincter of Oddi relaxes, and up to 80% of the gallbladder contents are discharged into the duodenum
•The bile acids impart their functions of excretion, digestion, endocrine signaling, and it’s antimicrobial effect directly in the upper and indirectly in the lower intestine.
•Acidity and Estrogen http://www.taseerlabs.com/Hepatitis/gallstones.html
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Bile Flow
•There is some conversion of primary bile acids to secondary bile acids, and some deconjugation of bile acids.
•Most of the bile acids are reabsorbed in the small intestine, some make it to the colon and impart antimicrobial effects there as well before being reabsorbed, and some (5%) are lost in the stool
•The reabsorbed bile acids both primary and secondary are sent back to the liver to be recycled.
•This is what should happen but poor diet, lifestyle, medications, antibiotics – disrupt this system.
Bile Acid Production in Liver•Primary pathway:
Cholesterol to Cholic Acid (CA) and CDCA via CYP7A1•Occurs in Liver•90% of bile acid production
•Alternative Pathway: Cholesterol to Chenodeoxycholic Acid (CDCA) via CYP27A1•Extrahepatic•10% of bile acid production
https://www.researchgate.net/publication/272297681_Bile_acids_and_sphingosine-1-phosphate_receptor_2_in_hepatic_lipid_metabolism
Bile Acid Conjugation in the
Liver•Once the primary Bile Acids are made they are conjugated with Glycine and Taurine
•Makes them stronger acids = Bile salts
•Prevents reabsorption
•Increases amphipathic properties allowing the formation of polymolecularaggregates termed micelles.
•These micelles can solubilize other lipids in the form of mixed micelles.
https://www.david-bender.co.uk/metabonline/lipids/bile/bile12.html
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Formation of Bile
•Betaine and Homocysteine with BHMT and Zn forms Methionine
•Methionine and ATP/Mg utilize MAT to form SAMe
•SAMe reacts with PE and PEMT to form PC
•Multiple transporters translocate PC, cholesterol and other substances into the canniluculus to incorporated into the micelles
https://www.researchgate.net/publication/10704326
Micelle Formation
•Bile salts bind with micelles•Micelle formation allows for fewer “free” Bile Acids / Salts in bile to damage bile ducts http://www.jlr.org/content/50/Supplement/S406/F1.expansion.html
Bacterial alterations of bile acids
https://basicmedicalkey.com/alimentary-tract-and-pancreatic-disease/
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Excretory Functions of Bile
•Bile helps remove waste products, toxins, and metabolites
• WEIGHT LOSS •Cholesterol, amino acids, steroids, enzymes, porphyrins, vitamins, and heavy metals, exogenous drugs, xenobiotics and environmental toxins are all removed via flow into bile.
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Digestive Function of Bile
•When bile enters the small intestine, phosphatidylcholine is hydrolyzed and absorbed and cholesterol precipitates from solution enhancing its elimination.•The amphipathic nature of bile acids allows them to have detergent action on particles of dietary fat, which causes fat globules to break down or be emulsified into minute, microscopic droplets.
Digestive Function
•Bile salts bind to fats / lipids they form a micelle
• Increase the surface area allowing for pancreatic lipase to interact
•Pancreatic lipase breaks down lipids to free fatty acids and monoglycerides
•Micelles broken down FFA and MG absorbed
•Bile salts released into intestines to be reabsorbed lower in small intestine
•Fats re-esterfied and released into lymph
https://hackyourgut.com/2016/11/11/the-most-important-thing-to-know-if-you-have-ibs/
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Fat Digestion Review•Step 1: Luminal phase. Fatty acids stimulate cholecystokinin (CCK) release from the duodenum and upper jejunum. The CCK stimulates release of amylase, lipase, colipase and proteases from the pancreas, causes gallbladder contraction and relaxes the sphincter of Oddi, leading bile to flow into the intestine.
•Step 2: Fat solubilization. Bile acids and salts combine with dietary fat to form mixed micelles, which also contain cholesterol and fat-soluble vitamins.
•Step 3: Digestion. Pancreatic lipase, in the presence of its co-factor, colipase, cleaves long-chain triglycerides, yielding fatty acids and monoglycerides.
Fat Digestion Review•Step 4: Absorption. Mixed micelles diffuse to the brush border of the enterocytes. Within the brush border, long-chain fatty acids bind to proteins, which transport the fatty acids into the cell, whereas cholesterol, short-chain fatty acids, phospholipids and fat-soluble vitamins enter the cell directly. The bile salts remain in the small intestinal lumen and are actively transported from the terminal ileum into the portal circulation and returned to the liver (the enterohepatic circulation).
•Step 5: Re-esterification. Within the enterocyte, fatty acids are re-esterified to form triglycerides. Triglycerides combine with cholesterol ester, fat-soluble vitamins, phospholipids and apoproteins to form chylomicrons.
•Step 6: Transport. Chylomicrons leave the enterocytes by exocytosis, enter mesenteric lymphatics, pass into the thoracic duct, and eventually reach the systemic circulation.
Effect of Bile on Vitamin B12 Absorption
PMCID: PMC1714280
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Antimicrobial Impact of Bile
Direct Antimicrobial Effect
•Upper intestine•Attack and damage bacterial cell membranes
•Concentration of bile is important
•Porcine Bile salts more similar to human bile salts than ox bile
•Gram(–) bacteria more resistant to Bile salts
•Bile acid signaling downregulates NF-κB–controlled proinflammatory responses
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Curr Opin Gastroenterol. 2014 May; 30(3): 332–338.
Bile Acids and the Gut Microbiome
The host and microbiome appear to regulate bile acid pool size. The host The host produces a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of FXR in intestine and liver. Members of the microbiome utilize bile acids and their conjugates resulting in agonism of FXR in intestine and liver resulting in a smaller, unconjugated hydrophobic bile acid pool. Hydrophilicity of the bile acid pool is associated with disease states. Reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation. Diet, antibiotic therapy, and disease states affect the balance of the microbiome-bile acid pool.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215539/
Endocrine Signaling of Bile
•Three major signaling mechanisms of BA have been identified: •Activate nuclear hormone receptors such as farnesoid X receptor a (FXRa; NR1H4)•Activate mitogen-activated protein kinase (MAPK) pathways•Ligands for the G-protein-coupled receptor (GPCR) TGR5
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Bile Acids and FarnesoidX Receptor (FXR)
•Plays a pivotal role in regulating bile acid homeostasis
•Bile acids self regulate through a negative feedback mechanism on hepatocytes and enterocytes
• ASBT - apical sodium-dependent bile salt transporter
• Klotho B -
• FGF19 - fibroblast growth factor 19
• FGFR4 - fibroblast growth factor receptor 4
• RXR – retinoid x receptor
• SHP - small heterodimer partner
• OST - organic solute transporterhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440314/pdf/7601049a.pdf
Bile Acids & Farnesoid X Receptor (FXR)•FXR activation in the liver:
•Increased conjugation of BA•Excretion of BAs from hepatocyte → bile canaliculus
•Activates SHP to inhibit bile synthesis
•FXR activation in the intestine:•Increased activation of OST Transporter to move BA into portal circulation
•Activation of SHP to inhibit ASBT – reduced bile acid absorption
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440314/pdf/7601049a.pdf
Endocrine Signaling – TGR5
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Bile Acids Are Associated with Energy Expenditure and Thyroid Function in Humans
http://press.endocrine.org/doi/10.1210/jc.2011-2329
Bile and Endocrine Signaling
1. Inhibits gluconeogenesis and promotes glycogen synthesis
2. Increase GLP-1 / insulin
3. Biome integrity / BA conversion
4. Maintain tight junctions
Bile and Endocrine Signaling
5. Mediates satiety6. Increases energy
expenditure7. Increase insulin
secretion8. Increase GLP-1
secretion9. Immune
modulation
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Physiological Functions of Bile Acids Review
•Elimination of cholesterol:•Bile acids eliminate cholesterol from the body by converting it to bile acid and by micellar solubilization of cholesterol in bile
•Lipid transport in the form of mixed micelles:•In the small intestine, bile acids promote dietary lipid absorption by solubilizing dietary lipids and their digestion products as mixed micelles.
• In the biliary canaliculus, bile acids solubilize biliary phospholipids and cholesterol in mixed micelles. Such micelle formation promotes cholesterol elimination.
•Stimulation of bile flow:•Bile acids are actively transported into the biliary canaliculi between hepatocytes and induce bile flow by their osmotic properties.
Physiological Functions of Bile Acids Review
•Stimulation of biliary phospholipid secretion•Bile acids promote the transfer of phospholipids from the canalicular membrane into bile.
•The presence of phospholipids in bile results in a greater fraction of bile acids existing in the form of mixed micelles and a lower monomer concentration of bile acids, thereby preventing bile acids from damaging the bile duct epithelium.
•Negative feedback regulation of bile acid and cholesterol biosynthesis. •The concentration of bile acids in the hepatocyte seems to act as a signal: when high, bile acid synthesis is low; when low, bile acid synthesis increases up to 15-fold.
•Because bile acids are synthesized from cholesterol, cholesterol synthesis undergoes a parallel increase.
Physiological Functions of Bile Acids Review
•Bile acids solubilize polyvalent metals such as iron and calcium in the duodenum, promoting their absorption.
•Bile acids also seem to stimulate the release of motilin, which coordinates the inter-digestive migrating motility complex.
•Bile acids also affect the absorption of water and electrolytes by the colonic mucosa, and affect colonic motility.
•Antimicrobial affect:•Bile acids have bacteriostatic effects and stimulate mucin secretion; these actions are likely to affect intestinal flora of the small intestine.
•Bile acids, because of their surface activity, should inhibit bacterial adhesion, and they might bind enterotoxin in the intestinal lumen.
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What Disrupts Bile Physiology?
•Cholesterol and statins•Inflammation/cytokines•Dysbiosis•Methylation problems•Sulfation problems•Estrogen imbalances•Vitamin A and D deficiencies•Insulin resistance and diabetes•Thyroid hormone dysregulation•Medications
Clinical Goals
•We know bile production & flow is important
•Phases 1, 2 & 3 must INHERENTLY work in unison!
•Goldilocks
BIGGEST ASSUMPTION!
Phase 2
water-soluble toxins
Phase 3
bile
We assume that as we push and optimize phase 1 and 2 that their products actually make it into the bile and are excreted.
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Phase 1+2/2.5 MORE important
•Products of phase 1 that are processed by Phase 2 detox NEED TO BE TRANSPORTED into BILE.
•“Opening up detox pathway”
•The DOOR MUST BE OPEN + Bile + PC
Normal LIVER CELL
http://www.townsendletter.com/FebMarch2018/pushcatch0218.html#.Wq5fuKmPt7w.email
Phase 2.5 Detoxification
•DOOR SHUT •toxins enter circulation – adipose to protect •place heavy burden on kidneys, skin, hepatocyte•excess intestinal binders ineffective
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MRP2
The Multi-Drug Resistant Transmembrane Proteins (MRP)
•The major endogenous substrates for this transporter include: bilirubin (conjugated), GSH conjugates, leukotrienes, heavy metals, sulfated and glucuronidated substrates, including bile salts, some drug conjugates, antibiotics & a number of other exogenous compounds
The Multi-Drug Resistant Transmembrane Protein (MRP)
• Excrete organic solutes into bile against large concentration gradients
• Mediates ATP-dependent multi-specific organic-anion & cation transport into bile
•GSH conjugates (transported into bile by the MRP2) are largely responsible for the secretion of canalicular Bile Sale Independent Flow (BSIF).
•Mutations --> cholestatic liver disease
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The Multi-Drug Resistant Transmembrane Protein (MRP2)
•The major ABC conjugate export pump in the canalicular membrane, the primary determinant of BSIF, and the gene, when mutated —-> Dubin-Johnson Syndrome
•ABCC2 gene
ABCC2 gene codes for MRP2
•Dubin-Johnson Syndrome (DJS) • recurrent or persistent jaundice, abdominal pain, fever,
conjugated hyperbilirubinemia with or without elevations in liver function tests.
• Formal diagnosis liver biopsy where darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I & III metabolites in the urine.2
• increased leukotriene levels in the urine, implying elimination into bile is defective.
ABCC2 gene codes for MRP2
• Homozygosity or total deletion can cause Dubin-Johnson Syndrome, whereas heterozygosity is not without clinical and negative physiological manifestations, especially when allostatic load of the host is increased.
• Akin to HFE genetic mutations
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ABCC2 studies
• Studies on mercury excretion after exposure show that certain polymorphisms in genes encoding for mercury transporters, such as the ABCC2 are associated with increased urine mercury concentrations, thereby suggesting in vivo decreases in ability of excretion when SNPs are found.
• Increased concentrations of mercury in maternal hair of pregnant females have also been identified in those with ABCC2 polymorphisms, which may cause the fetus to be overexposed to mercury, causing developmental problems.
ABCC2 alleles• rs717620; rs3740066; rs2273697 —> cause a decreased excretion of the
aforementioned organic anions, thus putting a burden on efforts of detoxification - in a sense “backing up” the normal excretion flow of metabolized toxins.
• Even heterozygosity in one or more of these alleles can affect what is known as “Detoxification Phase 2.5”
• When Phase 2.5 Detoxification is not working well chronic disease can be perpetuated, as the terrain of the body cannot be optimized without proper removal of burdens set upon it.
• Look for ABCC2 gene polymorphisms - in pts chronic disease - may be your bad “detoxers”
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ABCC2 codes for MRP2
•Clinical management:•Up-regulating/optimizing Phase 2.5 Detoxification (work on lowering inflammation, gut work) BEFORE pushing Phases 1 & 2 while using comprehensive intestinal binders •Enzyme function support- 1) address antimony toxicity 2) B vitamins 2) aluminum 3) Ca++/Mag++ balance 4) iodine/fluoride ratio
Support of MRP2
•Sulforaphane•Luteolin•Taurine•Choline •Vitamin D•Caloric restriction•St. John's Wort
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Stabilize Multi-Drug Resistant Transmembrane Protein (MRP2)
•Stabilized by TUDCA•Bile salts can stimulate TGR5 via D2 •SO don’t over do it
•Milk Thistle – BUT…• shuts down MCT8 = major transporter of thyroid hormone into the cell
BSEP
The Bile-Salt Export Protein (BSEP)
• Substrate specificity primarily restricted to bile salts
• Rate limiting step of hepatocellular bile salt transport and drives enterohepatic circulation of bile salts.
• It is extensively regulated to keep intracellular bile salt levels low under normal and pathophysiologic situations.
• GENETIC = Mutations can lead to severe progressive familial intrahepatic cholestasis.
• Inhibition by endogenous metabolites or by drugs -->lead to acquired cholestasis -->liver injury
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Drugs that inhibit BSEP• Cyclosporin A (immunosuppressive)
• Glibenclamide (anti-diabetic)
• Rifamycin (antibiotic)
• Rifampicin (antibiotic)
• Bosentan (anti-hypertensive)
• Flutamide (chemotherapy)
• Thiazolidinedione derivatives (anti-diabetic)
MDR
The Multi-Drug Transporter (MDR)
•Transporter for phospholipids
•In the absence of phospholipid in bile, the continuous exposure to hydrophobic bile salts is thought to exert direct toxic effects on the apical epithelial membrane of the cholangiocyte, resulting in liver injury.
•Expression increased in several different forms of liver injury
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LIVER CELLPHASE 2.5 DETOX
1. Conjugated toxins produced (Phase 1 & 2) & move through MRP2
2.Production & proper recycling of bile (salts) - Acetyl CoA (ACAT + PANK enzymes), gut health, hormone balances, glucose
3. Phosphatidylcholine status -fluidity, PEMT enzyme, diet, gut health
PHASE 2.5 DETOX
1. Conjugated toxins produced by Phase 1 & 2 move through MRP2
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2. Production & Recycling of Bile
2. Production & Recycling of Bile
•ACAT1 enzyme
•protein & fat and make the “Acetyl”
•PANK enzyme
•make the “CoA”
•Bile salt recycling – get the gut right
Acetyl-CoA
© 2012 NutriGenetic Research Institute.
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ACAT
ACATACAT
Beta-ketothiolase Deficiency
•Inherited disorder of ACAT-1 -cannot effectively process a isoleucine.•impairs the body's ability to process ketones.•The signs and symptoms of typically appear 6-24 months. Episodes of vomiting, dehydration, difficulty breathing, extreme tiredness & occasionally, seizures. •Heterozgous affect?
http://omim.org/entry/607809
ACAT Genes
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Decreases ACAT1 activity
•Iron
•Resveratrol
•Acetaminophen
•Tobacco
•Aflatoxin
• Copper
• PC
• Quercetin
• Soy bean oil
• Vitamin E
Increases ACAT activity
•Fatty acids•Potassium•Palm oil
PANK enzyme
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PANK enzyme• Pantothenate kinase family
• Catalyzes the ATP-dependent phosphorylation of vitamin B5 to give 4′-phosphopantothenate.
• This reaction is the first and rate limiting step in the synthesis of coenzyme A (CoA).
• pantothenic acid derived metabolite that is essential for many crucial cellular processes including energy, lipid and amino acid metabolism.
• CoA synthesis requires cysteine, vit B5 & ATP.
PANK enzyme
•About 4% of all known enzymes utilize CoAas a cofactor and CoA thioesters •Essential for over 100 different reactions of the intermediary metabolism, such as the Krebs Cycle.
PANK Enzyme Alleles
*Pantethine
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3. Production of Phosphatidylcholine (PC)
3. Production of Phosphatidylcholine (PC)
• Only 8% of the US population meet the requirements
for phosphatidylcholine
• PEMT enzymes - make PC
• Foods high in PC
• Gut function - absorbing from the diet?
PEMT Enzyme
• = phosphatidylethanolamine N-methyltransferase gene
• PEMT converts phosphatidylethanolamine (PE) to
phosphatidylcholine (PC) by catalyzing three sequential
methylation reactions.
• Estrogen is required activate & function normally.
•Men and postmenopausal women have an elevated risk of
choline deficiency due to low estrogen levels.
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PEMT Enzyme
•Commonly slowed down by polymorphisms•74% of women have at least one copy of a slowed PEMT•Homozygous carriers of PEMT have much higher risk of choline deficiency
PEMT Enzyme alleles
PC functions
•Cell membranes = cholesterol + glycolipids + phospholipids•lipid transport•liver repair•nerve conductivity•brain development •controls deposition of fat into organs —> NAFLD
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Indirect measurement of cell membrane health -BIA
• Bio-impedance (BIA) has been used to determine body composition since the 1970s.
• Passing an alternating electrical current of low intensity through the body and measuring the opposition of tissues to the passage of this current.
• Phase angle & Intra/extracellular water ratio
Indirect measurement of cell membrane health
•Phase angle
•Intracellular/Extracellular ratio
Foods high in PC
•beef•almonds•cauliflower•navy beans•amaranth •eggs - may be aggravating to the GB
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Summary
•Evaluate & optimize MRP2•Genetics, nutrients, decrease inflammation•Increase expression sulforaphane, luteolin, vitamin D, SJW, caloric restriction•+/- Stabilize with TUDCA•Artichoke – bile stimulant; Bitters – dandelion
•Evaluate & Optimize Bile salt production•ACAT1 & PANK - pantethine•Provide conjugation for BA = glycine & taurine
•Optimize PEMT with food +/- PC
Comprehensive binders
•chlorella - biotoxins & metals•charcoal - LPS, mold toxins, pesticides, herbicides, VOCs•brown algae - heavy metals•zeolites - mold toxins, pesticides, herbicides, •clays - mold toxins, healing to gut lining
What limits Phase 2.5 Detoxification?
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What limits Phase 2.5? ★inflammation
• endotoxin
• hormone imbalances
• certain supplements
• genetic snps in ABCC2 (codes for MPR2)
• lack of fluidity – phosphatidylcholine (gut, PEMT)
• proper production & recycling of bile salts (gut, ACAT, PANK)
• glutathione gradient
MRP2
BSEPMDR
INFLAMMATORY STATE
INFLAMMATION
•Definition of inflammation
1: a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, and pain and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue
2: the act of inflaming : the state of being inflamed
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http://jpet.aspetjournals.org/content/290/3/1427
GAME CHANGER #1
The Ringleader of Inflammation
Mast cell
“I tend to think that the mast cell orchestratesthe inflammatory response.”
Dr. T.C. Theohardies, MD, Ph.D, MS
Mast Cell Mediators
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Mast Cell Activators
• Pathogens - Lyme, H. pylori, viruses
• Heavy metals
• Stress - CRH
• LPS/Endotoxins
• Neurotensin & Substance P
• Complement
• IgE cross-linking (e.g. peanuts, milk)
Symptoms of Activated Mast Cells• GI - Rapid onset after eating or drinking of sweating, flushing, palpitations, itching, swelling of the
tongue, wheezes, abdominal bloating, gas, pain, nausea (often with vomiting) and diarrhea.
• General - Malaise, Fatigue, Temperature dysregulation, weight loss or gain.
• Sensitivities - chemicals (MCS), food, smell, sound, EMF.
• Pulmonary - wheezing, SOB, air hunger
• Integumentary - rashes, eczema, hives.
• Sinus/Oral - post nasal drip, congestion, sinusitis, rhinitis & Itching in throat, post nasal pharyngitis
• Cardiovascular - Lightheadedness, weakness, dizziness, vertigo, syncope, palpitations, arrhythmias, chest pain, POTS & unusual edema.
• Musculoskeletal - muscle & joint pain (resembling FM)
• Neuro - HA, paresthesias, tremors, seizures, autonomic dysregulation.
Dr. Neil Nathan, MD “Mast Cell Activation” April 2018 ICAM conference
© 2018 NutriGenetic Research Institute.https://www.hoffmancentre.com/2017/11/mast-cell-activation-syndrome-histamine-immune-system-runs-rampant/
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INFLAMMATION STRATEGY preview
• Stop activating the Mast Cells! ELIMINATE ROOT CAUSES & work on FOUNDATIONS - air, water, nutrition, dentistry, sleep & stress
• Stabilize the Mast Cells - nutraceuticals, stress management, hydrogen water
• Optimize histamine- clean up the excess, DAO, low histamine diet, block H1/H2 receptors.
• Optimize iron metabolism – iron, bioavailable copper, retinol
• Balance mTOR/Autophagy
Phase 2.5 “broken”?
•History•Signs•Symptoms•Blood work•Diagnostic Imaging
History
•Poor response to traditional “detox” protocols•fatigue, brain fog, weight gain or no loss, skin problems, kidney pain, low back pain, hair loss, inflammation
•PMHx = GERD, constipation, SIBO, “leaky gut”, IBD, parasites, food allergies, nausea, thyroid issues, autoimmunity, cellulite yeast overgrowth, depression, indigestion, hormone imbalances, Type 2 DM, weight gain.
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Signs & Symptoms• Hypothyroid symptoms
• Constipation
• Nausea or vomiting
• Pain with sudden onset & quickly worsens; located on right side (under ribcage), between shoulder blades, in right shoulder or up right side of neck.
• Headache over eyes
• Belching, reflux, gas, bloating, feeling “full”
• Bitter taste in mouth after meals
• Varicose veins
• Jaundice
• Light-colored stools
• Floating stools
• Hemorrhoids
• Cannot lose weight
• Depression, anxiety, irritability
• Dry skin & hair (fatty acid deficiencies)
• Easily intoxicated
• Itchy skins (palms & soles)
Diagnostic Imaging
•Abdominal x-rays = Ca+ containing gallstones•CT = rupture or infection•MRI = stones in the bile ducts, can miss infection •Ultrasound = gallstones, nothing about inflammation
Genetic weakness
INFLAMMATION
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Labs Inflammation
• HA1c > 5.3
• Bilirubin > 8
• Uric Acid > 6
• Alk phos > 90
• AST, ALT, GGT > 26
• Ferritin > 25
• RDW > 13
• WBC < 5 or >8
• VLDL > 20
• RT3 > 18 &/or ratios off
• Fibrinogen > 350
• Insulin > 8
• high 1,25 OHD
• Homocysteine > 8
• CRP-hs > 1
• elevated nagalase
Genetic weakness
IMPAIRED DETOXIFICATION
Redox BalanceROS RNS Lipid Protein and DNA Radical Battle
REDOX
O2 •, superoxide anion; 1O2, singlet oxygen; 3O2, ozone; •OH, hydroxyl
anion; ClO, chlorite ion; HOCl, hypochlorite anion;
ONOO, peroxynitrite; NO, nitrosoniumion; NO, nitroxyl anion;
oxLDL, oxidized LDL; •LOO, lipid peroxyl; •LO, lipid alkoxyl.
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Kidneys taking the hit!
Clinical strategies
•NON-VACCINATED
•DETOXIFYING THE VACCINATED
•HOMEOPATHIC VACCINATION
Clinical strategiesACROSS THE BOARD
•FOUNDATIONAL SUPPORT - clean air, water, nutrition, sleep, stress •Evaluation of Physical, Chemical, Emotion & Microbial stress – stop closing the phase 2.5 door. •Vitamin and mineral status •FIRST, open the 2.5 door & LYMPH DRAINAGE before pushing “detox”•Protect kidneys •Optimize gut & BIND toxins that go through the door
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OPENING UP PHASE 2.5
•STABILIZE – decrease inflammation, gut work, nutritional deficiencies•BUILD & EXCRETE BILE – Artichoke, bitter herbs, conjugating factors (taurine & glycine), pantethine, hydration status, Arsenicum 30 C 5 pellets BID, Phytolacca and Conium
•PC
LYMPH DRAINAGE
•Curcumin, Quercetin, Bilberry, Sterolins & sterols•Homeopathic remedies – Histaminum, phytolacca, conium, Cal Carb, Mellalotis, Diosmin, Arsenicum, Bana rufo, Vipera•Rebounding•Exercise•Massage
Protect the KIDNEYS
•Oligo Mn Cu, Oligo Cu Ag Au, Oligo Phosphorus, Artichoke extract, Phosphatidylcholine, Stinging Nettle, NADH, Curcumin, Cordyceps, Glutamine, Melatonin, bitter herbs (dandelion), NAC, Aged Garlic, Grape Seed Extract, Pomegranate, Vitamin C •Homeopathic remedies •Innate antioxidants – SOD, Catalase, Glutathione•ALKALIZE – green drinks, magnesium
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