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Managing CFS/ME: a clinical approach

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Around 250,000 people in the UK are currently thought to be affected by CFS/ME. The high level of disability that is often associated with this debilitating condition can be both physically and mentally challenging for patients and appears to stem from a combination of symptoms such as fatigue, pain, sleep disturbance, cognitive impairment, depression and, in many cases, symptoms mirroring those of irritable bowel syndrome.

With no current cure and no validated, universally accepted, ‘one-size-fits-all’ approach to the treatment, many clients are seeking natural alternatives to conventional approaches.

Taking a personalised and functional medicine approach, Dr Nina Bailey reviews the latest science on ME/CFS and the underlying mechanisms that can be targeted with nutritional interventions and explains how to ensure your therapeutic approach is right for your clients.

Covered in the webinar:

1. CFS/ME background /causes/symptoms
2. Update on the mechanisms associated with CFS/ME:
- Immune disturbances
- Oxidative stress and inflammation
- The kynurenine pathway and neurotransmitter dysregulation
- Mitochondrial dysfunction and related mechanisms
* Methylation
* Detoxification
* Glycolysis
* Citric acid cycle/Krebs
* Oxidative phosphorylation
3. An overview of current treatment options
4. Nutritional intervention – an evidence-based approach
5. Nutritional supplementation

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Managing CFS/ME: a clinical approach

  1. 1. Dr Nina Bailey BSc, MSc, PhD, RNutr 1 Managing CFS/ME: a clinical approach
  2. 2. CFS/ME is a condition that causes fatigue severe enough to interfere with a person’s normal life According to the NHS, it’s estimated that approximately 250,000 people in the UK have CFS/ME The high level of disability that is often associated with this debilitating condition can be both physically and mentally challenging for patients and appears to stem from a combination of symptoms With no current cure and no validated, universally accepted, ‘one-size-fits all’ approach to the treatment, many clients are seeking natural alternatives to conventional approaches
  3. 3. Causes / triggers • Viral / bacterial infections (e.g. glandular fever, pneumonia) • Immune dysfunction (e.g. Th2 dominance, reduced NK-cells) • Mental health problems (e.g. stress or emotional trauma) • Genetic predisposition • Environmental factors (e.g. multiple chemical sensitivity) • Mitochondrial dysfunction
  4. 4. CFS/ME symptoms • Severe fatigue that's not improved by rest and not explained by other causes • Post-exertional malaise, where symptoms get worse after any physical or mental activity • Loss of memory or concentration (brain fog) • Unrefreshing sleep and/or insomnia • Flu-like symptoms • Muscle pain • Frequent headaches • Feeling sick/dizzy/palpitations
  5. 5. ‘energy currency’ Cellular respiration is a 4-stage process in which biochemical energy from nutrients are converted into the energy currency adenosine triphosphate (ATP) ATP consists of an adenine nucleotide (ribose sugar, adenine base and phosphate group, PO4 -2) plus two other phosphate groups The bond that holds the third phosphate molecule is easily broken and when phosphate is removed, energy is released and ATP becomes ADP which must then be ‘recycled’ back to ATP
  6. 6. Pyruvate Acetyl CoA Electron Transport Chain & oxidative phosphorylation Citric acid cycle Glucose Pyruvate Produces 2 ATP Cytosol Mitochondria Lactate Anaerobic fermentation ATP production stops Chest pain & muscle pain Aerobic - moves to mitochondria Produces 2 ATP Produces 34 ATP The final product of glycolysis is pyruvate in aerobic conditions and lactate in anaerobic conditions Net yield aerobic = 38 ATP Net yield anaerobic = 2 ATP GLYCOLYSIS
  7. 7. Glycolysis occurs in the cytosol of the cell and produces pyruvate (from glucose) which is transformed into acetyl-CoA Pyruvate moves from the cytosol to the mitochondria and is converted to acetyl-CoA by the enzyme pyruvate dehydrogenase complex (consisting of three enzymes & five coenzymes) The coenzymes are derived from water-soluble vitamins: • Thiamine pyrophosphate (derived from thiamine) • Nicotinamide adenine dinucleotide (NAD+ [derived from niacin]) • Flavin adenine dinucleotide (FAD [derived from riboflavin]) • Lipoic acid • Coenzyme A (derived from pantothenic acid) Pyruvate Acetyl CoAGlucose Fat (b-oxidation) Protein catabolism
  8. 8.  Mitochondria function to generate ATP (energy rich) from ADP (energy spent) and CFS is characterised by slow recycling of ADP to ATP  The reserves of ATP are generally very low and ADP to ATP ‘recycling’ has to be an efficient process to keep the cell constantly supplied with energy  If ATP is not available, then the body can use ADP instead (by spending one of its phosphate groups) resulting in the production of AMP which, unlike ADP, cannot easily be recycled (2 ADPs = 1 ATP + 1 AMP) meaning that the ADP ‘pool’ (for making ATP) is reduced  When patients overdo things and "hit a brick wall" this is because they have inadequate levels of ATP and ADP
  9. 9. • The transporter facing outwards ('c- state') ‘catches’ an ADP molecule then inverts (‘m-state') to release the ADP into the matrix • An ATP molecule then moves into the 'empty' transporter which inverts, transferring it to the cytoplasm (and the process starts again) • Mitochondrial synthesis of ATP requires ADP transport from cytosol into mitochondria • Transport of ADP into the matrix is required to ensure that there is a level high enough for ATPase to convert it to ATP. Once generated, ATP must then be transported out of the matrix to the cytoplasm • Both ADP and ATP are highly charged (ADP-3 & ATP-4) and cannot diffuse across the membrane but must be actively transported across the membrane and the mitochondrial ADP/ATP ‘transporter’ functions to exchange free ATP with free ADP across the inner mitochondrial membrane (as ATP moves out, ADP moves in)
  10. 10. ADP/ATP transporter inhibition • If this transfer is blocked then ATP and ADP cannot be exchanged • Changes in the acid/base balance will affect the proton-motive force which drives ATP synthesis, thereby reducing ATP synthesis • Compounds which induce calcium efflux from calcium-loaded mitochondria generally provoke membrane leakiness (exacerbated by low magnesium status) • Low magnesium status, the presence of toxic metabolic products (byproducts of viral or bacterial pathogens), cellular debris due to oxidative damage and some environmental chemicals can inhibit the ADP/ATP transporter (explaining the multiple chemical sensitivities experienced by some sufferers) ADP/ATP transporter results in the compensatory activation of glycolysis to pyruvate
  11. 11. Inflammation in CFS/ME • Increased levels of inflammatory cytokines can induce /contribute to glutathione depletion, which, in turn, may activate redox-sensitive transcription factors, such as NF- κB (driving inflammation by triggering pro-inflammatory cytokine production) • Poor sleep quality (common in CFS/ME) has been shown to be associated with greater pro-inflammatory cytokine levels (e.g. IL-1β, IL-6 & TNF-α) and, in turn, greater fatigue, fatigue-related interference with daily activities and more severe and frequent core CFS/ME symptoms • The subsequent ATP deficit together with inflammation and ROS/NOS are responsible for the landmark symptoms of CFS/ME including post-exertional malaise • Depletion of glutathione (high ROS) results in lowered Th1 activity and higher Th2 activity Fletcher MA et al., Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96. Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17. Milrad SF et al., Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women. J Neuroimmunol. 2017 Feb 15;303:43-50 OXIDATIVE STRESS INFLAMMATION
  12. 12. Immune disturbances in ME/CFS • ME/CFS patients routinely present with impaired Th1 function (adaptive immunity critical to antiviral defence), a Th2 shift (innate defence), pro-inflammatory cytokine up-regulation, increase in T- regulatory (Treg) cells and down-regulation of important mediators of cytotoxic cell function (natural killer cells [NK cells]) • Because NK cells play a role in the generation of Th1 immune responses, the loss of NK activity might be related to the presence of a Th2 bias and persistent viral activation and chronic infection that is often seen in CFS/ME (explaining the frequent episodes of flu- like symptoms) Brenu EW et al., Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011 May 28;9:81. Rivas JL, Palencia T, Fernández G, García M.Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Immunol. 2018 May 9;9:1028. Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014 Mar;29(1):19-36
  13. 13. The mitochondrial permeability transition pore • Opening of mPTP aids to eliminate dysfunctional mitochondria by mitophagy (the process by which damaged parts of mitochondria are degraded as a protective mechanism to prevent apoptosis) • Opening of mPTP causes the collapse of the mitochondrial membrane potential which interferes with the production of ATP • This is because the mitochondria requires the electrochemical gradient to provide the driving force for ATP production (pumping H+ through ATPase to provide the energy for the phosphorylation of ADP to make ADP) • Oxidative stress/inflammation/CoQ10 and (or) glutathione deficiency cause mPTP to open • Magnesium also helps to keep the mPTP closed by competing with calcium for the binding sites on the matrix and/or the cytoplasmic side of the mPTP (high calcium can open mPTP) Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012 Sep;25(9):1073-87 Papucci, L., Schiavone, N., Witort, E., Donnini, M., Lapucci, A., Tempestini, A., Formigli, L., Zecchi-Orlandini, S., Orlandini, G., Carella, G., Brancato, R. and Capaccioli, S., 2003. Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial CoQ10 deficient-induced depolarization independently of its free radical scavenging property. Journal of Biological Chemistry, 278(30), pp.28220–28228.
  14. 14. CoQ10, mitochondrial function & ATP • CoQ10 deficiency decreases the numbers of healthy mitochondria – CoQ10 is an essential cofactor for the enzyme dihydrooratate dehydrogenase (DHODH) involved in de novo pyrimidine synthesis that is required for the generation of mitochondrial DNA – reduced gene expression related to mitochondrial biogenesis (related to fision and fusion) • CoQ10 deficiency triggers the opening of the mitochondrial permeability transition pore (mPTP) leading to increased ROS • Opening of mPTP causes the collapse of mitochondrial membrane potential and lowers the production of ATP (mitochondria require an electrochemical gradient to provide the driving force for ATP production) triggering mitophagy • Excessive mitophagy induces ATP-dependent apoptosis (cell death) thereby exacerbating ATP depletion with the potential to induce further production of pro- inflammatory cytokines Rodríguez-Hernández A, Cordero MD, Salviati L, Artuch R, Pineda M, Briones P, Gómez Izquierdo L, Cotán D, Navas P, Sánchez-Alcázar JA. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009 Jan;5(1):19-32.
  15. 15. • ATP production is accompanied by production of ROS as a ‘normal’ by-product through leakage of electrons from the electron transport chain • Low levels of ROS are directly removed by antioxidants (such as ubiquinol) within mitochondria • Because of their role in metabolism, mitochondria are very susceptible to ROS damage and excessive accumulation of ROS during stress damages mitochondrial components including mitochondrial DNA, protein and lipids, which further exacerbates ROS production and mitochondrial dysfunction • Normal mitochondria will eventually accumulate oxidative stress and poor quality mitochondria may enhance cellular oxidative stress, generate apoptosis signals and induce cell death • Owing to their bacterial origin, mitochondria have their own genome and can autoreplicate via ‘mitochondrial biogenesis’ ROS and mitochondria
  16. 16. ROS leads to damaged mitochondria Fission (dissection) Selection Mitophagy (elimination) Autophagosome ROS production also activates pathways to prevent detrimental consequences of ROS by activating pathways and transcription factors that regulate mitochondrial biogenesis Mitochondrial biogenesis Fusion Biogenesis
  17. 17. Biogenesis AMPK: AMP-activated protein kinase; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α AMPK acts as an energy sensor and regulator of biogenesis activating PGC-1α the “master regulator” Fusion of the outer mitochondrial membrane is mediated mitofusins (Mtf 1 & 2), and fusion of the inner membrane mediated by Opa1 mtDNA transcription and replication (e.g. nuclear respiratory factors Nfr1 & Nfr2) Fission is regulated by dymin-1-like protein (Drp1) Mitochondrial bioenergetics and dynamics (balancing fission with fusion)
  18. 18. Biogenesis AMPK: AMP-activated protein kinase; SIRT-1: sirtuin-1; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α AMPK acts as an energy sensor and regulator of biogenesis activating PGC-1α the “master regulator” Fusion of the outer mitochondrial membrane is mediated mitofusins (Mtf 1 & 2), and fusion of the inner membrane mediated by Opa1 mtDNA transcription and replication (e.g. nuclear respiratory factors Nfr1 & Nfr2) CoQ10 deficiency and mitochondrial bioenergetics Low mitochondrial fusion proteins result in increased mitochondrial fragmentation (high numbers of low quality mitochondria) Low mtDHA can also be caused by low CoQ10 which is also an essential cofactor for the enzyme dihydroorotate dehydrogenase (DHODH) involved in de novo pyrimidine synthesis Depleting cells of Drp1 leads to mitochondrial dysfunction (mitochondria cannot fragment), leading to an increase in cellular ROS levels, loss of mtDNA which is accompanied by a drop in cellular ATP levels, a proliferative arrest and apoptosis Fission is regulated by dymin-1-like protein (Drp1)
  19. 19. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-7. Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648. doi: 10.1371/journal.pone.0124648. eCollection 2015. Glutathione Depletion-Methylation Cycle Block Homocysteine is a natural by-product of the methylation cycle and can be remethylated to methionine or directed to the transsulfuration pathway Sulfur containing amino acids (e.g. methionine and cysteine) are extremely sensitive to almost all forms of ROS/RNS which can have direct impact on methylation processes Increased concentrations of homocysteine have been found in the cerebrospinal fluid in patients with ME/CFS/FMS
  20. 20. Methionine recycling Methionine Homocysteine SAM SAH Methionine synthase 5-methyl THF Increased oxidative stress in CFS can cause a partial block of the methylation cycle through inhibition of methionine synthase with a subsequent negative impact on glutathione FOLIC ACID CYCLE Disrupts gene expression Decreased neurotransmitter function Decreased myelination Disrupted cellular energy transfer Disrupted fatty acid metabolism Increased allergic reactions Cystathionine Reduced detoxification of toxins and heavy metals Cysteine Glutathione Metallathionines Affects potent metal- binding and redox capabilities Cysteinesulflinic acid Phenol sulfur- transferase Poor phenol processing Poor digestion Sulphate Sulphite Taurine Production of bile salts SULPHATIONTRANSSULFURATION METHYLATION Gut and blood brain barrier integrity compromised Poor detoxification Inactivates MAT and decreases SAM synthesis Villi flatten and lose function Reduced antioxidant function Th1 decreases Th2 increases S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH); methionine adenosyltransferase (MAT); tetrahydrofolate (THF) THF Glutathione levels drop, ROS increases, with a shift from Th1 to Th2 that leaves the patient immune compromised Chronically impaired detoxification leads to xenobiotic accumulation, increased ROS and inflammation
  21. 21. Increase glutathione levels Up-regulate glutathione-related enzymes including glutathione reductase and glutathione S-transferase Anthocyanins are members of the flavonoid group of phytochemicals, a group predominant in teas, honey, wine, fruits, vegetables, nuts, olive oil & cocoa Cruciferous vegetables such as broccoli, kale and cabbage contain antioxidants that increase the production of detoxifying enzymes in the body Sulphur-rich foods such as onions and garlic, cauliflower, eggs, Brussels sprouts & broccoli Cysteine-rich foods: soya beans, egg white, oats & tofu, providing the body with the balance of nutrients that make (glutathione = L-cysteine + L-glutamic acid + glycine) Increasing glutathione helps keep the mPTP ‘closed’ and by doing this, supports the proton-motive force required to drive ATP synthesis
  22. 22. Inflammation and oxidative stress (IFN-g, TNF-a, IL-1, IL-6 & cortisol) increase the activity of the enzyme IDO which catalyses the oxidation of tryptophan to N-formylkynurenine, kynurenine and the downstream QA Kynurenine Quinolinic acid (QA) NMDA receptor Tryptophan Symptoms Sleep disturbance Depression Low libido Fatigue Brain fog Cognitive dysfunction IDO The NMDA receptor is important for controlling synaptic plasticity and memory function. Magnesium supplementation plays a ‘calming’ role in the regulation of NMDA by acting as a gatekeeper and preventing overstimulation Glutamate (excitatory neurotransmitter) GABA (inhibitory neurotransmitter) Requires vitamin B6 and magnesium Omega-3 EPA & ubiquinol can all reduce the conversion of tryptophan to QA glutamate decarboxylase QA promotes glutamate release and blocks its reuptake leading to overstimulation of NMDA receptors. QA inhibit glutamine synthetase that breaks down glutamate to glutamine. While glutamate is the primary excitatory neurotransmitter, gamma- aminobutyric acid (GABA) is the chief inhibitory neurotransmitter derived from glutamate and that serves to balance glutamate. QA also inhibits the activity of glutamate decarboxylase - an enzyme that catalyses the decarboxylation of glutamate to GABA. QA can decrease the activity of antioxidant enzymes thereby promoting oxidative stress and generating lipid peroxidation. QA inhibits the activity of mitochondrial complexes required for ATP production
  23. 23. While glutamate is the primary excitatory neurotransmitter, gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter that serves to balance glutamate . Therefore both neurotransmitters work together to control many processes, including the brain's overall level of excitation. Magnesium and GABA In addition to low magnesium status, an imbalance between GABA and glutamate is exacerbated by dietary factors, stress & inflammation. Glutamate decarboxylase catalyzes the decarboxylation of glutamate to GABA (requires pyridoxal-5-phostaphate and magnesium as cofactors).
  24. 24. Fatigue Inflammation/ROS/RNS Mitochondrial dysfunction Impaired ETC and oxidative phosphorylation • Reduced citrate synthase activity (an essential enzyme in the citric acid cycle) • Reduced levels of succinate reductase (Complex II) and cytochrome-c oxidase (Complex IV) • Reduced CoQ10 levels Impaired energy production • Dysfunctional ADP/ATP concentration • Low quality mitochondria • Dysfunctional ATP recycling Increased oxidative stress • Low antioxidants (e.g. glutathione, superoxide dismutase, catalase, GSH peroxidase, GSH reductase) • Increased oxidative stress (e.g. ROS/RNS, malondialdehyde, F2-isoprostanes) Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature Maes M, Twisk FN.Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677- 93. Review.
  25. 25. Inflammation, leaky gut and CFS/ME? • NF-kB, proinflammatory cytokines and oxidative and nitrosative stress (ROS/RNS) can lead to a disruption of epithelial tight junctions in the intestine, allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, stimulating TLR4 mediated pathways (hypersensitive microglia often appear in ME/CFS/FMS) • Prolonged and /or excessive stimulation of membrane-bound TLR4 results in the further production of pro-inflammatory cytokines and ROS/RNS • Increasing levels of ROS/RNS damage mitochondrial lipids and proteins leading to dissipation of the mitochondrial membrane potential and inhibition of the electron transport chain • This leads to compromised oxidative phosphorylation and to the further production of ROS, making another major contribution to the inflammatory milieu related to fatigue Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature.BBA Clin. 2014 Jun 1;1:12-23. Schulzke JD, Ploeger S, Amasheh M, Fromm A, Zeissig S, Troeger H, Richter J, Bojarski C, Schumann M, Fromm M. Epithelial tight junctions in intestinal inflammation. Ann N Y Acad Sci. 2009 May;1165:294-300. Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85.
  26. 26. Improving gut health – improve nutrient absorption Several probiotic strains such as Lactobacillus Bacteroides thetaiotaomicron, Bifidobacterium longum and Lactobacillus rhamnosus, Bifidobacterium infantis, Lactobacillus plantarum shown to have beneficial effects on tight junction - and intestinal barrier function  Increasing zonula occludens-1 (ZO-1)  Increased transcription of occludin and cingulin genes  Decreased faecal zonulin levels (a marker indicating enhanced gut permeability)  Decreased proinflammatory cytokines  Short-chain non-digestible carbohydrates (inulin-type fructans, fructo- oligosaccharides (FOS) and galacto-oligosaccharides (GOS)) are the quintessential prebiotics (occurring naturally in cereals, fruits and vegetables) and the target bacterial groups are typically Bifidobacterium and Lactobacillus  Fermented foods like sauerkraut, kimchi, yogurt, kefir  L-glutamine, vitamins A & D (SigA) Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC Regulation of tight junction permeability by intestinal bacteria and dietarycomponents. Nutr. 2011 May;141(5):769-76. Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J Int Soc Sports Nutr. 2012 Sep 20;9(1):45.
  27. 27. Current treatments include  Pain killers (e.g. NSAIDS, COX-2 inhibitors)  Antidepressants (e.g. SSRIs)  Exercise therapy/pacing (balancing activity and rest)  Lightening process® (a combination of osteopathy, life- coaching and brain training)  Cognitive behavioural therapy (CBT)  Lymphatic massage (Perrin Technique)
  28. 28. Tests? • Homocysteine (methylation) • Magnesium (RBC) • B12 (RBC) • Tryptophan/kynurenine ratio • Omega-3 (inflammation) • ATP-profile (mitochondrial function) • Leaky gut
  29. 29. Mitochondrial Function Test (Acumen Laboratory) ATP profiles (3 tests) •Measure the rate at which ATP is recycled in cells (magnesium dependent) •Measure the efficiency with which ATP is made from ADP via the oxidative phosphorylation process (can be linked to magnesium deficiency and/or low levels of Co-enzyme Q10 and/or low levels of vitamin B3 and/or low levels of acetyl L-carnitine) •Measure the efficiency for the transfer of ATP from the mitochondria into the cytosol where it can release its energy as needed Additional tests •Nicotinamide adenine dinucleotide (NAD+/functional B3) – metabolic cofactor •Superoxide dismutase (SODase) - superoxide free radical scavenger •L-carnitine – transports long-chain fatty acids into the mitochondria •Cell-free DNA – a marker of tissue injury •Glutathione peroxidase – major endogenous antioxidant •Coenzyme Q10 – antioxidant and critical component of the electron transfer chain Booth NE, Myhill S, McLaren-Howard J.Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20. Myhill S, Booth NE, McLaren-Howard J.Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
  30. 30. Nutritional interventions for CFS/ME can target: Mitochondrial dysfunction in CFS/ME • Deficiency in substrate • Inhibition of function Mechanisms related to mitochondrial function/dysfunction • Methylation • Detoxification • Glycolysis • Citric acid cycle/Krebs • Electron transport chain • Oxidative phosphorylation • ADP/ATP transporter • Mitochondrial permeability transition pore (mPTP) Mitochondrial biogenesis • Changes in mitochondrial numbers, size and/or shape Booth NE, Myhill S, McLaren-Howard J.Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20. Myhill S, Booth NE, McLaren-Howard J.Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
  31. 31. Interventions for CFS/ME Remove the trigger Restore function (nutrition)
  32. 32. Increase mitochondrial biogenesis Activating pathways and transcription factors (e.g. AMPK, SIRT1 & PGC-1a) via diet and exercise increases mitochondrial biogenesis and controls mitochondrial DNA (mtDNA) replication Exercise Nitric oxide NAD+ Cold treatment Ubiquinol EPA, DHA & CLA Calorie restriction/intermittent fasting Polyphenols (e.g. resveratrol, EGCG & curcumin) AMPK: AMP-activated protein kinase; SIRT-1: sirtuin-1; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α
  33. 33. Enzyme function (many involved in energy) ATP-Mg (as the primary source of energy in cells, ATP must be bound to a magnesium ion to be biologically active) Protein kinase B (plays a crucial role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration Hexokinase (glycolysis) Creatine kinase (plays a major role in the production of energy) Protein kinase (involved in phosphorylation –’switching on’) ATPases & GTPases (involved in de-phosphorylation – ‘switching off’) Na+ /K+-ATPase (involved in sodium/potassium regulation) Ca2+-ATPase (involved in calcium regulation) Adenylate cyclase (intracellular signalling – catalyses ATP into the secondary messenger cAMP) Guanylate cyclase (involved in vasodilation [and therefore blood pressure regulation]) Phosphofructokinase (activated by magnesium and then phosphorylates fructose 6-phosphate in glycolysis and therefore ATP production) Creatine kinase (catalyzes the conversion of phosphocreatine, the energy reservoir for regeneration of ATP) 5-Phosphoribosyl-pyrophosphate synthetase (converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP) which provides the ribose sugar for the synthesis of purines and pyrimidines, used in the nucleotide bases that make up DNA & RNA) ATP, adenosine triphosphate; GTP, guanosine triphosphate; K, potassium; Mg, magnesium; Na, sodium; Ca, calcium. Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J. 2012 Feb;5(Suppl 1):i3-i14. Restore magnesium
  34. 34. • ADVANCED TRIPLE MAGNESIUM BLEND: combining magnesium citrate, taurate and bisglycinate enhances magnesium absorption by utilising multiple magnesium uptake pathways, avoiding saturation. Taurine and glycine are highly effective carriers for magnesium. • FULLY REACTED FORMULA: only fully reacted (not blended or buffered) magnesium forms are free from poorly absorbed magnesium oxide. The enhanced solubility of these fully reacted magnesium forms optimises absorption potential. • MULTIPLE HEALTH BENEFITS: magnesium supports normal energy release, muscle function, electrolyte balance, nervous system function and normal psychological function. • CONSISTENT PRODUCT QUALITY GUARANTEED: manufactured in the UK in GMP-accredited facilities.
  35. 35. • FULL TRANPARENCY: unlike many of our competitors who combine two or more magnesium sources without disclosing the ratios (which can mislead consumers into thinking a product is high in a specific magnesium), we list the bulk and elemental amounts of each of our magnesiums. • NO UNNECESSARY FILLERS: we choose to encapsulate our magnesium to avoid the use of bulking agents commonly found in tablets. • SPLIT DOSING FOR ENHANCED UPTAKE: as the relative absorption of magnesium is inversely related to the ingested dose, magnesium absorption is significantly improved by taking smaller doses throughout the day. • WE DELIVER 52 % RI: because it’s not how much you take, but how much you retain. Excess magnesium cannot be stored and our ethos is to focus on efficacy of delivery by tripling our magnesium with the most absorbable and synergistic ‘carriers’ that target multiple, unopposed uptake pathways.
  36. 36. ‘RESTORE’ pure EPA ‘MAINTAIN’ EPA, DHA and GLA Minimum 3-6 months  AA to EPA ratio  Inflammatory regulation  Symptoms of inflammatory illness  Optimum brain, cell, heart, immune and CNS function  Optimum wellbeing  Omega-3 index  AA to EPA ratio  Long-term general and cellular health  Heart, brain and eye health  Reduce risk of chronic illness and help protect against inflammatory disease Therapeutic role of Pharmepa® RESTORE & MAINTAIN™
  37. 37. Primary structural function & anti-inflammatory docosanoid production Resolvins Protectins Anti-inflammatory eicosanoid production REDUCED INFLAMMATION Series-3 prostaglandins Series-3 thromboxanes Series-5 leukotrienes Hydroxy fatty acids Resolvins DHA Anti-inflammatory eicosanoid production REDUCED INFLAMMATION Series-1 prostaglandins Series -1 thromboxanes DGLA GLA LA EPA ETA SDA ALA Delta -6 desaturase Elongase/ desaturaseDelta -5 desaturase Cyclooxygenase (COX)/lipoxygenase (LOX) Elongase Pro-inflammatory eicosanoid production INFLAMMATION Series-2 prostaglandins Series-2 thromboxanes Series-4 leukotrienes Hydroxy fatty acids AA COX/LOX COX Pro-resolving Lipoxins Omega-6 Omega-3 Elongase enzyme requirements Niacin (B3) Pyridoxial-5-phosphate (B6) Pantothenic acid (B5) Biotin (B7) Vitamin C Desaturase enzyme requirements Flavin adenine dinucleotide (FAD) Riboflavin (B2) Niacin (B3) Pyridoxial-5-phosphate (B6) Vitamin C Zinc Magnesium
  38. 38. Astaxanthin inhibits oxidative stress-induced mitochondrial dysfunction Kim SH, Kim H. Inhibitory Effect of Astaxanthin on Oxidative Stress-Induced Mitochondrial Dysfunction-A Mini-Review. Nutrients. 2018 Aug 21;10(9) Pashkow FJ, Watumull DG, Campbell CL. Astaxanthin: a novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am J Cardiol 2008;101(suppl):58D-68D Kidd P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev. 2011 Dec;16(4):355-64. Review
  39. 39. INGREDIENTS: Cold-pressed extra-virgin olive oil; AstaPure® from Haematococcus pluvialis (H. pluvialis) microalgae (10% astaxanthin); capsule shell (gelatine, glycerol, beta-carotene, caramel E150a). Astaxanthin’s ROS-scavenging capacity has been shown to be 6000x more than vitamin C, 800x more than coenzyme Q10, 550x more than vitamin E, 200x more than polyphenols, 150x more than anthocyanins, and 75x more than alpha lipoic acid - the majority of the research to date used between 2 mg and 24 mg of astaxanthin daily Nishida Y., Yamashita E., Miki W. Quenching activities of common hydrophilic and lipophilic antioxidants against singlet oxygen using chemiluminescence detection system. Carotenoid Science. 2007;11(6):16–20. Nutritional information Per capsule AstaPure® Haematococcus pluvialis microalgae (10% astaxanthin complex) 42 mg of which astaxanthin 4 mg of which lutein 36 mg of which canthaxanthin 20 mg of which zeaxanthin 3 mg of which violaxanthin 0.5 mg
  40. 40. CoQ10 is a powerful, fat-soluble, vitamin-like substance • Two main functions: • Energy production – cellular respiration • Antioxidant/antioxidant recycling CoQ10 – ubiqinone vs ubiquinol  Ubiquinone – oxidised form  Ubiquinol – reduced form 96% of CoQ10 within the body is in the form of ubiquinol Ubiquinol is considered the active form of CoQ10 Ubiquinol wasn’t available in supplements until 2006 - not only is it more absorbable than ubiquinone but may also exhibit better neuroprotective effects than ubiquinone Langsjoen PH, Langsjoen AM. Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin Pharmacol Drug Dev. 2014 Jan;3(1):13-7
  41. 41. VESIsorbTM Oil-based Time (hours) AUC(0-10hours)mg/mL*h PlasmaCoQ10(mg/mL) VESIsorbTM Therapeutic level VESIsorbTM delivered CoQ10 is absorbed FASTER, reaching concentrations that are STRONGER and stays in the body LONGER than generic delivery methods  Fully reduced form of CoQ10  VESIsorb® technology for enhanced bioavailability and tissue distribution  100 mg therapeutic dose 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Oil-based Cmax Tmax
  42. 42. • CoQ10 synthesis is a complex, multi-step process, requiring several vitamin cofactors (including vitamin B2 [riboflavin], vitamin B3 [nicotinamide], vitamin B5 [pantothenic acid], vitamin B6 [pyridoxal-5- phosphate], vitamin B9 [folic acid], vitamin B12 [methylcobalamin] and vitamin C) as well as several trace elements • A deficiency in, or low intake of, any of these nutrients has the potential for negative impact on CoQ10 levels • The first step in CoQ10 synthesis is biosynthesis of the quinone nucleus of CoQ10 from the amino acid tyrosine, a step requiring vitamin B6 (specifically in the form of pyridoxal-5-phosphate) • It is well established that this initial step is dependent on vitamin B6 and that low vitamin B6 status has a direct negative impact on blood levels of CoQ10 Willis R, Anthony M, Sun L, Honse Y, Qiao G. Clinical implications of the correlation between coenzyme Q10 and vitamin B6 status. Biofactors. 1999;9(2-4):359-363
  43. 43. Nutritional information Per dose % RI* Vitamin C (ascorbic acid) 160 mg 200 Vitamin B3 (niacin) 48 mg 300 Vitamin B5 (pantothenic acid) 36 mg 600 Vitamin B1 (thiamine ) 20 mg 1818 Vitamin B6 (pyridoxal-5-phosphate) 20 mg 1429 Vitamin B2 (riboflavin-5-phosphate 14 mg 1000 Vitamin B12 (methylcobalamin) 900 mg 36000 Folate ([6S]-5-methyltetrahydrofolate) 400 mg 200 Vitamin B7 (biotin) 300 mg 600 *Reference Intake; Quatrefolic® is a registered trademark owned by Gnosis S.p.A. Methylation support BIOAVAILABLE FORMS: Super B-Complex delivers maximum levels of key nutrients: ​Quatrefolic® provides the body-ready form of folate, as [6S]-5-methyltetrahydrofolate the active form of riboflavin, riboflavin-5-phosphate vitamin B6 as pyridoxal-5-phosphate with cofactor activity vitamin B12 as methylcobalamin, for enhanced uptake HIGH DOSE B6, B12 & folate support efficient homocysteine metabolism and methylation pathways, for heart health & brain function SPLIT DOSE FOR ENHANCED ABSORPTION: vitamin B12 uptake is optimised by taking tablets twice daily, morning & evening SUSTAINED RELEASE: offers longer-lasting action
  44. 44. Protocol summary  Increase mitochondrial biogenesis  Reduce inflammation  Reduce oxidative stress  Support methylation  Support detoxification  Improve energy via ATP production
  45. 45. Dosing guide The Opti-O-3 biomarker test is highly effective when used in conjunction with our therapeutic range of supplements. By identifying the actual dose required to achieve an omega-3 index of ≥8% and an AA to EPA ratio of 1.5-3:1, it offers the ideal solution to personalised nutrition. Product Dose Duration Pharmepa RESTORE* 4 x 1 capsule daily 6-12 months Pharmepa MAINTAIN* 3 x 1 capsule daily Follow on from RESTORE Super-B Complex 2 x 1 tablet daily 6 months minimum VESIsorb® Ubiquinol 2 capsules daily 6 months minimum Triple Magnesium Complex 3 x 1 capsule daily 6 months minimum Astaxanthin 1 capsule daily 6 months minimum *Suggested minimum doses when it is not possible to use the Opti-O-3 biomarker test. Capsules and tablets should be taken as a split-dose and with food for optimum absorption and to improve bioavailability
  46. 46. Extra reading?
  47. 47. Get in touch! Dr Nina Bailey Head of Nutrition ninab@igennus.com Twitter @DrNinaBailey
  • HalaKaaki

    Jun. 12, 2020
  • JanePugh1

    Apr. 29, 2019

Around 250,000 people in the UK are currently thought to be affected by CFS/ME. The high level of disability that is often associated with this debilitating condition can be both physically and mentally challenging for patients and appears to stem from a combination of symptoms such as fatigue, pain, sleep disturbance, cognitive impairment, depression and, in many cases, symptoms mirroring those of irritable bowel syndrome. With no current cure and no validated, universally accepted, ‘one-size-fits-all’ approach to the treatment, many clients are seeking natural alternatives to conventional approaches. Taking a personalised and functional medicine approach, Dr Nina Bailey reviews the latest science on ME/CFS and the underlying mechanisms that can be targeted with nutritional interventions and explains how to ensure your therapeutic approach is right for your clients. Covered in the webinar: 1. CFS/ME background /causes/symptoms 2. Update on the mechanisms associated with CFS/ME: - Immune disturbances - Oxidative stress and inflammation - The kynurenine pathway and neurotransmitter dysregulation - Mitochondrial dysfunction and related mechanisms * Methylation * Detoxification * Glycolysis * Citric acid cycle/Krebs * Oxidative phosphorylation 3. An overview of current treatment options 4. Nutritional intervention – an evidence-based approach 5. Nutritional supplementation

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