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  1. 1. “Senza il pane tutto diventa orfano” Gluten Sensitivity, (Without bread everyone’s an orphan) Coeliac Disease and Chronic Brain Syndromes Along with dairy products, wheat has become the most James Braly, MD commonly eaten food in the USA and UK….
  2. 2. Gluten is an elastic, malleable, storage protein found in all gluten grains. Gluten is composed of two smaller proteins called peptides or prolamines. Glutenin is one peptide and the other peptide, gliadin, is responsible for Coeliac Disease.
  3. 3. Gluten grains Wheat Rye Barley Oats (contains gluten but not gliadin) Spelt Kamut Triticale
  4. 4. Non-gluten grains Corn Rice Amaranth Quinoa Flaxseed Millet Buckwheat Teff
  5. 5. Key historical events in the early domestication of gluten grains Ancestors & Events Time Period Location Cereal-less homo sapiens 500,000 – 8,000 BC Worldwide First Wheat Farmers 8,000 BC Near East 3,500 BC England Domestication of Wheat & Barley 8,000 BC Near East Domestication of Rye 3,000 BC SW Asia Domestication of Oats 1,000 BC Europe
  6. 6. Wheat & Dairy Products Dominant U.S. Diet Today Top nine American foods rated by calories eaten annually Whole cow’s milk 7. Refined sugars (accounts 2% cow’s milk for 10% to 20% of all calories) Processed American 8. Soda, fruit juice (more soda cheese consumed each year in the U.S. & England than water - 20% of all calories now consumed as White wheat bread liquids) White wheat flour 9. Ground beef (grain-fed) Wheat rolls U.S. Department of Agriculture
  7. 7. “From great hunters & meat eaters to canaries in only 10,000 years.” Harlan JR: Crops and Man (1992) American Society of Agronomy
  8. 8. Gluten, Coeliac Disease & Cancer “Malignancy may be the first manifestation of subclinical [silent] coeliac disease.” Cronin & Shanahan Lancet, April 12, 1997; 349: 1096-1097.
  9. 9. “Overall mortality in adult coeliacs is approximately twice that of the general population, mostly due to cancer deaths…Deaths are greatest within the first year of diagnosis.” Logan RF et al. Mortality in coeliac disease. Gastroenterology, 1989 Aug; 97(2):265-271.
  10. 10. Coeliac disease affects ~2.5 million in USA (more than twice as common as ulcerative colitis, Crohn’s disease, Down’s syndrome, multiple sclerosis, & cystic fibrosis combined) Ulcerative colitis 500,000 Crohn's disease 500,000 Down’s syndrome 350,000 Multiple sclerosis 333,000 Cystic fibrosis 30,000 Total = 1,713,000 Source: National Institute of Health
  11. 11. Coeliac disease genetically linked to many autoimmune diseases, including: Thyroid disease (Hashimoto’s thyroiditis, Graves disease) Insulin-dependent diabetes Rheumatoid arthritis Psoriasis & psoriatic arthritis Autoimmune liver disease Systemic lupus erythematosus Sjogren’s syndrome (dry eyes, dry mouth & rheumatoid arthritis)
  12. 12. Coeliac disease is the most common autoimmune genetic disorder in Europe, United Kingdom, and the United States.
  13. 13. “Untreated coeliac disease increases the risk of over 185 different medical conditions, including many chronic brain disorders in children & adults.” Braly & Hoggan. Dangerous Grains Penguin Putnam, 2003.
  14. 14. Gluten Sensitivity, Coeliac disease and the Brain Weepy, irritable children Irritable bowel syndrome Autism Depression ADHD Epilepsy Down’s syndrome Schizophrenia Low IQ children & maternal thyroid disease
  15. 15. What is Coeliac Disease? (“The great modern-day imposter”) A genetic, autoimmune disorder caused by sensitivity to gluten, a protein found in wheat, barley, rye, (oats), spelt, kamut and triticale. Gluten-caused inflammation results in damage to mucosal lining of the small intestine, bringing about both autoimmune diseases and malabsorption of essential nutrients.
  16. 16. Normal small intestinal villi
  17. 17. Surface area of the inside lining of the small intestine is size of a tennis court…
  18. 18. Intestinal lesions according to the Marsh Classification
  19. 19. Total Villous Atrophy “Flat Gut” of Coeliac Disease
  20. 20. Coeliac disease & malnutrition Iron deficiency & anemia Folate deficiency & anemia Vitamin B12 deficiency & anemia Vitamin B6 (pyridoxine) deficiency Vitamin B2 (riboflavin) deficiency Vitamin B1 (thiamine) deficiency Vitamin A deficiency Vitamin D & calcium deficiencies Magnesium & potassium deficiencies Zinc deficiency Selenium deficiency Vitamin K deficiency Essential fatty acids deficiencies (omega-3 & omega-6 fatty acids, the most commonly & severely affected nutrients)
  21. 21. A good set of stomach and bowels is more important to human health and happiness than a large amount of brains…
  22. 22. Coeliac Disease, a worldwide problem Studies have expanded to other regional areas, including Middle East, North Africa, India, Asia, Oceania, and South America where coeliac disease is now recognized as a frequent condition affecting approximately 0.5 to 1 percent of the general population, almost the same as that in Western countries Catassi C et al. The Global Village of Celiac Disease. Basel, Switzerland: Karger Press; 2005. Alencar ML et al. Prevalence of celiac disease among blood donors in Sao Paulo City, Brazil. Gastroenterology. 2006; vol 130:A-668. [#S1110] Mendez-Sanchez N et al. Seroprevalence of anti-gliadin and anti-endomysium antibodies in Mexican adults. Gastroenterology. 2006; vol 130:A-155.
  23. 23. Coeliac disease is now thought to have a prevalence of between 1:100 and 1:200 in the UK population. Hourigan CS. The molecular basis of coeliac disease. Clin Exp Med. 2006 June; vol 6(2): pp53-59
  24. 24. Prevalence of Coeliac Disease among American adults & children 1 : 111 of the 2,785 healthy, asymptomatic adults tested had coeliac disease 1 : 167 of the 1505 healthy, asymptomatic children tested had coeliac disease Gerarduzzi T, et al. J Pediatric Gastroenterology and Nutrition 2000; volume 31 (Suppl.3): S29.
  25. 25. Prevalence of coeliac disease among of high risk groups Children testing positive for both IgG and IgA anti-gliadin antibodies….… 90:100 Identical twins………………................ 70:100 HLA-identical siblings……………….. 30:100 First-degree relatives…...................... 22:100 Down’s syndrome…………………….. 16:100 Autoimmune thyroid disease……….. 14:100 Insulin-dependent diabetes…….…… 11:100
  26. 26. Other at-risk for coeliac groups Children testing positive for only IgG antigliadin antibodies………………. 7.7:100 Osteoporosis………………………….… 4.5:100 Irritable bowel syndrome……………… 3.3:100 Second-degree relatives…………….… 3:100 Iron deficiency anemia………………… 2.8:100 ADHD……………………………………… 2.5:100 Women with recurring pregnancies of poor outcomes ……………………. 2:100
  27. 27. Four Types of Coeliac Disease Clinical – symptomatic, positive serology & positive small intestine biopsy for coeliac disease Silent – asymptomatic even on gluten diet, but with positive serology & positive intestinal biopsy Latent – asymptomatic, positive IgG/IgA anti- gliadin antibodies, but negative intestinal biopsy Abortive – biopsy-proven coeliac disease which remits for some unknown reason
  28. 28. Clinical, symptomatic coeliac disease, the tip of the iceberg Clinical CD (positive serology, symptoms, flat gut) Silent CD (positive serology, no symptoms, flat gut) Latent CD (positive serology, no symptoms & normal mucosa--later converts)
  29. 29. Gluten sensitivity, coeliac disease and chronic brain syndromes Weepy, irritable children Irritable bowel syndrome Autism Depression ADHD Epilepsy Downs syndrome Schizophrenia Low IQ children & maternal thyroid disease
  30. 30. WEEPY, IRRITABLE, UNHAPPY CHILDREN Coeliac children are often weepy, often discontented or surly, quiet, turned inward, and apparently lack all joy in living. Kaser. J of Pediatrics 1961
  31. 31. Coeliac children often have foul smelling stools, occasionally big and bulky stools. A small number of children will develop severe diarrhea.
  32. 32. Children with strong food cravings, including for bread, crackers, & cereals…
  33. 33. Gluten Allergy – Gluten Addiction Possible mechanisms of addiction include: Gluten sensitivity often results in significant serotonin, norepinephrine, and dopamine depletion, the same brain neurochemistry often associated with addictive behavior. Gluten sensitivity suppresses gut hormone release (secretin, VIP, & CCK), adversely affecting cognition, emotions, appetite/satiation, and behavior.
  34. 34. Gluten’s mood & behavior modulating morphine-like peptides When gluten is broken down in the intestines during digestion, opioid-like peptides are formed; specifically, certain peptides, called Gluteomorphin and Gliadorphin, mimic the effects of morphine on the brain as they enter the bloodstream.
  35. 35. Irritable bowel syndrome in children Irritable bowel syndrome (IBS) is a digestive disorder that causes abdominal pain, bloating, gas, diarrhea, and constipation—or some combination of these problems. IBS physically and psychologically affects people of all ages, including children.
  36. 36. Irritable bowel syndrome (IBS), depression, anxiety & panic attacks There is an association of panic disorder with IBS symptoms (1/3 of patients presenting with panic disorder have IBS symptoms) Chronically constipated patients with IBS as a group are more anxious and more depressed than the general population
  37. 37. Link between IBS symptoms & IgG-mediated food allergy Recent evidence suggests significant reduction in IBS symptom severity in patients on elimination diets, provided that dietary elimination is based on foods against which the individual has generated food-specific IgG antibodies. Isolauri E et al. Gut. 2004 Oct;53(10):1391-1393
  38. 38. Up to one-third of all coeliac disease patients have been previously diagnosed with IBS &/or lactose intolerant.
  39. 39. IBS children at higher risk of coeliac disease The prevalence of undiagnosed coeliac disease in irritable bowel syndrome was 3.3% (4 out of 123 tested). Sanders DS et al. Eur J Gastroenterol Hepatol. 2003;15:407-413.
  40. 40. Depression is a common presenting symptom of coeliac disease. Hallert C et. al. Scandinavian J of Gastroenterology, 1982.
  41. 41. Over two-thirds of depressed people are not responsive to any prescription anti-depressants now available.
  42. 42. In December 2004 Britain's drug regulatory agency issued a report that warned that all SSRIs "may be associated with withdrawal" and noted that Paxil and Effexor "seem to be associated with a greater frequency of withdrawal reactions."
  43. 43. Depression & Coeliac Disease In all 3 biopsy-proven coeliac teenagers, depressive symptoms improved quickly on a gluten-free diet. “Coeliac disease should be considered in the presence of depression, particularly if not responsive to the usual antidepressant therapy.” Corvaglia et al. American Journal of Gastroenterol, 1999.
  44. 44. Depression-coeliac disease clusters Both depression and coeliac disease are found more often in: Hypothyroidism Insulin-dependent diabetes IBS, depression, anxiety and panic attacks Osteoporosis Problem pregnancies Heart attacks Migraine headaches
  45. 45. Omega-3 fatty acids & depression: A review of the evidence In controlled studies, concentrations of omega-3 fatty acids were lower in participants with unipolar and postpartum depression. Infrequent fish consumption (the major source of omega-3 fatty acids) is associated with depression in epidemiological studies. In four of seven double-blind, randomized controlled trials, depression was significantly improved with at least 1 gram a day of EPA fish oil. Sontrop J et al. Preventive Medicine. 2006 Jan; 42(1): 4-13.
  46. 46. Alternative Therapies for Depression Staying clean & sober Fish oil (DHA & EPA) Folic acid, B12, B6 Oily fish 2-3X/week NADH Daily sunlight 5-HTP + B6 Daily exercise L-Tryptophan + B6 L-Tyrosine + B6 Deep, restful sleep SAMe Reduce refined sugars St. John’s Wort (std) Zinc Ginkgo biloba (std) Magnesium Gluten-free diet for Others… depressed gluten sensitive clients
  47. 47. As high as 1 in six Down’s syndrome subjects have coeliac disease…
  48. 48. “It is recommended that children with Down’s syndrome be screened for coeliac disease.” 10% of first-degree relatives of coeliac Down’s children test positive for coeliac disease. Book L et al. Am J Med Genetics 2001 Jan; vol 98: pages 70-74.
  49. 49. Coeliac-related diseases commonly found in Down’s syndrome individuals Epilepsy occurs in 5-10% of all Down’s syndrome subjects About 15% suffer from autoimmune thyroid disease (hypo- and hyperthyroidism) Suffer higher incidence of Type 1 diabetes than the general population Shortness/small stature Some Down’s individual suffer from autism Short 5th finger
  50. 50. Short 5th Finger Is often observed in • Down’s syndrome • Coeliac disease • Autoimmune hypo- & hyperthyroidism ↔ distal joint ring finger
  51. 51. Short Fifth Finger & Autoimmune Thyroid Disease Ber. A. Fingers and toes in Endocrinology, Endokrynologia Polska 1956; volume 7: page 9. O’Donovan DK, O’Sullivan J. Hyperthyroidism with fifth finger abnormalities. Irish J Med Sci, 6th series 1996; volume 491: p 540.
  52. 52. “It is advisable to screen all autoimmune thyroid disease patients for coeliac disease…” Sategna-Guidetti C et al. Eur J Gastroenterol Hepatol, 1998. Coeliac disease occurs up to 14 times more frequently in patients with autoimmune thyroid disease (14:100) than in normal patients. Not T et al. Dig Dis Sci 2000; volume 45: pages 403-406.
  53. 53. Low IQ children & mothers with autoimmune thyroid disease Approximately one out of every 50 women in the UK & U.S. is thyroid deficient during pregnancy.
  54. 54. Hypothyroidism during pregnancy, risk of miscarriage & low IQ children Women with untreated thyroid deficiency during pregnancy are four times more likely to have children with lower I.Q. scores. Nineteen percent of the children whose mothers had undiagnosed hypothyroidism during pregnancy averaged 85 or less on their I.Q. tests. Children who have an I.Q. less than 85 are more likely to have difficulties in school, and may be less successful in their careers and interpersonal relationships. Allan W et al. Journal of Medical Screening, Nov 2002 (specialty publication of the British Medical Journal ) Allan W et al. New England Journal of Medicine, August 18, 1999.
  55. 55. Egger’s Epilepsy with Migraine &/or Hyperactivity Study The Subjects of the Study: 63 of epileptic children were included in the study. 18 of the 63 children had seizures every day; 11 had seizures several times a week; and 5 had weekly seizures. 46 children entered the study on anti-convulsive medication, 36 of whom were “poor responders” to the drugs. 45 of the 63 children had epilepsy with migraine headaches and/or hyperactivity; 18 of the 63 children had epilepsy without headaches or hyperactivity.
  56. 56. Epilepsy with Migraine &/or Hyperactivity Study, continued… 25 of 45 children with epilepsy, migraines and/or hyperactivity (55.5%) completely stopped having seizures; 11 of the same 45 (24.4%) had significantly fewer seizures (80% were responders). 19 of 46 children who entered the study on anti-seizure medication were able to completely stop medication. None of the 18 epileptic children without a history of migraines and/or hyperactivity responded with fewer seizures. Egger et al. Journal of Pediatrics 1989; 114(1): 51-58
  57. 57. Four Most Frequent Seizure-Provoking Foods Foods # of children % with seizures tested to foods eaten Cow milk 35..…...…........37% Cow cheese 11..........………36 Citrus fruits 24......…………29 Wheat 35....…..........29%
  58. 58. Autism much more common than once thought Autism and similar disorders may affect up to one in 100 children, UK researchers now suggest. "Prevalence of autism and related autism spectrum disorders (ASDs) is substantially higher than previously recognized.” Professor Gillian Baird et al. Guy's and St Thomas' Hospital, London The Lancet. July 2006
  59. 59. Change in symptoms in 70 autistic children following a gluten/casein-free diet are shown below. Mean scores were recorded for 8 common autistic symptoms. 0-Normal, 1-Good, 2-Fair, 3-Poor, & 4-Very Poor - - - On Diet - - - Control 1 month 3 mo 6 mo 12 months Social Isolation: 3.5 2.9 1.9 1.4 1.4 Eye Contact: 3.2 2.4 2.7 1.2 1.2 Mutism: 2.8 2.1 1.5 0.9 0.8 Learning Skills: 3.3 2.8 2.1 1.6 1.2 Hyperactivity: 3.1 2.1 1.7 1.6 1.5 Stereotypic activity: 3.3 2.8 2.1 1.5 1.1 Self-Mutilation: 0.63 0.57 0.37 0.47 0.30 Panic Attacks: 1.5 1.3 0.80 0.83 0.45 J. Robert Cade, M.D. Professor of Medicine and Physiology, U. of Florida -
  60. 60. ADHD and food allergy “An elimination diet is effective in most cases [of ADHD]…behavior often reverts to normal to the great relief of all concerned…In view of the potential toxicity of medications in [ADHD] children, all families with hyperactive children should be offered help in detecting offending foods. It is more appropriate to reserve medication in those who fail.” Anthony HM et al. Archives of Disease in Childhood 1999; 81: 189.
  61. 61. ADHD and food allergy 62 of 76 (81%) severely hyperactive children improved on an oligoantigenic (few, hypoallergenic foods); other symptoms such as migraines, epilepsy, abdominal pain, conduct disorders, growing pain, etc. also improved. Egger J et al. The Lancet, March 9, 1985
  62. 62. Before change in diet On diet 1) antisocial 32 13 2) headaches 48 9 3) seizures/fits 14 1 4) abdominal pain 54 8 5) chronic rhinitis 33 9 6) leg aches 33 6 7) skin rashes 28 9 8) mouth ulcers 15 5 9) emotional problems 7 0 10) Mean Conner’s score 24 12
  63. 63. Gluten sensitivity and ADHD Foods # of ADHD kids tested # and % of kids Tested to food items that reacted Food dyes/additives 34 27 (79%) Soya 15 11 (73%) Cow’s milk 55 35 (64%) Chocolate 34 20 (59%) Grapes 18 9 (50%) Wheat 53 28 (49%) Rye 29 15 (52%)
  64. 64. Coeliac Disease & Schizophrenia Coeliac disease victims are three times more likely to develop schizophrenia than those without the disease, according to Danish and Johns Hopkins School of Public Health researchers. British Medical Journal. February 21, 2004
  65. 65. Gluten sensitivity & schizophrenics A double-blind control trial of gluten-free versus a gluten-containing diet was carried out in a ward of maximum security hospital: 24 patients were studied for 14 weeks. Most suffered from psychotic disorders, particularly schizophrenia. Two patients (8%) improved during the gluten-free period and relapsed when the gluten diet was reintroduced. Vlissides DN et al. A double-blind gluten-free/ gluten-load controlled trial in a secure ward population. Br J Psychiatry 1986 April;48:447-452.
  66. 66. Casein & gliadin polypeptides in the urine of schizophrenics & autistic children 95% of patients with schizophrenia or childhood autism have a significant hyperpolypeptiduria. All of these patients have a greatly increased amount of peptides derived from either casein or gliadin.
  67. 67. Wheat polypeptides in urine of schizophrenics & autistic children, continued… The degree of the polypeptiduria can be decreased by either dialysis, diet or the two in combination. As the polypeptiduria decreases, the symptoms of schizophrenia or autism decreases. If the polypeptiduria can be reduced to normal range, most patients either improve dramatically or become completely normal.
  68. 68. Gliadorphin and IgG anti-casein & anti-gluten antibodies Gliadorphin was found in very large amounts in 48% of schizophrenics and 54% of autistic patients, while it was found in 32% of normals in very small amounts. Among autistic children, 87% had high titer IgG antibodies to gluten and 90% to casein, while among schizophrenic patients, 86% had high titer IgG antibodies to gluten and 93% to casein. J. Robert Cade, M.D. Professor of Medicine and Physiology, U. of Florida -
  69. 69. 80 out of every 100 coeliacs remain undiagnosed in England. 97 out of every 100 coeliacs remain undiagnosed in America
  70. 70. “The rate of diagnosis of coeliac disease is proportional to suspicion." Joseph Murray, MD Associate Professor of Medicine University of Iowa Hospitals and Clinics
  71. 71. Testing for coeliac disease In the past 2 decades, a number of accurate blood tests have been developed that now have a definitive role in the coeliac disease diagnostic process.
  72. 72. Blood tests for diagnosis of coeliac disease Total serum IgA IgG & IgA anti-gliadin antibodies (AGA) IgA endomysial antibodies (EMA) IgA (IgG if IgA deficient) anti-tissue transglutaminase antibodies (tTG)
  73. 73. Two Key Steps Needed to Diagnose Coeliac Disease 1. Begin with a high degree of suspicion 2. Commit to routinely testing high risk candidates whether symptomatic or not; if initial tests are negative, commit to retesting every few years (concern here with retesting is with latent coeliac disease in high risk patients)
  74. 74. A 10 minute In-Office or Self-Test The first self-test for coeliac disease is now available in Europe and England. Speeds up diagnosis with a kit that lets people self-test with a finger pinprick blood sample, with results in under 10 minutes. “Results are as accurate as a doctor’s or lab blood test which needs a GP consultation and a 7 day wait for results.”
  75. 75. Accuracy of new medical office tests for coeliac disease These two commercial kits (rapid detection of IgA anti-human-transglutaminase antibodies (tTG) in serum and tTG antibodies in one drop of whole blood) produced sensitivities of 96-100% and specificities of 95-100%, offering the general practitioner a means of quickly and easily looking for coeliac disease his own office during a standard visit at a low cost. Nemec G et al. Am J Gastroenterology. 2006 July;101(7):1597-600.
  76. 76. THERAPY FOR COELIAC DISEASE There is no cure for coeliac disease. The only treatment of coeliac disease is a strict, life-long, gluten- free diet.
  77. 77. New digestive enzyme therapy for Coeliacs An enzyme in barley seeds, EP-B2, normally digests gluten proteins. A recombinant form of EP-B2 has now been produced that only activates under acidic conditions similar to the conditions found in the human stomach. EP-B2 efficiently digests gluten protein and is most specific for those parts of gluten that are known to trigger coeliac disease. An even more potent double enzyme therapy for detoxifying gluten has evolved, one including both EP- B2 and a 2nd enzyme, PEP.
  78. 78. PEP and EP-B2 enzyme combination completely abolishes gluten immunotoxicity within ten minutes under simulated stomach and duodenal conditions. “Hopefully this two enzyme cocktail will help coeliacs resume a more normal diet in the future.” Siegel et al. "Rational Design of Combination Enzyme Therapy for Celiac Sprue." Chemistry & Biology, June 2006; 13: 649–658
  79. 79. “The rate of diagnosis of coeliac disease is proportional to suspicion." Joseph Murray, MD Associate Professor of Medicine University of Iowa Hospitals and Clinics
  80. 80. Prevalence of coeliac disease among of high risk groups Children testing positive for both IgG and IgA anti-gliadin antibodies….… 90:100 Identical twins………………................ 70:100 HLA-identical siblings……………….. 30:100 First-degree relatives…...................... 22:100 Down’s syndrome…………………….. 16:100 Autoimmune thyroid disease……….. 14:100 Insulin-dependent diabetes…….…… 11:100
  81. 81. Other at-risk for coeliac groups Children testing positive for only IgG antigliadin antibodies………………. 7.7:100 Osteoporosis………………………….… 4.5:100 Irritable bowel syndrome……………… 3.3:100 Second-degree relatives…………….… 3:100 Iron deficiency anemia………………… 2.8:100 ADHD……………………………………… 2.5:100 Women with recurring pregnancies of poor outcomes ……………………. 2:100
  82. 82. No more gluten-induced • Infertility • Recurring miscarriages • Premature births • Low birth weight, low IQ babies • Spina bifida • Cleft palate, cleft lip • Down’s syndrome
  83. 83. No more gluten-induced • Weepy, irritable, & surly • Low IQ • Poor school performance • Epilepsy • Autism • ADHD • IBS, anxiety & depression • Short stature • Insulin-dependent diabetes • Recurring canker sores • Low impact bone fractures • Iron deficiency anemia • Bed wetting
  84. 84. Gluten-free at last…