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Autistic Spectrum Disorders And Intestinal Health

MIND THE GUT

MINDD Sydney, Australia

August, 2011

Nancy O’Hara, M.D. www.ihealthnow.org

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Vicious Cycles

Gut inflammation

Abnormal intestinal permeability

Food sensitivities Malabsorption

Dysfunctional enzymes

Abnormal Methylation biochemistry

Increased oxidative

stress

Environmental toxins

Impaired detoxification

Increased damage from

toxins

TH1 to TH2 shift

Increased autoimmunity and allergy

Chronic viral and fungal infections

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Intestinal Inflammation and Malabsorption

Gut inflammation

Abnormal intestinal permeability

Food sensitivities Malabsorption

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GI/Autism Issues: How prevalent

Taylor (2002) reports chronic GI complaints in 17% of autistic children evaluated

Fombonne (2001) cites GI complaints in an autism cohort at 18.8%

Malloy (2003) reports 24% have chronic GI Issues

Horvath (2002) reports over 40% have GI/food sensitivity issues by survery

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GI/Autism: How Prevalent?

Valicenti-McDermott (2006), evaluated children with ASD and control groups matched for age, sex, and ethnicity (50 children/group)

70% of children with ASD had GI issues 42% of children with developmental disorder

other than ASD had GI issues 28% of children with typical development had GI

issues

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GI Symptoms: Prospective Studies

GI symptoms (constipation, cramping, diarrhea) 80% ASD vs 34% controls (D’Souza et al, Pediatrics, 2006)

Colitis in 88% and Ileal LNH in 93% ASD vs 14.3% controls; both with pain, diarrhea, constipation, bloating (Wakefield et al, 2002)

GI symptoms in 54% (Richler et al, J Autism Dev Disord, 2006)

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Dr Nancy O’Hara

Gastro Intestinal Issues and Autism

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GI/Autism Issues: How prevalent

MGH/Vanderbilt review of the AGRE database supports high frequency of GI issues

In 460 children, 385 ASD, 75 unaffected siblings - frequency of GI complaints is 43% in ASD vs. 4% in unaffected siblings

This compares to previous reports of higher prevalence than “controls”

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Specific Conditions

Problems seen in children with ASD Gastroesophageal Reflux Food allergy Irritable Bowel Syndrome Colitis Constipation/Motor disorder

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Increased size and number of lymphoid follicles particularly in ileum

Merging of lymphoid follicles Luminal infiltration of neutrophils, and eosinophils Crypt cell proliferation Ulceration of epithelium* Thickening of basement membrane Decreased production of brush border associated

digestive enzymes Up-regulated Th2 and Th1 response.

All above responses are consistent with the establishment of a chronic inflammatory condition

Pathological Mucosal Alteration Observed with Autistic Subjects

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The gut in autistic children V

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What do we see?

Bloating, gassy Constipation – huge, hard stools; small pebbles; infrequent Diarrhea, encopresis Muscle wasting and failure to thrive Foul smelling stools and gas Foul breath, body odor, foul stools Pain or pain behaviors, SIB Posturing Irritability (especially just prior to bowel movements) Probing and smearing Behavioral changes

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Extra-esophageal Symptoms of GERD in Children

Extra

Esophageal

Manifestations of GERD

Wheezing/ asthma

Hoarseness

Otitis /sinusitis

Dental erosions

Chronic sore throat

Chronic Cough

Apnea/bradycardia

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GERD and Autism

Russell (1989) reported 2 patients with SIB unresponsive to psycho-pharmacological intervention who had resolution on antiemetics

Horvath (1999) evaluated 36 patients: 69% had Grade 1-2 esophagitis histologically

Linday (2001) described 4 of 9 children randomized to famotidine (Pepcid) therapy showed improved behavior.

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Food Allergy

Food allergy is common, 5-8% prevalence in pediatric patients (Sampson, 1999)

Food allergy is reported in 36% of autistic children (Lucarelli, 1995)

Food allergy may present as skin rash, GI symptoms of diarrhea, pain and constipation and behavioral changes

Up to 50% of surveyed families report their autistic children had a food allergy or sensitivity (Horvath 2002)

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Food Allergy

Mechanisms by which it contributes to symptoms: Inflammatory effect Pain Chemical mediator release and altered

neurotransmission, histamine, cytokines and opioid effect.

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In survey of 500 autistic subjects, the highest frequency of food intolerance was observed with wheat and milk products. (Lightdale et al 2001)

Breakdown of gluten by pancreatic and intestinal peptidases produces short chain peptides similar in structure to endogenous endorphins. These peptides have been termed “exorphins” and have opiate like qualities.

In normal circumstances intestinal production of these exorphins is mainly transitory because brush border enzymes such as dipeptidyl peptidase IV effectively degrade them. (Wakefield et al 2002)

Diminished brush border activity results in exorphin excess in the blood. (Horvath et al 2002)

Gluten and Casein V

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In patients with co-morbidity of celiac disease and autism, improvements in autistic symptoms coincide with exclusion of gluten and deteriorate again when gluten is reintroduced (Goodwin et al 1971)

Elimination of milk and gluten from the diet resulted in improvement in social, cognitive and communication skills, commensurate with reduction of urinary exorphin level. (Knivsberg et al 1990)

Elder et al (J. Autism Dev Disorders (2006)) double blind crossover in 12 week study of 15 children with ASD no benefit [parents reported benefits not identified by study]

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Allergy Testing

All allergy testing has limited accuracy IgE tests (skin test, RAST blood tests and patch

testing) can be negative even if clinical symptoms of food allergy

IgG tests and IgE tests can be positive but not correlate to a clinical symptom

Any testing is a guide to think about what foods may be worthy to consider a problem

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Upper GI Problem

Gastro-esphageal Reflux Gastritis/Peptic Ulcers Allergic Esophagitis/Gastritis/Enteritis Delayed Gastric Emptying/Motility disorder Intestinal or pancreatic malabsorption Inflammatory Bowel Disease Overgrowth of microbes (bacteria etc.)

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Lower GI Problems

Chronic Recurrent Abdominal Pain Irritable Bowel Syndrome Constipation Diarrhea Colitis Toilet training issues

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Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is a motor and sensory condition of the colon, an example of visceral sensitivity

Abdominal pain +/- constipation +/- Diarrhea Painful stimuli outside the bowel are tolerated

better than in patients without IBS; but bowel distention or contraction may be excruciating

This makes IBS a “sensory processing disorder of bowel”

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Impaired CHO Digestion and Germogrowth

Williams, IMFAR 2010 Abstract 130.073 In AUT-GI subjects, ileal transcripts for the

disaccharidases sucrase isomaltase, maltase glucoamylase, and lactase, and the monosaccharide transporter, and glucose transporter 2 were significantly decreased

This study supports our previous enzymatic findings of disaccharide deficiency and goes further to show associated flora alteration is present

This supports rational for overgrowth syndrome (so called dysbiosis of bacteria, yeast, clostridia)

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Impaired CHO Digestion and Germogrowth

Bacterial 165 rRNA gene pyrosequence analysis of biopsy material from ileum and cecum revealed significantly decreased Bacteroides, increased Firmicutes and Proteobacteria, and increased Betaproteobacteria in AUT-GI as compared with Control-GI biopsies

The findings support Dr. Feingold’s work suggesting overgrowth in children with autism

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Some Guiding Principles

What does each child need to:

Get Get rid of

Treatment pyramid

Dietary interventions Correct nutritional deficiencies Treat gastrointestinal problems

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What do we need to give to or get out of our children?

Exercise/Activity Basic nutritional changes (change in diet..)

Fresh, unprocessed, unrefined, unadulterated, organic (chix, rice) Varied and rotational (try to vary day to day) Non-allergenic (crave that which most sensitive to) Protein (every 4-5 hours); not necessarily meat Vegetable juicing Fermented foods

3 R’s (not just as it applies to the gut) Remove – sugars, junk food, preservatives, toxins, germs, allergenic foods

GF/CF/SF/YF/SCD/LOD/BED Replenish – healing diets, probiotics, enzymes, nutrients, zinc Repair/Restore

Oxidative stress (alkalinize, antioxidants, HBOT) Immune modulation (EFAs, gamma globulins) Hormonal (thyroid, adrenal)

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Treatment of Constipation

Fiber Fluids Exercise, especially swimming Vitamin C: 1000-2000 mg/day, sometimes up to 6000

mg/day Magnesium Citrate (100-500 mg/day) Aloe Vera: 1oz (children) to 2 oz (teens) (George’s

Always Active) Senna (Smooth Move Tea) Oils Enemas if impacted

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Prescription Treatment for Constipation

Carnitine (Carnitor) Lactulose Glycolax (now available OTC) Colace (OTC) IBS treatments: Fiber, Antispasmodics Misoprostil (Miralax)

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Core GI Evaluation

CBC ESR Iron/Ferritin Standard Chemistry Profile including Liver

Function Vitamin D levels (25 OH) Immunoglobulins and subclasses Celiac Panel (TTG, Gliadin, HLA) Food Allergies (IgG and IgE)

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Core GI Evaluation

Urine Metabolic Anaylsis (OAT) Stool for blood Stool for H Pylori Stool for culture, ova and parasite, and C

Difficile Stool for Elastase CDSA (beneficial flora, inflammatory markers,

absorption markers) Abdominal X ray Scope

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What To Do

• Treat constipation (Mg, Vitamin C, fiber, senna, diet changes)

• Remove stressors (e.g., allergenic foods, gluten, casein, toxins)

• Supply nutrients (e.g., vitamin A & C, zinc, pantothenic acid, folic acid, L-glutamine)

• Supply immunoglobulin production (nutrients, probiotics, saccharomcyes boulardii)

• Treat germ overgrowth (bacteria, fungus, parasites)

• Treat inflammation - Anti-inflammatories (Ibuprofen, Mesalamine, Sulfasalazine, Steroids, EFAs, Minocycline)

• Treat underlying conditions (reflux, motility)

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What to do Consequences of Zinc Deficiency

Limited appetite, decreased taste Oxidative stress Dysfunctional metallothionein Impaired brain function

poor short term memory, decreased cognition

Behavioral changes hyperactivity, aggression

Acne, canker sores, spots on nails

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What to do Zinc

Zinc supplementation tightens leaky gap junctions in Crohn’s disease(Sturniolo

et al, Inflammatory Bowel Dis., May 2001) Piccolinate, Acetate Best given at night, alone Zinc taste test

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What To Do Probiotics

• Discourage pathogens • Support digestion • Produce SCFAs, reduce pH, synthesize

vitamins • Control inflammation and promote oral

tolerance • Encourage peristalsis • Minimum of 10 billion CFU/day (50 billion),

taken on empty stomach

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What To Do

Saccharomyces boulardii • Discourages pathogens, including Candida

• Stimulates IgA production & mucosal repair

• Natural yeast, skin of lycee fruit

• Destroyed by antifungals, not antibiotics

• Dose: 5 billion cells (250 mg) 2 X day

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What To Do: Treat Germ Overgrowth Bacteria (history of positive response to

antibiotics, OCD, tics) Antibiotics

Gram Negative bacteria (Klebsiella, Enterobacter) Bactrim Gentamycin

Anti-clostridial (smearing, probing, diarrhea after abx, OCD, temper) • Metronidazole • Alinia • Vancomycin • If response is significant, may need to extend

treatment past 14 days

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What To Do – Treat Parasites

Parasites (bizarre behavior, insatiable appetite, aggression, worse at full moon, picking/biting/itching/grinding/smearing) Blastocystis hominis (treat with Bactrim and Humatin) Probiotics Antiparasitics (Metronidazole, Paromomycin,

Mebendazole) Natural remedies (artemesia, pumpkin seeds,

coconut) TSO therapy

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What To Do – Treat Germ Overgrowth The Antifungal Parade

(mood swings, inappropriate laughter, thickened nails, sugar cravings, urinary frequency, spaciness)

Non-absorbable S.boulardii: 3 months (at least 3-9/day) Nystatin: 1,000,000 units 4X day Amphotericin B: 250mg 4X day x 10 days, then 500mg 4X day x 10

days Systemic

Sporanox (Itraconazole): 100mg 2X day x 10 days, then 200mg x 10 days

Diflucan (Fluconazole): 5 mg/kg/day up to 200mg day x 10 days, then 400mg day x 10 days

Lamisil (Terbinafine): 250mg day x 10 days, then 500mg day x 10 days Nizoral (Ketoconazole): 200mg day x 10 days, then 400mg day x 10

days May need to extend treatment longer Follow liver and kidney function at least every 2 months

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What To Do – Natural

Natural Antimicrobials and Antifungals Oil of Oregano (0.2 ml 2x/day) Grapefruit Seed Extract (1/3 adult dose) Caprylic acid (500-1000 mg with meals) Biocidin Berberine Plant Tannins Garlic (1-2 fresh cloves or pills/day)

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Allergy Treatment

Gastrocrom Singulair Digestive Enzymes Antihistamines Probiotics Bioflavinoids

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Anti-inflammatories

Ibuprofen Mesalomine Sulfasalazine Steroids Omega-3 essential fatty acids Actos, spironolactone, curcumin Immune Therapy (TSO, IVIG)

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Treatment for UGI Conditions

For H. Pylori: Antibiotics and a Proton Pump Anti-Acid, course is 2 weeks

For GE reflux: Anti-Antiacids including H2 blockers like Zantac or Pepcid or Proton Pump Blockers like Prilosec or Prevacid

Carafate is a topical binding RX Motility drugs including Reglan, E-mycin,

Baclofen, Carnitine

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What Does It Mean Digestive enzyme impairment Inflammation, leaky gut Immune dysreguatlion greater

susceptibility to germs, inflammation, and food sensitivities further immune deficiency (vicious cycle)

Germ overgrowth

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The Gut-Brain Axis of Pathology in Autism

Intestinal permeability Inflammation

In autism patient • High TNF-α titre • High IL-1 and IL-6 titre • Skewing to Th2 • Depression of Th1 immunity - Decreased NK cell - Decreased Th1 CD cell - Decreased Ig A

Systemic carriage

Low active tissue peptidases with antagonism

endorphins

Dietary Protein

Defective enzyme/ Microbial

environment

Opioid peptides excess

Opioid peptides excess

Low sensitivity to pain

Repetitive behaviour

Social deficiencies

Some retardation in Cognitive development

Opioid receptors in brain

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Conclusions

GI issues are common in autism GI conditions in autism may promote autistic

behaviors. Willingness to consider underlying medical

factors in children with autism may impact autism

Ideal methods to identify flora disruption, Inflammatory markers is needed

Treat the child as individual not a label

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