autism and the gi tract
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GI Issues in Autism: Co-Morbidity or Causation
Autism: Bridging the Gap Between Knowledge and Practice
Augusta Maine 5/12/09
Timothy Buie MDMassachusetts General Hospital for Children/
Harvard Medical School
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Goals for this talk
Discuss differences in children with autism that might be relevant to medical issues
Review medical literature regarding GI issues in autism and touch on current treatment topics
Demonstrate difficulties in diagnosis of medical issues in autism
Explore one diagnosis (GERD) in autism as an example
Suggest how research should consider GI conditions in autism research
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Autism (ASD): Definition
Qualitative impairment in social interaction
Qualitative impairments in communication
Restrictive, repetitive and stereotyped patterns of behavior, interests and activity
• Sensory processing abnormalities
DSM-IV
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The Fall and Rise of Disease Prevalence in the last 50 years
Bach , J NEJM 2002;347:911-920, California Department.of Social Services, CDCSlide Courtesy of Bernard Kinane MD
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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 76% have GI issues by survey
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GI/Autism Issues: 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 compared to
42% of children with developmental disorder other than ASD
28% of children with typical development
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GI Issues in Children with Autism
The jury is in. Parents are in.
GI conditions are more common in children with autism than unaffected children
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Autism is Treatable
Without question the best data for successful treatment is educational intervention
Early (earliest) intervention is also gaining clear data showing that children do better with early diagnosis and intensive intervention
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Autism is Treatable
Medical and “Biomedical” therapies may have value in treating children with autism
It remains less clear whether treatments specifically treat the condition of autism or medical issues in children with autism
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Autism/GI Issues Historical Review
In 1943, Leo Kanner described autism in his seminal paper
6 of 11 of his patients were described to have “feeding or dietary” issues
Feeding issues were attributed to autistic behavioral issues
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Autism/GI Issues Historical Review
Opioid Peptide Theory -- Shattock (1990) and Reichelt (1991) -- peptides from milk and gluten caused schizophrenia and autism.
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Food Allergy/Sensitivity
Food allergy reported in 36% of autistic children (Lucarelli 1995)
Up to 50% of surveyed families report their autistic children had a food allergy or sensitivity (Horvath 2002)
Sensitivity may = allergy, “drug-like” effect of food, maldigestion
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Gluten-Free Diet trials Knivsberg, 1990: Selected patients
with high gluten opioid peptides in urine. 8/10 were reported to have behavioral improvements noted, study repeated in 2002 similar findings
Sponheim 1991: Selected 4 autistics for gluten-free diet, behavior worsened
Where else? Unraveling the Mystery of Autism, by Karen Seroussi (Simon and Schuster, N.Y.N.Y. 2000)
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Diet trials
Elder et al* 2006 double-blind crossover trial Casein-free, Gluten-free diet in 15 autistic children showed no benefit of diet in a 12-week study
Parents reported benefits not identified by testing
*J Autism Dev Disord. 2006 Apr;36(3):413-20
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Autism/GI Issues
Lactose and sugar intolerance reported by Horvath (1999) and Kushak (2002)
Our recent data submitted for publication suggests high frequency of lactase deficiency in autistic children undergoing endoscopy, BUT comparison group has likewise high frequency.
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Autism/GI Issues
Horvath (1998) suggested potential neurological benefit in a number of autistic children receiving secretin during gastrointestinal testing
Several subsequent studies refuted this claim, including Sandler (1999), Lightdale (2001)
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Secretin does not work
The jury is in Parents are ? in
Research looking at Secretin as a neurotransmitter continues
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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*),
Up to 50% of surveyed families report their child with autism has food allergy or sensitivity (Horvath, 2002*)
*Both small studies but were not biased by presenting symptoms
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Gluten-Free Diet trials
Knivsberg, 1990, 2002: Selected patients with high gluten opioid peptides in urine. 8/10 were reported to have behavioral improvements noted
Sponheim 1991: Selected 4 autistics for gluten-free diet, behavior worsened
Where else? Unraveling the Mystery of Autism, by Karen Seroussi (Simon and Schuster, N.Y.N.Y. 2000)
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Diet and Autism Parent Survey Autism Research
Institute Casein-free: Better 51%, No better 48%
n=6113
Wheat-free: Better 50%, No better 48% n=3665
CF, GF: Better 65%, No better 32% n=2208
Feingold: Better 55%, No better 43% n=850
Yeast-free: Better 55%, No better 43% n=867
SCD: Better 66%, No better 28% n=195
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Diet works for treatment of autism
The jury is out. (many) Parents are in.
Diet may be working in a subset of patients accounting for insufficient data in medical studies
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Other speculated treatments
To continue with some of the discussed biomedical treatments…
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Other Diets
Feingold (Sodium Benzoate free, dye –free)
Specific Carbohydrate Diet Low Oxalate Diet Yeast-Free Diets
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Other Biomedical Intervention
Vitamins Minerals Fish Oil/Essential Fatty Acids Chelation of Heavy Metals Hyperbaric Oxygen Therapy Music Therapy Massage
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Vitamins
A Data insufficient 49%/59% n=990
B-6 Data insufficient 48%/48% n=6387
mB-12 Data insufficient 62%/34% n=688
C Data insufficient 42%/56% n=2171
Jury
Parents better/no
effect
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Minerals
Calcium Children need it 35%/62% n=1871
Magnesium Children need it 29%/65% n=301
Zinc Children need it 49%/49% n=1736
Studies evaluating bone density in adults with developmental disability showed high frequency of osteopenia or osteoporosis (45%)
Jury
Parents better/no
effect
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Fish Oil/Omega 3
Fish Oil Data Promising 55%/43% n=995
Here is an example of deciding what you are trying to treat. This has promise especially for mood disorder, anxiety and attention issues. It is probably deficient in most diets of children with autism.
Jury
Parents better/no
effect
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Chelation
No controlled studies 73%/24% n=627
Mercury debate
Jury
Parents better/no
effect
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Hyperbaric Oxygen Therapy
Two published papers 52%/42% n=66
Most published data for HBOT is based on hard chamber, high pressure protocols
Jury
Parents better/no
effect
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The PLACEBO response
Is not imagining a benefit Helps to mark response over chance
observation of benefit Happens with high frequency in
treatment protocols for autism If the treatment is difficult or
expensive, the likelihood of a positive response is higher
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Music Therapy
Reported as helpful, improving communication over long term for children with autism
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Auditory Integration Therapies
Review of several controlled studies does not support the recommendation of this modality
My nurse says she doesn’t care about the data here, it worked for her son Doug!
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Sensory Therapy/Massage
Data is promising and merits ongoing research
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Sleep
Sleep disorders are shown to affect pain perception, learning targets, anxiety among many outcomes
Vicious cycles Sleep and GE Reflux
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Back to GI
Please allow me to return away from treatment ideas back to GI problems reported
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Autism/GI Issues
Wakefield (1998) identified a group of autistic children with GI issues. At colonoscopy, lymphoid nodular
hyperplasia (7 of 12) in the distal ileum and frank colitis in 11 of 12 patients identified
Retraction of this article by most authors (2004)
In 2/09 trial, early vaccine injury compensation cases were determined to be unsupported
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Autism/GI Issues Recent Speculation
Wakefield 2000 describes “autistic enterocolitis” as a unique intestinal lesion with prominent LNH and colitis
Hypothesis: Increased GI permeability allows opioid peptides to cause neurological dysfunction or encephalopathic type issues
MMR vaccine is proposed as etiology of GI pathology
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Is Measles Virus in Gut Refuted?
Epidemiology data find no difference in prevalence of autism in vaccinated or unvaccinated for MMR (20+ Studies)
Hornig M, Briese T, Buie T, Bauman ML, Lauwers G, et al. (2008) Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A
Case-Control Study. PLoS ONE 3(9): e3140. doi:10.1371/journal.pone.0003140
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Autism/GI Issues Immune/Inflammation
Literature characterizing GI differences in autistic and unaffected children continues:
Furlano (2001), Torrente (2002), Ashwood (2004) discuss immune abnormalities and abnormal cytokine profiles in autistic children with GI issues
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Autism/GI Issues Immune/Inflammation
Ashwood and Wakefield 2006 describe “unique” pattern of inflammatory cytokines in autistic children
In both peripheral blood and mucosa, CD3+ TNFalpha+ and CD3+ IFNgamma+ were increased in ASD children compared with NIC (p < 0.004) and reached levels similar to CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls (p < 0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p < 0.007) in ASD compared with NIC
J Neuroimmunol. 2006 Apr;173(1-2):126-34. Epub 2006 Feb 21
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Thoughts on the GI Literature
In May 2008, a consensus meeting of experts was brought to Boston in an attempt to review and vet the quality of the literature and research regarding Autism and GI issues (Sponsored by Easter Seals)
The data for most issues are poor and need reinforcement
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Pitfalls of Autism/GI Research
Largely anecdotal studies Absence of population-based data
(referral and selection bias) Current claims remain
uncorroborated by other researchers Much work tries to offer GI issues as
causation of autism, is there a compromise such as a contribution to autistic behaviors?
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Gastrointestinal Problems in Autism
o I would like to show 4 videos of children with autism.
o These 3 children all have gastrointestinal problems accounting for the behavior you will see.
o None of these children had strong symptoms of a gastrointestinal condition.
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Patient 1
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Patient 2
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Patient 3
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Patient 4
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What did we see?
All these patients presented have autism and all have the same gastrointestinal condition: Gastroesophageal reflux disease with esophagitis
Their presentation is different from general population presentations because they are different
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Prevalence of GERD in Children
Children ages 3 - 9 years old: 24% (History of symptoms
consistent with GERD) Children ages 10 - 17 years old:
8%-25% (Experienced GERD symptoms child or parental report)
Children with autism have the right to usual medical conditions
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GERD and Autism
Russell (1989) reported 2 patients with SIB unresponsive to psycho-pharmacological intervention who had resolution on anti-emetics
Horvath (1999) evaluated 36 patients endoscopically. 69% had Grade 1-2 esophagitis histologically
Linday (2001) described 4 of 9 children randomized to famotidine therapy showed improved behavior
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Case 2
Patient with Sandifer’s Syndrome
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Case 2: Esophagitis
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Case 3: Self-Injurious Behavior
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Case 3: Esophagitis
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SIB resolved on treatment
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GERD is an example of Co-Morbidity
Gastritis Colitis Irritable Bowel Syndrome Constipation and motility based
disorders Food allergy and sensitivity Overgrowth syndromes
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Co-Morbidity Vs. Syndromic
In Down’s or other syndromes there is a well characterized list of medical issues seen as a manifestation of the gene abnormality (Phenotype)
In Autism there are dozens of suspect gene abnormalities and no defined phenotypes (YET)
Current controversy rests often around causation versus association
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GI Symptoms in ASD and MET Gene
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16621-2.
A genetic variant that disrupts MET transcription is associated with autism. (Chromosome 7q31 polymorphism G>C) This genetic variant is know to impair intestinal repair.
Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P.
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GI Biomarker ?: MET Gene Polymorphism
Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions
Daniel B. Campbell, PhD Timothy M. Buie, MD Harland Winter, MD Margaret Bauman, MD James S. Sutcliffe, PhD James M. Perrin, MD Pat Levitt, PhD
Pediatrics 2009;123;1018-1024
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GI Symptoms in ASD and MET Gene
Subjects were 918 individuals from 214 Autism Genetics Resource Exchange (AGRE) families
Stratification by the presence of GI conditions revealed that the MET ‘C’ allele was associated with both ASD (P=0.009) and GI conditions (P=0.042) in 118 families containing at least one child with co-occurring ASD and GI conditions.
In contrast, there was no association of the MET polymorphism with ASD in the 96 families lacking a child with co-occurring ASD and GI conditions (P=0.373).
? Biomarker for Child with ASD and GI disease
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Unsettled Issues
Could GI issues CAUSE autism? Environmental/nutritional factors
modulating genetically predisposed individuals
An inflammation model where some body process (colitis, allergy, infection) releases chemical or immune mediators that affect brain function (Vargas 2005, Welch 2005)
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Working Model
Children with autism have limited capability to characterize medical symptoms
Behaviors in autism (at least sometimes) may represent a medical symptom
Sensory variance may be a primary factor in atypical presentation
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Conclusions
o GI issues are common in autism and may be more common than in the general population
o GI conditions in autism certainly may promote “autistic behaviors”, more work is needed to determine any causation issues
o The GI tract is accessible for study and may be a valuable (if messy) window to the body
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Thanks to:
Northwest Autism Foundation Autism Treatment Network Autism Research Institute Newman’s Own Foundation, Clea
Newman Autism Speaks Foundation Margaret Bauman MD, Harland
Winter MD, Rafail Kushak PhD, Katherine Murray RN