GI Issues in Autism: CoMorbidity or Causation

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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 MD
• Massachusetts 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
DSM-IV

• Qualitative impairment in social interaction
• Qualitative impairments in communication
• Restrictive, repetitive and stereotyped patterns
  of behavior, interests and activity
• Sensory processing abnormalities

5
The Fall and Rise of Disease Prevalence in the
last 50 years
Bach , J NEJM 2002347911-920, California
Department.of Social Services, CDC Slide 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 Apr36(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 n6113
• Wheat-free Better 50, No better 48 n3665
• CF, GF Better 65, No better 32 n2208
• Feingold Better 55, No better 43 n850
• Yeast-free Better 55, No better 43 n867
• SCD Better 66, No better 28 n195

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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
Jury
Parents better/no effect

• A Data insufficient 49/59
  n990
• B-6 Data insufficient 48/48
  n6387
• mB-12 Data insufficient 62/34 n688
• C Data insufficient 42/56
  n2171

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Minerals
Jury
Parents better/no effect

• Calcium Children need it 35/62 n1871
• Magnesium Children need it 29/65 n301
• Zinc Children need it 49/49
  n1736
• Studies evaluating bone density in adults with
  developmental disability showed high frequency of
  osteopenia or osteoporosis (45)

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Fish Oil/Omega 3
Jury
Parents better/no effect

• Fish Oil Data Promising 55/43 n995
• 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.

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Chelation
Jury
Parents better/no effect

• No controlled studies 73/24 n627
• Mercury debate

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Hyperbaric Oxygen Therapy
Jury
Parents better/no effect

• Two published papers 52/42 n66
• Most published data for HBOT is based on hard
  chamber, high pressure protocols

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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 doesnt 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.
  doi10.1371/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 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 addition, mucosal CD3 IL-4 cells were increased
  (p
• J Neuroimmunol. 2006 Apr173(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

• I would like to show 4 videos of children with
  autism.
• These 3 children all have gastrointestinal
  problems accounting for the behavior you will
  see.
• None of these children had strong symptoms of a
  gastrointestinal condition.

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Patient 1
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Patient 2
47
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 Sandifers 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 Downs 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
  7103(45)16621-2.
• A genetic variant that disrupts MET transcription
  is associated with autism. (Chromosome 7q31
  polymorphism GC) 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 20091231018-1024

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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 (P0.009) and GI conditions
  (P0.042) 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
  (P0.373).
• ? 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

• GI issues are common in autism and may be more
  common than in the general population
• GI conditions in autism certainly may promote
  autistic behaviors, more work is needed to
  determine any causation issues
• 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
• Newmans Own Foundation, Clea Newman
• Autism Speaks Foundation
• Margaret Bauman MD, Harland Winter MD, Rafail
  Kushak PhD, Katherine Murray RN