Autism and the GI Tract


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Autism and the GI Tract

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. The Fall and Rise of Disease Prevalence in the last 50 years Bach , J NEJM 2002;347:911-920, California Department.of Social Services, CDC Slide Courtesy of Bernard Kinane MD
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. Autism/GI Issues Historical Review  Opioid Peptide Theory -- Shattock (1990) and Reichelt (1991) -- peptides from milk and gluten caused schizophrenia and autism.
  12. 12. 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
  13. 13. 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)
  14. 14. 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
  15. 15. 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.
  16. 16. 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)
  17. 17. Secretin does not work  The jury is in  Parents are ? in  Research looking at Secretin as a neurotransmitter continues
  18. 18. 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
  19. 19. 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)
  20. 20. 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
  21. 21. 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
  22. 22. Other speculated treatments  To continue with some of the discussed biomedical treatments…
  23. 23. Other Diets  Feingold (Sodium Benzoate free, dye –free)  Specific Carbohydrate Diet  Low Oxalate Diet  Yeast-Free Diets
  24. 24. Other Biomedical Intervention  Vitamins  Minerals  Fish Oil/Essential Fatty Acids  Chelation of Heavy Metals  Hyperbaric Oxygen Therapy  Music Therapy  Massage
  25. 25. 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 Jur y Parents better/no effect
  26. 26. 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%) Jur y Parents better/no effect
  27. 27. 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. Jur y Parents better/no effect
  28. 28. Chelation  No controlled studies 73%/24% n=627  Mercury debate Jur y Parents better/no effect
  29. 29. Hyperbaric Oxygen Therapy  Two published papers 52%/42% n=66  Most published data for HBOT is based on hard chamber, high pressure protocols Jur y Parents better/no effect
  30. 30. 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
  31. 31. Music Therapy  Reported as helpful, improving communication over long term for children with autism
  32. 32. 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!
  33. 33. Sensory Therapy/Massage  Data is promising and merits ongoing research
  34. 34. Sleep  Sleep disorders are shown to affect pain perception, learning targets, anxiety among many outcomes  Vicious cycles  Sleep and GE Reflux
  35. 35. Back to GI  Please allow me to return away from treatment ideas back to GI problems reported
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 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
  42. 42. 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?
  43. 43. 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.
  44. 44. Patient 1
  45. 45. Patient 2
  46. 46. Patient 3
  47. 47. Patient 4
  48. 48. 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
  49. 49. 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
  50. 50. 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
  51. 51. Case 2  Patient with Sandifer’s Syndrome
  52. 52. Case 2: Esophagitis
  53. 53. Case 3: Self-Injurious Behavior
  54. 54. Case 3: Esophagitis
  55. 55. SIB resolved on treatment
  56. 56. GERD is an example of Co-Morbidity  Gastritis  Colitis  Irritable Bowel Syndrome  Constipation and motility based disorders  Food allergy and sensitivity  Overgrowth syndromes
  57. 57. 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
  58. 58. GI Symptoms in ASD and MET Gene  Proc Natl Acad Sci U S A. 2006 Nov 7;103(45)  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.
  59. 59. 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
  60. 60. 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
  61. 61. 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)
  62. 62. 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
  63. 63. 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
  64. 64. 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