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Gastrointestinal Disorders of Children with Autistic Spectrum Disorders Joseph Levy, M.D. Professor of Clinical Pediatrics Director, Program in Neurogastroenterology.

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Presentation on theme: "Gastrointestinal Disorders of Children with Autistic Spectrum Disorders Joseph Levy, M.D. Professor of Clinical Pediatrics Director, Program in Neurogastroenterology."— Presentation transcript:

1 Gastrointestinal Disorders of Children with Autistic Spectrum Disorders Joseph Levy, M.D. Professor of Clinical Pediatrics Director, Program in Neurogastroenterology Columbia University Medical Center Morgan Stanley Children’s Hospital of NY Presbyterian

2 Outline and Goals Review the GI and nutritional issues impacting on the health of children on the autism spectrum Review the GI and nutritional issues impacting on the health of children on the autism spectrum Prepare parents and professionals to critically appraise the pertinent information…or how much can we trust anecdotes? Prepare parents and professionals to critically appraise the pertinent information…or how much can we trust anecdotes? Propose guidelines for assessing adequacy of nutritional intake and the need for supplements Propose guidelines for assessing adequacy of nutritional intake and the need for supplements

3 Autistic Spectum Disorders 1. Social interaction 2. Verbal and nonverbal communication 3. Repetitive behaviors or interests 4. ? GI disorders

4 GI symptoms reported in ASD Nonspecific symptoms: Nonspecific symptoms: Chronic Diarrhea Chronic Diarrhea Constipation Constipation Foul-smelling stools Foul-smelling stools Excessive gas Excessive gas Abdominal bloating Abdominal bloating Abdominal pain Abdominal pain Vomiting Vomiting

5 GI symptoms in ASD Do children with ASD really have more gastrointestinal symptoms than other children? Do children with ASD really have more gastrointestinal symptoms than other children? Lack of published rigorous data that show increased GI symptoms in children with ASD Lack of published rigorous data that show increased GI symptoms in children with ASD

6 Prevalence of GI symptoms: A Little Perspective Gastrointestinal complaints are very common in children with normal development: Gastrointestinal complaints are very common in children with normal development:  Constipation rates 16%-37%  Cow’s milk protein intolerance % of otherwise normal infants Loening-Baucke, NEJM 1998

7 Prevalence of GI symptoms There is very little reliable information about whether GI symptoms are part of ASD. There is very little reliable information about whether GI symptoms are part of ASD. Bias: Bias: Selection Selection Referral Referral Recall Recall

8 Prevalence of GI symptoms Retrospective survey comparing 412 children with ASD and 43 siblings: Retrospective survey comparing 412 children with ASD and 43 siblings: 85.3% ASD had at least one GI symptom compared to 28.6% siblings. 85.3% ASD had at least one GI symptom compared to 28.6% siblings. Horvath & Perman, Current Gast Reports 2002a, Current Op Ped 2002

9 Prevalence of GI symptoms Survey of 500 parents: Survey of 500 parents: 50% reported daily loose stools or frequent diarrhea 50% reported daily loose stools or frequent diarrhea 33% abdominal pain 33% abdominal pain 20% more than 3 stools a day 20% more than 3 stools a day No control group, no note of selection criteria No control group, no note of selection criteria Lightdale, Siegel & Heyman, Clin Perspect Gast, 2001

10 Prevalence of GI symptoms Review of medical histories of 285 children with PDD, 48 non-autistic siblings, and 102 unrelated controls: Review of medical histories of 285 children with PDD, 48 non-autistic siblings, and 102 unrelated controls: 19% of children with PDD had constipation 19% of children with PDD had constipation 19% diarrhea, 7% alternating constipation/diarrhea. 19% diarrhea, 7% alternating constipation/diarrhea. <10% controls had diarrhea or constipation. <10% controls had diarrhea or constipation. Melmed, Schneider, Fabes, Phillips & Reichelt, J Ped Gastro & Nut, 2000

11 Prevalence of GI symptoms: Asking a few questions goes a long way… How was the survey developed? How was the survey developed? How were the patients selected? How were the patients selected? Was information obtained from the parents or from medical records? Was information obtained from the parents or from medical records? What was the working definition of ‘diarrhea’ and ‘constipation’ ? What was the working definition of ‘diarrhea’ and ‘constipation’ ?

12 Prevalence of GI symptoms: A matter of timing Case-controlled study from UK evaluated the frequency of GI complaints before ASD was diagnosed: Case-controlled study from UK evaluated the frequency of GI complaints before ASD was diagnosed: Exactly the same percentage (9%) of autistic and normally developing children had GI symptoms before the date of diagnosis. Exactly the same percentage (9%) of autistic and normally developing children had GI symptoms before the date of diagnosis. Black, Kaye & Jick, Brit Med J, 2002

13 Prevalence of GI symptoms in ASD vs. Controls Most recent study compared 50 ASD children with 50 having other developmental delays (DD) and 50 with normal development: Most recent study compared 50 ASD children with 50 having other developmental delays (DD) and 50 with normal development: History of GI symptoms: 70% ASD 70% ASD 28% Normal Children 28% Normal Children 42% Other DD 42% Other DD Valicenti-McDermott, McVicar, Rapin, et al. J Dev Behav Pediatr, 2006

14 Prevalence of GI symptoms in ASD vs. Controls Abnormal stooling pattern: Abnormal stooling pattern: 18% ASD 18% ASD 4% Normal 4% Normal 2% DD 2% DD Food selectivity: Food selectivity: 60% ASD 60% ASD 22% Normal 22% Normal 36% DD 36% DD

15 Prevalence of GI symptoms in ASD vs. Controls Limitations of this study: Limitations of this study: Relies on family reports of symptoms (recall bias) (recall bias)

16 Prevalence of GI symptoms: It’s all over! Most of the data published regarding GI symptoms is derived from parental recall or medical records Most of the data published regarding GI symptoms is derived from parental recall or medical records Places the prevalence of GI symptom somewhere between… Places the prevalence of GI symptom somewhere between…17%-86%! (Erickson, Stigler, Corkins, et al, J Autism & Dev Disorders, 2005)

17 What Triggers GI Symptoms? Immaturity of the nerves and muscles responsible for moving food along Immaturity of the nerves and muscles responsible for moving food along Enzyme deficiencies Enzyme deficiencies Malabsorption of nutrients (sugars, fats, proteins) Malabsorption of nutrients (sugars, fats, proteins) Immune-mediated inflammation and damage Immune-mediated inflammation and damage

18 Structure of the GI Tract

19 Structural relations of the ENS

20 Sources of Intestinal Pain Overstretching of muscles (gas, spastic contractions) Overstretching of muscles (gas, spastic contractions) Acid-mediated irritation of esophagus (GERD) Acid-mediated irritation of esophagus (GERD) Hypersensitive “second brain” (The brain in the gut or the ENS) Hypersensitive “second brain” (The brain in the gut or the ENS) Abnormal blood flow Abnormal blood flow

21 Consequences of GI Dysfunction Acute and chronic pain Acute and chronic pain Interference with consumption of adequate nutrients Interference with consumption of adequate nutrients Aversive conditionings Aversive conditionings Food intolerance and protein allergy Food intolerance and protein allergy Limited food choices Limited food choices Abnormal stooling patterns Abnormal stooling patterns

22 Diet and Nutrition Repetitive behaviors and insistence on sameness in ASD can have negative effect on diet Repetitive behaviors and insistence on sameness in ASD can have negative effect on diet Limited food choices is frequent complaint of families with autistic children Limited food choices is frequent complaint of families with autistic children A higher incidence of pica has also been noted by parents of autistic children A higher incidence of pica has also been noted by parents of autistic children

23 Pica (hair ball) in ASD Child

24 Diet and Nutrition Nutritional status has been evaluated by several small controlled and uncontrolled studies Nutritional status has been evaluated by several small controlled and uncontrolled studies Overall, it appears their nutrition is adequate Overall, it appears their nutrition is adequate Selectivity does not result in malnutrition Selectivity does not result in malnutrition Raiten &Massaro, J Autism and Dev Disorders, 1986; Shearer, et al, J Autism and Dev Disorders, 1982; Ahearn et al, J Autism and Dev Disorders, 2001; Field & Williams, J Ped Child Health, 2003

25 Food Intolerance and Allergy Anecdotal reports from parents of children with ASD Anecdotal reports from parents of children with ASD Most report intolerance for Most report intolerance for cow’s milk (casein protein) or cow’s milk (casein protein) or wheat (gluten protein) wheat (gluten protein)

26 Food Intolerance and Allergy In 1971 investigators reported a case of a child with ASD and celiac disease: In 1971 investigators reported a case of a child with ASD and celiac disease: Autistic behaviors worsened when exposed to gluten after a period with gluten-free diet Autistic behaviors worsened when exposed to gluten after a period with gluten-free diet (Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971)

27 Food Intolerance and Allergy This case inspired a study which measured trancephalic direct current (TDC) in children with ASD and GI symptoms: This case inspired a study which measured trancephalic direct current (TDC) in children with ASD and GI symptoms: ASD children showed inhibition of frontal voltage in response to 1 g PO dose gliadin ASD children showed inhibition of frontal voltage in response to 1 g PO dose gliadin No inhibition with 1 g sugar No inhibition with 1 g sugar Siblings and normal controls showed no response to either gliadin or sugar Siblings and normal controls showed no response to either gliadin or sugar “Gluten has a direct effect on the central nervous system” “Gluten has a direct effect on the central nervous system” Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971

28 Another source of bias All the ASD children in study had previous GI complaints. All the ASD children in study had previous GI complaints. Error: Error: Generalizing differences found in a subset of children Generalizing differences found in a subset of children Do all children with ASD have changes in response to a gluten challenge? Do all children with ASD have changes in response to a gluten challenge? We do not know We do not know

29 Food Intolerance and Allergy Long-term prospective study of gluten and milk-free diet in children with abnormal urinary peptide levels: Long-term prospective study of gluten and milk-free diet in children with abnormal urinary peptide levels: 15 children in first report, original new participants in second report 15 children in first report, original new participants in second report Behavioral improvement noted by parents and teachers in both reports Behavioral improvement noted by parents and teachers in both reports Urine peptide levels normalized by one year Urine peptide levels normalized by one year Reichelt, et al. J App Nutr, 1990 Reichelt, et al. Brain Dysfunction, 1991

30 Food Intolerance and Allergy Another study with 15 participants: Another study with 15 participants: Improved behavior and communication after 1 and 4 year periods Improved behavior and communication after 1 and 4 year periods Also limited to ASD children with abnormal urinary peptides; no control group Also limited to ASD children with abnormal urinary peptides; no control group None of the studies controlled for concomitant educational or other behavioral interventions that could have caused improvement None of the studies controlled for concomitant educational or other behavioral interventions that could have caused improvement

31 Food Intolerance and Allergy Single study with control group and blinded evaluators: Single study with control group and blinded evaluators: Found significant improvement in social abilities, cognition and attention after 1 year Found significant improvement in social abilities, cognition and attention after 1 year Knivsberg, et al, Scan J Edu & Research, 1995 Knivsberg et al, Nutri Neurosci 2002

32 Food Intolerance and Allergy Most studies of gluten and/or casein-free diets have included only children with abnormal urine peptide levels Most studies of gluten and/or casein-free diets have included only children with abnormal urine peptide levels Cannot generalize to all children with ASD Cannot generalize to all children with ASD Little evidence that dietary protein intolerance is more prevalence in ASD population Little evidence that dietary protein intolerance is more prevalence in ASD population Small sample size, lack of control group also make the studies hard to interpret. Small sample size, lack of control group also make the studies hard to interpret.

33 The Leaky Gut Hypothesis Based on the observations that autistic behaviors improved on dietary protein-free diets Based on the observations that autistic behaviors improved on dietary protein-free diets Theory is that a ‘leaky’ intestinal mucosa allows foods to enter the bloodstream. Theory is that a ‘leaky’ intestinal mucosa allows foods to enter the bloodstream.

34 The Leaky Gut Hypothesis Digestion of gluten and casein releases short chain peptides which are similar to endorphins. Digestion of gluten and casein releases short chain peptides which are similar to endorphins. These peptides are called ‘exorphins’ These peptides are called ‘exorphins’ Wheat products gliadomorphins Wheat products gliadomorphins Milk protein caseomorphins Milk protein caseomorphins Zioudrou, Streaty, Klee. J Biol Chem. 1979

35 A Close Look At Membranes

36 Abnormal Gut Permeability: Associated Conditions

37 Symptoms Associated with A Leaky Gut

38 The Leaky Gut Hypothesis Orally administered gluten fragments have been detected in rat brains Orally administered gluten fragments have been detected in rat brains Opiate receptors in brain bind gluten exorphins Opiate receptors in brain bind gluten exorphins Casein exorphins infused into bloodstream of rats activates the rat brain. Casein exorphins infused into bloodstream of rats activates the rat brain. Dohan, Adv Biochem Psychopharmocol, 1980; Hemmings, Proc Roy Coc London Ser B, 1978)

39 The Leaky Gut Hypothesis Hypothesis: Gliadomorphins and casomorphins from partially digested gluten and casein are: Hypothesis: Gliadomorphins and casomorphins from partially digested gluten and casein are: Absorbed through a leaky gut Absorbed through a leaky gut Enter the CNS Enter the CNS Interfere with normal brain function by mimicking the opioid hormone beta-endorphin. Interfere with normal brain function by mimicking the opioid hormone beta-endorphin.

40 Lymphoid Nodular Hyperplasia (LNH)

41 LNH: What does it supposed to mean?... Enhanced activation of lymphoid tissue in the intestine Triggered by food or viral antigens Causing an inflammatory reaction Resulting in increased permeability and a leaky gut

42 ASD and the GI Tract: Lessons Learned Future Directions and Challenges

43 Getting It Right: Commonsense Principles No two ASD/PDD children are exactly alike No two ASD/PDD children are exactly alike Generalizing is always tempting and an easier path to take Generalizing is always tempting and an easier path to take Human behavior is controlled by a complex interplay of factors Human behavior is controlled by a complex interplay of factors “Cookbook” recommendations are not going to benefit all children “Cookbook” recommendations are not going to benefit all children Pushing the envelope of conventional medicine is commendable…up to a point Pushing the envelope of conventional medicine is commendable…up to a point

44 Expanding Knowledge Anecdotal reports are the landmines of medicine Anecdotal reports are the landmines of medicine Sound principles of science should not be sacrificed in the name of ideologies Sound principles of science should not be sacrificed in the name of ideologies Progress will only evolve from well gathered information and data interpretation Progress will only evolve from well gathered information and data interpretation Medical providers and families can be a powerful team…or they can easily become antagonistic aliens! Medical providers and families can be a powerful team…or they can easily become antagonistic aliens!

45 Summary Providing adequate nutrition to children with ASD remains a major challenge Providing adequate nutrition to children with ASD remains a major challenge Working close with a nutritionist or dietitian is important to avoid preventable deficiencies (or excesses) Working close with a nutritionist or dietitian is important to avoid preventable deficiencies (or excesses) Understanding the neurobiology of autism will foster development of well founded interventions Understanding the neurobiology of autism will foster development of well founded interventions

46 And Finally….   To understand the proper role of GI complaints and nutritional issues impacting on the behavior of ASD children requires constant reevaluation and an open (but always critical) mind


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