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
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

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

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

5. GI symptoms in ASD
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

6. Prevalence of GI symptoms: A Little Perspective
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.
Bias:
Selection
Referral
Recall

8. Prevalence of GI symptoms
Retrospective survey comparing 412 children with ASD and 43 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:
50% reported daily loose stools or frequent diarrhea
33% abdominal pain
20% more than 3 stools a day
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:
19% of children with PDD had constipation
19% diarrhea, 7% alternating constipation/diarrhea.
<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 were the patients selected?
Was information obtained from the parents or from medical records?
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:
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:
History of GI symptoms:
70% ASD
28% Normal Children
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:
18% ASD
4% Normal
2% DD
Food selectivity:
60% ASD
22% Normal
36% DD

15. Prevalence of GI symptoms in ASD vs. Controls
Limitations of this study:
Relies on family reports of symptoms
(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
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
Enzyme deficiencies
Malabsorption of nutrients (sugars, fats, proteins)
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)
Acid-mediated irritation of esophagus (GERD)
Hypersensitive “second brain” (The brain in the gut or the ENS)
Abnormal blood flow

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

22. Diet and Nutrition
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
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
Overall, it appears their nutrition is adequate
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
Most report intolerance for
cow’s milk (casein protein) or
wheat (gluten protein)

26. Food Intolerance and Allergy
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
(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:
ASD children showed inhibition of frontal voltage in response to 1 g PO dose gliadin
No inhibition with 1 g sugar
Siblings and normal controls showed no response to either gliadin or sugar
“Gluten has a direct effect on the central nervous system”
TDCs: slowly changing voltages recorded from the surface of the head and originating from the cortex of the brain.
Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971

28. Another source of bias
All the ASD children in study had previous GI complaints.
Error:
Generalizing differences found in a subset of children
Do all children with ASD have changes in response to a gluten challenge?
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:
15 children in first report, original new participants in second report
Behavioral improvement noted by parents and teachers in both reports
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:
Improved behavior and communication after 1 and 4 year periods
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

31. Food Intolerance and Allergy
Single study with control group and blinded evaluators:
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
Cannot generalize to all children with ASD
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.

33. The Leaky Gut Hypothesis
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.

34. The Leaky Gut Hypothesis
Digestion of gluten and casein releases short chain peptides which are similar to endorphins.
These peptides are called ‘exorphins’
Wheat products gliadomorphins
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
Opiate receptors in brain bind gluten exorphins
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:
Absorbed through a leaky gut
Enter the CNS
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. Lessons Learned Future Directions and Challenges
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
Generalizing is always tempting and an easier path to take
Human behavior is controlled by a complex interplay of factors
“Cookbook” recommendations are not going to benefit all children
Pushing the envelope of conventional medicine is commendable…up to a point

44. Expanding Knowledge Anecdotal reports are the landmines of medicine
Sound principles of science should not be sacrificed in the name of ideologies
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!

45. Summary
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)
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