Gastrointestinal Disorders of Children with Autistic Spectrum Disorders Joseph Levy, M.D. Professor of Clinical PediatricsDirector, Program in Neurogastroenterology Columbia University Medical Center Morgan Stanley Children’s Hospital of NY Presbyterian
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
Autistic Spectum Disorders • Social interaction • Verbal and nonverbal communication • Repetitive behaviors or interests • ? GI disorders
GI symptoms reported in ASD • Nonspecific symptoms: • Chronic Diarrhea • Constipation • Foul-smelling stools • Excessive gas • Abdominal bloating • Abdominal pain • Vomiting
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
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 0.3-7.5% of otherwise normal infants Loening-Baucke, NEJM 1998
Prevalence of GI symptoms • There is very little reliable information about whether GI symptoms are part of ASD. • Bias: • Selection • Referral • Recall
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, CurrentOp Ped 2002
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
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
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’ ?
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
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
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
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)
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
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
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
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
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
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)
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)
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” Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971
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
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 15 + 15 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
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
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
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.
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.
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
A Close Look At Membranes www.biology.arizona.edu/
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)
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.
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
ASD and the GI Tract: Lessons Learned Future Directions and Challenges
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
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!
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
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