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

Gastrointestinal Gastrointestinal Disorders of Children Disorders of Children

with Autistic Spectrum with Autistic Spectrum DisordersDisordersJoseph Levy, M.D.

Professor of Clinical PediatricsDirector, Program in Neurogastroenterology

Columbia University Medical CenterMorgan Stanley Children’s Hospital of NY Presbyterian

Outline and GoalsOutline and Goals Review the GI and nutritional issues Review the GI and nutritional issues

impacting on the health of children on the impacting on the health of children on the autism spectrumautism spectrum

Prepare parents and professionals to Prepare parents and professionals to critically appraise the pertinent critically appraise the pertinent information…or how much can we trust information…or how much can we trust anecdotes?anecdotes?

Propose guidelines for assessing adequacy Propose guidelines for assessing adequacy of nutritional intake and the need for of nutritional intake and the need for supplementssupplements

Autistic Spectum Autistic Spectum DisordersDisorders

1.1. Social interactionSocial interaction

2.2. Verbal and nonverbal Verbal and nonverbal communicationcommunication

3.3. Repetitive behaviors or Repetitive behaviors or interests interests

4.4. ? GI disorders? GI disorders

GI symptoms reported in GI symptoms reported in ASDASD

Nonspecific symptoms:Nonspecific symptoms: Chronic DiarrheaChronic Diarrhea ConstipationConstipation Foul-smelling stoolsFoul-smelling stools Excessive gas Excessive gas Abdominal bloatingAbdominal bloating Abdominal painAbdominal pain VomitingVomiting

GI symptoms in ASDGI symptoms in ASD

Do children with ASD really Do children with ASD really have have more more gastrointestinal gastrointestinal symptoms than other symptoms than other children?children?

Lack of published rigorous Lack of published rigorous data that show increased GI data that show increased GI symptoms in children with symptoms in children with ASDASD

Prevalence of GI Prevalence of GI symptoms:symptoms:

A Little PerspectiveA Little Perspective Gastrointestinal complaints Gastrointestinal complaints

are very common in children are very common in children with normal development:with normal development:

Constipation rates 16%-37%Constipation rates 16%-37%

Cow’s milk protein intolerance Cow’s milk protein intolerance 0.3-7.5% of otherwise normal 0.3-7.5% of otherwise normal infantsinfants

Loening-Baucke, NEJM 1998Loening-Baucke, NEJM 1998

Prevalence of GI Prevalence of GI symptomssymptoms

There is very little reliable There is very little reliable information about whether GI information about whether GI symptoms are part of ASD.symptoms are part of ASD.

Bias:Bias: SelectionSelection ReferralReferral RecallRecall


Retrospective survey comparing 412 Retrospective survey comparing 412 children with ASD and 43 siblings:children with ASD and 43 siblings:

85.3% ASD had at least one GI symptom 85.3% ASD had at least one GI symptom compared to 28.6% siblings.compared to 28.6% siblings.

Horvath & Perman, Current Gast Reports 2002a, CurrentHorvath & Perman, Current Gast Reports 2002a, Current Op Ped Op Ped 20022002


Survey of 500 parents:Survey of 500 parents: 50% reported daily loose stools or frequent 50% reported daily loose stools or frequent

diarrheadiarrhea 33% abdominal pain33% abdominal pain 20% more than 3 stools a day20% more than 3 stools a day

No control group, no note of selection No control group, no note of selection criteriacriteria

Lightdale, Siegel & Heyman, Clin Perspect Gast, 2001Lightdale, Siegel & Heyman, Clin Perspect Gast, 2001


Review of medical histories of 285 Review of medical histories of 285 children with PDD, 48 non-autistic children with PDD, 48 non-autistic siblings, and 102 unrelated controls:siblings, and 102 unrelated controls:

19% of children with PDD had constipation19% of children with PDD had constipation 19% diarrhea, 7% alternating 19% diarrhea, 7% alternating

constipation/diarrhea.constipation/diarrhea. <10% controls had diarrhea or constipation.<10% controls had diarrhea or constipation.

Melmed, Schneider, Fabes, Phillips & Reichelt, J Ped Gastro & Nut, 2000Melmed, Schneider, Fabes, Phillips & Reichelt, J Ped Gastro & Nut, 2000

Prevalence of GI Prevalence of GI symptoms: symptoms:

Asking a few questions goes a long Asking a few questions goes a long way…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 Was information obtained from the parents or from medical the parents or from medical records?records?

What was the working definition What was the working definition of ‘diarrhea’ and ‘constipation’ ?of ‘diarrhea’ and ‘constipation’ ?

Prevalence of GI symptoms: Prevalence of GI symptoms:

A matter of timingA matter of timing Case-controlled study from UK Case-controlled study from UK

evaluated the frequency of GI evaluated the frequency of GI complaints complaints beforebefore ASD was diagnosed: ASD was diagnosed:

Exactly the same percentage (9%) of Exactly the same percentage (9%) of autistic and normally developing children autistic and normally developing children had GI symptoms before the date of had GI symptoms before the date of diagnosis.diagnosis.

Black, Kaye & Jick, Brit Med J, 2002Black, Kaye & Jick, Brit Med J, 2002

Prevalence of GI symptoms in Prevalence of GI symptoms in ASD vs. ControlsASD vs. Controls

Most recent study compared 50 ASD Most recent study compared 50 ASD children with 50 having other children with 50 having other developmental delays (DD) and 50 developmental delays (DD) and 50 with normal development:with normal development:

History of GI symptoms:History of GI symptoms: 70% ASD70% ASD 28% Normal Children28% Normal Children 42% Other DD42% Other DD

Valicenti-McDermott, McVicar, Rapin, et al. J Dev Behav Pediatr, 2006Valicenti-McDermott, McVicar, Rapin, et al. J Dev Behav Pediatr, 2006

Prevalence of GI symptoms in Prevalence of GI symptoms in ASD vs. ControlsASD vs. Controls

Abnormal stooling pattern:Abnormal stooling pattern: 18% ASD18% ASD 4% Normal4% Normal 2% DD2% DD

Food selectivity:Food selectivity: 60% ASD60% ASD 22% Normal22% Normal 36% DD36% DD

Prevalence of GI Prevalence of GI symptoms: symptoms: It’s all over!It’s all over!

Most of the data published Most of the data published regarding GI symptoms is regarding GI symptoms is derived from parental recall or derived from parental recall or medical recordsmedical records

Places the prevalence of GI Places the prevalence of GI symptom somewhere between… symptom somewhere between…

17%-86%!17%-86%!

(Erickson, Stigler, Corkins, et al, J Autism & Dev (Erickson, Stigler, Corkins, et al, J Autism & Dev Disorders, 2005)Disorders, 2005)

What Triggers GI What Triggers GI Symptoms?Symptoms?

Immaturity of the nerves and muscles Immaturity of the nerves and muscles responsible for moving food alongresponsible for moving food along

Enzyme deficienciesEnzyme deficiencies

Malabsorption of nutrients (sugars, Malabsorption of nutrients (sugars, fats, proteins)fats, proteins)

Immune-mediated inflammation and Immune-mediated inflammation and damagedamage

Structure of the GI TractStructure of the GI Tract

Structural relations of Structural relations of the ENSthe ENS

Sources of Intestinal Sources of Intestinal PainPain

Overstretching of muscles (gas, spastic Overstretching of muscles (gas, spastic contractions)contractions)

Acid-mediated irritation of esophagus Acid-mediated irritation of esophagus (GERD)(GERD)

Hypersensitive “second brain” (The Hypersensitive “second brain” (The brain in the gut or the ENS)brain in the gut or the ENS)

Abnormal blood flowAbnormal blood flow

Consequences of GI Consequences of GI DysfunctionDysfunction

Acute and chronic pain Acute and chronic pain

Interference with consumption of Interference with consumption of adequate nutrientsadequate nutrients Aversive conditioningsAversive conditionings Food intolerance and protein allergyFood intolerance and protein allergy Limited food choicesLimited food choices

Abnormal stooling patternsAbnormal stooling patterns

Diet and NutritionDiet and Nutrition

Repetitive behaviors and insistence on Repetitive behaviors and insistence on sameness in ASD can have negative sameness in ASD can have negative effect on dieteffect on diet

Limited food choices is frequent Limited food choices is frequent complaint of families with autistic complaint of families with autistic childrenchildren

A higher incidence of pica has also been A higher incidence of pica has also been noted by parents of autistic childrennoted by parents of autistic children

Pica (hair ball) in ASD Pica (hair ball) in ASD ChildChild

Diet and NutritionDiet and Nutrition

Nutritional status has been evaluated Nutritional status has been evaluated by several small controlled and by several small controlled and uncontrolled studiesuncontrolled studies

Overall, it appears their nutrition is Overall, it appears their nutrition is adequateadequate

Selectivity does not result in Selectivity does not result in malnutritionmalnutrition

Raiten &Massaro, J Autism and Dev Disorders, 1986; Raiten &Massaro, J Autism and Dev Disorders, 1986; Shearer, et al, J Autism and Dev Disorders, 1982; Shearer, et al, J Autism and Dev Disorders, 1982;

Ahearn et al, J Autism and Dev Disorders, 2001; Ahearn et al, J Autism and Dev Disorders, 2001; Field & Williams, J Ped Child Health, 2003Field & Williams, J Ped Child Health, 2003

Food Intolerance and Food Intolerance and AllergyAllergy

Anecdotal reports from parents of Anecdotal reports from parents of children with ASD 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)


In 1971 investigators reported a case In 1971 investigators reported a case of a child with ASD and celiac disease:of a child with ASD and celiac disease:

Autistic behaviors worsened when Autistic behaviors worsened when exposed to gluten after a period with exposed to gluten after a period with gluten-free dietgluten-free diet

(Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971)(Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971)


This case inspired a study which This case inspired a study which measured trancephalic direct current measured trancephalic direct current (TDC) in children with ASD and GI (TDC) in children with ASD and GI symptoms:symptoms: ASD children showed inhibition of frontal ASD children showed inhibition of frontal

voltage in response to 1 g PO dose gliadinvoltage in response to 1 g PO dose gliadin No inhibition with 1 g sugarNo inhibition with 1 g sugar Siblings and normal controls showed no Siblings and normal controls showed no

response to either gliadin or sugarresponse to either gliadin or sugar ““Gluten has a direct effect on the Gluten has a direct effect on the

central nervous system”central nervous system”

Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971Goodwin, Cowen & Goodwin, J Autism Child Schizophrenia, 1971

Another source of biasAnother source of bias

All the ASD children in study had All the ASD children in study had previous GI complaints.previous GI complaints.

Error:Error: Generalizing differences found in a Generalizing differences found in a

subset of childrensubset of children Do Do allall children with ASD have children with ASD have

changes in response to a gluten changes in response to a gluten challenge? challenge? We do not knowWe do not know


Long-term prospective study of gluten and Long-term prospective study of gluten and milk-free diet in children with abnormal milk-free diet in children with abnormal urinary peptide levels:urinary peptide levels:

15 children in first report, original 15 + 15 15 children in first report, original 15 + 15 new participants in second reportnew participants in second report

Behavioral improvement noted by parents and Behavioral improvement noted by parents and teachers in both reportsteachers in both reports

Urine peptide levels normalized by one yearUrine peptide levels normalized by one year

Reichelt, et al. J App Nutr, 1990 Reichelt, et al. J App Nutr, 1990 Reichelt, et al. Brain Dysfunction, 1991Reichelt, et al. Brain Dysfunction, 1991


Another study with 15 participants:Another study with 15 participants:

Improved behavior and communication after Improved behavior and communication after 1 and 4 year periods1 and 4 year periods

Also limited to ASD children with abnormal Also limited to ASD children with abnormal urinary peptides; no control groupurinary peptides; no control group

None of the studies controlled for None of the studies controlled for concomitant educational or other concomitant educational or other behavioral interventions that could have behavioral interventions that could have caused improvementcaused improvement


Single study with control group and Single study with control group and blinded evaluators:blinded evaluators:

Found significant improvement in social Found significant improvement in social abilities, cognition and attention after 1 abilities, cognition and attention after 1 yearyear

Knivsberg, et al, Scan J Edu & Research, 1995 Knivsberg, et al, Scan J Edu & Research, 1995

Knivsberg et al, Nutri Neurosci 2002Knivsberg et al, Nutri Neurosci 2002


Most studies of gluten and/or casein-Most studies of gluten and/or casein-free diets have included only children free diets have included only children with abnormal urine peptide levelswith abnormal urine peptide levels

Cannot Cannot generalizegeneralize to all children with ASD to all children with ASD Little evidence that dietary protein Little evidence that dietary protein

intolerance is more prevalence in ASD intolerance is more prevalence in ASD populationpopulation

Small sample size, lack of control group Small sample size, lack of control group also make the studies hard to interpret.also make the studies hard to interpret.

The Leaky Gut The Leaky Gut HypothesisHypothesis

Based on the observations that Based on the observations that autistic behaviors improved on autistic behaviors improved on dietary protein-free dietsdietary protein-free diets

Theory is that a ‘leaky’ intestinal Theory is that a ‘leaky’ intestinal mucosa allows foods to enter the mucosa allows foods to enter the bloodstream.bloodstream.


Digestion of gluten Digestion of gluten and casein releases and casein releases short chain peptides short chain peptides which are similar to which are similar to endorphins.endorphins.

These peptides are These peptides are called ‘exorphins’called ‘exorphins’ Wheat products Wheat products

gliadomorphinsgliadomorphins Milk protein Milk protein

caseomorphinscaseomorphinsZioudrou, Streaty, Klee. J Biol Chem. 1979Zioudrou, Streaty, Klee. J Biol Chem. 1979

A Close Look At A Close Look At MembranesMembranes

www.biology.arizona.edu/

Abnormal Gut Permeability: Abnormal Gut Permeability: Associated Conditions Associated Conditions

Symptoms Associated with Symptoms Associated with A Leaky GutA Leaky Gut


Orally administered gluten fragments have Orally administered gluten fragments have been detected in rat brainsbeen detected in rat brains

Opiate receptors in brain bind gluten Opiate receptors in brain bind gluten exorphinsexorphins

Casein exorphins infused into bloodstream Casein exorphins infused into bloodstream of rats activates the rat brain.of rats activates the rat brain.

Dohan, Adv Biochem Psychopharmocol, 1980; Hemmings, Proc Roy Coc London Ser Dohan, Adv Biochem Psychopharmocol, 1980; Hemmings, Proc Roy Coc London Ser B, 1978)B, 1978)


Hypothesis: Gliadomorphins and Hypothesis: Gliadomorphins and casomorphins from partially casomorphins from partially digested gluten and casein are:digested gluten and casein are:

Absorbed through a leaky gutAbsorbed through a leaky gut Enter the CNS Enter the CNS Interfere with normal brain function by Interfere with normal brain function by

mimicking the opioid hormone beta-mimicking the opioid hormone beta-endorphin. endorphin.

Lymphoid Nodular Lymphoid Nodular Hyperplasia (LNH)Hyperplasia (LNH)

LNH: LNH: What does it supposed to What does it supposed to

mean?...mean?...

Enhanced activation of lymphoid tissue in Enhanced activation of lymphoid tissue in the intestinethe intestine

Triggered by food or viral antigensTriggered by food or viral antigens

Causing an inflammatory reactionCausing an inflammatory reaction

Resulting in increased permeability and a Resulting in increased permeability and a leaky gutleaky gut

ASD and the GI ASD and the GI Tract:Tract:

Lessons LearnedLessons Learned

Future Directions and Future Directions and ChallengesChallenges

Getting It Right:Getting It Right:Commonsense PrinciplesCommonsense Principles

No two ASD/PDD children are exactly No two ASD/PDD children are exactly alikealike

Generalizing is always tempting and an Generalizing is always tempting and an easier path to takeeasier path to take

Human behavior is controlled by a Human behavior is controlled by a complex interplay of factorscomplex interplay of factors

““Cookbook” recommendations are not Cookbook” recommendations are not going to benefit all childrengoing to benefit all children

Pushing the envelope of conventional Pushing the envelope of conventional medicine is commendable…up to a pointmedicine is commendable…up to a point

Expanding KnowledgeExpanding Knowledge Anecdotal reports are the Anecdotal reports are the

landmines of medicinelandmines of medicine

Sound principles of science should Sound principles of science should not be sacrificed in the name of not be sacrificed in the name of ideologiesideologies

Progress will only evolve from well Progress will only evolve from well gathered information and data gathered information and data interpretationinterpretation

Medical providers and families can Medical providers and families can be a powerful team…or they can be a powerful team…or they can easily become antagonistic aliens!easily become antagonistic aliens!

SummarySummary

Providing adequate nutrition to children Providing adequate nutrition to children with ASD remains a major challengewith ASD remains a major challenge

Working close with a nutritionist or Working close with a nutritionist or dietitian is important to avoid dietitian is important to avoid preventable deficiencies (preventable deficiencies (or excessesor excesses))

Understanding the neurobiology of Understanding the neurobiology of autism will foster development of well autism will foster development of well founded interventionsfounded interventions

And Finally….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

Documents

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