GI Issues in Autism: Co-Morbidity or Causation

Autism: Bridging the Gap Between Knowledge and Practice

Augusta Maine 5/12/09

Timothy Buie MDMassachusetts General Hospital for Children/

Harvard Medical School

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

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

The Fall and Rise of Disease Prevalence in the last 50 years

Bach , J NEJM 2002;347:911-920, California Department.of Social Services, CDCSlide Courtesy of Bernard Kinane MD

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

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

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

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

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

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

Autism/GI Issues Historical Review

Opioid Peptide Theory -- Shattock (1990) and Reichelt (1991) -- peptides from milk and gluten caused schizophrenia and autism.

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

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)

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

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.

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)

Secretin does not work

The jury is in Parents are ? in

Research looking at Secretin as a neurotransmitter continues

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

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)

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

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

Other speculated treatments

To continue with some of the discussed biomedical treatments…

Other Diets

Feingold (Sodium Benzoate free, dye –free)

Specific Carbohydrate Diet Low Oxalate Diet Yeast-Free Diets

Other Biomedical Intervention

Vitamins Minerals Fish Oil/Essential Fatty Acids Chelation of Heavy Metals Hyperbaric Oxygen Therapy Music Therapy Massage

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

Jury

Parents better/no

effect

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%)

Jury

Parents better/no

effect

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.

Jury

Parents better/no

effect

Chelation

No controlled studies 73%/24% n=627

Mercury debate

Jury

Parents better/no

effect

Hyperbaric Oxygen Therapy

Two published papers 52%/42% n=66

Most published data for HBOT is based on hard chamber, high pressure protocols

Jury

Parents better/no

effect

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

Music Therapy

Reported as helpful, improving communication over long term for children with autism

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!

Sensory Therapy/Massage

Data is promising and merits ongoing research

Sleep

Sleep disorders are shown to affect pain perception, learning targets, anxiety among many outcomes

Vicious cycles Sleep and GE Reflux

Back to GI

Please allow me to return away from treatment ideas back to GI problems reported

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

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

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

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

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

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

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?

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.

Patient 1

Patient 2

Patient 3

Patient 4

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

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

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

Case 2

Patient with Sandifer’s Syndrome

Case 2: Esophagitis

Case 3: Self-Injurious Behavior

Case 3: Esophagitis

SIB resolved on treatment

GERD is an example of Co-Morbidity

Gastritis Colitis Irritable Bowel Syndrome Constipation and motility based

disorders Food allergy and sensitivity Overgrowth syndromes

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

GI Symptoms in ASD and MET Gene

Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16621-2.

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.

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

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

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)

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

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

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