A gluten

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A gluten- casein-free diet as an intervention
for autism spectrum disorder (ASD).

• Paul Whiteley, Research Fellow
• Autism Research Unit
• Department of Pharmacy, Health Wellbeing
• Faculty of Applied Sciences, University of
  Sunderland, UK

http//osiris.sunderland.ac.uk/autism
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Aims of presentation

• The diet / health relationship.
• Dietary interventions for ASD.
• Gluten casein-free diets.
• Evidence currently available.
• ScanBrit trial.
• Potential mode(s) of action.

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Caveats

• Much of the research in this presentation
  remains
• under investigation.
• Based on peer-reviewed research articles
• (published or in press) not grey
  literature.
• Dietary intervention should be viewed as
• complimentary to other approaches for ASD.
• Consultation with your childs physician is
  advised
• before embarking on any dietary change.

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Interventions for ASD

• Any intervention for ASD needs to bear in mind
  four very important factors
• that will affect outcome
• (1) ASD (or PDD) is Pervasive.
• Spread throughout, all encompassing.
• (2) ASD is Heterogeneous.
• Not uniform in structure or composition.
• (3) ASD is often accompanied by co-morbidities.
• e.g. epilepsy, ADHD, anxiety-related problems
• (4) People with ASD differentially develop
  without specific intervention.
• Age environment may play a role

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Diet health are linked not just another
casual relationship!
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Diet health relationship

• Examples of a relationship between diet health
• Physical health
• Obesity malnutrition significantly increased
  risk of developing several
• physical symptoms health-related diseases
  (including death).
• Cognitive-mental health
• PKU (Phenylketonuria) a leading causes of
  learning disability
• prior to the discovery of Imbecillitas
  Phenylpyruvica. (Følling,1934)
• Physical cognitive-mental health
• Coeliac (see-lee-ak) disease reaction to gluten
  protein causing
• GI malabsorption, failure to thrive linked to
  increased risk of
• psychiatric co-morbidity (see later).
  (Aretaeus the Cappadocean, 200AD Gee, 1887)

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Diet ADHD acknowledgement of a relationship
Schonwald A. (2008) AAP Grand Rounds 19 17
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Could diet also affect ASDs?
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Q How many types of dietary intervention are
being used as an intervention for ASD?

• A Numerous !
• Including (individually or combinations of)
• Gluten / casein-free diets (Cereal and
  mammalian dairy produce)
• MSG / aspartame free diets (Flavour
  enhancer/artificial sweetener)
• Lutein-free diet (Carotenoid from fruit /
  vegetables)
• Feingold diet (Artificial flavourings /
  colourings)
• SCD (Complex carbohydrates / starches /
  processed sugars)
• Combined with various dietary supplements
  (?-3 oils, vitamins).

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Q How much evidence is there to support the use
of these dietary interventions in ASD?
A It depends on who you talk to! Parents
/ primary caregivers Health / education /
social care professionals Researchers
Media Government (All with varying degrees
of persuasiveness!)
Autism Research Institute Feb 2008
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Q How much scientific evidence is there to
support the use of dietary intervention in ASD?
A Some, of varying degrees of objectivity
e.g. Ketogenic diet and autism (?fat ?protein,
carb) N30 children (4-10 years old) 60
of children showed improvement (varying degrees)
on CARS. Evangeliou A. et al (2003)
Application of a ketogenic diet in children with
autistic behaviour pilot study. Journal of
Child Neurology 18 113-118
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Q Which dietary intervention for ASD has been
studied the most?
A Gluten and casein-free diets As of
2001 11 Group studies 2 Surveys 3 Case
reports multiple anecdotal reports Several
other studies have been added to the list since.
Knivsberg A-M. et al (2001) Reports on
Dietary Intervention in Autistic Disorders.
Nutritional Neuroscience 4 25-37
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Gluten casein

• What is gluten ?
• A mixture of two proteins, gliadin glutenin
  that give
• flour a cohesive, elastic property to turn
  into dough.
• Present in wheat, barley rye (oats lt20
  avenin).
• What is casein ?
• Primary protein found in mammalian dairy
  sources.
• Several variants according to order / species.
• Present in milk, cheese yogurts.
• Kaminski S. et al (2007) Polymorphism of
  bovine beta-casein and its potential effect on
  human health.
• Journal of Applied Genetics 48 189-198

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History of gf-cf diets in psychiatry

• Schizophrenia psychotic disorders.
• Improvement in psychiatric symptoms on diet.
• Dohan FC. et al (1973) Relapsed
  schizophrenics earlier discharge from the
  hospital after cereal-free, milk-free diet.
• American Journal of Psychiatry 130
  685-688.
• Vlissides DN. et al (1986). A double-blind
  gluten-free/gluten-load controlled trial in a
  secure ward population.
• British Journal of Psychiatry 148 447-452
• Extrapolation to autism related ASDs.
• Several trials suggestive of amelioration of
  symptoms.

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Dietary intervention studies

• Knivsberg A-M. et al (1990) Dietary intervention
  in autistic syndromes. Brain Dysfunction 3
  315-327
• Effect of both a gluten- casein-free diet
  (n15 6-22 years)
• Open trial (non-blinded / non-randomised).
• Improvements reported in several areas
• Social interaction
• Language use / comprehension
• Sensory / motor abilities
• Reduction in peptide-like urinary material
• Participants followed-up after 4 years
  improvements continued.

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Dietary intervention studies

• Lucarelli S. et al (1995) Food allergy and
  infantile autism, Panminerva Medica 37 137-141
• Effect of casein-free diet (alone)
• (n36 age 8-13 yrs) control group (n20)
• Blind casein-challenge (placebo vs. casein
  capsules).
• Significant changes (improvement) after 8 weeks
  of diet (BSE).
• (e.g. isolation, verbal communication,
  cognition)
• Detrimental changes to scores following dietary
  challenge.

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Dietary intervention studies

• Whiteley P. et al (1999) A gluten free diet
  as an intervention for autism. Autism 3 45-65
• Effect of a gluten-free diet (alone) (n22 mean
  age 4 years).
• Open trial (non-blinded / non-randomised)
  control groups.
• Significant changes (improvement) after 5 months
  of diet (BSE)
• motor (p0.04) eating disturbances (p0.01),
  attention (p0.02)
• Improvement on 3 out of 6 cognitive subtests.
• Changes to levels of urinary IAcrGly.

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Behavioural effects 1

• From the research trials conducted so far, the
• behavioural effects of dietary intervention
  include
• Attention concentration
• Communication language
• Social integration
• Motor co-ordination
• Self-injurious behaviours But

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Behavioural effects 2

• Some indications of significant changes in group
  
• results although not universally successful.
• More detailed analysis of individual results
  suggested
• that the younger, more severely affected
  children
• were best responders.
• Parents tended to be more pleased with the
  results
• than teachers.

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Transient negative effects

• Withdrawal phase is common at the early stages
  of
• dietary intervention.
• Variable more apparent in younger children.
• Anxiety clinginess
• Crying general whinginess
• Staring into space
• Dizziness / decrease in movement
• Increased frequency of urination / defecation
• Flu type symptoms (adults)

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Breaking the diets

• Transient but sometimes extreme reactions to the
  
• ingestion of even small amounts of gluten /
  casein.
• e.g. Increased hyperactivity
• Spacing out
• Increased aggression
• Abatement of reactions following re-adoption of
  the
• dietary intervention.

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Somatic symptoms in ASD

• Evidence for the existence of somatic features
  co-morbid
• to ASD diagnostic features.
• Preliminary reports of improvement in somatic
  symptoms
• following dietary intervention.
• Whiteley P. et al (1998) Clinical features
  associated with autism observations of symptoms
  outside the diagnostic boundaries of
• autism spectrum disorders. Autism 2
  415-422
• Whiteley P. (2004) Developmental, behavioural
  and somatic factors in pervasive developmental
  disorders preliminary analysis.
• Child Care, Health Development 30 5-11

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Abnormal bowel habits / conditions

• One quarter of children with ASD have at least
  one
• chronic gastrointestinal (GI) symptom.
• Molloy CA. et al (2003) Prevalence of
  chronic gastrointestinal symptoms in children
  with autism and autistic spectrum disorders.
• Autism. 7165-171
• Consumption of milk is a strong predictor of
  constipation.
• Afzal N. et al (2003) Constipation with
  acquired megarectum in children with autism.
  Pediatrics 112 939-942
• Significant ? in mucosal eosinophil infiltrate
  on gluten
• and casein-free diet.
• white blood cell responsible for combating
  infection controlling mechanisms involved in
  allergy
• Ashwood P. et al (2003) Intestinal
  lymphocyte populations in children with
  regressive autism evidence for extensive mucosal
• immunopathology. Journal of Clinical
  Immunology 23 504-517

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Nutritional status on diet

• Not a widely researched area but
• No significant differences in energy, protein
  nutrient intake
• whilst on a gluten- casein-free diet.
• Cornish E. (2002) Gluten and casein free diets
  in autism a study of the effects on food choice
  and nutrition.
• Journal of Human Nutrition Dietetics. 15
  261-269
• Stewart PA. et al (2008) Nutritional quality
  of the gluten-free and casein-free diet. IMFAR
  poster proceedings
• Trend towards ? levels of plasma tryptophan
  tyrosine
• (? tryptophan has been found in non-dietary
  participants).
• Arnold GL. et al (2003) Plasma amino acids
  profiles in children with autism potential risk
  of nutritional
• deficiencies. JADD 39 449-454

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Bone thickness calcium

• Hediger et al (2008) Reduced bone cortical
  thickness in boys with autism or ASD. JADD
• Bones were growing longer but not thicker than
  normal.
• Possible explanations
• Use of casein-free diet (? calcium vitamin D
  intake).
• Lack of variety in food habits.
• GI issues affecting absorption of vitamins /
  minerals.
• Stewart C. Latif A. (2008) Symptomatic
  nutritional rickets in a teenager with autistic
  spectrum disorder.
• Child Care, Health Development 34
  276-278
• Requires further research on actual bone density
  (not thickness).
• Reiterates the need for involvement of dietetic
  support.

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The British Dietetic Association Effective
Practice Bulletin Issue 37 November 2003
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Methodological issues

• Issues yet to be addressed
• Open-trials not controlled trials.
• Confirmation of diagnosis (ADI-R, ADOS-G).
• Clarity on why the diet/s are working.
• Recommendations of the Cochrane Review report
• (2004) MRC report on autism research (2001).

Millward C. et al (2004 2008) Gluten and
casein-free diets for autistic spectrum disorder.
CD003498
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Double-blind study

• Elder et al (2006) The gluten-free,
  casein-free diet In autism results of a
  preliminary double blind clinical trial. JADD
• Effect of a gluten-free /casein-free diet (n15
  age 2-6 yrs).
• Double-blind cross-over trial.
• 12 week study (6 weeks on diet / 6 weeks off).
• No significant changes to scores or peptide
  levels but
• some reports of improvements on diet (real /
  placebo?).
• Author criticism Low study power / not long
  enough on diet?

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ScanBrit dietary study

• Effect of a gluten-free casein-free diet
  (n72 age 4-11 yrs).
• (ClinicalTrials.gov ID NCT00614198)
• Single-blind, randomised-controlled,
  matched-pair trial.
• Comprehensive assessments (SCQ, ADOS, VABS,
  GARS, ADHD-IV)
• Additional measures (dietary habits, somatic
  symptoms, urine
• profiles, anthropometric data, quality of
  life).
• Adaptive design with interim analysis based on
  pre-defined
• thresholds of positive improvement (A 24
  months, B 12 months).

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Why might these diets work for people with ASD?
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The role of classical allergy?

• Classical allergy response by the immune system.
• Production of antibodies called Immunoglobulins
  (Ig-) to
• an allergen (inflammatory response).
• Various isotypes / classes of Ig- (IgA, IgE,
  IgG, IgM).
• IgE (Type-1 hypersensitivity) classical
  allergy.
• Some indication of possible allergy to milk in
  ASD. (Lucarelli et al, 1996)
• Contradictory evidence from skin prick tests.
  (Bakkaloglu et al, 2008)
• Male D. et al (1996) Immunology (7th Edition).
  Mosby. (Prof. J. Brostoff as co-author)
• Lucarelli S. et al (1995) Food allergy and
  infantile autism, Panminerva Medica 37 137-141
• Bakkaloglu B. et al (2008) Atopic features in
  early childhood autism. European Journal of
  Paediatric Neurology

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Lessons from coeliac disease?

• Autoimmune-type GI disease genes
  environment.
• Most prevalent in the West of Ireland (potato
  famine ca.1845).
• Familial risk factor (approx. 4.5 prevalence
  amongst 1 relatives)
• Can be clinically silent (no serious overt
  symptoms).
• Various somatic symptoms (present or not present)
  including
• Functional bowel habit problems
• Fatigue / muscle wasting
• Dyspepsia (pain / discomfort in upper GI tract)
• Malabsorption
• Anaemia (?Fe or folate)
• Walker-Smith J. Murch S. (1999) Diseases
  of the small intestine in childhood (4th
  edition). Isis Medical Media.

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Lessons from coeliac disease?

• Interesting parallels in somatic symptoms but
• Co-morbidity of CD ASD rare?? (no routine
  screening!).
• People with CD do not necessarily present with
  autism.
• Untreated CD is however associated with the
  appearance of various
• behavioural / psychological symptoms including
• Depression (Ciacci et al, 1998)
• Disruptive behaviours (Pynnönen et al, 2004)
• Anxiety (Addolorato et al, 2001)
• Learning disorders (Zelnik et al, 2004)
• Schizophrenia (De Santis et al, 1997)

A peripheral association between CD ASD cannot
be ruled out.
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A role for opiates?

• Opioids class of natural synthetic
  compounds
• that bind to opioid receptors found in the CNS
• and gastrointestinal tract (agonists).
• Morphine is an exogenously derived opiate.
• Endorphins enkephalins are endogenous opiates.
• Opioid peptides (chains of amino-acids) formed
  as a
• consequence of the digestion of proteins.
• e.g. gluten (cereal produce) gluten
  exorphins
• Zioudrou C. et al (1979) Opioid peptides derived
  from food proteins the exorphins. Journal of
  Biological Chemistry 254 2446-49
• Terenius L. et al (1986) Opioid peptides in the
  cerebrospinal fluid of psychiatric patients.
  Progress in Brain Research 65 207-219
• Teschemacher H, Koch G. (1991) Opioids in the
  milk. Endocrine Regulations 25 147-150
• Fukudome S. et al (1997) Release of opioid
  peptides, gluten exorphins by the action of
  pancreatic elastase. FEBS 412 475-479

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Opiate effects overlap with ASD

• Psychological
• ? desire for social contact diminished
  clinging behaviour.
• opioids inhibit the release of oxytocin the
  social hormone
• ? stereotypic behaviours (effects of
  apomorphine).
• Impaired developmental, behavioural
  organisational abilities.
• Somatic
• Altered EEG patterns.
• ? tolerance to pain (analgesia).
• Functional bowel habit problems (e.g.
  constipation).
• Physiological / psychological effects following
  withdrawal.
• Urca G. et al (1977) Morphine and
  enkephalin analgesic and epileptic properties.
  Science 4298 83-86
• Kalat JW. (1978) Speculations on
  similarities between autism and opiate addiction.
  JACS 8 477-479
• Panksepp, J. (1979) A neurochemical theory
  of autism. Trends in Neurosciences 2 174-177
• Mihatsch WA. et al (2005) Hydrolysis of
  casein accelerates gastrointestinal transit via
  reduction of opioid receptor agonists
• released from casein in rats. Biology of the
  Neonate 87 160-163
• Martindale The complete drug reference
  (2007) Pharmaceutical Press

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Opiate-related findings in ASD

• ? levels of endorphin fragments in CSF samples.
• Gillberg C. et al (1985) Endorphin activity in
  childhood psychosis. Spinal fluid levels in 24
  cases.
• Archives of General Psychiatry 42 780-783
• ? in plasma samples and family members - broader
  phenotype?
• Leboyer M. et al (1999) Whole blood serotonin
  and plasma beta-endorphin in autistic probands
  and their first-degree
• relatives. Biological Psychiatry 45
  158-163
• ? in blood of neonates who went on to develop
  ASD.
• Still under investigation following
  replication of these findings (Nelson et al,
  2006)
• Nelson K. et al (2001) Neuropeptides and
  neurotrophins in neonatal blood of children with
  autism or mental retardation.
• Annals of Neurology 49 597-606
• Clinical use of opioid antagonists (e.g.
  Naloxone / Naltrexone).
• Low dose naltrexone (LDN) also
  potentially effective for the treatment of
  inflammatory bowel disease (Crohns disease)
• Elchaar GM. et al (2006) Efficacy and
  safety of naltrexone use in pediatric patients
  with autistic disorder.

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Autism as a metabolic disorder?

• Body Brain Mind Behaviour
• GI tract brain derived from the same
  embryonic tissue.
• Initial indications of ? GI permeability (40).
• Walker-Smith J, Andrews J. (1972)
  Alpha-1-antitrypsin, autism coeliac disease.
  Lancet 7782 883-884
• DEufemia P. et al (1995) Abnormal
  intestinal permeability in children with autism.
  Acta Paediatrica 851076-1079
• ? transport of peptides ( other material)
  across to the CNS.
• Gardner ML. (1988) Gastrointestinal
  absorption of intact proteins. Annual Review of
  Nutrition 8 329-350
• Indications of abnormal GI conditions (bacteria,
  enzymes, etc).
• Finegold SM. et al (2002) Gastrointestinal
  microflora studies in late-onset autism. Clinical
  Infectious Diseases 35 S6-S16
• Parracho H. et al (2005) Differences between
  the gut microflora of children with autistic
  spectrum disorders and that of
• healthy children. Journal of Medical
  Microbiology 54 987-991
• Amelioration of some symptoms by physical
  therapy.
• Shattock P, Whiteley P. (2002) Biochemical
  aspects in autism spectrum disorders updating
  the opioid-excess theory and
• presenting new opportunities for biomedical
  intervention. Expert Opinion on Therapeutic
  Targets 6175-183

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Conclusions

• Exclusion diets may be helpful in ameliorating
  some of the
• core and/or secondary symptoms of PDD for some
  people.
• Balancing a constraining intervention with
  quality of life.
• Further data/research required on long-term
  safety.
• Theoretical basis to the diets is still under
  investigation although
• may include a GI element.
• Requirement for clinical support when using
  diets.
• Evidence for the use of diet as good as most
  other interventions
• (specialised education/behavioural plans).

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Acknowledgments
ScanBrit partners Dr. Demetrious Haracopos
1 Prof. Ann-Mari Knivsberg 2 Dr. Kalle (Tiny)
Reichelt 3 Dr. Judith Jacobsen 4 Dr. Anders
Seim Dr. Lennart Pedersen 1 Paul Shattock 5 Sarah
Parlar-Lorentzen 1 Maja Schondel 1 Maureen
Pilvang 1 Jonna Deibjerg 1 Charlotte Mathiesen
1 Prof. Stefan Samuelsson 6
Partner affiliations 1 The Center for Autisme,
Herlev, Denmark 2 National Centre for Reading
Education Research, University of Stavanger 3
Faculty of Medicine, University of Oslo 4 Statcon
ApS 5 Faculty of Applied Sciences, University of
Sunderland 6 Department of Behavioural Sciences,
Linköping University Thanks also to our study
funders The Center for Autisme The Nils O. Seim
Family Fund for Medical Research The Eric Birger
Christensen Fond The Norwegian Protein
Intolerance Association The Robert Luff
Foundation A huge thank you to a very important
group The families and children who
participated in the study.
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As we know, there are known knowns. There are
things we know we know. We also know there are
known unknowns. That is to say we know there are
some things we do not know. But there are also
unknown unknowns, the ones we don't know we don't
know" Donald Rumsfeld, February 12th
2002
The final word on not knowing

• Paul Whiteley, Research Fellow
• Autism Research Unit
• Department of Pharmacy, Health Wellbeing
• Faculty of Applied Sciences, University of
  Sunderland, UK

http//osiris.sunderland.ac.uk/autism