Barbara McElhanon, MD (1) & William G. Sharp, PhD (1, 2)
1 Department of Pediatrics, Emory University School of Medicine (Atlanta, GA), 2Marcus Autism Center (Atlanta, GA)
Background
Gastrointestinal dysfunction is frequently cited among children with autism spectrum disorders (ASD) and many causal and therapeutic hypotheses of ASD involve the gastrointestinal system (Buie et al., 2010). The importance of the gut in ASD, however, is not thoroughly understood. Multiple aspects of gastrointestinal physiology are being investigated, including possible deviations in the intestinal microbiome (Mulle, Sharp, & Cubells, 2013), gene variants (Campbell, Li, Sutcliffe, Persico, & Levitt, 2008), and intestinal permeability (D’Eufemia et al., 1996). Moreover, interventions such as restricted diets, nutritional supplements, enzymes, and antimicrobial agents are being promoted and implemented, but not founded on a large body of scientific evidence.Many diets target gluten and casein, dietary components first proposed in the 1950′s by Asperger and others to be involved in the emergence and/or maintenance of autistic behaviors (Mahikoa, 1996).This molecular hypothesis proposes that opioid-like peptides, gliadomorphin and casomorphin, escape the intestinal barrier, are absorbed into the blood stream, and subsequently disrupt brain functioning as the body’s immune system attacks these molecules and substances (Reichelt, Knivsberg, Lind, & Nodland, 1991). There is no strong evidence, however, indicating that gluten-free and/or casein-free diets improve autistic symptoms or that individuals with ASD have increased intestinal permeability to support the “opioid excess theory” or “leaky gut hypothesis” (Elder et al., 2006; Millward, Ferriter, Calver, & Connell-Jones, 2008).
The development of causal and therapeutic hypotheses relating the gastrointestinal system to ASD is driven by many factors including: 1) an apparent increase in the prevalence of ASD, with approximately 1 in every 88 children currently meeting diagnostic criteria in the United States (CDC, 2012); 2) a level of urgency by primary caregivers and practitioners to determine the etiology of ASD and identify interventions to remediate symptoms; 3) frequent reporting of gastrointestinal symptoms with associated cost burden(Croen et al., 2012); and 4) a fivefold increase in the odds of developing a feeding problem in ASD when compared with peers, often with unknown organic origin (Sharp et al., 2013). Unfortunately, research focusing on gastrointestinal disease in children with ASD has been clouded by Dr. Andrew Wakefield’s now retracted publications naming a new pathologic entity, “autistic enterocolitis” related to the MMR vaccine, as responsible for developmental regression in 12 children (Wakefield, Murch, Anthony, et al., 1998 [Retracted]). The medical community has blamed Wakefield directly and indirectly for causing a decrease in vaccination rates and a re-emergence of once eradicated pediatric diseases. Furthermore, while the nature of the impact on gastrointestinal research in ASD is speculative, this controversy likely averted investigators from dedicating resources to examine the relationship between gastrointestinal symptoms and ASD.
The Evidence Base
In the last few years, the most cited paper on this topic involved a literature review and consensus report that found “an absence, in general, of high-quality clinical research data” supporting an increased risk of gastrointestinal disorders in ASD and, consequently, children with ASD should be treated to have as many gastrointestinal disorders as their non-ASD peers (Buie et al., 2010). This conclusion was based on a pool of 11 studies involving a wide degree of methodological variability; only 5 studies involved a comparison groups and there was a extremely wide range of prevalence estimates of gastrointestinal disorders in patients with ASD (range: 9% to 91%). This article has been cited 26 times in peer-reviewed publications (as of April 2013) and is likely a primary source of guidance for caregivers and healthcare providers faced with these issues, highlighting the need for further research in this area.
More recently, our research group completed the first comprehensive review and meta-analysis surveying the medical literature in order to identify studies using empirical methods to investigate gastrointestinal symptoms among children with ASD using a comparison group (McElhanon, McCracken & Sharp, 2013 – manuscript in preparation). We identified a total of 15 studies published between January 1980 and September 2012 involving a total sample of 2215 children with ASD. The results of the meta-analysis suggest children with ASD are at increased risk for gastrointestinal issues. Specifically, our analysis indicated greater levels of general concerns regarding gastrointestinal symptoms reported by parents compared with siblings (roughly an 8 fold increase in the risk) and peers (roughly a 3.5 fold increase in the risk), with areas of specific concern including abdominal pain, constipation, and diarrhea. The summarized research was based largely on parent report and medical chart reviews and often did not account for variation in diet, behavior problems (e.g., toileting issues), and/or ASD diagnostic status. As a result, conclusions regarding the relationship between these factors and possible gastrointestinal dysfunction are unavailable at this time.
In line with conclusions by Buie et al. (2010), our results suggests, at a minimum, parents and health care providers should be educated about possible underlying gastrointestinal problems in children with ASD. Children suspected of possible gastrointestinal issues should then be screened accordingly. With this in mind, one difficulty in identifying and studying gastrointestinal dysfunction in ASD is that individuals often present with limited verbal communication and their symptom presentation may be atypical compared with peers (Buie et al., 2010). For example, aggression and irritability without clear environmental influence (i.e., antecedents or consequences) may be the only indication of an underlying gastrointestinal problem. This highlights the need to promote greater awareness in the ASD community regarding possible gastrointestinal concerns in this population. Clinical and research activities would also benefit from an ASD-specific gastrointestinal screening instrument which, combined with increased awareness in the ASD community, would promote early detection and intervention.
In addition to better screening and early treatment, special considerations must be addressed when developing treatment plans for children with autism. For example, Furuta et al. (2012) published details on managing constipation in children with ASD. Of note, the guidelines are the same as the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition for all constipated children, with added details such as the expert opinion that children with ASD may not like the taste of magnesium citrate(Glenn et al., 2010). Moving forward, ongoing research is required to elucidate the role of the gut in autistic characteristics, including whether certain phenotypes of children with autism do have different gastrointestinal physiology which could, as an example, respond to dietary changes. In addition, standardized clinical screening of gastrointestinal symptoms in patients should be pursued to promote early intervention and, thus, the best standard of care.
References
Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125(suppl 1):S1-18
Mulle JG, Sharp WG, Cubells JF. The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep. 2013;15(2):337. doi: 10.1007/s11920-012-0337-0. Epub 2013 Feb 15
Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008; 1: 159–168. doi: 10.1002/aur.27
D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagiiini M, Cardi E, Giardini 0. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85:1076-9. Stockholm. ISSN 0803-5253
Kulani Mahikoa, Gastrointestinal Illness in Autism: An Interview with Tim Buie, M.D. Autism Advocate 5th edition 2006
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Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006; 36 (3): 413–20
Millward C, Ferriter M, Calver SJ, Connell-Jones GG. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003498. DOI: 10.1002/14651858.CD003498.pub3
Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders — autism and developmental disabilities monitoring network, 14 sites, United States, 2008. Morbidity and Mortality Weekly Report. Vol. 61, March 30, 2012. Available online: http://www.cdc.gov/ncbddd/autism/documents/ADDM-2012-Community-Report.pdf
Croen LA, Najjar DV, Ray GT, Lotspeich L, Bernal P. A comparison of health care utilization and costs of children with and without autism spectrum disorders in a large group-model heath plan. Pediatrics. 2006; 118(4): e1203 – e1211
Sharp WG, Berry RC, McCracken C, Nuhu NN, Marvel E, Saulnier CA, Klin A, Jones W, Jaquess DL. Feeding Problems and Nutrient Intake in Children with Autism Spectrum Disorders: A Meta-analysis and Comprehensive Review of the Literature. J Autism Dev Disord. 2013; DOI 10.1007/s10803-013-1771-5. Epub 2013 Feb 1
Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet. 1998; 351(9103): 637-641
McElhanon, BO, McCracken C, Sharp WG.Gastrointestinal Disorder in Children with Autism Spectrum Disorders: A meta-analysis and comprehensive review of the literature. Oral presentation at Mead-Johnson North American Pediatric Gastroenterology, Hepatology and Nutrition 3rd Year Fellows’ Research Conference. Scottsdale, Arizona, 2013, February.
Furuta, et al. Management of constipation in children and adolescents with autism spectrum disorders. Pediatrics. 2012; 130;S98
Glenn T. Furuta, Kent Williams, Koorosh Kooros, Ajay Kaul, Rebecca Panzer, Daniel L. Coury and George Fuchs. Management of Constipation in Children and Adolescents with Autism Spectrum Disorders. Pediatrics 2012;130;S98
