JOURNAL WATCH: Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.

Pediatrics. 2010 Jan;125 Suppl 1:S1-18.

Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H.

Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. tbuie@partners.org

Abstract

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

CONSENSUS STATEMENTS

Because of the absence, in general, of high-quality clinicalresearch data, evidence-based recommendations are not possibleat the present time. However, the panel agreed on a number ofstatements based on expert opinion that arose from a reviewof existing evidence. It is acknowledged that, in many areas,evidence is generally confined to case reports, observationalor descriptive studies, and poorly controlled or uncontrolledstudies.

The expert panel reached consensus on the following statements.

Statement 1 (Key Statement)
Individuals with ASDs who present with gastrointestinal symptoms warrant a thorough evaluation, as would be undertaken for individuals without ASDs who have the same symptoms or signs. Evidence-based algorithms for the assessment of abdominal pain, constipation, chronic diarrhea, and gastroesophageal reflux disease (GERD) should be developed.

Individuals with ASDs deserve the same thorough diagnostic workup for gastrointestinal symptoms as should occur for other patients. There is no evidence for pathogenic mechanisms specific to ASDs that warrant a distinct diagnostic approach. Guidelines for the evaluation of common gastrointestinal symptoms have been developed by medical societies, medical centers, and managed care practices.9–12 Few, if any, published documents haveaddressed modifications in the diagnostic evaluation on thebasis of the needs of persons with disabilities such as impairedlanguage. An evidence base is needed to guide evaluation andtherapy, but until appropriate studies are conducted, guidelinesmust be based on expert opinion.

Statement 2
Gastrointestinal conditions that are reported to be common in individuals without ASDs are also encountered in individuals with ASDs.

In persons with ASDs, gastrointestinal conditions can presenttypically or atypically as nongastrointestinal manifestations,including behavioral change and/or problem behaviors. Symptomseverity can be quite variable in patients with ASDs, as inother patients.

The most common gastrointestinal symptoms and signs reportedfor persons with ASDs are chronic constipation, abdominal painwith or without diarrhea, and encopresis as a consequence ofconstipation. Other gastrointestinal abnormalities that havebeen described for individuals with ASDs include GERD, abdominalbloating, and disaccharidase deficiencies, as well as pathologicfindings such as inflammation of the gastrointestinal tractand abnormalities of the enteric nervous system.

Gastrointestinal disorders can present as nongastrointestinal problems. For example, Horvath and Perman13 reported disturbed sleep and nighttime awakening for 52% of children with ASDs who had gastrointestinal symptoms (vs 7% of age-matched healthy siblings; P < .001). Children with ASDs who had reflux esophagitis exhibited unexplained irritability more frequently (43%) than those who did not (13%).13 Behaviors, including problem behavior, may be markers of abdominal pain or discomfort in individuals with ASDs.14,15 Table 2 identifies some vocal and motor behaviors,as well as changes in overall state, that may indicate abdominalpain or discomfort.

The diagnostic evaluation of potential gastrointestinal disorders can vary depending on the possible problem (Table 3). For example,if one suspects that maldigestion or malabsorption is causingabdominal distension or is associated with self-injurious behavior,an upper endoscopy with measurement of disaccharidases mightbe considered. Lactose intolerance is common in the generalpopulation and therefore common in individuals with ASDs. Toclarify the diagnosis, empiric trials of lactase supplementationor dietary restriction might be considered, in the proper clinicalcontext, before referral to a gastrointestinal specialist.

As for individuals without ASDs, functional abdominal pain (FAP)and irritable bowel syndrome (IBS) can present in individualswith ASDs with behavioral indicators of pain, disordered sleep,diarrhea and/or constipation, and bloating and/or flatulence.The diagnosis of FAP or IBS is a clinical one that is made onthe basis of a pattern of predominant symptoms occurring overtime in the absence of organic disease. Empiric treatment, initiatedby a gastroenterologist or specialist skilled in understandingneurenteric dysregulation, may be warranted for some patientswithout other indicators of disease, such as weight loss, fever,and bloody stools, before proceeding to invasive evaluations.However, for children with ASDs, behavioral indicators may bethe only manifestation of pain, and determining who should beevaluated medically and who should be treated empirically canbe problematic. Evaluating all children may result in some withIBS and FAP having potentially unnecessary invasive evaluations;treating children empirically may delay identification of morbiditiesthat could be remedied by medical or surgical intervention.Clearly better biomarkers of disease in children with ASDs areneeded to reliably identify those individuals who are most likelyto benefit from the more comprehensive diagnostic evaluation.

Statement 3
The prevalence of gastrointestinal abnormalities in individuals with ASDs is incompletely understood.

The reported prevalence of gastrointestinal symptoms in children with ASDs has ranged from 9% to 70% or higher (Table 4). 13,16–25 Prospective descriptive reports from autism clinics have described significant gastrointestinal symptoms in at least 70% of patients,22 data that might reflect a referral bias. In contrast, secondary analysis of a UK database indicated that the prevalence of gastrointestinal symptoms was no different in children with ASDs compared with children without ASDs (9%) at the time of their initial ASD diagnosis.16

Most of these studies had 1 or more methodologic limitations,in particular a lack of appropriate (nonrelated) control groups.Despite the limitations in type and quality of available evidence,the preponderance of data were consistent with the likelihoodof a high prevalence of gastrointestinal symptoms and disordersassociated with ASDs.

The panel agreed that to unequivocally answer the importantquestion of prevalence of gastrointestinal dysfunction in thispopulation, prospective multicenter studies need to be performedby using validated instruments and outcome measures administeredto persons with a diagnosis of ASD established by accepted methodsand appropriate control groups. Population-based studies arealso needed to avoid referral bias and overestimation of theprevalence of gastrointestinal symptoms in patients with ASDs.

Statement 4
The existence of a gastrointestinal disturbance specific to persons with ASDs (eg, “autistic enterocolitis”) has not been established.

Some health care providers and researchers have proposed thatcertain gastrointestinal pathologies are specific to individualswith ASDs. An immune or inflammation-mediated mechanism specificto ASDs, possibly vaccine-triggered in the setting of abnormalimmune function or increased gut permeability (“leaky gut”),has been hypothesized to underlie the gastrointestinal disordersseen in individuals with ASDs, mainly on the basis of a findingof ileal nodular lymphoid hyperplasia (NLH) and/or chronic colitisseen on colonoscopy.

In 1998, Wakefield et al26 reported an association between ileocolitis and developmental regression in 12 children and coined the term “autistic enterocolitis.” From the same uncontrolled study they reported NLH of the ileum and colon as an abnormal finding in most children with ASDs. However, similar findings are known to be present in children with typical development, as well as children with food allergies and immunodeficiencies.27,28 The significance of these findings, therefore, is unclear. Wakefield et al29 also proposed a causal relation between measles, mumps,and rubella (MMR) vaccination and autism, a suggestion thatwas later retracted by many of the original authors.

Other study-design limitations in these reports included flawedcontrol groups, lack of validated and standardized definitions,and speculative interpretation of results. In summary, publishedreports have not established the presence of a unique gastrointestinalpathophysiology specific to ASDs.

Statement 5
The evidence for abnormal gastrointestinal permeability in individuals with ASDs is limited. Prospective studies should be performed to determine the role of abnormal permeability in neuropsychiatric manifestations of ASDs.

Altered intestinal permeability was reported in 9 of 21 (43%) children with ASDs and 0 of 40 healthy age-matched controls.30 The authors of the study speculated that the alteration might be the mechanism for increased passage of food-derived peptides through a damaged gut mucosa. Increased permeability (or a “leaky gut”) has been cited as having a key role in various hypotheses regarding the biology of ASDs, including excess opiate activity, diminished peptidase activity, and immune dysfunction.31 Some investigators have reported decreased serum sulfate levels in children with ASDs and hypothesized a link between such deficits and increased gut permeability.13

The available literature has not confirmed the presence of abnormalgastrointestinal permeability in individuals with ASDs, andthe presence of increased intestinal permeability has not beencorrelated with an underlying gastrointestinal disorder or neuropsychiatricmanifestations. Studies to date have had methodologic limitationsincluding small subject populations and poor controls; properlypowered prospective studies with appropriate controls are needed.

Statement 6
Individuals with ASDs and gastrointestinal symptoms are at risk for problem behaviors. When patients with gastrointestinal disorders present with behavioral manifestations, the diagnostic evaluation can be complex.

An emerging literature suggests that individuals with ASDs and gastrointestinal symptoms may be at higher risk for problem behaviors than those with ASDs who do not have gastrointestinal symptoms.32 Problem behaviors are recurrent behaviors that interfere with an individual’s functioning; their occurrence often affects family and community members as well. Problem behaviors are the single most important factor in determining quality of life for individuals with ASDs and their caretakers.33 Vocal and motor behaviors, including problem behaviors such as self-injury and aggression, as well as overall changes in state of being (eg, sleep disturbance or irritability), may be behavioral manifestations of abdominal pain or discomfort in persons with ASDs (Table 2).14,15

The evaluation of individuals with ASDs and gastrointestinal symptoms can be complex. Sleep disturbances and the other problem behaviors mentioned above may indicate abdominal discomfort. In turn, abdominal discomfort, as well as other symptoms (constipation, flatulence, bloating, diarrhea, straining), may be manifestations of neurenteric dysregulation or IBS. A diagnosis of exclusion, IBS is difficult to distinguish from other underlying conditions without invasive testing. For the patient who is not losing weight, has no blood in the stool, and has normal findings on a complete blood count and urinalysis, evaluations are recommended in the order described in Table 3. No evidence-based guidelinesare available to guide the evaluation. For this reason, primarycare physicians, psychiatrists, psychologists, pediatricians,and gastroenterologists may need to work together to improvethe evaluation and treatment of gastrointestinal symptoms inindividuals with ASDs.

Statement 7
For a person with an ASD who presents for treatment of a problem behavior, the care provider should consider the possibility that a gastrointestinal symptom, particularly pain, is a setting event, that is, a factor that increases the likelihood that serious problem behavior (eg, self-injury, aggression) may be exhibited. Sudden and unexplained behavioral change can be the hallmark of underlying pain or discomfort. Behavioral treatment may be initiated as the possible concurrent medical illness is being investigated, diagnosed (or excluded), and treated, but the behavioral treatment should not substitute for medical investigation. The behavioral treatment plan should be developed, implemented, and changed as needed in collaboration with the medical caregivers who are leading the medical investigation.

Clinical practice guidelines for the management of ASDs have not included routine consideration of potential gastrointestinal problems.1,3–5 As previously noted, for individuals with ASDs, symptoms associated with gastrointestinal disorders, especially pain, may function as setting events for problem behaviors.34 In this context, a setting event is any gastrointestinal symptom that influences how a person will respond to a given environment. For example, the presence of pain (a gastrointestinal setting event) can result in simple daily tasks and routines being perceived by the child as much more aversive than would be the case if the child were healthy and free of pain. As a consequence, these tasks and routines now trigger bouts of severe problem behavior as the child attempts to escape from the now-aversive situation. Once the gastrointestinal condition has been treated successfully, it is likely that pain will diminish, the situation will be perceived as less aversive, and the child will, therefore, no longer be motivated to engage in problem behavior. A review of both gastrointestinal symptoms and behaviors clinically associated with gastrointestinal problems (see Tables 2 and 3), along withother potential sources of pain and discomfort (such as ear,dental, urologic, musculoskeletal, and cutaneous problems),should be incorporated into the clinical behavioral assessment.

The presence of gastrointestinal symptoms and/or related behaviors (Table 3), regardless of whether they are clearly temporallyrelated to problem behavior, should be considered a strong andurgent indication for medical investigation. Clinical judgmentwill determine if medical investigation should precede or occurconcurrently with behavioral and/or psychopharmacologic intervention;the latter, however, should never substitute for medical investigation.Clearly, reliable biomarkers of gastrointestinal function areneeded to identify those individuals who are highly likely tohave conditions that may respond to medical or surgical intervention.Until such biomarkers are shown to be helpful, clinicians withexpertise in both medical and behavioral interventions shouldwork together on an integrated care plan.

Recognition that abdominal pain and discomfort can function as a setting event has important implications for the treatment of problem behavior.15 First, time-consuming behavioral treatments that address only psychosocial triggers and consequences for problem behavior may likely be ineffective. Behavioral treatments that promote means of communication in the affected individual may be more effective. For example, it would be extremely useful, from the standpoint of medical diagnosis, to teach a child to identify the location and type of pain that he or she is currently experiencing.35 Second, the individual can be taught skills for coping with task demands appropriately during moments of pain or discomfort, and psychosocial environments that have become aversive because of gastrointestinal pain can be restructured to attenuate their aversive properties.36,37 Third, if the gastrointestinaldisorder is recognized and medical treatment is effective, theproblem behaviors may diminish. When abdominal pain or discomfortis a setting event, psychotropic medications are likely to beineffective and may even aggravate the problem if they haveadverse gastrointestinal effects.

Statement 8
Education of caregivers and health care providers is necessary to impart knowledge of how to recognize typical and atypical signs and symptoms of gastrointestinal disorders in individuals with ASDs.

The clinical presentation of gastrointestinal disorders in individualswith ASDs may differ from that of individuals with typical development.For example, behavioral alterations can complicate the diagnosisof GERD in persons with compromised communication skills. Expertclinicians have observed that aggressive and self-injuriousbehavior may be the primary clinical manifestations of GERDin individuals with ASDs, but these symptoms are frequentlyattributed to nonmedical causes. As a result, manifestationsmay go unrecognized as signs and symptoms of GERD and, importantly,may go untreated. Caregivers should be informed about atypicalmanifestations of gastrointestinal disorders. Greater awarenessof this association by health care providers may result in theseconditions being diagnosed and treated in more affected individuals.Additional research is needed to evaluate the usefulness ofadding behavior to screening for gastrointestinal problems inpersons with ASDs.

Educational programs designed to increase awareness of medicalconditions that can go unrecognized because of atypical symptompresentation should be a priority at meetings of professionalsocieties such as the American Academy of Pediatrics, AmericanAcademy of Family Physicians, and National Association of PediatricNurse Practitioners.

Statement 9
Pediatricians and other primary care providers should be alert to potential nutritional problems in patients with ASDs. Evaluation by a nutritionist who is familiar with nutrition support for individuals with ASDs is recommended if caregivers raise concern about the patient’s diet or if the patient exhibits selectivity of intake or is on a restricted diet.

Nutritional deficiencies have been reported in patients with ASDs, which is not surprising because of the narrow food preferences of many affected individuals and/or purported therapeutic diets that might be nutritionally inadequate. In a study of 36 children with ASDs, regardless of unrestricted or restricted diet, essential amino acid deficiencies consistent with poor protein nutrition occurred more frequently than in age- and gender-matched controls.38 Low dietary intake of calcium and vitamin D and iron deficiency have been implicated in compromised bone development and sleep disturbances, respectively, in children with ASDs receiving an unrestricted or restricted diet.39,40 Resources for general nutritional guidance are available that may be helpful for families.41–43

Statement 10
Primary care nutritional assessment for each person with an ASD should include (1) weight for height or BMI, (2) weight for age, (3) height for age, and (3) any marked changes in growth rate (percentiles over time).

It is recommended that pediatricians routinely monitor anthropometryas part of the evaluation of children with ASDs. Abnormalitiesin nutritional status (wasting, stunting) or changes in growthrate should alert the clinician to inadequate growth and thepossibility of inadequate caloric intake or poor nutritionalquality of the diet, malabsorption, or maldigestion. Any childwhose growth is of concern should be referred to a nutritionist,preferably one who is familiar with nutritional support forindividuals with ASDs.

In addition to nutritional inadequacy, children with ASDs have the potential to be obese. In a retrospective review of charts from 1992 to 2003 in children aged 3 to 18 years with ASDs, the prevalence rates of at risk for overweight (BMI ≥ 85th percentile) and overweight (BMI ≥ 95th percentile) were 35.7% and 19.0%, respectively.44 These prevalence data are similar to rates in children aged 6 to 19 years in the general population of 31.0% and 16.0% for at risk for overweight and overweight, respectively, in 1999–2002.45 However, children with ASDs in the 12- to 19-year age range were reported to have 80% and 50% rates of being at risk for overweight and overweight, respectively, compared with 30.9% and 16.1%, respectively, in the general population.44

Statement 11
Anecdotal reports have suggested that there may be a subgroup of individuals with ASDs who respond to dietary intervention. Additional data are needed before pediatricians and other professionals can recommend specific dietary modifications.

Dietary modifications such as removal of milk for symptoms oflactose intolerance may be approached empirically, as with anyother pediatric patient with consistent symptoms. The data onthe value of specific diets being effective in the treatmentof individuals with ASDs are difficult to assess. Many dietarymodifications are believed to have a beneficial outcome, althoughplacebo effects are likely to be high in this setting. The fewstudies in the literature are difficult to interpret withoutadequate control groups.

Statement 12
Available research data do not support the use of a casein-free diet, a gluten-free diet, or combined gluten-free, casein-free (GFCF) diet as a primary treatment for individuals with ASDs.

Few studies have examined the effects of a casein-free diet, a gluten-free diet, or combined GFCF diet on the behavior of individuals with ASDs. To our knowledge, only 1 double-blind placebo-controlled study has been published to date.46

In this double-blind crossover trial of GFCF or typical diet in 15 children with ASDs, there were no differences in measures of severity of ASD symptoms, communication, social responsiveness, and urinary peptide levels after 12 weeks.46 Nevertheless, afterbeing informed of the results, 9 parents wanted to continuethe diet and reported positive subjective clinical changes whiletheir child was on the GFCF diet. Study limitations includedthe small sample size and heterogeneity, concerns about complianceand possible dietary infractions by study subjects, and lackof a direct observational outcome measure.

Parents need information to help plan a balanced diet withinthe restrictions imposed by the chosen diet. Given the realhardships associated with implementation of a strict GFCF diet,additional studies are needed to assess risk factors and possiblemarkers that identify individuals who might benefit from thesediets. The panel emphasized that parents and care providersshould agree on objective measures, which ideally are to beevaluated by blinded observers, to assess the intervention effectas well as a reasonable time frame before embarking on restrictiveor unusual diets. The current literature does not permit a recommendationas to the length of a trial of dietary intervention. In theabsence of data, any trial will need to be long enough to ensurethat variability in behavior is not responsible for the perceiveddiet response.

Statement 13
For patients with ASDs, a detailed history should be obtained to identify potential associations between allergen exposure and gastrointestinal and/or behavioral symptoms.

It has been estimated that 25% to 65% of children in westernized societies have evidence of allergen sensitization, with food allergy present in 6% to 8% of infants and young children and ~4% of adolescents and adults. It is assumed that a similar proportion of children with ASDs exhibit allergic disorders.47–49 Table 5 lists symptoms associated with immune-mediated gastrointestinal food allergies as well as suggested diagnostic approaches.50The patient’s parents, teachers, or other caretakers are animportant source of information, because they are in a positionto observe an association between exposure and the person’sresponse.

Statement 14
Standardized definitions of adverse reactions to foods would be helpful in discussions with patients/providers. These definitions also should be used in studies of adverse food reactions in individuals with ASDs.

Health care providers can reduce the potential for misunderstandingby defining terms with patients and their families early inthe evaluation process and reviewing with them the differenttypes of adverse reactions to foods. In doing so, they establisha framework for discussions about whether the diagnosis is foodallergy, another type of adverse reaction to a food, or someother entity unrelated to food ingestion.

In a logical scheme developed for categorization of food-induced reactions according to mechanism, an adverse reaction to a food is the general term used to refer to any unpleasant reaction that occurs as a result of food ingestion.51 An adverse reaction to a food may be toxic or nontoxic.52 In toxic reactions the symptoms are caused by a toxin synthesized by the food or by an organism or substance that contaminated the food. Although sensitivity to different toxins may vary from person to person, a characteristic of toxic reactions is that they occur in virtually every person who ingests enough of the food that contains the toxin.51

Nontoxic reactions are further categorized into food intolerance or food allergy, depending on whether the immune system is the primary cause of the reaction.52 Reactions in which the immunesystem is not involved are categorized as examples of food intolerance.Categories of food intolerance include metabolic, pharmacologic,and idiosyncratic reactions. Individuals are more likely toexperience metabolic reactions to foods if they are malnourishedor ill, take certain medications, or have acquired or inheritedmetabolic disorders. Pharmacologic food reactions occur afterthe ingestion of foods that contain pharmacologically activeingredients. Idiosyncratic reactions resemble allergic reactionsto foods but are not mediated by the immune system and resultfrom a quantitatively abnormal response to a food or food additivethat is not caused by a pharmacologic or physiologic effectof the food.

Food allergy is the term used to refer to nontoxic reactions to foods that are mediated by the immune system.52 Allergic reactions to foods are further categorized as mediated by immunoglobulin E (IgE), non–IgE mediated, or combined (both IgE- and non–IgE-mediated mechanisms are implicated).49 Disorders caused by IgE-mediated reactions to foods typically involve the gastrointestinal tract, the skin, and the respiratory tract either alone or in combination. For example, gastrointestinal anaphylaxis presents with cramping abdominal pain, nausea, and vomiting that occurs within minutes to hours of ingestion of the offending food and is often accompanied by cutaneous or respiratory symptoms. IgE-mediated cutaneous symptoms include acute urticaria, angioedema, generalized pruritus, and flushing, whereas respiratory disorders associated with IgE-mediated reactions to foods include acute rhinoconjunctivitis and acute-onset bronchospasm. The most severe form of an IgE-mediated allergic reaction to a food is anaphylaxis involving multiple organ systems.53

Non–IgE-mediated allergic reactions to foods may be cell mediated. Examples that involve the gastrointestinal tract include food protein–induced syndromes such as food protein–induced enterocolitis, food protein–induced proctocolitis, and food protein–induced enteropathy syndromes.54,55 These disorders are seen primarily in infants or young children who present with abdominal complaints such as vomiting, cramping abdominal pain, diarrhea, and occasionally blood in the stool. Celiac disease, which results from sensitivity to gliadin (found in grains such as wheat, rye, and barley), is another example of a non–IgE-mediated gastrointestinal reaction to a food.56,57 Dermatitis herpetiformis and contact dermatitis are examples of cutaneous non–IgE-mediated reactions to food. Mixed IgE- and cell-mediated allergic reactions to foods are exemplified by eosinophilic gut disorders, such as eosinophilic esophagitis and allergic eosinophilic gastroenteritis, or potentially other entities such as atopic dermatitis or asthma.58

The potential for a food aversion should be considered in patientswith ASDs. Aversion may be present because of a previous noxiousevent that occurred after ingestion of a specific food. Theaversion to the specific food may then be generalized to a broaderfood category. An example is a child who becomes ill after eatinga tomato; a child with an ASD who has that experience may subsequentlyavoid all red foods. This aspect of food intolerance is oftenoverlooked in the search for the cause of an individual’s refusalof a specific food.

Statement 15
For patients with ASDs, a detailed history (including personal history of allergic disease, dietary history, and family history) and physical examination should be performed to accurately identify potential comorbid allergic disease.

A comprehensive history and physical examination always provideimportant information for the clinician who is evaluating theperson with an ASD and possibly co-occurring allergies. A positivehistory of allergic disease in parents and siblings is a significantrisk factor, placing the person at higher risk for the developmentof allergies. The typical pattern of allergen sensitization,often referred to as the “atopic march,” begins with sensitizationto food allergens and/or eczema within the first 2 years oflife, followed by sensitization to inhalant allergens manifestedby allergic rhinitis, animal dander sensitivity, and/or allergen-drivenasthma. Many children outgrow IgE-mediated reactions to foodssuch as milk, egg, soy, and grains as they age, although mostindividuals who are sensitized to peanuts, tree nuts, fish,and shellfish remain allergic. Non–IgE-mediated reactionsto foods such as allergic proctocolitis and food protein–inducedenterocolitis are outgrown in the first few years of life, whereasceliac disease is lifelong. Combined IgE- and non–IgE-mediatedallergic reactions to foods such as eosinophilic esophagitisand eosinophilic gastroenteritis are often long lived, withsymptoms that wax and wane.

Older children who present for allergic evaluation are unlikelyto have allergic colitis, a non–IgE-mediated conditionthat is often outgrown by 3 or 4 years of age in typically developingchildren. In individuals with ASDs, some experts have commentedthat resolution of a non–IgE-mediated condition may bedelayed, possibly related to underdiagnosis at a young age.There are no data to support this speculation.

Because allergic diseases are common and individuals with ASDsmay have atypical presentations or difficulty verbalizing complaints,it is important for caregivers to be vigilant in monitoringsymptoms and looking for signs of allergic disease. If the presenceof allergic disease is suggested by the history or physicalexamination, patients with ASDs should undergo appropriate allergytesting (eg, skin testing, measurement of allergen-specificIgE levels, elimination diets, food challenges) and gastrointestinalevaluation (including laboratory testing and endoscopy, if indicated),as would be done for patients without ASDs.

Statement 16
Involvement of specialists (allergists, gastroenterologists, dietitians, and feeding therapists) for the management of individuals with ASDs may be beneficial.

The management of uncomplicated gastrointestinal disorders,such as constipation or GERD, in individuals with ASDs can beinitiated and followed by the pediatrician or other primaryhealth care provider. Patients who are unresponsive to standardcare may benefit from a referral to a gastroenterologist. Thepanel emphasized that specialist referral should be undertakenonly after a patient has not responded to standard treatmentdirected by the primary health care provider.

Similarly, patients with ASDs who have allergic disease canreceive effective care under the supervision of a pediatricianor other primary care provider. Involvement of an allergistis recommended for patients with multiple allergies or complexallergic disease. Working with a dietitian to optimize nutritionis helpful, because these patients often have specific foodpreferences and limited diets or are on supplements that shouldbe critically evaluated from a nutritional standpoint. A knowledgeablefeeding therapist should be consulted when feeding disordersare suspected or the patient is difficult to feed. The potentialbenefits of an allergy program with input from experts in otherareas include not only reduction in symptoms of allergic diseasebut also fewer medication adverse effects and, in some instances,an improvement in behavior.

Statement 17
Immunologic aberrations have been reported in individuals with ASDs. However, a direct cause-and-effect relationship between immune dysfunction and ASDs has yet to be proven.

There has been research to suggest that immune responses caninfluence neurodevelopment and that significant immunologicalterations may play a key pathogenic role in some individualswith ASDs. Two lines of research are promising: (1) dysregulationof cytokine production; and (2) the effect of maternal autoantibodiesduring early neurodevelopment.

Researchers in a number of laboratories have described intestinal inflammatory changes in individuals with ASDs.59–61 A few studies have suggested that activation of circulating lymphocytes and monocytes may lead to dysregulated cytokine production.62–66 Some investigators have speculated that increased peripheral cytokine levels may act directly on the central nervous system (CNS) or may trigger a CNS-mediated inflammatory response via glial cells. In turn, these actions could affect neurodevelopment or directly elicit autistic behaviors (reviewed by Ashwood and Wakefield67). Other researchers have observed increased production of cytokines from the innate immune system in the plasma and CNS, including interleukin 6 (IL-6), tumor necrosis factor {alpha} (TNF-{alpha}), and macrophage chemoattractant protein 1 (MCP-1).63,68,69

An increase in autoimmune disorders has been reported in the families of individuals with ASDs. The findings of (1) a family history of autoimmune disease and (2) antibrain antibodies suggest that, in some individuals with ASDs, autoantibodies that target the CNS may be related to the neurobiology of the disorder.70–74

Immunoprotective maternal IgG antibodies and autoantibodies that react to fetal “self” proteins have been shown to cross the placenta.75 In a recent study, reactivity to human fetal brain protein, but not adult brain protein, was observed with antibodies from 7 of 61 (11.5%) mothers of children with ASDs.76 In contrast, immunoreactivity was observed in neither the mothers of children with typical development nor the mothers of children with developmental delays but no ASDs. In a population-based study by the same group with samples taken during gestation, a pattern of maternal antibody reactivity to fetal brain protein (simultaneous reactivity to 39- and 73-kDa molecular weight bands) was reported only for mothers of children with early-onset ASDs.77 More recently, introduction of maternal IgG in a Rhesus monkey model resulted in profound behavioral changes in the offspring.78 These clinical and animal observations are of potentialinterest in understanding a possible mechanism for the behavioralchanges observed in ASDs. At present, their clinical relevanceis speculative.

We are now able to accurately define immune status in individualswith ASDs. Well-defined studies are needed using larger samplesets and age- and geographically matched controls, with extensiveimmune analysis, to determine the precise relationship of immunedysfunction to clinical symptoms.

Statement 18
The role of immune responses in the pathogenesis of gastrointestinal disorders in individuals with ASDs warrants additional investigation.

A few studies have suggested a relationship between gastrointestinal inflammation and gastrointestinal symptoms associated with ASDs. The gastrointestinal tract is the largest immune organ in the body, containing up to 80% of Ig-producing cells in the body. In children with ASDs, immunohistochemistry and flow-cytometry studies have consistently shown marked pan-enteric infiltration of lymphocytes and eosinophils in the gut mucosa.59,61,79,80 Torrente et al61,80 suggested an autoimmune component to theinflammatory response (co-localized deposition of IgG and complementC1q on the surface epithelium of the gastrointestinal tract).These studies suggest an underlying chronic inflammatory processin some individuals with ASDs and co-occurring gastrointestinaldisturbances, characterized by NLH, enterocolitis, and mucosalinfiltration by immune cells along the length of the gastrointestinaltract. These findings should be considered preliminary and willrequire confirmation.

Statement 19
The role of gut microflora in the pathogenesis of gastrointestinal disorders in individuals with ASDs is not well understood.

The microbiological ecosystem of the gut is complex and poorlyunderstood but likely plays a significant role in both healthand disease. Few researchers, however, have attempted to criticallyexamine the relationship of gut microflora to ASDs. Future studieswill require molecular approaches aimed at identification andquantification of microbial species. If an association is identified,it may lead to novel treatment trials. Careful selection ofstudy subjects will be important for controlling for antimicrobialexposure, diet, and other factors.

It should be noted that empirical antibiotic and antifungaltherapy in patients with ASDs is not recommended. Cliniciansshould obtain an abnormal culture result from a duodenal aspirateor abnormal stool culture before starting any treatment designedto alter intestinal flora.

Statement 20
Given the heterogeneity of persons with ASDs and the many inconsistent research findings regarding ASDs, it is imperative that the phenotype (biological, clinical, and behavioral features) of future study subjects be well defined. This will help to clarify the underlying pathophysiology and the clinical aspects of the disorder and guide focused evaluations and treatments.

A number of factors make the generalization of study findingsdifficult. Individuals with ASDs share a common behavioral diagnosisand, although at present we are unable to establish an etiologicdiagnosis for most cases of ASDs, we are nonetheless aware ofnumerous uncommon or rare causes of this behaviorally definedcondition. It is likely, therefore, that different pathogenicmechanisms underlie ASDs in individuals who have received thisdiagnosis. Consequently, future studies relating to diagnostic,pathophysiologic, and therapeutic aspects of ASDs should endeavorto characterize in detail the clinical, behavioral, metabolic,genetic, and imaging phenotypes of the subjects to the extentpossible.

Statement 21
Studies of gastrointestinal disorders in ASDs should include genetic testing for all participants.

Future research studies to examine gastrointestinal function in people with ASDs should include characterization of the genotype. Guidelines for the genetic evaluation of individuals with ASDs have been published by the American College of Medical Genetics.81 Our recommendations include consideration of determinations of chromosomal microarray analysis, mutation analysis of the FMR1 gene (to evaluate for fragile X syndrome), mutation analysis of the MECP2 gene in females, as well as mutation analysis ofclinically relevant candidate genes and selected metabolic testingbased on the clinical and family histories and physical examination.

Statement 22
Prevalence and characterization of specific gastrointestinal symptoms should be examined in well-defined genetic syndromes with high rates of ASDs.

It is recommended that gastrointestinal disorders be studiedin individuals with genetically well-defined disorders withwhich ASD rates are high. Such disorders are rare and includeRett, Smith-Lemli-Opitz, and fragile X syndromes. There havebeen minimal published data regarding gastrointestinal dysfunctionin these and other monogenic or chromosomal disorders that arestrongly associated with ASDs.

Gastrointestinal dysfunction in persons with ASDs and a monogenicdisorder could result from a direct effect of the mutated geneon a specific gut function. Alternatively, abnormal neurologicfunction rather than an intrinsic, genetically programmed abnormalitywithin the gastrointestinal tract could be the basis of disturbedgastrointestinal function. Differentiating between these pathophysiologiccategories is difficult at present.

Detailed description of gastrointestinal dysfunction in individuals with ASDs and defined genetic conditions will increase our knowledge of the natural histories of these conditions and ideally translate to improved clinical care. It may also provide insight into the pathogenetic basis of the gastrointestinal dysfunction with these conditions. Lessons learned about gastrointestinal abnormalities from monogenic conditions will likely have relevance for similar gastrointestinal abnormalities that occur not only in individuals with idiopathic ASDs but also in individuals without ASDs. Recent data regarding the MET gene are provocative in this regard.82

Statement 23
Clinical trials of treatment of gastrointestinal symptoms should include banking of DNA samples.

Investigators are strongly encouraged to obtain blood samplesfor banking of DNA in their research protocols. An unknown butpotentially large fraction of patients may have specific mutationsas the cause of their ASDs. The value of the research will besignificantly greater if causative mutations are identifiedin some of the subjects and the data reanalyzed in light ofthis information.

CONCLUSIONS

Medical disorders, including gastrointestinal problems, occurcommonly in individuals with ASDs, but because symptoms maybe atypical, these medical conditions may be undiagnosed. Whetherthe prevalence is higher than in the general population is notknown with certainty, because prospective well-controlled studiesare unavailable. Many parents and care providers have observedand reported improvements in problem behaviors with nutritionalor medical interventions. Some of these therapies are basedon purely observational reports; many are based on studies thatmay have reached erroneous conclusions because of recruitmentbias, lack of validated or standardized outcomes, or inadequatecontrols. In this document we focused on gastrointestinal disordersand related conditions including allergy, inflammation, metabolicdisease, genetics, and nutrition.

The care of individuals who are nonverbal or have difficultiesin communication or who display self-injurious or other problembehaviors presents special challenges. Nevertheless, the approachto evaluation and diagnosis of possible underlying medical conditions,in particular gastrointestinal disorders, should be no differentfrom the standard of care for persons without ASDs. Managementof co-occurring gastrointestinal problems in individuals withASDs usually begins with the primary care provider and may eventuallywarrant multidisciplinary consultation.

Anecdotal reports that restricted diets may ameliorate symptomsof ASDs in some children have not been supported or refutedin the scientific literature, but these data do not addressthe possibility that there exists a subgroup of individualswho may respond to such diets. Professional supervision of restricteddiets is recommended to prevent nutritional inadequacies.

Future research is expected to clarify the role of metabolic disorders, allergic/toxic reactions, immune dysregulation, and inflammatory changes in the etiology of gastrointestinal disturbances in individuals with ASDs. Whether unique genetic, metabolic, or physiologic conditions exist and are specific to ASDs remains to be determined. Accrual of new knowledge will advance our approach to the management of ASDs and co-occurring medical conditions. Recognition that problem behaviors might indicate an underlying medical condition will facilitate diagnosis and treatment and ultimately improve the quality of life for many persons with ASDs. This expert panel has addressed considerations in the diagnostic evaluation of gastrointestinal symptoms in individuals with ASDs that may lead to effective treatment options, with the hope that patients will have better access to enlightened care.

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