Points of Interest
• Gastrointestinal problems appear to be relatively common in children with autism.
• Speculation on a gastrointestinal cause of autism has not been supported by findings.
• The clinical presentation of gastrointestinal symptoms in children with autism may include behavioral problems including self-injury, aggression, and sleep disorder.
• Dietary restriction trials have not shown a benefit for the treatment of autism.
• The use of nutritional supplementation such as vitamin therapy is discussed.
• Inflammation in the GI tract and the potential neurological impact is reviewed.
Leo Kanner (1943) coined the term “autism.” In his seminal paper, 11 children were described as having unusual neurobehavioral presentations but were otherwise reported to be healthy. Interestingly, eating disorders were identified in 6 of these children. Kanner believed these symptoms to be behavioral in nature rather than having a medical etiology. One child required a gastrostomy for nutrition support, and eventually the GI issues were reported to have resolved spontaneously.
We currently understand autism to be a condition with manifold presentations, complex genetic and potential environmental associations, and likely therefore no single cause or pathway. When training medical professionals, we point to conditions like Down’s syndrome or William’s syndrome with well-characterized medical presentations. These conditions have, through consistency of outcomes, taught us to be aware of a variety of medical complications seen as a result of the genetic condition. In autism, we lack this characteristic or phenotypical pattern.
Medical providers often hear from families that some children improve with dietary alterations or vitamin supplements, yet when these interventions are applied under study conditions, the response is often not seen. Perhaps an unrecognized subset of individuals with autism would respond to such treatments, but the research has provided no evidence of this.
Discussion of gastrointestinal issues in individuals with autism is important for several reasons:
1. A variety of studies support a high frequency of gastrointestinal complaints in this patient population.
2. Although the gastrointestinal complaints may or may not be related to the cause of autism, underlying gastrointestinal problems may exacerbate behaviors in children with autism.
3. There may become evident a phenotypical subgroup of individuals with autism who have characteristic gastrointestinal problems.
4. Ongoing genetic and environment studies may help to explain linkage of gastrointestinal problems and the neurobehavioral problems in autism.
This chapter will discuss the prevalence of gastrointestinal symptoms in individuals with autism. Some of the unusual clinical presentations of pain will be characterized. Speculated dietary and nutritional issues in children will be addressed. Inflammation in the GI tract will be discussed. Finally, some reflection on research pathways involving the GI problems in children with autism will be offered.
Overview of GI Problems in Children with ASD
Gastrointestinal function is profoundly complex, involving the gut (esophagus, stomach, the small and large intestines) and the central nervous system, which are impacted by exterior factors such as food intake, psychological influences, and the environment. In his book The Second Brain (1998), Gershon discusses the concept “neuro-gastroenterology.” He describes the interaction between the big brain in the head and the nervous system of the GI tract (the second brain). We know little about the messages the gut sends to the brain and how that information is processed.
The prevalence of GI problems in individuals with autism must be understood relative to the prevalence of GI problems in the general population. Gastroesophageal reflux disease may be experience by 1 in 4 children at some time during childhood (Rudolph et al., 2001). Constipation accounts for 2% of all visits to the pediatrician (North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition [NASPGHAN], 2006). Food allergy has been reported to be on the rise in the last few decades. All food allergies are currently reported at a prevalence of 5–8% (Sampson, 1999a) in pediatric patients. Peanut and nut allergy reports have doubled in the last 20 years to a prevalence of 2% of the population (Skripak, 2008). At a minimum, comorbidity of these GI conditions should be expected with similar frequency in individuals with autism.
Earlier papers evaluating gastrointestinal symptoms or problems in individuals with autism suggested a relatively low frequency. In a retrospective study presented by Fombonne & Chakrabarti (2001), a medical record review of 261 autistic children found a history of gastrointestinal symptoms in 18.8%. Taylor (2002) reported that 17% of individuals with autism had associated bowel problems, including 9% with constipation, 1.4% with constipation and diarrhea, 4% with diarrhea, 1.5% with food allergy, and 0.04% reporting nonspecific colitis with ileal lymphoid hyperplasia. Constipation and food allergy actually have a higher reported frequency in the general pediatric population (Bernheisel-Broadbent, 2001; Yong, 1998), which might suggest that the medical data were not complete in this study or that ascertainment of GI symptoms in these groups were difficult.
More recent papers show a wide range of prevalence of GI problems in individuals with autism. Malloy et al. (2003) reported a prevalence of GI problems in 24% of a general autism population, based on medical history intake information. Horvath and Perman (2002) reported a prevalence of GI disturbance in 76% of children in a survey study of a general autism population in the Baltimore area. This broad prevalence discrepancy could be due to differences in the groups evaluated or differences in the interpretation of GI problems assessed.
Perhaps the most compelling study that suggests a high prevalence of GI problems among individuals with autism was conducted by Valicenti-McDermott (2006). In this study, three groups of children were evaluated: children with autism, children with other neurological conditions (e.g., cerebral palsy or mental retardation), and children without neurological problems. Seventy percent of the children with autism had GI complaints, compared with 42% of the children with other neurological conditions and 28% of the nonneurologically impaired children. This not only suggests a higher frequency of GI issues in individuals with neurodevelopmental disorders but also suggests the problem is not simply related to nonspecific neurological dysfunction. The consistent pattern in most studies showing a higher-than-“baseline” frequency of GI issues continues to fuel discussion about possible autism/GI etiological relationships. Might we find reasons for a higher frequency of GI disease in this community of individuals?
Children with autism have impaired or at least atypical communication. Because of this, families report difficulty recognizing when their child is sick. Certainly some children have obvious GI symptoms. Horvath (2002) described diarrhea (3 or more loose, watery stools per day) in 27% of 112 children with autism compared to 44 unaffected siblings who had no chronic diarrhea. This survey also reported constipation in 9.5% of children with autism (no greater frequency than unaffected comparisons), and that gaseousness, bloating, abdominal pain, and GE reflux were more frequent in children with autism than comparison. Afzal (2003) studied children with autism and unaffected children presenting to the gastroenterologist with abdominal pain; 36% of the children with autism had evidence of constipation by radiograph compared to 10% of the unaffected children. Both groups showed a higher frequency of constipation than reported in the general pediatric population. This study suggested that an abdominal x-ray may be useful in evaluating for constipation in children with autism. This may be valuable for two reasons: history of stool frequency may not be easily obtained from communication-impaired children, and even if regular stools are seen, it is not possible to assess for incomplete evacuation symptoms in many children with autism.
The Horvath study also described many non-GI presentations of GI pain or distress including sleep disturbance: “Children with ASD and GI symptoms had a higher prevalence of sleep disturbances (55%) compared with those who did not have GI symptoms (14%).” In this study of 36 children with autistic spectrum disorder, 61% of those with ASD and reflux esophagitis had nighttime wakings compared with 13% of those without reflux esophagitis. It is well known that sleep disturbance occurs frequently in this population (Honomichl et al., 2002). Many studies speak of difficulties with sleep induction as well as night awakening and early awakening (Patzold, 1998). GE reflux may be one of several potential factors in sleep disturbance, but should be considered. A trial of treatment for reflux may be warranted if this symptom is present.
The Horvath study also describes sudden irritability, unexplained crying, or aggressiveness as manifestations of pain. We have observed tapping or rubbing areas of the body where pain has occurred. Self-injurious behavior such as head-banging or self-biting may be a way of communicating distress in nonverbal individuals. Posturing behaviors as seen in Sandifer’s syndrome have occurred in our practice. One nonverbal child went to the freezer and put an ice cube on her chest. She responded well to antiacid therapy for GE reflux. Another clinical observation suggested by several GI professionals is that children with autism and abdominal distress will seek pressure on the abdomen. This may include asking a parent to rub or press the abdomen or leaning over furniture to exert pressure.
The idea that children with autism merit consideration of medical treatment for GI disturbance seems to be common sense. However, because of communication impairment, many of the presentations are behaviors such as sleep disorder, aggression, and sudden irritability among others. Caregivers are taught to take a behavioral approach, prompting the child to calm down, have quiet hands or redirect the behaviors. In verbal children who may be able to explain their behaviors, we would ask What’s wrong? or Why did you do that? It seems important to ask the same from children who are not able to explain. We should consider the possibility that some children acting out may have pain or distress in addition to other reasons for acting out.
Burd (1995) describes children with ASD who exhibit food selectivity or textural selectivity. Feeding difficulties are common (>30%) in children with developmental delays (Gouge, 1975), but reports of mealtime or feeding problems in unaffected children are common as well (18). Ahearn (2001) evaluated 30 ASD children with difficult eating behaviors and found food type or texture selectivity in 17 of 30 children. Palmer (1975) used applied behavioral analysis to broaden food acceptance in a child with food selectivity. Using a behavioral treatment plan, acceptance of a normal variety was achieved and maintained. Palmer makes the point that medical reasons should be considered when there is prolonged subsistence on pureed foods, delay or difficulty in sucking, swallowing, or chewing, and delay in self-feeding.
Toilet training is often delayed in ASD as in other developmental disorders. Dalrymple (1992) described problems of toilet training in autism. Of his surveyed patients with a mean age of 19.5 years, 22% did not have full success with toileting. Underlying medical issues such as constipation may present a barrier to successful toilet training.
Dietary and Nutritional Factors That May Be Seen in Children with ASD
Perhaps the greatest interest among researchers and families alike considering GI issues in autism focuses on the possibility that diet and nutrition play a role in autism causation and management.
When considering this relationship, several food-related factors need to be considered:
2. Food intolerance, as might be seen with inadequate digestion (e.g., lactose intolerance), which could be a cause of symptoms (abdominal pain, gas, and diarrhea).
3. Deficiency of vitamins or building block substances affecting normal neurotransmission.
Food Allergy and Celiac Disease
Food allergy and inflammation of the gut for other reasons could account for problems and symptoms in children with autism by several mechanisms. The GI symptoms of allergy could include pain, constipation, diarrhea, rash, and sleep disturbance. Determining food allergy is difficult, and various types of testing for allergy have pitfalls. Food elimination trials are fairly reliable at defining food intolerance, but do not lead to an exact diagnosis of food allergy, which by definition is an immune-mediated response (Sampson et al., 1999). Allergy can be evaluated by skin testing such as IgE RAST testing or IgG RAST testing among others. All tests risk identifying a clinically nonrelevant result and probably best serve as a guide to consider certain foods that could be an allergy culprit.
Studies concluding that children with ASD have a dietary allergy are often debated. Lucarelli (1995) evaluated 36 children with autism. These patients were evaluated by allergy skin testing for IgE levels, along with serum levels of IgG, IgA, and IgM specific antibodies for cow milk and egg proteins. The findings included: positive skin testing in 36% of children with autism compared to 5% in a control group of unaffected children. IgE level elevation was noted in 33% of the children with autism. In a separate study, Reichelt (1990) found IgA specific antibodies for gluten, gliadin, B-lactoglobulin, and casein in individuals with autism. Gluten proteins, which are present in wheat, rye, barley, and malt, have been suggested to contribute to autism and behavioral problems. In addition to the possibility of specific allergy to these foods, celiac disease or gluten enteropathy may occur. Celiac disease is an immune sensitivity to gluten proteins, which requires lifelong elimination of these foods.
Pursuing the question of the gut permeability and the potential for food sensitivity, D’Eufemia et al. (1996) evaluated 21 children with autism and 42 unaffected control children. The purpose of the study was to determine if increased passage of larger molecular sized substances across the gut barrier was present in children with autism, as increased permeability of larger molecular substances from the gut into the bloodstream might explain the potential for an increased sensitivity to certain peptides or proteins. The study found that 43% of the children with autism had increased permeability compared to unaffected control children, who showed no increased permeability, and suggested that with increased permeability, food-based or like-sized peptides that enter the bloodstream might induce allergic sensitization or cause “pharmacological” effects. This study attempted to address a theory known as opioid-excess theory (Panksepp, 1981).
Endogenous opioids may control developmental processes (Zagon, 1978). Self-stimulatory and self-injurious behavior has been linked to B-endorphin levels (Barron, 1983). Altered pain sensitivity has also been reported, and opioid antagonists such as naloxone and naltrexone have been used extensively in children with autism in attempts to modulate opioid associated symptoms (Panksepp, 1981). Sandyk (1986) briefly focuses on specific symptoms of autism that can be caused by abnormal endogenous opioid regulation. Sahley and Panksepp (1987) delineated the idea that abnormal brain opioid activity could play a role in the genesis of many autistic symptoms.
Maldigestion of dietary peptides forms the basis of the opioid peptide theory of autism. Several investigators have proposed that maldigestion of dietary proteins, particularly foods containing casein and gluten, produces small peptide molecules that may function as exogenous opioids. Peptides described as casomorphin (derived from milk) and gliadomorphin (derived from gluten foods) were identified in the urine of patients with schizophrenia and autism by Reichelt (1991). These peptides were shown, in vitro, to bind to opioid receptors and therefore are speculated to cause CNS effects by modulating opioid levels in the brain. Shattock (1990) supported this theory. Opioid peptide theory could provide a possible explanation for reports of clinical improvement when some autistic children are placed on restrictive diets without proof of allergic sensitivity. One criticism of the theory is the observation that these urinary peptides are also present in asymptomatic children and therefore may not exhibit a physiological effect.
Knivsberg (1990) placed a selected group of autistic children in a residential school on a gluten-free diet and reported improvement. He had screened these children prior to the diet and found evidence of the peptide gliadomorphin in their urine. He suggested this finding identified children who may have a problem with gluten. The gluten-free diet prescribed in this study would have potentially been helpful for children with celiac disease, food allergy to gluten products, or maldigestion of these food products. The conclusions may support the notion that at least a subgroup of patients could benefit from dietary change. Sponheim (1991) offered a limited study evaluating autistic children placed on a gluten-free diet and observed no behavioral improvement. He did not qualify the participants by identifying a gluten sensitivity marker. Several studies attempting to evaluate dietary reductions have been put forward since (Lucarelli, 1995; Whiteley 1999; Cade, 1999). These studies suggest that some participants do show behavioral response to dietary restriction.
A more recent trial by Knivsberg (2002), which addressed earlier limitations to tracking progress, suggested developmental progress was seen in individuals who had elevated urinary peptides to milk and gluten. Patients were divided into 2 groups, a casein-free, gluten-free group and a group that continued on milk and gluten. Ten children per group were monitored for a year by a blinded tester, and the dietary restricted group showed beneficial progress over unrestricted comparisons. This may represent a clear subset of proper candidates for dietary withdrawal.
Elder (2006) evaluated 15 children who were placed on a 12-week treatment cycle of a casein-free and gluten-free diet. This study was a blinded study, where the children received a diet that was free of casein and gluten for 12 weeks or a diet spiked with casein and gluten, and then the children were crossed over for 12 weeks to the alternative diet. Caregivers and observers were not aware what the child was receiving. No differences in developmental markers or behaviors were seen. This was a group of children with autism, unselected by any markers suggesting food intolerance. Interestingly, urinary peptides were evaluated for milk and gluten peptides during the diets and no differences were identified in children’s urinary peptides while on or off milk or gluten.
At this time, the studies attempting to treat autistic symptoms with diet have not been sufficient to support the general institution of a diet for autism. Symptoms suggesting food allergy or dietary intolerance may prompt institution of a diet for these symptoms.
As we move forward, we need to consider the heterogeneity of the autism population. It seems unlikely that any diet, supplement, medicine, or even educational modality will work for every individual. Especially for dietary interventions, identifying a subgroup with characteristic presentation may allow a better prediction of response.
There is research that argues against a link between celiac disease and autism. Pavone (1997) evaluated a limited number of autistic children (11) for markers of celiac disease and found no correlation. He also conducted evaluations on 120 children documented with identifiable celiac disease for any indication of behavioral abnormalities. He found that none of the children exhibited autistic-like behaviors, concluding there was no connection between celiac disease and autism. This study is too small to conclude that celiac disease is no more frequent in autism, however with the high prevalence of both conditions in the general population (ASD seen in 1/166 individuals or even greater; Yeargin-Allsopp, 2003; and celiac disease seen in 1/133 individuals; Fasano, 2003), there will be an expected coincidence of these conditions. With such a common prevalence of celiac disease in the general population, celiac screening may be prudent in children with autism and any issues with GI disturbance or growth issues.
There is often disagreement between parent and professional (Ho, 1994) on the management of children with autism and what constitutes therapeutic benefit. Many parents institute dietary restrictions and report anecdotally that various benefits have occurred. Validated tracking tools are lacking to assess progress from therapeutic or nutritional trials. In her paper, Elder et al. (2006) reported that although measurable changes were not identified in children on a casein-free, gluten-free diet, some parents did notice subtle differences in their children when the diet was restricted. Perhaps alternate assays will allow recognition of currently subtle changes with intervention.
Beyond allergy or immune-mediated food problems that may account for dietary contribution to behavioral problems, food intolerance or nonimmune reaction to foods could result from inadequate digestion of food (e.g. lactose intolerance). Horvath (1999) described diminished lactase activity, measured via intestinal biopsy of autistic children with diarrhea who underwent endoscopies, 58% of the time. The reported prevalence of lactose intolerance in the general pediatric population falls well below the frequency reported in the Horvath study (Kretchmer, 1981). Possible reasons for lactase enzyme deficiency might include intestinal injury or diminished genetic expression of these enzymes. In the same study, Horvath measured pancreatic enzyme activity by performing secretin stimulation studies during endoscopy. He did not identify pancreatic enzyme deficiency when a limited number of children were evaluated.
Alberti (1999) suggests that poor breakdown of some food products could allow them to have a neurotransmitter effect, potentially accounting for altered behavior. He tested sulfation by dosing Paracetamol (acetaminophen) in children with autism and measuring metabolites in the urine compared to an age-matched unaffected control group. The sulfated metabolite of acetaminophen was lower in autistic children, raising the question whether consumption of certain foods requiring sulfation processing might exacerbate a metabolic dysfunction. Murch et al. (1993) discussed disruption of sulfation in intestinal inflammation (colitis). McFadden (1996) suggests that impaired sulfation has been found with increased frequency in individuals with several degenerative neurological and immunological conditions and might account for chemical and diet sensitivities in some children with autism.
Model research regarding vitamin supplementation and neurological functioning is seen with the condition tryptophan deficiency. Young (1991) looked at the effects of dietary components including amino acids, carbohydrates, and folic acid supplementation on behavior. He reported that tryptophan depletion decreased serotonin levels and affected mood. Other studies suggest that tryptophan depletion alters pain perception. Some types of pain may improve with supplementation of tryptophan; others, including postoperative pain, actually worsened when supplemented with tryptophan. McDougle et al. (1996) found that autism symptoms worsened with tryptophan depletion.
Considering the model of tryptophan deficiency, debate has ensued regarding the use of specific vitamin supplementation as a potential treatment for autistic symptoms. Researchers have reported that various supplements may bring clinical improvement, including Vitamin B-6, Vitamin B-12, folic acid, calcium, magnesium, and zinc.
One theoretical reason that folate, B-6, and B-12 may have value is that they are necessary for serotonin production. It is also possible that these agents may alter metabolic pathways or modulate gene expression. Folic acid deficiency has been identified in patients with depression (Young, 1989), schizophrenia (Godfrey, 1990), and affective disorders (Coppen, 1986). Vitamin B-12 deficiency has been considered a potential factor contributing to neurological dysfunction perhaps because it aids protein synthesis and myelination (Herbert, 1975). Lowe (1981) could not identify deficiency of either folic acid or vitamin B-12 in autistic patients. More recent discussion of vitamin B-12 supplementation, particularly methyl B-12, focuses on the potential of methylation processing defects (James, 2009).
Vitamin B-6 (pyridoxine) supplementation was noted to improve behavior in autism (Rimland, 1974). A subsequent double blind, placebo-controlled trial supported the earlier report (Rimland, 1978). Discussing the metabolic approaches to the treatment of autism spectrum disorders, Page (2000) suggests that several well-designed studies including Coleman (1989), Kleijnen and Knipschild (1991), and Lelord (1988) support the idea that pyridoxine improves some symptoms of autism. Although the potential value is discussed, a Cochrane review (2005) of 14 studies evaluating B-6 supplementation did not find adequate data to support supplementation.
Several studies looking for nutritional deficiencies raise preliminary red flags. Hediger et al. (2008) reported decreased cortical bone thickness in a group of 75 children with ASD. This finding was present despite normal growth and unrestricted diet. Of the children studied, 12% had been in a milk-free diet, and this group had a significantly greater loss of cortical thickness. The long-term implications are not clear, but those children on calcium supplementation in their study were not spared. More work investigating malabsorption or required supplementation may be needed. Arnold et al. (2003) reported that children with autism had plasma amino acid profiles showing more essential amino acid deficiencies than age-matched controls and a trend for children on restricted diets to show greater deficiency. These studies do suggest there may be potential negative outcomes from restrictive diets and the need to continue a diet should be supported.
Many children with autism spectrum disorders receive vitamin and mineral supplements and other products every day on the basis of limited data. This limited information underscores the need for well-constructed clinical trials to evaluate these nutrients and better clarify if supplementation is a value and for whom it provides a benefit.
Mucosal Inflammatory Conditions Described in ASD
There are a number of reports discussing the findings of inflammation at endoscopy in children with autism. It is important to begin by saying that inflammation is going to be identified only in children who have presented with symptoms justifying an endoscopic procedure. This is true for all of the reports. Therefore discussion of GI findings cannot imply any known prevalence in the autism population, and at best describes abnormalities in a subset of individuals.
In his study of 36 children with GI symptoms and ASD brought to endoscopy, Horvath (1999) described esophagitis in 69.4%, gastritis in 42%, and duodenitis in 67% of these children. The high frequency of esophagitis was especially noteworthy because the children were primarily under evaluation for diarrhea.
Wakefield (1998) was the first to discuss inflammation in the lower GI tract among children with developmental disorders. This study evaluated 12 children with “regressive developmental disorder.” Eleven of the patients were reported to have colitis by histology, and all had the endoscopic finding of prominent lymphoid nodules in the ileum (lymphoid nodular hyperplasia or LNH), colon, or both. He suggested that measles virus from vaccine potentially caused these intestinal changes, which led to GI symptoms and increased intestinal permeability and the subsequent development of autistic regression. In a larger study (Wakefield, 2000), he evaluated a group of 60 children with “regressive” autism. This study also evaluated a control group of unaffected children undergoing colonoscopy. In the affected group, 93% had ileal LNH; 14.3% of the unaffected children had these changes. Histologic colitis was seen in 88% of the affected but only 4.5% of the unaffected children.
Several contentious questions were raised by these reports:
1. The frequency of inflammation found was quite high. This may have reflected the severity of the patients being evaluated. As was seen in Horvath’s study, there was a notable frequency of inflammation in endoscopy testing.
2. The finding of lymphoid nodular hyperplasia (LNH) was interpreted as an abnormality. Pediatric gastroenterologists have reported this finding as a developmentally normal or prominent following allergy or constipation (Turunen, 2004; MacDonald, 2007).The finding of lymphoid nodular hyperplasia has been noted in other conditions (Sabra, 1998). Allergy has been associated with LNH. Kokkonen (2002) reported that LNH was seen in the colon in 46 of 140 children undergoing colonoscopy for persistent and severe gastrointestinal symptoms. These children were not noted to have autism or other developmental issues. In this same study, ileal LNH was seen in 53 of 74 children tested, suggesting that LNH is common in children and not specific to the ASD population. He suggests LNH may be an expression of immune response. Wakefield et al. (2005) supports the contention that LNH is more prominent in autism and seems independent of allergy or constipation. This topic is one of ongoing discussion in the literature.
3. Wakefield suggested that the potential reason for colitis and LNH was measles virus infection from the measles, mumps, and rubella vaccination (MMR) accounting for the lesion. Alarge number of papers refute the idea that MMR administration is associated with the development of autism (Chen, 2004; Dales, 2001; DeStefano, 2004; Fombonne & Chakrabarti, 2001; Honda, 2005; Madsen, 2002; Afzal, 2006; D’Souza, 2006; among others). Taylor (2002) saw no change in the frequency of regression before and after the institution of MMR vaccination in England. He did note a possible association between nonspecific bowel problems and regression, but did not find that this related to MMR vaccination. Fombonne and Chakrabarti (2001) evaluated patient groups before and after the institution of MMR vaccination. He found no difference in the age of parent concern, the rate of developmental regression did not differ before and after MMR vaccine, and the intervals from MMR vaccine to parental recognition of autistic symptoms were comparable in autistic children with or without regression.
In 2008, Hornig et al. reported that in 25 children with autism and 13 unaffected controls, measles RNA was identified in only one affected and one unaffected child on intestinal biopsy. Although the presenting perception of most parents of children with autism was that they regressed following vaccination with MMR (regression was identified in 88% of the children with autism), the sequence of symptoms that would support Wakefield’s theory was not present. Eighty percent of the children with autism did not present with a sequence of vaccination -> onset of GI symptoms -> autistic regression.
The discussion about vaccination as a cause of autism profoundly overshadowed the GI findings. If the children studied had significant GI pathology, regardless of suspected etiology, symptoms of pain, GI dysfunction, and perhaps behavioral issues would benefit from treatment of these noted GI disturbances.
Furlano (2001) reported that, although the histologic findings of colitis described in the autistic children were less severe than classical inflammatory bowel disease (IBD), immunohistochemical testing showed increased basement membrane thickness and mucosal gamma delta cell density compared to IBD. The significance of these findings is unclear.
Torrente (2002) described duodenal biopsy findings in 25 children with “regressive” autism. The biopsy findings were compared to 11 celiac patients, 5 patients with cerebral palsy and mental retardation, and 18 control patients with normal histology. Twenty-three of 25 autistic children had normal histology or nonspecific increased cellularity. Immunohistochemical studies showed an overall marked increase in mucosal lymphocyte density in autistic children compared to controls and MR-CP patients. The density of CD8 T-cells was also greater in the autistic patients than controls and MR-CP patients. IgG deposition in the basolateral enterocyte membrane and subepithelial basement membrane was seen in 23 of 25 autistic children but was not seen in the control or MR-CP patients. The significance of these findings remains unclear, as this specialized testing is not usually done on all patients undergoing intestinal biopsy. Evaluating the group of children Wakefield studied, Ashwood (2006) reported, “There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.”
We may need to reconsider what we consider normal biopsies. We also need to consider the significance of microscopic inflammation. It may be that these findings are important in children with autism because these are a source of inflammation. Because children with autism have sensory processing abnormalities, perhaps low-grade inflammation can cause significant dysfunction in this population. It may be that the findings are not always clinically relevant. This is a primary focus of ongoing research.
Other considerations of impaired bowel health include an unhealthy bowel flora. Sandler et al. (2000) suggests that disruption of indigenous gut flora might promote colonization with bacteria that produce neurotoxins. He treated autistic children with oral Vancomycin, and 8 of 10 showed transient behavioral improvements. Brudnak (2002) and Linday (2001) describe the potential use of probiotic (nonpathogenic bacteria and yeast) agents such as Lactobacillus species and Saccharomyces Boulardii. The value of these organisms may be to normalize intestinal flora, provide digestive enzymes aiding nutrient absorption, minimizing allergen exposure, and to stimulate local immune responses in the intestine.
Evaluating children with ASD and GI symptoms, Horvath (1998) performed endoscopy and pancreatic function testing by administering secretin. Secretin is a neurotransmitter produced in the duodenum and stimulates the washout of pancreatic enzymes into the intestine. Following the procedure, he reported improvements in social behaviors including better eye contact, increased social awareness, and improved expressive language in 3 children. A flurry of studies followed, in effort to assess if secretin had a therapeutic benefit to treat the greater community of autistic children. Sandler (1999), Lightdale (2001), Roberts (2001) and others reported no sustained gastrointestinal or neurological benefit of secretin over placebo.
Functional GI issues include gastroesophageal reflux, recurrent abdominal pain, and irritable bowel syndrome. Population-based survey studies remain sorely lacking to fully determine how often children with ASD have gastrointestinal function problems. We cannot speculate on how frequently this will be seen in ASD, but should not assume that these conditions happen less frequently in the nonverbal child than in the verbal child.
Conditions such as recurrent abdominal pain, abdominal migraine, and irritable bowel syndrome (IBS) have no defining test to clarify the diagnosis. Symptom history is the best current method to identify these disorders and therefore may be difficult to ascertain in this population. Many children with ASD exhibit significant sensory processing dysfunction. Symptoms seen in sensory integration disorder such as altered pain perception are a primary component of IBS as well and may be a reason to consider this diagnosis in children with GI issues and ASD.
Speculations and Conclusions
In 2009, Campbell described the results of an exploratory, retrospective study indicating a genetic association of a functional variant of the MET gene (chromosome 7) in ASD patients in families with affected individuals who are reported to have co-occurring gastrointestinal conditions. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, the authors hypothesized that association of the autism spectrum disorder–associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions. The sample consisted of 992 individuals from 214 families. Because the C allele disrupts transcription of the MET gene, the biological translation of these genetic findings is consistent with a hypothesis that reduced MET signaling may contribute to a syndrome that includes ASD with co-occurring gastrointestinal conditions. This finding may be one “biomarker” that if present may suggest a subgroup of individuals vulnerable to autism and comorbid gastrointestinal issues.
Another topic that may be relevant to GI issues and autism is the description of a higher frequency of children with mitochondrial dysfunction exhibiting autism (Oliviera et al., 2007). Children with mitochondrial dysfunction often have generalized motor dysfunction of the GI tract causing GER or constipation symptoms (Chitkara, 2003). The subgroup of children with autism and GI issues may suggest a subgroup of children meriting additional work-up for mitochondrial dysfunction.
Berney (2000) stated, “In the absence of a cure, the implementation of ideas will continue to outstrip factual evidence.” Medical providers need to recognize that families of children with autism are not only looking for a cause or cure for autism, they are trying to assure that their child is as healthy as possible to prevent barriers to progress. As part of this, many children will be on diets or supplements. The use of complementary approaches to care is common in this population. Families have reported that 31.7% to 52% of children with autism have been treated with complementary approaches (Levy, 2003; Wong, 2006). Diets and complementary treatments are not unique to autism. Pediatric patients with chronic diseases often receive supplements to traditional treatments. Forty percent of pediatric patients with chronic disease report using CAM as part of their management (McCann, 2006). As we provide more definitive data about pathology and expectations in this population, one may expect speculative care to be reduced.
As a result of research to date, GI practitioners are now being asked to participate in the evaluation of children with ASD and GI symptoms. Pediatricians, family physicians, and gastroenterologists, first and foremost, need to be willing to consider that children with autism have a right to comorbid GI issues. The conditions of reflux, food sensitivity or allergy, constipation, diarrhea, and inflammatory bowel conditions are common in general pediatrics and should be expected to be identified in children with autism. As more prevalence data are available, we may find that some of these issues are more common in children with autism and may even be related to the phenotype of a subgroup. Until then, thoughtful care and evaluation should be offered to children with autism presenting for evaluation is needed.
Gastrointestinal conditions are common in children with autism. They may represent a comorbidity, but their presence may well exacerbate behaviors of autism. There remains debate about whether an underlying inflammatory condition of the bowel or environmental, dietary triggers might account for a contribution to causation of autism.
Challenges and Future Directions
• Broader understanding of the impact of medical comorbidity (including gastrointestinal illness and functional GI disorders such as constipation, acid reflux, and food allergy) on the well-being and behavior in children with autism is imperative.
• Evaluation of intestinal microflora in the setting of food allergy, inflammation, and functional GI motility conditions in children with autism may be valuable in explaining immune variation or autoimmune response in some individuals.
• Prospective tracking of GI conditions in children at risk for developing autism may help in characterizing GI phenomena versus outcomes that have resulted from intervention such as dietary selectivity, diet therapies, or other treatments.
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