Gastrointestinal Pathology in Autism Spectrum Disorders…
March 28, 2011
…The Venezuelan Experience
By Lenny G. González, MD
AutismFile.com
Recent studies in the medical literature have confirmed that gastrointestinal (GI) symptoms are common in patients with autism spectrum disorders (ASD). In two prospective studies, GI symptoms were present in 80% and 70% of autistic children, respectively.1 In contrast with the ASD group in the latter study, Valicenti-McDermott et al. reported GI symptoms in only 28% of neurotypical controls.1,2,10. Retrospective studies that rely only upon review of the children’s existing clinical records are likely to underestimate the true size of the problem since these records rarely document GI symptoms. The inadequacy of this approach means that it is impossible to determine whether symptoms were not present or, more likely, that the clinician just failed to document them. On the other hand, prospective studies that systematically ask about the presence or absence of specific symptoms provide a much more accurate picture of the size of the problem.
Clinical manifestations of GI disease in ASD children Physical symptoms in ASD children are often misinterpreted as just autistic behaviors. In our experience, symptoms of what turns out to be GI distress often present as inexplicable irritability, aggressive or auto-aggressive (self-injurious) behaviors, discomfort, sleep disorder s, and other behavioral disturbances. The problem of physical symptoms such as abdominal pain being interpreted simply as aberrant behaviors is particularly problematic in children who are nonverbal and who have serious difficulties expressing themselves.10.
Detailed case histories often provide evidence of abdominal colic and sleep disorders during the nursing stage and frequent infections of the upper respiratory tract (such as otitis and tonsillitis) and GI tract caused by bacterial, viral, parasitic, or yeast infections. Affected children are often hypersensitive to sounds, light, flavors, smells, and clothing labels. In addition, there is often a history of intolerance to certain foods containing gluten and casein as well as indicators of food allergies.5-7. Children with autism often present with GI and extra-intestinal symptoms.
The digestive symptoms include abdominal pain, pyrosis (heartburn), chronic diarrhea, flatulence, drooling or excessive salivation, vomiting, regurgitations, weight loss, rumination, bruxism (teeth grinding), irritability, dysentery, constipation, and fecal impaction. During symptomatic episodes, periods of irritability, insomnia, and auto-aggressive behaviors are observed. In ASD children, it is common to observe abnormal toileting patterns. Diarrhea and constipation are common, and constipation can coexist with episodes of diarrhea. In the case of diarrhea, the stools are semi-liquid, very fetid with mucus and undigested food; sometimes they can have a sandy/grainy consistency and other times show blood. Diarrhea is one of the most common symptoms as reported in the studies of D’Eufemia, Torrente, Horvath, Wakefield, Furlano, and Sabrá. This has been our experience in Venezuela, also.14 The extra-intestinal problems experienced by our ASD children with GI symptoms include respiratory, neurological, and dermatological disorders.
These include frequent coughing (often dry), upper respiratory tract infections, skin rashes, eczema, atopic dermatitis, seborrheic dermatitis, and itching. The most common clinical signs are Dennie Morgan infraorbital skin folds (caused by edema or fluid collecting in areas of inflammation), dark circles under the eyes, long eyelashes, abdominal distension, halitosis, perianal erythema (diaper rash), anal fissures, dry skin, angular cheilosis (sore cracks at the corners of the lips), and greenish anterior rinorrhea (runny nose).
There are also alterations in the stool consistency, color, and smell (excessively offensive) as well as the presence of mucus or blood, food remains, and visible fat (often semi-liquid, acidic, excessively fetid, greasy feces, with mucus and/or blood).
Etiopathogenesis
Recent studies of ASD children report chronic inflammation of the gastrointestinal tract that may be present anywhere from the esophagus down to the rectum: this inflammation may well explain the GI symptoms and at least some of the behaviors.18-15, 35-40 Several theories have been proposed for how deterioration in gastrointestinal function might influence neurological functioning. The epithelial cell layer that lines the GI mucosa forms a barrier that restricts the contents of the gut from getting into the blood stream. It it is composed of cells with absorptive surfaces (the brush border) that interact with the contents of the lumen. Between these cells are gates called tight junctions, the integrity of which is important in preventing noxious substances from entering the bloodstream without passing directly
through the cells.10. One explanation might be that part of the neurological disability in children with autism results from absorption across an inflamed intestinal lining of molecules that are toxic to the developing brain.10-14 Inflammation of the intestinal wall can be induced by diverse causes such as food allergy, use of antibiotics and non-steroidal anti-inflammatory drugs, infection, or by enzymatic insufficiency, mycotoxins from yeast/fungi, gluten, casein, chemical additives, colorings, preservatives, malabsorption of proteins, heavy metal intoxications, and pesticides.3-6.
The integrity of the intestinal wall also plays an important role in the adequate absorption of nutrients and the exclusion of potentially harmful toxins, bacteria, allergens, and peptides coming from certain foods. In our experience, food components such as gluten and casein can provoke the behavioral abnormalities characteristic of autism4, possibly when they enter the systemic circulation. Increased intestinal permeability (leaky gut) may be the link that explains the association of autism with an abnormal intestinal immune response, multiple food allergies, dysbiosis, fungal overgrowth (Candida albicans), as well as with micronutrient deficiencies.4,5. Probably due to GI inflammation and abnormal immune function, children with autism may have increased levels of harmful bowel organisms. Frequent antibiotic use in the first years of life can also contribute to the chronic imbalance, referred to as intestinal dysbiosis.
Several investigators have found evidence of this imbalance in autistic children. A good example of a pathogenic (diseasecausing) bacterium is Clostridium difficile. This organism is a common cause of severe colitis that occurs when broadspectrum oral antibiotics have killed off the beneficial gut bacteria and have allowed this antibiotic-resistant opportunistic organism to overgrow and cause inflammation.10. The gut-brain connection is recognized as playing a role in the neurological complications of a number of gastrointestinal diseases. Symptoms like constipation, pain, or abdominal distension are reported by adults with degenerative disorders of the central nervous system like Parkinson’s disease, 4 while parents of autistic children report similar symptoms, although the precise nature of any link between the gut and the brain is unknown.
Ileo-colonoscopy and autistic enterocolitis
In 1998, a team of doctors at the Royal Free Hospital in London reported the results of ileocolonoscopies on 12 children who presented with autism and GI symptoms. In a series of papers, Wakefield and colleagues described a new variant of intestinal inflammatory disease, which was named autistic enterocolitis. The disease is characterized by mild-to-moderate chronic patchy inflammation of the mucosa and lymphoid nodular hyperplasia (LNH) (swelling of the lymph glands) in the bowel lining. Visible features suggestive of inflammatory bowel disease included the red halo sign – an expression of pre-ulcerative reddening around the swollen lymphoid tissues – typically located at the terminal ileum, potentially extending to involve the whole colon, loss of vascular pattern, and mucosal granularity, erythema (redness), and ulceration.
When compared with neurotypical children, including those with ulcerative colitis (a well described inflammatory bowel disease), the findings suggested a novel disease process.14. In the UK study and in our own experience, these abnormal findings are more frequent in autistic children than in developmentally normal children with GI symptoms. The only exception was ulceration, which was uncommon in both groups. The biopsies from the children with autism showed reactive LNH in 88.5% of the children compared with only 29% of children with ulcerative colitis, and 0.0% in the control group without IBD. In many cases, the researchers also saw infiltration of inflammatory cells like neutrophils (pus cells) and lymphocytes (chronic inflammatory cells) in the epithelium of the bowel mucosa. Active neutrophilic inflammation in the ileum was present in 8% of the children with autism and in none of the non-inflammatory bowel disease controls.
Chronic lymphocytic inflammation in the colon was present in 88% of the autistic cases, 4% of the controls, and 100% of ulcerative colitis cases. In our published study of 45 ASD children and 57 developmentally normal controls presenting for GI assessment, chronic inflammation and LNH in the colon and ileum was present in 100% of the autistic cases compared with 66.66% of the controls, reflecting a high background rate of infectious enterocolitis in Venezuelan children (see below.)13 Since then, other studies carried out in the United States, Brazil, Italy, and Venezuela have confirmed the finding of inflammation and LNH in ASD.10-14, 29. 
