Letters to the Editor

ALPHA-1-ANTITRYPSIN, AUTISM, AND CŒLIAC DISEASE

Many studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms.

Children were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASD^GI), children with ASD but without current or previous GI symptoms (ASD^NoGI), typically developing children with GI symptoms (TD^GI) and typically developing children without current or previous GI symptoms (TD^NoGI). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition.

Following Toll-Like receptor (TLR)-4 stimulation, the ASD^GI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASD^NoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASD^GI group compared with both the ASD^NoGI and TD^NoGI groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASD^GI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups.

Overall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome.

Alpha-1-antitrypsin deficiency (AATD) is a relatively common but under-recognized condition that predisposes to lung disease (e.g., emphysema, chronic bronchitis, and bronchiectasis), liver disease (e.g., chronic hepatitis, cirrhosis, and hepatocellular carcinoma), and skin disease (i.e., panniculitis). AATD has also been associated with vasculitis [especially anticytoplasmic antibody-positive vasculitides like granulomatosis with polyangiitis (GPA), previously called Wegener’s granulomatosis].

This chapter will first discuss the overall prevalence of AATD and the evidence that AATD is under-recognized. The clinical manifestations of individuals with AATD will then be reviewed, with the discussion of each organ system involvement addressing the epidemiology; clinical features, including signs and symptoms and associated laboratory features; natural history; and prognosis. Where appropriate, the specific clinical manifestations associated with particular genotypes are discussed. The most common clinical sequelae—lung and liver disease—are discussed first, followed by a discussion of panniculitis, vasculitis, and a brief discussion of other clinical conditions for which associations with AATD have been speculated but not confirmed.

Objectives: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. Methods: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn’s disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. Results: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal γδ cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8⁺ density and intraepithelial lymphocyte numbers were higher than those in the Crohn’s disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR^–, suggesting a predominantly T_H2 response. Interpretation: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism. (J Pediatr 2001;138:366-72)

To evaluate a possible etiologic role of a _α-antitrypsin deficiency (α₁AD), most frequently caused by a Z allele mutation, in ulcerative colitis (UC) and Crohn disease (CD).

This retrospective study included 10 patients diagnosed with and/or treated for inflammatory bowel disease (IBD) between 1976 and 1997 and identified from the Mayo Clinic Medical Index System. All 10 patients had either α₁ AD and CD or α₁AD and UC. The α₁-antitrypsin (α₁AT)types and levels were determined with isoelectric focusing testing. The allele types, representing genotypes, were designated PiZZ (or ZZ) for homozygotes and PiMZ (or MZ) for heterozygotes.

Seven patients had UC: 4 were genotype ZZ and 3 MZ. Four of these 7 patients had emphysema, 2 had asthma, and 1 had chronic bronchitis. Five were cigarette smokers, but only 1 had smoked coincident with activity of her UC. Two of the UC patients never smoked, and 1 of these 2 had asthma. Three of the 10 patients had CD, 2 genotype ZZ and 1 MZ. Two of the 3 patients were longterm cigarette smokers, and both had emphysema. Nine of the 10 patients with UC and α₁ AD required surgery.

The need for surgery in patients with UC and α₁-AD may point to a unique phenotypic subgroup of patients with α₁AD and severe UC. Further studies are required to substantiate the etiologic role of α₁AD in IBD. Our observations, if confirmed by future studies, suggest that in patients with both IBD and chronic obstructive pulmonary disease, α₁AD testing should be considered.

This chapter discusses the role of secretin in autistic spectrum disorders. Autism is a neurobiological disorder involving the central nervous system (CNS), immune system, and, as studies show, the gastrointestinal (GI) tract. One of the most unusual observations associated with the examination of the possible role of the gut in children with autism has been the increased volume of secreted fluid, following secretin administration. This high secretory response to secretin administration may reflect an upregulation of the secretin receptors in the duct cells of pancreas or in the bile-duct epithelium. The average basal secretin level in blood was lower than the lower limit of normal adult values in many children with autism. The secretin content per gram tissue for pituitary and pineal tissues were higher than in duodenum, whereas the levels reported for hypothalamus, thalamus, and olfactory lobe were comparable to those of small intestine. It is suggested that a group of children, with pervasive developmental disorder, may have both cerebral and pancreatic dysfunctions, both of which improve following secretin administration.

Objectives: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. Study design: Thirty-six children (age: 5.7 ± 2 years, mean ± SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. Results: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth’s cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea. Conclusions: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder. (J Pediatr 1999;135:559-63)