Gut Histopathology and other Abnormalities in Autism

Symptomatic changes

There has been great argument as to the gastrointestinal (GI) clinical changes that have been considered.  One of the problems is that many of the reports by parents were originally considered to be due to psychological changes rather than anything physical.  Between 10% and 40% (or greater) of autistic children are considered to have chronic non-specific GI symptoms.

 

 Specific Changes.

 

Histopathology: The change in science of autism

A few hard working but determined researchers in the field had created the literature until the reports by the group in London showed that there were regular physical changes could be shown in the gut wall of symptomatic children.  Following this the amount of research into autism throughout the world multiplied in many directions, even though the London work was under argument.  The reason for this massive increase was that it became considered that autism was not merely a genetic or psychological illness but rather something that might be treated in some way.  

 

 

 

Staining of a biopsy of the gut wall in autism.  Mucosal cells are blue and the darker cells between the mucosal lines are areas of the villus in which a greater amount of inflammation is present as indicated by Class II antigen.

 

Gut histopathology

It would be ethically difficult to carry out gut biopsies on asymptomatic children, because and element of risk was involved.  As such commonly the only autistic children that could be tested for gut histopathological changes were ones with symptomatic changes.  Also, controls would be difficult to find and match for their age, often only resulting from biopsies taken for other symptoms or conditions or post mortems.   

 

The statement at a press conference in 1998 that there was a physical difference between GI symptomatic autistic children and controls was such a surprise and the possibility that this was associated with MMR vaccine, led to a determination by the UK Government that this could not be so.  Pressure was put to withdraw the findings but, as they were what the researchers had found, they were not withdrawn, merely the statement of involvement with MMR.   Several years (and to some degree this still continues) of denial of the histopathology has led to research problems,  but, as this is now being repeated elsewhere this appears to be largely accepted.

 

The appearance under H and E stain was of a non-specific lymphonodular hyperplasia and that appeared to alter the surface appearance of the gut wall because of the hyperplasia underneath it.   Attempts to assess the lymphoid cells, the production of cytokines showed,  the basal membrane and other factors suggested that this was not a classical IBD but rather a separate condition.   Biopsies were generally taken from the large bowel but samples taken from the duodenum and jejunum also showed changes indicating an inflammatory change, with increased turnover of cells.   There are many examples of the appearance as histopathology of the biopsies: see links or Thoughtful House which has a good description of what has been found.

 

Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 Feb 28;351(9103):637-41.  (They found this in all 12 of the cases of autism with chronic gut problems.  They could state that this was odd compared to other cases and stated that the work should be done again with major control numbers)

 

White JF. Intestinal pathophysiology in autism. Exp Biol Med (Maywood). 2003 Jun;228(6):639-49.  (a review of the pathology seen from the gut in autism and how this may be a cause of the clinical syndrome). 

 

Diagram 2.  (Left) Biopsy of a villus in autism with a fluorescent stain (red) of cytokine C1q suggesting that this is created in adequately large amounts to produce this effect, which is much greater than that seen in a control.

 

Diagram 3. (Right) View of terminal ileum as shown through the endoscope.  You can see the lumps in the surface that might turn out to be lymphoid hyperplasia under the mucosa.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

.Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004 Nov;24(6):664-73. There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities.

 

Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999 Nov;135(5):559-63 

 

Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002 Oct;14(5):583-7. Review (discusses the chronic gut symptoms and the histopathology). (he did more work on the small bowel)

 

Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002 Jun;4(3):251-8. Review. (discusses the chronic gut symptoms and the histopathology, particularly of the small bowel).

 

Horvath K et al, Gastrointestinal abnormalities in children with autistic disorder,” J. Pediatrics 135 no. 5 (1999) 559-563.

 

Wakefield et al., Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95.

 

Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34.

 

Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004 Nov;24(6):664-73.  Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002)

 

Ashwood P, Anthony A, Pellicer AA, Torrente F, Walker-Smith JA, Wakefield AJ. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003 Nov;23(6):504-17.

 

Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375-82, 334.

 

Torrente F, Anthony A, Heuschkel RB, Thomson MA, Ashwood P, Murch SH. Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis. Am J Gastroenterol. 2004 Apr;99(4):598-605. (Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium.  The idea here was to look for a way at taking a gastric biopsy for diagnosis rather than doing endoscopy)

Torrente F, Anthony A.  Focal-enhanced gastritis in regressive autism with features distinct from Chohn’s disease and helicobacter pylori gastritis.  Am J Gastroenterol 2004:99:598-605

 

Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001 Mar;138(3):366-72

 

Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002 Apr;16(4):663-74. Review.

 

Wakefield AJ, Ashwood P, Limb K, Anthony A. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol. 2005 Aug;17(8):827-36.

 

Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, WalkerSmith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 Feb 28;351(9103):637-41. (the major article that started off progressive research in the condition: showing that there was potentially a gut inflammatory problem in autism)

 

Kokkonen J, Ruuska T, Karttunen TJ, Mäki M. Lymphonodular hyperplasia of the terminal ileum associated with colitis shows an increase gammadelta+ t-cell density in children. Am J Gastroenterol. 2002 Mar;97(3):667-72.

 

Balzola F, Barbon V, Repici A, Rizzetto M, Clauser D, Gandione M, Sapino A. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome?

Am J Gastroenterol. 2005 Apr;100(4):979-81.

 

Van Heest R, Jones S, Giacomantonio M.  Rectal prolapse in autistic children  J Pediatr Surg. 2004 Apr;39(4):643-4  (This is really very uncommon and they report 3 cases that required surgery.  They say this is very odd for mentally retarded groups.)

 

Krigsman A, Boris M, Goldblatt A.  frequency of histologic enterocolitis and lymphonodular hyperplasia in autistic children presenting for ileogolonoscopy at IMFAR  (May 7th 2004).

 

 

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Other signs of gut inflammation?

Currently (2008) I could not find measurements of C-reactive protein, acute inflammatory protein in serum, ESR etc simply looking for signs of the inflammation that may be taking place.  These are found in the acute exacerbations of other IBDs, but during chronic changes the effect may not be great. 

 

Fernell E, Fagerberg UL, Hellström PM. No evidence for a clear link between active intestinal inflammation and autism based on analyses of faecal calprotectin and rectal nitric oxide. Acta Paediatr. 2007 Jul;96(7):1076-9. (this is unlike ulcerative colitis in which the protein, an inflammatory protein produced by the body is found in the stool.  Also the lack of rectal nitric oxide disagrees.  However, this is not all that damaging to the findings of histopathology in autism because of the amount of inflammation is much less and the samples could only be taken as faeces)

 

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Treatment involving gut inflammation

The most obvious treatments might be the ones being used in other IBDs e.g. steroids, 5-ASA, thalidomide,  anti-immune drugs, specific antibodies against cytokines.  However few have been tried.  Also, changes in gut flora might be of significant.  See treatment.

 

Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-Moore J, Ostrem JA. Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. J Autism Dev Disord. 2006 Nov;36(8):1053-64. (Following eight weeks of treatment, 50% of the subjects met prespecified criteria for response in GI signs and symptoms and showed significant behavioral improvement as assessed by the Autism Behavior Checklist and parent and physician rated Clinical Global Impression of Improvement.)

 

Welch MG, Welch-Horan TB, Anwar M, Anwar N, Ludwig RJ, Ruggiero DA.  Brain effects of chronic IBD in areas abnormal in autism and treatment by single neuropeptides secretin and oxytocin  J Mol Neurosci. 2005;25(3):259-74.  (an attempt was may to use rat model inflammatory bowel disease – and the mental effects that they claim – and attempts to treat it using oxytocin and secretin, which are also found in the brain.  They fully discuss the problems with the model and realise that work with clinical children would be of more value than the current model that they could put forward.  

 

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Symptomatic GI in autistic children

The parents for a long time were quite aware of this but in text books from th 1980s and 1990s it was hardly mentioned.   Several major assessments have been made of this but a good review has been by Valincenti.  Argument as to the proportion of cases with GI symptoms has been great, probably simply because of the definition given to the parents of what the interviewer was looking for.

 

Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen H, Shinnar S.  Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease.  J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.  A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development.  Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021).  Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001)

 

Molloy CA, Manning-Courtney P. Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders.  Autism. 2003 Jun;7(2):165-71.  (shows that 24 percent had a history of at least one chronic gastrointestinal symptom. The most common symptom was diarrhea, which occurred in 17 percent. There was no specific association between chronic gastrointestinal symptoms and a history of developmental regression.  This figure has been argued in that others have found that constipation was more prevalent than diarrhoea, but they also found that this gut syndrome was different from the non-ASD population i.e. it is a symtom of the ASD condition)

 

Afzal N, Murch S, Thirrupathy K, Berger L, Fagbemi A, Heuschkel R. Constipation with acquired megarectum in children with autism  Pediatrics. 2003 Oct;112(4):939-42.  (they discuss the problem with constipation being repeatedly reported in autistic children but to see a megarectum is uncommon.  The histopathology is looked into but, being a single case it is difficult to interpret)

 

 

 

 

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