Autism and the gut

Ben Goldacre's dissection of the woeful Observer autism article (defended by the Observer's readers' editor, and oh so unconnected with the same journalist's interview with Wakefield before his GMC hearing) has finally been published in the Guardian and the BMJ.

I don't need to bang on any more on that topic, but something that has baffled me is the continuing support for Wakefield from so many parents. What is it that the MMR 'link' with autism does for them? I suppose it gives them someone to blame (or sue), and perhaps lets them off the hook if they have the misguided worry that it is somehow their fault (say from upbringing or genetics), although I'm not too sure how it is anymore palatable than that they gave their child autism by giving them the MMR.

Of course there are always cranks and crackpots, and the anti-vaccine movement has a long and not so illustrious history preceding the MMR controversy, but looking at the comments from these parents in many of the above discussions it struck me that something many of them mentioned was the gut symptoms that their autistic children showed. This has been something of a focus of Wakefield, who originally set out to blame Crohn's disease on measles infection. So how many people would we expect to show this association?

MMR is given in two injections at ages 1-5yrs, on a back of the envelope calculation (assuming no connection, which may well not be valid), if we just look at proper inflammatory bowel disease rather than just vague gut symptoms we find that taking annual incidence of 6/100k for IBD, and 8/10k for autism spectrum, and estimating around 4 million of the little blighters in the UK, that we'd only expect about one child to show both over that period.

However, if we broaden our coverage to gut symptoms in general we get a rather different story, it turns out that GI symptoms are rather common, with some 16% of 10-11yr olds (you find the data for the under 5s!) fulfilling criteria for recurrent abdominal pain, and 2% showing lymphonodular hyperplasia on endoscopy, suggesting several hundred autistic spectrum children with lymphoid changes in the 1-5yr old age range. Funnily enough it is ileal lymphonodular hyperplasia that Wakefield reports as being associated with autism (with gut symptoms), rather than true IBD, and it looks like he will have a steady supply of patients with the right symptoms and timing to keep supporting him.

An interesting review appeared recently in Histopathology:

Aims: To review the literature on the histopathological diagnosis of the condition termed ‘autistic enterocolitis’.

Methods and results: We have reviewed all published works where mucosal biopsy specimens from autistic children have been examined histopathologically. Abstracts were excluded. Our review of the published works, nearly all from a single centre, identifies major inconsistencies between studies, lack of appropriate controls and misinterpretation of normal findings as pathology. Ileal lymphoid hyperplasia may be more prevalent in children with regressive autism but is also seen in children with food allergies and severe constipation, the latter being an extremely common finding in autistic children.

Conclusion: The histopathological diagnosis of autistic enterocolitis should be treated with caution until a proper study with appropriate methodology and controls is undertaken.

And concluded:

There is no doubt that autistic children suffer considerable gut symptoms and these have a significant effect on their quality of life. But is the claim that these children have an underlying IBD justified? We can only speculate why severe constipation was not acknowledged as a significant gut symptom in the original paper1 and was revealed only in correspondence.8 Having accepted, however, that this was a major problem in these children, subsequent studies from this group should have explicitly included developmentally normal children with severe constipation as the appropriate control group. The conclusions of the 1998 and 2000 papers from the Royal Free must therefore be regarded as unreliable because of the use of inappropriate controls. By the time this group did include a control group with ILNH and constipation and indeed reported the lack of significant difference in mucosal pathology between autistic children and controls,3 media and public opinion were already entrenched.

Significant bias was introduced to the studies from the Royal Free by the interpretation of histological changes seen in normal lymphoid follicles as pathology...It is also disturbing that the investigators have not attempted to re-inforce the histopathological diagnosis of enterocolitis by having the slides examined in an open forum by independent pathologists, especially since another small series has found no abnormalities...

There is no evidence from the papers discussed above that a significant number of autistic children have ‘enteritis’, i.e. inflammation of the small intestine. The only consistent abnormality seen in these children may be ILNH, but we have explained why this finding is not unexpected in constipated individuals...

Evidence has been presented to suggest that autistic children have a ‘colitis’. In their efforts to present convincing findings, however, the authors have failed to use appropriate controls and rigorous methodology, leading to serious flaws and unreliable conclusions...As to the aetiology of the colitis in autistic children, there is no convincing evidence that the changes are due to the autism per se. Indeed, as pointed out in the Royal Free papers, many autistic children have severe constipation and/or food allergy, either of which could be responsible for the pathological abnormalities seen. Other possible causes of inflammation in these children include parasitic infestation and swallowing foreign bodies.

...

In conclusion, we are highly sceptical that ‘autistic enterocolitis’ is a genuine histopathological entity in children with regressive autism. Further studies with rigorous methodology and appropriate control groups could be carried out, but if these are not possible, the histology slides from the autistic children seen at the Royal Free Hospital should be examined by independent experts in an open forum. The results of this exercise would, in our opinion, show that ‘autistic enterocolitis’ does not exist.