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Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database

BMJ 2002; 325 doi: (Published 24 August 2002) Cite this as: BMJ 2002;325:419

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If one asks the wrong questions one can get the wrong answers.

I do not believe we have been looking at gastrointestinal disorders
as we should especially in the case of those conditions associated with
drug ingestion, the common assumption being that the pathology is confined
to the gut or more commonly gut mucosa. If the gut mucosa is the"canary of
the body"in acute and possibly chronic organ dysfunctions(1), as an
overwhelming amount of evidence would suggest (2), then it may commonly be
a manefestation of a systemic disease process.

In animal models the metabolic effects of salicylate, for example,
may exert their ulcerogenic actions by making the mucosa more susceptible
to the deleterious effects of luminal acid (3,4,5). On the other hand in
a possibly unpublished logistic regression analysis of our data (7)the
likelihhood of bleeding from stress ulceration in patients increased as
the luminal pH increased possibly reflecting the effect of a fall in
intramucosal pH which is to impair the ability of parietal cells to
secrete acid (8) in accordance with the Daniel Atkinson energy charge
hypothesis (9). The tissue pH is a stochiometric surrogate of the energy
charge with estalished pathological associations (10). It is this fact
that makes gut mucosal injury of pathophysiological concern in the
context of mood and behavioiural disoders such as autism (11).

In the acutely ill the organ dysfunctions putatively associated with
a decrease in intramucosal pH, and by inference energy charge, include
nosocomial pneumonia, myocardial depression, sepsis from enteric
organisms, and multiple system organ failure (12). What has been poorly
assessed in these patients is cerebral dysfunction for the patients are
intubated and ften medicated. The reality is that the brain is probably a
far better or more sensitive "canary" of the body than gut mucosa for
cerbtal early dysfucntion is the rule in conscious patients who develop
acute illnesses. The cogntive effects of hypobaric hypoxia, which usually
occur in the absence of other organ dysfunctions, are particularly
noticible in pilots flying without oxygen and mountaneeers. Subtle
manefestations of cerebral dysfunction, such as those seen in mood and
behavioral disoders such as autism, may be a particularly early and
sensitive measure of a decline in intracerebral energy charge possibly of
a focal nature.

It was concluded in the summary points that, "Less than 10% of
children diagnosed with autism have a history of gastrointestinal
disorders, and for most the symptoms are mild"(11). That would seem an
unusually large number. If, these children had been compared with a
cohort of healthy children of appropriate size the 10% might well prove to
be highly significant. The real question is whether these children might
have an abnormal decrease in energy charge, or its stochiometric
surrogate, of which gut mucosal pathology was relative to the autism an
insensitive measure. The only significnt finding in Wafefield's origin
report, wa raised urinary methylmalonic acidosis (P=0.003), is consistent
with this conclusion (13) and suggests that the cause might be systemic
rather than regional or focal.

"No evidence was found that children with autism were more likely
than children without autism to have had defined gastrointestinal
disorders at any time before their diagnosis of autism". This may be the
correct answer to the wrong question.

"No temporal association was found between measles, mumps, and
rubella vaccination and the onset of gastrointestinal symptoms in children
with autism". That too may be the correct answer to the wrong question the
answer to which many parents have known for a long time.

1 Dantzker DR.The gastrointestinal tract. The canary of the body?
JAMA. 1993 Sep 8;270(10):1247-8.

2. Fiddian-Green RG, McGough E, Pittenger G, et al. Predictive value
of intramucosal pH and other risk factors for massive bleed-ing from
stress ulceration. Gastroenterology 1983;85:613-20.

3. Hansen DG, Aures D, Grossman MI Histamine augments gastric
ulceration produced by intravenous aspirin in cats.
Gastroenterology. 1978 Mar;74(3):540-3.

4. Fromm D, Kolis M. Effects of sodium salicylate and acetylsalicylic
acid on intramural pH and ulceration of rabbit antral mucosa.
Surgery. 1982 Apr;91(4):438-47.

5. Whittle BJ, Hansen D, Salmon JA. Gastric ulcer formation and cyclo
-oxygenase inhibition in cat antrum follows parenteral administration of
aspirin but not salicylate.
Eur J Pharmacol. 1985 Oct 8;116(1-2):153-7.

6. Fiddian-Green RG, McGough E, Pittenger G, Rothman E. Predictive
value of intramural pH and other risk factors for massive bleeding from
stress ulceration.
Gastroenterology. 1983 Sep;85(3):613-20.

7. Fiddian-Green RG: Stress ulceration. In:Marston A, Bulkley GR,
Fiddian-Green RG, et al (eds). Splanchnic Ischemia and Multiple Organ
Failure. London: Edward Arnold/St. Louis, CV Mosby; 1989.

8. Higgins D, Mythen MG, Webb AR Low intramucosal pH is associated
with failure to acidify the gastric lumen in response to pentagastrin.
Intensive Care Med. 1994;20(2):105-8.

9. AMP-activated protein kinase: the energy charge hypothesis
Bioessays. 2001 Dec;23(12):1112-9. AMP-activated protein kinase: the
energy charge hypothesis revisited.
Bioessays. 2001 Dec;23(12):1112-9.

10. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and
acid-base balance.
Br J Anaesth. 1995 May;74(5):591-606.

11. Corri Black, James A Kaye, and Hershel Jick
Relation of childhood gastrointestinal disorders to autism: nested case-
control study using data from the UK General Practice Research Database
BMJ 2002; 325: 419-421

12. Fiddian-Green RG Associations between intramucosal acidosis in
the gut and organ failure.
Crit Care Med. 1993 Feb;21(2 Suppl):S103-7.

13. MMR, IBD, autism and methylmalonic acidosis
Richard G Fiddian-Green, 29 Mar 2003 eLetter re: Helen Bedford and David Elliman
Press: MMR: the onslaught continues
BMJ 2003; 326: 718

Competing interests:
None declared

Competing interests: No competing interests

03 November 2004
Richard G Fiddian-Green
c/o Sanders, Temple, Gdns, Moor Park.