2154 Editorials
9, 2000
study of these cells. This may offer the best hope for the
development of rational treatments that can be based on
biological control mechanisms of dormancy or clearance.
Whether specific immune, antiangiogenic, or chemoradio-
therapeutic strategies are adopted, the study of systemic
micrometastatic disease in esophageal cancer will be critical
for predicting and assessing clinical responsiveness, and is
likely to provide valuable insights for the management of
other solid tumors.
Gerald C. OSullivan, M.Ch., F.R.C.S.I., F.A.C.S.
Fergus Shanahan, M.D., F.R.C.P.I., F.A.C.P.
Departments of Surgery and Medicine
and Cork Cancer Research Centre,
University College Cork
National University of Ireland
Cork, Ireland
REFERENCES
1. OSullivan G, Sheahan D, Clarke A, et al. Micrometastases in
esophagogastric cancer: High detection rate in resected rib
segments. Gastroenterology 1999;116:543 8.
2. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy fol-
lowed by surgery compared with surgery alone for localised
esophageal cancer. N Engl J Med 1998;339:1979 84.
3. Lighdale CJ. Esophageal cancer. Am J Gastroenterol 1999;94:
20 9.
4. Akiyama H, Tsuramaru M, Udagawa H, et al. Systematic
lymph node dissection for esophageal cancerEffective or
not. Dise Esophagus 1994;7:213.
5. Altorki NK, Skinner DB. Occult cervical nodal metastases in
esophageal cancer: Preliminary results of three field lymph-
adenectomy. J Thorac Cardiovasc Surg 1997;113:540 4.
6. Sporn MB. The war on cancer. Lancet 1996;347:1377 81.
7. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence
of adenocarcinoma of the esophagus and esophagogastric
junction. Gastroenterology 1993;104:510 3.
8. Bytzer P, Christensen PB, Damkier P, et al. Adenocarcinoma
of esophagus and Barretts esophagus: A population based
study. Am J Gastroenterol 1999;94:86 91.
9. Walsh TN, Noonan N, Hollywood D, et al. A comparison of
multimodal therapy with surgery for esophageal adenocarci-
noma. N Engl J Med 1996;335:4627.
10. Shanahan F, OSullivan GC. Progress in treating esophageal
adenocarcinoma. Gastroenterology 1997;112:1417 8.
11. OBrien MG, Fitzgerald E, Lee G, et al. A prospective com-
parison of laparoscopy and imaging in the staging of esopha-
gogastric cancer before surgery. Am J Gastroenterol 1995;90:
2191219.
12. Pantel K, Dockmanns A, Zippelius A, et al. Establishment of
micrometastatic carcinoma cell lines: A novel source of tumor
cell vaccines. J Natl Cancer Inst 1995;87:1162 8.
Reprint requests and correspondence: Professor Gerald C.
OSullivan, Department of Surgery, Mercy Hospital, Cork, Ireland.
Received Mar. 27, 2000; accepted Apr. 4, 2000.
AJG Vol. 95, No.
Autism and the Gastrointestinal Tract
Autism is a behavioral disorder characterized by impairment
of social contact and communication and by restricted and
repetitive interests and behaviors (1). Of these cardinal
features, deficits in social contact and interaction are usually
the most prominent; typically, at least one of these features
is apparent by the age of 3 yr. Children often seem normal
at birth, only to develop regression to autistic behavior
between the first or second years of life: a most distressing
scenario for the parents and caregivers (2). The manifesta-
tions of this disorder may vary in severity and may be
associated with a wide range of levels of intelligence from
normal to impaired. Related disorders include Aspergers
syndrome, pervasive development disorder, not otherwise
specified (PDD-NOS), childhood disintegrative disorder,
and Rett syndrome.
The etiology of autism remains unknown. Recent studies
have suggested a possible genetic contribution (3), and there
is also evidence for a developmental abnormality in the
brainstem (4). Others have emphasized the possible impact
of a number of postnatal factors ranging from environmental
toxins to dietary factors, and a variety of infectious agents.
Of these, the possible relationship to casein and gluten
intolerance (5), on one hand, and measles and MMR vac-
cination (6), on the other, have generated particular interest.
As a consequence of the former, many of these children,
who often already have a very limited diet because of highly
selective eating patterns, are placed on casein and gluten-
free diets, rendering an already precarious dietary intake
even more so. The association between autism and measles
virus and measles vaccination has generated considerable
controversy (7) reaching the lay press and even a Congres-
sional hearing (8).
Autistic children frequently develop gastrointestinal
symptoms including constipation, diarrhea, abdominal dis-
comfort, gaseousness, and distension. Horvath et al. re-
ported a 69% prevalence of histological esophagitis and a
58% prevalence of intestinal disaccheridase deficiency in a
group of 36 autistic children studied by upper gastrointes-
tinal endoscopy and biopsy (9). Pancreatic insufficiency has
also been suggested (10). However, it is the possible asso-
ciation of autism with ileocolonic disease that has attracted
the most attention. Wakefield et al. first reported prominent
ileal lymphoid nodular hyperplasia (LNH) and ileocolitis in
an uncontrolled study of 12 autistic children and went on to
speculate a link to MMR vaccination (6). The same group
had previously postulated a similar link between measles,
MMR, and inflammatory bowel disease in adults (11, 12). In
this issue of the Journal, Wakefield et al. report on a total 60
children with developmental disorders (primarily autism)
and compare their ileocolonoscopic findings (both macro-
scopic and histological) with those of 22 control children
and 20 with ulcerative colitis. In all, 93% of affected chil-
dren had LNH in comparison to 29% of controls and
chronic colitis was identified in 88% of affected children in
AJG September, 2000
comparison to 5% of controls (13). The authors conclude
that children with developmental disorders frequently ex-
hibit a new variant of inflammatory bowel disease: autistic
enterocolitis.
The gut brain connection is now recognized as a basic
tenet of physiology and medicine, and examples of gastro-
intestinal involvement in a variety of neurological diseases
are extensive (14). The pathophysiology of these gastroin-
testinal expressions of a central nervous system is often
unclear, but may variably reflect the parallel involvement of
the gut and brain by the same disease process or the con-
sequences of a primary disease of the brain or gut on the gut
or brain, respectively. The description of gastrointestinal
dysfunction in autism should come as no surprise, therefore.
Indeed, some of the symptoms manifested by these children
are quite similar to those reported by adults with degener-
ative central nervous system disorders, such as Parkinsons
disease, for example (15). What is of particular interest is
the suggestion that a developmental disorder may be asso-
ciated with inflammatory bowel disease. How firm is this
association? Certain features of the study limit our ability to
adequately address this question. With regard to the asso-
ciation with LNH, it remains unclear whether this finding
reflects a true abnormality, given the differences in median
age between patients and controls. This group was also
confronted with a ubiquitous issue in pediatric research: that
of obtaining a true control population. Their controls
were, in fact a group of symptomatic children in whom the
diagnosis of inflammatory bowel disease had been exclud-
ed: hardly a perfect comparator. LNH could also be a
secondary phenomenon, related to infections or infestations,
immunodeficiency, or even constipation (16). The histolog-
ical appearances of the ileal biopsies, reviewed blindly by
three pathologists, commonly included reactive follicular
hyperplasia, marked expansion of lymphoid tissue, and
acute cryptitis; ileitis, eosinophil infiltration, and an increase
in intraepithelial lymphocytes (IELs) were unusual. In the
colon, biopsies showed appearances that were similar to, but
less severe than, those seen in the children with established
ulcerative colitis, being perhaps more reminiscent of the
features of lymphocytic colitis, as seen in adults (17). It is of
interest, given the proposed association of autism with glu-
ten intolerance, that colonic inflammation has also been
described in adult celiac disease (18).
These findings also need to be interpreted with caution. In
particular, one must bear in mind that this was a highly
selected series children referred to a highly specialized
center being selected for investigation on the basis of the
presence of gastrointestinal symptoms. Pending the perfor-
mance of appropriate studies, which should include both
asymptomatic autistic children as well as children with other
developmental disorders, these findings cannot and should
not be extrapolated to children with autism in general.
Indeed, a strategy development subgroup of the Medical
Research Council in the UK recently concluded that the case
for autistic enterocolitis had not been proven (16). Nor is
Editorials 2155
there sufficient evidence to enable us, in any way, to
define the nature of the relationship between these gas-
trointestinal findings and the neurodevelopmental disor-
der. In particular there is, at present, insufficient evidence
to establish either a direct or indirect link, (e.g., through
an associated alteration in intestinal permeability (19)
between an inflamed gut and the brain, in autism. We
must, in particular, resist the temptation to predict cau-
sation without the necessary evidence; to do so could
engender false hope and further burden families who
already have more than their fair share of crosses to bear.
Furthermore, there is at present no evidence to suggest
that the presence or absence of these features influences
the expression or progression of this distressing disorder,
nor is there any suggestion that therapy based on these
findings might ameliorate either the developmental dis-
order itself or the associated gastrointestinal symptoms.
Ileocolonoscopy should continue to be regarded, there-
fore, in the absence of other indications, as an investiga-
tional tool in these patients.
Wakefield et al. (13) are to be congratulated on open-
ing yet another window onto the ever-broadening spec-
trum of gut brain interactions. Their findings raise many
challenging questions that should provoke further much-
needed research in this area, research that may provide
true grounds for optimism for affected patients and their
families.
Eamonn M. M. Quigley, M.D., F.A.C.G.
David Hurley, M.B.
Department of Medicine
National University of Ireland
Cork, Ireland
REFERENCES
1. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC: Amer-
ican Psychiatric Association, 1994.
2. Frith U, ed. Autism and Asperger syndrome. Cambridge:
Cambridge University Press, 1991.
3. Rodier PM. The early origins of autism. Sci Am 2000;282:
38 45.
4. Rodier PM, Ingram JL, Tisdale B, et al. Embryological origin
for autism: Developmental anomalies of the cranial nerve
motor nuclei. J Compar Neurol 1996;370:247 61.
5. Reichelt KL, Scott H, Ekrem J. Gluten, milk proteins and
autism: The results of dietary intervention on behaviour and
peptide secretion. J Appl Nutr 1990;42:111.
6. Wakefield AJ, Murch SH, Anthony A, et al. Ileal nodular
hyperplasia, non-specific colitis and pervasive developmental
disorder in children. Lancet 1998;351:637 41.
7. Taylor B, Miller E, Farrington CP, et al. Autism and measles
mumps and rubella vaccine: No epidemiological evidence for
a causal association. Lancet 1999;353:2026 9.
8. Anonymous. Measles, MMR, and autism: The confusion con-
tinues. Lancet 2000;355:1379.
9. Horvath K, Papadimitriou JC, Rabsztyn A, et al. Gastrointes-
tinal abnormalities in children with autistic disorder. J Pediatr
1999;135:559 63.
2156 Editorials
10. Lightdale JR, Hayer CA, Duer A, et al. Evaluation of gastro-
intestinal symptoms in autistic children before and following
secretin infusion. Gastroenterology 2000;118:A66.
11. Wakefield AJ, Montgomery SM, Pounder RE. Crohns
disease: The case for measles virus. Ital J Gastroenterol 1999;
31:24754.
12. Wakefield AJ, Montgomery SM. Measles virus as a risk factor
for inflammatory bowel disease: An unusually tolerant ap-
proach. Am J Gastroenterol 2000;95:1389 92.
13. Wakefield AJ, Anthony A, Murch SH, et al. Enterocolitis in
children with developmental disorders. Am J Gastroenterol
2000;95:228595.
14. Pfeiffer RF, Quigley EMM. Neurogastroenterology. Semin
Neurol 1996;16.
15. Edwards LL, Pfeiffer RF, Quigley EMM, et al. Gastrointesti-
nal symptoms in Parkinsons disease. Mov Disord 1991;6:
151 6.
16. Medical Research Council. Report of the strategy develop-
ment group subgroup on research into inflammatory bowel
disorders and autism. London: MRC, 1999.
17. Fernandez-Banares F, Salas A, Forne M, et al. Incidence of
collagenous and lymphocytic colitis: A 5-year population-
based study. Am J Gastroenterol 1999;94:418 23.
18. McCashland TJ, Donovan JP, Strobach SJ, et al. Collagenous
enterocolitis: A manifestation of gluten-sensitive enteropathy.
J Clin Gastroenterol 1992;15:52 4.
19. DEufemia P, Celli M, Finocchiaro R, et al. Abnormal intes-
tinal permeability in children with autism. Acta Paediatr 1996;
85:1076 9.
Reprint requests and correspondence: Eammon M. M. Quigley,
M.D., F.A.C.G., National University of Ireland, Cork University
Hospital, Clinical Sciences Building, Cork, Ireland.
Received June 26, 2000; accepted June 26, 2000.
The Effect of Alcohol
on Body Composition
Epidemiologic data suggest that alcohol may account for up
to 10% of total energy intake in consumers of alcohol and
may supply more than 50% of dietary energy in individuals
who are alcoholic (1 6). Because alcohol is a high energy
compound/nutrient (7.1 kcal/g), it is commonly assumed
that excessive alcohol consumption is a risk factor for
weight gain and for the development of obesity (79). As
obesity itself, along with its associated hepatic steatosis, is
a risk factor for liver injury (10 12), the interactions among
alcohol, body composition, and hepatic steatosis have
gained clinical importance (13). However, much of the
available data are conflicting regarding the relationship be-
tween alcohol consumption and body weight, with studies
showing a positive (14 17), a negative (18 21), or no
relationship (2225).
In the current issue of the Journal, Addolorato et al.
report the latest of their studies regarding the relationship
between alcohol and body composition (26). This work
makes three important observations in a group of 34 alco-
holics (consuming 194 g of alcohol daily) who were com-
pared to 43 matched controls (consuming 36 g of alcohol
AJG Vol. 95, No. 9, 2000
daily). First, despite consuming 40% more total calories, the
alcoholic groups weighed the same as the control group.
Second, fat mass was decreased, whereas lean body mass
was maintained in the alcoholic group. Third, despite a
lower fat mass, alcoholics have an increased visceral fat
mass (as estimated by waist-to-hip ratios).
Before the implications of these important observations
are discussed, it is appropriate to address a few factors that
are important in the performance and interpretation of stud-
ies investigating the effect of alcohol and body composition.
Perhaps most important for the accuracy of such studies is
the method by which body composition is measured. Ad-
dolorato et al. are to be commended for assessing fat mass
by dual energy x-ray absorptiometry. As recently reviewed
(27), DEXA provides an accurate assessment of fat mass;
thereby strengthening the findings of decreased fat mass in
alcoholics, which the authors also observed in previous
work using less precise methods (28, 29). However, DEXA
is less accurate in the assessment of lean body mass because
it cannot separate intra- from extracellular water (the two
largest components of lean body mass). This has been
shown to be important in alcoholic cirrhotics (30) and is
particularly relevant to the present work, as the finding of
similar body weights in the two groups, with less fat mass
in the alcoholic group, would indicate an increase in lean
body mass in the alcoholic group. Such a finding would be
difficult to interpret without the recent information that
extracellular water is also increased in alcoholics without
liver disease (31).
The assessment of visceral fat mass may also be prob-
lematic, but to a lesser degree. The waist-to-hip ratio (as
performed in the study of Addolorato et al.) is frequently
used to estimate visceral fat because it is inexpensive, easy
to perform, and has been shown to correlate with visceral fat
as assessed by CT (32, 33). However, changes in this ratio
may be more difficult to interpret (34). The waist circum-
ference is composed of both subcutaneous and intra-abdom-
inal fat. Therefore, waist diameter may be influenced by a
lax abdominal wall and/or intestinal contents. Similarly, the
hip circumference is dependent on stature, the size of gluteal
muscles, and subcutaneous fat. Because of these issues,
some investigators believe that waist-to-hip ratios should be
considered as relative rather than absolute measures of vis-
ceral fat (35).
Another important consideration is the appropriateness of
the study and control groups. Addolorato et al. again are to
be commended for having the alcohol and control groups
well matched for age, height, and gender. However, no
female subjects were included in either group. Although the
lack of female subjects does not alter the results of the
present study, its unisex nature does prevent the extrapola-
tion of these data to female alcoholics. This is important not
only because alcohol is more hepatoxic in women (13);
alcohol also influences sex steroid metabolism and, there-
fore, may influence women differently from men, as evi-
denced by the observation that relatively low body weight in