Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7437.438 (Published 19 February 2004) Cite this as: BMJ 2004;328:438
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Dear Sir:
By and large, coeliac disease (CD) is reported to be a very rare
disease. It is silent in early part of human life cycle including among
children and adults but its incidence tends to increase in old age. It has
well defined clinical and diagnostic criteria; diarrhoea, weight loss,
anti-glidin and anti-dymosial antibodies, jejunal villous atrophy and
other features. This disease is reported to have a very interesting but
controversial co-morbid relationship with a variety of psychiatric
disorders in particular schizophrenia, pervasive developmental disorder
that is autistic disorder (AD), attention-deficit-hyperactive disorder
(ADHD), and mood disorders (MDs).
Notably, there are numerous implications of co-morbidity of coeliac
disease with schizophrenia. These implications may include epidemiological
trends, genetic etiological pooling and sharing, phenomenological
overlapping, diagnostic clues, therapeutic relationship and finally
prognostic and outcome trajectories. With regard to schizophrenia, CD is
reported to share genetic pool (chromosome 6) and can precipitate
psychotic decompensation in terms of schizophrenia-like psychosis.
Likewise, psychosis may also precipitate the onset of coeliac disease.
Patients with CD are sensitive to cereals containing gluten and milk,
which contain casein. There could be exacerbations both of coeliac and
psychotic symptoms after use of gluten-load diet. Conversely, gluten free
diet (also casein free milk)certainly improves coeliac symptomatology as
well as psychotic manifestations. However, gluten free diet has no
therapeutic role in the treatment of schizophrenia without coeliac disease
and likewise gluten is not a pathogenic risk factor for the development of
schizophrenia. Hence when both disorders have mutual causative
relationship as regards gluten, they may improve with gluten free diet.
Notably, gluten free diet is reported to have some adverse psychological
effects in various trials that recruited patients with schizophrenia.
The therapeutic role of gluten free diet in AD, MDs and ADHD is
equivocal and now better drug options like effective atypical
antipsychotics, SSRIs and mood stabilizers are available in the market.
Reference:
William Eaton, Preben Bo Mortensen, Esben Agerbo, Majella Byrne, Ole
Mors, and Henrik Ewald. Coeliac disease and schizophrenia: population
based case control study with linkage of Danish national registers. BMJ
2004; 328: 438-439
Competing interests:
None declared
Competing interests: No competing interests
TO THE EDITOR: We read with great interest the recent paper by Eaton
et al (1) on the association between coeliac disease (CD) and
schizophrenia. The authors conclude with an important question about the
start of gluten-free diet (GFD) in the small proportion of patients
affected by schizophrenia who screen posetively for CD but not show its
classic symptoms.
Several neurological, psychiatric (including schizophrenia) and affective
disorders have been reported in coeliac patients; these complication
occurr in approximatively 8%-10% of subjects affected by coeliac disease
(CD) (2). At present the etiology and pathogenesis of these disorders is
uncertain.
In a recent study our group evaluated regional cerebral perfusion assessed
by single photon emission computed tomography (SPECT) in untreated CD
patients, comparing them with CD patients on GFD and with healthy
controls. The study showed the the presence of regional cerebral
hypoperfusion in 73% of the untreated CD patients, compared with only 7%
of CD patients on GFD and none of the controls (3). An overall
multivariate test showed a significant difference in cerebral perfusion
among the three groups of subjects. (p = 0.01). Considering each single
region, a significant lower cerebral perfusion was found in untreated
celiac patients compared to controls in seven of the 26 cerebral regions
evaluated. There were no significant differences in cerebral perfusion
between untreated patients and those on GFD, or between patients on GFD
and healthy controls, reflecting a beneficial effect of a GFD on these
alterations (3). Perfusion defects were predominant in the superior and
anterior areas of the frontal cortex with the involvement of the adjacent
anterior cingulated cortex. Similar cerebral blood flow changes have been
reported in patients suffering from different psychiatric disorders (4).
Our previous paper reported a case of brain perfusion abnormalities,
assessed by SPECT examination, in a CD patient with schizophrenia;
regression of both cerebral hypoperfusion and schizophrenic symptoms was
observed after 6 months of a GFD (5). In conclusion psychiatric and/or
neurological disorders in CD patients could be related, in part, to brain
perfusion alterations. These hemodynamic changes seems to be linked to
disease activity, and resolved after GFD. For these reasons GFD should
started as soon as possible, also in patients which do not show the
classic form of CD.
REFERENCES
1. Eaton WW, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac
disease and schizophrenia: population based case control study with
linkage of Danish national register. BMJ 2004; 328: 438-9.
2. Finelli PF, McEntee WJ, Ambler M, Kestenbaum D. Adult celiac disease
presenting as cerebellar syndrome. Neurology 1980; 30:245-9.
3. Addolorato G, DiGiuda D, DeRossi G, Valenza V, Domenicali M, Caputo F,
Gasbarrini A, Capristo E, Gasbarrini G. Regional cerebral hypoperfusion in
patients with celiac disease. Am J Med 2004; 116: 312-7.
4. O’Connel RA. SPECT brain imaging in psychiatric disorders: current
clinical status. In Grünwald F, Kasper S, Biersack H-J, Möller H-J, Eds.
Brain SPECT Imaging in Psychiatry. De Gruiter W, Berlin, New York 1995: 35
-57.
5. De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G,
Taranto C, Manna R, Gasbarrini G. Schizophrenic symptoms and SPECT
abnormalities in a coeliac patient: regression after a gluten-free diet. J
Intern Med 1997; 242: 421-3.
Competing interests:
None declared
Competing interests: No competing interests
Eaton et al. (1) are to be commended for their convincing
demonstration of
the association between celiac disease and schizophrenia. While in
patients
with both celiac disease and schizophrenia, the celiac disease-associated
schizophrenia may respond dramatically to a gluten-free diet (2), the work
of the late F.
C. Dohan and others indicates that a gluten-free diet may also benefit a
significant number of patients with the more common, idiopathic form of
schizophrenia.
Dohan believed that the genotype for idiopathic schizophrenia
overlaps
somewhat with that of celiac disease, and on the basis of extensive
epidemiological studies correlating grain consumption with the incidence
of
schizophrenia (3,4) he concluded that gluten is a major factor in causing
this disorder in genetically susceptible individuals within the general
population. The results of trials of a gluten-free diet in the treatment
of
idiopathic schizophrenia have been inconsistent but have been well
reviewed
by Lorenz (5). In two trials, a statistically significant beneficial
effect
of the diet was noted. In other trials, some patients responded
favorably,
but the overall results were not statistically significant. In still
other
trials, the diet had no discernible beneficial effect. These studies
varied considerably in a number of important
parameters including their duration, the number of patients studied, and
the
subtype and stage of schizophrenia in the treated patients. In most of
the
trials, milk (casein) was also omitted from the diet, an omission that
benefits some patients with celiac disease.
Although his gluten hypothesis remains as yet unproven, Dohan's
epidemiological studies and the overall results of the gluten-free diet
trials indicate that a gluten-free diet may benefit a significant number
of
patients with idiopathic schizophrenia, particularly those in an early
stage of their illness and those who are acutely psychotic. For this
reason, future studies using a gluten-free diet to treat celiac
disease-associated schizophrenia should include as well a group of
patients
with idiopathic schizophrenia, some of whom may also respond to the diet.
References
1. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac
disease and schizophrenia: population based case control study with
linkage
of Danish national registers. BMJ 2004;328:438-9.
2. De Santis A. Addolorato G. Romito A. et al. Schizophrenic symptoms
and
SPECT abnormalities in a coeliac patient: regression after a gluten-free
diet. J Intern Med. 1997;242(5):421-3.
3. Dohan FC. Wartime changes in hospital admissions for
schizophrenia. A
comparison of admission for schizophrenia and other psychoses in six
countries during World War II. Acta Psychiatrica Scandinavica.
1966;42(1):1-23.
4. Dohan FC. Cereals and schizophrenia: data and hypothesis. Acta
Psychiatrica Scandinavica. 1966;42(2):125-52..
5. Lorenz K. Cereals and schizophrenia. In: Pomeranz Y, editor.
Advances
in Cereal Science and Technology, Vol. X. St. Paul: American Association
of
Cereal Chemists;1990, p. 435-469.
Competing interests:
None declared
Competing interests: No competing interests
The study by Eaton and colleagues suggests that a history of coeliac
disease is a risk factor for schizophrenia possibly in relation to the
vicinity of respective genetic markers on chromosome 6. While the study is
thought-provoking, we believe that the true validity of the causal
relationship remains to be demonstrated.
In 1997, we have reported the case of young woman with a four-year
history of schizophrenia receiving a pharmacological treatment with a
combination of two conventional antipsychotics and a benzodiazepine, who
came to our attention because of severe diarrhoea and weight loss.1 She
would eventually receive a diagnosis of coeliac disease based on the
presence of anti-endomysial antibodies and on a jejunal biopsy showing
subtotal villous atrophy with Lieberkuhn crypts hyperplasia. She was then
put on a gluten-free diet and her physical and psychiatric symptoms
improved rapidly. Most notably, SPECT-documented areas of hypoperfusion in
the left frontal and temporal cortex also normalized, and pharmacologic
treatment was discontinued without recurrence of schizophrenic symptoms.
After several years now, she remains symptom-free and well.
This case demonstrates that schizophrenia may indeed represents even
the exclusive clinical expression of a coeliac disease rather than be a
primary psychiatric illness. This case also illustrates that a gluten-free
diet could dramatically improve symptoms in patients with schizophrenia
who screen positive for coeliac disease.
1. De Santis A, Addolorato G, Romito A, Caputo S, Giordano A,
Gambassi G, Taranto C, Manna R, Gasbarrini G. Schizophrenic symptoms and
SPECT abnormalities in a coeliac patient: regression after a gluten-free
diet. J Intern Med 1997;242:421-3
Competing interests:
None declared
Competing interests: No competing interests
While the immediate science of this assertion is
unconvincing the principles within the inquiry are indeed
intriguing. Given the chaos and processing challenges
represented in both situations coherent links appear to me
as worth consideration and observation. Given the frequency
I find wheat flour & gluten sensitivity unappreciated even
by the most modern testing I don't myself believe science
can realistically limit itself in study to the presumed
certainty of lab methods in this matter.
Competing interests:
None declared
Competing interests: No competing interests
Eaton et al propose that Coeliac disease is a significant risk factor
for schizophrenia based on their large case-control trial. However, I
suggest that there is likely to be a degree of selection bias in the cases
of schizophrenia. Those requiring admission to a psychiatric facility may
represent a more severely affected group than those with schizophrenia
overall. Conversely, they may be more willing to accept medical help and
agree to participate in a clinical trial. Such a group may also be more
likely to present themselves for investigation of gastrintestinal symptoms
leading to the diagnosis of Coeliac disease.
As the authors infer, the concept of a 'Coeliac Iceberg' exists,
whereby most cases of the disease remain undiscovered. Coeliac disease can
be diagnosed at almost any age, making it feasible that the diagnosis of
schizophrenia could precede that of Coeliac disease by as much as six
decades. This prompts questions regarding the validity of using a case-
control study to examine the relationship between these two diseases.
Furthermore, the use of odds ratios rather than relative risks would have
been more appropriate, given the case-control design of the study.
Competing interests:
None declared
Competing interests: No competing interests
William Eaton and colleagues have demonstrated an interesting
association between coeliac disease and schizophrenia (1). However much
more research is needed before screening for coeliac disease can be
recommended as part of the routine assessment of people with
schizophrenia, not to speak of the recommendation of a gluten free diet
for those who screen positive for coeliac disease but are free of clinical
symptoms.
A gluten free diet may well be safe and inexpensive, but, in the
absence of evidence of any benefit, it would impose a considerable
additional burden on patients who are already coping with a serious mental
illness and possibly the side effects of antipsychotic medication.
The tests for coeliac disease may be inexpensive in themselves and
“carry minimal risk and discomfort” in their application, but much more
than this needs to be taken into consideration. We believe that simply
applying the Wilson and Jungner criteria (2) provides ample reasons to
reject this as a screening test.
1 Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac
disease and schizophrenia: population based case control study with
linkage of Danish national registers. BMJ 2004;328:438-439
2 Wilson JM, Jungner G. Principles and practice of screening for
disease. Geneva: World Health Organization, 1968. (Public Health Paper
Number 34.)
Competing interests:
None declared
Competing interests: No competing interests
Editor- Eaton et al report a strong risk relation between
schizophrenia and celiac disease.(1) We do not believe their data supports
this hypothesis.
They define their case sample as 7997 patients with schizophrenia, in
whom they found four cases of celiac disease. Eaton et al then include the
data on parents’ celiac status ( 8 cases) in their analysis and this is
potentially misleading. If the parent data is excluded from the analysis,
then the prevalence of celiac disease in new onset schizophrenics is only
0.5 per 1000, which is the same as in their control group.
They describe celiac disease as rare in Denmark and this was the
traditional view. Their sample population dated from 1981-1998, during
which time diagnostic testing for celiac disease has advanced. Recent data
using endomysial antibody to screen the Danish population suggests a
prevalence of 1 in 400, more akin to neighbouring Scandinavian
countries.(2) Therefore, underascertainment of the true prevalence of
celiac disease is a real possibility and a potential confounding factor.
1. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac
disease and schizophrenia: population based case control study with
linkage of Danish national registers. BMJ. 2004 Feb 21;328(7437):438-9.
2. Weile I, Grodzinsky E, Skogh T et al. High prevalence rates of
adult silent coeliac disease, as seen in Sweden, must be expected in
Denmark. APMIS. 2001 Nov;109(11):745-50.
Competing interests:
None declared
Competing interests: No competing interests
Rheumatoid arthritis and schizophrenia:there is also a well documented inverse correlation between the two diseases?
EDITOR--It was interesting to read the paper of Eaton et al[BMJ 2004;328:438
-439], Coeliac disease and schizophrenia:population based case control
study with linkage of Danish national registers. My comment:
It is well
known for long time that schizophrenia is unknown among patients with
rheumatoid arthritis[1]. It was suggested that it might be due to the
possibility that both of them share a common infectious or immune etiology
and that once a person gets one of the diseaes then they are relatively
immune to the other[2], so further research work in those areas might help
us to reach a firm conclusion about the etiology of schizophrenia.
Thanking
you,
Yours sincerely,
AK.Al-Sheikhli
References,
1.Gorwood P, Pouchot J, Vinceneux P, et al, Rheumatoid arthritis and
schizophrenia: a negative association at a dimensional level,Schizophr Res,
2004,66(1);21-9
2.Torrey EF and Yolken RH,The schizophrenia-rheumatoid arthritis
connection :infectious,immune,or both?,Brain Behav Immun,2001;15(4):401-10
Competing interests:
None declared
Competing interests: No competing interests