|Celiac Disease in CFS Patients and a Bit More!
By Alan Cocchetto
Medical studies are beginning to show now that Celiac disease
can be present in CFS patients. During the past six months, I have had several long-term
patients phone me with various test results confirming that Celiac disease is a definite
problem among some of us with CFS. Most of these patients have been scoped and had
intestinal biopsy proven Celiac disease. One doctor, from one of the 'top five'
clinics in the US, concluded that the PWC had a type of neurological celiac disease!
This is very interesting in light of the pathogens that we have been looking at
(HHV-6, HTLV-II, etc.) with respect to their roles in the central nervous system.
I have included the latest CFS referenced article as well as one from the Celiac Sprue
Association and Vanderbilt University. (Please note that I feel CBT therapy is not a
viable therapeutic option for serious diseases such as celiac disease or CFS!) An
excellent and new Celiac disease panel is now available through Specialty Labs
in California (1-800-421-7110).
High prevalence of serum markers of celiac disease in
patients with Chronic Fatigue Syndrome
A Skowera, M Peakman, A Cleare, E Davies, A Deale and S Wessely Department of Immunology,
Guy's King's and St Thomas's School of Medicine, Denmark Hill Campus, London SE5 9RS, UK;
Department of Psychological Medicine, Guy's King's and at Thomas's School of Medicine
Journal of Clinical Pathology Vol. 54, pp: 335-336 April 2001
There has been recent interest in the possibility that undiagnosed coeliac disease (CD)
might be the cause of diverse clinical symptoms, most
particularly "tired all the time".  A recent study reported a prevalence of
three in 100 cases in a primary care environment in which samples were taken from patients
with a range of symptoms and signs.  The second most frequent symptom reported by the
endomysial antibody (EMA) positive patients was "being tired all the time". We
decided to examine the prevalence of EMA in patients attending our tertiary referral
centre with the diagnosis of chronic fatigue syndrome (CFS).
We tested serum from 100 consecutive patients (47 men, 53 women; median age, 40 years;
range, 18-57) referred to our specialist clinic and satisfying the standard CDC criteria
for a diagnosis of CFS, and from 100 healthy control subjects (45 men, 55 women; median
age, 40 years; range, 18-68) who were blood donors at the South East Thames Blood
Transfusion Service. The CFS samples had been stored as part of other studies, and were
analysed retrospectively. EMA of the IgA class were detected by indirect
immunofluorescence (IF) using
cryostat sections of distal primate oesophagus as substrate (Binding Site, Birmingham,
UK). Positive samples were confirmed using an enzyme linked immunosorbant assay (ELISA)
for the detection of antitissue transglutaminase antibodies  (Menarini Diagnostics,
Wokingham, UK), tissue transglutaminase being the autoantigen responsible for the IF
pattern of EMA. To exclude selective IgA deficiency, serum IgA concentrations were
measured by laser nephelometry using specific antisera according to the manufacturer's
instructions (Behring Laser Nephelometer II; Dade Behring, Dortmund, Germany).
Two of the 100 CFS samples were positive for EMA using IF, and this was confirmed by
ELISA, but none of the 100 control samples was positive. None of the subjects had
selective IgA deficiency. Mean (SD) serum IgA concentrations among patients with CFS were
2.1 g/litre (0.98). Neither of the positive cases, both women aged 27 and 54, had reported
symptoms typical of CD, although one had a history of constipation. Routine blood tests
including serum proteins and full blood count were normal, and both had been seen by
consultant physicians before referral. Both had histories of hypothyroidism, were taking
long term thyroxine, and were currently euthyroid. Before the diagnosis of CD was made
retrospectively, both had received cognitive behaviour therapy (CBT), a standard treatment
for CFS. In both cases, CBT led
to a substantial improvement in the quality of life and physical activity, but neither
patient was symptom free at the end of treatment or at six months follow up. In both
cases, CD was subsequently confirmed on jejunal biopsy after the retrospective
In general, it remains true that although a wide range of physical illnesses can be
misdiagnosed as CFS (see Wessely et al for review ), in practice this is uncommon. In
particular, if basic physical examination, investigations, and history are unremarkable,
misdiagnosis of CFS and other physical illnesses is very unusual. Until now there have
only been two reports concerning three cases of CD being misdiagnosed as CFS. [5,6]
However, there is now evidence from primary care of a surprisingly high frequency of
unsuspected positive EMA tests in people with non-specific symptoms and a suggestion that
a higher index of suspicion is needed when assessing such patients.  We now extend that
observation to our CFS clinic.
Indeed, given our prevalence of 2%, and the fact that there is a treatment for CD, we
now suggest that screening for CD should be added to the relatively short list of
mandatory investigations in suspected cases of CFS.
 Feighery F. Coeliac disease. BMJ 1999;19:236-9.
 Hin H, Bird G, Fisher P, et al. Coeliac disease in primary care: case
finding study. BMJ 1999;318:164-7.
 Lock R, Gilmore J, Unsworth D. Anti-tissue transglutaminase,
anti-endomysum and anti-R1-reticulin autoantibodies - the antibody trinity of coeliac
disease. Clin Exp Immunol 1999;116:258-62.
 Wessely S, Hotopf M, Sharpe M. Chronic fatigue and its syndromes.
Oxford: Oxford University Press, 1998.
 Watson R, McMillan S, Dickey W, et al. Detection of undiagnosed
celiac disease with atypical features using antiretulcin and antigliadin antibodies. Q J
 Empson M. Celiac disease or chronic fatigue syndrome - can the
current CDC working case definition discriminate? Am J Med 1998;104:79-80.
The 'Nuts and Bolts' of Celiac Disease Defined:
The condition of celiac disease results in a malabsorption syndrome. Symptoms relate to
intrinsic factors (genetic, immune) and to environmental factors (virus and gluten
interaction) to cause the enteropathy, celiac sprue. In the condition there is:
* Malabsorption of nutrients in that portion of the small intestine (the jejunum)
which is damaged a characteristic, though not specific, a lesion of the small intestinal
mucosa prompt clinical improvement following the withdrawal of selected cereal grains from
Dateline for Celiac Sprue
1888 - described clinically by Samuel Gee;
1952 - recognized as being caused by ingestion of wheat proteins;
1954 - histologic damage to intestinal mucosa described by Dicke;
Celiac Sprue as an Immunologic Disease:
* A genetic, inheritable disease linked to genetically transmitted
histocompatibility cell antigens [HLA DR3-DQ2,
DR5/7 DQ2, and DR4-DQ8]
* It is common [1 in 2000 to 2500 carry the diagnosis, undiagnosed GSE may be as
common as 1 in 200-400]
* The disease is characterized by damage to the mucosal lining of the small
intestine which is known as villous atrophy
the damage resulting in malabsorption produces malnutrition
* May be linked to skin blisters known as dermatitis herpetiformis
The Mucosal Damage of Celiac Sprue:
* The actual damage to intestinal mucosa is almost certainly mediated by the immune
system associated with ANTIBODIES to gliadin, reticulin and/or endomysial [smooth muscle]
* The antibodies probably do not directly cause the damage, though they may be
signals for cell-mediated immunity the cellular immune system [T cells] probably produces
the actual enterocyte injury, but only when gluten-type prolamins are present
Celiac Sprue as a Pathological Response to Dietary
* Technically, gluten-sensitive enteropathy is NOT a food allergy
* It is NOT an idiosyncratic reaction to food proteins mediated by IgE
* It is NOT typified by rapid histamine-type reaction [typified by bronchospasm,
The Nature of the Injury: :
* Slow to develop and is insidious
* Directly related to ingestion of certain grain prolamins, esp. wheat gliadin
proteins [proteins found in wheat, barley, rye, oats, etc.]
* Results in loss of intestinal villi in the upper small intestine, the jejunum,
with loss of absorptive function and the development of inflamation
* Reversible, if injurious protein is excluded from the diet reversible to
completely normal bowel histology and function
The Damaging Proteins:
* Proteins which are especially rich in proline and glutamine [especially, the amino
acid sequences which are in the following orders: Pro-Ser-Gln-Gln and Gln-Gln-Gln-Pro]
* These sequences or analogues are especially found in wheat gliadins, rye secalins,
barley hordeins and in a much lower amount in oat avenins. It is important to note that
these sequences are NOT found in the proteins of corn zein and rice oryzenin
Clinical Features at Onset
There is a remarkable variability in age of GSE diagnosis, from the first to the eighth
decade. This variability is due both to delays in making the diagnosis after symptoms
develop and to variability in the age of symptom onset.
Severity of Disease and Sensitivity to Gluten:
Sprue patients demonstrate a great variability in apparent "sensitivity" to
gliadins. Some may experience adverse intestinal function promptly after ingestion of
minute amounts of gluten; but most experience a delayed and insidious detrimental effect
on intesinal absorption after repeated exposure to [often small amounts] of gluten
proteins. The severity of malabsorption also varies.
Treatment for Gluten-Sensitive Enteropathy:
Strict adherence to the clinical diet, the gluten-free diet, is the essential mainstay of
therapy for GSE. In the absence of gliadin-type protein ingestion, persons with GSE are
generally perfectly normal and healthy. Some persons with a long history of damage, or
with apparent high "sensitivity," may require an immunosuppressive medication
such as prednisone.
Complications of Disease and Failure to Treat:
Celiac Sprue which has been of long duration or is neglected by non-compliance to the
clinical diet, can be complicated by intestinal lymphoma or other gastrointestinal
malignancies. There is a much higher incidence of intestinal lymphoma in GSE patients, an
incidence which is reduced by strict adherence to the gluten-free diet.
Role of the Food Industry in Celiac Disease:
Persons with GSE recognize that grain proteins are very important diet components for most
persons, but they wish for--and depend upon--accurate and understandable product labeling.
Since there is no clear minimal amount of gliadin-type protein which is reliably harmless,
it is also important that small amounts of gliadin NOT be included in foods which are
labeled as gluten-free [for example, as excipients or contaminants, such as might be
carried over in multipurpose grain processing equipment]. Secondly, the availability of
food variety and quality in the "gluten-free" category is also an important wish
of individuals with celiac sprue.
Trier, JS, Celiac Sprue, New England Journal of Medicine,
Marsh, MN, Gluten, Major Histocompatibility Complex and the Small
Intestine, Gastroenterology, 102:330-354, 1992.
Maki, M and Collin, P, Coeliac Disease, Lancet 349:1755-1759,
Sturgess, RP et al, Cereal Chemistry, Molecular Biology and Toxicity in
Coeliac Disease, Gut 32:1055-1060, 1991.
Sturgess, RP et al, Wheat Peptide Challenge in Coeliac Disease, Lancet,
Celiac Disease in Children:
Celiac disease is an intolerance to certain cereal grains causing small bowel villous
atrophy and thus malabsorption. Specifically, the gliadin component of wheat, and
the prolamin component of rye and barley are implicated in causing disease.
The disease is found at different frequencies in different countries, and at different
times within a given country. For example in Ireland in the 1960's and early 1970's,
incidence was found to be 1:300; later studies in the same population showed an incidence
of 1:1370. Incidence in Sweden has ranged from 1:6500 to 1:1300. There is a definite
association with certain HLA types, especially HLA B8, DR3, DR7, and DQ2.
Familial risk is approximately 2-3% in first degree relatives; 70% concordance is reported
in monozygotic twins. Patients with Down's syndrome, known to be at higher risk for many
autoimmune diseases, have also been reported to have a higher incidence of celiac disease
(5% according to Castro et al, 1993)
Symptoms suggesting celiac disease are: Apathy, irritability, pain, vomiting, chronic
diarrhea, steatorrhea, abdominal distension, and failure to thrive.
Physical findings may include those of chronic disease and wasted muscle mass, clubbing,
and peripheral edema.
Typical age of presentation is late in the first year of life, with irritability,
frequent loose, pale, foul smelling stools, and failure to thrive. Less typical
presentations include prominent vomiting, good appetite, constipation, and presentation in
older childhood or even adulthood. Poor growth and muscle wasting tend to be consistent
features. An occasional child will have short stature alone.
Laboratory data supportive of the diagnosis of celiac disease includes anemia, usually
iron deficiency; hypoalbuminemia; hypocalcemia; and low serum levels of fat soluble
vitamins (eg vitamins D,A). Stool studies show increased fat, up to 10% of intake in
quantitative collections. Bone age is delayed in up to 80% of patients. The most specific
lab data by far is the presence of gliadin antibodies. One prospective study found
sensitivity of gliadin antibodies to be at least 86%, with specificity at least 97% (Bode,
et al 1993). The authors recommend use of this
test to select patients who should have small intestinal biopsy to confirm a diagnosis of
celiac disease (rather than as a replacement of biopsy for diagnosis). They also suggest a
role for following gliadin antibodies to monitor the course of disease over time.
Diagnostic criteria of celiac disease are based on small bowel biopsy, specifically
demonstration of active disease, then of improvement on a gluten free diet, then of
deterioration on gluten rechallenge 2-4 years afterward (total 3 biopsies). Abnormalities
characteristic of celiac disease include villous atrophy with deepened crypts and
irregular epithelium with lymphocytic infiltrates. Desire to eliminate need for so many
biopsies has led in part to the interest in gliadin antibodies as discussed above, however
most authors still recommend the initial biopsy. Some have argued against the need for a
rechallenge of gluten based on a very low negative rate (64/67 patients rechallenged had
abnormal biopsies, Danielsson, 1990).
Treatment is complete elimination of gluten from the diet, including all wheat, rye, and
barley. Corn and rice are tolerated normally. Aside from the obvious sources of gluten,
hidden sources must be eliminated, such as malt, starches in dairy products, and fillers
in tablet medications . During the short term after diagnosis, vitamin A, D, and iron are
indicated. In most patients symptomatic improvement on a gluten free diet begins within a
week. The diet should be observed lifelong once the diagnosis is established, although
with time patients are able to tolerate small amounts of gluten without symptoms. There is
some evidence of increased incidence of intestinal malignancy in
adults with long standing celiac disease, however the impact of dietary therapy on this is
Behrman, ed. Nelson Textbook of Pediatrics, 4th Ed. p977-979,
Bode, et al, "The diagnostic value of the gliadin antibody test in
celiac disease in children: a prospective study", J
Peds Gastroenterology and Nutrition 17:260-4, 1993.
Bonamico, et al "Short stature as the primary manifestation of
monosymptomatic celiac disease" J Peds
Gastroenterology and Nutrition 14(1): 12-16, 1992.
Castro, et al "Down's Syndrome and celiac disease: the prevalence of
high IgA antigliadin antibodies and HLA DR
and DQ antigens in trisomy 21" J Peds Gastroenterology and Nutrition
Danielsson, et al "Is gluten challenge necessary for the diagnosis
of coeliac disease in young children?" Scandinavian
J Gastroenterology 25(9):957-60, 1990.
Oderda, et al "Endoscopic and histologic findings in the upper
gastrointestinal tract of children with coeliac disease",
J Ped Gastroenterology and Nutrition 16:172-177, 1993.