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 [Correspondence]

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". [1] 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. [2] 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 [3] (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 identification.

In general, it remains true that although a wide range of physical illnesses can be misdiagnosed as CFS (see Wessely et al for review [4]), 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. [2] 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.

[1] Feighery F
. Coeliac disease. BMJ 1999;19:236-9.
[2] Hin H, Bird G, Fisher P, et al. Coeliac disease in primary care: case finding study. BMJ 1999;318:164-7.
[3] 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.
[4] Wessely S, Hotopf M, Sharpe M. Chronic fatigue and its syndromes. Oxford: Oxford University Press, 1998.
[5] Watson R, McMillan S, Dickey W, et al. Detection of undiagnosed celiac disease with atypical features using antiretulcin and antigliadin antibodies. Q J Med 1992;84:713-18.
[6] 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 the diet

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] proteins
*  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 Antigens:

*  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, urticaria, etc.]

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.

Selected Bibliography:
Trier, JS, Celiac Sprue, New England Journal of Medicine, 325:1709-1719, 1991.
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, 1997.
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, 343:759-761, 1994.

Source:  http://www.csaceliacs.org/celiacdisease.html

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 unknown.

Behrman, ed. Nelson Textbook of Pediatrics, 4th Ed. p977-979, 1992
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 16:265-8, 1993.
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.

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