Fifteen experts from seven countries met in London in February 2011 to work on a consensus paper on the classification of gluten-related diseases, to include the emerging condition of non-coeliac gluten sensitivity (NCGS). A year on, the paper has been published in BMC Medicine. Alex Gazzola reviews its key points, and those of another new paper setting out proposed naming of gluten-related disorders and terminology.
“The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fuelling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010.”
So say the authors in their introduction to the newly published paper, Spectrum of gluten-related disorders: consensus on new nomenclature and classification. Previously, this discrepancy had always been attributed to dieters or ‘detoxers’ experimenting with the GF lifestyle and so boosting sales, but could an additional gluten-related medical condition underlie the staggering growth in ‘free from’?
The experts think so, and evidence is emerging to support the idea of non-coeliac gluten sensitivity (NCGS) – a reaction to gluten different to that involved in coeliac disease or wheat allergy – which has demanded a reclassification of gluten-related disorders into three groups, as follows.
Wheat allergy (WA) is usually an IgE-mediated response, which can cause rhinitis, urticaria, gastrointestinal or respiratory distress. It can also manifest as wheat-dependent exercise-induced anaphylaxis (WDEIA) and occupational asthma (baker’s asthma). Skin prick tests (SPTs) and IgE assays are used to diagnose WA, but their positive predictive value is under 75%, mostly because of cross reactivity between wheat and grass pollens, to which many hay fever sufferers are sensitised. A food challenge may be required to diagnose with confidence.
Coeliac disease (CD) is the main autoimmune gluten-related disorder. Blood testing for CD has improved in recent years, and the final step to diagnosis is a biopsy of the small intestine.
Dermatitis herpetiformis (DH), considered the skin manifestation of CD, is diagnosed via a biopsy of healthy skin.
Lastly, gluten ataxia (GA), which is characterised by gluten-related autoimmune damage to the cerebellum, resulting in symptoms of loss of co-ordination / feeling in extremities. Symptomatic patients should be screened for coeliac antibodies, and any found positive to anti-tTG should undergo a biopsy. Even biopsy-negative patients should be encouraged to undertake a GFD if there is no other plausible cause for their ataxia, with remission of symptoms after a year being considered strongly diagnostic of GA.
Non-coeliac gluten sensitivity (NCGS) is the proposed name for a condition with similar symptoms to CD, but with a prevalence of “extraintestinal symptoms, such as behavioural changes, bone or joint pain, muscle cramps, leg numbness, weight loss and chronic fatigue”. The researchers suggest that patients who improve on a GFD in the absence of any auto-immune or allergic condition may instead have NCGS, and have proposed raised anti-gliadin antibodies (AGA IgA / IgG) as possible markers for the condition. Diagnosis is made by excluding both CD and WA, followed by an exclusion diet and a blinded gluten challenge.
Evidence for NCGS
There are a few studies which suggest certain groups of non-coeliacs may benefit from a GFD.
According to one, one in five patients with schizophrenia have higher than expected levels of anti-gliadin antibody IgA and may benefit from a GFD even if they don’t have CD (see here), while a subset of children with autism spectrum disorders appear to derive benefit from the GFD too (see here).
Over a recent six-year period, almost 6,000 patients were seen at the Center for Celiac Research at the University of Maryland, and 6% were found to fulfil the criteria for NCGS, with abdominal pain (68%), eczema/rash (40%) and headache (35%) being the three top symptoms.
But could NCGS be a precursor to or form of CD? There are two pieces of evidence which suggest it may be.
The HLA-DQ2 or -DQ8 genes found in virtually 100% of coeliacs are found in 50% of the population with NCGS. This is considerably higher than the figure of 30% for the population at large, and therefore statistically significant.
Additionally, a German study described an association between CD-like abnormalities and a sub-group of IBS patients who tested positive for anti-gliadin antibodies. All these individuals were put onto a GFD and experienced symptomatic improvements, with those carrying the coeliac gene HLA-DQ2 more likely to enjoy a better response.
Both pieces of research would suggest NCGS may be a pre-coeliac condition, at least in some cases, and support the notion of a ‘grey area’ on the coeliac spectrum.
But a more recent blinded study from an Australian group has confused the picture. The group recruited people claiming to experience gut symptoms when consuming gluten and who tested negative to coeliac genes. They divided these individuals into two groups, feeding one ordinary bread and muffins and the other gluten-free equivalents. Measurements of pain, stool consistency and tiredness were made. 70% had persistent symptoms in the gluten-consuming group, and only 40% in the gluten-free group.
According to Professor David Sanders of Royal Hallamshire Hospital, Sheffield, and one of the fifteen involved in the BMC Medicine paper, this is the first description of non-coeliac gluten-sensitive IBS, which implies a symptomatic mechanism at work which cannot be related to CD.
He adds that this is a “real hot area for research” and that work needs to be done to explore the immune pathways involved.
The naming of gluten-related disorders
A separate paper, The Oslo definitions for coeliac disease and related terms, was published in February 2012 in the journal Gut, by a group of sixteen specialists, many of whom were involved in the BMC Medicine paper above.
The paper lays down a standardised form of naming of all gluten-related disorders, since the experts had previously identified lack of consensus and contradictory use in scientific literature. Here is a summary of their recommendations and key definitions:
Coeliac disease (CD) is defined as a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals.
Asymptomatic coeliac disease is CD not accompanied by symptoms at initial diagnosis, and in which no subsequent symptomatic improvements are noted following a GFD.
Classical coeliac disease is CD presenting with diarrhoea, malnutrition and weight loss / failure to thrive.
Non-classical coeliac disease is CD presenting with symptoms other than those related to malabsorption (ie diarrhoea and malnutrition).
Subclinical coeliac disease is CD below the threshold of clinical detection, without signs or symptoms sufficient to suggest testing in routine practice.
Symptomatic coeliac disease is characterised by clinically evident gastrointestinal
and/or extraintestinal symptoms attributable to gluten intake.
Potential coeliac disease relates to those with normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive serology.
Non-coeliac gluten sensitivity (NCGS) relates to symptomatic disease in response to gluten ingestion, in the absence of CD and WA.
Gluten-related disorders is the preferred umbrella term to describe all conditions
related to gluten, including GA, DH, NCGS and CD.
Typical coeliac disease was previously taken to be CD with symptoms of diarrhoea, malnutrition and wasting/weight loss, but as clinical presentations have changed so much over time, the term is no longer recommended.
Atypical coeliac disease was previously used alongside ‘typical coeliac disease’ to denote CD characterised by less common symptoms.
Silent coeliac disease – ‘asymptomatic coeliac disease’ is preferred instead.
Overt coeliac disease – ‘symptomatic coeliac disease’ is preferred instead.
Latent coeliac disease has been used to describe several different scenarios, including positive coeliac serology with negative villous atrophy, and villous atrophy which has recovered on a gluten-containing diet. Because of possible confusion, experts recommend it no longer be used.
Gluten intolerance has been used to describe both CD and NCGS, but also the poor digestion of gluten, the effects of lectin-like properties of gluten, or responses to other components of wheat. Because of this in consistency, the term should no longer be used.
Gluten sensitivity has been used synonymously with CD by some, as an umbrella term by others, and more recently to describe reactions to gluten in the absence of CD or WA. It should not be used, ‘Non-coeliac gluten sensitivity’ being preferred in the last of these cases.
First published in March 2012
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