Evolving Diagnostics

The Gluten File


Moving Toward A Broader Recognition

The Oslo definitions for coeliac disease and related terms.
PMID:22345659  Feb 2012

ABSTRACT: A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.
Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
PMID: 22313950  Feb 2012

METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities.
A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495. 
Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet.
PMID 21471568  Nov 2011

Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms.
Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet.
PMID:21471568  April 2011

This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.
Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
PMID:21392369  Mar 2011

Between Celiac Disease and Irritable Bowel Syndrome: The "No Man's Land" of Gluten Sensitivity. 
PMID: 19455131  May 2009 

The gluten syndrome: A neurological disease.
PMID: 19406584  April 2009

"The Role of  Serological  Screening  Must  Be  Re-evaluated
The diagnostic criteria for CD remain inadequate to encompass the whole range of presentations of gluten sensitivity. The diagnostic "gold standard" requires demonstration of biopsy evidence of small bowel villous atrophy which normalises with dietary restriction and deteriorates upon rechallenge. This will allow most patients with symptomatic gut disease to be diagnosed, but excludes a significant number of people with "latent" coeliac disease, dermatitis herpetiformis, gluten-induced ataxia, and other conditions. In most of the studies of coeliac serology to date, positive antibody results in the absence of demonstrable bowel pathology have been labelled falsely positive, thus reducing the diagnostic specificity of serology. It is quite possible that many of these patients with "normal" small bowel biopsies but high titre antibodies to endomysial, gliadin or transglutaminase antigens could be included in the category of gluten sensitivity syndrome if other clinical features are evident, particularly if these occur in the setting of appropriate HLA haplotypes, family history, IgA deficiency, or other autoimmune conditions such as IDDM or autoimmune thyroiditis."

"As this is a screening rather than a diagnostic strategy, any loss of specificity incurred by measuring IgG AGA is acceptable to ensure that the possibility of gluten sensitivity or CD is not prematurely discounted on the basis of a negative serological test. "

Coeliac Disease and Gluten Sensitivity Syndrome  (Australia)

"In clinics our aim is to widen the diagnosis of coeliac disease to what we have started to call genetic gluten intolerance, gluten-induced disease entities with or without manifest mucosal lesion. Our clinical focus is also on gluten-induced extraintestinal manifestations and to know the true prevalence of the disease."
Coeliac Disease Study Project   (Finland)

MRI in Diagnostics?

The overall specificity and accuracy were 100%, and sensitivity was 79% and 75% for increased number of ileal folders and reversed fold pattern abnormality, respectively. CONCLUSION: MRI is able to demonstrate intra- and extraintestinal features that may lead to the diagnosis of celiac disease in adults

Adult celiac disease: What is the role of MRI?
PMID: 16888777 Aug 2006

Seronegative?  Without Villous Atrophy??

Although the classical histopathology changes of coeliac disease with partial or total villous atrophy are well recognized, the pathology classification of coeliac disease is changing, with recognition that coeliac disease may show minimal pathology (normal architecture and an intraepithelial lymphocyte count/100 enterocytes ≥ 25). This entity is also described as lymphocytic duodenosis, and recommendation of follow-up serology testing is paramount in this condition. Follow-up of patients with coeliac disease is warranted, as normal serology does not predict mucosal recovery.
An update in the diagnosis of coeliac disease.
PMID: 21054494   Nov 2010

Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease.
PMID: 16886921 Aug 2006

Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits.
PMID: 16571636 Mar 2006

Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia.
PMID: 16476935 Feb 2006

Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study.
PMID: 16036509 May 2005

In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies.
PMID: 15082580 May 2004

New Antibody Tests?

Anti-Actin IgA Antibodies Identify Celiac Disease Patients with a Marsh 3 Intestinal Damage among Subjects with Moderate Anti-TG2 Levels.
PMID: 24083232  Sept 2013
Celiac disease is a multisystemic dietary, gluten-induced autoimmune disorder characterized by the presence of transglutaminase (TG) 2 serum autoantibodies. Distinct autoantibodies targeting members of the TG family (TG2, TG3 and TG6) are found deposited in small-bowel mucosa and in extraintestinal tissues affected by the disease. Serum autoantibodies against other self-antigens also emerge in untreated celiac disease patients. Although villous atrophy and crypt hyperplasia in small-bowel biopsy samples are still the gold standards in diagnostics, celiac disease-specific antibodies are widely used as diagnostic aids. Gluten-induced small-bowel mucosal T-cell response is the cornerstone in the pathogenesis of the disorder, but humoral immunity may also play a central role. This review article is focused on the autoantibodies that occur in the context of celiac disease. The article summarizes the diagnostic utility of different celiac-related antibodies and discusses their roles in the pathogenesis of the disease.Cellular & Molecular Immunology advance online publication, 31 January 2011; doi:10.1038/cmi.2010.65.
Antibodies in celiac disease: implications beyond diagnostics.
PMID: 21278768  Jan 2011

The role and relevance of deamidated gliadin antibodies specific for celiac disease in gluten-sensitive ataxia/neuropathy is unknown. We investigated the association of celiac-specific serology with gluten-sensitive ataxia/neuropathy, in patients with and without gliadin-induced enteropathy. 51 patients with unexplained ataxia/neuropathy suspected to have gluten sensitivity were included in the study and their serum celiac-specific markers were measured. Deamidated gliadin-IgA (83% vs. 22%), deamidated gliadin-IgG (50% vs. 3%), tissue transglutaminase-IgA (78% vs. 11%), and anti-endomysial-IgA (70% vs. 0%), were significantly more positive in ataxia/neuropathy patients with celiac disease versus those without enteropathy (P<0.001). Our findings suggest that the serological profile of gluten-sensitive ataxia/neuropathy without intestinal involvement lacks the recognition of deamidated gliadin and tissue transglutaminase epitopes.
Serology of celiac disease in gluten-sensitive ataxia or neuropathy: Role of deamidated gliadin antibody.
PMID: 21056914 Nov 2010

INTERPRETATION: Antibodies against transglutaminase 6 can serve as a marker in addition to human leukocyte antigen type and detection of anti-gliadin and anti-transglutaminase 2 antibodies to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease.
Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase.
PMID: 18825674  Sep 2008

Antibody responses to deamidated gliadin peptide show high specificity and parallel antibodies to tissue transglutaminase in developing coeliac disease.
PMID: 17803713   Nov 2007

CONCLUSION: The detection of a-GDP antibodies was the most reliable tool in order to identify gluten sensitivity in DH patients presenting a wide range of intestinal damage. Further studies should explore if these findings can be extrapolated to patients with CD having mild enteropathy.
Celiac disease serology in dermatitis herpetiformis. Which is the best option for detecting gluten sensitivity?
PMID: 17225447 Dec 2006

Other Methods of Testing?

RESULTS: Consent was obtained from 4242 parents (84.8%) for the screening to be performed, and adequate saliva samples were collected from 4048 children (95.4%). Thirty-two children were found to be salivary tTG IgA positive and 9 with borderline autoantibody levels. Thirty-one of the 32 and 3 of the 9 subjects were also serum positive. Twenty-eight children showed villous atrophy when undergoing intestinal biopsy, whereas 1 had Marsh 1 lesions; 3 children were suggested to start GFD without performing endoscopy. CD prevalence in the population investigated (including 19 CD known cases) was 1.16%. The ratio between screening-detected patients and those diagnosed before the screening was 3:2. The ratio between symptomatic and asymptomatic patients was 1:1.6.

CONCLUSIONS: We demonstrated that it is possible to perform a powerful, simple, well-accepted, and sensitive CD screening using saliva. Until now, the compliance with GFD in children with CD has been optimal.
First Salivary Screening of Celiac Disease by Detection of Anti-transglutaminase Autoantibody Radioimmunoassay in 5000 Italian Primary Schoolchildren.

PMID: 2105733  Nov 2010

Fecal Calprotectin Concentration in Celiac Disease.
PMID: 20054281  Jan 2010

CONCLUSIONS: This study demonstrates that it is possible to detect salivary tTG-Abs with high sensitivity not only at CD diagnosis, but also during GFD.
Radioimmunological detection of anti-transglutaminase autoantibodies in human saliva: a useful test to monitor coeliac disease follow-up.
PMID: 19086333 Aug 2008

More on:  stool testing

Evolving Treatments?

Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. 
PMID: 16635908 April 2006  

"Alba Therapeutics Corporation today announced the successful completion of multidose safety studies in normal volunteers, concluding Phase I trials for its lead compound, oral AT-1001. Combined with Alba's previous single dose study and Phase Ib demonstration of intestinal permeability decrease in gluten-challenged celiac disease patients, this safety data brings the company closer to its goal of delivering an autoimmune treatment based upon modulation of mucosal barrier function. "We look forward to filing a diabetes IND and to entering Phase II trials for celiac disease as early as this summer," stated Dr. Blake Paterson, CEO of Alba, "and continue to develop the breadth of our core technology platform for multiple applications."  
Alba Therapeutics Press Releases

A constraining life-long gluten-free-diet is the only current treatment for celiac disease. The human gastrointestinal tract does not possess the enzymatic equipment to efficiently cleave the gluten-derived proline-rich peptides driving the abnormal immune intestinal response in coeliac patients. Oral therapy by exogenous prolyl-endopeptidases able to digest ingested gluten was therefore propounded as an alternative treatment to the diet. The feasibility of this approach is discussed by confronting recent data on the intestinal transport of gliadin peptides, properties of available enzymes and preliminary clinical assays. Development of new enzymes or enzymatic cocktail offers potentially more potent therapeutic tools that need however meticulous evaluation based on clinical, biological and histological criteria.
Oral proteases: a new approach to managing coeliac disease
PMID: 16950833

Celiac disease is caused by an immune response to the dietary protein gluten. The only available treatment is the strict exclusion of gluten from the diet; however, this is marred by the virtual omnipresence of this protein. The enzymatic degradation of gluten might become an alternative to the gluten-free diet, and recent work indicates that such approaches are getting close to being tested in clinical trials.
Enzymatic gluten detoxification: the proof of the pudding is in the eating!
PMID: 16934352 Aug 2006