Limitations of Blood Tests and Biopsy Results
The Gluten File
Diagnostic Tests Are Not Perfect
And new tests are constantly evolving....
Intestinal biopsy is not always required to diagnose celiac disease: a retrospective analysis of combined antibody tests.
PMID:23343249 Jan 2013
For children younger than 3 years of age, IgA +
IgG EMA is highly sensitive and specific. Use of IgA + IgG DGP or IgA
TTG as a single serological marker is insufficient for definite
diagnosis of CD in this age group. Based on our results, it might be
reasonable to postpone the biopsy for asymptomatic children with
Celiac disease screening assays for children younger than 3 years of age: the performance of three serological tests.
PMID:21847565 Jan 2012
IgG AGA were positive in 56.4% of GS patients and in 81.2%
of celiac patients, with high antibody titers in both groups. IgA AGA
were detected in 7.7% of GS patients and in 75% of celiac patients,
showing lower enzyme-linked immunosorbent assay activities in GS than
those found in celiac disease. Only 1 of the 78 patients with GS was
positive for IgG DGP-AGA (detected in 88.7% of patients with celiac
disease). IgA tTGA and IgA EmA were negative in all GS patients, whereas
their positivity in celiac patients was 98.7% and 95%, respectively.
Patients with GS displayed a variegated clinical picture with intestinal
and extraintestinal symptoms (abdominal pain, bloating, diarrhea,
constipation, foggy mind, tiredness, eczema/skin rash, headache,
joint/muscle pain, numbness of legs/arms, depression, and anemia)
together with normal or mildly abnormal small intestinal mucosa.CONCLUSIONS:
The serological pattern of GS is characterized by IgG AGA
positivity in more than half of cases associated to IgA AGA in a few
patients, but without EmA, tTGA, and DGP-AGA, which are the specific
markers of celiac disease.
Serological Tests in Gluten Sensitivity (Nonceliac Gluten Intolerance).
PMID 22138844 Dec 2011
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
Celiac disease (CD) is a gluten-triggered enteropathy, presenting with insidious clinical patterns. It can occasionally be diagnosed in asymptomatic subjects. Our aim was to define the relationship among symptoms at diagnosis, serological markers [tissue transglutaminase antibodies (tTGA), anti-endomysium antibodies (EMA) anti-actin antibodies (AAA)] and degree of mucosal damage. A total of 68 consecutive adult patients with CD were enrolled. Intestinal biopsies were scored according to the Marsh classification modified by Oberhuber: I-II minimal lesions or absent villous atrophy; IIIA partial villous atrophy; IIIB-C total villous atrophy (TVA). HLA-typing was done for all patients. No association between clinical presentation and severity of mucosal damage was found. Presence of EMA or tTGA was significantly associated with more severe mucosal damage (P < 0.001). Of 12 patients, 11 with AAA were also positive for TVA. The severity of mucosal damage is the main factor governing the detectability of serological markers of CD. The sensitivity of serological testing is questionable in patients with minimal lesions
Serology in adults with celiac disease: limited accuracy in patients with mild histological lesions.
PMID:21468695 April 2011
Background Accuracy of intraepithelial lymphocytes counts for diagnosing mild enteropathy coeliac disease in absence of villous atrophy can be limited by inappropriate controls included in the studies. Aim To determine the diagnostic accuracy of intraepithelial lymphocytes counts utilising controls lacking HLA coeliac disease-associated alleles. Methods Intraepithelial lymphocytes counting at villus tip and per 100 enterocytes was performed at haematoxylin and eosin (H&E) and CD3-stainings in: 29 cases (21 with potential coeliac disease and 8 affected by latent coeliac disease) representing the patient population and 14 noncoeliac controls lacking HLA-DQ2/DQ8 alleles. Results Threshold (mean + 2 s.d.) of duodenal intraepithelial lymphocytes at villus tip and per 100 enterocytes in noncoeliac controls was respectively: 3.5 and 18 at H&E, 3.2 and 17 following CD3-staining. Considering the whole patient population, the sensitivity of tip intraepithelial lymphocytes in detecting mild enteropathy coeliac disease was 90% (95% CI = 72.6-97.8) both at H&E and CD3-stainings. The sensitivity of intraepithelial lymphocytes per 100 enterocytes was 93% (95% CI = 77.2-99.2) both at H&E and CD3-staining. Specificity of both intraepithelial lymphocytes counts was 100% (95% CI = 76.8-100). Using a threshold of 25 intraepithelial lymphocytes per 100 enterocytes could miss 59% of cases at H&E and 48% following CD3-staining. Conclusions Intraepithelial lymphocytes counts are diagnostic feasible tools to detect mild enteropathy coeliac disease. Threshold of duodenal intraepithelial lymphocytes may be lower than currently accepted.
Redefining the intraepithelial lymphocytes threshold to diagnose gluten sensitivity in patients with architecturally normal duodenal histology.
PMID: 21255060 Jan 2011
RESULTS: A total of 34
patients (aged 29-59 years, 4 men) completed the study as per protocol.
Overall, 56% had human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8.
Adherence to diet and supplements was very high. Of 19 patients (68%) in
the gluten group, 13 reported that symptoms were not adequately
controlled compared with 6 of 15 (40%) on placebo (P=0.0001; generalized
estimating equation). On a visual analog scale, patients were
significantly worse with gluten within 1 week for overall symptoms
(P=0.047), pain (P=0.016), bloating (P=0.031), satisfaction with stool
consistency (P=0.024), and tiredness (P=0.001). Anti-gliadin antibodies
were not induced. There were no significant changes in fecal
lactoferrin, levels of celiac antibodies, highly sensitive C-reactive
protein, or intestinal permeability. There were no differences in any
end point in individuals with or without DQ2/DQ8. CONCLUSIONS: "Non-celiac gluten intolerance" may exist, but no clues to the mechanism were elucidated.
Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial.
PMID: 21224837 Jan 2011
An update in the diagnosis of coeliac disease.
PMID: 21054494 Nov 2010
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
CONCLUSIONS: a) We have found that most of the duodenal biopsies compatible with CD are not diagnosed with positive serology; and b) we found a low correlation between serological diagnostic tests.
Low serological positivity in patients with histology compatible with celiac disease in Perú
PMID: 20575597 June 2010
CONCLUSIONS: The study provided evidence that children who are EmA positive have a celiac-type disorder and benefit from early treatment despite normal mucosal structure, indicating that the diagnostic criteria for celiac disease should be re-evaluated.
Celiac Disease without Villous Atrophy in Children: A Prospective Study.
J Pediatr. 2010 Apr 16.
PMID: 2040010 April 2010
CONCLUSIONS:: Measurement of >/=25 IELs/100 ECs correlated with
serological indicators of celiac disease; a higher IEL threshold could
miss 50% of cases. Quantification of tTg is a sensitive test for celiac
disease; diagnosis can be confirmed by observation of >/=25
IELs/100ECs in duodenal biopsies. Lymphocytic enteropathy (celiac
disease and LD) is common in the population (5.4%).
Detection of Celiac Disease and Lymphocytic Enteropathy by Parallel Serology and Histopathology in a Population-Based Study.
Gastroenterology. 2010 Apr 13.
PMID: 20398668 April 2010
PMID: 20022984 Dec 2009
PMID: 20022983 Dec 2009
CONCLUSIONS: Patients with endomysial antibodies benefit from a GFD regardless of the degree of enteropathy. The diagnostic criteria for celiac disease need re-evaluation: endomysial antibody positivity without atrophy belongs to the spectrum of genetic gluten intolerance, and warrants dietary treatment.
Diagnosing Mild Enteropathy Celiac Disease: A Randomized, Controlled Clinical Study.
PMID: 19111551 Nov 2008
PMID: 18852634 Oct 2008
IgA endomysium antibodies - an early predictor for celiac disease in children without villous atrophy.
PMID: 18489624 May 2008
Adult celiac disease with severe or partial villous atrophy: A comparative study.
PMID: 18359595 Mar 2008
Coeliac disease: a biopsy is not always necessary for diagnosis.
PMID: 18194500 April 2008
Serological and histological correlations in celiac disease.
HLA-DQ and Susceptibility to Celiac Disease: Evidence for Gender Differences and Parent-of-Origin Effects.
PMID: 18177450 Jan 2008
Determinants of endomysial antibody status in untreated coeliac disease.
PMID: 17873614 Oct 2007
Our study clearly revealed that over-reliance on standard histological findings results in failure to diagnose celiac disease.
CONCLUSIONS: Clinically pertinent coeliac disease exists despite normal small-bowel mucosal villous architecture. Mucosal transglutaminase 2-specific IgA deposits can be utilized in detecting such patients with genetic gluten intolerance.
Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study.
PMID: 16036509 May 2005
Among 115 adults with biopsy-proven celiac disease who fulfilled strict criteria, including serologic testing at the time of diagnosis and response to a gluten-free diet, 71% had total villous atrophy and 29% partial villous atrophy. Endomysial antibody was positive in 77% of those with total villous atrophy, compared to 33% with partial villous atrophy (P < 0.001) Seronegative celiac disease occurs. Endomysial antibody positivity correlates with more severe villous atrophy and not mode of presentation of celiac disease. Serologic tests, in clinical practice, lack the sensitivity reported in the literature.
Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.
PMID: 15185855 April 2004
EmA-negative coeliac disease is common. Reliance on EmA testing to select patients for biopsy will result in significant underdiagnosis.
Reliance on serum endomysial antibody testing underestimates the true prevalence of coeliac disease by one fifth.
At this time small bowel biopsy seems to be the only correct procedure to diagnose a case of suspected celiac disease, especially in patients with mild symptoms or suspected for celiac disease, because they belong to high-risk groups.
Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent celiac disease.
Low specificity of anti-tissue transglutaminase antibodies in patients with primary biliary cirrhosis. PMID: 16960894 Sept 2006
Accuracy of Testing for Antibodies to Synthetic Gliadin-Related Peptides in Celiac Disease.
PMID: 16860613 July 2006
Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy.
PMID: 16774628 July 2006
Antibody to Tissue Transglutaminase May Fall Short for Accurate Triage of Celiac Disease Medscape Nov 2004
The positive predictive value of IgA anti-tTG was 90% and the negative predictive value, 98%. In comparison, results for IgA EMA were 100% and 97%, IgA AGA 94% and 90%, and IgG AGA 70% and 98%, respectively.
Diagnosing celiac disease: a comparison of human tissue transglutaminase antibodies with antigliadin and antiendomysium antibodies.
PMID: 15184223 June 2004
The most remarkable cases were two patients who presented with severe debility and no apparent haematological or biochemical abnormalities, and who subsequently made a dramatic recovery on a gluten-free diet.
Detection of undiagnosed coeliac disease with atypical features using antireticulin and antigliadin antibodies.
Serological markers detect asymptomatic coeliac disease among first-degree relatives of patients with sprue. However, some relatives with coeliac disease-related antibodies have 'normal' jejunal mucosa by conventional histology. Our study shows quantitative histological evidence that relatives of probands with positive coeliac disease-related serology are not false-positives, and that they should be considered as individuals with latent coeliac sprue.
Serological markers identify histologically latent coeliac disease among first-degree relatives.
PMID: 9718937 July 1998
Using tTGA as a single test in screening may result in missing up to 60-70% of celiacs with mild mucosal abnormalities. Combination with other screening tests (at least with AGA) is essential and strongly recommended.
Autoantibodies and Histogenesis of Celiac Disease
Anti-endomysium and anti-tissue transglutaminase antibodies are both highly efficient for routine laboratory screening: the choice of one or the other will depend on the available facilities. However, neither can replace intestinal biopsy for general population screening because, in this case, their respective positive predictive values are only 15.7% and 21.8%. During follow-up, anti-gliadin retain their value as an early predictor of gluten ingestion.
Serological markers for coeliac disease: is it time to change?
There is an association between IgA deficiency and low/negative EmA/AGA. Routine measurement of total serum IgA in patients suspected of having coeliac disease, either with EmA or where AGA is low, improves selection of patients for small bowel biopsy.
Association between serum levels of total IgA and IgA class endomysial and antigliadin antibodies: implications for coeliac disease screening.
Although the ELISA tTGA assay is more convenient than EmA testing, it offers no advantages in sensitivity or specificity if used in isolation. However, incomplete concordance between EmA and tTGA positivity means that combination screening with both assays offers higher sensitivity, as almost a third of patients have only one antibody. As some coeliac patients with normal serum IgA are negative for both antibodies, biopsies should still be performed in seronegative individuals deemed at high risk for coeliac disease.
Sensitivity of serum tissue transglutaminase antibodies for endomysial antibody positive and negative coeliac disease.
IgG anti-tTG and IgG EMA autoantibody tests are highly efficient in detecting coeliac disease in IgA deficient patients. The high prevalence of coeliac antibodies among symptom free IgA deficient blood donors who also carry coeliac-type HLA-DQ genes indicates that all IgA deficient persons should be evaluated for coeliac disease.
Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency.
In conclusion, AEM-negative CD is common and detection is only modestly enhanced by testing for IgA anti-tTG antibodies. Duodenal biopsy is still recommended for the accurate diagnosis of CD.
Anti-endomysial antibody negative celiac disease: does additional serological testing help? PMID: 11270789
While the tTG assay may be a useful predictor of celiac disease, small intestinal biopsy is still required to confirm the diagnosis. In clinical practice, even strongly positive tTG results are not specific in individual patients, do not necessarily correlate with the degree of severity of biopsy change and, as a result, are also unlikely to be useful for monitoring diet compliance.
Strongly positive tissue transglutaminase antibody assays without celiac disease.
CONCLUSIONS: IgA TTGA and EMA levels correlate with duodenal villous atrophy in pediatric CD patients. IgA TTGA >100 or EMA >1:1280 were nearly always associated with CD histopathology. With further validation of this observation, strongly positive titers might be considered sufficient for diagnosis of pediatric patients at risk for CD.
Correlation of Duodenal Histology With Tissue Transglutaminase and Endomysial Antibody Levels in Pediatric Celiac Disease.
PMID: 17428743 April 2007
Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations?
PMID:15867045 Pediatrics. 2005 May;115(5):1341-6.
Variability of histologic lesions in relation to biopsy site in gluten-sensitive enteropathy. PMID: 15654798 Jan 2005
Symptoms disappeared after GFD in patients suspected to have celiac disease but with slight histologic lesions. Although Marsh I-II lesions cannot be classified as celiac lesions (ESPGAN criteria), the patients' symptoms at presentation and the clear improvement of symptoms when on GFD, with or without improvement of histologic lesions, supports the assumption that these patients are sensitive to gluten and may justify treatment with a GFD.
The symptomatic and histologic response to a gluten-free diet in patients with borderline enteropathy.
In the present study we demonstrated that a gluten challenge might be useful in identifying patients as being sensitive to gluten if initial small intestinal biopsies reveal only minor abnormalities.
Gluten challenge in borderline gluten-sensitive enteropathy.
Gluten sensitivity can be associated with 'minimal' mucosal changes not detectable with conventional light microscopy. Such lesions, which primarily involve microvillous structure, may imply a reduction of intestinal absorptive surface already in the latent stage of the disease.
Gluten sensitivity and 'normal' histology: is the intestinal mucosa really normal?
Anti-tTG does not seem effective to assess histologic recovery in the follow-up of celiac patients after they have started GFD due to its poor correlation with histologic damage.
Lack of usefulness of anti-transglutaminase antibodies in assessing histologic recovery after gluten-free diet in celiac disease.
EmA is a poor predictor of persisting VA after patients have started gluten-free diet, although it may be of value in monitoring dietary compliance.
Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery.
Endoscopic markers have disappointing sensitivity even in a population at high risk of celiac disease, particularly for partial VA. As celiac disease is an important cause of dyspepsia, consideration should be given to serological screening to further improve diagnosis rates, as few centers will have the resources to routinely biopsy all patients.
Disappointing sensitivity of endoscopic markers for villous atrophy in a high-risk population: implications for celiac disease diagnosis during routine endoscopy.
Our results suggest that serial testing with TGA and AEA might allow, in some cases, the avoidance of intestinal biopsy to confirm the diagnosis of CD.
Is intestinal biopsy always needed for diagnosis of celiac disease?
The counting of intraepithelial lymphocytes (IELs) in the villous tips of architecturally normal small bowel biopsy specimens was proposed as a method to measure mucosal infiltration in gluten sensitive patients. This is a very simple and sufficiently reliable method to count IELs. In patients with an architecturally normal duodenal mucosa, the IEL count in villous tips helps to distinguish between patients with PCD and non-coeliac controls.
Intraepithelial lymphocytes in the villous tip: do they indicate potential coeliac disease?
Villous tip analysis seems to distinguish early coeliac from non-specific changes, thus providing a valuable tool in routine practice, especially when borderline findings are involved. Its value appears to be similar to counting of gammadelta+ cells, which, however, requires frozen biopsy samples.
Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease.
When all is said and done, the best test may be one's response to the diet. An elimination diet may be very useful because frequently other food intolerances are involved. Nobody needs a doctors prescription or permission to make dietary changes. I believe it is a good idea to run the blood work in case an easy diagnosis can be had, and perhaps a biopsy even when blood tests are negative, but in the event the tests are negative or inconclusive~ consider a dietary trial.