Celiac disease (CD) is a disorder of small bowel
malabsorption. It is characterized by mucosal inflammation, villous atrophy and
crypt hyperplasia that occur upon exposure to gluten, and clinical and histological
improvement with withdrawal of gluten from the diet. The classical presentation of
CD has now been shown to be less common than silent or atypical presentation, in
which patients do not have intestinal symptoms. Untreated CD is associated with
multiple important short- and long-term complications including nutritional
derangements, anemia, reduced bone density, as well as intestinal lymphoma. In the
vast majority of patients, CD is effectively treated with dietary modifications that
eliminate gluten. Mounting evidence suggests that CD is actually considerably more
common than previously believed and, therefore, this disorder warrants consideration
for screening of at-risk patients, as well as possibly the general population.
The data obtained from this review fell into several
broad categories, which correspond in large part to the individual study objectives.
Data for the sensitivity and specificity of each serological marker was considered
separately, and studies were further divided according to the age group of the study
population. Attempts were made to identify, explain, and minimize clinical and
statistical heterogeneity in the included studies. A Pearson's Chi Square with n-1
degrees of freedom, where n represents the number of included studies in an
analysis, was calculated to assess statistical heterogeneity. Pooled estimates were
only calculated if clinically and statistically appropriate. In situations where
pooling was not performed, a qualitative systematic review was conducted.
To produce clinically useful pooled statistics, a weighted mean of the overall
sensitivity and specificity from the included studies was calculated, along with 95%
confidence intervals (CIs). The pooled estimates for the sensitivity and specificity
were compared with a summary receiver operating characteristic (ROC) curve,
calculated for the same group of studies as a second check of the estimates.
This report has provided a systematic review of
five broad areas (and corresponding sub-areas) of CD. Perhaps one of the most
important findings of this report is the significance of how one chooses to define
CD in the era of serological testing, and how this apparently clear-cut task has
profound implications on all the results presented in this report. Specifically, can
CD be diagnosed solely on the basis of serology? Is some degree of villous atrophy
necessary for a diagnosis of CD. These questions have important implications
downstream of the diagnosis as well. For example, do CD patients without symptoms or
villous atrophy have the same risk of complications as those with villous atrophy.
Is serological improvement on a GFD sufficient to reduce CD complications, or must
there be documented histological improvement, and what degree of histological
improvement is necessary?
The results of the Celiac 1 objective suggest that in the era of EMA and tTG antibody
testing, AGA antibody testing in both children and adults has a limited role. The
sensitivity and specificity of EMA and tTG are quite high (over 95% for sensitivity,
and close to 100% for specificity), as are their positive and negative predictive
values; however, one has to be aware that the reported diagnostic parameters are
taken from studies in which the prevalence of CD was, for the most part, much higher
than that seen in usual clinical practice. The positive predictive values reported
for these tests will certainly not be as high as that reported when these tests are
used to screen the general population. The bulk of the evidence on the diagnostic
characteristics of these tests was derived from studies that defined CD as having at
least some degree of VA.
HLA DQ2/DQ8 testing appears to be a useful adjunct in the diagnosis of CD. The test
has high sensitivity (in excess of 90%–95%), however, since approximately 30% of the
general population, and an even higher proportion of “high-risk” subjects (e.g.,
diabetics and family members) also carry these markers, the specificity of this test
is not ideal. The greatest diagnostic utility of this test appears to be its
negative predictive value.
Biopsy itself, when used with a strict cut-off requiring villous atrophy, appears to
have high specificity, but poor sensitivity. Using a lower grade cut-off clearly
improves sensitivity, but because of the wide differential of causes of histological
lesions similar to Marsh I to IIIa, the specificity suffers. The use of
histomorphometric measures such as quantification of gamma delta positive
intraepithelial lymphocytes (γδ+ IELs) are likely to allow for the use of lower
grade cut-offs, while maintaining reasonable specificity. Ultimately, a trial
utilizing multiple diagnostic tests in an attempt to capture as many CD patients in
a clinically-relevant population as possible, along with a time dimension such as a
response to a GFD or gluten challenge, is required to fully assess the diagnostic
characteristics of biopsy alone. This type of study would be able to characterize
the false-positive and false-negative rates, provided that all studied patients are
followed forward in time.
The included prevalence studies demonstrated important differences between the
studies including, execution, tests for prevalence assessment, and patient sampling.
Thus, results have to be interpreted in the light of some of the limitations that
have been identified regarding the diagnostic performance of the tests for CD.
Nonetheless, the results of this report suggest that CD is a very common disorder
with a prevalence in the general population that is likely close to 1:100 (1%).
Several high-risk groups with a prevalence of CD greater than that of the general
population have been identified and include: those suspected of having CD; family
members of CD patients; type I diabetics; and, those with iron-defiency anemia (IDA)
or low bone mineral density (BMD). Additionally, the review identified many other
high-risk groups, including those with Down Syndrome, short stature, and
infertility, to name a few. Their inclusion was however, beyond the scope of this
The results of this report confirm that, apart from a few limitations, there is a
strong association between CD and GI lymphoma. The report identified standard
incidence ratios (SIR) for lymphoma that ranged from 4 to 40, and standard mortality
ratios (SMR) that ranged from 11 to 70. A diagnostic delay—in particular a diagnosis
of CD in adulthood as apposed to in childhood—is associated with poorer outcomes.
Fortunately, several studies suggest that adherence to a GFD reduces the risk of
lymphoma in CD patients.
The consequences of testing for CD in at-risk and symptomatic patients appears to be
more straightforward, since these patients appear to be more compliant with a GFD
and would be expected to benefit from this intervention. The data is less clear for
asymptomatic screen-identified patients, particularly those who have truly silent CD
and/or don't have fully-developed villous atrophy. On the one hand the outcome of
such patients has not been extensively studied, and on the other hand compliance
with a GFD appears problematic, particularly for those diagnosed in adulthood.
Finally, no specific interventions have been identified that promote adherence to a
GFD, but education of patients and family members about CD and about the intricacies
of a GFD, and participation in local celiac societies, has been shown to improve
compliance. Although somewhat controversial, biopsy monitoring of adherence to a GFD
appears to be important, since improvement in histological grade has been associated
with improved BMD, IDA, and nutritional status. The serological markers appear to be
adequate for detecting gross dietary indiscretion, and respond to a gluten
challenge, but appear to have poor sensitivity for detecting lesser degrees of
dietary indiscretion, and inadequately correlating with histological improvement at
least in the short-term. It should, however, be noted, that we could not identify a
controlled study that objectively determined the level of histological improvement
that would be associated with improved outcomes, and this is an area for future
study. Nonetheless, based on this report it would appear that follow-up biopsy, at
least 1 year after a GFD in adults to document improvement of the histological
grade, would be valuable.