Celiac Disease is an inflammatory disease of small intestinal caused by ingestion of wheat gluten or related proteins from rye or barley.  There is the characteristic villous atrophy of the small intestinal mucosa, rapid improvement clinically and histologically after adherence to a strict gluten-free diet, and clinical relapse when gluten is reintroduced.

The prevalence of celiac disease was estimated to be approximately 1 case in every 250 in one study screening blood donors.(1)  This is likely an underdiagnosed entity (prevalence in the US is 1:4500 in the clinical setting), and the average length of time it takes for a symptomatic person to be diagnosed with celiac disease in the U.S. is 11 years.(2)  A significant number of patients present with iron deficiency anemia or bone disease in the absence of gastorintestinal pathology. In a study by Fasano et al., only 35% of newly diagnosed pateints had chronic diarrhea, thus showing that diarrhea does not have to be present to diagnose celiac disease.  From the same study, 41% of adults diagnosed were asymptomatic.(3)  The risk in first degree relatives is 10-20%.

Diagnosis is made with a combination of small intestinal biopsy and serologic tests (IgA endomysial antibody (IgA EMA), IgA tissue transglutaminase antibody (IgA tTG), IgA antigliadin antibody (IgA AGA), and IgG antigliadin antibody (IgG AGA)).  These tests should be done while the patient is on a non-gluten-free diet as antibodies may disappear when individuals are gluten free. Intestinal biopsy remains the gold standard for diagnosis.

"Gluten" encompasses the prolamins and the glutenins.  The prolamins in wheat are called "gliadins".  Prolamins from other cereals are also considered to be gluten and are named according to their source (secalins from rye, hordeins from barley, avenins from oats, and zeins from nontoxic corn).(4) (Visual 1)

From a genetics standpoint, HLA-DQ2 (heterodimer) has been found in 95% of sprue patients and HLA-DQ8 in the remaining.  After gluten is absorbed, antigen presenting cells that express HLA-DQ2 or DQ8 present gliadin peptides to gluten-specific T-cells.(5)

The mechanism behind celiac sprue is not an "allergy".  A true allergy to an ingested protein (such as milk or soy) leads to an IgE-mediated response.  In celiac sprue, plasma cells produce IgA and IgG, with little or no IgE involvement.(1)

Endomysium is the connective tissue structure surrounding smooth muscle and tTG is contained within the endomysium.  Ingested gliadin peptides bind with tissue transglutaminase in enterocytes, which deamidates glutamine residues, forming glutamic acid.  Deamidation enhances immunogenicity of gliadin, by creating epitopes that are recognized as foreign by host cell-mediated immunity.  Plasma cells produce IgA and IgG that are directed against a variety of antigens, such as tTG, endomysium, gliadin, and reticulin.  An intense local inflammatory response follows, leading to the destructive changes seen in the mucosa of the small bowel.(1)(6)  (Visual 2)

Gliadin is broken down into four fractions (alpha, beta, gamma, omega).  Prolamins from wheat, rye, and barley are rich in glutamine (>30%) and proline (>15%), whereas the nontoxic prolamins of rice and corn have a lower glutamine and proline content. 

Recently, a 33-amino acid peptide (alpha-gliadin, peptide 56-89) was discovered that has features suggesting that it is the primary initiator of the inflammatory response to gluten in celiac sprue patients.  It was shown that this peptide could be completely degraded by enterocytes in controls but only partly in celiac patients.  It was stable toward breakdown by all gastric, pancreatic, and intestinal brush-border membrane proteases.  Homologs of this peptide were found in all food grains that are toxic to sprue patients, but are absent from all nontoxic food grains.   The amount and location of proline residues are what seem to be crucial in creating the resistance that the peptide has to gastrointestinal breakdown.  Preliminary in vitro studies have shown that a prolyl endopeptidase could catalyze breakdown of this 33-mer gliadin peptide, thus decreasing its toxic effects.  This suggests a possible future strategy for oral peptidase supplemental therapy (7).  A second peptide (31-49) appears to have toxic effects and behaves similarly (8).  Several other short peptide sequences have since been discovered.

Normal villous height to crypt depth ratio is 3-5:1.  There are many causes of villous atrophy.(9) (Visual 3)

There is clear association with other autoimmune disorders.  Nutrient malabsorption leads to many extraintestinal manifestations.(1)(5)   (Visual 4) (Visual 5)