Background
Celiac disease (CD) is a multifactorial, autoimmune disorder that occurs in genetically susceptible individuals.[1] It is triggered by a well-identified environmental factor (gluten and related prolamins), and the autoantigen is also well known (ie, the ubiquitous enzyme tissue transglutaminase). The disease primarily affects the small intestine, where it progressively leads to flattening of the small intestinal mucosa. Three cereals contain gluten and are toxic for patients with celiac disease: wheat, rye, and barley.
The genetic susceptibility to celiac disease is conferred by well-identified haplotypes in the human leukocyte antigen (HLA) class II region (ie, DR3 or DR5/DR7 or HLA DR4). Such haplotypes are expressed on the antigen-presenting cells of the mucosa (mostly dendritic cells); approximately 90% of patients express the DQ2 heterodimer, and approximately 7% of patients express the DQ8 heterodimer. The remaining 3% of patients possess only half of the DQ2 heterodimer.
Celiac disease can occur at any stage in life; a diagnosis is not unusual in people older than 60 years.
Because the historical prevalence and long-term outcome of undiagnosed celiac disease were unknown, Rubio-Tapia et al collected serological information on 3 cohorts.[2] These included 9,133 healthy young adults from whom sera were collected between 1948-1954 and 12,768 gender-matched subjects from 2 recent cohorts, one whose years of birth were similar to those of members of the first cohort, and one in which age at sampling was similar. Sera was tested for tissue transglutaminase and, if abnormal, for endomysial antibodies.
In the older cohort, during 45 years of follow-up, all-cause mortality was nearly 4-fold greater in persons with undiagnosed celiac disease than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2-7.5; P < 0.001). Comparison of the older and newer cohorts suggested that undiagnosed celiac disease in the United States has dramatically increased in the past half century; 0.2% of the older cohort had undiagnosed celiac disease compared with 0.8% of the cohort with similar years of birth and 0.9% of those with similar age at sampling (P ≤.0001).
Pathophysiology
Pathogenesis
Celiac disease is an autoimmune disease, and the enzyme tissue transglutaminase (tTG) has been discovered to be the autoantigen against which the abnormal immune response is directed. Gluten is the single major environmental factor that triggers celiac disease, which has a narrow and highly specific association with class II haplotypes of HLA DQ2 (haplotypes DR-17 or DR5/7) and, to a lesser extent, DQ8 (haplotype DR-4).
Scientific knowledge on the pathogenesis of celiac disease has markedly increased in the past few years; the combined roles of innate and adaptive immunity are now better understood.
Innate immunity
Intraepithelial lymphocytes (IELs) play an important role in the destruction of epithelial cells. Through specific natural killer receptors (NKR) expressed on their surface, IELs recognize nonclassical major histocompatibility complex (MHC)-I molecules induced on the surface of enterocytes by stress and inflammation. This interaction leads to activation of these armed effector IELs to become lymphokine-activated killing cells; they cause epithelial cell death in a T-cell receptor (TCR)–independent manner. This killing is particularly enhanced through the cytokine interleukin (IL)-15, which is highly expressed in celiac mucosa. NKG2D has been found to play a crucial role in intestinal inflammation in celiac disease.[3]
Adaptive immunity
The adaptive immune response to gluten has been well described, with the identification of specific peptide sequences demonstrated in specific binding to HLA-DQ2 or DQ8 molecules and in stimulating gluten-specific CD4 T cells. These T cells express α/β TCR, and can be isolated from the lamina propria and cultivated. In vitro, they have been shown to recognize specific gluten peptides presented through interaction with DQ2 or DQ8 molecules.
Gluten is a complex macromolecule that contains abundant proline and glutamine residues, rendering it largely indigestible. Under usual circumstances, gluten is left (in part) unabsorbed by the GI tract. Gluten is composed of glutenins and gliadins, the alcohol-water soluble fraction. These gliadins are further divided into alpha, gamma, and omega fractions based on electrodensity.
Among these fractions, one particular peptide fragment is the alpha gliadin 33-mer, which contains an immunodominant peptide fragment. This fragment is deamidated by tTG. tTG is a ubiquitous enzyme and is known to deamidate glutamine to glutamic acid, creating a strong negative charge within the peptide. This modification is crucial in increasing selection to the positive charges within the binding pocket of HLA-DQ2 or DQ8 molecules on antigen-presenting cells in the lamina propria. When conveyed to gluten specific CD4+ T cell, it induces proliferation and induction of a Th1 cytokine response, primarily with the release of interferon-γ.
B cells receive signals through this HLA interaction, leading to tTG autoantibody production. The role of these autoantibodies is still unclear; they have been shown to be deposited along the subepithelial region even in normal-appearing intestinal biopsy findings prior to positive serology and without the onset of overt epithelial cell damage.
Relevant anatomy
Celiac disease primarily affects the small intestine. This organ is schematically divided into 3 areas: the duodenum (which begins beyond the pylorus, located at the end of the stomach), the jejunum, and the ileum (ending at the ileocecal junction, the beginning of the large intestine). These 3 parts share similar tissue architecture and are responsible for most of the body's nutrient absorption. The intestinal wall has 4 layers, which (from the lumen inward) are termed the mucosa, submucosa, muscularis, and serosa. The 2 main functions of the mucosa are to accomplish all digestive-absorptive processes for nutrients and electrolytes and to provide a barrier function by excluding foreign antigens and toxins.
Celiac disease affects the mucosal layer: here, a cascade of immune events leads to the changes that can be documented by histology.
Pathology
The classic celiac lesion occurs in the proximal small intestine with typical histological changes of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytosis. Three distinctive and progressive histological stages have been described and are termed the Marsh classification.[4] The histological changes of celiac disease are classified as follows:
- Type 0 or preinfiltrative stage (normal)
- Type 1 or infiltrative lesion (increased intraepithelial lymphocytes)
- Type 2 or hyperplastic lesion (type 1 plus hyperplastic crypts)
- Type 3 or destructive lesion (type 2 plus villous atrophy of progressively more severe degrees [termed 3a, 3b, and 3c])
Epidemiology
Frequency
United States
The availability of sensitive and specific serological tests has made it possible to assess the true prevalence of celiac disease by detecting minimally symptomatic or even asymptomatic cases with typical mucosal changes.[5] Screening studies have shown that celiac disease has a very high prevalence, occurring in almost 1% of the general population throughout North America.
International
Celiac disease is as common in Europe as it is in North America; recent estimates suggest the prevalence in Europe is actually increasing,[6] as is the prevalence of other autoimmune conditions, possibly as a result of the reduced exposure in early life to environmental bacterial stimuli (the "hygiene hypothesis").[7]
The prevalence of celiac disease in other areas of the world has been less studied. However, data are available from Latin America, North Africa, the Near East and Middle East, and northwest India; celiac disease has been reported in these areas, and prevalence data did not significantly differ from that seen in Europe and North America. A notable exception is represented by the Sub-Saharan African population, where an astounding prevalence of 5% has been reported.[8] Thus, celiac disease constitutes one of the most common genetically induced chronic diseases worldwide.
However, celiac disease is considered extremely rare in people of African, Chinese, or Japanese descent, in whom the prevalence of the HLA haplotypes DQ2 and DQ8 is negligible.
Mortality/Morbidity
The morbidity rate of celiac disease can be high. Its complications range from osteopenia, osteoporosis, or both to infertility in women, short stature, delayed puberty, anemia, and even malignancies (mostly related to the GI tract [eg, intestinal T-cell lymphoma]). As a result, the overall mortality in patients with untreated celiac disease is increased.
Evidence also suggests that the risk of mortality is increased in proportion to the diagnostic delay and clearly depends on the diet; subjects who do not follow a gluten-free diet have an increased risk of mortality, as high as 6 times that of the general population. The increased death rates are most commonly due to intestinal malignancies that occur within 3 years of diagnosis.[9] Some indirect epidemiological evidence suggests that intestinal malignancies can be a cause of death in patients with undiagnosed celiac disease.[10]
Race
In some ethnicities, such as in the Saharawi population, celiac disease has been found in as many as 5% of the population. As mentioned, celiac disease is considered extremely rare or nonexistent in people of African, Chinese, or Japanese descent.
Sex
Most studies indicate a prevalence for the female sex, ranging from 1.5:1 to 3:1.
Age
Celiac disease can occur at any stage in life; a diagnosis is not unusual in people older than 60 years. Classic GI pediatric cases usually appear in children aged 9-18 months. Celiac disease may also occur in adults and is usually precipitated by an infectious diarrheal episode or other intestinal disease.
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