Celiac Disease

Celiac disease (CD), also known as gluten-sensitive enteropathy and celiac sprue, is a malabsorptive disease in which the intestinal mucosa is injured as a result of ingestion of gluten-containing foods in genetically predisposed individuals. Withdrawal of dietary gluten causes prompt improvement of nutrient absorption and improvement of the characteristic mucosal lesions unless refractory sprue has developed.

Epidemiology

Celiac disease is the most common cause of malabsorption in Western populations. The prevalence of CD in Europe and North America is 0.5% to 1% (489,490,491). Celiac disease is rare in Japanese, Chinese, and African patients. The disorder is more common in women than men. It is now recognized that there is a substantial number of undiagnosed cases in the general population possibly ten times as many as actually have been diagnosed (492).

Celiac disease appears to have a strong genetic component, demonstrating a higher incidence in siblings than in the general population (493). There is 70% concordance for CD in identical twins (494). About 10% of first-degree relatives of celiac patients also have the disease (495), although a significant proportion (about 50%) remain asymptomatic and are said to have latent CD. The incidence of CD increases 10- to 30-fold in patients with other autoimmune disorders when compared with the normal population (496).

Pathogenesis

Celiac disease has a complex etiology that results from the interaction of environmental agents, genetic predispositions, and immunologic factors (497).

Gluten and Other Prolamines

Celiac disease is an autoimmune enteropathy triggered by ingestion of wheat gluten (gliadins), barley (hordeins), rye (secalins), and possibly oats (avenins). Gluten is found in grains such as wheat and buckwheat. Gluten is also found in many processed foods such as gravies, sausage, beer, ale, bread, and bread products. It can be separated electrophoretically into four major fractions: α–, β–, γ–, and v-gliadins. Gliadins are prolamines with a high proline and glutamic acid content. All four types appear to be toxic, although α-gliadin is the most pathogenic (498). Toxic gliadins contain pro-ser-gln-gln and gln-gln-gln-pro sequences. These sequences are absent from nontoxic
peptides (499). A 33-mer peptide generated by digestion of α-gliadin by intestinal enzymes is highly stimulatory for CD4+ T cells (500). This peptide is resistant to further digestion by intestinal brush border enzymes and is a highly specific substrate for deamidation by tissue trans-glutaminase. This 33-mer peptide is not present in cereal proteins that do not cause CD.

CD may be triggered in genetically susceptible individuals by activation of the immune system by a virus, usually an adenovirus. Later the mucosal system mistakenly reacts against gliadins bound to the intestine. α-Gliadin contains an amino acid region that is homologous to the 54-kDa E1b protein coat of adenoviruses. In addition, CD patients have a significantly higher prevalence of past adenovirus 12 infections than control subjects (501).

CD has the strongest association of any illness with a specific class II HLA molecule. The disorder is triggered by an environmental insult (gluten consumption), and the HLA haplotype acts as a classic immune response gene that operates at either the T-cell or antigen-presenting cell level to favor gliadin-specific responses. The primary HLA association in most CD patients is with DQ2. Fewer patients are of haplotype DQ8. An increased risk for CD also exists among individuals who are DR3-DQ2 homozygous and DR3-DQ2/DR7-DQ2 heterozygous (497).

In addition to the HLA linkage, CD has also been linked to several other chromosomal regions. Linkage to 2q33, an area of regulation for T-lymphocyte activation, has been seen in a Finnish family (502). Linkage to other regions on other chromosomes has also been reported, but linkage to 5p31-33 is the most consistently identified (503).

Gluten-reactive T cells can be isolated from small intestinal biopsies of celiac patients but not from nonceliac controls. These T cells are CD4+ and express the a/b TCR. A number of distinct T-cell epitopes within gluten exist. Lamina propria antigen-presenting cells that express HLA-DQ2 or -DQ8 present gliadin peptides bound to their a/b heterodimer antigen, presenting grooves to sensitized T lymphocytes that express the a/b TCR. These lymphocytes then activate B lymphocytes to produce immunoglobulins and stimulate other T cells to produce cytokines including interferon (IFN)-γ, IL-4, IL-5, IL-6, IL-10, IL-15, tumor necrosis factor (TNF)-α and TGF-β.

Tissue Transglutaminase and Other Autoantigens

Tissue transglutaminase (tTG) is expressed in many different tissues and is found both extra- and intracellularly. tTG is expressed just beneath the epithelium in the gut wall. Calcium-dependent tTG catalyzes selective cross-linking or deamidation of protein-bound glutamine residues. Deamidation of the glutamine residues of gliadin by tTG prepares the gliadin molecule to bind with HLA-DQ molecules (504). In addition, tTG can also cross-link glutamine residues of peptides to lysine residues in other proteins, including tTG itself. This may result in the formation of gluten–tTG complexes. These complexes may permit gluten-reactive T cells to stimulate tTG-specific B cells, thereby explaining the occurrence of gluten-dependent tTG autoantibodies that are a characteristic feature of active CD. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. tTG is necessary for activation of TGF-β, which is involved in differentiation of intestinal epithelium, regulates IgA expression, and modulates immune responses (505). Antibodies to tTG in CD patients interfere with fibroblast-induced differentiation of epithelial cells, possibly by inhibiting the cross-linking activity of tTG.

Cell-mediated and Antibody-mediated Immune Responses

Gluten ingestion in untreated CD induces nonproliferative activation of CD4+ TCR-a/b–positive cells in the lamina propria accompanied by proliferative activation of intraepithelial lymphocytes (a/b– and g/b-positive T cells) in the epithelial compartment. CD patients harbor a population of DQ2+ (or DQ8+) antigen-presenting dendritic cells that efficiently capture and present deamidated gluten peptides leading to the activation of gluten-reactive T cells (506). Activated CD4+ T cells activate B lymphocytes and plasma cells that produce autoantibodies and T lymphocytes to secrete cytokines. These cytokines not only damage the enterocytes, but also induce expression of aberrant HLA class II cell surface antigens on the luminal surface of enterocytes, facilitating additional direct antigen presentation by these cells to the sensitized lymphocytes. Cytokines produced by DQ2- restricted T cells are of the Th1 type and are dominated by the secretion of IFN-γ. Cytokines produced by DQ8-restricted T cells have a Th0 profile. Increased γ/δ– cells in the epithelium and lamina propria of the small intestine have also been observed in CD patients, and these cells persist even after gluten withdrawal. These cells may play a protective role through activation of a nonspecific immune response that helps to lessen the antigen-specific immune response (497).

Celiac disease characteristically results in accumulation of IgA-, IgM-, and IgG-producing plasma cells within the mucosa. The antibodies produced by them are directed against gliadin, transglutaminase, endomysium, reticulin, and enterocyte actin. The exact physiologic role of these antibodies is still unclear.

Recent evidence also suggests that gliadin or its metabolites may directly injure the intestinal mucosa. Up-regulation of mucosal HLA-DR and intercellular adhesion molecule within 2 hours of in vitro exposure to gliadin suggests an early effect that may not be immune mediated (507). This early effect is followed by activation of CD4+ CD25+ T cells, producing the immunologic injury.

There may also be a role for intraepithelial lymphocytes in the pathogenesis of CD (508). In fact, these cells may play
a key role in the development of refractory sprue and the development of enteropathy-associated T-cell lymphomas (509).

Clinical Features

Celiac disease is well known to be associated with gastrointestinal manifestations and malabsorption. However, over the years there has been increasing awareness of nongastrointestinal manifestations of the disease such as osteoporosis, cancer, and infertility. The clinical spectrum of CD is diverse and includes the following forms:

Typical CD: This is fully expressed gluten-sensitive enteropathy associated with classic features of malabsorption. The full expression includes positive serology for endomysial and tTG antibodies and a diagnostic biopsy. This form of the disease usually affects younger patients.
Atypical CD: This is fully expressed gluten-sensitive enteropathy found in association with atypical manifestations including short stature, anemia, infertility, etc.
Latent CD: Patients have normal small bowel villous architecture on biopsy, but villous atrophy develops later on. Two variants have been described. The first includes patients in whom CD was diagnosed in childhood and who recovered completely with a gluten-free diet. The disease then remains latent in these individuals even after a normal diet is adopted. In the second variant, a normal mucosa is present in early biopsies while the patient is consuming gluten, but more typical features of CD develop later. The conversion of the latent state to active disease is often precipitated by nutritional deficiencies, by the effects or complications of a tumor, or by other environmental triggers, especially intracurrent infections, changes in the environment, or physiologically imposed stresses such as surgery, trauma, or pregnancy. Such patients exhibit abnormal jejunal permeability and high levels of antiendomysial antibodies. Such patients may have increased numbers of IELs in their biopsies (510) in the absence of villous changes.
Potential CD: This includes patients who never had biopsy changes but have characteristic serologic abnormalities. HLA-DQ2 is more frequent in these patients and they frequently have a first-degree relative affected by CD.
Silent CD: This includes asymptomatic patients with positive serologic autoantibodies and diagnostic biopsy.
Refractory CD: These patients have severe, symptomatic, intestinal atrophy not responding to at least 6 months of a strict gluten-free diet.

The clinical presentation of any given patient with CD depends on the severity of the damage and patient age at presentation. The classic presentation of CD is that of steatorrhea with abdominal cramps and vomiting. In infants, the symptoms begin after weaning, when cereals are first introduced into the diet. Signs of nutritional deficiency, such as anemia, are the next most common presenting findings affecting children. Other manifestations include growth retardation, failure to thrive, short stature, muscle wasting, hypotonia, abdominal distension, and watery diarrhea. Celiac disease should be suspected in children with mild GI symptoms who have signs of nutritional deficiencies or a first-degree relative with celiac disease. It should also be suspected in children with IgA deficiency, dental enamel hypoplasia, or dermatitis herpetiformis or in children who have other diseases known to be associated with celiac disease (Table 6.35).

TABLE 6.35 Diseases Commonly Associated with Gluten-sensitive Enteropathy

Dermatitis herpetiformis
Ulcerative colitis
Sarcoid
Primary biliary cirrhosis
Pericarditis
Autoimmune chronic active hepatitis
Vasculitis
Dental enamel defects
Pseudohypoaldosteronemia
Selective Ig deficiency
Cystic fibrosis
Arthritis
IgA nephropathy
Splenic atrophy
Posterior cerebral calcifications
Epilepsy
Floating harbor syndrome
   Speech impediment
   Developmental delay
   Short stature
   Facial anomalies
Polyglandular autoimmune syndrome III
   Autoimmune thyroid disease
   Insulin-dependent diabetes
   Hypoparathyroidism
   Sarcoid
Autoimmune eye lesions
   Choroiditis
   Papillitis
Lung lesions
   Cavitary lung lesions
   Bronchiolitis
   Interstitial pulmonary fibrosis
Alopecia areata
α₁-Antitrypsin deficiency
Cavitary lymph nodes
Tumors
Enteropathy-associated T-cell lymphoma
Small intestinal carcinoma
   Oropharyngeal
   Breast
   Esophagus (squamous cell carcinoma)

Celiac disease in adults is most often diagnosed in the 3rd and 4th decades of life, but it may develop at any age.
Approximately 20% of cases are diagnosed in individuals over the age of 60 (511). Women are more frequently affected than men and are generally diagnosed at a younger age. Many adults with CD present with diarrhea, but as many as 50% do not (512). The classic presentation includes prolonged diarrhea, flatulence, weight loss, and fatigue. The degree of weight loss reflects the severity of the steatorrhea and an individual’s ability to compensate for the nutritional deficit by increasing caloric intake. Patients with celiac disease may only have subtle signs of chronic malnutrition or nonspecific GI complaints. Patients may also present with anemia, short stature, nutritional deficiencies, or motility disturbances in the absence of diarrhea. Since the introduction of highly sensitive autoantibody tests, the number of patients presenting with classic features of CD has decreased. In fact, iron deficiency anemia, formerly regarded as an atypical presenting sign, is now the most common presentation of adult patients with
CD (512). Iron deficiency is primarily due to iron malabsorption. Changes attributable to malabsorption and mineral, vitamin, and other essential nutrient deficiencies are listed in Table 6.36. The clinical presentation often reflects the degree of malabsorption present.

Atypical presentations include neurologic manifestations, osteopenia, and dermatitis herpetiformis without gastrointestinal manifestations. The most common neurologic finding is ataxia followed by epilepsy, cerebral calcification, cerebral white matter lesions on magnetic resonance imaging (MRI), myelopathy, peripheral neuropathy, seizures, and myopathy. CD also associates with an adverse fetal outcome in women with undiagnosed CD (513). Gastrointestinal bleeding occurs occasionally, and may represent an indicator of complications such as ulcerative jejunoileitis or malignancy.

Other extraintestinal features of the disease include vague abdominal pain, bone disease, abnormal peripheral blood smear findings, infertility (both male and female), amenorrhea, recurrent abortion or low-birth-weight babies, and hypoglycemia (494). Up to 8% of patients are detected due to mucosal changes on duodenal endoscopy performed for other conditions (494). From 7% to 15% of patients are detected through serum antibody tests performed because of a family history of CD.

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