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Celiac disease: Managing a multisystem disorder

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ABSTRACTCeliac disease is a multisystem autoimmune disorder that can cause symptoms involving the gastrointestinal tract and other organ systems such as the skin and bones. This paper reviews the pathogenesis, diagnosis, and management of celiac disease and associated diseases.

KEY POINTS

  • Besides gastrointestinal symptoms, celiac disease is associated with a variety of diseases, including dermatitis herpetiformis, malabsorption of several nutrients (potentially leading to osteoporosis, iron deficiency anemia, and other disorders), and intestinal malignancies.
  • While serologic testing for immunoglobulin A antibodies to tissue transglutaminase can be used as an initial screening test for this condition, the confirmatory tests are invasive, involving upper endoscopy for duodenal biopsy in celiac disease and skin biopsy in dermatitis herpetiformis.
  • The only effective treatment is lifelong adherence to a gluten-free diet, and nonadherence is a common cause of refractory disease.
  • Concomitant conditions such as anemia and vitamin deficiency often require nutritional supplements. In addition, patients with dermatitis herpetiformis often require treatment with dapsone.


 

References

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.1

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The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,2 and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.5

Figure 1. Celiac disease is an autoimmune disorder that, in genetically susceptible individuals, is triggered by ingestion of foods containing gluten. IgA = immunoglobulin A; tTG = tissue transglutaminase.

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.4 The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.6 Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).7

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,14 as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,15 more recent studies have not confirmed these benefits.16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.18,19

Abdominal pain and weight loss are also common.20

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.23 A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.24 If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.24

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,25 type 1 diabetes mellitus,26 primary biliary cirrhosis,27 primary sclerosing cholangitis,28 and Addison disease.29

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.30

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

Figure 2. Eroded and crusted erythematous plaques with scalloped borders on the elbow of a patient with dermatitis herpetiformis.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks31 (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa32 or purpura on the palms and soles.33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

Figure 3. Vesicles in a patient with dermatitis herpetiformis.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.36 In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.40 Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.41

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.46

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.47 Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.50 T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.51

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.52

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.55

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Figure 4.

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).56 The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

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