Definition

Celiac disease (CD) is an immune-mediated disorder that develops in genetically susceptible persons when gluten, a major protein found in wheat, barley, and rye is ingested in the diet. Also called nontropical sprue, celiac sprue, or gluten-sensitive enteropathy, CD is primarily an enteropathy characterized by inflammation of the small bowel mucosa and atrophy of the villi, resulting in nutrient malabsorption, wasting, and diarrhea. These symptoms define the classic or typical symptoms of CD (Table 1).

Any organ system may be involved in CD, and patients can develop extraintestinal manifestations—also called atypical manifestations—such as anemia, bone disease, infertility, unfavorable outcomes of pregnancy, lymphoma, and liver disease. The clinical presentation can include a wide range of symptoms, or even lack of symptoms as in silent CD, but patients can have abnormal celiac serology (endomysial [EMA] and tissue transglutaminase [tTG] antibodies) and varying degrees of small bowel involvement on biopsy. A definition of the various forms of CD based on clinical, pathologic and serologic findings is listed in Table 1.

Genetic susceptibility defines persons who possess the gene pair encoding the major histocompatibility complex class II HLA DQ2 or DQ8. These genes are virtually required for CD to occur, and lack of these genes makes CD very unlikely.

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Prevalence and epidemiology

Availability of highly sensitive and specific serologic tests such as endomysial and tissue transglutaminase antibodies (EMA and tTG) has made it possible to assess the true prevalence of CD. Epidemiologic studies using such tests along with small bowel biopsies report a higher prevalence of CD than previously thought. Prevalence in Western Europeans and in the United States is reported to range between 1 in 250 and 1 in 133, and it is higher in relatives of persons with CD, occurring in 1 in 22 first-degree relatives and in 1 in 39 second-degree relatives. It is rarely, if ever, reported in people with pure ethnic backgrounds from Africa, the Caribbean, China, and Japan. Women are affected more commonly than men, but there is no age predilection.

Other than persons who have relatives with CD, persons at increased risk include those with Down syndrome, Turner syndrome, type 1 diabetes mellitus, thyroid disease, lymphocytic colitis, and autoimmune disorders (Box 1).

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Pathophysiology

Celiac disease is a multifactorial and a multisystem disorder involving a genetic predisposition, environmental exposure of the small bowel mucosa to gluten, and an immunologic response to gluten.

Genetic

The majority (>90%) of persons with CD possess the HLA DQ2 haplotype, and 5% to 10% possess the DQ8 haplotype, conferring a negative predictive value greater than 98%. These haplotypes are encoded within the HLA class II region of the major histocompatibility complex on chromosome 6p. However, about 40% of the general population carry these haplotypes without having the disease, which makes their presence necessary but not sufficient for its development. Other non-HLA genes have been proposed, but their role in influencing the disease has not been clearly defined.

Environmental

It was a serendipitous observation that children with CD improved during World War II when cereals used to make bread were scarce, and they relapsed after the war when the supply of these cereals was reinstituted. Risk for developing CD is increased with the introduction of gluten in the diet of infants before the age of 4 months. Grains that activate the disease contain proteins that can form gluten (prolamins: glutenins and gliadins) and include wheat, barley, and rye. Grains that do not activate the disease include rice, corn, sorghum, and millet. Oats contain a very small proportion of prolamins and should be avoided initially.

Immunologic

Exposure of the upper small bowel mucosa to gluten in susceptible persons precipitates an inflammatory reaction characterized by infiltration of the lamina propria and the epithelium with inflammatory cells, which eventually leads to destruction and atrophy of the mucosa.

Ingestion of gluten induces the antigen-precipitating cells, which express HLA DQ2/DQ8, in lamina propria to sensitize T lymphocytes in both lamina propria and in epithelium. Activated T lymphocytes, particularly CD8+ intraepithelial lymphocytes expressing γ/δ receptors, become abundant and their numbers increase about sixfold. These in turn activate B lymphocytes and other lymphocytes to secrete immunoglobulins, cytokines, interferons, tumor necrosis factor, and other inflammatory mediators, notably interleukin (IL)-15, and cause damage to the enterocytes, resulting in villous atrophy. Additionally, tTG, a ubiquitous enzyme that is released by inflammatory and endothelial cells, deamidates glutamine residues in gluten to glutamic acid, which is negatively charged and in turn facilitates further reactivation of more lymphocytes and potentially affects more organ systems in the body.

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Clinical manifestations

Celiac disease exhibits a spectrum of clinical and pathologic manifestations. Left untreated, CD can progress to involve multiple organ systems with severe complications and nutritional deficiencies.

Symptoms can manifest in infancy and as early as cereals are introduced in the diet. Crampy abdominal pain, steatorrhea, failure to thrive, apathy and irritability, muscle wasting, and hypotonia are described. Any of these symptoms should trigger a diagnostic workup. Catch-up growth is well documented once a gluten free-diet is introduced.

In adults, the clinical symptoms are variable and not specific. The classic symptoms of malabsorption are less and less encountered since testing with serological antibodies has become available, and diagnosis is recognized before the full-blown clinical wasting occurs. On the other hand, atypical presentations are increasingly recognized and becoming more common.

Patients with CD can exhibit weakness, fatigue, and dyspnea as a result of vitamin B₁₂, folate, and iron deficiency; bone fractures, muscular atrophy, and tetany as a result of osteoporosis and osteopenia due to vitamin D and calcium deficiencies; peripheral neuropathy and ataxia as a result of cerebellar and posterior column inflammatory damage; and secondary hyperparathyroidism, edema, petechiae, and dermatitis herpetiformis. Infertility is observed in men and women. Amenorrhea, intrauterine growth retardation, and unfavorable outcomes of pregnancy have been reported. Liver enzyme abnormalities and nonspecific hepatitis have been incidentally recognized in patients with CD, and advanced liver disease and cirrhosis have been reported, with improvement of the liver disease upon withdrawal of gluten from the diet. It is generally accepted that patients with abnormal elevation of liver enzymes should be tested for celiac disease.

Dermatitis herpetiformis may be the clinical presentation of a latent CD. It is characterized by a papulovesicular rash that is intensely pruritic and affects the buttocks and the extensor surfaces of elbows and knees. It is characterized by granular immunoglobulin (Ig)A deposits in the dermo-epidermal junction. Most patients have abnormalities of the intestinal mucosa. Treatment consists of withdrawing gluten from the diet. If skin lesions do not improve, dapsone may be added at 1 to 2 mg /day.

Other manifestations of CD include weight gain and obesity, gastroesophageal reflux disease, irritable bowel syndrome with abdominal pain and constipation, pancreatitis, myocarditis, aphthous ulcers of the oral mucosa, lymphocytic and collagenous colitis, hyposplenism, and asymptomatic IgA nephropathy. There is a slightly higher risk for gastrointestinal malignancies and lymphomas in CD patients than in the general population.

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Diagnosis

Once the clinical suspicion in patients at risk factors is raised, the initial step toward a diagnosis is to obtain celiac serology antibody testing. This should be followed by a small bowel biopsy. The patient should be tested while following a gluten-containing diet.

The most sensitive and specific serologic tests are endomysial antibody IgA EMA and tissue transglutaminase antibody IgA tTG. Sensitivities and specificities are higher than 85% and 97%, respectively, for EMA and 90% and 97%, respectively, for tTG. Gliadin antibodies have lower sensitivities and specificities and are not recommended for screening; however, gliadin antibodies may have a role in monitoring adherence to a gluten-free diet.

About 2% to 5% of patients with CD have selective IgA deficiency, in which case serum IgG tTG or IgG EMA testing should be performed.

Pathologic changes on small-bowel biopsy are characterized by a spectrum of abnormalities described by Marsh and known as the Marsh criteria (Box 2). The hallmark of CD is Marsh 3 or villous atrophy; however, this may be patchy or present in other disorders as in hypogammaglobulinemia, acute infectious gastroenteritis, or milk intolerance. Additionally, there is growing evidence that CD may be diagnosed when changes of earlier phase on biopsy such as Marsh 1 or Marsh 2 are seen.

Establishing Diagnosis in the Absence of Typical Symptoms

The wide range of clinical manifestations of the disease coupled with less than Marsh 3 on biopsy makes the diagnosis of CD challenging for the clinician. In these situations, genetic testing or gluten challenge may be necessary for a definite diagnosis. A few scenarios may be encountered in a clinical setting and their proposed diagnostic workups include:

• Positive serology and villous atrophy: Diagnosis established. Patient should be treated.
• Positive serology and normal small bowel mucosa biopsy: Disease is considered latent and biopsy should be repeated after a gluten challenge or a few months later on a normal diet.
• Positive serology and increased intraepithelial lymphocytes: Potential celiac disease; repeat biopsy after a gluten challenge or in a few months on a normal diet, or obtain HLA typing. If any is positive, start a gluten-free diet.
• Normal serology and normal biopsy: Look for other causes of the patient's symptoms.
• Normal serology and villous atrophy: Exclude other causes of villous atrophy, immunodeficiency, IgA deficiency.

Gluten challenge should be done in patients who embarked on a gluten-free diet empirically without serologic or pathologic abnormalities. It can also be done in patients with latent celiac disease and in patients with potential celiac disease. Gluten should be started in small increments beginning with one slice of bread and doubling this amount every 3 days if tolerated until at least 10 g of gluten are ingested daily or the equivalent of 4 slices of bread, after which serologic testing and small bowel biopsy should be repeated and signs and symptoms observed. If tests remain negative, patients should remain on a normal diet.

Screening

Although CD is fairly common, is underdiagnosed, and can lead to serious complications, mass screening is not yet recommended. Screening with EMA and tTG may be warranted in patients with high risk factors, notably first-degree relatives of patients with the disease.

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Complications

Patients with refractory disease have persistent symptoms despite 6 months on a gluten-free diet. Glucocorticoids and at times immunosuppressants are indicated to induce remission. Patients often progress to ulcerative jejunitis or malignancy.

Malignancy, including intestinal lymphoma such as enteropathy-associated intestinal lymphoma or enteropathy-associated T-cell lymphoma, is usually not responsive to a gluten-free diet. Other malignancies include various carcinomas along the gastrointestinal tract.

Ulcerative jejunoileitis consists of ulcers and strictures of the small bowel, requiring surgical resections.

Acute celiac crisis is rare and usually occurs when patients undergo rapid and nonincremental gluten challenge. It is characterized by severe diarrhea, electrolyte abnormalities, and metabolic acidosis. Glucocorticoids and volume replacement are often required.

Collagenous sprue defines CD that is refractory to therapy and characterized by the deposition of collagen in subepithelial regions of the small bowel with a thickness greater than 10 mm. Prognosis is very grim.

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Treatment

Treatment consists of withdrawing gluten from the diet for life. It entails eliminating wheat, barley, and rye. This allows healing of the small bowel mucosa and restitution of nutritional status. Oats may initially be withdrawn in severely symptomatic patients until symptoms begin to resolve.

Lactose-containing products can worsen gastrointestinal symptoms and should be avoided in these situations until restitution of normal mucosa. Deficiencies of vitamins D and B₁₂, folic acid, calcium, and iron and nutritional deficiencies should be replaced as necessary. Prevention of bone loss and pneumococcal vaccination due to hyposplenism are necessary. Complications of CD should be managed appropriately, and increased vigilance in recognizing and managing lymphoma and cancer is important.

Adherence to a gluten-free diet is often difficult because of cost and lack of palatability and because it requires the patient's commitment and perseverance. Therefore, alternative therapies are increasingly in demand, and trials are ongoing to assess for their efficacy. These therapies include gluten-degrading enzymes, modified grains that lack immunogenic compounds, zonulin inhibitors that decrease intestinal permeability, and anti-inflammatory and immunotherapy.

Referral of patients to nutritional counseling for education and for monitoring adherence and response to therapy is essential to safeguard and good outcome. Information on gluten-containing and gluten-free foods is available on various websites along with a wide variety of gluten-free recipes.

Response to the gluten-free diet is assessed by clinical and serologic improvement. There is no clear consensus on whether a repeat small bowel biopsy is necessary. However, repeat biopsy may be indicated in cases where adherence to diet is proved but response to diet is equivocal or lacking.

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Other malabsorption disorders

The small intestine is the site of absorption of nutrients necessary to maintain life. Several disorders, including CD, affect the intestinal mucosa or the intestinal chyme and can cause malabsorption and wasting. These may be classified into small bowel mucosal diseases and luminal or digestive diseases. Potential etiologies include infectious causes, as in parasitic or bacterial and viral enteritis; iatrogenic causes by means of surgical resection of the small bowel or administration of medications; structural defects, as in strictures causing stasis with bacterial overgrowth; and lack of digestive enzymes in the brush border or the lumen of the gastrointestinal tract (Table 2 and Box 3).

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Conclusion

CD is a multisystem disorder with a wide range of clinical presentations. Clinicians should have a heightened awareness of these presentations and a low threshold for testing with EMA and tTG antibodies. Education and surveillance of patients on a gluten-free diet are crucial to safeguard adherence to the diet and prevent further complications of the disease.

Other malabsorptive disorders should be included in the differential diagnosis of CD, bearing in mind the similarities in signs and symptoms even pathologic findings on biopsy. Further testing may be required, and a multidisciplinary approach may be necessary for a definite diagnosis.

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Summary

• Celiac disease is an immune-mediated disorder that develops in genetically susceptible persons when gluten is ingested in the diet. Exposure of the upper small bowel mucosa to gluten precipitates an inflammatory reaction characterized by infiltration of the lamina propria and the epithelium with inflammatory cells, which eventually leads to destruction and atrophy of the mucosa.
• Prevalence in Western Europe and in the United States ranges between 1 in 250 and 1 in 133. It is higher in relatives of persons with celiac disease, occurring in 1 in 22 in first-degree relatives and in 1 in 39 in second-degree relatives. It is rarely if ever, reported in people with pure ethnic backgrounds from Africa, the Caribbean, China, and Japan. Women are affected more commonly than men, but there is no age predilection.
• Diarrhea and fat malabsorption is most often observed. Often patients present with extraintestinal manifestation of deficiencies caused by prolonged malabsorption, including anemia, bone disease, infertility, unfavorable outcomes of pregnancy, lymphoma, and liver disease.
• The diagnosis should be suspected in any patient with chronic diarrhea, and in those with unexplained deficiency states including iron, folate, and fat-soluble vitamins. The most sensitive and specific serologic tests are endomysial antibody IgA EMA and tissue transglutaminase antibody IgA hTTG. Biopsy of the small intestine plays a confirmatory role.
• Treatment consists of withdrawing gluten from the diet for life. It entails eliminating wheat, barley, and rye. This allows healing of the small bowel mucosa and restitution of nutritional status. Oats may initially be withdrawn in severely symptomatic patients until symptoms begin to resolve.

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Suggested Readings

• AGA Institute. AGA Institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology. 2006, 131: (6): 1977-2002.
• Dickey W. Symposium 1; Joint BAPEN and British Society of Gastroenterology Symposium on Coeliac Disease: “Basics and Controversies”. Coeliac disease in the twenty-first century. Proc Nutr Soc. 2009, 3: 1-8.
• Kaukinen K, Collin P, Mäki M. Latent celiac disease or celiac disease beyond villous atrophy? Gut. 2007, 56: (10): 1339-1340.
• Kurppa K, Collin P, Viljamaa M, et al: Diagnosing mild enteropathy celiac disease: A randomized, controlled clinical study. Gastroenterology. 2009, 136: (3): 816-823.
• Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology. 1992, 102: (1): 330-354.
• NIH Consensus Development Conference on Celiac Disease. NIH Consens State Sci Statements. 2004, 21: (1): 1-23.
• Qiao SW, Sollid LM, Blumberg RS. Antigen presentation in celiac disease. Curr Opin Immunol. 2009, 21: (1): 111-117.
• Richey R, Howdle P, Shaw E, Stokes T. Recognition and assessment of celiac disease in children and adults: Summary of NICE guidance. Guideline development group. BMJ. 2009, 338: b1684.
• Sollid LM, Markussen G, Ek J, et al: Evidence of a primary association of celiac disease to a particular HLA DQ γ/δ heterodimer. J Exp Med. 1989, 169: (1): 345-350.