The Spectrum of Celiac Disease: Epidemiology, Clinical Aspects and Treatment

Greetje J. Tack; Wieke H. M. Verbeek; Marco W. J. Schreurs; Chris J. J. Mulder

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Complications

The long-term consequences of celiac disease are a matter of debate, particularly since the recognition of its broad clinical spectrum. The influence of noncompliance to a gluten-free diet and the substantial number of patients being undiagnosed are of greatest concern, as these factors could possibly contribute to the refractory form of celiac disease and to the development of malignancies.

Refractory Celiac Disease

Some patients with adult-onset celiac disease, especially among those diagnosed above the age of 50, show a lack of response to a gluten-free diet. They are diagnosed as having RCD when clinical and histological symptoms persist or recur after a former good response to a strict gluten-free diet and despite strict adherence to the diet for more than 12 months, unless earlier intervention is necessary.[4] The prevalence of RCD is currently unknown, but we believe that it might affect approximately 5% of patients with celiac disease. According to the European Celiac Disease working group, RCD can be subdivided into types I and II, with phenotypically normal and aberrant intraepithelial T lymphocytes in the small intestinal mucosa, respectively.[69] Intraepithelial T lymphocytes are considered aberrant when expressing cytoplasmic CD3, but lacking surface expression of the T-cell markers CD3, CD4, CD8[4] and the T-cell receptor.[70] To discriminate between RCD I and RCD II, a clinically validated cut-off value of 20% aberrant intraepithelial T lymphocytes, determined by analysis of small intestinal biopsy samples by flow cytometry, is used (Figure 2).[70] As flow cytometry cannot be performed in all medical centers, immunohistochemistry for CD3 and CD8 as a first-line screening, before performing flow-cytometric analysis, in all patients diagnosed as having celiac disease and who are above 50 years of age would also probably be helpful in identifying patients with RCD II, but proper studies are lacking.

Figure 2.

Algorithm for diagnosis of complicated celiac disease. Abbreviations: EATL, enteropathy-associated T-cell lymphoma; EMA, endomysial antibody test; GFD, gluten-free diet; IEL, intra-epithelial lymphocyte; RCD, refractory celiac disease; TCRγ, T-cell receptor, γ chain; TGA, tissue transglutaminase antibody test.

Patients with RCD I have a less dismal prognosis compared with those diagnosed as having RCD II: the 5-year survival rates are 80–96% and 44–58%, respectively.[3,71,72] The reason for this difference is the higher risk of developing lymphoma in RCD II, as a consequence of clonal expansion and further transformation of aberrant intraepithelial T lymphocytes into EATL.[3,4] EATL occurs in more than half of patients with RCD II within 4–6 years after RCD II diagnosis and is the main cause of death in this group of patients.[3,71] Development of EATL was also observed in patients with RCD I in a single-center study, albeit less frequently than in patients with RCD II (14%).[72] Furthermore, whereas RCD I can be treated effectively with prednisone with or without azathioprine,[71,73,74] no standardized approach has yet been developed for RCD II, apart from aggressive nutritional support and strict adherence to a gluten-free diet.[72,75] In the past decade several conventional and more experimental therapies have been evaluated to treat RCD II (Box 2), however this condition is usually resistant to any known therapy and transition into EATL could not be prevented successfully. Cladribine therapy[76] and autologous stem cell transplantation[5] might be successful, but long-term results are awaited. Interleukin-15-blocking antibodies, which have been successfully used in the treatment of rheumatoid arthritis, might be promising new therapeutic alternatives, as this cytokine has a key role in the pathogenesis of RCD.[77]

Malignancies

Celiac disease is thought to be associated with an increased risk of malignancies, in particular lymphomas, but the risk currently estimated for this association, 1.3-fold greater than that of the general population,[78] is much lower than that recorded in the 1970s and 1980s.[79] Earlier detection and treatment of celiac disease in the past two decades may have contributed to this decline. Whether continued gluten exposure is associated with the high incidence of malignancies in patients with celiac disease is widely debated, as many patients are not recognized as having the disease and are, therefore, untreated. A Finnish cohort study showed no additional risk for malignancies among adult patients with celiac disease who were diagnosed exclusively by serologic screening and followed for almost 20 years.[79]

The principal malignancy associated with celiac disease is EATL, which has an annual incidence of only 0.5–1.0 cases per million people in Western countries.[80] Unexplained weight loss, abdominal pain, fever and night sweating should alarm physicians of the presence of an overt EATL. EATL can involve all areas of the small intestine, stomach and colon, being particularly frequent in the proximal jejunum. In some patients with celiac disease, EATL may even occur outside the gastrointestinal tract, for example in the lungs, ribs and spleen, without abdominal pain.[81] EATL is one of the main causes of death in patients with adult-onset celiac disease, with 2-year and 5-year overall survival rates of 15–20% and 8–20%, respectively.[3,82] This poor prognosis is mainly due to incomplete response to currently available therapies (Box 2), high rates of life-threatening complications such as perforation of the gut, and poor nutritional conditions.[75,83]

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