Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions

Abstract

The clinical spectrum of celiac disease continues to evolve. What was once thought to be a rare disorder affecting young children is now recognized to be very common with a range of symptoms from asymptomatic disease to severely affected persons. Screening for celiac disease has become relatively easily with reliable antibodies against self-antigens (TG) and modified environmental antigens (DGP). Diagnosis is confirmed by small intestinal biopsy with characteristic changes graded by the Marsh score. Elimination of gluten from the diet has been the standard of care for the last half century. Patients often have difficulty adhering to a gluten-free diet, and the failure of symptoms, antibody levels, or pathologic changes to improve after initiating the diet may be largely due to this difficulty. The genetic risk for celiac disease is largely related to HLA genotypes, with over 90% of subjects with celiac disease positive for DQ2 and the remainder positive for DQ8. The HLA association with celiac disease is largely accountable for its link to other autoimmune diseases, including type 1 diabetes and autoimmune thyroid disease, and the majority of risk for celiac disease in these populations is related to HLA genotype. Celiac disease also carries an increased risk for type 1 diabetes and autoimmune thyroid disease. Genetic syndromes such as Turner and Down syndromes are associated with an increased risk for celiac disease. Practitioners can identify groups of subjects at high risk for celiac disease and perform screening with celiac disease-related antibodies.

Figure 1

Gliadin ingestion results in activation of gliadin-reactive T cells in the intestine. These CELIAC DISEASE4 T cells are hypothesized to provide immunologic help to B cells to produce TG autoantibodies, in addition to promoting a favorable cytokine milieu to help drive the celiac disease process. Gliadin ingestion is also directly toxic to the enterocytes, resulting in IL-15 release and subsequent upregulation of MIC-A on the enterocyte surface. Infiltrating intraepithelial lymphocytes also differentiate in the presence of IL-15 into lymphocyte-activated killer cells that are cytolytic to enterocytes through the NKG2D/MIC-A interaction. (From Hum Immunol. 2006 Mar;67(3):204-7. Epub 2006 Mar 31, with permission.)

Figure 2

Proposed algorithms for the diagnosis of celiac disease in patients with symptoms (figure 2A) or those at increased risk (figure 2B). For subjects with symptoms, an initial history and physical exam should be performed evaluating growth and for conditions associated with celiac disease. Screening with a tissue transglutaminase (TTG) antibody and then referral to a gastroenterologist are recommended for small bowel biopsy in TTG positive subjects. In subjects in groups at an increased risk, the first step is screening with TTG antibodies and then referral of positive subjects to a gastroenterologist for further evaluation.

Figure 2

Proposed algorithms for the diagnosis of celiac disease in patients with symptoms (figure 2A) or those at increased risk (figure 2B). For subjects with symptoms, an initial history and physical exam should be performed evaluating growth and for conditions associated with celiac disease. Screening with a tissue transglutaminase (TTG) antibody and then referral to a gastroenterologist are recommended for small bowel biopsy in TTG positive subjects. In subjects in groups at an increased risk, the first step is screening with TTG antibodies and then referral of positive subjects to a gastroenterologist for further evaluation.