Abstract
Algorithm, Autoantibodies, Celiac Disease, Gastroenterology, Genetic Testing, Gliadin, IgA Deficiency, Intestinal Mucosa, T-Lymphocytes, T ransglutaminases Clin Lab Sci 2015;28(4):212-217 INTRODUCTION Celiac disease (CD) can be a devastating immunological disease that encompasses multiple signs and symptoms and where the only current treatment regimen is absolute adherence to a gluten-free diet (GFD). Prevalence Celiac disease, also known as non-tropical sprue, is an autoimmune enteropathy that affects as many as 1 in 141 individuals in the United States and this rate could be on the rise due to the number of undiagnosed individuals with symptoms of CD.2 There is racial and ethnic variation with non-Hispanic whites holding the highest incidence rate of 1% indicating at least 1.7 million in this population have CD, compared to the national average of .71%.2 Risk factors of CD include, but are not limited to, other autoimmune-mediated diseases such as diabetes and thyroiditis, genetic factors like Down's syndrome, Turner's syndrome and IgA deficiency or a first-degree relative with these conditions or a diagnosis of CD.3 Patients with IgA deficiency are 10-15 times more prone to CD than those without the deficiency.1 Presentation There are four main presentations of CD that have been determined by a task force of physicians from seven different countries: classic CD, non-classic CD, subclinical and potential CD and can be seen in Table 1 below.1'3'4 Nutritional deficiency is a common sign in the pediatric population, which can cause growth and psychomotor delays, rickets, and other hematological symptoms.3 Infants have presented with severe diarrhea, dehydration, lethargy, and marked abdominal distention, which left untreated or undiagnosed can cause severe malnutrition.3 Non-classic CD does not manifest with typical gastrointestinal distress and may account for as much as 70% of CD cases.3 Most of the symptoms seen in nonclassical CD are due to the nutritional deficiency that ensues from malabsorption in the small intestines, as seen in the majority of pediatric cases, or in anemia in the teenage and young adult population.3 In subclinical CD, many patients already suffer from another autoimmune disease such as diabetes type 1, thyroiditis, psoriasis, or genetic conditions such as Downs Syndrome, Turners Syndrome, and IgA deficiency.3 Pathophysiology Celiac disease is an autoimmune, gastrointestinal disorder caused by the destruction of the small intestine mucosa leading to malabsorption and gastrointestinal distress.5 Proline- and glutamine-rich residues compose the protein subunits of gliadins and glutenins which make up the wheat, rye and barley glutens that are the main culprits of the disease.6 CD4+ aß T cells, coded for by the HLA-DQ2 variant 2.5 and HLA-DQ8 genes, become sensitized to these gluten proteins after translation modification deamidation by transglutaminase 2 and secrete an increased amount of interferon-у (INFy).6'7 Transglutaminase is an enzyme responsible for transamination, or cross-linking, and deamination of glutamine residues, such as gluten, and is the primary autoantigen seen in CD.7 This sensitization allows T cell infiltration of mucosa causing damage, villous atrophy, crypt hyperplasia and eventual activation of B cells which produce IgA antibodies to gliadin, endomysium and transglutaminase.6'7 In addi- tion, CD8+ aß T cells and yô T cells, also called intraepithelial lymphocytes (IEL), are activated by gluten as the body responds to the gluten onslaught. The IELs act as natural killer cells destroying the self s mucosa and with CD demonstrate memory and effector receptors against intestinal epithelial cells.5 Both types of IEL in patients that are programed prior to being enlisted from the GALT to the small intestines.5 These receptors and memory functions indicate that after a GFD is stopped, symptoms and intestinal damage will resume.5 Plasma cells secrete IgA class 2 antibodies to gliadin, endomysium and transglutaminase.7 The endomysium is a connective tissue component where only a small portion of autoantibodies are targeted against.7 B cells can act as antigen-presenting cells to T cells, further exacerbating the autoimmune response to gluten as well as acting as effector cells by direct damage to small intestinal mucosa, preventing angiogenesis and interfering with epithelial cell differentiation.7 Undiagnosed or untreated CD can cause severe intestinal damage and lead to other autoimmune diseases such as diabetes or intestinal lymphoma.1'5 The IELs associated with CD have been shown to transform into enteropathy-associated T-cell lymphoma (EATL) which has a poor prognosis.5 EATL has been found in those with poor adherence to a GFD, HLA-DQ2 homozygous state, and those with a late diagnosis of CD, all of which cause an extreme intensity of classic CD symptoms and tumor growth.8 The 5-year survival in some patient populations with EATL is as low as 8%.8 Current Laboratory Tests Current laboratory testing includes measurements of antibodies to AGA IgA and IgG, TTG IgA and IgG, ARA IgA, EMA IgA by immunoassay and/or immunofluorescence and testing levels of total IgA. Gliadin antibodies were once thought to be accurate assays for CD, however, in the last several years the sensitivity and specificity were found to be much less than previously thought, giving rise to inaccurate results that do not correlate with other serological testing or symptoms of CD.10 HLA typing for the DQ2.5 and DQ8 variants is highly sensitive and a negative result all but rules out CD.4 However, the HLA typing should not be performed alone because a positive result without other assay results or current symptoms cannot be used to diagnose CD since as much as 30% of the general population have the DQ2.5 and DQ8 HLA genotype.11 The biopsy of the small intestine is still considered the gold standard for diagnosis of CD, despite the advances in serological and genetic testing.9 Upper gastrointestinal endoscopy is the method of choice for obtaining biopsies and should include a minimum of 4 biopsies with two from the distal duodenum and two from the bulbus, however, the American Gastroenterology Association recommends at least six biopsies.11 Newer Testing Options One biochemical marker that is being used more often is the DGP.