October 2009: Volume 34, Number 10
2009 Annual Meeting Highlights
Experts Review Advances in Celiac Disease Diagnostics
Evolving Testing Methods, Algorithms Ensure Labs’ Central Role in Diagnosis, Treatment
By Genna Rollins
Diagnostic tests for celiac disease are well-known, but the role of labs could change in the future as testing algorithms and assays evolve, predicted James D. Faix, MD, associate professor of pathology at Stanford University during the symposium, “Laboratory Diagnosis of Celiac Disease.” “In terms of how labs can help as we move forward, it’s not so much in diagnosis but in management of celiac disease,” he said, noting that physicians want to know whether patients are adhering to gluten-free diets and that their lesions are resolving. He also noted that multiplex assays are being developed that will be able to test for all the various celiac disease-related biomarkers, a change laboratorians should be on the lookout for.
The incidence of celiac disease in asymptomatic adults in the general population is about 1%, and about 1.5% in adults with symptoms. The condition traditionally had been considered a disease of childhood, but advances in serology testing and a wider understanding of the disease have enabled more people to be diagnosed, according to Vijay Kumar, PhD, FACB, president and CEO of IMMCO Diagnostics in Buffalo. “What happened that the incidence was one in 10,000 25 years ago and now it’s one in 100? There are several factors, but mainly increasing awareness among physicians of the symptoms, which are not very specific, and laboratory diagnostics, which have helped identify patients who have celiac disease but are asymptomatic,” he observed.
Today, physicians also have a better understanding of the many co-morbidities and other autoimmune diseases associated with celiac disease. For instance, the incidence of infertility of unknown etiology in patients with celiac disease is 6.25%. Common clinical manifestations of the disease include diarrhea, abdominal pain, constipation, and fatigue, but in many adults these general symptoms may not be put together for a workup as possible celiac disease. Interestingly, many people first learn they have the disorder when they are being evaluated for bone loss, according to Faix. “It’s become common to order a TTG [tissue transglutaminase antibody] test in people with osteoporosis,” he observed. The celiac disease link with other autoimmune diseases is so well-acknowledged today that “in most hospitals, pediatric endocrinologists are probably routinely ordering TTGs on type 1 diabetics,” he added.
Evolving Testing Patterns
Development of the various serology tests for celiac disease has dramatically changed the diagnostic workup. Prior to introduction of an assay for anti-endomysial antibodies in the early 1990s, it was common for patients to undergo three intestinal biopsies to check for the presence of characteristic celiac disease-related villous atrophy, at the time of initial diagnosis, after six months on a gluten-free diet, and after a gluten challenge. While intestinal biopsy remains the gold standard diagnostic test, today it is more common to have only one, in conjunction with a positive serology test, to diagnose the disease. Further confirmation of the disease would come if symptoms disappear and the serology normalizes after the patient adheres to a gluten-free diet.
“A gluten challenge is not necessary anymore. No one is doing them these days,” Kumar observed. If properly performed with optimum substrates and dilutions, the various serology tests have high sensitivity for detecting celiac disease-related antibodies. However, “sometimes you will find that one marker is negative when another is positive, so my thinking has always been that it’s good to use two serologic markers,” said Kumar.
In addition, while many labs test for the presence of IgA antibodies, a fair number of patients with celiac disease have IgA deficiency, with very low levels of <7 mg/dL versus 90 to 450 mg/dL in a normal population. Kumar recommended two possible testing algorithms. One would be to test IgA levels first, and if they were low to then test for other antibodies, or start by testing for a combination of TTG, anti-gliadin and/or IgG antibodies.
Consensus guidelines recommend testing for IgA anti-TTG antibodies as the initial screening algorithm in patients with symptoms of celiac disease. “If the TTG serology is abnormal, then a biopsy is required to confirm, and if that shows disease, the patient is committed to a gluten-free diet. If the TTG is negative, people generally consider celiac disease to be unlikely and they will investigate other causes,” explained Faix. Other serology tests should come into play when the pathology is negative but anti-TTG results are positive, he added.
Recent published reports have called for performing a battery of tests in patients with suspected celiac disease, including IgA anti-TTG antibodies, IgA anti-endomysial antibodies, IgA anti-gliadin antibodies, and IgG anti-gliadin antibodies when the individual is IgA-deficient. “If they’re all positive, then the patient probably has celiac disease and needs to go on a gluten-free diet. If they’re all negative, celiac disease can be excluded. If they’re not all positive a biopsy would be needed,” explained Faix. “This may be where we’re headed. It needs to be validated and adopted by the various organizations.”
The Role of Genetic Testing
Faix also suggested that genetic testing for the disease may take on more prominence as the interaction between genetic susceptibilities and triggers becomes clearer. Although celiac disease stands out as an autoimmune disease with a well-described genetic profile, the genetics of the disorder are not completely understood, he noted. For example, about 90% of people with celiac disease have the human leukocyte antigen (HLA) protein DQ2, and most of the rest probably have DQ8. However, these HLAs also are present in about 40% of the general population and may only account for about half of the genetic susceptibility for celiac disease. A genome-wide assay project is underway to identify other genes associated with the disorder, and in a recent update, researchers reported that most of those detected are in the 4q27 associated region, including the cytokine IL-2, which has a role in activating natural killer cells. Other celiac disease-associated genes involve G-protein signaling, chemokine receptors, and T-cell activation. For now, genetic testing in celiac disease largely has a rule-out role. “The role of HLA testing thus far has been its negative predictive value,” observed Faix. “If you suspect the patient has celiac disease but the serology is equivocal, showing that the patient doesn’t have these haplotypes is an important negative tool.”