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Clinical Manifestation of Celiac Disease

As noted above, the symptoms of celiac disease are nonspecific and are often overlooked. In addition, the disease may develop at any time in life from infancy to very old age. In children, the disease typically presents between 6 and 24 months, following weaning, and is characterized by abnormal stools, poor appetite and irritability. In adults, diarrhea is the main presenting symptom, but presenting symptoms may be entirely nonspecific, such as anemia or infertility. "Typical" or "classical" celiac disease refers to the presence of malabsorption, while "atypical" celiac disease consists primarily of extraintestinal manifestations. Finally, silent celiac disease may be entirely asymptomatic and discovered only on biopsy or with serologic testing (see further discussion below). For example, population-based screening serologic surveys suggest a prevalence of 1 in 250-500 in most countries, including the United States. Celiac disease is an HLA-associated disease and therefore there is a hereditary component to the disease, with a 10% prevalence among first degree relatives. Celiac disease is associated with a number of other conditions, including type 1 diabetes mellitus, rheumatoid arthritis and primary biliary cirrhosis.

Given the nonspecific nature of the symptoms, definitive diagnosis has been based on the results of small intestinal biopsies showing a flattened intestinal mucosa in association with an inflammatory infiltrate. Diagnostic criteria were first established in 1969 by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHN) and consisted of a series of three intestinal biopsies, one at diagnosis, one after institution of a gluten free diet, and the third after a repeat gluten challenge. This cumbersome method of diagnosis was revised in 1990 by simplifying the diagnostic criteria to a positive biopsy at presentation in conjunction with consistent history and serologic results, followed by a clinical response to a gluten free diet.

While a positive biopsy is still considered the gold standard for diagnosis, there has been considerable interest in the serologic evaluation of patients with possible celiac disease, in part as a technique to triage the large number of patients with nonspecific symptoms for biopsy. Serologic diagnosis is focused on the detection of IgA antibodies. In the presence of gluten, the intestine produces large amounts of antibodies that are secreted intraluminally, but spill over into the serum, where they can be detected. Antigliadin antiendomysial, and tissue transglutaminase IgA antibodies have been most extensively studied. Gliadin is a component of gluten, while antiendomysial antibodies (referred to as EMA) are directed against the reticulin network surrounding the smooth muscle bundles of the gastrointestinal tract. Tissue transglutaminase is the enzyme responsible for deamidation of gliadin in the lamina propria, increasing its immunogenicity and allowing interaction with HLA-DQ2 or HLA-DQ8.

Antigliadin antibodies can be detected using an ELISA test. EMA antibodies are detected using an indirect immunofluroscence technique using either primate esophagus or human umbilical cord as a substrate. More recently the EMA antigen has been identified as the tissue enzyme tissue transglutaminase (tTG), allowing the development of an ELISA based test or a dot blot procedure that can be performed in the physician's office. A total of 2-3% of patients with celiac disease are IgA deficient; in these patients IgG antibodies are assayed instead of IgA antibodies. Among the approximately 10% of cases where clinical suspicion, serologic testing  and intestinal biopsy are equivocal, the 2007 review by Green and Cellier suggests that negative tests for HLA-DQ2 and HLA-DQ8 (present in 90-95% and 5+% of patients with celiac disease respectively) can rule out a diagnosis of celiac disease.

The newest serologic tests are deamidated gliadin peptide (DGP) antibody tests. Deamidation refers to a chemical reaction in which an amide group is removed from an organic compound. Deamidated gliadin is produced when gluten undergoes acid or enzymatic treatment so that tissue transglutaminase converts some of the glutamines to glutamic acid. Deamidated peptides are believed to be more specific to celiac disease than native peptides. A limitation of human antigen-based tTG tests for diagnosing celiac disease is that they have relatively low specificity and can result in false-positive findings in patients with chronic liver disease, inflammatory bowel disease, diabetes and other conditions. Some of the DGP antibody tests are able to assay both IgA and IgG, so they can be used in patients regardless of IgA deficiency status.

Antibody testing for celiac disease is widely available and HLA typing for celiac disease is offered by several laboratories such as Quest, LabCorp and Promethus. 

Serologic measurement of antigliadin antibodies may be considered medically necessary in children under 24 months of age with signs or symptoms suggestive of celiac disease.

Serologic measurement of deamidated gliadin peptide antibodies is considered investigational in patients with signs or symptoms suggestive of celiac disease.

HLA-DQ2 and HLA-DQ8 testing may be considered medically necessary to rule out celiac disease in patients with discordant serologic and histologic (biopsy) findings or if persistent symptoms warrant testing despite negative serology and histology.

Screening of asymptomatic at risk patient groups for celiac disease using one or more serologic IgA or IgG measures is considered investigational.

Population screening for celiac disease using one or more serologic IgA or IgG measures is considered investigational.

None

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

10/19/2006: Policy updated to allow testing as medically necessary

5/29/2008: Policy statement updated with the following as medically necessary: addition of tissue transglutaminase, the use of antigliadin antibiodies for children under 18 months of age and HLA-DQ2 and –DQ8 testing to rule out celiac disease where serology and histology are equivocal. Additional policy statements added that screening both the general population and asymptomatic at risk subgroups are investigational.

04/19/2011: Policy description updated regarding available tests. Policy statement updated to state that serologic measurement of deamidated gliadin peptide antibodies is considered investigational in patients with signs or symptoms suggestive of celiac disease. Also, added that the use of more than one antibody test is considered not medically necessary.

04/19/2012: Deleted the following policy statement: Use of more than one antibody test is considered not medically necessary. The age limit for testing in children was changed from 18 months to 24 months.

Blue Cross Blue Shield Association policy # 2.04.30

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document.

Covered Codes

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