Celiac Disease

January 26, 2010 by CLF
Filed under Blog, Gluten-Free Diets/Celiac Disease

Disease characteristics. Celiac disease is a systemic immune disease that can be associated with gastrointestinal findings (diarrhea, weight loss, abdominal pain, anorexia, lactose intolerance, abdominal distention, and irritability) and/or highly variable non-gastrointestinal findings (iron-deficiency anemia, dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms.

Diagnosis/testing. The diagnosis of celiac disease relies on characteristic histologic findings on small-bowel biopsy and clinical and/or histologic improvement on a gluten-free diet. Most individuals with celiac disease have celiac disease-associated antibodies and specific pairs of allelic variants in two HLA genes, HLA-DQA1 and HLA-DQB1. Because 30% of the general population has one of the celiac disease-associated HLA alleles and only 3% of individuals with one or both of these alleles develop celiac disease, presence of celiac disease-associated HLA alleles is not diagnostic of celiac disease; however, their absence essentially excludes a diagnosis of celiac disease.

Management. Treatment of manifestations: lifelong adherence to a strict gluten-free diet (avoidance of wheat, rye, and barley); treatment of nutritional deficiencies (iron, zinc, calcium, fat-soluble vitamins, folic acid); standard treatment of osteoporosis. Prevention of primary manifestations: lifelong gluten-free diet. Surveillance: for symptomatic individuals responsive to a gluten-free diet, periodic physical examination and assessment of growth, nutritional status, and non-gastrointestinal disease manifestations; repeat small-bowel biopsy one to three years following diagnosis. For symptomatic individuals unresponsive to a gluten-free diet, periodic evaluation for refractory sprue, ulcerative enteritis, T-cell lymphoma, and other gastrointestinal cancers. Agents/circumstances to avoid: dietary gluten. Testing of relatives at risk: when the celiac disease-associated HLA alleles in the family are known, molecular genetic testing of first-degree relatives (including young children) to monitor those with known celiac disease-susceptibility alleles for early evidence of celiac disease in order to institute gluten-free diet early in the disease course.

Genetic counseling. Celiac disease is a multifactorial disorder resulting from the interaction of HLA-DQA1 and HLA-DQB1 gene variants known to be associated with celiac disease susceptibility, less well-recognized variants in non-HLA genes, gliadin (a subcomponent of gluten), and other environmental factors. Some empiric risk data are available for at-risk relatives.

Diagnosis

Clinical Diagnosis

The diagnosis of celiac disease is made through the combination of the following [Hill et al 2005, NIH Consensus Committee 2005, Green & Cellier 2007]:

· Small-bowel biopsy that shows characteristic histologic abnormalities

· Subsequent improvement (clinical and/or histologic) on a gluten-free diet

· Additional findings in most affected individuals:

· Clinical findings or abnormal laboratory findings (although some individuals are asymptomatic and lack laboratory abnormalities)

· Celiac disease-associated antibodies
Note: Although positive specific antibody testing is highly associated with celiac disease and greatly facilitates its diagnosis [Fasano 2001, Farrell et al 2002], small-bowel biopsy remains the gold standard in confirming the diagnosis of celiac disease.

· Celiac disease-associated human leukocyte antigen (HLA) alleles

Testing

Celiac-associated antibody testing

Note:

(1) It is important for the individual being tested to remain on a gluten-containing diet before celiac disease-associated antibody testing and small-bowel biopsy are performed because antibody levels and histologic abnormalities gradually revert to normal on a gluten-free diet.

(2) For individuals on a gluten-free diet, diagnostic celiac disease-associated antibody testing and small-bowel biopsy should follow a gluten challenge (i.e., eating gluten-containing foods [the equivalent of one to three slices of bread per day] for one to three months and sometimes longer if no symptoms are observed). However, the gluten challenge can make some individuals very ill.

· Tissue transglutaminase (tTG) IgA. Measurement of serum concentration of tissue transglutaminase (tTG) immunoglobulin A (IgA) is often recommended for initial testing because of its high sensitivity and specificity for celiac disease, relatively low cost, and ease of test performance and reliability. However, the sensitivity and specificity differ among laboratories [Abrams et al 2006]. False positive test results may occur in persons with acute coronary syndromes and in individuals with cirrhosis and chronic liver disease.

· Endomysial antibody (EMA) IgA. Serum concentration of endomysial antibody (EMA) IgA has the highest specificity (~99%), but is more expensive and more time-consuming to perform and is potentially more prone to false negative results than serum concentration of tTG IgA. Because it is determined by indirect immunofluorescence, serum concentration of EMA IgA is subject to observer variability, which affects its sensitivity [Murray 2004]. When performed in an experienced laboratory, this test has a higher specificity (approaching 100%) than tTG antibody testing and is useful in individuals with cirrhosis.

· Anti-deamidated gliadin-related peptide (a-DGP) antibodies IgA and IgG. This new test detects antibodies binding synthetic deamidated gliadin-related peptides (DGPs). In preliminary studies examining groups with a high prevalence of celiac disease, both isotypes (IgA and IgG) were shown to be highly sensitive and specific for active celiac disease. Specificity is greater than in antigliadin (AGA) testing and similar to that for tTG testing. An increase in DGP antibody levels may precede an increase in serum concentration of tTG-IgA in young children [Liu et al 2007, Niveloni et al 2007]. However, as in all antibody tests, a minority of individuals have false negative results.

· Measurement of serum concentration of total IgA to evaluate for selective IgA deficiency. The prevalence of selective IgA deficiency, a condition of unknown cause, is 1:700 in the general population. For unknown reasons the prevalence of selective IgA deficiency is higher (1:50) in individuals with celiac disease than in the general population [Wong el al 2003, Alaedini & Green 2005].
Note: Because individuals with selective IgA deficiency do not produce IgA antibodies, the celiac-associated IgA antibodies tTG IgA and EMA IgA are not present in these individuals. Therefore, in these individuals, testing for celiac-associated IgG antibodies (tTG IgG) or DGP-IGG should be performed instead.

· Antigliadin antibody (AGA) IgA and IgG. The NIH Consensus Development Conference on Celiac Disease recommended against the use of AGA in the diagnosis of celiac disease because of the low specificity of this assay and the availability of more specific and sensitive tests, including tTG and EMA IgA [Hill et al 2005].

Note: (1) The overall sensitivity of celiac disease-associated antibody testing may be slightly increased when all four tests (serum concentrations of tTG IgA, EMA IgA, total IgA, and AGA IgA and IgG) are performed. However, the use of panels that incorporate AGA markedly increase the false positive rate as a result of a lone positive AGA antibody and drop the positive predictive value to low levels except in the case of a very high pre-test prevalence. (2) Although a positive result on celiac disease-associated antibody testing is likely to be diagnostic of celiac disease, false positive results occur. (3) Conversely, normal celiac-associated antibody test results do not exclude the diagnosis of celiac disease, especially in the presence of lesser degrees of villous atrophy or in persons on a gluten-free diet prior to testing.

Small-bowel biopsy generally refers to multiple (four or more) biopsies taken endoscopically from the post-bulbar duodenum.

Characteristic histologic findings that are the gold standard for the diagnosis of celiac disease include partial or complete villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Based on the dynamic development of the pattern of the intestinal lesions and the frequency of mild lesions in celiac disease, Marsh [1992] proposed a four-stage grading classification to establish the diagnosis and to assess improvement in response to a gluten-free diet (Table 1). Although these changes are not unique to celiac disease, reversion of intestinal damage after gluten withdrawal is unique to celiac disease. The positive predictive nature of the biopsies depends on the relative prevalence of celiac disease as compared to other causes of enteropathy in the population.

Authored by:

Cara L Snyder, MS, CGC

Certified Genetic Counselor
Kimball Genetics, Inc
Denver

Danielle O Young, MS, CGC

Certified Genetic Counselor
Kimball Genetics, Inc
Denver

dyoung@kimballgenetics.com

Peter HR Green, MD

Director, Celiac Disease Center
Professor of Clinical Medicine
Columbia University
New York

pg11@columbia.edu

Annette K Taylor, MS, PhD, FACMG

President and CEO
Kimball Genetics, Inc.
Denver

aktaylor@kimballgenetics.com 03072008celiac
Initial Posting: July 3, 2008.