November Laboratory Testing for Celiac Disease. Inflammation in Celiac Disease

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November 2011 Gary Copland, MD Chair, Department of Pathology, Unity Hospital Laboratory Medical Director, AMC Crossroads Chaska and AMC Crossroads Dean

disorder triggered by the ingestion of gluten and related proteins found in wheat, barley and rye.

CD is more common in females (2-3:1), and may be diagnosed at any age.

1 November 2011 Gary Copland, MD Chair, Department of Pathology, Unity Hospital Laboratory Medical Director, AMC Crossroads Chaska and AMC Crossroads Dean Lakes Laboratory Testing for Celiac Disease Celiac disease (gluten-sensitive enteropathy, celiac sprue, CD) is a chronic, multisystem, autoimmune disorder triggered by the ingestion of gluten and related proteins found in wheat, barley and rye. The prevalence of the disease may be as high as 1% in the population of the United States. CD is more common in females (2-3:1), and may be diagnosed at any age. Gluten and similar proteins are poorly digested in the upper gastrointestinal tract and, in genetically susceptible individuals, immunogenic peptides induce an inflammatory response in the proximal small bowel mucosa, resulting in chronic inflammation and villous atrophy. Normal small intestinal villi Villous atrophy and Inflammation in Celiac Disease

2 Groups at increased risk for CD include: First-degree relatives of patients with CD Patients with Down syndrome, Turner syndrome or Williams syndrome Patients with other autoimmune disorders, including Addison s disease, autoimmune thyroiditis, insulin-dependent diabetes mellitus, Sjogren s syndrome, primary biliary cirrhosis, and autoimmune hepatitis. Patients may present with: 1. Gastrointestinal complaints (diarrhea, abdominal pain, anorexia, constipation) 2. Skin rash (dermatitis herpetiformis) 3. Signs and symptoms related to malnutrition (iron deficiency, vitamin deficiencies, premature-onset osteoporosis, failure to thrive, short stature, delayed puberty) 4. Non-specific complaints (chronic fatigue, headache, arthralgias, infertility, aphthous ulcers) 5. Neuropsychologic symptoms (ataxia, peripheral neuropathy, depression) 6. Elevated liver enzymes. 7. Iron deficiency anemia refractory to iron supplements may be the sole manifestation of CD. 8. Ulcerative jejunitis, refractory sprue, non-hodgkin lymphoma, and small bowel adenocarcinoma are rare complications. The diagnosis of celiac disease typically involves serologic testing, small bowel biopsy (or biopsy-confirmed dermatitis herpetiformis) and response to a glutenfree diet. An accurate diagnosis of CD requires the patient be consuming a gluten-containing diet prior to serologic testing and small bowel biopsy. Serologic studies may be negative in up to 10% of untreated CD patients. Screening of asymptomatic individuals in the general population is not recommended at this time. Serologic Markers Tissue transglutaminase IgA Antibody is recommended as a single screening test for CD because of its high sensitivity (95-98%) and specificity (94-95%). Gliadin (Deamidated) Antibody, IgA is an alternative antibody test. Endomysial Antibody IgA titers are also highly sensitive and specific, but are more difficult to perform and are more prone to variation in interpretation. Antibody titers should return to normal within 6-12 months after adopting a strict gluten-free diet, and can be used to monitor dietary compliance, although follow-up antibody titers may not correlate with histology. Immunoglobulin A (IgA). Serum IgA antibody levels should be determined at the time of obtaining IgA tissue transglutaminase levels, as selective IgA deficiency (more common in patients with celiac disease than in the general population) can be a cause of falsely negative tissue transglutaminase antibody testing. Serologic tests for IgG antibodies (Tissue transglutaminase IgG; Gliadin (Deamidated) Antibody IgG; and Endomysial 2

3 Antibody IgG) are sensitive and specific in patients who are IgA deficient, but are less sensitive in patients with normal IgA levels. Celiac-Associated HLA-DQ Alpha 1 and DQ Beta 1 High Resolution DNA Typing, Blood. Almost all patients with CD carry genes for the human leukocyte antigen class II (HLA) markers HLA-DQ2 (> 90%) or HLA-DQ8 (<10%), although most individuals with those markers (30-40% of the general population) do not have CD. Absence of HLA-DQ2 and HLA- DQ8 essentially eliminates the possibility of CD, since only 0.4% of CD patients are negative for both. HLA testing may be helpful in patients who are already following a gluten-free diet, as antibody levels may be normal in those cases. Positive serologic test results are followed by small bowel biopsy. Villous atrophy (Marsh type 3 lesion) seen on a small bowel biopsy supports a diagnosis of CD. Duodenal involvement may be patchy, so 4-6 biopsies from the duodenal bulb and distal duodenum are recommended. Biopsies should be performed even if the mucosa appears normal. If there is a clinical response to a gluten-free diet, a follow-up biopsy is not required. Small bowel biopsy should also be performed in patients with negative serologic test results and clinical features of malabsorption to detect inflammatory changes that may be seen in early celiac disease or other clinical conditions. Small bowel inflammatory infiltrates without villous atrophy (Marsh type 1 lesion) or with partial villous blunting (Marsh type 2 lesion) may reflect mild forms of celiac disease but are less specific than Marsh 3 lesions. Patients with sprue symptoms, negative ttg testing, and Marsh 1 or 2 lesions on biopsy might warrant either HLA DQ testing (to determine if a sprue-prone genotype exists) or a gluten free diet trial (if measurable symptoms are present). Inflammatory cell infiltrates in the duodenal mucosa may also be seen with: viral enteritis Milk or soy intolerance Crohn s disease Common variable immunodeficiency Autoimmune enteropathy Non-steroidal anti-inflammatory drugs Giardia and Tuberculosis 3

4 Additional algorithms for diagnosis and monitoring are available from Mayo Medical Laboratories: ( Unfortunately, there are patients for whom neither a diagnosis of CD nor exclusion of the disease is possible after serologic testing, HLA typing and small bowel biopsy. A gluten challenge may be considered if a patient has been on a gluten-free diet prior to testing or if the histology is equivocal, but gluten may cause a severe reaction in CD patients on a glutenfree diet. Finally, the possibility that some patients may have gluten sensitivity unrelated to CD is an emerging concept. 4

5 References: Alaedini, A and PHR Green. Narrative review: celiac disease: understanding a common autoimmune disorder. Ann Intern Med. 142:289-98, American Gastroenterological Association. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterol. 131: , Barton, SH and JA Murray. Celiac Disease and Autoimmunity in the Gut and Elsewhere. Gastroenterol Clin N Am. 37:411-28, Catassi, C and A Fasano. Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med. 123:691-3, Green, PHR and C Cellier. Celiac Disease. N Engl J Med. 357: , See also correspondence: N Engl J Med 357:747-9, Halfdanarson, TR, et al. Hematologic manifestations of celiac disease. Blood. 109(2), , Hill, ID, et al. North American Society of Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the Diagnosis and Treatment of Celiac Disease in Children: Recommendations of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 40(1):1-19, National Institutes of Health. NIH Consensus Conference on Celiac Disease Nimmo, M. Celiac disease: an update with emphasis on diagnostic considerations. Lab Med. 36 (6):366-9, For questions, comments, or suggestions about this newsletter or other laboratory issues, please contact Lauren Anthony, MD, Medical Director of Allina Medical Laboratories, (612) or Lauren.Anthony@allina.com 5

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