FAQ for Physicians

1. What is Celiac Disease?

Celiac disease is an immune-mediated disorder that is characterized by small intestinal mucosal injury and nutrient malabsorption. Celiac disease occurs in genetically susceptible individuals following the dietary ingestion of gluten, a group of glutamine and proline rich storage proteins in wheat, rye, and barley.

2. What causes Celiac Disease?

Celiac disease is activated in genetically susceptible individuals by the dietary ingestion of "gluten". Although the disease activating proteins in wheat, rye and barley that activate celiac disease are popularly termed "gluten", strictly speaking, gluten is only present in wheat and the more scientific terms for the disease activating proteins in rye and barley, respectively, are secalins and hordeins. Wheat gluten is a combination of gliadins and glutenins. Gliadins, glutenins as well as hordeins, and secalins all characteristically have a high proline and glutamine content. For convenience and because of its widespread use, the disease activating proteins will be mostly referred to on this website as "gluten".

Gluten is resistant to proteolytic digestion by gastric, pancreatic, and brush border enzymes in the intestine. This is because there is a relative lack of enzymes with prolyl endopeptidase activity in human small intestine. As a result there are many relatively large peptides of gluten in the small intestine that have not been fully digested. Tissue transglutaminase, an enzyme produced by cells in the intestinal mucosa, and that is activated during tissue injury, can convert some of the glutamine residues in these peptides to glutamic acid. This increases the binding of those peptides to the celiac disease associated HLA–DQ2.5 and –DQ8 molecules on cells in the mucosa that can then activate populations of gluten specific CD4+ T cells that produce gamma interferon. Those T cells in combination with other populations of lymphocytes that are present within the epithelial lining (i.e., intraepithelial lymphocytes) cause tissue damage, leading to a loss of the absorptive surface. Current thinking is that both acquired and innate immune mechanisms are important contributors to the pathogenesis of celiac disease.

3. What are the symptoms of Celiac Disease?

While celiac disease in children more often than in adults manifests with classical gastrointestinal symptoms related to digestion and nutritional issues such as diarrhea, vomiting, malabsorption, malnutrition, and failure to thrive, the symptoms may be more subtle and mainly manifest as an irritable child with more vague abdominal complaints. In adults screened for celiac disease, between 2.6 to 3.8% of patients with constipation, abdominal pain or diarrhea were found to have celiac disease, while only one third of patients with newly diagnosed celiac disease reported chronic diarrhea. Many patients present with non-gastrointestinal symptoms such as aphthous stomatitis, iron deficiency anemia, reduced bone density, infertility, rash, arthralgias, neurological symptoms (ataxia, peripheral neuropathy, autonomic dysfunction, and headache) or general complaints such as fatigue and depression.

4. What is the prevalence of Celiac Disease?

Celiac disease occurs in approximately 1 in 100 people in the United States. First-degree relatives of patients have a 10-15% chance of developing celiac disease while second-degree relatives have a lesser (approximately 5%) risk.

5. Who should be tested for Celiac Disease?

A number of conditions are associated with celiac disease and in those people, testing for celiac disease is warranted. The risk of celiac disease is related to a genetic predisposition such that first-degree relatives of patients with celiac disease should be screened for the disease. Antibody testing of asymptomatic children at high risk for celiac disease should begin around 3 years of age provided that the child has had an adequate gluten-containing diet for 1 year before testing. Antibody testing of first-degree relatives of patients with celiac disease should be repeated every 3 to 5 years unless HLA genetic testing is performed and the individual does not carry HLA–DQ2.5 or –DQ8.

A high incidence of celiac disease occurs in association with a number of other genetic diseases and screening should be considered in these patients as well.

The following symptoms warrant testing for celiac disease:

  1. Short stature
  2. Delayed puberty
  3. Dermatitis herpetiformis
  4. Dental enamel hypoplasia
  5. Premature onset of osteoporosis
  6. Unexplained elevated liver transaminases
  7. Unexplained iron-deficiency anemia
  8. Unexplained infertility or miscarriages
  9. Peripheral neuropathy, ataxia or other unexplained neurological symptoms

The following conditions are associated with celiac disease and screening for celiac disease should be considered:

  1. Type 1 diabetes mellitus
  2. Selective IgA deficiency
  3. Down syndrome
  4. Turner syndrome
  5. Williams syndrome
  6. Autoimmune thyroiditis
  7. Sjogren’s disease
  8. Primary biliary cirrhosis
  9. Microscopic colitis

If you suspect a patient has celiac disease, the first approach is to perform serologic screening. The best initial serologic test is the IgA tissue transglutaminase antibody. If this test is normal and you still suspect celiac disease, the serum IgA level should be checked to exclude IgA deficiency which results in a false negative test. If the patient is IgA deficient, you can order an IgG tissue transglutaminase antibody test. Note, however, that the IgG tissue transglutaminase antibody is not a useful test in patients who are not IgA deficient. Screening can also be done using the IgA and IgG deamidated gliadin antibody test.

6. What is the risk of Celiac Disease for relatives?

Relatives of patients with celiac disease have a significantly higher risk of celiac disease. First-degree relatives of patients have an approximately 10% to 15% chance of developing celiac disease while second-degree relatives have about half the risk of first degree relatives. The risk is higher in groups of patients with DR17 (also known as DR3 in which both of the alleles that code for the disease-associated DQ2.5 molecule are found on one chromosome).

7. Doesn't Celiac Disease only occur in children? It would seem my adult patients are too old to develop Celiac Disease.

Celiac disease was once thought of as a disease that occurred only in childhood. Some even thought the disease disappeared as patients entered their teen years. We now know that celiac disease can occur at any age. Although remission is common with compliance to a gluten-free diet, the disease is a lifelong condition. The average delay in diagnosis for adults with celiac disease is approximately 11 years. Frequently patients will have carried other diagnoses for some time before celiac disease is considered.

8. Why did my patient first present with symptoms to a specialist who is not a gastroenterologist?

Certain conditions occur together with celiac disease. For example, dermatitis herpetiformis is an intensely pruritic skin disease that is characterized by IgA deposition in the skin. Patients with this disease often present to the dermatologist or allergist. Most patients with this skin disease also have celiac disease and the skin disease as well as the intestinal disease improves on a gluten-free diet. Other patients with celiac disease may present to the endocrinologist with diabetes or thyroid disease, the neurologist with peripheral neuropathy or ataxia, or the rheumatologist.

9. How do I test for and make the diagnosis of Celiac Disease?

The initial screening test recommended by the National Institute of Health consensus statement and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) is the IgA tissue transglutaminase antibody (TTG). The IgA endomysial antibody (EMA) test also recognizes the antigen tissue transglutaminase and is often used as a followup test to confirm a positive IgA TTG. All tests for celiac disease, including antibody testing, should be done when the patient is on a gluten-containing diet for the 4 to 6 weeks prior to testing. Standard antigliadin antibody (AGA) and anti-reticulin antibody tests are no longer recommended as screening tests due to their much lower sensitivity and specificity compared to TTG. The deamidated gliadin peptide antibody test performs similarly to the tissue transglutaminase antibody and can be considered as part of the evaluation. Serum IgA levels should be checked to exclude selective IgA deficiency that results in a false negative test.

Biopsy of the small intestinal mucosa remains the "gold standard" for the diagnosis of celiac disease. It is important to obtain at least 6 biopsies from the more distal parts of the duodenum as the disease can be patchy. Biopsies should be properly oriented and sectioned, and interpreted by a pathologist experienced in small intestinal morphology. Biopsies should be noted for the extent of villous atrophy and crypt hyperplasia, the presence and magnitude of an increase in intraepithelial lymphocytes and an increase in inflammatory cells in the lamina propria and the nature of that increase (e.g. lymphocytes, plasma cells, eosinophils). Further interpretation should include whether or not there is an increase in crypt mitotic figures. It is helpful if the pathologist classifies the extent of biopsy abnormality according to the modified Marsh criteria (i.e., lymphocytic enteritis (Marsh I), lymphocytic enteritis with crypt hyperplasia (Marsh II), and villous atrophy, subdivided into partial, subtotal and total villous atrophy (Marsh IIIA,B, or C, respectively).

A positive tissue transglutaminase antibody coupled with a positive biopsy indicates the patient has celiac disease. Celiac disease should not be diagnosed solely based on results of an antibody test or symptom improvement after initiation of a gluten-free diet. Physicians should strongly encourage patients to undergo diagnostic endoscopic biopsy prior to initiation of a gluten-free diet since the biopsy findings can disappear in patients taking a gluten-free diet.

10. What use is genetic testing?

The major known susceptibility genes are found in the HLA class II DQ region. Approximately 95% of celiac patients have genes in that region that code for the protein HLA–DQ2. The remaining 5% of patients with celiac disease have HLA DQ alleles that code for a –DQ8 protein. Many other non HLA genes are less prominent and less well defined in terms of their contribution to disease. HLA testing is most useful to exclude the possibility of celiac disease. The negative predictive value for excluding the possibility of celiac disease is 99.9% when patients do not have HLA–DQ2.5 or –DQ8. Testing should use molecular methods (e.g. allele specific testing by PCR) to define the alleles at the DQA1 and DQB1 locus. It is helpful to concurrently determine the alleles present at the DRB1 locus.

11. What if my patient's symptoms strongly suggest Celiac Disease but the serology is negative?

This may happen for several reasons. First,testing must be done when the patient is NOT on a gluten free diet as that can result in false negative test. Alternatively, the patient may not have celiac disease or have only very minimal mucosal damage. However, it also must be considered that the individual may have both celiac disease and selective IgA deficiency, the latter being verified by measuring serum IgA levels. If the patient is IgA deficient, the physician should request the IgG tissue transglutaminase, IgG deamidated gliadin antibody (dglAb), or IgG endomysial antibody. If celiac disease is strongly suspected and the IgA TTG is negative, the IgA TTG or dglAb can be repeated. Some family members of patients who initially test negative for celiac disease are subsequently found to have positive serology testing on subsequent tests, suggesting that some patients may have "latent" celiac disease that is missed by initial serology testing.

12. What if my patient has a positive IgA tissue transglutaminase antibody but the small intestinal biopsy is read as not showing Celiac Disease?

Three possibilities may explain this. First, the antibody test may be a false positive. Second, the histologic changes can be missed because the disease can be patchy. Third, the disease may be in its early stage.

13. My patient asks to be tested for Celiac Disease, what should I do?

Celiac disease can have many different presentations. Given its high prevalence, it should be suspected in many instances where the diagnosis remains elusive. Patients may have heard about celiac disease from various sources, including the internet and may feel, either correctly or incorrectly, that they have this disorder. In the proper setting, serologic tests offer excellent diagnostic value and should be done if there is a suspicion the patient has celiac disease. In those individuals who have "self-started" a gluten-free diet and have negative testing for celiac disease by serology, genetic testing for –DQ2.5 and –DQ8 can be helpful to determine if the patient has the genes necessary for developing celiac disease.

14. Should I advocate antibody screening in relatives of patients with Celiac Disease?

First degree relatives of patients with celiac disease should be screened by serology testing, even if asymptomatic. Testing should also be considered in second degree relatives, particularly when symptomatic. In some individuals, histologic damage can exist in the small intestine while the patient experiences few symptoms. It is likely that early screening, diagnosis and treatment in high risk populations will help prevent health problems later in life, and reverse damage to the small bowel which may already be present.

15. How should I follow my patients with Celiac Disease?

Celiac disease is treated by having your patient follow a strict gluten-free diet. In most patients the symptoms will resolve and the intestinal abnormalities will improve following the initiation of a gluten-free diet, which removes patient exposure to disease activating proteins in wheat, rye and barley. The role of the physician should focus on the maintenance of health in celiac disease patients. If patients show evidence of nutrient deficiency, nutrient replacement is essential. Celiac disease patients should have the serology retested after 6 months on a gluten-free diet and again at 1 year and yearly thereafter as a surrogate marker of compliance to the gluten-free diet.

Consultation with a dietitian skilled in the gluten-free diet is essential and contacts with a local Celiac Disease Support Group provide important information for patients in managing the day-to-day aspects of living that are special to those with celiac disease. In patients with symptoms despite adherence to a gluten-free diet, additional diagnostic approaches and therapy may be needed and such individuals may require special additional attention by gastroenterologists experienced in the management of celiac disease.


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