Draft Recommendation Statement
Celiac Disease: Screening
This opportunity for public comment expired on May 30, 2016 at 8:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Draft: Recommendation Summary
Celiac disease is a multisystem autoimmune disorder in genetically predisposed adults and children that is triggered by dietary gluten. Ingestion of gluten by persons with celiac disease can cause immune-mediated inflammatory damage to the small intestine, which can cause gastrointestinal and nongastrointestinal illness. The clinical presentation, severity of symptoms, and natural history of the disease varies, and includes asymptomatic (or “silent”) celiac disease.
In studies of U.S. populations, the estimated prevalence of celiac disease among adults ranges from 0.40% to 0.95%.1 Prevalence is higher than average among non-Hispanic whites, persons with a family history of celiac disease, and those with other autoimmune conditions.
The USPSTF found inadequate evidence regarding the accuracy of screening tests for celiac disease in asymptomatic populations.
Benefits of Early Detection and Intervention or Treatment
The USPSTF found inadequate evidence on the effectiveness of screening for celiac disease in asymptomatic adults, adolescents, and children with regard to morbidity, mortality, or quality of life. The USPSTF also found inadequate evidence on the effectiveness of targeted screening in persons who are at increased risk for celiac disease (e.g., persons with family history or other risk factors).
The USPSTF found inadequate evidence on the effectiveness of treatment of screen-detected, asymptomatic celiac disease to improve morbidity, mortality, or quality of life compared to no treatment or treatment initiated after clinical diagnosis.
Harms of Early Detection and Intervention or Treatment
The USPSTF found inadequate evidence on the harms of screening for or treatment of celiac disease.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons. Evidence is lacking, and the balance of benefits and harms cannot be determined.
Draft: Clinical Considerations
Patient Population Under Consideration
This recommendation applies to adults, adolescents, and children who do not have signs or symptoms of celiac disease.
Suggestions for Practice Regarding the I Statement
Potential Preventable Burden
Classic celiac disease is associated with symptoms of malabsorption, including diarrhea, abdominal pain, and weight loss. However, it is also associated with nonspecific, nongastrointestinal manifestations, including anemia, osteoporosis, chronic fatigue, peripheral neuropathy or ataxia, and short stature.2 Evidence suggests that celiac disease is associated with excess mortality, intestinal adenocarcinoma, and lymphoma.3
In three U.S.-based studies, prevalence of celiac disease ranged from 0.40% to 0.95% among adults.1 Some variations in prevalence can be attributed in part to the method used to confirm diagnosis.3 For example, some population-based studies on prevalence rely on serologic testing without histologic confirmation, which may result in false-positive diagnoses and overestimates of prevalence. However, in a systematic review of 38 studies from North America and Western Europe, prevalence of celiac disease was similar among studies that included biopsy confirmation (0.15% to 1.9%) and among studies that did not include biopsy confirmation (0.15% to 2.7%).1
Celiac disease affects children and adults. Seroconversion to antibodies associated with celiac disease may occur at any time, and disease progression can take months or years, if at all. Data suggest that the average age at diagnosis is now in the fourth to sixth decade of life.4, 5 There are limited data on the proportion of persons with silent celiac disease (positive histology but no symptoms) who later develop symptomatic celiac disease. Three long-term studies of U.S. adults with followup ranging from 10 to 45 years reported rates of progression to clinical diagnosis of celiac disease of 0% to 15%.6-8 The natural history of potential celiac disease (positive serology but absent or mild intestinal damage on biopsy) is not well known.
Persons who are at increased risk for celiac disease include those who have a positive family history (e.g., a first- or second-degree relative), with prevalence estimates of 5% to 20%.9-11 Persons with other autoimmune diseases (e.g., type 1 diabetes mellitus, inflammatory luminal gastrointestinal disorders, Down syndrome, Turner syndrome, immunoglobulin A [IgA] deficiency, and IgA nephropathy) are also at increased risk. Reported prevalence among racial/ethnic minorities is lower than among non-Hispanic whites.3
Potential harms of screening for celiac disease in asymptomatic populations include false-positive, inconclusive, or unnecessary serologic tests and biopsies, with possible anxiety or complications from testing. Based on estimated likelihood ratios in the general population,3 the positive predictive value of serologic tests for celiac disease is 12% to 40%, assuming a prevalence of approximately 1%. In a higher-risk population, with an assumed prevalence of 5%, the positive predictive value is 40% to 70%, depending on the serologic test used. Some patients with positive serology who do not undergo histologic confirmation may embark on efforts to avoid dietary gluten, which can increase costs and burdens and may result in decreased quality of life. Limited evidence from long-term followup studies have shown that some persons with biopsy-confirmed celiac disease may never develop symptoms or complications; thus overdiagnosis is also a potential concern.6-8
Reliable data on the frequency of screening for celiac disease in asymptomatic persons in clinical practice are not available.12 It is not known how many patients with positive serology without biopsy confirmation are treated with a gluten-free diet.
Screening for celiac disease is typically not performed in average-risk persons.3 The standard method of diagnosing celiac disease in persons older than age 2 years who have symptoms is the tissue transglutaminase (tTG) IgA test, followed by intestinal biopsy for histologic confirmation.3
Treatment and Interventions
Treatment of celiac disease is lifelong adherence to a gluten-free diet, which reverses disease manifestations in a majority of patients.3
Additional Approaches to Prevention
The National Institutes of Health provides current, comprehensive, science-based information about the symptoms, diagnosis, and treatment of celiac disease (available at http://celiac.nih.gov).
Draft: Other Considerations
Research Needs and Gaps
Studies that randomly assign participants to screening versus no screening and evaluate clinical outcomes are lacking. Screening studies that target populations at increased risk for celiac disease would likely be more informative than trials that target the general population, due to the higher prevalence of disease. More information is needed about the accuracy of serologic testing in asymptomatic persons, particularly those with disease risk factors.
Treatment studies in screen-detected, asymptomatic persons are also needed to understand the effects of adherence to a gluten-free diet (compared to no dietary intervention), as well as the effects of immediate versus delayed dietary changes (i.e., at the time of screen-detected diagnosis vs. when symptoms develop). Ideally, studies would report both short-term effects on symptoms and quality of life and long-term outcomes (e.g., osteoporotic fractures, cancer, and mortality). More research is needed to better understand the natural history of positive serology in patients without histologic changes or with histologic confirmation but no symptoms. Also, treatment studies should report results stratified according to baseline histologic findings, given the current uncertainty about the natural history of celiac disease in persons with mild histologic abnormalities.
Burden of Disease
Celiac disease is caused by an immune response in persons who are genetically susceptible to dietary gluten, leading to small intestine inflammation and malabsorption of nutrients. Gluten is a protein complex found in wheat, rye, and barley. Ingestion of gluten by persons with celiac disease causes immune-mediated inflammatory damage to the small intestine mucosa, resulting in malabsorption of nutrients.
Classic celiac disease is associated with diarrhea, abdominal pain, and weight loss. Patients with silent celiac disease have been diagnosed by serologic testing and intestinal biopsy but do not present with typical signs or symptoms of celiac disease. Potential celiac disease refers to patients with positive serology and mild or no intestinal damage on biopsy; affected persons may or may not have symptoms. The natural history of silent and potential celiac disease are not well-defined, and it is not entirely clear if they represent progressive stages of celiac disease or distinct subtypes.3
Data on the prevalence of silent celiac disease in the United States, as well as the proportion of these individuals who later develop symptomatic celiac disease, are limited.3 Reported prevalence of celiac disease in the literature varies, due to the different ethnic populations studied and the method used to confirm diagnosis.3 In a systematic review of 38 studies from North America and Western Europe, prevalence was similar among studies that included biopsy confirmation (0.15% to 1.9%) and among studies that did not include biopsy confirmation (0.15% to 2.7%).1 In the three U.S.-based studies, prevalence among adults ranged from 0.40% to 0.95%.1
Scope of Review
The USPSTF reviewed the evidence on the accuracy of screening in asymptomatic adults, adolescents, and children; the potential benefits and harms of screening versus not screening, as well as targeted versus universal screening; and the benefits and harms of treatment of screen-detected celiac disease. For questions regarding the benefits and harms of screening and treatment, outcomes of interest included morbidity, mortality, and quality of life. The USPSTF also reviewed contextual information on the prevalence of celiac disease among patients without overt symptoms and the natural history of subclinical or silent celiac disease.3 The USPSTF did not review the evidence on nonceliac gluten sensitivity because this condition is defined based on the presence of symptoms rather than diagnostic tests, and it is not thought to lead to the health complications associated with celiac disease.
Accuracy of Screening Tests
A recent good-quality systematic review on the accuracy of diagnostic tests for celiac disease, which included studies of persons with symptoms or those in whom symptom status was not described, found high strength of evidence that the tTG IgA test is associated with high (>90%) sensitivity and specificity and endomysial antibody (EMA) IgA tests are associated with high specificity, based on consistent results from prior systematic reviews and new studies.13
The systematic review included only two studies reporting diagnostic accuracy in asymptomatic persons. These cross-sectional studies, which were both conducted outside the United States, found lower sensitivity and specificity for the tTG and EMA IgA tests (sensitivity, 57% to 71%; specificity, 83% to 98%) compared to studies that were not restricted to asymptomatic patients. One study was conducted in Iraq among patients with type 1 diabetes mellitus, no symptoms of celiac disease, and no family history of celiac disease or thyroid disorders. It reported sensitivity of 71% for both the tTG and EMA IgA tests. Specificity was 93% for both tTG tests and 96% for the EMA IgA test.14 The second study was conducted in the Czech Republic among children and adolescents who were at higher risk for celiac disease due to family history or presence of type 1 diabetes mellitus. Among asymptomatic patients, the specificity and sensitivity of detecting antiTG levels of more than 10 times the upper limit of normal and a positive EMA IgA test in patients with a Marsh histologic classification of stage 2 or 3 were 67% and 83%, respectively. Among first-degree relatives of patients with celiac disease (n=32), specificity was 70% and sensitivity was 81%. Among patients with type 1 diabetes mellitus (n=40), specificity was 64% and sensitivity was 93%.15
Effectiveness of Early Detection or Treatment
The USPSTF found no trials or controlled observational studies conducted in asymptomatic populations on the benefits of screening versus not screening or targeted versus universal screening.
The USPSTF found no studies on the benefits of treatment of screen-detected celiac disease compared to treatment initiated after clinical diagnosis. The USPSTF found one small fair-quality trial on the benefits of treatment of screen-detected, asymptomatic adults compared to no treatment.16 This study (n=40) reported that a gluten-free diet was associated with small improvements in gastrointestinal symptoms (<1 point on a 7-point scale) compared to a nongluten-free diet after 1 year; there were no changes in most quality of life outcomes. After 2 years, more than 90% of participants reported adherence to the gluten-free diet, and improvements in histopathologic findings were observed in the gluten-free diet group at 1 year compared to the nongluten-free diet group.
Potential Harms of Screening or Treatment
The USPSTF found no trials or controlled observational studies on the harms of screening for celiac disease in asymptomatic populations. Potential harms of screening in asymptomatic populations include false-positive, inconclusive, or unnecessary serologic tests and biopsies, with possible anxiety or complications from testing. However, the USPSTF found no studies on these harms. Some persons with biopsy-confirmed celiac disease may never develop symptoms; therefore, overdiagnosis is also a potential concern.
One small fair-quality trial of treatment with a gluten-free diet16 reported no withdrawals due to major symptoms or complications. The USPSTF found no other studies on the harms of treatment with a gluten-free versus nongluten-free diet in persons with screen-detected celiac disease.
Estimate of Magnitude of Net Benefit
The USPSTF found inadequate evidence on the accuracy of screening for celiac disease in asymptomatic populations. The USPSTF found inadequate evidence on the potential benefits and harms of screening versus not screening, as well as targeted versus universal screening of asymptomatic populations. The USPSTF found inadequate evidence on the potential benefits and harms of treatment of screen-detected celiac disease compared to no treatment or treatment after clinical diagnosis. Therefore, the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons.
Draft: Recommendations of Others
The American College of Gastroenterology recommends that asymptomatic persons with a first-degree relative who has a confirmed diagnosis of celiac disease be considered for testing. Patients with type 1 diabetes mellitus should be tested for celiac disease if there are any digestive symptoms, signs, or laboratory evidence suggestive of celiac disease.17
The U.K. National Institute for Health and Care Excellence recommends offering serologic testing for celiac disease to persons with a first-degree relative with celiac disease or persons with type 1 diabetes mellitus or autoimmune thyroid disease upon diagnosis. Serologic testing for celiac disease should be considered for persons with any of the following: metabolic bone disorder (reduced bone mineral density or osteomalacia), unexplained neurologic symptoms (particularly peripheral neuropathy or ataxia), unexplained subfertility or recurrent miscarriage, persistently elevated liver enzymes with unknown cause, dental enamel defects, Down syndrome, or Turner syndrome.18
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends testing for celiac disease in asymptomatic children who have conditions associated with celiac disease (type 1 diabetes mellitus, autoimmune thyroiditis, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, and first-degree relatives with celiac disease). It recommends testing asymptomatic children who are at risk beginning around age 3 years, provided they have had an adequate gluten-containing diet for at least 1 year before testing. It recommends that asymptomatic persons with negative serology who are at risk be considered for repeat testing.19
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4. Rampertab SD, Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease. Am J Med. 2006;119(4):355.e9-14.
5. Green PH. The many faces of celiac disease: clinical presentation of celiac disease in the adult population. Gastroenterology. 2005;128(4 Suppl 1):S74-8.
6. Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009;137(1):88-93.
7. Catassi C, Kryszak D, Bhatti B, Sturgeon C, Helzlsouer K, Clipp SL, Gelfond D, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010;42(7):530-8.
8. Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, Van Dyke CT, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology. 2010;139(3):763-9.
9. Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-92.
10. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538-44.
11. Murray JA. Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis? Gastroenterology. 2005;128(4 Suppl 1):S52-6.
12. Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012;367(25):2419-26.
13. Maglione MA, Okunogbe A, Ewing B, Grant S, Newberry SJ, Motala A, et al. Diagnosis of Celiac Disease. AHRQ Publication No. 15(16)-EHC032-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
14. Mansour AA, Najeeb AA. Coeliac disease in Iraqi type 1 diabetic patients. Arab J Gastroenterol. 2011;12(2):103-5.
15. Nevoral J, Kotalova R, Hradsky O, Valtrova V, Zarubova K, Lastovicka J, et al. Symptom positivity is essential for omitting biopsy in children with suspected celiac disease according to the new ESPGHAN guidelines. Eur J Pediatr. 2014;173:497-502.
16. Kurppa K, Paavola A, Collin P, Sievänen H, Laurila K, Huhtala H, et al. Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology. 2014;147(3):610-617.e1.
17. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-76.
18. Richey R, Howdle P, Shaw E, Stokes T; Guideline Development Group. Recognition and assessment of coeliac disease in children and adults: summary of NICE guidance. BMJ. 2009;338:b1684.
19. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40(1):1-19.
Internet Citation: Draft Recommendation Statement: Celiac Disease: Screening. U.S. Preventive Services Task Force. May 2016.