2012-03-27 16:07:27 UTC

The Case for Screening: Detecting Celiac Disease Hidden Below the Waterline

March 27, 2012



Alberto Rubio-Tapia, MD

Assistant Professor of Medicine; Associate Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN


Joseph A. Murray, MD

Professor of Medicine; Director, Celiac Disease Research Program; Consultant, Division of Gastroenterology and Hepatology and Department of Immunology, Mayo Clinic, Rochester, MN


Celiac disease is a lifelong disorder that affects approximately 1 percent of the U.S. population. The prevalence of celiac disease in the U.S. increased four times in the last 50 years.1 However, the prevalence of clinically detected celiac disease is much lower than screen-found celiac disease, suggesting that for every patient diagnosed, at least five to 10 individuals remain undiagnosed. Celiac disease epidemiology is like an iceberg where the tip represents few diagnosed cases (often symptomatic), while the vast majority of cases remain undiagnosed below the waterline. Many cases are not diagnosed because of poor awareness of disease, wide spectrum of clinical manifestations or absence of gastrointestinal symptoms.

Consequences of undiagnosed celiac disease

Undiagnosed celiac disease may increase morbidity, economic burden and mortality. Many people with undiagnosed celiac disease may seek substantial health care before being correctly diagnosed. Increased mortality risk is a concern and may require further comment. All-cause mortality was increased four-fold among young men with undiagnosed celiac disease compared to seronegative referent subjects during 45 years of follow-up.1 This finding was supported by a European study that demonstrated a two-fold increased mortality risk among adults with positive tissue transglutaminase antibody.2 However, other studies failed to confirm these observations.3 The mortality risk might be influenced by the amount and duration of gluten consumed before and after celiac disease onset. Thus, detection of celiac disease — to be effective — should be started early in life if it will impact survival.

Current strategies for detection

The historical strategy of passive identification of celiac disease cases by testing only individuals with malabsorption will detect just a few symptomatic cases.

Case finding is a more proactive strategy, effectively increasing detection by testing individuals who belong to clinically identifiable groups at increased risk. These at-risk groups include those with a family history of celiac disease, Hashimoto’s thyroiditis, unexplained anemia, chronic liver disease of unknown etiology, Type I diabetes, Down’s syndrome and others.4 The rationale to test most of these conditions is well established and largely accepted. However, most individuals with undiagnosed celiac disease do not belong to at-risk groups or have suggestive symptoms. Thus, although useful and desirable, case finding is not enough and will fail to uncover a large portion of undiagnosed disease. Data from Olmsted County, MN suggest that case finding may detect at most 25 percent of cases (unpublished data). Only a minority (approximately 15 percent) of individuals with evidence of celiac disease-specific autoimmunity will be clinically detected by case finding over a period of 10 years.3 The highest rate of clinical diagnosis of celiac disease in the world was achieved in Finland (0.55 percent) where doctors have had a low threshold for serological testing.

Population screening can detect a large portion of hidden cases among presumptively healthy individuals that may benefit from early intervention. A good screening strategy must combine both a high sensitivity, so that it does not miss the relatively few cases of celiac disease present among the entire population, with high specificity to avoid overdiagnosis. Sensitivity of immunoglobulin A (IgA) tissue transglutaminase antibody is approximately 95 percent, making this test suitable for initial screening. Thus, the first step of screening will require only a blood test. More invasive evaluation would be recommended to differentiate between true- and false-positive serology results. Although, high IgA tissue transglutaminase titers greater than or equal to five to 10 times the upper limit of normal may have excellent correlation with other markers of celiac disease (e.g., abnormal intestinal biopsy), implying that upper endoscopy with biopsy may not be universally necessary to confirm the diagnosis.5 A positive IgA endomysial antibody (specificity approximately 99 percent) is a very accurate way of confirming positive IgA tissue transglutaminase antibodies even when used in population screening.6

Wilson and Jungner described a set of criteria against which a decision to implement a population screening program could be taken.7 Celiac disease meets several of these criteria while additional clinical research is still needed to obtain some crucial information about others.


Celiac Disease


The condition should be an important health problem.

Celiac disease affects ~1 percent of the population. High morbidity for clinical cases.

Natural history of the condition should be well understood.


Undiagnosed celiac disease may be associated with increased morbidity and mortality. However, the size of the risk remains controversial.

There should be a detectable early stage.

Celiac disease can be detected before symptoms occur, and exists for long periods before clinical diagnosis.

There should be an accepted treatment.

Gluten-free diet is effective and safe.

A suitable test should be devised for the early stage.

Tissue transglutaminase antibody is easy to perform and sensitive for initial screening. A more complex sequential testing paradigm may be necessary to confirm the diagnosis.

The test should be acceptable.

Initial screening for celiac disease requires only a blood test.

Intervals for repeating the test should be determined.


Information not available.

Adequate health service provision should be made for the extra clinical workload resulting from screening.

General support to diagnosis and treatment is available by current health system. However, a major health policy change will likely be needed, including opening of celiac clinics, legislation about gluten-free food, etc.

The risk, both physical and psychological, should be less than benefits.


More information is needed about risks related to screening for celiac disease (e.g., psychological implications of testing positive, long-term outcomes).

The costs should be balanced against benefits.


Diagnosis and treatment of celiac disease substantially reduced medical costs. Cost-effectiveness studies are needed.

Medical intervention

While the central concept for screening states that the earlier the disease is found, the better the outcome, it has not yet been proven whether screening and early intervention with a gluten-free diet (GFD) may reduce the development of complications. Adherence to GFD appears to be good in screen-detected cases and can improve nutritional deficiencies and symptoms (when present). Many screen-found patients, while initially claiming to be asymptomatic, go on to report substantial symptom improvement on a GFD. Dietary treatment is effective in patients with positive endomysial antibodies and early non-atrophic intestinal lesions. Population screening and early intervention led to health improvement in most children without deterioration of health-related quality of life after 10 years of follow-up.8

Areas of uncertainty

The best time to screen (and need of re-testing seronegative individuals) remains to be determined. While theoretical modeling suggests that population screening could be cost effective, formal cost-effectiveness analysis based on outcome data is required. Further studies about the natural history of undiagnosed celiac disease (especially symptom-free disease), including estimation of risks and potential benefits, are urgently needed.


In summary, effective methods to detect and treat the majority of hidden cases with celiac disease are needed. Currently, active case-finding is becoming accepted to increase detection, but will fail to uncover most cases. General population screening is feasible and will be required if we want to find most patients with celiac disease. 

Dr. Rubio-Tapia had no conflicts to disclose.

Dr. Murray received research support from Alba Therapeutics Corporation, and is on the advisory board of Alvine Pharmaceuticals, Inc. and Nexpep. He received consultant fees from 2G Pharma, Inc.; Actogenix; Bayer Healthcare Pharmaceuticals; Ferring Research Institute, Inc.; Flamentera; lmmunosanT, Inc.; lronwood, Inc.; and Vysera Biomedical.



1. Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, Brantner TL, Kim WR, Phelps TK, Lahr BD, Zinsmeister AR, Melton LJ, 3rd, Murray JA. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 2009;137:88-93.

2. Metzger MH, Heier M, Maki M, Bravi E, Schneider A, Lowel H, Illig T, Schuppan D, Wichmann HE. Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998. Eur J Epidemiol 2006;21:359-65.

3. Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, Van Dyke CT, Lahr BD, Larson JJ, Rubio-Tapia A, Melton LJ, 3rd, Zinsmeister AR, Kyle RA, Murray JA. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology 2010;139:763-9.

4. Catassi C, Kryszak D, Louis-Jacques O, Duerksen DR, Hill I, Crowe SE, Brown AR, Procaccini NJ, Wonderly BA, Hartley P, Moreci J, Bennett N, Horvath K, Burk M, Fasano A. Detection of Celiac disease in primary care: a multicenter case-finding study in North America. Am J Gastroenterol 2007;102:1454-60.

5. Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol Nutr 2012;54:136-160.

6. Walker MM, Murray JA, Ronkainen J, Aro P, Storskrubb T, D’Amato M, Lahr B, Talley NJ, Agreus L. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112-9.

7. Wilson JM, Jungner YG. Principles and practices of screening for disease. Geneva, World Health Organization, 1968.

8. van Koppen EJ, Schweizer JJ, Csizmadia CG, Krom Y, Hylkema HB, van Geel AM, Koopman HM, Verloove-Vanhorick SP, Mearin ML. Long-term health and quality-of-life consequences of mass screening for childhood celiac disease: a 10-year follow-up study. Pediatrics 2009;123:e582-8.

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