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NEJM
Editorial

Volume 348:2568-2570June 19, 2003Number 25

Celiac Disease — How to Handle a Clinical Chameleon

Alessio Fasano, M.D.

Celiac disease is an immune-mediated enteropathy triggered bythe ingestion of gluten-containing grains (including wheat,rye, and barley) in genetically susceptible persons. The diseaseis associated with HLA-DQ2 in 90 to 95 percent of cases andwith HLA-DQ8 in 5 to 10 percent of cases and is self-perpetuatingin the continued presence of gluten.¹It is the interplay betweengenes (both HLA and other types) and environment (i.e., gluten)that leads to the intestinal damage that is typical of the disease.²Under physiologic circumstances, this interplay is preventedby competent intercellular tight junctions, structures thatlimit the passage of macromolecules (including gluten peptides)across the intestinal epithelial barrier. Recent evidence suggeststhat the gluten-induced up-regulation of zonulin, an intestinalpeptide involved in the regulation of tight junctions, is responsible,at least in part, for the aberrant increase in gut permeabilitythat is characteristic of the early phase of celiac disease³and the subsequent abnormal passage of gluten into the laminapropria. The protein is deamidated by tissue transglutaminasein the lamina propria and is then recognized by antigen-presentingcells bearing HLA-DQ2 or DQ8, thereby triggering the autoimmunereaction of celiac disease.²Given the undisputable role ofgluten in causing inflammation and immune-mediated tissue damage,celiac disease represents a unique model of autoimmunity inwhich, in contrast to all other autoimmune diseases, a closegenetic association with HLA-DQ2, DQ8, or both; a highly specifichumoral autoimmune response (autoantibodies against tissue transglutaminase);and most important, the triggering environmental factor (gluten)have all been identified. This information provides the rationalefor the treatment of the disease based on complete avoidanceof gluten-containing grains, a task complicated by the lackof a clear food-labeling policy.

Epidemiologic studies conducted during the past decade, usingspecific and sensitive serologic tests, have revealed that celiacdisease is one of the most common lifelong disorders in bothEurope⁴and the United States.⁵The clinical presentation ofthis condition can range from the typical syndrome of malabsorption(chronic diarrhea, weight loss, and abdominal distention) tosymptoms and conditions that can affect any organ system (Table 1).⁵Since the onset of celiac disease may be atypical or evensilent, many cases remain undiagnosed and thus carry a riskof long-term complications, including osteoporosis, infertility,and cancer.

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Table 1. Atypical Clinical Manifestations of Celiac Disease.

In this issue of the Journal, the article by Mäki and coworkersconfirms that celiac disease often goes undiagnosed, even ina country such as Finland, where the level of awareness of thedisease is high.⁶ Using the most sensitive and specific serologictests available — tests for endomysial and tissue transglutaminaseantibodies — combined with HLA typing, the authors screeneda cohort of children whose serum samples had been collectedseven years earlier. Fifty-six had positive serologic tests,only 10 (18 percent) of whom had been given a diagnosis of celiacdisease between the serum collection in 1994 and screening in2001. In 27 children, the diagnosis was confirmed by an intestinalbiopsy at follow-up in 2001, suggesting that the prevalenceof celiac disease among Finnish children is 1 case in 99 children.The prevalence of the celiac disease trait, defined as seropositivityfor autoantibodies and an HLA haplotype associated with celiacdisease, was even higher: 1 case in 67 children.

These results raise many interesting questions. How can a diseasethat, if not treated, is associated with a high rate of morbidityand increased mortality not be segregated by genetic evolutionand thus remain one of the most frequent genetically based disordersin humans? One possible explanation is that gluten, a proteinintroduced in large quantities into the human diet only afterthe advent of agriculture, activates "by mistake of evolution"mechanisms of innate immunity (such as the zonulin pathway^7,8)that are too important to the survival of the species to beeliminated.

Another question concerns the variables that dictate the durationof clinical latency and the type of symptoms that occur onceceliac disease becomes clinically apparent. In recent years,the age at the onset of symptoms has increased and the clinicalpresentation has changed. These changes seem to be associatedwith the introduction of smaller amounts of gluten into thediet at older ages.

A third question concerns the complications of untreated celiacdisease. Multiple studies that have focused on the biochemistryand toxicity of gluten-containing grains and the immune responseto these grains suggest that patients with celiac disease shouldbe treated, whether or not they have symptoms or associatedconditions. However, no well-designed prospective clinical studieshave addressed this point, nor do such studies seem likely to,given the ethical implications. Nevertheless, there is generalagreement that persistent mucosal injury, with or without typicalsymptoms, can lead to serious complications in adults with celiacdisease who do not strictly comply with a gluten-free diet.²

Perhaps the most controversial issue raised by the findingsof Mäki and coworkers is the question of who should bescreened for celiac disease. The prevalence of the disease andthe burden of illness related to this condition, particularlyif it is not treated, are so high as to potentially supporta policy of screening of the general population. Celiac diseasesatisfies the five criteria of the World Health Organizationfor justifying general screening.⁹ First, early clinical detectionof the disease could be difficult, as suggested by Mäkiet al. Second, with an overall prevalence approaching 1 percent,²celiac disease is a common disorder, causing substantial morbidityin the general population. Third, the screening tests for celiacdisease are highly sensitive and specific, as demonstrated bymany reports in the literature, including that by Mäkiet al. Fourth, a treatment for the disease — a gluten-freediet — is available. Finally, if it remains unrecognized,celiac disease could increase the risk of life-threatening complicationsthat are difficult to manage, such as intestinal lymphoma.

Nevertheless, the justification for screening of the generalpopulation for celiac disease will depend on the results ofcomprehensive, well-performed cost-effectiveness analyses. Althoughit is well established that complications may develop in theabsence of treatment, the natural history of undiagnosed celiacdisease remains unclear. Published studies have necessarilybeen limited to patients who have received a clinical diagnosis,an approach that ultimately leads to a biased estimate of therisks.² Despite the high sensitivity of the serologic testsfor celiac disease, the positive predictive value of these testsdecreases when they are used in the general population ratherthan in groups at increased risk.²

The appropriate age for screening and the need for periodicrepetition of screening to rule out late-onset gluten sensitizationare unclear.² The difficulties of treating patients with apparentlysilent celiac disease should also be considered. A five-yearfollow-up study revealed a 30 percent decrease in adherenceto the gluten-free diet among patients in whom the disease wasdetected by screening, as compared with age-matched patientswith symptomatic celiac disease identified during a regulardiagnostic workup.¹⁰ At the moment, the best epidemiologic approachto the diagnosis of celiac disease seems to be a systematicprocess of case-finding in which patients with symptoms or conditions,both typical and atypical (Table 1), known to be associatedwith the disease are targeted. Because of the high rate of morbidityrelated to untreated celiac disease and the typical delay indiagnosis,² increased awareness of the disease on the part ofhealth care professionals, especially primary care physicians,and a low threshold for the use of serologic tests are pivotalboth to alleviate the social and personal costs of the diseaseand to increase the quality of life of the many patients affectedby celiac disease.

Dr. Fasano reports having served as a paid lecturer to Prometheus.

Source Information

From the Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore.

References

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5. Fasano A, Berti I, Gerarduzzi T, 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;163:286-292. [Abstract/Full Text]
6. Mäki M, Mustalahti K, Kokkonen J, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348:2517-2524. [Abstract/Full Text]
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8. Clemente MG, De Virgiliis S, Kang JS, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 2003;52:218-223. [Abstract/Full Text]
9. Fasano A. European and North American populations should be screened for coeliac disease. Gut 2003;52:168-169. [Full Text]

10. Fabiani E, Taccari LM, Rätsch IM, Di Giuseppe S, Coppa GV, Catassi C. Compliance with gluten-free diet in adolescents with screening-detected celiac disease:         a 5-year follow-up study. J Pediatr 2000;136:841-843. [CrossRef][ISI][Medline]