Celiac disease: From basic immunology to bedside practice

doi:10.1016/S1529-1049(02)00060-0

Clinical and Applied Immunology Reviews

Volume 3, Issues 1–2, November 2002, Pages 61-71

https://doi.org/10.1016/S1529-1049(02)00060-0 Get rights and content

Abstract

Celiac disease (CD), or gluten-sensitive enteropathy, is a life-long disorder characterized by a severe damage of the small intestinal mucosa when ingesting gluten, a protein fraction found in wheat, rye and barley. Both in Europe and in the United States, the prevalence of CD in the general population is high, ranging between 0.3 and 1%. The clinical spectrum is highly variable, and most cases remain currently undiagnosed because of atypical presentation (the celiac iceberg). CD is a multi-factorial disorder with an immunological pathogenesis that depends on both genetic and environmental factors. The diagnosis of CD is based on the small intestinal biopsy findings, but can be suspected using serological testing (e.g., the anti-gliadin antibody (AGA), the anti-endomysial antibody (EMA) and the recently developed anti-tissue transglutaminase (tTG) assay). The latter, coupled with the determination of total serum immunoglobulin A (IgA), currently seems the best buy for the screening of CD. EMA should be used as a pre-biopsy (confirmatory) test while AGA determination should be restricted to the diagnostic work-up of younger children (IgG and IgA in parallel) or patients with IgA deficiency (IgG only). In selected cases, the high negative predictive value of human leukocyte antigen (HLA) typing can be useful for diagnostic purposes.

Introduction

Celiac disease (CD), or gluten-sensitive enteropathy, is a life-long disorder characterized by a severe damage of the small intestinal mucosa when ingesting gluten, a protein fraction found in wheat, rye and barley. In typical cases the celiac enteropathy is associated with signs of intestinal malabsorption, such as chronic diarrhea, weight loss, abdominal distention and anemia. Many cases are however atypical or even silent on clinical ground [1]. CD is a multi-factorial disorder that depends on both genetic and environmental factors. Although the pathogenesis of CD is not completely understood yet, several lines of evidence point to a possible immunological origin. Many experts go even further and regard CD as an intriguing model of an autoimmune disease that is triggered and maintained by an external antigen, namely gluten in the diet [2].

CD is much more common than previously thought. Currently most cases remain however undiagnosed unless actively searched for, a situation usually described as the celiac iceberg. Untreated patients are exposed to the risk of long-term complications, such as osteoporosis, infertility and cancer. The diagnosis of CD requires the small intestinal biopsy, but can be suspected using serological testing, for example, the anti-gliadin antibodies (AGA), the anti-endomysial antibody (EMA) and the recently developed anti-tissue transglutaminase (tTG) antibody [3].

In this paper we will: (a) briefly review the epidemiology, the pathophysiology and the clinical spectrum of CD; (b) describe in detail the immunological CD markers and their application in the diagnostic algorithm; and (c) discuss the possible strategies for discovering the celiac iceberg (mass screening vs. case-finding on at-risk groups).

Section snippets

CD is a common disorder

In countries where most people are of European ancestry, CD is one of the commonest life-long disorders. This well-proven concept is still not widely acknowledged by the scientific community. By screening samples of the general population using a serological test, for example, AGA and/or EMA antibodies, it has been shown that, both in Europe and in the United States, the prevalence of CD in the general population ranges between 0.3 and 1% 4, 5, 6, 7. It has also been found that most cases

Genetic background and CD pathophysiology

The primary role of genetic factors is well established. In identical twins the concordance for CD is about 70%. First-degree relatives of a celiac patient carry a tenfold risk of having CD compared to the general population. The major component of the genetic predisposition to celiac disease resides in the HLA region of chromosome 6. CD is strongly associated with HLA class II antigens, and approximately 90% of cases show a particular DQ2 alpha/beta heterodimer encoded by DQA1*0501 and

Clinical spectrum and treatment

The clinical spectrum of CD is wide (Table 1). Typical forms of CD present usually in young children with impaired growth, chronic diarrhea, abdominal distention, muscle wasting and hypotonia, poor appetite and unhappy behavior. Within weeks to months of starting to ingest gluten, weight gain velocity decreases and finally weight loss can be observed. Despite a wide variability between countries, classical CD still represents a common presentation in the pediatric age group.

Atypical CD is

Diagnostic tools

Still today, the mainstay of CD diagnosis is a small intestinal biopsy showing the typical celiac enteropathy (see below), followed by clinical and histological remission after treatment with the GFD 3, 14. In these last decades however, a number of serological tests have been developed, which have now a definite role in the diagnostic process, particularly when the clinical suspicion is low or in the patient's follow-up:

1.
AGA. Historically this (together with the anti-reticulin antibody) was the

Diagnostic algorithm

For reasons outlined in the previous paragraph, we propose the following diagnostic algorithm for CD. The IgA class human anti-tTG antibody, coupled with the determination of total serum IgA, currently seems the best buy for the screening of CD. Due to the wide clinical spectrum of CD, the anti-tTG test should definitely find a place in the repertoire of the primary care physician. As far as the total serum IgA is concerned, this could alternatively be determined only in subjects showing very

Case finding or mass screening?

How to deal with the submerged part of the celiac iceberg is currently a matter of debate within the scientific community. A growing line of opinion is in favor of early, mass screening of CD, since this condition apparently fulfills the requirements for a worthwhile screening program: (a) it is a common disorder causing significant morbidity in the general population; (b) early detection is often difficult on a clinical basis; (c) if not recognized, it can manifest itself with severe

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Cited by (14)

Gluten-free diet adherence and its consequences on the nutritional and health status of 100 celiac patients in Tébessa, Algeria
2014, Medecine des Maladies Metaboliques
L’objectif de la présente étude, menée chez des sujets porteurs d’une maladie cœliaque, est la mesure de l’observance du régime sans gluten et ses effets sur l’état nutritionnel et sanitaire des patients. Une enquête auprès de 100 malades cœliaques a été réalisée dans deux services de la santé de la ville de Tébessa (Algérie), entre 2008 et 2013. Les résultats obtenus montrent que l’observance du régime sans gluten est médiocre pour la majorité des sujets suivis. Il apparaît comme difficile à réaliser chez la plupart des patients pour des raisons diverses.
La principale conséquence immédiate est nutritionnelle : effet sur la corpulence des sujets. Chez les sujets âgés de moins de 18 ans, 16 % des garçons et 39 % des filles présentent une maigreur. Chez les adultes, 52 % des patients ont un IMC normal, 18 % souffrent de dénutrition grade I, 7 % de dénutrition grade II, et 4 % de dénutrition grade III. La corpulence des patients adultes est influencée par le niveau d’instruction et le niveau socioprofessionnel.
La deuxième conséquence est l’anémie, qui affecte 64 % des patients.
L’effet sur l’activité reproductrice semble réel : 7 % des patients mariés n’ont pas d’enfants, et chez ceux qui en ont eu, pour 67 %, le poids de naissance était inférieur à 2 600 g.
The purpose of this study, conducted in 100 patients with celiac disease, is the measure of gluten-free diet adherence and its effects on the nutritional and health status of patients. This study was conducted in two health services of the city of Tébessa (Algeria) between 2008 and 2013. Results show that adherence to gluten-free diet is poor for the majority of the patients followed. It appears to be difficult to achieve in most patients for various reasons. The main immediate consequence is malnutrition. Among those aged under 18 years, 16% of boys and 39% of girls presents with thinness. In adults, 52% of patients have a normal BMI, 18% shows malnutritional status grade I, 7% grade II malnutrition and 4% grade III malnutrition. BMI in adult patients is influenced by the level of education and socioprofessional level. The second effect is anemia that affects 64% of patients. The effect on reproductive activity seems real: 7% of married patients did not have children and for those who have had 67% of birth weight was less than 2600 g.
Celiac disease in adults: New aspects
2004, Revue de Medecine Interne
Propos. – La maladie cœliaque, d’étiopathogénie complexe, est définie comme une entéropathie sensible au gluten, constituant protéique majeur des céréales, survenant chez des sujets génétiquement prédisposés. Elle se traduit classiquement par un tableau de malabsorption lié à une atrophie villositaire totale ou subtotale de l’intestin grêle, régressive sous régime sans gluten. Le traitement repose sur l’exclusion alimentaire à vie de trois céréales de l'alimentation (blé, seigle, orge).
Actualités et points forts. – Au cours des deux dernières décennies, le spectre de présentations cliniques de la maladie de l’adulte s’est modifié : actuellement, les formes extradigestives révèlent la maladie dans 60 % des cas. L’utilisation des tests sérologiques a par ailleurs permis de détecter des formes silencieuses et latentes de la maladie. L’émergence de ces formes atypiques explique que la fréquence de cette affection a longtemps été sous-estimée et que le diagnostic de maladie cœliaque peut être méconnu pendant plusieurs années, exposant les patients aux complications carentielles et néoplasiques de la maladie. Parallèlement aux progrès de l’épidémiologie de la maladie, la démonstration de la relation entre maladie cœliaque et certains groupes HLA, et l’identification récente de la transglutaminase tissulaire comme autoantigène, cible majeure des anticorps anti-endomysium, ont permis d’émettre de nouvelles hypothèses physiopathologiques pour cette affection, et de proposer de nouveaux outils performants pour le diagnostic.
Perspectives et projets. – Les nouvelles données épidémiologiques de la maladie cœliaque de l’adulte doivent inciter les praticiens à un dépistage plus systématique de la maladie, devant certains tableaux atypiques que l’on sait à présent évocateurs, ou dans certaines populations dites à risque. La mise au point de tests sérologiques recherchant la présence d’anticorps anti-transglutaminase tissulaire par technique Elisa apporte un nouvel outil diagnostique facile à mettre en œuvre, aux performances prometteuses, qui pourrait constituer, dans un avenir proche, le principal test de dépistage de la maladie.
Introduction. – Celiac disease also known as gluten-sensitive enteropathy is a complex disorder where genetically susceptible individuals develop in typical cases signs of malabsorption after ingestion of cereals. Malabsorption is due to total or subtotal atrophy of the small intestinal mucosa regressing after adherence to a gluten-free diet. The only effective therapy is life-long strict abstinence from wheat, rye and barley.
Current knowledge and key points. – During the last two decades spectrum of clinical features of adult celiac disease has been modified. About 60% of cases are now revealed by extraintestinal manifestations. Moreover, recent studies that used serological methods revealed existence of both latent and silent celiac sprue. The finding of the high frequency of atypical celiac sprue contributed to underestimation of the true prevalence of celiac disease until now, and explained that celiac disease could be unknown for a long time, with increased risk of nutritional deficiencies and malignancy. Concurrently, the finding that celiac disease is primarily associated to a few HLA class II molecules, and recent advent of tissue transglutaminase as the main auto-antigen eliciting anti-endomysial antibodies allowed to propose new pathogenesis hypothesis and efficient screening tests for celiac disease diagnosis.
Future prospects and projects. – New epidemiological data concerning adult celiac disease must incite to a more systematic screening in patients with atypical but evocative features, or in at-risk subjects. Introduction of enzyme linked immunosorbent assays (ELISA) for the detection for anti-tissue transglutaminase antibodies allows to make use of a new available and efficient diagnosis parameter, which could constitute the main screening test in the near future.
Microstructure of Gluten-Free Baked Products
2016, Food Engineering Series
Celiac disease in children with atopic dermatitis
2014, Pediatric Dermatology
Screening for coeliac disease in preschool Greek children: The feasibility study of a community-based project
2013, Acta Paediatrica, International Journal of Paediatrics
Coeliac disease: Eating habits and quality of life
2012, British Food Journal

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^☆: Abbreviations: AAA, anti-actin antibodies; AGA, anti-gliadin antibodies; AU, arbitrary units; CD, celiac disease; ELISA, enzyme linked immunosorbent assay; EMA, anti-endomysial antibody; GFD, gluten-free diet; HLA, human leukocyte antigen; IEL, intra epithelial lymphocyte; IFN-γ, interferon-gamma; IgA, immunoglobulin A; PCR, polymerase chain reaction; SSO, sequence specific oligonucleotide; tTG, tissue transglutaminase.

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ReviewCeliac disease: From basic immunology to bedside practice☆

Abstract

Introduction

Section snippets

CD is a common disorder

Genetic background and CD pathophysiology

Clinical spectrum and treatment

Diagnostic tools

Diagnostic algorithm

Case finding or mass screening?

Gastroenterology

Lancet

Lancet

Lancet

Gastroenterology

Lancet

Am J Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

J Autoimmun

J Pediatr

Coeliac disease

Celiac sprue

Gastroenterology

Undiagnosed coeliac disease is common in Finish adults

Scand J Gastroenterol

The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects

Acta Paediatr Suppl

Celiac disease in the USAhigh prevalence of antiendomysium antibodies in healthy blood donors

Scand J Gastroenterol

Coeliac diseasea potentially treatable health problem of Saharawi refugee children

Bull World Health Organ

Molecular basis of celiac disease

Annu Rev Immunol

Review
Celiac disease: From basic immunology to bedside practice☆