Coeliac disease: changing views

Best Practice & Research Clinical Gastroenterology Vol. 19, No. 3, pp. 313–321, 2005 doi:10.1016/j.bpg.2005.01.006 available online at http://www.sciencedirect.com

1 Coeliac disease: changing views C.J.J. Mulder* Gastroenterologist Department Gastroenterology, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam

C. Cellier Gastroenterologist Department Gastroenterology, Hospital European de Georges Pompidou, Paris

A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of new concepts of pathophysiology and clinical considerations. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6, immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies. The understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs, the disease may present with less severe symptoms of malabsorption and the screening studies suggest an overall prevalence of up to 1 in 200–300. Histopathology has been standardized; lymphocytic enteritis (Marsh I), lymphocytic enteritis with crypthyperplasia (Marsh II), and villous atrophy, subdivided in partial, subtotal and total (Marsh IIIABC). Special attention is given to a subgroup of ‘refractory coeliacs’, including the identification of pre-malignant T-cells in the intestinal mucosa. The management of coeliacs primarely consists of monitoring for compliance and complications. Dietetic and medical associations need to establish protocols and offer additional training to undergraduetes, internships, general practitioners and other allied health professionals. It might be relevant to have a low threshold for intestinal biopsies. However, screening asymptomatics may be harmful for individuals. Research is needed to assess the benefits of massscreening in the future. HLA analysis can contribute towards recognising populations at increased risk. Keywords: coeliac disease; serology; marsh-classification; screening; refractory coeliac disease; HLA-typing; pathology; quality of life; gluten-free products.

* Corresponding author. Tel.: C31 20 4440613; Fax: C31 20 4440554. E-mail address: [email protected] (C.J.J. Mulder).

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DIAGNOSTIC CRITERIA (1969–2001) Until the 1950s, the diagnosis of coeliac was made when a child or adult had malabsorption in the absence of infection. When techniques for peroral small bowel biopsy were introduced during the 1960s, patients with malabsorption were found to have either a normal or a grossly abnormal jejunal biopsy. It is now more than 35 years since the diagnostic criteria for coeliac disease (CD) were proposed at the Interlaken Meeting of the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) in 1969.1 These criteria were further enunciated at the Second International Symposium of Coeliac Disease in 1974, and are as follows (A) structurally abnormal jejunal mucosa when taking a diet containing gluten; (B) clear improvement of villous structure when taking a gluten-free diet (GFD); (C) deterioration of the mucosa during gluten challenge.2 The ‘Interlaken criteria’ were reviewed by ESPGAN in 1990.3 Challenge was no longer required except for children under 2 years of age, where it still is. Criteria for the diagnosis of CD in adults have been defined in anticipation of the 2001 United European Gastroenterology Week (UEGW) in Amsterdam.4 It was concluded that CD does not require further confirmation if is based on duodenal histology showing villous atrophy (VA), crypt hyperplasia and intraepithelial lymphocytosis while using a gluten-containing diet, which normalizes on a GFD. It was stated that pathologists and clinicians become familiar with the pitfalls in diagnosis. Findings of circulating antibodies such as against endomysium and/or tTG before a GFD support the diagnosis, but are not essential. HLADQ2 or HLA-DQ8 are still considered circumstantial evidence. Gluten challenge might be useful for minor histological abnormalities, such as intraepithelial lymphyocytosis.5,6 Traditionally, the coeliac condition was known as a disease of childhood, managed by paediatricians and characterised by severe malabsorption due to VA, with a clear response to GFD. In the 1990s intensified scientific interest led to impressive steps forward in the understanding of the disease. Through in vitro studies, Marsh demonstrated a spectrum of consecutive stages of mucosal abnormalities that can be seen in gluten sensitivity, which was in contrast to the on/off phenomenon of total VA that was previously believed to be present in the ‘allergic’ reaction of the intestinal mucosa to gluten.7 Immunological studies demonstrated that in active coeliac disease antibodies to endomysium and tissue transglutaminase can be detected, which opened the way for new diagnostic strategies and population screening.8 Immunogenetic research located coeliac related patterns on the immunology-related HLA region on the short arm of chromosome 6, giving way to the formation of new concepts of the etiology of the inflammatory response that is seen in coeliac disease.9 Clinical studies, including population screening with antibodies, suggested that CD can present with milder symptoms than severe malabsorption, and that case-finding was disappointing in medical practice. Catassi even proposed the analogy of ‘a coeliac iceberg’, when in screening studies in a population of Italian school children he found an incidence of coeliac disease of up to 1 in 200, implicating a prevalence more than 10-fold higher than previously found.10 This ‘iceberg’ of coeliac disease has been confirmed by many studies.

THE COELIAC SPECTRUM ACCORDING TO MARSH The spectrum of gluten sensitive enteropathy as Marsh described, consists of consecutive stages of progressive abnormalities of the small intestinal mucosa,

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comprising infiltration of the epithelium with lymphocytes, hyperplasia of crypts, progressive loss of surface epithelial cells and, ultimately, VA. In the Marsh I lesion (lymphocytic enteritis) the architecture of the mucosa appears normal and the mucosal epithelium is invaded by lymphocytes. Marsh II (lymphocytic enteritis with crypthyperplasia), is characterised by intraepithelial lymphocytosis accompanied by hyperplasia of the crypts. Marsh III (flat lesion) consists of intraepithelial lymphocytosis, crypthyperplasia and VA.7 Marsh also recognised a type 4 lesion (irreversible hypoplastic/atrophic lesion) in which malignant (lymphomatous) transformation can develop.

INTESTINAL BIOPSIES FROM THE DISTAL DUODENUM Traditionally, the diagnosis of CD is made by the recognition of villous atrophy in mucosal specimens from the jejunum. Reliable mucosal specimens could be taken from the distal duodenum, this allows us to take biopsies in patients with less obvious symptoms and signs of CD.11

THE MARSH SPECTRUM OF GLUTEN SENSITIVE ENTEROPATHY IN VIVO When looking more carefully to the intestinal biopsies the consecutive stages of intraepithelial lymphocytosis, crypthyperplasia and VA have been recognized.7 Additional criteria for the distinct stages have been introduced.12 In Marsh I (lymphocytic enteritis) we assume intraepithelial lymphocytosis is present when more than 30 lymphocytes per 100 epithelial cells are counted. In Marsh II (lymphocytic enteritis with crypthyperplasia) we recognise intraepithelial lymphocytosis and crypthyperplasia, with elongation and branching of crypts in which there is a much higher proliferation rate. Considering Marsh III we recognise three distinct stages of VA. In Marsh IIIA (partial VA) villi are shortened and blunt. Arbitrarily, we classify as Marsh IIIA if the villous/crypt ratio is below 1:1. In Marsh IIIB (subtotal VA) the villi are clearly atrophic, but still recognisable. Finally, in Marsh IIIC, total VA, the villi are absent or rudimentary, the mucosa resembling colonic mucosa. In coeliacs, i.e. patients with persisting villous atrophy or with a relapse to villous atrophy despite strict adherence to a gluten-free diet, we recognise two immunohistological subgroups.4 When performing T-cell immunophenotyping of the intraepithelial population of lymphocytes, one group is characterised by the absence of the surface expression of cytoplasmic CD3 and surface expression of CD8, CD30, CD103 (mucosa-associated).The transition to Enteropathy Associated T-cell Lymphoma is high in these patients with a premature population of intraepithelial lymphocytes (refractory coeliac disease type II).13–15 In the other refractory coeliacs (type I), villous atrophy is seen without aberrant T-cell populations, and the incidence of lymphoma is low in this group.16

HISTOLOGICAL FOLLOW-UP According to the diagnostic criteria, mucosal pathology in coeliacs should normalise in response to a gluten-free diet. Scientific reports on histological recovery, including time

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schemes and end-stage histology are limited. Histological recovery in coeliacs after starting a gluten-free diet takes its time, is incomplete in a substantial subgroup of patients and recovery is correlated to the degree of initial mucosal pathology.17,18

SEROLOGICAL STUDIES Coeliac related serological tests have had great attention in the last decade. Formerly, antibodies to reticulin and gliadin were introduced, but their sensitivity proved to be disappointing. The introduction of antibodies to endomysium and recently tissue trans-glutaminase was welcomed with great enthusiasm. Reports suggested a sensitivity and specificity of up to nearly 100%, implicating those small intestinal biopsies would become obsolete. However, sero-negative coeliac disease seems a reality and the presence of anti-endomysial antibodies seems to correlate with the degree of VA.12,19–21 They suggest a limited value of antibodies in coeliac disease. A remarkable correlation between sero-negative coeliac disease and smoking has been reported, which may partly explain sero-negativity in coeliacs.21 If the sensitivities for EMA and tTG are below 90% when histological grades milder than Marsh IIIC are considered, than the nearly perfect negative predictive value of serology drops dramatically. Futhermore, the majority of studies about serology have been performed in situations of high CD prevalence. Therefore, the positive predictive value of these tests is likely lower than reported, when serology is applied in general population screening. Tissue transglutaminase (tTG) was identified as the endomysial autoantigen of CD.8 tTG is released from intracellular stores during mechanical stress or cellular wounding brought about by inflammation, infection or during apoptosis. tTG can also deamidate glutamyl donor substrates. This deamidation converts a glutamine residue into a negatively charged glutamic acid which fits better into the peptide binding groove for HLA-DQ2 or DQ8.22 Antibodies to tTG are very promising in CD screening, if they will be superior to anti-endomysium antibodies in milder histological presentations will probably be answered in the next years.

REFRACTORY COELIAC DISEASE Although reports on the prevalence of refractory coeliac disease (RCD) are scarce, it is assumed to be 0–5% in adults. We consider coeliacs to be refractory, when symptoms of malabsorption due to villous atrophy are seen, persisting or regressing after a former good response despite a strict adherence to a gluten-free diet. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of coeliac disease must be looked for, including the presence of antibodies (tTG) in the untreated state and the presence of coeliac related HLA-DQ markers. We suggested to divide refractory patients in two categories; type I without aberrant T-cells and type II with aberrant T-cells detected by immunophenotyping by flowcytometric analysis or immunohistology of the intestinal mucosa.4,15 We recognise these refractory lesions in all subgroups of villous atrophy, including Marsh IIIA. Especially RCD-II is considered to be a pre-malignant condition.15

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EPIDEMIOLOGY The clinical presentation of CD is proven to be diverse, varying from severe, debilitating malabsorption states to mild symptoms as fatigue, abdominal complaints and isolated iron deficiency. At present, more than 60% of newly diagnosed patients are adults; 15–20% are over 60 years of age.23 Still, in society and among general practitioners and internists it generally remains to be considered a disease of children. Due to scientific research and increasing attention in postgraduate teachings and in general publicity, the growing knowledge of CD has had its repercussions on incidence and prevalence of the disease. Probably this reflects a better recognition of patients, instead of a real increment of prevalence of CD. Screening studies in the general population throughout Europe and USA suggest that the true prevalence of CD may estimate even 1 in 100–200 inhabitants.10,24,25

GENETIC AND ENVIRONMENTAL FACTORS The environmental factor is mainly ingestion of gluten, while several genes contribute to the genetic predisposition.26 The main genetic factors, as mentioned before, are given HLA-DQ genes, i.e. the genes encoding DQ2 or DQ8 in the HLA complex on 6p21.9 Approximately 95% of coeliacs have a DQ2 heterodimer comprised of DQB1*02 and DQA1*05 and most of the remaining 5% have a DQ8 heterodimer comprised of DQB1*302 and DQA1*03. A small number of individuals lacking either of those heterodimers have DQB1*02 or DQA1*05 alone.9,27,28 Gene dosage also affects CD susceptibility, f.i. homozygous individuals who carry DQB1*02 and DQA1*05 in cis on both chromosomes have a greater risk of disease.29 Non-HLA complex genes seem to contribute, but the nature and effects of these genes are less well known. The identification and knowledge of the function of additional genetic factors should improve the understanding of the actual pathogenesis of CD and lead to new diagnostic strategies in case-finding and screening high risk groups.

SCREENING ISSUES Case-finding is the current approach for CD. Efficient case-finding in high-risk groups is more and more accepted as an effective strategy. The accuracy, cost-effectivity and acceptability seem good for individuals diagnosed by this attitude. The question is if the natural course of these high risk groups will be changed by GFD. Epidemiology has to focus which test is the best for disease detection. A combination of DQ typing and serology might be attractive, data about such an approach are limited. The following high risk groups might benefit from case-finding through antibody testing; first degree relatives of coeliacs, up to 10–20% may have villous atrophy; diabetics type I in whom the risk of CD is about 1:20; auto-immune thyroid disease, this association is so common, that we screen (vice-versa) all our coeliacs and hashimoto patients; patients with unexplained infertility or miscarriage; patients with unexplained osteoporosis; patients with unexplained (auto-immune) liver diseases; patients with irritable bowel syndrome. Medical societies have to discuss, which risk groups must be screened, once a life or with certain intervals.

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Nation-wide screening programmes have not started yet, which are common for phenylketonury, congenital hypothyroidism and other metabolic defects. Asympotomatic coeliacs found by screening have shown poor compliance with a GFD. At present, there is inadequate evidence from the literature on the magnitude of the benefits and harms of screening the general population and the potential risks of undetected CD. Research seems recommended to adequately address the consequences of screening high and low-risk groups in the general population. Coeliac disease is an important candidate for public health genetic screening based upon HLA-DQ alleles. Outside of the newborn period, and particularly for populations at increased risk, HLA analysis can contribute to defining a population not needing repeated testing over time to identify the development of positive coeliac serology.

QUALITY OF LIFE Ever since Dicke’s work on the gluten-free diet in the 1930–1940s, striking effect of the GFD on mood and behaviour have been witnessed.30,31 Even patients without apparent symptoms remark on a new-experienced vitality and perceived well-being, conforming the idea that in CD removal of gluten from the diet leads to ‘full clinical remission’. However, clinical evidence, poorly documented in literature, is accumulating that signs of depression and/or tiredness are typical symptoms of untreated coeliacs and unfortunately continue to be so in a subgroup of coeliacs who are taking the gluten-free diet. Intriguingly excessive tiredness that may interfere with daily activities seems to be confined to female coeliacs. This is a cause for concern.31 Follow-up data about these subgroups are mandatory.

LIVING WITH COELIAC DISEASE It is essential that the physician initiates on immediate referral to a registered dietician with expertise in CD. Because of the limited access of qualified dietician in a lot of countries not only in the second or third world, coeliac societies took on the role of making and revising diet recommendations, restrictions and guidelines unfortunately often without scientific, evidence-based qualifications for the changes. The diet is complicated to implement in daily life in the second and third world and can be overwhelming if not presented using a proactive approach. Although CD is considered to be high priority by the majority of dieticians, many patients are not referred to a dietician. More and more patients must pay for these services, as there is limited or lack of reimbursement for the counselling by insurance companies. A significant number of coeliacs in Europe and North-America also report difficulties following the GFD, especially in restaurants, at social functions, and while travelling.31 Some patients still report that half their luggage are gluten-free products. In order to effectively counsel individuals with CD, physicians and dietician must understand the emotional and psychological impact of the disease and diet to help them successfully follow the GFD. It is important not only for coeliacs but also for restaurants and for caterers to be aware about food allergy and CD. Ingredient information is often missing, inaccurate, and hard to read or is misunderstood. Staff-management does not realise that ingredients are different to what they normally use. When you have been ordered to

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prepare food that does not contain a certain ingredient like gluten, we have to make them sure that all equipment is thoroughly cleaned and to train the staff to prevent amounts of such from getting into your products and/or product-lines. More and more staff working in catering is quiet well trained to cover food hygiene and food allergyissues. Eating out is improving, however eating at friends’ houses still involves vetting the menus, advising on ingredients etc. It does not make coeliacs the easiest of dinner guests. We have the impression that staff in restaurants are starting to realize that it is better to tell coeliacs that they do not know if a product contains gluten than to guess. In the United States and Europe, food labelling does not clearly state, whether gluten is present in a product. The American Coeliac Task Force made its debut in 2003 (http://capwiz.com/celiac/home) to advocate for changing the food labelling law. In 2004 the senate passed the ‘Food Allergen Labelling and Consumer Protection Act’. These bills require food manufacturers to clearly state if a product contains the top eight food allergens, including wheat. In the European Community a new food labelling regulation is about to be introduced, which we hope will widen the range of gluten-free products.

CONCLUSION Coeliac disease continues to fascinate clinical and basic scientists. The chapters in this volume fall into two distinct groups. First, there are chapters mainly concerned with pathogenesis, and second, chapters describing clinical aspects of coeliac disease. Some authors look into the future and try to predict where these efforts in research might be leading us. It is timely, therefore, that Best Practice publish a volume on Coeliac Disease. It is ten years since the volume on Coeliac Disease in Bailliere’s Clinical Gastroenterology and 30 years since the volume on coeliac disease in Clinics in Gastroenterology appeared and there have been many developments since then.32 Scientific studies on pathophysiology, immunogenetics and clinical aspects of coeliac disease have had a great impact on the understanding of CD. One of the great breakthrough has been the recognition of a spectrum of the mucosal pathology. The identification of a subgroup of refractory patients in which the incidence of malignancy is high, has placed us for a great clinical challenge. As the understanding of CD is growing and publicity on the subject is increasing, the prevalence rates are continuously rising. The ‘coeliac iceberg’ is steadily being brought to the surface or better to say is fading/melting away. Still, considering the surprisingly low prevalence rates in some parts of the world, particularly pathologists should be alert for recognising the less severe histopathological abnormalities such as Marsh I and II. Furthermore, the demonstration of sero-negative coeliac disease, especially anti-endomysium negativity, may explain the missing of diagnoses, for at present these antibodies are often unjustly considered almost 100% sensitive for detecting coeliac disease. We underline the major progresses made during the last ten years in epidemiology, the genetics, the pathophysiology of the intestinal lesions, serology, the clinical aspects of CD and the more accurate evaluation of the risk of lymphoma, lesser than previously estimated. We hope that this volume of Best Practice of Gastroenterology about CD will fulfil the expectations of our readers and help them to manage their coeliacs in and outside their clinics. For the coeliacs we hope that access to gluten-free food will be more readily available and that insurance reimbursement is available as gluten-free diet is too expensive for some of them.

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