Guidelines for the Diagnosis and Follow-up of Celiac Disease

Transcription

1 Guidelines for the Diagnosis and Follow-up of Celiac Disease By Comitato Scientifico Nazionale

2 published in the Official Gazette of 7 February 2008 Comitato Scientifico Nazionale (CSN-AIC): Antonio Calabrò, Carlo Catassi, Italo De Vitis, Paolo Lionetti, Stefano Martelossi,Antonio Picarelli, Riccardo Troncone, Umberto Volta 2008 edition Edited by Associazione Italiana Celiachia Genoa tel fax Translated by: Debra Levine Graphic Project and Layout: Nova Era Conegliano TV Printed by: Grafiche Scarpis - San Vendemiano Tv No part of this publication may be reproduced in any form without the express authorization of the AIC

3 Guidelines for the Diagnosis and Follow-up of Celiac Disease by Comitato Scientifico Nazionale AIC

4 Permanent Conference of the Government, Regions and Autonomous Provinces of 20 December 2007 Agreement, pursuant to article 4 of legislative decree n. 281 of 28 August 1997, between thegovernment, Regions and Autonomous Provinces on the Classification Document for the Diagnosis and Monitoring of Celiac Disease and Associated Pathologies. Published in the Official Gazette of 7 February 2008, n. 32, S.O. (1) Of 20 December Agreement, pursuant to article 4 of legislative decree n. 281 of 28 August 1997, between the government, the regions and the autonomous provinces on the Classification Document for the Diagnosis and Monitoring of Celiac Disease and (2) Associated Pathologies. (1) Published in the Official Gazette of 7 February 2008, n. 32, S.O. (2) Issued by the Permanent Conference for relations between the government, regions and autonomous provinces of Trento and Bolzano. The Permanent Conference for relations between the government, the regions and the autonomous provinces of Trento and Bolzano In today's session of 20 December 2007; Considering articles 2, paragraph 1, letter b) and 4 of legislative decree n. 281 of 28 August 1997, which give this Conference the authority to promote and sanction agreements between the government and the regions and the autonomous provinces, in carrying out the principle of fair competition, in order to coordinate the exercise of the respective competences and carry out activities of common interest; Considering law n. 123 of 4 July 2005, Regulations for the protection of subjects suffering from Celiac Disease and in particular art. 3, paragraph 1, letters b) and c) in which it is prescribed that the regions and the autonomous provinces of Trento and Bolzano show the local health authorities the operative interventions for preventing complications and monitoring the pathologies associated with Celiac Disease, as well as for defining the diagnostic and follow-up tests for subjects affected by Celiac Disease; 4 Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

5 Considering the note of 20 December 2006 with which the Ministry of Health submitted the proposal of a classification document for the diagnosis and monitoring of Celiac Disease and associated pathologies; Whereas technical meetings to examine the proposal were held on 29 January 2007 and 9 July 2007; Considering the note dated 21 November 2007 with which the Ministry of Health sent the final version of the proposed agreement to discuss, enclosure sub A, an integral part of the present agreement; Considering the letter dated 23 November 2007, with which the Ministry of the Economy and Finance expressed its approval of the above-mentioned final version; Whereas with the note dated 27 November 2007, the Tuscany region, the interregional health coordinator, expressed a favourable technical opinion; Having acquired in the course of the present session the approval of the government, the regions and the autonomous provinces; Sanctions the agreement Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 5

6 Text of the resolution Between the Government, the regions and the autonomous provinces of Trento and Bolzano in the terms reported below: 1. The Classification Document for the Diagnosis and Monitoring of Celiac Disease and Associated Pathologies is approved in accordance with the terms in enclosure sub A, referred to in the premise, an integral part of the present document. 2. The implementation of the present agreement must not entail new or greater expenses for the public finance. The administrations concerned shall take steps to implement the provisions within the limits of the human, financial and instrumental resources available at the time of the current legislation. Enclosure A CLASSIFICATION DOCUMENT FOR THE DIAGNOSIS AND MONITORING OF CELIAC DISEASE AND COMPLICATIONS PREMISE 1) INTRODUCTION 2) CLINICAL PICTURES AND DISEASES ASSOCIATED WITH CELIAC DISEASE 3) DIAGNOSTIC PROTOCOL AND LABORATORY TESTS OF CELIAC DISEASE 4) MONITORING OF CELIAC DISEASE 5) COMPLICATIONS OF CELIAC DISEASE 6) BIBLIOGRAPHY PREMISE In reference to what is provided for by article 3, paragraphs b) and e) of law n. 123 of 4 July 2005, the Celiac Disease Work Group", on 3 March 2006, adopted the present document bearing the classification specified in the title. The document in question was subjected to a written procedure of acceptance by the Scientific Council on Food Safety and was approved on 24 April Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

7 1. Introduction Celiac Disease (CD) is an immune-mediated enteropathy that develops in genetically predisposed subjects following the ingestion of gluten, the alcohol-soluble protein component present in certain cereals like wheat, rye, and barley. Genetic predisposition consists in the condition of homozygosis and/or heterozygosis for the alleles DQ2/DQ8 of the major histocompatibility complex of class II (HLA). The disease manifests itself with very different and polymorphic clinical pictures. The classic form usually begins in the first 6-24 months, shortly after the introduction of gluten during weaning, and presents gastrointestinal symptoms such as chronic diarrhoea, vomiting, globose abdomen, meteorism, lack of appetite. These are accompanied by laboratory results and symptoms that are the consequence of malabsorption such as anaemia, alterations of coagulation, oedema, vitamin and mineral deficiencies. This form is becoming rare by now, but there has been an increasing incidence in the late-onset type characterised by atypical gastrointestinal symptoms and by extra-gastrointestinal manifestations, isolated or associated with each other. Moreover, the development of serological tests that can identify the presence of specific antibodies for CD (antiendomysium antibodies and anti-transglutaminase antibodies) has made it possible to define the silent form of the disease (presence of pathognomonic intestinal lesions in the absence of signs and symptoms) and the potential form (positive serology without intestinal lesions). In recent years, greater knowledge and awareness of the disease by health workers and the availability of serological tests to identify subjects at risk to send for endoscopic exams has made it possible to identify celiac subjects who would have remained undiagnosed otherwise. Currently it is estimated that one individual out of every 100/150 is affected by Celiac Disease, for a prevalence of 0.6-1% in the general population. Only some of these patients are aware of the disease however. In fact, in Italy there are just over 70,000 known celiac individuals, against a real number calculated to be around 500,000. Therefore, for every celiac individual that is diagnosed, roughly 7 go undiagnosed and/or are misdiagnosed. The only therapy available now for subjects affected by CD is the complete and permanent exclusion of gluten-containing foods from the diet. This therapy not only enables the rapid disappearance of the symptoms and diseases associated with CD (clinical recovery usually occurs about 1-2 months from the time that gluten is excluded), but prevents the development of the neoplastic and autoimmune complications that continued and prolonged exposure to gluten provokes in celiac subjects. Considering the diligence that the gluten-free diet requires, its costs for the National Health Service (due to the elevated number of patients and the costs of gluten-free products, a part of which are covered by the National Health Service) and its importance Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 7

8 not only in the short term, but above all in the prevention of complications in the long term, the diagnosis of Celiac Disease must be early and accurate. In recent years, there has been considerable scientific evidence regarding the eziopathogenesis and immunological alterations of CD, based on which new tests have been introduced to identify subjects at risk of Celiac Disease. The greater availability of clinical tests has led to wide variability in the diagnostic process, which, together with the clinical variability of CD and the invasiveness of the gastroduodenoscopy with biopsy, often makes the diagnosis difficult and late, if not altogether wrong. For these reasons, it is necessary to define a classification document for the diagnosis and monitoring of the subjects affected. The present document has the aim of harmonizing the diagnostic path of CD, increasing its sensitivity and specificity, allowing the diagnosis of cases that still escape medical attention, introducing the use of more effective serological and instrumental examinations in clinical practice and preventing the complications that celiac subjects are at greater risk of developing. 2. Clinical Pictures and Diseases Associated with Celiac Disease! In the classic form, with early onset (first 6-24 months of life), the disease generally presents itself shortly after weaning with chronic diarrhoea, vomiting, globose abdomen, lack of appetite, arrested growth or weight loss, and irritability.! Currently Celiac Disease tends to manifest itself ever more frequently in the late-onset form, with intestinal disturbances that are both typical and atypical (such as recurrent abdominal pain, constipation, meteorism) and especially with extra-intestinal manifestations (Tab. 1) Table 1. Extra-intestinal manifestations Herpetiform dermatitis Anaemia Low stature Delayed puberty Infertility and recurrent miscarriages Alopecia areata Aphthous stomatitis Dental enamel hypoplasia Hypertransaminasemia of unknown cause Neurological disturbances: drug-resistant epilepsy, ataxia, polyneuropathy Osteoporosis Dilative myocardiopathy Arthritis 8 Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

9 ! There also exist:! Silent forms: typical gluten enteropathy occasionally found in genetically predisposed, asymptomatic individuals with positive serology, often among those who undergo screening because they are members of at risk groups;! Potential forms: positive serology, normal mucosal architecture.! If Celiac Disease is not adequately treated, it predisposes the celiac individual to a series of complications such as osteoporosis and tumours, in particular non-hodgkin's lymphoma of the intestine. There are also various diseases associated with Celiac Disease (Tab. 2). Table 2. Associated diseases Insulin-dependent diabetes mellitus Hashimoto's Thyroiditis Sjogren's Syndrome Down's Syndrome Turner Syndrome IgA deficiency Multiple sclerosis Primitive biliary cirrhosis, autoimmune hepatitis! Finally, there is strong evidence that parents and siblings of celiac individuals have an increased risk of developing the disease, with a prevalence that ranges from 6-12%. * "Celiac disease" Work Group: S. Auricchio, A.Calabrò, E. Cardi, A.M.Castellazzi, M. De Vincenzi, P.Fagioli, G.B. Gasbarrini, L.Guidarelli, S.Moretti, M.P. Patrizi, N. Pogna, A.Pucci, F. Romano, V. Silano 3. Diagnostic protocol and laboratory tests of Celiac Disease From the perspective of public health, it is essential to establish guidelines that permit having simple protocols, based on essential tests, that are applicable throughout the national territory and that can identify the greatest number of celiac subjects possible and ensure that they are monitored (Tab.3). Table 3. Criteria of the Diagnostic Protocol for Celiac Disease Simple (few essential tests) Applicable in all the Centres in the national territory Able to identify the greatest number of celiac individuals (reducing the number of missed diagnoses) and to avoid false diagnoses (still very high) It is possible to identify three different diagnostic paths depending on whether one is up against a strong clinical suspicion of Celiac Disease, patients with a low probability of Celiac Disease, and parents and siblings of celiac individuals (Tab. 4). Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 9

10 Table 4. Diagnostic Protocol High clinical suspicion of Celiac Disease Moderate-low probability of Celiac Disease First-degree relatives of celiac individuals, including brothers and sisters The tests to use for the diagnosis of Celiac Disease are antibody markers and intestinal biopsy (Tab. 5). Table 5 First level tests Antibodies *(1) A. Human anti-ttg type IgA (IgG in presence of IgA deficiency) Duodenal Biopsy The Marsh classification, as modified by Oberhuber, to be set in the clinical, antibody and genetic context * EMA as a corroborating test to be performed in Centres of reference in doubtful cases * The search for AGA of IgA class should be confined to children under two years of age (1) The services to the search for anti-transglutaminase antibodies (IgG, IgA) and the search for anti-endomysium antibodies are not currently included in the list of ambulatory specialist services supplied by the National Health Service pursuant to the Ministerial Decree of 22 July 1996 (currently being updated) The Marsh classification, as modified by Oberhuber, is universally accepted and utilized to interpret histological alterations in the small intestine (Tab. 6). Table 6. Histological Classification of Intestinal Lesions in Celiac Disease Increasing IEL (greater than 40*/100 ec) *(according to new criteria, (type 1) greater than 25/100 ec) Crypt hyperplasia (type 2) Slight villous atrophy (type 3a) Partial villous atrophy (type 3b) Subtotal villous atrophy (type 3c) IEL: intraepithelial lymphocytes; ec: epithelial cells The Marsh classification, as modified by Oberhuber, Eur J Gastroenterol Hepatol 1999 The HLA is a second level test able to assess compatibility with the diagnosis of Celiac Disease in those cases that are doubtful (Tab. 7). Table 7 II level tests: HLA (after non-diagnostic antibodies and/or biopsy) Test performed to exclude Celiac Disease Negative DQ2/DQ8: very low probability of Celiac Disease Positive DQ2 or DQ8: predisposition for the disease (e.g. in parents and siblings of celiac subjects) 10 Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

11 The detailed analysis of the various paths of the diagnostic protocol is illustrated in Figures 1, 2 and 3. Fig.1 Subjects with a high risk of Celiac Disease (forms of manifest malabsorption with weight loss, asthenia and diarrhoea) Celiac disease highly suspected Duodenal biopsy +serum IgA + anti ttg* IgG anti ttg (if IgA deficient) IgA anti ttg (if IgA are normal) Positive serology + normal biopsy HLA DQ2 DQ8 determination Positive serology + positive biopsy CELIAC DISEASE Negative serology + positive biopsy Exclusion of other causes of flat mucosa If positive, monitor anti-ttg and repeat multiple endoscopic biopsies or GFD trial to verify clinical antibody response If negative, anti ttg false positive^ HLA DQ2 DQ8 determination If positive, CELIAC DISEASE, to be confirmed by GFD and challenge (histology type 1-2 monitor and repeat multiple endoscopic biopsies) If negative, low probability of Celiac Disease^ and further investigation for other causes of mucosal damage *In subjects under 2 years of age test for AGA as well as anti-ttg ^ rare cases of DQ2-DQ8 negative Celiac Disease Particularly discordant cases as regards histology and serology to be sent to Centres of high specialisation Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 11

12 Fig.2 Subjects with a low or medium risk of Celiac Disease: with one or few symptoms Cases with one or few symptoms Serum IgA+anti ttg* IgG anti ttg (if IgA deficient) Negative serology Diagnosis of Celiac Disease excluded Positive histology (type 3a - 3c) IgA anti ttg (If IgA are normal) Positive serology Duodenal biopsy Negative histology or type 1-2 Fig.3 - First degree relatives, including siblings CELIAC DISEASE HLA DQ2 DQ8 determination If positive, monitor anti ttg and repeat multiple endoscopic biopsies If negative, false positive anti ttg^ *If under 2 years old, test for AGA as well as for anti ttg ^rare cases of Celiac Disease are not positive for DQ2, DQ8 Particularly discordant cases as regards histology and serology to be sent to Centres of high specialisation IgG anti ttg (if IgA deficient) First degree relatives, including siblings Serum IgA + anti ttg* IgA anti ttg (if IgA are normal) Negative serology HLA DQ2 DQ8 determination Positive serology Duodenal biopsy If positive, predisposition to Celiac Disease. Monitor with anti ttg If negative diagnosis of Celiac Disease is excluded Positive histology (type 3a-3c) CELIAC DISEASE If positive or normal histology, monitor. If positive and type1-2, evaluate case by case Negative histology or type 1-2 HLA DQ2 DQ8 determination If negative, anti ttg false positive^, check anti ttg *If under 2 years old, test for AGA as well as for anti ttg ^rare cases of Celiac Disease are not positive for DQ2, DQ8 Particularly discordant cases as regards histology and serology to be sent to Centres of high specialisation 12 Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

13 4. Monitoring of Celiac Disease The principal aims of monitoring are summarized in Table 8: Table 8. Indications for monitoring Verification of compliance with the diet Development of associated autoimmune pathology despite the gluten-free diet (e.g. autoimmune thyroiditis) Metabolic alterations (dyslipidemia, non-alcoholic steatohepatitis) Possible development of neoplastic (lymphoma) and other complications (refractory Celiac Disease, ulcerative jejunum ileitis, collagenous sprue), particularly in cases diagnosed in an advanced age The recommended examinations for all celiac subjects are summarized in Table 9: Table 9. Monitoring of Celiac Disease in all cases It is suggested to have a first follow-up examination 6 months from diagnosis and then yearly by means of: Medical exam with dietary interview at a specialized centre blood absorption tests ferritin, blood count Immunological and autoimmune markers ttga IgA (of the IgG class if IgA deficit) TSH, anti-tpo, anti-thyroglobulin antibodies Motivation: assessment of the absorbing function of the intestine, of compliance with the gluten-free diet and the development of autoimmune thyroiditis The exams to perform in selected cases are summarized in Table 10: Table 10. Monitoring of Celiac Disease in selected cases Blood tests useful in selected cases: metabolic tests: cholesterol, HDL, triglycerides, glycaemia, transaminases immunological tests: organ and non-organ specific autoantibodies Motivation: assessment of the metabolic state (in relation to the possible weight gain favoured by resumed absorption and the gluten-free diet, which is high in lipids) and the possible development of autoimmune disorders (the longer the celiac subject follows an unrestricted diet, the greater the autoimmune disorders) One of the most important examinations involved in the follow-up of Celiac Disease is bone densitometry, which should always be carried out at the moment of diagnosis to document the presence of osteopenia or osteoporosis (table 1), and which has to be repeated every 18 months if it is pathological. The problem is known to be more important in adults, even though cases of osteopenia and osteoporosis have also been reported in children, in whom in general the gluten-free diet leads to significant Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 13

14 improvements within the first year of exclusion of gluten from the diet. 5. Complications of Celiac Disease Moving on to consider the complications of Celiac Disease, it has been widely documented how Celiac Disease, especially if diagnosed late (unfortunately still a frequent occurrence) and not followed by a rigorously gluten-free diet, can induce significantly higher mortality than what is found in the general population. Some of the most dangerous complications of Celiac Disease, fortunately very rare, include hyposplenism, "sprue or refractory Celiac Disease", collagen colitis, ulcerative jejunum-ileitis, non-hodgkin lymphoma and other neoplasms (especially those involving the small intestine and oesophagus). These complications are always suspected in any patient who complains about an unjustified persistence or reappearance of diarrhoea, abdominal pains, weight loss, fever, intense asthenia and sensation of serious malaise despite following a rigorously glutenfree diet. The possible onset of these complications should be considered especially in cases in which the diagnosis of Celiac Disease was made at an advanced age and/or in which the gluten-free diet was not followed painstakingly. The diagnosis and treatment of the complications often require specialist skills different from those that are purely gastroenterological (e.g., the contribution of a haematologist is often crucial). Even though the dangerous complications of Celiac Disease can reduce the celiac patient's hopes and quality of life, often dramatically so, it must be specified that in the overwhelming majority of cases early diagnosis and a strict diet can significantly reduce their incidence. 14 Associazione Italiana Celiachia Genova, Via Caffaro, 68 A rosso tel fax segreteria@celiachia.it

15 6. Bibliography 1. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of Celiac Disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol : National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, Gastroenterology. 2005;128:Sl Chand N, Mihas AA. Celiac Disease: current concepts in diagnosis and treatment. J Clin Gastroenterol. 2006;40: Cataldo F, Marino V, Ventura A, Bottaro G, Corazza GR. Prevalence and clinical features of selective immunoglobulin A deficiency in Celiac disease: an Italian multicentre study. Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and "Club del Tenue" Working Groups on Celiac Disease. Gut. 1998; 42: Collin P, Maki M, Keyrilainen 0, Hallstrom 0, Reunala T, Pasternack A.Selective IgA deficiency and Celiac disease. Scand J Gastroenterol. 1992; 27: Cataldo F, Marino V, Bottaro G, Greco P, Ventura A. Celiac Disease and selective immunoglobulin A deficiency. J Pediatr. 1997;131: Hill PG, CD Millan SA Anti-tissue transglutaminase antibodies and their role in thè investigation of Celiac disease Ann Clin Biochem 2006; 43: Burgin-Wolff A, Dahlbom I, Hadziselimovic F, Petersson CJ. Antibodies against human tissue transglutaminase and endomysium in diagnosing and monitoring Celiac disease. Scand J Gastroenterol. 2002; 37: Tesei N, Sugai E, Vazquez H, Smecuol E, Niveloni S, Mazure R, Moreno ML, Gomez JC, Maurino E, Bai JC. Antibodies to human recombinant tissue transglutaminase may detect Celiac disease patients undiagnosed by endomysial antibodies. Aliment Pharmacol Ther. 2003;17: Hill PG, Forsyth JM, Semeraro D, Holmes GK. IgA antibodies to human tissue transglutaminase: audit of routine practice confirms high diagnostic accuracy. Scand J Gastroenterol. 2004;39: Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J; European Genetics Cluster on Celiac Disease. HLA types in Celiac Disease patients not carrying the DQA1*O5-DQB1*O2 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease.Hum Immunol Apr;64(4): Louka AS, Moodie SJ, Karell K, Bolognesi E, Ascher H, Greco L, Momigliano-Richiardi P, Partanen J, Ciclitira PJ, Sollid LM; European Genetics Cluster on Celiac Disease A collaborative European search for non-dqal*05-dqbl*02 Celiac Disease loci on HLA- DR3 haplotypes: analysis of transmission from homozygous parents. Hum Immunol Mar;64 (3): Associazione Italiana Celiachia tel fax Genova, Via Caffaro, 68 A rosso segreteria@celiachia.it 15

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