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Elwenspoek MM, Thom H, Sheppard AL, Keeney E, O'Donnell R, Jackson J, Roadevin C, Dawson S, Lane D, Stubbs J, Everitt H, Watson JC, Hay AD, Gillett P, Robins G, Jones HE, Mallett S, Whiting PF. Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling. Health Technol Assess 2022; 26:1-310. [PMID: 36321689 PMCID: PMC9638887 DOI: 10.3310/zuce8371] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Coeliac disease is an autoimmune disorder triggered by ingesting gluten. It affects approximately 1% of the UK population, but only one in three people is thought to have a diagnosis. Untreated coeliac disease may lead to malnutrition, anaemia, osteoporosis and lymphoma. OBJECTIVES The objectives were to define at-risk groups and determine the cost-effectiveness of active case-finding strategies in primary care. DESIGN (1) Systematic review of the accuracy of potential diagnostic indicators for coeliac disease. (2) Routine data analysis to develop prediction models for identification of people who may benefit from testing for coeliac disease. (3) Systematic review of the accuracy of diagnostic tests for coeliac disease. (4) Systematic review of the accuracy of genetic tests for coeliac disease (literature search conducted in April 2021). (5) Online survey to identify diagnostic thresholds for testing, starting treatment and referral for biopsy. (6) Economic modelling to identify the cost-effectiveness of different active case-finding strategies, informed by the findings from previous objectives. DATA SOURCES For the first systematic review, the following databases were searched from 1997 to April 2021: MEDLINE® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), Cochrane Library, Web of Science™ (Clarivate™, Philadelphia, PA, USA), the World Health Organization International Clinical Trials Registry Platform ( WHO ICTRP ) and the National Institutes of Health Clinical Trials database. For the second systematic review, the following databases were searched from January 1990 to August 2020: MEDLINE, Embase, Cochrane Library, Web of Science, Kleijnen Systematic Reviews ( KSR ) Evidence, WHO ICTRP and the National Institutes of Health Clinical Trials database. For prediction model development, Clinical Practice Research Datalink GOLD, Clinical Practice Research Datalink Aurum and a subcohort of the Avon Longitudinal Study of Parents and Children were used; for estimates for the economic models, Clinical Practice Research Datalink Aurum was used. REVIEW METHODS For review 1, cohort and case-control studies reporting on a diagnostic indicator in a population with and a population without coeliac disease were eligible. For review 2, diagnostic cohort studies including patients presenting with coeliac disease symptoms who were tested with serological tests for coeliac disease and underwent a duodenal biopsy as reference standard were eligible. In both reviews, risk of bias was assessed using the quality assessment of diagnostic accuracy studies 2 tool. Bivariate random-effects meta-analyses were fitted, in which binomial likelihoods for the numbers of true positives and true negatives were assumed. RESULTS People with dermatitis herpetiformis, a family history of coeliac disease, migraine, anaemia, type 1 diabetes, osteoporosis or chronic liver disease are 1.5-2 times more likely than the general population to have coeliac disease; individual gastrointestinal symptoms were not useful for identifying coeliac disease. For children, women and men, prediction models included 24, 24 and 21 indicators of coeliac disease, respectively. The models showed good discrimination between patients with and patients without coeliac disease, but performed less well when externally validated. Serological tests were found to have good diagnostic accuracy for coeliac disease. Immunoglobulin A tissue transglutaminase had the highest sensitivity and endomysial antibody the highest specificity. There was little improvement when tests were used in combination. Survey respondents (n = 472) wanted to be 66% certain of the diagnosis from a blood test before starting a gluten-free diet if symptomatic, and 90% certain if asymptomatic. Cost-effectiveness analyses found that, among adults, and using serological testing alone, immunoglobulin A tissue transglutaminase was most cost-effective at a 1% pre-test probability (equivalent to population screening). Strategies using immunoglobulin A endomysial antibody plus human leucocyte antigen or human leucocyte antigen plus immunoglobulin A tissue transglutaminase with any pre-test probability had similar cost-effectiveness results, which were also similar to the cost-effectiveness results of immunoglobulin A tissue transglutaminase at a 1% pre-test probability. The most practical alternative for implementation within the NHS is likely to be a combination of human leucocyte antigen and immunoglobulin A tissue transglutaminase testing among those with a pre-test probability above 1.5%. Among children, the most cost-effective strategy was a 10% pre-test probability with human leucocyte antigen plus immunoglobulin A tissue transglutaminase, but there was uncertainty around the most cost-effective pre-test probability. There was substantial uncertainty in economic model results, which means that there would be great value in conducting further research. LIMITATIONS The interpretation of meta-analyses was limited by the substantial heterogeneity between the included studies, and most included studies were judged to be at high risk of bias. The main limitations of the prediction models were that we were restricted to diagnostic indicators that were recorded by general practitioners and that, because coeliac disease is underdiagnosed, it is also under-reported in health-care data. The cost-effectiveness model is a simplification of coeliac disease and modelled an average cohort rather than individuals. Evidence was weak on the probability of routine coeliac disease diagnosis, the accuracy of serological and genetic tests and the utility of a gluten-free diet. CONCLUSIONS Population screening with immunoglobulin A tissue transglutaminase (1% pre-test probability) and of immunoglobulin A endomysial antibody followed by human leucocyte antigen testing or human leucocyte antigen testing followed by immunoglobulin A tissue transglutaminase with any pre-test probability appear to have similar cost-effectiveness results. As decisions to implement population screening cannot be made based on our economic analysis alone, and given the practical challenges of identifying patients with higher pre-test probabilities, we recommend that human leucocyte antigen combined with immunoglobulin A tissue transglutaminase testing should be considered for adults with at least a 1.5% pre-test probability of coeliac disease, equivalent to having at least one predictor. A more targeted strategy of 10% pre-test probability is recommended for children (e.g. children with anaemia). FUTURE WORK Future work should consider whether or not population-based screening for coeliac disease could meet the UK National Screening Committee criteria and whether or not it necessitates a long-term randomised controlled trial of screening strategies. Large prospective cohort studies in which all participants receive accurate tests for coeliac disease are needed. STUDY REGISTRATION This study is registered as PROSPERO CRD42019115506 and CRD42020170766. FUNDING This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 44. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Martha Mc Elwenspoek
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Howard Thom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Athena L Sheppard
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Edna Keeney
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Rachel O'Donnell
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Joni Jackson
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Cristina Roadevin
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sarah Dawson
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | - Hazel Everitt
- Primary Care Research Centre, Population Sciences and Medical Education, University of Southampton, Southampton, UK
| | - Jessica C Watson
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Alastair D Hay
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Peter Gillett
- Paediatric Gastroenterology, Hepatology and Nutrition Department, Royal Hospital for Sick Children, Edinburgh, UK
| | - Gerry Robins
- Department of Gastroenterology, York Teaching Hospital NHS Foundation Trust, York, UK
| | - Hayley E Jones
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sue Mallett
- Centre for Medical Imaging, University College London, London, UK
| | - Penny F Whiting
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Sahin Y, Mermer S. Frequency of celiac disease and distribution of HLA-DQ2/DQ8 haplotypes among siblings of children with celiac disease. World J Clin Pediatr 2022; 11:351-359. [PMID: 36052110 PMCID: PMC9331400 DOI: 10.5409/wjcp.v11.i4.351] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/18/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Celiac disease (CD) is a multifactorial disease, but genetic factors play a major role in its etiology. It has been known that human leucocyte antigen (HLA)-DQ2/DQ8 haplotypes are one of the most important predisposing genetic factors. The risk of developing CD in first-degree relatives and especially siblings of celiac patients is quite high because of having the same HLA haplotypes. AIM To evaluate the frequency of CD and the distribution of the HLA-DQ2/DQ8 haplotypes in siblings of celiac patients. METHODS Patients with biopsy-proven CD and their siblings were included in the study; those who did not have HLA genotyping were excluded from the study. All siblings were on a gluten-containing diet. The HLA genotyping, tissue transglutaminase antibody IgA antibody test, and total IgA test were performed in all participants. RESULTS A total of 57 celiac patients and their 112 siblings were included in the study. The mean age of celiac patients and siblings were 10.30 ± 3.87 years and 9.90 ± 6.11 years, respectively. HLA-DQ2/DQ8 alleles were detected in 98.2% of patients with CD and 90.2% of siblings of celiac patients. HLA-DQ genotypes were present in all siblings diagnosed with CD. Tissue transglutaminase antibody IgA test was found to be positive in 16 siblings. CD was diagnosed in 12 siblings (10.7%) by intestinal biopsy. CONCLUSION The prevalence of CD was found to be 10.7% in siblings of celiac patients in our study. One-third of the siblings diagnosed with CD were asymptomatic. We detected HLA-DQ alleles in 98.2% of celiac patients and 100% in siblings diagnosed with CD. In addition, 1 of the 2 siblings was diagnosed with CD 1 year later and the other 4 years later. Therefore, we suggest that siblings of celiac patients should be followed up with clinical findings as well as HLA analysis and serological examination. Since the risk of developing CD is much higher in asymptomatic siblings, we recommend that siblings should be screened for CD even if they are asymptomatic.
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Affiliation(s)
- Yasin Sahin
- Department of Pediatric Gastroenterology, Mersin Training and Research Hospital, Mersin 33240, Mersin, Turkey
| | - Serdar Mermer
- Department of Medical Genetics, Mersin Training and Research Hospital, Mersin 33240, Mersin, Turkey
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Fallah H, Akbari MT, Mirzajani S, Ranjbaran F, Mehdizadeh B, Sayad A, Taheri M. Association between HLA alleles and risk of celiac disease in Iranian patients. Hum Antibodies 2020; 28:123-129. [PMID: 31658053 DOI: 10.3233/hab-190398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Celiac disease (CD) is a common autoimmune disease that is manifested by inflammation of the small intestine and varying extra intestinal symptoms, also considered to be associated with human HLA-DQ genes. In this study, 40 patients of CD and 40 healthy control samples were genotyped for HLA-DQB1 and 14 patients of CD and 14 healthy control samples were genotyped for HLA-DQA1genes using the SSP-PCR technique and a commercial kit.The DQA1*05 allele had the highest frequency among the patient group (42.86%). The frequency of this allele was 28.57% in healthy controls, and there was no statistically significant difference in this case (p= 0.771).The DQB1*02 allele was the most common in patients (33.75%) followed by the DQB1*03 allele (31.25%).The difference in frequency of the HLA-DQB1*02 allele in the patient and control groups was statistically significant (P= 0.0002, OR = 4.72). The remarkable differences in the distribution of HLA-DQ2 in Iranian patients compared to controls and relative risks signified the role of these alleles in the development of CD in Iranian patients and confirmed the likelihood of using HLA-DQ typing in the substantiation of the disease.
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Affiliation(s)
- Hamid Fallah
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Akbari
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Mirzajani
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Bijan Mehdizadeh
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Sayad
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Mearns ES, Taylor A, Boulanger T, Craig KJ, Gerber M, Leffler DA, Drahos J, Sanders DS, Lebwohl B. Systematic Literature Review of the Economic Burden of Celiac Disease. PHARMACOECONOMICS 2019; 37:45-61. [PMID: 30221333 DOI: 10.1007/s40273-018-0707-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND The prevalence of celiac disease (CD) has rapidly increased over recent decades, but costs related to CD remain poorly quantified. OBJECTIVE This systematic review assessed the economic burden of CD in North America and Europe. METHODS MEDLINE, EMBASE, EconLit, and the Cochrane Library databases were systematically searched to identify English-language literature from 2007 to 2018 that assessed costs, cost effectiveness, and health resource utilization for CD. RESULTS Forty-nine studies met the inclusion criteria, of which 28 (57.1%) addressed costs of testing and diagnosis; 33 (67.3%) were from Europe. The cost per positive CD diagnosis of testing patients already undergoing esophagogastroduodenoscopy for other indications ranged from 1300 Canadian dollars ($Can) in Canada (2016 value) to €44,712 in the Netherlands (2013 value). Adding the CD test was cost effective when it combined diagnostic modalities (e.g., serology and biopsy). Direct annual excess costs to a US payer per diagnosed CD patient totaled $US6000 (2013 value) more than for a person without CD, chiefly due to outpatient care. Hospitalizations, emergency visits, and medication use were more common with CD. After initiating a gluten-free diet (GFD), patients visited primary care providers less often, used more medications, and missed fewer days from school and work. CONCLUSIONS Most of the few available economic studies of CD assess testing and diagnosis costs, especially in Europe. Methods of testing generally are considered cost effective when they combine diagnostic modalities in symptomatic patients. Most costs to a payer of managing CD derive from outpatient care. Following GFD initiation, patients lose fewer days from work and school than pretreatment.
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Affiliation(s)
| | | | | | - Kelly J Craig
- Truven Health Analytics, An IBM Company, Cambridge, MA, USA
| | - Michele Gerber
- Takeda Pharmaceuticals International Co, Cambridge, MA, USA
| | | | | | - David S Sanders
- Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK
| | - Benjamin Lebwohl
- Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA
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Erlichster M, Tye-Din JA, Varney MD, Skafidas E, Kwan P. Rapid, Loop-Mediated Isothermal Amplification Detection of Celiac Disease Risk Alleles. J Mol Diagn 2018; 20:307-315. [PMID: 29458095 DOI: 10.1016/j.jmoldx.2018.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/20/2017] [Accepted: 01/19/2018] [Indexed: 02/07/2023] Open
Abstract
Human leukocyte antigen (HLA) genotyping has become a useful investigation in the diagnostic work-up of celiac disease (CD), with utility in risk stratification and screening. However, broad application of this technology has been hindered by the cost and time burden of conventional laboratory-based assays. We have developed and validated CD-loop-mediated isothermal amplification (CD-LAMP), a LAMP assay, which enables rapid identification of the signature CD risk genotypes, HLA-DQ2.5, HLA-DQ8, HLA-DQ2.2, and HLA-DQA1*05. Sample-to-answer is achieved in approximately 65 minutes without DNA purification, thermal cycling, or specialized analytical equipment. CD-LAMP genotyping of samples was 100% concordant with accredited pathology genotyping on a panel of 40 blood and 20 saliva samples. In a panel of 100 purified DNA samples, genotyping of the high-risk DQ2.5 genotype was 100% concordant with accredited pathology genotyping, with slightly reduced sensitivity for the DQ8 genotype (97.1%) and reduced specificity for the DQ8 (93.9%) and DQ2.2 (95.1%) genotypes. CD-LAMP results are easily visualized and instrument free through the addition of a DNA intercalating dye after amplification. Combined with point-of-care antibody testing, CD-LAMP may enable immediate, confident CD diagnosis at a low cost in the clinical setting.
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Affiliation(s)
- Michael Erlichster
- Centre for Neural Engineering, University of Melbourne, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Michael D Varney
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Victoria, Australia
| | - Efstratios Skafidas
- Centre for Neural Engineering, University of Melbourne, Melbourne, Victoria, Australia; Department of Electrical and Electronic Engineering, University of Melbourne, Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
| | - Patrick Kwan
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Department of Electrical and Electronic Engineering, University of Melbourne, Melbourne, Victoria, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
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Zhou Z, Reyes-Vargas E, Escobar H, Chang KY, Barker AP, Rockwood AL, Delgado JC, He X, Jensen PE. Peptidomic analysis of type 1 diabetes associated HLA-DQ molecules and the impact of HLA-DM on peptide repertoire editing. Eur J Immunol 2016; 47:314-326. [PMID: 27861808 DOI: 10.1002/eji.201646656] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 10/21/2016] [Accepted: 11/10/2016] [Indexed: 11/08/2022]
Abstract
HLA-DM and class II associated invariant chain (Ii) are key cofactors in the MHC class II (MHCII) antigen processing pathway. We used tandem mass spectrometry sequencing to directly interrogate the global impact of DM and Ii on the repertoire of MHCII-bound peptides in human embryonic kidney 293T cells expressing HLA-DQ molecules in the absence or presence of these cofactors. We found that Ii and DM have a major impact on the repertoire of peptides presented by DQ1 and DQ6, with the caveat that this technology is not quantitative. The peptide repertoires of type 1 diabetes (T1D) associated DQ8, DQ2, and DQ8/2 are altered to a lesser degree by DM expression, and these molecules share overlapping features in their peptide binding motifs that are distinct from control DQ1 and DQ6 molecules. Peptides were categorized into DM-resistant, DM-dependent, or DM-sensitive groups based on the mass spectrometry data, and representative peptides were tested in competitive binding assays and peptide dissociation rate experiments with soluble DQ6. Our data support the conclusion that high intrinsic stability of DQ-peptide complexes is necessary but not sufficient to confer resistance to DM editing, and provide candidate parameters that may be useful in predicting the sensitivity of T-cell epitopes to DM editing.
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Affiliation(s)
- Zemin Zhou
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | | | | | - Kuan Y Chang
- Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung, Taiwan
| | - Adam P Barker
- Department of Pathology, University of Utah, Salt Lake City, UT, USA.,ARUP Laboratories, University of Utah, Salt Lake City, UT, USA
| | - Alan L Rockwood
- Department of Pathology, University of Utah, Salt Lake City, UT, USA.,ARUP Laboratories, University of Utah, Salt Lake City, UT, USA
| | - Julio C Delgado
- Department of Pathology, University of Utah, Salt Lake City, UT, USA.,ARUP Laboratories, University of Utah, Salt Lake City, UT, USA
| | - Xiao He
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Peter E Jensen
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
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Aguayo-Patrón S, Beltrán-Sauceda L, Calderón de la Barca AM. A population-wide applicable HLA-DQ2 and DQ8 genotyping using DNA from dried blood spots and duplex allele-specific qPCR amplification. Scandinavian Journal of Clinical and Laboratory Investigation 2016; 76:581-587. [PMID: 27670799 DOI: 10.1080/00365513.2016.1230773] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Genotyping of HLA-DQ2 and DQ8 haplotypes is important for diagnosis or for screening of early risk detection of celiac disease or type 1 diabetes. Usually, venous blood DNA extraction and expensive and time consuming amplification are used, that hinder population-wide studies. We assayed a friendly HLA-DQ2 and DQ8 genotyping procedure using a combination of DNA from dried blood spot (DBS) and duplex allele-specific qPCR amplification using SYBR Green. DNA was extracted using home-made buffers and compared to an extraction commercial kit. Duplex reactions by qPCR were designed using each Tm allele amplicon for reference samples (positive HLA-DQ2 or DQ8) with allele-specific primers. DBS samples from 558 children (7.99 ± 2.47 y) were collected. The DNA final yield obtained by the home-made extractive procedure was higher than from the commercial kit (1.11 ± 0.56 vs 0.23 ± 0.14 μg), while the quality was similar for both DNA samples. There was concordance in the amplification profiles for DNA samples obtained with both methods. All of four alleles from DQ2 and DQ8 haplotypes were accurately identified in duplex reactions. By using DBS samples and DNA extraction home-made procedure, the costs were reduced by 60%. The whole procedure is cost-effective for HLA-DQ2 and DQ8 genotyping.
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Affiliation(s)
- Sandra Aguayo-Patrón
- a Coordinación de Nutrición , Centro de Investigación en Alimentación y Desarrollo , Hermosillo , Sonora , México
| | - Lizbeth Beltrán-Sauceda
- a Coordinación de Nutrición , Centro de Investigación en Alimentación y Desarrollo , Hermosillo , Sonora , México
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Tye-Din JA, Cameron DJS, Daveson AJ, Day AS, Dellsperger P, Hogan C, Newnham ED, Shepherd SJ, Steele RH, Wienholt L, Varney MD. Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective. Intern Med J 2015; 45:441-450. [PMID: 25827511 PMCID: PMC4405087 DOI: 10.1111/imj.12716] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/08/2015] [Indexed: 12/25/2022]
Abstract
The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results.
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Affiliation(s)
- J A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical ResearchMelbourne, Victoria, Australia
- Departments of Medical Biology, The University of MelbourneMelbourne, Victoria, Australia
- Department of Gastroenterology, The Royal Melbourne HospitalMelbourne, Victoria, Australia
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
| | - D J S Cameron
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Gastroenterology, Monash Children's Hospital, The Royal Children's HospitalMelbourne, Victoria, Australia
- Department of Paediatrics, Monash UniversityMelbourne, Victoria, Australia
| | - A J Daveson
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Gastroenterology, Queen Elizabeth II Jubilee Hospital, Brisbane and School of Medicine, University of QueenslandBrisbane, Australia
| | - A S Day
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Paediatrics Department, University of OtagoChristchurch, New Zealand
| | - P Dellsperger
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Coeliac New South WalesNew South Wales, Australia
| | - C Hogan
- General Practice, The University of MelbourneMelbourne, Victoria, Australia
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
| | - E D Newnham
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Eastern Health Clinical School, Monash UniversityMelbourne, Victoria, Australia
- Department of Gastroenterology, Box Hill HospitalMelbourne, Victoria, Australia
| | - S J Shepherd
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Dietetics and Human Nutrition, La Trobe UniversityMelbourne, Victoria, Australia
| | - R H Steele
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Immunology, Wellington HospitalWellington, New Zealand
| | - L Wienholt
- Medical Advisory Committee, Coeliac AustraliaMelbourne, Victoria, Australia
- Department of Clinical Immunology, Royal Prince Alfred HospitalSydney, Australia
| | - M D Varney
- Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood ServiceMelbourne, Victoria, Australia
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Barakauskas VE, Lam GY, Estey MP. Digesting all the options: Laboratory testing for celiac disease. Crit Rev Clin Lab Sci 2014; 51:358-78. [PMID: 25244521 DOI: 10.3109/10408363.2014.958813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA. Clinical utility of celiac disease-associated HLA testing. Dig Dis Sci 2014; 59:2199-2206. [PMID: 24705698 PMCID: PMC4149591 DOI: 10.1007/s10620-014-3143-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 03/26/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Negative predictive value (NPV) of celiac disease (CD)-related human leukocyte antigens (HLA) DQ2 and DQ8 approaches 100 % in individual patients. However, studies evaluating its exclusionary utility in patient groups are lacking. AIM We aim to assess the performance of HLA testing when applied to patient groups with varying characteristics and propose evidence-based recommendations for its clinical use. METHODS Demographic and clinical information was recorded in patients undergoing HLA testing. Using predetermined criteria, patients were classified as CD, non-CD, or indeterminate. Diagnostic yield of HLA testing was defined as the percentage of patients in whom CD could be excluded based on negative HLA test. RESULTS Two hundred and fifty-six patients underwent testing for CD-related HLA DQ2 and DQ8. 102 (100 non-CD, 2 CD) patients tested HLA negative for a 98 % NPV and 39 % diagnostic yield. Diagnostic yield was highest (60 %) in patients with intraepithelial lymphocytosis plus normal IgA tissue transglutaminase antibody (IgA-tTG) and lowest in patients with positive IgA-tTG plus villous atrophy (0 %). CD was diagnosed in two HLA-negative patients, who carried half of DQ2.5 trans genotype. CONCLUSIONS Diagnostic yield of CD-related HLA testing varies widely depending on clinical indication. HLA testing is a practical and valuable test for most patients in whom initial evaluation for CD is inconclusive. A negative HLA result usually obviates the need for further celiac testing including endoscopy and gluten challenge. Rarely, in patients reported as HLA negative, half of HLA DQ2.5 (cis or trans) is sufficient for development of CD.
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Affiliation(s)
- Kumar Pallav
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Toufic Kabbani
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Sohaib Tariq
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Rohini Vanga
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Ciaran P. Kelly
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Daniel A. Leffler
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
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Schyum AC, Rumessen JJ. Serological testing for celiac disease in adults. United European Gastroenterol J 2014; 1:319-25. [PMID: 24917978 DOI: 10.1177/2050640613502788] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 08/02/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIM We present a systematic review on the performance of currently available methods for serological diagnosis of celiac disease (CD) and the role of human leukocyte antigen (HLA) typing. OBJECTIVE A literature survey was conducted using PubMed, MeSH database, Web of Science as well as manual searches. RESULTS Tissue transglutaminase antibodies (tTG) (IgA) (tested in nine studies) show sensitivities and specificities in the range of 0.76-0.968 and 0.909-0.98, and deamidated gliadin peptide (DGP) (IgA and IgG) (tested in eight studies) show sensitivities and specificities in the range of 0.69-0.984 and 0.903-1. Endomysial antibodies (EMA) (tested in five studies) show sensitivities and specificities in the range of 0.61-0.937 and 0.98-1, respectively. Combination assays (tested in three studies) using DGP + tTG and DGP (IgA + IgG) show sensitivities and specificities in the range of 0.87-1 and 0.8-1, respectively. HLA DQ2/DQ8 may be necessary for the development of CD-HLA DQ2 in particular. A possible close correlation may also exist between CD and HLA-G. CONCLUSION DGP and tTG for serological testing for CD show equivalent diagnostic performance. More studies with, in particular, DGP alone and in combination with tTG are necessary before a firm recommendation can be made. HLA typing to exclude CD may still be controversial. It still seems premature to diagnose celiac disease in adults based on serology alone.
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Affiliation(s)
- Astrid Collatz Schyum
- Gentofte Hospital HR-Research Unit and Department of Gastroenterology F, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jüri Johannes Rumessen
- Gentofte Hospital HR-Research Unit and Department of Gastroenterology F, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
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Abstract
BACKGROUND Serological markers of coeliac disease (CD) lack diagnostic value to identify mild histopathological lesions mainly in adults at risk of CD. AIMS The aim of this study was to evaluate the usefulness of human leukocyte antigen (HLA)-DQ2/8 genotyping, followed by duodenal biopsy for the detection of CD in adult first-degree relatives (FDRs) of patients with CD. MATERIALS AND METHODS Ninety-two adult DQ2/8 positive FDRs were consecutively included. A duodenal biopsy was offered irrespective of the serology result or associated symptoms. The clinical features, associated autoimmune diseases and biochemical parameters were recorded. RESULTS Sixty-seven FDRs (mean age 34 years) underwent a duodenal biopsy. Histopathological alterations were found in 32 (48%) and showed the following stages: 12 Marsh I (18%), one Marsh II (1.5%), four Marsh IIIA (6%), five Marsh IIIB (7.5%) and 10 Marsh IIIC (15%). Positive serological markers were present in 17/67 (25%), with only one showing Marsh I and the remainder presenting some degree of duodenal atrophy (Marsh III). In addition, 33/67 (54%) had gastrointestinal symptoms, with dyspepsia being the most prevalent. The distribution of symptoms, anaemia and autoimmune disease was independent of the duodenal histopathological stage. Serology-based screening would diagnose 50% of the cases showing any degree of CD spectrum and miss 6% of the cases with mucosal atrophy. CONCLUSION Adult FDRs of patients with CD can benefit from a screening strategy on the basis of HLA-DQ genotyping, followed by a duodenal biopsy. Gastrointestinal symptoms and lymphocytic enteritis are common findings that may benefit from a gluten-free diet.
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Uenishi RH, Gandolfi L, Almeida LM, Fritsch PM, Almeida FC, Nóbrega YKM, Pratesi R. Screening for celiac disease in 1st degree relatives: a 10-year follow-up study. BMC Gastroenterol 2014; 14:36. [PMID: 24552206 PMCID: PMC3941942 DOI: 10.1186/1471-230x-14-36] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Background Although it is known that first degree relatives of celiac patients have an increased risk for celiac disease few studies are available on its incidence. We investigated the incidence of serologic conversion and of new cases of celiac disease among first degree relatives with negative results at a first screening. Methods From a total of 634 first degree relatives of 186 biopsy-proven celiac disease patients diagnosed between October 2000 and October 2010, 450 subjects agreed to participate in the study (Group I), and underwent serologic screening. Between January 2010 and October 2012, out of the initial group of 450, 205 previously sero-negative subjects consented to participate in a second stage of the study and undergo new serologic testing (Group II). All serologically positive individuals of both groups (I and II) were genotyped for celiac disease-predisposing alleles (HLA-DQ2/DQ8). Results 19 subjects (4.2%) out of the 450 subjects of Group I disclosed positive serologic results, presence of DQ2 and/or DQ8 alleles and celiac disease-compatible mucosal abnormalities. The 205 previously negative first degree relatives from Group II that underwent new serologic testing disclosed eight sero-converted subjects. Mucosal abnormalities in five of these patients confirmed the diagnosis of celiac disease. During the 10-year period of the study the incidence of sero-conversion was 8/205 and the incidence of biopsy-proven celiac disease cases was 5/205. Conclusions Our data are coincident with other works on this subject and confirm once again that relatives of celiac patients, especially first degree relatives are at high risk of developing celiac disease. In view of the relatively low incidence further studies are needed to try to establish a useful and cost-effective algorithm for follow-up of relatives of celiac patients.
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Affiliation(s)
| | | | | | | | | | | | - Riccardo Pratesi
- Graduate Program in Health Sciences, University of Brasilia School of Health Sciences, Brasilia, DF, Brazil.
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McCarthy JJ, McLeod HL, Ginsburg GS. Genomic medicine: a decade of successes, challenges, and opportunities. Sci Transl Med 2014; 5:189sr4. [PMID: 23761042 DOI: 10.1126/scitranslmed.3005785] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Genomic medicine--an aspirational term 10 years ago--is gaining momentum across the entire clinical continuum from risk assessment in healthy individuals to genome-guided treatment in patients with complex diseases. We review the latest achievements in genome research and their impact on medicine, primarily in the past decade. In most cases, genomic medicine tools remain in the realm of research, but some tools are crossing over into clinical application, where they have the potential to markedly alter the clinical care of patients. In this State of the Art Review, we highlight notable examples including the use of next-generation sequencing in cancer pharmacogenomics, in the diagnosis of rare disorders, and in the tracking of infectious disease outbreaks. We also discuss progress in dissecting the molecular basis of common diseases, the role of the host microbiome, the identification of drug response biomarkers, and the repurposing of drugs. The significant challenges of implementing genomic medicine are examined, along with the innovative solutions being sought. These challenges include the difficulty in establishing clinical validity and utility of tests, how to increase awareness and promote their uptake by clinicians, a changing regulatory and coverage landscape, the need for education, and addressing the ethical aspects of genomics for patients and society. Finally, we consider the future of genomics in medicine and offer a glimpse of the forces shaping genomic medicine, such as fundamental shifts in how we define disease, how medicine is delivered to patients, and how consumers are managing their own health and affecting change.
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Affiliation(s)
- Jeanette J McCarthy
- Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA
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Martins RDCA, Gandolfi L, Modelli IC, Almeida RCD, Castro LC, Pratesi R. Serologic screening and genetic testing among brazilian patients with celiac disease and their first degree relatives. ARQUIVOS DE GASTROENTEROLOGIA 2011; 47:257-62. [PMID: 21140086 DOI: 10.1590/s0004-28032010000300009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Accepted: 01/07/2010] [Indexed: 12/12/2022]
Abstract
CONTEXT Celiac disease susceptibility has been shown to be associated with the HLA alleles DQA1*0501 and DQB1*0201 (together encoding the DQ2 heterodimer) that are present in practically all celiac disease patients. The DQ8 heterodimer (coded by DQA1*03-DQB1*0302), which is carried on a DRB1*04 (DR4) haplotype, is commonly encoded for by the few celiacs who do not carry the DQ2 heterodimer. Only a few celiac disease patients have been reported without these known risk alleles. OBJECTIVE To assess the prevalence of celiac disease in a group of first degree relatives of celiac patients, and the frequency of HLA predisposing alleles both in the group of celiac patients and in their first degree relatives, identifying those first degree relatives who would need further screening for celiac disease. METHODS Ninety celiac disease patients and 207 first degree relatives underwent serologic screening for celiac disease (endomysial and transglutaminase antibodies) followed by intestinal biopsy in positive patients. The HLA-DQA1*0501, DQB1*0201 and DRB1*04 frequencies of celiac patients and their first degree relatives were determined utilizing the PCR method. RESULTS All the celiac disease patients (n = 90) with the exception of one (1.1%) carried at least one of the alleles investigated. Altogether 11 (5.3%) of the investigated first degree relatives did not carry any of the alleles studied. Fourteen (6.7%) new cases of celiac disease were found among the 207 celiac disease patients first degree relatives. CONCLUSIONS Considering the cost-benefit of the HLA typing of all the first degree relatives of celiac patients, their HLA status should be decided on an individual basis, taking account of their profile and preferences, and the existence of other medical conditions.
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Abstract
The advent of highly sensitive and specific serological markers has led to some protagonists proposing that coeliac disease can be diagnosed without the need for a biopsy. However, this is an area of controversy. Lack of consensus about diagnostic degrees of histological change, paucity of symptoms, antibody-negative disease and immunodeficiency can make diagnosis difficult even with a biopsy. Conversely, an argument can be put forward for a 'no biopsy' approach based on the large number of patients with typical symptoms and positive serology who experience a diagnostic delay. In addition, endoscopy is not without discomfort. This article discusses the use of antibodies and duodenal biopsy within this context. Finally, we propose a pragmatic diagnostic algorithm for clinicians to use when investigating patients for coeliac disease.
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Affiliation(s)
- K E Evans
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.
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Castro-Antunes MM, Crovella S, Brandão LAC, Guimaraes RL, Motta MEFA, Silva GAPD. Frequency distribution of HLA DQ2 and DQ8 in celiac patients and first-degree relatives in Recife, northeastern Brazil. Clinics (Sao Paulo) 2011; 66:227-31. [PMID: 21484038 PMCID: PMC3059855 DOI: 10.1590/s1807-59322011000200008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Accepted: 11/03/2010] [Indexed: 02/06/2023] Open
Abstract
AIMS The aim of this study was to evaluate the frequencies of the HLA genotypes DQ2 and DQ8 and the alleles A1*05, A1*0201, B1*0201 and B1*0302 in individuals with celiac disease in Recife, northeastern Brazil. METHODS HLA DQ2 and DQ8 genotyping was performed for 73 individuals with celiac disease and 126 first-degree relatives with negative transglutaminase serology. The alleles DQA1*05, DQA1*0201, DQB1*02 and DQB1*0302 were identified by sequencing using specific primers and the EU-DQ kit from the Eurospital Laboratory, Trieste, Italy and double-checked by the All Set SPP kit (Dynal). RESULTS Among the 73 cases, 50 (68.5%) had the genotype DQ2, 13 (17.8%) had DQ8, 5 (6.8%) had DQ2 and DQ8, and 5 did not have any of these genotypes. Among the 5 negative individuals, four had the B1*02 allele and one did not have any of the alleles studied. B1*02 was the most frequent allele in both groups (94% in the patients and 89% in the control relatives). CONCLUSIONS In this study, celiac disease was associated with the genotypes DQ2 and DQ8. DQ2 predominated, but the distribution of the frequencies was different from what has been found in European populations and was closer to what has been found in the Americas. The high frequencies of the HLA genotypes DQ2 and DQ8 that were found in first-degree relatives would make it difficult to use these HLA genotypes for routine diagnosis of celiac disease in this group.
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Affiliation(s)
- Margarida Maria Castro-Antunes
- Department of Postgraduate Studies on Children and Adolescents' Health, Health Sciences Center, Federal University of Pernambuco.
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Tack GJ, Verbeek WHM, Schreurs MWJ, Mulder CJJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol 2010; 7:204-13. [PMID: 20212505 DOI: 10.1038/nrgastro.2010.23] [Citation(s) in RCA: 175] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Celiac disease is a gluten-sensitive enteropathy that affects people of all ages worldwide. This disease has emerged as a major health-care problem, as advances in diagnostic and screening methods have revealed its global prevalence. Environmental factors such as gluten introduction at childhood, infectious agents and socioeconomic features, as well as the presence of HLA-DQ2 and/or HLA-DQ8 haplotypes or genetic variations in several non-HLA genes contribute to the development of celiac disease. Growing insight into the variable clinical and histopathological presentation features of this disease has opened new perspectives for future research. A strict life-long gluten-free diet is the only safe and efficient available treatment, yet it results in a social burden. Alternative treatment modalities focus on modification of dietary components, enzymatic degradation of gluten, inhibition of intestinal permeability and modulation of the immune response. A small group of patients with celiac disease (2-5%), however, fail to improve clinically and histologically upon elimination of dietary gluten. This complication is referred to as refractory celiac disease, and imposes a serious risk of developing a virtually lethal enteropathy-associated T-cell lymphoma.
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Affiliation(s)
- Greetje J Tack
- Department of Gastroenterology and Hepatology, VU University Medical Center, P. O. Box 7057, 1007 MB Amsterdam, The Netherlands.
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First-degree relatives of celiac patients: are they at an increased risk of developing celiac disease? J Clin Gastroenterol 2009; 43:3-4. [PMID: 19020460 DOI: 10.1097/mcg.0b013e31818ca609] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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