|
1
|
Sange I, Mohamed MWF, Aung S, Mereddy N, Hamid P. Celiac Disease and the Autoimmune Web of Endocrinopathies. Cureus 2020; 12:e12383. [PMID: 33527061 PMCID: PMC7842251 DOI: 10.7759/cureus.12383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Gluten-sensitive enteropathy or Celiac disease (CD) is a disease that has become very prevalent in most parts of the globe especially in the western world. Resulting from a chaotic interplay between the backgrounds of autoimmunity and genetics, this disorder targets primarily the gastrointestinal tract with ominous extraintestinal counterparts that have a very discrete presentation. Among those counterparts, the one that has been reviewed in this article is the involvement of the endocrine system as concurrence of hormonal disorders with CD possesses numerous challenges that lead to a refractory treatment and a dull prognosis. This review article aims to feature the effect of the CD and endocrine disorders on one another, especially if either of the diseases is asymptomatic, explore the clinical dilemma faced by clinicians in various specialties, and, hence, further pave a path into the importance of rigorous screening and diagnosis.
Collapse
Affiliation(s)
- Ibrahim Sange
- Medicine, K. J. Somaiya Medical College and Research Centre, Mumbai, IND
| | | | - Su Aung
- Medicine/Surgery, University of Medicine, Yangon, MMR.,Neurosciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nakul Mereddy
- Neurosciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pousette Hamid
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| |
Collapse
|
|
2
|
Bishop J, Ravikumara M. Coeliac disease in childhood: An overview. J Paediatr Child Health 2020; 56:1685-1693. [PMID: 33197972 DOI: 10.1111/jpc.14674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 10/04/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022]
Abstract
Coeliac disease (CD) is an autoimmune condition, characterised by an immunological response to ingestion of gluten in genetically susceptible individuals, affecting about 1% of the population in many regions of the world. Increased knowledge regarding the pathogenesis, improved diagnostic techniques and increased awareness over the years have transformed our understanding of CD such that it is no longer a rare enteropathy, but rather a common multisystem disorder which affects individuals of all ages and results in wide-ranging clinical manifestations. Only a minority of children now present with the classical clinical picture of profound diarrhoea and malnutrition. An increasing number of children with CD present with either mild, non-specific gastrointestinal symptoms or extra-intestinal manifestations or even be asymptomatic, as in many screening-detected children. Knowledge about these diverse manifestations and a high index of suspicion is essential so that appropriate investigations can be undertaken, diagnosis established and treatment initiated. Although traditionally small bowel biopsy is considered essential for the diagnosis, recent guidelines from various professional bodies have paved the way to a biopsy-free diagnosis in a subset of symptomatic children. Life long, strict gluten-free diet still remains the only effective treatment at present, although several novel therapeutic agents are in various phases of clinical trials.
Collapse
Affiliation(s)
- Jonathan Bishop
- Department of Gastroenterology, Starship Hospital, Auckland, New Zealand
| | - Madhur Ravikumara
- Department of Gastroenterology, Perth Children's Hospital, Perth, Western Australia, Australia
| |
Collapse
|
|
3
|
Popp A, Mäki M. Gluten-Induced Extra-Intestinal Manifestations in Potential Celiac Disease-Celiac Trait. Nutrients 2019; 11:nu11020320. [PMID: 30717318 PMCID: PMC6412544 DOI: 10.3390/nu11020320] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 12/24/2022] Open
Abstract
Celiac disease patients may suffer from a number of extra-intestinal diseases related to long-term gluten ingestion. The diagnosis of celiac disease is based on the presence of a manifest small intestinal mucosal lesion. Individuals with a normal biopsy but an increased risk of developing celiac disease are referred to as potential celiac disease patients. However, these patients are not treated. This review highlights that patients with normal biopsies may suffer from the same extra-intestinal gluten-induced complications before the disease manifests at the intestinal level. We discuss diagnostic markers revealing true potential celiac disease. The evidence-based medical literature shows that these potential patients, who are “excluded” for celiac disease would in fact benefit from gluten-free diets. The question is why wait for an end-stage disease to occur when it can be prevented? We utilize research on dermatitis herpetiformis, which is a model disease in which a gluten-induced entity erupts in the skin irrespective of the state of the small intestinal mucosal morphology. Furthermore, gluten ataxia can be categorized as its own entity. The other extra-intestinal manifestations occurring in celiac disease are also found at the latent disease stage. Consequently, patients with celiac traits should be identified and treated.
Collapse
Affiliation(s)
- Alina Popp
- University of Medicine and Pharmacy "Carol Davila" and National Institute for Mother and Child Health "Alessandrescu-Rusescu", Bucharest 020395, Romania.
- Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33520 Tampere, Finland.
| | - Markku Mäki
- Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33520 Tampere, Finland.
| |
Collapse
|
|
4
|
Shahramian I, Bazi A, Sargazi A. An Overview of Celiac Disease in Childhood Type 1 Diabetes. Int J Endocrinol Metab 2018; 16:e66801. [PMID: 30214462 PMCID: PMC6119207 DOI: 10.5812/ijem.66801] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 06/09/2018] [Accepted: 06/13/2018] [Indexed: 02/08/2023] Open
Abstract
CONTEXT Celiac disease (CD) is a common phenomenon in children with Type 1 diabetes (T1D). In the present review, we have discussed the pathogenesis, diagnostic biomarkers, risk factors, and prognosis of CD in the context of pediatric T1D. EVIDENCE ACQUISITION Literature published in Web of Science, PubMed, Scopus, Google Scholar, and Cochrane Library were scrutinized up to the end of 2017. The keywords of celiac disease, Type 1 diabetes, children, and pediatric were used in different combinations. RESULTS Immune cytotoxic reactions along with dampen immune regulatory functions contribute to CD in the context of pediatric T1D. Many children with simultaneous CD and T1D do not represent with the clinical signs of the enteropathy rendering a diagnostic challenge. The most common screening tests in these children are routine serological tests of CD, anti - endomysial, anti - transglutaminase, and anti - deamidated gliadin peptide antibodies. Typing for human leukocyte antigens of DQ - 2 and DQ - 8 may assist in the diagnosis of silent CD in children with T1D. The most significant shared non - HLA genetic loci of CD and T1D comprise CTLA - 4, TAGAP, IL - 18RAP, PTPN2, RGS1, SH2B3, CCR5. Interactions between these loci can be important in susceptibility to CD in T1D. Some new biomarkers have been suggested for diagnosis of CD including ischemia-modified albumin (IMA), soluble syndecan-1 (SSDC-1), regenerating gene Iα (REG-Iα), Neurotensin, and Zonulin, which can be useful for diagnosis and screening of CD in childhood T1D. CONCLUSIONS Overall, active seropositive CD seems to be of clinical importance in T1D with significant impacts on the quality of life and predisposition to diabetes associated complications. It is important to detect CD in the context of T1D to prevent potential risks contributing to morbidities and mortalities associated with either CD or T1D.
Collapse
Affiliation(s)
- Iraj Shahramian
- Pediatric Ward, Amir - Al - Momenin Hospital, Zabol University of Medical Sciences, Zabol, Iran
| | - Ali Bazi
- Clinical Research Development Unit, Amir - Al - Momenin Hospital, Zabol University of Medical Sciences, Zabol, Iran
| | - Alireza Sargazi
- Student Research Committee, Zabol University of Medical Sciences, Zabol, Iran
| |
Collapse
|
|
5
|
Freeman HJ. Endocrine manifestations in celiac disease. World J Gastroenterol 2016; 22:8472-8479. [PMID: 27784959 PMCID: PMC5064028 DOI: 10.3748/wjg.v22.i38.8472] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/05/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is an autoimmune small intestinal mucosal disorder that often presents with diarrhea, malabsorption and weight loss. Often, one or more associated endocrine disorders may be associated with CD. For this review, methods involved an extensive review of published English-language materials. In children and adolescents, prospective studies have demonstrated a significant relationship to insulin-dependent or type 1 diabetes, whereas in adults, autoimmune forms of thyroid disease, particularly hypothyroidism, may commonly co-exist. In some with CD, multiple glandular endocrinopathies may also occur and complicate the initial presentation of the intestinal disease. In others presenting with an apparent isolated endocrine disorder, serological screening for underlying subclinical CD may prove to be positive, particularly if type 1 diabetes, autoimmune thyroid or other autoimmune endocrine diseases, such as Addison’s disease are first detected. A number of reports have also recorded hypoparathyroidism or hypopituitarism or ovarian failure in CD and these may be improved with a strict gluten-free diet.
Collapse
|
|
6
|
Affiliation(s)
- Hugh J Freeman
- Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
7
|
Simmons K, McFann K, Taki I, Liu E, Klingensmith GJ, Rewers MJ, Frohnert BI. Reduced Bone Mineral Density Is Associated with Celiac Disease Autoimmunity in Children with Type 1 Diabetes. J Pediatr 2016; 169:44-8.e1. [PMID: 26561381 PMCID: PMC4849876 DOI: 10.1016/j.jpeds.2015.10.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 08/24/2015] [Accepted: 10/07/2015] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To evaluate the association between bone mineral density (BMD), glycemic control (hemoglobin A1c [HbA1c]), and celiac autoimmunity in children with type 1 diabetes mellitus (T1D) and in an appropriate control population. STUDY DESIGN BMD was assessed cross-sectionally in 252 children with T1D (123 positive for anti-tissue transglutaminase antibody [tTGA] and 129 matched children who were negative for tTGA). In addition, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR, DQ genotypes (71 positive for tTGA and 70 negative). RESULTS Children with T1D who were positive for tTGA had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for tTGA (-0.45 ± 1.22 vs 0.09 ± 1.10, P = .0003). No differences in growth measures, urine N-telopeptides, 25-hydroxyvitamin D, ferritin, thyroid stimulating hormone, or HbA1c were found. However, both higher HbA1c (β = -1.25 ± 0.85, P = .0016) and tTGA (β = -0.13 ± 0.05, P = .0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive vs negative for tTGA. CONCLUSIONS The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.
Collapse
Affiliation(s)
- Kimber Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA, 80045
| | - Kim McFann
- Colorado School of Public Health, University of Colorado, Aurora, CO, USA, 80045
| | - Iman Taki
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA, 80045
| | - Edwin Liu
- Department of Pediatrics, University of Colorado, Aurora, CO, USA, 80045
| | | | - Marian J. Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA, 80045
| | - Brigitte I. Frohnert
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA, 80045
| |
Collapse
|
|
8
|
Hansson T, Dahlbom I, Tuvemo T, Frisk G. Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. Acta Paediatr 2015; 104:185-91. [PMID: 25283799 DOI: 10.1111/apa.12823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 08/14/2014] [Accepted: 10/01/2014] [Indexed: 12/13/2022]
Abstract
AIM This study measured autoantibodies against tissue transglutaminase (anti-tTG) to detect untreated coeliac disease in children with type 1 diabetes and their siblings. METHODS Anti-tTG was measured in prospectively collected sera from 169 children at the onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. RESULTS Coeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6 months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. CONCLUSION Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease.
Collapse
Affiliation(s)
- Tony Hansson
- Department of Women's and Children's Health; Uppsala University; Uppsala Sweden
- Department of Immunology, Genetics and Pathology; Uppsala University; Uppsala Sweden
| | - Ingrid Dahlbom
- Department of Women's and Children's Health; Uppsala University; Uppsala Sweden
- Therapeutic Immune Design Unit; Department of Clinical Neuroscience; Karolinska Institute; Stockholm Sweden
| | - Torsten Tuvemo
- Department of Women's and Children's Health; Uppsala University; Uppsala Sweden
| | - Gun Frisk
- Department of Immunology, Genetics and Pathology; Uppsala University; Uppsala Sweden
| |
Collapse
|
|
9
|
Gonçalves CBCD, Silva IN, Tanure MG, Bahia M. [Study of prevalence of celiac disease in children with type 1 diabetes mellitus: result of 10 years of follow-up]. ACTA ACUST UNITED AC 2014; 57:375-80. [PMID: 23896804 DOI: 10.1590/s0004-27302013000500007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 01/29/2013] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To estimate the prevalence of celiac disease (CD) in children and adolescents with type 1 diabetes mellitus (T1DM) treated in the Children's Division of Endocrinology, at the Universidade Federal de Minas Gerais Hospital das Clínicas. SUBJECTS AND METHODS Children and adolescents diagnosed with T1DM, aged 0 to 18 year, were included in this study performed from March 1999 to April 2009. All patients were screened for CD at their first visit and, again, annually. The investigation was performed through the measurement of IgA (AGAA) and IgG (AGAG) antigliadin antibodies. Patients with values of AGAA and/or AGAG above two times the cutoff mark undertook intestinal biopsy. RESULTS A group of 21 patients were excluded from the initial total of 384 patients. Out of the remaining, 50 patients had positive serology and 29 underwent intestinal biopsy. The prevalence index was 3.1%. CONCLUSION The periodic screening of CD in diabetic patients should be encouraged, due to its high prevalence.
Collapse
Affiliation(s)
- Cristina Borim Codo Dias Gonçalves
- Programa de Pós-Graduação em Endocrinologia Pediátrica, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
| | | | | | | |
Collapse
|
|
10
|
Szaflarska-Popławska A. Coexistence of coeliac disease and type 1 diabetes. PRZEGLAD GASTROENTEROLOGICZNY 2014; 9:11-7. [PMID: 24868293 PMCID: PMC4027839 DOI: 10.5114/pg.2014.40844] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 01/17/2012] [Accepted: 03/27/2012] [Indexed: 12/30/2022]
Abstract
There is a selective review of the literature concerning the coexistence of coeliac disease and type 1 diabetes mellitus. This review focuses on the principles of serological tests towards coeliac disease in patients with type 1 diabetes mellitus and metabolic control measures as a result of a gluten-free diet.
Collapse
Affiliation(s)
- Anna Szaflarska-Popławska
- Department of Pediatric Endoscopy and Gastrointestinal Function Testing, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| |
Collapse
|
|
11
|
Popp A, Mihu M, Munteanu M, Ene A, Dutescu M, Colcer F, Raducanu D, Laurila K, Anca I, Mäki M. Prospective antibody case finding of coeliac disease in type-1 diabetes children: need of biopsy revisited. Acta Paediatr 2013; 102:e102-6. [PMID: 23211000 DOI: 10.1111/apa.12117] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 11/26/2012] [Accepted: 11/30/2012] [Indexed: 12/26/2022]
Abstract
AIM To evaluate whether coeliac disease (CD) can be diagnosed by measuring autoantibodies without small-intestinal mucosal biopsies in children with type 1 diabetes. METHODS Case finding of CD was undertaken in 181 consecutive IgA-competent children with type 1 diabetes using transglutaminase 2 (TG2) and endomysial IgA antibody (EMA) tests in serum and the rapid point of care test in fingertip whole-blood sample. Endoscopy with intestinal biopsies was recommended for patients with high TG2-IgA titres (>96 U) and in children with lower positive tests if either the EMA test or the rapid point of care test was additionally positive. The duodenal mucosal biopsies were graded according to the Marsh classification. RESULTS The TG2-IgA test had a 15.5% and the EMA test a 6.0% seropositivity. All seven biopsied high-titre TG2-IgA-positive children were symptom free and found to have CD (Marsh 3 type lesion). These patients were also positive for EMA and in the rapid point of care test. Lower titre TG2-IgA-positive children had histological Marsh 1 to 3a lesions. CONCLUSIONS None of the type 1 diabetes children with high TG2-IgA titres would have needed endoscopy with duodenal biopsies to reach a CD diagnosis. Lower TG2-IgA-positive patients need to be biopsied.
Collapse
Affiliation(s)
| | - Mihaela Mihu
- Diabetes Department; Emergency Hospital “Marie Curie”; Bucharest; Romania
| | - Mihai Munteanu
- Diabetes Department; Emergency Hospital “Marie Curie”; Bucharest; Romania
| | - Adina Ene
- Paediatric Department; Institute for Mother and Child Care “Alfred Rusescu”; Bucharest; Romania
| | - Monica Dutescu
- National Institute of Hematology and Blood Transfusion-HLA Laboratory; Bucharest; Romania
| | - Florin Colcer
- Paediatric Department; Institute for Mother and Child Care “Alfred Rusescu”; Bucharest; Romania
| | - Diana Raducanu
- Paediatric Department; Institute for Mother and Child Care “Alfred Rusescu”; Bucharest; Romania
| | - Kaija Laurila
- Tampere Center for Child Health Research; University of Tampere and Tampere University Hospital; Tampere; Finland
| | | | - Markku Mäki
- Tampere Center for Child Health Research; University of Tampere and Tampere University Hospital; Tampere; Finland
| |
Collapse
|
|
12
|
Ludvigsson JF, Leffler DA, Bai J, Biagi F, Fasano A, Green PHR, Hadjivassiliou M, Kaukinen K, Kelly C, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. The Oslo definitions for coeliac disease and related terms. Gut 2013; 62:43-52. [PMID: 22345659 PMCID: PMC3440559 DOI: 10.1136/gutjnl-2011-301346] [Citation(s) in RCA: 1147] [Impact Index Per Article: 95.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten. DESIGN A multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to 'CD', the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies. RESULTS CD was defined as 'a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals'. Classical CD was defined as 'CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.' 'Gluten-related disorders' is the suggested umbrella term for all diseases triggered by gluten and the term gluten intolerance should not to be used. Other definitions are presented in the paper. CONCLUSION This paper presents the Oslo definitions for CD-related terms.
Collapse
Affiliation(s)
- Jonas F Ludvigsson
- Department of Paediatrics, Örebro University Hospital, 701 85 Örebro, Sweden and Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Daniel A Leffler
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Julio Bai
- Department of Medicine, Dr C. Bonorino Udaondo Gastroenterology Hospital. Del Salvador University, Buenos Aires, (1264) Argentina
| | - Federico Biagi
- Coeliac Centre/1st Dept. of Internal Medicine, University of Pavia, Fondazione IRCCS Policlinico San Matteo, P.le Golgi, 19, Pavia, 27100 Italy
| | - Alessio Fasano
- Center for Coeliac Research University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Peter HR Green
- MD Coeliac Disease center at Columbia University, New York, NY, 10032, USA
| | | | - Katri Kaukinen
- School of Medicine, FIN-33014 University of Tampere, Finland
| | - Ciaran Kelly
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Jonathan N Leonard
- Department of Dermatology, Imperial College NHS Healthcare Trust, St Mary’s Hospital, London W2 1NY, UK
| | - Knut E Lundin
- Dept of Gastroenterology and Centre for Immune Regulation, Oslo University Hospital, 0027 Oslo, Norway
| | | | - David S Sanders
- Gastroenterology and Liver Unit, Royal Hallamshire Hospital & University of Sheffield, Sheffield, 2JF UK
| | - Marjorie M Walker
- Centre for Pathology, Faculty of Medicine, Imperial College, St Mary’s Hospital, London W2 1NY, UK
| | - Fabiana Zingone
- Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, 80131, Italy
| | - Carolina Ciacci
- Chair of Gastroenterology, University of Salerno, Salerno, 84084 Italy
| |
Collapse
|
|
13
|
Abstract
Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.
Collapse
Affiliation(s)
- Alessio Fasano
- Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| |
Collapse
|
|
14
|
Bashiri H, Keshavarz A, Madani H, Hooshmandi A, Bazargan-Hejazi S, Ahmadi A. Celiac disease in type-I diabetes mellitus: coexisting phenomenon. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2011; 16 Suppl 1:S401-6. [PMID: 22247725 PMCID: PMC3252773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 03/15/2011] [Indexed: 11/13/2022]
Abstract
BACKGROUND This study aimed to determine the prevalence of celiac disease in type I diabetic patients and to compare the symptoms and complications of celiac in patients with diabetes and celiac with patients with diabetes only. METHODS A total of 241 type I diabetic patients age ≥ 18 who needed insulin intake were recruited from diabetic patients attending the Diabetic Research Center in Kermanshah, Iran. Sample was screened for celiac disease by drawing 5cc blood for complete blood count (CBC), and anti-endomysial antibody test (AEA). Patients then were classified based on immunofluorescent method for the presence of AEA. Those with AEA positive underwent biopsy. The biopsy tissues were classified based on Marsh classification. RESULTS Twenty one patients tested positive for celiac disease based on AEA test (8.7%) and 20 (8.3%) tested positive based on the biopsy. Prevalence of celiac among diabetic patients in comparison to normal population was 8.3% vs. 0.6%; and 70% were in the stages III and IV. Weight loss was significantly more prevalent among the celiac patients, who were 4 times more likely to lose weight. Other parameters such as anemia, mucocutaneous and cutaneous hemorrhage, milk intolerance, related oral aphthous, diarrhea and steatorrhea, alopecia, dermatitis herpetiform and alopecia were higher in celiac patients but not high enough to be statistically significant. CONCLUSIONS There is a need to improve screening identification and treatment of celiac among all diabetic patients type I, especially in cases with uncontrolled diabetic or weight loss.
Collapse
Affiliation(s)
- Homayoon Bashiri
- Department of Internal Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran., Corresponding Author E-mail:
| | - Aliasghar Keshavarz
- Department of Internal Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamid Madani
- Department of Pathology, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ahmadreza Hooshmandi
- Department of Internal Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Alireza Ahmadi
- Department of Anesthesiology, Critical Care and Pain Management, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran., Department of Public Health Sciences, Division of Social Medicine, Karolinska Institute, Stockholm, Sweden
| |
Collapse
|
|
15
|
Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011; 91:151-75. [PMID: 21248165 DOI: 10.1152/physrev.00003.2008] [Citation(s) in RCA: 622] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a "leaky gut" in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.
Collapse
Affiliation(s)
- Alessio Fasano
- Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
| |
Collapse
|
|
16
|
Celiac disease without villous atrophy in children: a prospective study. J Pediatr 2010; 157:373-80, 380.e1. [PMID: 20400102 DOI: 10.1016/j.jpeds.2010.02.070] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Revised: 02/08/2010] [Accepted: 02/26/2010] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To establish whether children who are endomysial antibody (EmA) positive and have normal small-bowel mucosal villous morphology are truly gluten-sensitive and may benefit from early treatment with a gluten-free diet. STUDY DESIGN Children who were EmA positive with normal small-bowel mucosal villi were compared with children who were seropositive with villous atrophy by using several markers of untreated celiac disease. Thereafter, children with normal villous structure either continued on a normal diet or were placed on a gluten-free diet and re-investigated after 1 year. Seventeen children who were seronegative served as control subjects for baseline investigations. RESULTS Normal villous morphology was noted in 17 children who were EmA positive, and villous atrophy was noted in 42 children who were EmA positive. These children were comparable in all measured variables regardless of the degree of enteropathy, but differed significantly from the seronegative control subjects. During the dietary intervention, in children who were EmA positive with normal villi, the disease was exacerbated in children who continued gluten consumption, whereas in all children who started the gluten-free diet, both the gastrointestinal symptoms and abnormal antibodies disappeared. CONCLUSIONS The study provided evidence that children who are EmA positive have a celiac-type disorder and benefit from early treatment despite normal mucosal structure, indicating that the diagnostic criteria for celiac disease should be re-evaluated.
Collapse
|
|
17
|
Narula P, Porter L, Langton J, Rao V, Davies P, Cummins C, Kirk J, Barrett T, Protheroe S. Gastrointestinal symptoms in children with type 1 diabetes screened for celiac disease. Pediatrics 2009; 124:e489-95. [PMID: 19706580 DOI: 10.1542/peds.2008-2434] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The association between celiac disease (CD) and type 1 diabetes mellitus (DM) is recognized. Most cases of CD in patients with DM are reported to be asymptomatic. OBJECTIVES The objectives of this study were to (1) compare and audit our practice with the published standards for screening for CD in children with DM, (2) characterize the children with DM and biopsy-confirmed CD, in terms of growth and gastrointestinal symptoms, and compare them with children with DM and negative celiac serology, and (3) document the effects of a gluten-free diet (GFD) after 1 year of gastrointestinal symptoms, growth, and insulin requirement. METHOD We performed a retrospective case-note review of 22 children with DM, positive celiac serology +/- biopsy-confirmed CD, and 50 children with DM and negative celiac serology. RESULTS Twenty-two children (3.9% of the total diabetic population) had positive celiac serology on screening, with 17 (3%) having biopsy-confirmed CD. Ninety-four percent of the children had standardized celiac serology testing. At diagnosis of CD, 13 of the 17 biopsy-positive children (76.4%) had > or =1 gastrointestinal symptom. The frequency of gastrointestinal symptoms in negative celiac serology diabetic children was 6% (3 of 50) (P < .0005). Symptoms resolved in all children after introduction of a GFD. A significant improvement in weight SD score (P = .008) and BMI SD score (P = .02) was noted in those compliant with a GFD after 1 year. CONCLUSIONS Children with DM and CD have a higher frequency of gastrointestinal symptoms than their diabetic peers with negative celiac serology and are not truly asymptomatic. Institution of a GFD has a positive effect on nutritional status and symptom resolution in the short-term.
Collapse
Affiliation(s)
- Priya Narula
- Department of Gastroenterology, Birmingham Children's Hospital, Birmingham, UK.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Maglio M, Florian F, Vecchiet M, Auricchio R, Paparo F, Spadaro R, Zanzi D, Rapacciuolo L, Franzese A, Sblattero D, Marzari R, Troncone R. Majority of children with type 1 diabetes produce and deposit anti-tissue transglutaminase antibodies in the small intestine. Diabetes 2009; 58:1578-84. [PMID: 19401430 PMCID: PMC2699874 DOI: 10.2337/db08-0962] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Anti-tissue transglutaminase (TG2) antibodies are the serological marker of celiac disease. Given the close association between celiac disease and type 1 diabetes, we investigated the production and deposition of anti-TG2 antibodies in the jejunal mucosa of type 1 diabetic children. RESEARCH DESIGN AND METHODS Intestinal biopsies were performed in 33 type 1 diabetic patients with a normal mucosal architecture: 14 had high levels (potential celiac disease patients) and 19 had normal levels of serum anti-TG2 antibodies. All biopsy specimens were investigated for intestinal deposits of IgA anti-TG2 antibodies by double immunofluorescence. In addition, an antibody analysis using the phage display technique was performed on the intestinal biopsy specimens from seven type 1 diabetic patients, of whom four had elevated and three had normal levels of serum anti-TG2 antibodies. RESULTS Immunofluorescence studies showed that 11 of 14 type 1 diabetic children with elevated levels and 11 of 19 with normal serum levels of anti-TG2 antibodies presented with mucosal deposits of such autoantibodies. The phage display analysis technique confirmed the intestinal production of the anti-TG2 antibodies; however, whereas the serum-positive type 1 diabetic patients showed a preferential use of the VH5 antibody gene family, in the serum-negative patients the anti-TG2 antibodies belonged to the VH1 and VH3 families, with a preferential use of the latter. CONCLUSIONS Our findings demonstrate that there is intestinal production and deposition of anti-TG2 antibodies in the jejunal mucosa of the majority of type 1 diabetic patients. However, only those with elevated serum levels of anti-TG2 antibodies showed the VH usage that is typical of the anti-TG2 antibodies that are produced in patients with celiac disease.
Collapse
Affiliation(s)
- Mariantonia Maglio
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Fiorella Florian
- Department of Health Sciences, University of Trieste, Trieste, Italy
| | - Monica Vecchiet
- Department of Health Sciences, University of Trieste, Trieste, Italy
| | - Renata Auricchio
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Francesco Paparo
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Raffaella Spadaro
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Delia Zanzi
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Luciano Rapacciuolo
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Adriana Franzese
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
| | - Daniele Sblattero
- Department of Medical Sciences and Research Centre on Autoimmune Diseases, University of Eastern Piedmont, Novara, Italy
| | - Roberto Marzari
- Department of Health Sciences, University of Trieste, Trieste, Italy
| | - Riccardo Troncone
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy
- Corresponding author: Riccardo Troncone,
| |
Collapse
|
|
19
|
Larsson K, Carlsson A, Cederwall E, Jönsson B, Neiderud J, Jonsson B, Lernmark A, Ivarsson SA. Annual screening detects celiac disease in children with type 1 diabetes. Pediatr Diabetes 2008; 9:354-9. [PMID: 18774995 DOI: 10.1111/j.1399-5448.2008.00367.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the prevalence of celiac disease (CD) in a cohort of type 1 diabetes mellitus (T1DM) children and adolescents at the time of clinical diagnosis and to evaluate the screening procedure and possible role of human leukocyte antigen (HLA)-DQ during a 5-yr follow-up. RESEARCH DESIGN AND METHODS The study group was a cohort of 300 newly diagnosed T1DM children and youths younger than 20 yr followed for 5 yr at six clinical centers for pediatric diabetes in the region Skåne in Sweden. Immunoglobulin A endomysium antibodies were used to screen the patients annually to be considered for an intestinal biopsy. All patients were analyzed for HLA-DQA1-B1 genotypes. RESULTS While 0.7% (2/300) already had a diagnosed symptomatic CD, an additional 3% (10/300) had silent CD at the diagnosis of T1DM. During follow-up, another 6% (17/300) developed CD as follows: 10 after 1 yr, 5 after 2 yr, 1 after 3 yr, and 1 after 5 yr. Therefore, the cumulative frequency of CD confirmed by intestinal biopsies was 10% (29/300). HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone. CONCLUSIONS Our study confirmed the low prevalence (0.7%) of diagnosed symptomatic CD at the time of clinical diagnosis but document by screening an increasing prevalence of silent CD during a 5-yr follow-up to reach an overall prevalence of 10%. We suggest that children with T1DM should be screened for CD at the onset of T1DM and annually for a minimum of at least 2 yr. HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone.
Collapse
Affiliation(s)
- Karin Larsson
- Department of Paediatrics, Kristianstad Hospital, Kristianstad, Sweden.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Serologic screening for coeliac disease in risk groups: is once in the lifetime enough? Dig Liver Dis 2008; 40:101-3. [PMID: 18083085 DOI: 10.1016/j.dld.2007.10.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Accepted: 10/31/2007] [Indexed: 12/11/2022]
|
|
21
|
Abstract
Although there is a great deal of information on celiac disease and associated involvement of other non-intestinal sites, data on concomitant changes in the structure and function of the pancreas is limited. The present review critically examines pancreatic endocrine changes that have been well documented in the literature, including insulin-dependent diabetes mellitus. Pancreatic exocrine alterations may also occur, and if severe, marked malnutrition with pancreatic failure and ductal calcification have been observed. Finally, other pancreatic disorders have been recorded with celiac disease.
Collapse
|
|
22
|
Poulain C, Johanet C, Delcroix C, Lévy-Marchal C, Tubiana-Rufi N. Prevalence and clinical features of celiac disease in 950 children with type 1 diabetes in France. DIABETES & METABOLISM 2007; 33:453-8. [PMID: 17964843 DOI: 10.1016/j.diabet.2007.06.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2006] [Accepted: 06/06/2007] [Indexed: 01/17/2023]
Abstract
UNLABELLED The prevalence of celiac disease is higher in children with type 1 diabetes mellitus (DM) than in the general pediatric population, but may vary widely across countries. Sensitive and specific antibody tests are available for detecting celiac disease. AIMS To evaluate the prevalence in France of histologically documented celiac disease in a vast cohort of children with type 1 DM, and to describe the features of celiac disease and treatment response. METHODS Retrospective cohort study of 950 children with type 1 diabetes seen between 1994 and 2001. Antibodies to gliadin, reticulin, endomysium and transglutaminase were looked for one to seven times in each patient. RESULTS Fifteen patients (1.6%) had biopsy-confirmed celiac disease. Symptoms led to the diagnosis in six patients (mean age, 7 years) and screening tests in nine patients (mean age, 11 years). Anti-endomysium antibodies were consistently positive. Tests for HLA-DQB1 0201 and/or 0302 were positive. Anti-endomysium antibody seroconversion was seen in two patients, 2 and 6 years, respectively, after the diagnosis of diabetes. In another patient, the biopsy became abnormal 6 years after the first positive anti-endomysium antibody test (latent form). After a mean of 3 years on a gluten-free diet, significant increases were noted in body weight (P=0.04) and insulin dose (P=0.05); clinical symptoms completely resolved in five of the six symptomatic patients. CONCLUSIONS The prevalence of celiac disease is higher in children with type 1 DM than in the general pediatric population. Serological screening is useful for diagnosing asymptomatic celiac disease, detecting seroconversion and monitoring latent forms of disease.
Collapse
Affiliation(s)
- C Poulain
- Department of Endocrinology and Diabetology, Robert Debré Hospital, 48, boulevard Serurier, 75019 Paris, France
| | | | | | | | | |
Collapse
|
|
23
|
Mankaï A, Ben Hamouda H, Amri F, Ghedira-Besbes L, Harbi A, Tahar Sfar M, Sahloul Essoussi A, Jeddi M, Ghedira I. Screening by anti-endomysium antibodies for celiac disease in Tunisian children with type 1 diabetes mellitus. ACTA ACUST UNITED AC 2007; 31:462-6. [PMID: 17541335 DOI: 10.1016/s0399-8320(07)89413-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
AIM Celiac disease (CD) and type 1 diabetes mellitus (DM1) can frequently coexist, presumably due to a common genetic predisposition. The present study was designed to evaluate the frequency of CD among Tunisian children with DM1. PATIENTS AND METHODS A total of 205 diabetic children (92 girls, 113 boys, age range 6 months-15 years, median 11 years) were screened for CD by determination of IgA anti-endomysium antibodies (EMA). RESULTS EMA were positive in 17 out of 205 (8.3%) children with DM1. The median age of DM1 at onset was significantly lower in patients with EMA than those without EMA (P<10(-7)). In 13 of 17 EMA-positive patients, duodenal biopsy could be performed and a destructive type of CD was confirmed in 11 of them: 8 patients showed total villous atrophy, 3 patients showed a partial villous atrophy. The other two patients showed a normal histological picture with normal number of intraepithelial lymphocytes. Parents of the remaining EMA-positive children refused endoscopy. Thus the prevalence of biopsy-proven CD was 5.3% (11/205). It was 7.6% (7/92) in girls and 3.5% (4/113) in boys but the difference was not statistically significant. Seventy three percent of patients with CD were asymptomatic. CONCLUSIONS The prevalence of clinically unrecognized CD, found by EMA screening, is high in Tunisian children with DM1. We suggest that children with diabetes should be screened for CD.
Collapse
Affiliation(s)
- Amani Mankaï
- Department of Immunology, Research Unit, Faculty of Pharmacy, Monastir, Tunisia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Madani S, Kamat D. Clinical guidelines for celiac disease in children: what does it mean to the pediatrician/family practitioner? Clin Pediatr (Phila) 2006; 45:213-9. [PMID: 16708133 DOI: 10.1177/000992280604500302] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Shailender Madani
- Department of Pediatrics, Wayne State University School of Medicine, and Division of Gastroenterology, Children's Hospital of Michigan, Detroit, MI 48201, USA
| | | |
Collapse
|
|
25
|
Sblattero D, Ventura A, Tommasini A, Cattin L, Martelossi S, Florian F, Marzari R, Bradbury A, Not T. Cryptic gluten intolerance in type 1 diabetes: identifying suitable candidates for a gluten free diet. Gut 2006; 55:133-4. [PMID: 16344582 PMCID: PMC1856374 DOI: 10.1136/gut.2005.077511] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
26
|
Glastras SJ, Craig ME, Verge CF, Chan AK, Cusumano JM, Donaghue KC. The role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications. Diabetes Care 2005; 28:2170-5. [PMID: 16123485 DOI: 10.2337/diacare.28.9.2170] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to explore whether the presence of thyroid and endomysial autoantibodies at diagnosis of type 1 diabetes in children predicts development of thyroid and celiac disease, respectively, and whether diabetes-associated autoantibodies at diagnosis predict development of microvascular complications up to 13 years later. RESEARCH DESIGN AND METHODS Autoantibodies were measured at diagnosis of type 1 diabetes in 173 children aged 0-15 years and included thyroperoxidase antibody (TPOA), endomysial antibody (EMA), islet cell autoantibody, GAD antibody (GADA), and insulin autoantibody. Thyroid disease was defined as thyroid stimulating hormone level > or = 5 microU/ml. Celiac disease was confirmed by small-bowel biopsy. Assessment of microvascular complications included stereoscopic fundal photography, pupillometry, thermal threshold, and albumin excretion rate (AER). RESULTS The incidence rates for thyroid and celiac disease were 0.9 and 0.7 per 100 patient-years, respectively. Within 13 years, 6 of 13 children with positive TPOA tests at diagnosis developed thyroid disease compared with 5 of 139 children with negative TPOA tests (P < 0.001). All four patients with positive EMA titers at diagnosis had biopsy-proven celiac disease. Five of 11 patients who developed thyroid disease and 4 of 8 who developed celiac disease had negative TPOA and EMA tests at diagnosis, respectively. Retinopathy was detected in 39% and elevated AER in 36%. The presence of diabetes-associated autoantibodies at diagnosis did not predict microvascular complications though GADA titer levels predicted pupillary abnormality. CONCLUSIONS Elevated TPOA and EMA levels at diagnosis of type 1 diabetes predict the development of thyroid and celiac disease, respectively. In children with negative antibody titers at diagnosis, screening at 2-year intervals is recommended.
Collapse
Affiliation(s)
- Sarah J Glastras
- Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.
| | | | | | | | | | | |
Collapse
|
|
27
|
Londei M, Ciacci C, Ricciardelli I, Vacca L, Quaratino S, Maiuri L. Gliadin as a stimulator of innate responses in celiac disease. Mol Immunol 2005; 42:913-8. [PMID: 15829281 DOI: 10.1016/j.molimm.2004.12.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In celiac disease (CD) we have the prototype of an immune mediated response dominated by the activation of the adaptive immune system and in particular of CD4+ HLA class II restricted T cells. Various seminal studies have established the precise mechanism of how antigen (prolamine) specific activation of CD4+ mucosal T cells occurs. Thus, CD is a condition in which T cells and their activation is the essential hinge in the pathogenic process. These functional studies have provided the explanation for the genetic association between CD and certain HLA alleles (HLA DQ2 and DQ8). These genetic, molecular and functional studies have permitted the clarification of a powerful Th1 dominated pro-inflammatory response that characterises the small intestine of active CD patients. Despite this unassailable set of information and reports there are some intriguing points that have been raised by a series of studies which have indicated that CD is not only defined by an aberrant prolamine-induced activation of the adaptive immune system. New evidence and re-assessments of old studies, point to a more complex pathogenic cascade, which may help to unravel some of the residual obscure points of CD pathogenesis. Here, we outline the current concepts that indicate a direct involvement of the adaptive immune system and we discuss all the evidence supporting a direct activation of the innate immune system by fragments of prolamines, which are not recognized T cell epitopes and how they could influence CD. The gliadin-induced activation of the 'innate' immune system might also have a significant role in the induction and persistence of many CD complications and most definitively for the most aggressive one, namely mucosal T cell lymphomas. We further suggest a novel way to harness the unwanted immune response to toxic prolamine, and thus indicate new potential therapeutic strategies to treat or at least control CD.
Collapse
Affiliation(s)
- Marco Londei
- Marco Londei Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
| | | | | | | | | | | |
Collapse
|
|
28
|
Lenhardt A, Plebani A, Marchetti F, Gerarduzzi T, Not T, Meini A, Villanacci V, Martelossi S, Ventura A. Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency. Dig Liver Dis 2004; 36:730-4. [PMID: 15571003 DOI: 10.1016/j.dld.2004.06.017] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Selective IgA deficiency is associated with coeliac disease, and studies have shown an increased prevalence of coeliac disease in these patients ranging from 0.71 to 30.7%, depending on the test used for screening. AIMS To determine the sensitivity of IgG anti-gliadin-antibodies and of IgG human-tissue-transglutaminase for diagnosing coeliac disease and assessing its prevalence in subjects with IgA deficiency. SUBJECTS We tested serum samples from 126 IgA-deficient children (66 female, median age: 10.8 years). METHODS All samples were analysed to measure IgG anti-gliadin-antibodies and IgG anti-human-tissue-transglutaminase. Patients testing positive to either test underwent intestinal biopsy. Subjects testing positive for IgG anti-human-tissue-transglutaminase underwent genetic testing for the human leucocyte antigen heterodimer. RESULTS Twenty-seven of 126 subjects tested positive for IgG anti-gliadin-antibodies (five of whom tested positive also for IgG anti-human-tissue-transglutaminase) and 18 (including the aforementioned five) for IgG anti-human-tissue-transglutaminase. Intestinal biopsy was performed in 37 of the 40 patients who tested positive (three subjects refused). Eleven had positive intestinal biopsies all of whom tested positive for IgG anti-human-tissue-transglutaminase, but only five of these tested positive also for IgG anti-gliadin-antibodies. All 22 patients testing positive for anti-gliadin-antibody alone had normal intestinal mucosa. All the patients who tested positive for IgG anti-human-tissue-transglutaminase and underwent genetic screening (15/18) had the coeliac-related human leucocyte antigen. Overall, coeliac disease was diagnosed in 11 of the 126 subjects with IgA deficiency (8.7%). CONCLUSIONS The prevalence of coeliac disease in subjects with total IgA deficiency was 8.7%. Assay of IgG anti-human-tissue-transglutaminase can be recommended for screening coeliac disease in IgA-deficient subjects.
Collapse
Affiliation(s)
- A Lenhardt
- Department of Paediatrics, IRCCS Burlo Garofolo, University of Trieste, Via dell'Istria 65/1, 34100 Trieste, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Auricchio R, Paparo F, Maglio M, Franzese A, Lombardi F, Valerio G, Nardone G, Percopo S, Greco L, Troncone R. In vitro-deranged intestinal immune response to gliadin in type 1 diabetes. Diabetes 2004; 53:1680-3. [PMID: 15220190 DOI: 10.2337/diabetes.53.7.1680] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Dietary gluten has been associated with an increased risk of type 1 diabetes. We have evaluated inflammation and the mucosal immune response to gliadin in the jejunum of patients with type 1 diabetes. Small intestinal biopsies from 17 children with type 1 diabetes without serological markers of celiac disease and from 50 age-matched control subjects were examined by immunohistochemistry. In addition, biopsies from 12 type 1 diabetic patients and 8 control subjects were cultured with gliadin or ovalbumin peptic-tryptic digest and examined for epithelial infiltration and lamina propria T-cell activation. The density of intraepithelial CD3(+) and gammadelta(+) cells and of lamina propria CD25(+) mononuclear cells was higher in jejunal biopsies from type 1 diabetic patients versus control subjects. In the patients' biopsies cultured with peptic-tryptic gliadin, there was epithelial infiltration by CD3(+) cells, a significant increase in lamina propria CD25(+) and CD80(+) cells and enhanced expression of lamina propria CD54 and crypt HLA-DR. No such phenomena were observed in control subjects, even those with celiac disease-associated HLA haplotypes. In conclusion, signs of mucosal inflammation were present in jejunal biopsies from type 1 diabetic patients, and organ culture studies indicate a deranged mucosal immune response to gliadin.
Collapse
Affiliation(s)
- Renata Auricchio
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Wong RC, Steele RH, Reeves GE, Wilson RJ, Pink A, Adelstein S. Antibody and genetic testing in coeliac disease. Pathology 2003. [DOI: 10.1080/0031302031000150542] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
|
31
|
Rodríguez-Juan C, Sala-Silveira L, Pérez-Blas M, Valeri AP, Aguilera N, López-Santalla M, Fuertes A, Martín-Villa JM. Increased levels of bovine serum albumin antibodies in patients with type 1 diabetes and celiac disease-related antibodies. J Pediatr Gastroenterol Nutr 2003; 37:132-135. [PMID: 12883297 DOI: 10.1097/00005176-200308000-00009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To detect the presence of antibodies against bovine serum albumin in a cohort of Spanish patients with type 1 insulin-dependent diabetes. METHODS Antibodies were measured using an in-house enzyme-linked immunosorbent assay test in 80 patients with type 1 diabetes, subdivided according to the presence or absence in their serum of celiac disease-related antibodies. For comparison, 30 patients with celiac disease (nondiabetic), 13 patients with autoimmune thyroiditis, and 45 healthy volunteers were used. RESULTS Thirty-one percent of patients with diabetes yielded a positive result, with a mean value of 26.1 +/- 21.8 arbitrary units (AU). If the group was split into those with celiac disease-related antibodies and those lacking them, the percentages were 53% and 25%, respectively, with a mean value of 39.6 +/- 28.4 AU and 22.4 +/- 18.3 AU (P = 0.003), respectively. Seventy-three percent of celiac patients showed bovine serum albumin antibodies with a mean level of 38.8 +/- 27.7 AU, comparable to that of patients with diabetes with celiac antibodies, but higher than the group lacking them (P = 0.001). Although 46% of patients with autoimmune thyroiditis had positive results, the level detected (22.1 +/- 8.7 AU) was significantly lower than that recorded in patients with type 1 diabetes who had celiac disease antibodies (P = 0.04) and celiac patients (P = 0.04). Healthy volunteers showed no antibodies against bovine serum albumin. CONCLUSIONS These data suggest that bovine serum albumin antibodies appears in patients with a compromised epithelial permeability, and they reflect a general defect in the process of immunologic tolerance associated with a predisposition to autoimmunity, rather than immunity specific to beta cells.
Collapse
|
|
32
|
Crone J, Rami B, Huber WD, Granditsch G, Schober E. Prevalence of celiac disease and follow-up of EMA in children and adolescents with type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr 2003; 37:67-71. [PMID: 12827008 DOI: 10.1097/00005176-200307000-00011] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND The prevalence of celiac disease (CD) in children with diabetes mellitus type 1 (DM) is significantly higher than in the nondiabetic population. Most patients with DM and associated CD do not experience typical gastrointestinal symptoms of CD. There is no agreement on the necessity of screening and management of silent CD for patients with DM or on the time scale for screening. Only few data on follow-up evaluation of children with DM and CD-related antibodies are available. METHODS One hundred fifty-seven patients with DM (mean age, 14.8 years; range, 4-21 years; male, 83) were screened with endomysial antibodies (EMA) between 1993 and 2001. A follow-up period of at least 3 years, with at least 2 EMA measurements, was possible. Group 1 comprised 37 patients whose first measurement was at the onset of DM. Group 2 comprised 120 patients whose first measurement was during the course of the disease. In patients with positive EMA, small bowel biopsy was performed. Thyroid peroxidase (TPO), thyroglobulin (TgA), glutamate decarboxylase (GAD), antiinsulin (IAA), and islet cell antibodies (IA2) were measured in all patients. RESULTS EMA was positive in 16 patients, in 5 at onset of DM and in 11 during the course of DM (mean duration, 33.6 months; range, 11-105 months). Biopsy results showed normal mucosa in seven patients, increased intraepithelial lymphocyte counts in one, and flat mucosa in eight. There was no significant difference between EMA-positive and EMA-negative patients regarding height, weight, HbA1c level, frequency of hypoglycemia or hyperglycemia, TPO, TgA, GAD, IAA, or IA2. CONCLUSION This study emphasizes the high prevalence of CD in patients with DM. Although several patients already had positive EMA titers at the onset of DM, seroconversion may also occur during the course of the disease. Screening for CD with EMA or tissue transglutaminase should be included in the initial investigation of DM, but should also be repeated over time to detect late seroconversion.
Collapse
Affiliation(s)
- J Crone
- Children's Hospital, University of Vienna, Austria
| | | | | | | | | |
Collapse
|
|
33
|
Iughetti L, Bulgarelli S, Forese S, Lorini R, Balli F, Bernasconi S. Endocrine aspects of coeliac disease. J Pediatr Endocrinol Metab 2003; 16:805-18. [PMID: 12948292 DOI: 10.1515/jpem.2003.16.6.805] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coeliac disease (CD) is a permanent intolerance to gluten that results in damage of the small intestinal mucosa, and it is one of the common causes of chronic malabsorption in children. It is well known that patients with CD are at great risk of malignant complications, but in patients with CD many other disorders have been recognized. Autoimmunity diseases, such as type 1 diabetes mellitus, thyroid diseases, and autoimmune polyglandular syndromes are known to be associated with CD, and they seem to be related to gluten exposure. Growth, bone metabolism, and fertility can be affected in patients with CD, especially if they are not on a gluten-free diet. We review the literature on endocrine aspects of CD, because patients with CD are at great risk of developing endocrine disorders.
Collapse
Affiliation(s)
- Lorenzo Iughetti
- Department of Pediatrics, University of Modena & Reggio Emilia, Italy
| | | | | | | | | | | |
Collapse
|
|
34
|
Scoglio R, Di Pasquale G, Pagano G, Lucanto MC, Magazzù G, Sferlazzas C. Is intestinal biopsy always needed for diagnosis of celiac disease? Am J Gastroenterol 2003; 98:1325-31. [PMID: 12818277 DOI: 10.1111/j.1572-0241.2003.07455.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Intestinal biopsy is required for a diagnosis of celiac disease (CD). The aim of this study was to assess diagnostic accuracy of transglutaminase antibodies (TGA) in comparison and in association with that of antiemdomysial antibodies (AEA), calculating the post-test odds of having the disease, to verify whether some patients might avoid undergoing intestinal biopsy for a diagnosis of CD. METHODS A total of 181 consecutive patients (131 < 18 yr), referred to our celiac clinic by primary care physicians for suspect CD. Overall diagnostic accuracy, negative predictive value, and likelihood ratio (LR) were calculated both for each serological test and for serial testing (TGA and after AEA, assuming the post-test probability of TGA as pretest probability of AEA). Both serological determination and histological evaluation were blindly performed. Histology of duodenal mucosa was considered the gold standard. RESULTS The overall accuracy of TGA and of AEA were 92.8% (89.1-96.6) and 93.4% (89.7-97.0), respectively. The negative predictive value of TGA and AEA were 97.2% (91.9-102.6) and 87.2% (77.7-96.8), respectively. Positive likelihood ratios for TGA and AEA were 3.89 (3.40-4.38) and 7.48 (6.73-8.23), respectively. Serial testing, in groups of patients with prevalence of CD estimated higher than 75%, such as those with classic symptoms of CD, would provide a post-test probability of more than 99%. CONCLUSIONS Our results suggest that serial testing with TGA and AEA might allow, in some cases, the avoidance of intestinal biopsy to confirm the diagnosis of CD.
Collapse
Affiliation(s)
- Riccardo Scoglio
- Department of Pediatrics, GI Unit, University of Messina, Messina, Italy
| | | | | | | | | | | |
Collapse
|
|
35
|
Londei M, Quaratino S, Maiuri L. Celiac disease: a model autoimmune disease with gene therapy applications. Gene Ther 2003; 10:835-43. [PMID: 12732869 DOI: 10.1038/sj.gt.3302041] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Gene therapy (GT) is still at the 'experimental' stage and some recent setbacks have cooled the potential use of this therapeutic tool even in life-threatening conditions. However, this therapeutic approach has a potential, which is not limited to disease for which we have not other option. There are increasing evidence that GT will be soon used in diseases that are not life threatening. One group of diseases that can benefit from GT is the autoimmune one. Several experimental animal models have indicated the efficacy (proof of principle) of GT. In the present review, we have addressed the possibility that even extremely benign autoimmune-like diseases such as Celiac Disease (CD) might one day profit from this type of therapy. We further point that in conditions such as CD, where the trigger is well known and the pathogenic cascade is relatively well defined, a situation not common in autoimmunity, we can even have a better situation where to explore and use GT to control disease initiation and progression. Once the risks that are still intrinsic to GT will have been reduced the therapeutic options we outline in the present review might not appear too far from reality.
Collapse
Affiliation(s)
- M Londei
- Institute of Child Health, University College London, London, UK.
| | | | | |
Collapse
|
|
36
|
Troncone R, Franzese A, Mazzarella G, Paparo F, Auricchio R, Coto I, Mayer M, Greco L. Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus. Am J Gastroenterol 2003; 98:590-595. [PMID: 12650792 DOI: 10.1111/j.1572-0241.2003.07301.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The association between celiac disease and insulin dependent diabetes mellitus (IDDM) is well established. Rectal gluten challenge has been used in patients with celiac disease and in first degree relatives as a tool to assess the mucosal immune response to gluten. The aim of this study was to assess the mucosal immune response to gluten in IDDM children by rectal gluten challenge. METHODS Rectal biopsy specimens were obtained from 19 children with IDDM before and 6 h after rectal challenge with 2 g of a peptic tryptic digest of gliadin. A total of 16 treated celiac patients and 10 control subjects were also investigated. Epithelium and lamina propria CD3(+) and gamma delta(+) lymphocytes were counted with reference to a standard reference area of muscularis mucosae (10(4) microm(2)). RESULTS After a local instillation of gliadin, a significant (>mean + 1 SD) percentage increment of lamina propria and epithelium CD3(+) and of lamina propria and epithelium gamma delta(+) lymphocytes was observed in five IDDM children, as compared to 11 and 13 celiac patients and one and two controls, respectively. A discriminant analysis allowed correct classification of 100% of patients with celiac disease and controls. The same analysis classified four of 19 IDDM children in the group of celiac patients. The positivity was associated with normal serology (antigliadin antibody, antiendomysial antibody, and antitissue transglutaminase antibodies) and a morphologically normal jejunal mucosa. All four patients had HLA-DQ alleles associated with celiac disease. CONCLUSIONS Approximately 20% of IDDM children react to rectal instillation of gliadin. Long term follow-up is necessary to establish whether these subjects are at increased risk for developing celiac disease.
Collapse
Affiliation(s)
- Riccardo Troncone
- Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Abstract
Celiac disease is a permanent intolerance to dietary gluten. Its well known features are abdominal symptoms, malabsorption of nutrients, and small-bowel mucosal inflammation with villous atrophy, which recover on a gluten-free diet. Diagnosis is challenging in that patients often suffer from subtle, if any, symptoms. The risk of clinically silent celiac disease is increased in various autoimmune conditions. The endocrinologist, especially, should maintain high suspicion and alertness to celiac disease, which is to be found in 2-5% of patients with insulin-dependent diabetes mellitus or autoimmune thyroid disease. Patients with multiple endocrine disorders, Addison's disease, alopecia, or hypophysitis may also have concomitant celiac disease. Similar heredity and proneness to autoimmune conditions are considered to be explanations for these associations. A gluten-free diet is essential to prevent celiac complications such as anemia, osteoporosis, and infertility. The diet may also be beneficial in the treatment of the underlying endocrinological disease; prolonged gluten exposure may even contribute to the development of autoimmune diseases. The diagnosis of celiac disease requires endoscopic biopsy, but serological screening with antiendomysial and antitissue transglutaminase antibody assays is an easy method for preliminary case finding. Celiac disease will be increasingly detected provided the close association with autoimmune endocrinological diseases is recognized.
Collapse
Affiliation(s)
- Pekka Collin
- Department of Medicine, Tampere University Hospital and University of Tampere, 33014 Tampere, Finland.
| | | | | | | |
Collapse
|
|
38
|
Robles DT, Fain PR, Gottlieb PA, Eisenbarth GS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am 2002; 31:353-68, vi-vii. [PMID: 12092455 DOI: 10.1016/s0889-8529(01)00015-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A series of autoimmune disorders, often Addison's disease, type 1 diabetes mellitus, and thyroid autoimmunity, frequently occurs together in patients with the autoimmune polyendocrine syndrome type II (APS-II). The highest risk HLA genotype for Addison's disease, either as a single disease or in APS-II patients, consists of the genotype DR3/4, DQ2/DQ8 with DRB1*0404. As many as 30% of patients with Addison's disease have this genotype versus less than 0.5% of controls. An additional and important associated locus within the HLA region is the class I related gene, MIC-A. Patients who develop Addison's disease often have a delayed diagnosis and may die from Addisonian crisis; therefore, improved genetic testing combined with testing for 21-hydroxylase autoantibodies might allow the identification of relatively high-risk populations (greater than 1 in 200 defined genetic risk compared with 1 in 10,000 population risk).
Collapse
Affiliation(s)
- David T Robles
- Medical Scientist Training Program, Department of Immunology, University of Colorado Health Sciences Center, Box B140, 4200 East 9th Ave., Denver, CO 80262, USA
| | | | | | | |
Collapse
|
|
39
|
Barera G, Bonfanti R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, Bianchi C, Chiumello G. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 2002; 109:833-8. [PMID: 11986443 DOI: 10.1542/peds.109.5.833] [Citation(s) in RCA: 188] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the prevalence of celiac disease in a large cohort of children and adolescents at the onset of type 1 diabetes and the occurrence of new cases during a 6-year follow-up. METHODS We prospectively studied, by repeated serologic screening, 274 consecutive patients at the onset of type 1 diabetes (age [mean +/- standard deviation]: 8.28 +/- 4.65 years) for 6 subsequent years. One patient had a diagnosis of celiac disease before the onset of diabetes. The immunoglobulin A-antiendomysium antibody test was selected as the screening test; patients with positive results (++ or +++) or with 2 consecutive weak positive tests (+) were considered appropriate for the jejunal biopsy. RESULTS At diabetes onset, 15 (5.5%) of 273 patients tested positive with the antiendomysium test; jejunal biopsy was performed in 10, and celiac disease was diagnosed in 9. The prevalence of biopsy-confirmed celiac disease at the manifestation of diabetes was 3.6% (10 of 274 patients). Twelve more patients with a negative antiendomysium antibody test at diabetes onset tested positive during the follow-up within 4 years; 10 of them had biopsies performed, and 7 had celiac disease. Therefore, the overall prevalence of biopsy-confirmed celiac disease in the entire cohort of patients was 6.2%. The age at diabetes onset in patients with and without celiac disease was not different (7.88 +/- 5.69 vs 8.3 +/- 4.58 years). The majority of cases of celiac disease were asymptomatic in their presentation, and no signs of overt malnutrition were documented. CONCLUSIONS The prevalence of celiac disease in patients with type 1 diabetes is approximately 20 times higher than in the general population. Sixty percent of cases are already present at diabetes onset, mostly undetected, but an additional 40% of patients develop celiac disease a few years after diabetes onset. Extending screening programs for celiac disease after the onset of type 1 diabetes is recommended, even in the absence of clinical symptoms.
Collapse
Affiliation(s)
- Graziano Barera
- Department of Pediatrics, Scientific Institute H San Raffaele, Milan, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Li Voon Chong JSW, Leong KS, Wallymahmed M, Sturgess R, MacFarlane IA. Is coeliac disease more prevalent in young adults with coexisting Type 1 diabetes mellitus and autoimmune thyroid disease compared with those with Type 1 diabetes mellitus alone? Diabet Med 2002; 19:334-7. [PMID: 11943007 DOI: 10.1046/j.1464-5491.2002.00671.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM It is known that patients with Type 1 diabetes mellitus are more prone to develop coeliac disease and that autoimmune thyroid disease occurs more frequently in patients with coeliac disease. We therefore assessed whether coeliac disease, either known or occult, occurs more frequently in young/middle aged adults with Type 1 diabetes and coexisting autoimmune thyroid dysfunction than in adults with Type 1 diabetes alone. METHODS The prevalence of known coeliac disease was assessed in 509 (301 males, aged 16-55 years) patients with Type 1 diabetes, 28 (5.5%) of whom had treated autoimmune thyroid disease. In a second study 38 patients with Type 1 diabetes and coexisting autoimmune thyroid disease along with 112 patients with Type 1 diabetes alone were then screened for coeliac disease using serum IgA endomysial antibodies and IgA gliadin antibodies. RESULTS Seven of the 509 patients (1.4%) had been diagnosed with coeliac disease and two of these had later developed autoimmune thyroid disease (both hypothyroid). The subsequent screening exercise found that one of the 38 patients with both Type 1 diabetes and thyroid disease had positive endomysial antibodies on screening. However, duodenal biopsy was negative for coeliac disease. There were two patients with positive endomysial antibodies in the group of 112 patients with diabetes only. Both had duodenal biopsy but only one was consistent with coeliac disease. CONCLUSION The prevalence of known coeliac disease in this young adult Type 1 diabetes clinic in North-west England was 7/509 (1.4%). Two of these seven patients with coeliac disease were from the group of 28 who had autoimmune thyroid disease as well. Therefore we suggest that patients with known coeliac disease and Type 1 diabetes should be screened for autoimmune thyroid disease. The second screening study then found 3/150 (2%) to have a serological marker for coeliac disease. However, patients with both Type 1 diabetes and autoimmune thyroid disease were not more likely to have occult coeliac disease compared with those with Type 1 diabetes only.
Collapse
Affiliation(s)
- J S W Li Voon Chong
- Department of Diabetes and Endocrinology and Gastroenterology, University Hospital Aintree, Liverpool, UK.
| | | | | | | | | |
Collapse
|
|
41
|
Abstract
Serological testing is an important tool in the diagnostic work-up of suspected celiac disease. Our aim was to apply a decision analysis model to compare the costs of serological testing versus small bowel biopsy in the diagnostic work-up of celiac disease. A cost-minimization approach was employed. A decision analysis model with three diagnostic arms was designed using Data Version 3.5: anti-gliadin antibody versus endomysial antibody versus small bowel biopsy. Response to gluten-free diet was considered diagnostic of celiac disease; lack of response prompted a small bowel biopsy to definitively exclude celiac disease. Baseline probabilities were varied using sensitivity analysis. Sensitivity analysis revealed that the endomysial antibody strategy was least costly, provided the prevalence of celiac disease was less than 42%; above this anti-gliadin antibody became the most economical option. In conclusion, initial screening with endomysial antibody is the least costly strategy for diagnosing celiac disease in a low risk population. Antigliadin antibody becomes the cheaper strategy for higher risk populations.
Collapse
Affiliation(s)
- G C Harewood
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | | |
Collapse
|
|
42
|
Abstract
The face of celiac disease has changed significantly over the past 50 years. With the advent of new noninvasive and more sensitive screening tools, it has become increasingly apparent that this disease presents in a heterogeneous fashion, with symptomatic disease only occurring in a small number of patients. Furthermore, great insights have been made into the disease's genetic and immunological components, thus increasing the medical community's understanding of the disease. The current gold standard for diagnosis is histological confirmation, and the cornerstone of therapy is lifelong elimination of gluten. Further advances in immunobiological techniques will most likely aid in earlier detection and commencement of the appropriate diet, thus preventing the development of associated complications.
Collapse
Affiliation(s)
- R Lad
- Division of Gastroenterology, British Columbia Children's Hospital, Vancouver, British Columbia
| | | |
Collapse
|
|
43
|
Abstract
This case report details a child with coeliac disease and giardiasis. Treatment of the infection without recourse to a gluten-free diet cured the symptoms of diarrhoea and returned the small intestinal morphology to normal. Thus, the patient moved from active to latent coeliac disease. Potential and latent forms of coeliac disease are being increasingly recognized, since markers have become available to identify patients and investigations developed to test for gluten sensitivity in the small intestinal mucosa. This case provides an opportunity to consider potential and latent forms of coeliac disease and how these impact on clinical practice and the wider understanding of the disorder.
Collapse
Affiliation(s)
- G K Holmes
- Derbyshire Royal Infirmary, London Road, Derby DE1 1QY, UK
| |
Collapse
|
|
44
|
When is a coeliac a coeliac? Report of a working group of the United European Gastroenterology Week in Amsterdam, 2001. Eur J Gastroenterol Hepatol 2001; 13:1123-8. [PMID: 11564968 DOI: 10.1097/00042737-200109000-00023] [Citation(s) in RCA: 106] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgement regarding the propriety of any specific guideline must be made by the physician in light of all the circumstances presented by the individual patient.
Collapse
|
|
45
|
Kumar V, Rajadhyaksha M, Wortsman J. Celiac disease-associated autoimmune endocrinopathies. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY 2001; 8:678-85. [PMID: 11427410 PMCID: PMC96126 DOI: 10.1128/cdli.8.4.678-685.2001] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Celiac disease (CD) is an autoimmune disorder induced by gluten intake in genetically susceptible individuals. It is characterized by the presence of serum antibodies to endomysium, reticulin, gliadin, and tissue transglutaminase. The incidence of CD in various autoimmune disorders is increased 10- to 30-fold in comparison to the general population, although in many cases CD is clinically asymptomatic or silent. The identification of such cases with CD is important since it may help in the control of type I diabetes or endocrine functions in general, as well as in the prevention of long-term complications of CD, such as lymphoma. It is believed that CD may predispose an individual to other autoimmune disorders such as type I diabetes, autoimmune thyroid, and other endocrine diseases and that gluten may be a possible trigger. The onset of type I diabetes at an early age in patients with CD, compared to non-CD, and the prevention or delay in onset of diabetes by gluten-free diet in genetically predisposed individuals substantiates this antigen trigger hypothesis. Early identification of CD patients in highly susceptible population may result in the treatment of subclinical CD and improved control of associated disorders.
Collapse
Affiliation(s)
- V Kumar
- IMMCO Diagnostics, Inc., Buffalo, New York 14228, USA.
| | | | | |
Collapse
|
|
46
|
Bertini M, Sbarbati A, Valletta E, Pinelli L, Tatò L. Incomplete gastric metaplasia in children with insulin-dependent diabetes mellitus and celiac disease. An ultrastructural study. BMC Clin Pathol 2001; 1:2. [PMID: 11466133 PMCID: PMC34772 DOI: 10.1186/1472-6890-1-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2001] [Accepted: 06/25/2001] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND: The association of insulin-dependent diabetes mellitus (IDDM) and celiac disease (CD) has been widely reported in children but the relationship between the two conditions is incompletely understood. Moreover, specific studies on intestinal biopsies of patients with the association of the two diseases are still lacking. METHODS: We studied the ultrastructure of the duodenal mucosa in 12 patients with both IDDM and CD. RESULTS: All patients had either total or partial atrophy of duodenal mucosa. In seven subjects, an accumulation of electrondense granules in the apical cytoplasm of groups of enterocytes was found. In four of them, a double population of granules existed (mean diameter: 400-800 nm and 100-200 nm respectively) showing a biphasic pattern. In the other three patients, only smaller granules (100- 200 nm) were found in the enterocytes. CONCLUSIONS: The present work suggests that patients with IDDM/CD may represent a subgroup in the context of the CD population. Intestinal biopsies of such individuals often show accumulation of electrondense granules in the apical cytoplasm of enterocytes that can be interpreted as incomplete gastric metaplasia.
Collapse
Affiliation(s)
- Marina Bertini
- Department of Pediatrics, University of Verona, Verona, Italy
| | - Andrea Sbarbati
- Institute of Anatomy and Histology, University of Verona, Verona, Italy
| | - Enrico Valletta
- Department of Pediatrics, University of Verona, Verona, Italy
| | | | - Luciano Tatò
- Department of Pediatrics, University of Verona, Verona, Italy
| |
Collapse
|
|
47
|
Meloni GF, Tomasi PA, Bertoncelli A, Fanciulli G, Delitala G, Meloni T. Prevalence of silent celiac disease in patients with autoimmune thyroiditis from Northern Sardinia. J Endocrinol Invest 2001; 24:298-302. [PMID: 11407647 DOI: 10.1007/bf03343864] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Celiac disease (CD) is frequently associated with other autoimmune diseases such as Type 1 diabetes mellitus, autoimmune thyroiditis (AT), and Addison's disease. The frequency of these associations varies with the populations studied. We conducted this study to ascertain the prevalence of CD in patients with AT from Sardinia, an area with a very high prevalence of CD. To this aim, 297 consecutive patients with AT (as defined by elevated antithyroid antibody levels and a positive ultrasound scan) were studied. Immunoglobulin A and G-class antigliadin antibodies were assayed in serum; if either or both were positive, antiendomysium antibodies were determined. If two markers were positive, serum ferritin, folate, and vitamin B12 levels were measured and jejunal biopsy was suggested. Thirteen out of the 14 patients who showed at least two positive markers consented to jejunal biopsy and all of them showed histological features of CD. The prevalence of CD in AT patients was 4-fold greater than that observed in the general population (4.37 vs 1.06%, p<0.0001). Ferritin was low in 6 and vitamin B12 in 2 out of 13 patients; serum folates were normal in all patients. Molecular typing of HLA class II alleles showed an increased frequency of the extended haplotype DRB1*0301/DQA1*0501/DQB1*0201. None of our patients had a history of gastrointestinal symptoms. We confirm the increased prevalence of silent CD in patients with AT. Patients with AT ought to be regarded as a high-risk group for CD and should be screened routinely for it; if negative, screening tests should be repeated at regular intervals.
Collapse
Affiliation(s)
- G F Meloni
- Pediatric Clinic A. Filia, University of Sassari, Italy.
| | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
AIM To review the relationship between coeliac disease and Type 1 diabetes mellitus with emphasis on prevalence of coeliac disease, presentation and implications for screening. METHODS Papers collected over many years by the author have been included in the review and a literature search employing Medline was undertaken to August 2000. Search words used were coeliac disease and diabetes mellitus. RESULTS Twenty papers exploring the prevalence of coeliac disease by serological screening of Type 1 diabetes in children, eight in adults and two including both groups were found. An additional 48 papers are included and relate to serological screening tests for coeliac disease, expressions and complications of coeliac disease, the value of GFD and the genetics of the two conditions. Unless formal screening studies are undertaken coeliac disease will not be diagnosed because patients are asymptomatic, have atypical symptoms or even in those with symptoms the diagnosis is overlooked. Based on small bowel biopsy, diagnosis the prevalence of coeliac disease in Type 1 diabetes in children is 1:6 to 1:103 and in adults 1:16 to 1:76. Patients may improve following the start of a gluten-free diet (GFD) in terms of symptoms, growth in children, serum antibody levels, haematological and biochemical indices, morphology of the small intestinal mucosa and control of diabetes. CONCLUSION Coeliac disease commonly occurs in Type 1 diabetes. It is recommended that screening for coeliac disease should be part of the routine investigation and offered to all patients because of the high prevalence and the potential benefits of treatment with a GFD. This includes control of symptoms, stabilization of diabetes and prevention of complications associated with coeliac disease. The cost per patient diagnosed with coeliac disease from the existing population with Type 1 diabetes would be pound860 and for those newly arising pound950.
Collapse
|
|
49
|
Williams AJ, Norcross AJ, Lock RJ, Unsworth DJ, Gale EA, Bingley PJ. The high prevalence of autoantibodies to tissue transglutaminase in first-degree relatives of patients with type 1 diabetes is not associated with islet autoimmunity. Diabetes Care 2001; 24:504-9. [PMID: 11289476 DOI: 10.2337/diacare.24.3.504] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine the extent of celiac autoimmunity in type 1 diabetic patients and the overlap between islet and celiac autoimmunity in their nondiabetic relatives. RESEARCH DESIGN AND METHODS IgA antibodies to tissue transglutaminase were determined in serum taken from 433 type 1 diabetic patients and 1,442 nondiabetic first-degree relatives. Samples with transglutaminase antibodies above the 97.5th percentile of 347 schoolchildren were also assayed for IgA anti-endomysial antibodies (EMAs). Markers of islet autoimmunity (islet cell antibodies and autoantibodies to insulin, glutamate decarboxylase. and protein tyrosine phosphatase IA-2) had previously been measured in all relatives. RESULTS In the absence of known celiac disease, the prevalence of transglutaminase antibody levels above the 97.5th percentile of the schoolchildren was 13.4% in diabetic patients and 7.0% in nondiabetic relatives. ENMAs were found in addition to transglutaminase antibodies in 2.6% of probands and in 1.9% of first-degree relatives, but none of the schoolchildren. Transglutaminase antibodies were found to persist in 10 of 30 patients and in 30 of 59 relatives with follow-up samples taken at least 2 years after the initial sample. Of 186 nondiabetic relatives with islet autoantibodies, only 10 also had transglutaminase antibodies. CONCLUSIONS We found a high prevalence of celiac autoimmunity in patients and first-degree relatives of children with type 1 diabetes, but we found limited overlap between islet and celiac autoimmunity in nondiabetic relatives. The high prevalence of celiac autoimmunity may be explained by shared genetic susceptibility and identifies a population within which screening for the disease may be justified.
Collapse
Affiliation(s)
- A J Williams
- Diabetes and Metabolism Division of Medicine, University of Bristol, UK
| | | | | | | | | | | |
Collapse
|
|
50
|
Martín-Villa JM, López-Suárez JC, Pérez-Blas M, Martínez-Laso J, Ferre-López S, García-Torre C, Lledó G, Manzanares J, Arnaiz-Villena A. Coeliac- and enteropathy-associated autoantibodies in Spanish insulin-dependent diabetes mellitus patients and their relation to HLA antigens. J Diabetes Complications 2001; 15:38-43. [PMID: 11259925 DOI: 10.1016/s1056-8727(00)00122-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The frequency of reticulin (ARA), endomysium (EmA), and gut epithelial cell (GECA) autoantibodies, and gliadin antibodies (AGA), was investigated in 86 Spanish diabetic patients by indirect immunofluorescence (IFI) and ELISA, along with their HLA phenotype. Four patients (5%) showed ARA-IgG (R1 pattern), eight (9%) showed AGA-IgG, and eight (9%) showed AGA-IgA. No EmA or GECA-positive patients were found. In diabetic patients, HLA-DR7 is increased in ARA-IgG+ vs. ARA-IgG- (though not significantly), and HLA-DR6 and HLA-DQ1 are significantly increased in the AGA-IgG+ group vs. the AGA-IgG- group. Comparison with a non-diabetic coeliac group showed that HLA-DR4 and HLA-DQ3 are significantly increased in the AGA-IgA+ group, whereas HLA-DQ2 shows a significant decrease in the AGA-IgG+ and AGA-IgA+ patients. Finally, when compared to the healthy group, HLA-DR7 frequency is decreased in the ARA-IgG- group, while HLA-DQ3 is significantly increased and HLA-DR6 and HLA-DQ1 significantly decreased in the AGA-IgG- group.Altogether, these data suggest that the genetic background leading to the appearance of coeliac-specific autoantibodies in Spanish diabetic patients differ depending on the autoantibody produced and is also different to the genetic background leading to diabetes in Spain.
Collapse
Affiliation(s)
- J M Martín-Villa
- Departament of Immunology, Hospital 12 de Octubre, Universidad Complutense de Madrid, 28041 Madrid, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|