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  • Jefferson Adams
    Jefferson Adams

    Kids Can Get Accurate Celiac Diagnosis Without Biopsy

      Can doctors diagnose celiac disease correctly at least 99 times out of 100 in the office without biopsy?

    Caption: Can doctors diagnose celiac disease correctly in the office without biopsy? Photo: CC--Enokson

    Celiac.com 08/07/2017 - The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8.

    To validate this approach, a team of researchers recently performed a large, international prospective study. The primary goal was to see if the non-biopsy approach can identify children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. That means they want to make sure doctors can get it right at least 99 times out of 100 in the office. They also wanted to compare the performance of different serological tests and to see if the suggested criteria can be simplified.

    The research team included KJ Werkstetter, IR Korponay-Szabó, A Popp, V Villanacci, M Salemme, G Heilig, ST Lillevang, ML Mearin, C Ribes-Koninckx, A Thomas, R Troncone, B Filipiak, M Mäki, J Gyimesi, M Najafi, J Dolinšek, S Dydensborg Sander, R Auricchio, A Papadopoulou, A Vécsei, P Szitanyi, E Donat, R Nenna, P Alliet, F Penagini, H Garnier-Lengliné, G Castillejo, K Kurppa, R Shamir, AC Hauer, F Smets, S Corujeira, M van Winckel, S Buderus, S Chong, S Husby, S Koletzko; ProCeDE study group, P Socha, Bozena Cukrowska, H Szajewska, J Wyhowski, N Brown, G Batra, Z Misak, S Seiwerth, Y Dmitrieva, D Abramov, Y Vandenplas, A Goossens, MW Schaart, VTHBM Smit, N Kalach, P Gosset, JB Kovács, A Nagy, I Lellei, R KÅ‘bányai, K Khatami, M Monajemzadeh, K Dimakou, A Patereli, T Plato Hansen, R Kavalar, M Bolonio, H Kogler, G Amann, R Kosova, M Maglio, E Janssens, R Achten, P Frűhauf, H Skálová, T Kirchner, L Petrarca, FM Magliocca, F Martínez, V Morente, S Thanner-Lechner, M Ratschek, M Gasparetto, L Hook, D Canioni, C Wanty, A Mourin, K Laurila, M Vornane, V Nachmias Friedler, SL Morgenstern, J Amil Dias, F Carneiro, S Van Biervliet, S Vande Velde, H Banoub, S Sampson, AM Müller, A Ene, M Rafeey, and IAT Eftekhar Sadat. See the team’s individual affiliations below.**

    For their study, the team gathered data from consecutive pediatric patients 18 years or younger from 33 pediatric gastroenterology units in 21 countries. Patients all tested positive for TGA-IgA from November 2011 through May 2014, and all patients were on a gluten-containing diet. Local centers recorded patient symptoms, including measurements of total IgA, TGA, and EMA, and biopsy findings. The team recorded malabsorption when the children had chronic diarrhea, weight loss or insufficient gain, growth failure, or anemia.

    They directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers) 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. They based final diagnoses on local and central results. When all local and central results agreed for celiac disease, the team recorded those cases as proven celiac disease. Patients with TGA-IgA levels that were 3-fold or less below the ULN, but otherwise showed no indications of celiac disease, were classified as no celiac disease.

    The team conducted central histo-morphometry analysis on all other biopsies, and the cases were given a blind review. Inconclusive cases were regarded as not having celiac disease for better diagnostic accuracy and recruited 803 children for the study. They excluded 96 due to incomplete data, low level of IgA, or poor-quality biopsies, leaving 707 children, of whom 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. The group was 65.1% female, and patients averaged 6.2 years old.

    Results from local laboratories of TGA-IgA 10-fold or more above ULN, a positive EMA result, and any one symptom identified children with celiac disease (n=399) with a PPV of 99.75 (95% CI, 98.61-99.99). The PPV was 100.00 (95% CI, 98.68-100.00) in 278 patients when only malabsorption symptoms were used instead of any one symptom.

    Inclusion of HLA analyses did not increase accuracy.

    Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00).

    This study confirms that children can be accurately diagnosed with celiac disease without biopsy. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide.

    HLA analysis is not required for accurate diagnosis.

    Source:

     

    **The members of the research team are variously affiliated with the Dr. von Hauner Children’s Hospital, Ludwig-Maximilian’s University Munich, Celiac Disease Center Heim Pál Children’s Hospital, Budapest and Dept. of Pediatrics, University of Debrecen, Hungary, University of Medicine and Pharmacy “Carol Davila” and National Institute for Mother and Child Health “Alessandrescu-Rusescu”, Bucharest, Romania, Institute of Pathology, Spedali Civili, Bresci, Italy, Dept. of Clinical Immunology, Odense University Hospital, Denmark, Dept. of Pediatrics, Leiden University Medical Center, the Netherlands, Dept. of Pediatric Gastroenterology and Hepatology, La Fe University Hospital, Valencia, Spain, Dept. of Pediatric Gastroenterology, Royal Manchester Children's Hospital, Manchester, United Kingdom, Dept. of Translational Medical Sciences & European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy, Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland, Dept. of Pediatric Gastroenterology & Hepatology, Children Medical Center, Tehran University of Medical Sciences, Iran, Dept. of Pediatrics, University Medical center (UMC) Maribor, Slovenia, Hans Christian Andersen Children's Hospital, Odense University Hospital, Denmark, Division of Gastroenterology, Hepatology and Nutrition, First Dept. of Pediatrics, Children's Hospitals "Agia Sophia", University of Athens, Athens, Greece, Gastroenterology Outpatient Clinic, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria, Dept. of Pediatrics, First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic, Dept. of Pediatrics, Sapienza University of Rome, Italy, Dept. of Pediatrics, Jessa Hospital, Hasselt, Belgium, Dept. of Pediatric Gastroenterology, Addenbrookes Hospital, Cambridge, United Kingdom, Dept. of Pediatric Gastroenterology, Hepatology and Nutrition, Hôpital Necker-Enfants Malades, Paris, France, Dept. of Pediatric Gastroenterology and Nutrition, Hospital Universitari Sant Joan, Reus, Spain, Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Dept of Pediatrics, Medical University of Graz, Graz, Austria, Université Catholique de Louvain, IREC, PEDI, Cliniques universitaires Saint Luc, Brussels, Belgium, Dept. of Pediatric Gastroenterology, Hospital S. João, Porto, Portugal, Dept. of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium, Dept. of Pediatrics, St. Marien Hospital, Bonn, Germany, Queen Mary's Hospital for Children, Carshalton, United Kingdom, Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Pathology Department, Children's Memorial Health Institute, Warsaw, Poland, Pediatrics, Medical University of Warsaw, Pathomorphology, Pediatric University Hospital, Warsaw, Poland, Royal Manchester Children’s Hospital, Manchester, UK, Referral Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital Zagreb, Institute of Pathology, Medical School University of Zagreb, Zagreb, Croatia, Russian Medical Academy of Continuing Postgraduate Education, Pathology, Kidz Health Castle, UZ Brusses, Brussel, Belgium, Pediatrics, Pathology, Leiden University Medical Center (LUMC), Hôpital Saint Vincent de Paul, Catholic University, Gastroenterology & Nephrology, Pathology, Heim Pál Children's Hospital, Budapest, Pediatric Gastroenterology, Hepatology &Nutrition, Children Medical Center, Tehran University of Medical Science and Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Pathology Unit, Children Medical Center Hospital Tehran, Division of Gastroenterology and Hepatology, First Department of Pediatrics, Children’s hospital «Agia Sofia», University of Athens, Clinical Pathology, Odense University Hospital, Department of Pathology, University Medical Center Maribor, Maribor, Slovenia, Pediatric Gastroenterology & Hepatlogy and David Ramos, Pathology Unit, La Fe University Hospital Valencia, St. Anna Children's Hospital, Department of Pathology, Medical University Vienna, Dept. of Translational Medical Sciences & European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples Italy, Pediatrics, Pathology, Jessa Hospital, Hasselt, Pediatrics and Adolescent Medicine, pathologist, Institute of Pathology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic, Institute of Pathology, Ludwig Maximilian's University Munich, Munich, Germany, Pediatrics and Infantile Neuropsychiatry, Radiology, Oncology and Human Pathology, “Sapienza” University, Rome, Italy, Gastroenterology Unit, Pathology Unit, Hospital Universitari de Sant Joan de Reus, IISPV, URV, Pediatrics, Institute for Pathology, Medical University of Graz, Austria, Pediatric Gastroenterology, Hepatology & Nutrition, Pathology, Cambridge University NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK, Anatomo-Pathology, Hôpital Necker-Enfants Malades, Paris, France, Pediatric Gastroenterology, Pathology Unit, Université Catholique de Louvain, Cliniques universitaires Saint Luc, Brussels, Belgium, Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland, Institute of Gastroenterology, Nutrition & Liver Diseases, Schneider Children's Medical Center, Department of Pathology, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel, Hospital S. João, Porto, Portugal, Dept. of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Gent, Belgium, Queen Mary's Hospital for Children, Dept of Pathology, Epsom & St Helier University NHS Trust, Carshalton, UK, Department of Pathology, University of Bonn, Bonn, Germany, Histology Department National Institute for Mother and Child Health, Bucharest, Romania, and with the Liver & Gastrointestinal Research Center, Pathology Unit, Tabriz University of Medical Sciences.



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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Jefferson Adams
    Celiac.com 06/08/2016 - Sometimes, certain cases can stand out and grab the attention of clinicians or researchers. Such is the case of a 62-year-old woman who was suffering from severe malabsorption, and diagnosed with celiac disease based on the findings of flat, small intestinal mucosa and HLA-DQ2 positivity, although celiac blood tests were negative.
    A team of researchers questioned the diagnosis, because the woman showed no clinical or histological improvement after a long period of strict gluten-free diet.
    The research team included U Volta, MG Mumolo, G Caio, E Boschetti, R Latorre, F Giancola, P Paterini, and R De Giorgio. They variously are affiliated with the Department of Medical and Surgical Sciences at the University of Bologna, and with the Gastroenterology Unit in the Department of Gastroenterology at the University of Pisa in Italy.
    Based on the detection of enterocyte autoantibodies, the team found that the correct diagnosis for the woman was autoimmune enteropathy. After appropriate immunosuppressive treatment, the woman experienced the disappearance of all symptoms, and a complete recovery.
    Based on this case, the team notes that doctors should consider autoimmune enteropathy in the differential diagnosis of malabsorption with severe villous atrophy, including those cases with negative celiac-related serology.
    Source:
    Gastroenterol Hepatol Bed Bench. 2016 Spring;9(2):140-5.

    Jefferson Adams
    Celiac.com 01/09/2017 - Some researchers have criticized the usefulness of the 7 level Marsh-Oberhuber classification of mucosal damage in patients with celiac disease.
    Even though assessing duodenal biopsies with dissecting microscopy is a somewhat crude method, it can provide useful information in cases of obvious villous atrophy.
    For the past 15 years, one research team has analyzed duodenal biopsies with dissecting microscopy before sending them to the pathology department for histology. Their feeling is that, if dissecting microscopy and traditional histology were comparable, the grading of the histological lesion would be unnecessary, or even pointless, for proper diagnosis of most enteropathies.
    That research team recently set out to settle that question. The team included F Biagi, C Vattiato, M Burrone, A Schiepatti, S Agazzi, G Maiorano, O Luinetti, C Alvisi, C Klersy, and GR Corazza. They are variously affiliated with the First Department of Internal Medicine, the Biometry and Statistics, the Department of Pathology at University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; and with the Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
    They conducted a retrospective analysis of the clinical notes of all 2,075 patients undergoing duodenal biopsy between September 1999 and June 2015. They collected and statistically compared the results of duodenal mucosal evaluation with both dissecting microscopy and traditional histology.
    Their results, using κ statistics, showed a substantial agreement of the two methods (κ statistics 0.78). Sensitivity of dissecting microscopy for detection of severe villous atrophy was 85.1% (95% CI 81.2% to 88.5%) and specificity was 95% (95% CI 93.8% to 96%).
    Although dissecting microscopy is no substitute for traditional histology, these results suggest that most celiac disease-related and other flat enteropathies can be sufficiently diagnosed without grading villous atrophy.
    Source:
    J Clin Pathol. 2016 Dec;69(12):1051-1054. doi: 10.1136/jclinpath-2016-203711. Epub 2016 May 4.

    Jefferson Adams
    Celiac.com 06/05/2017 - Doctors diagnose celiac disease by confirming various clinical, genetic, serologic, and duodenal morphology features. Based on retrospective data, recent pediatric guidelines propose eliminating biopsy for patients with IgA-TTG levels more than 10-times the upper limit of normal (ULN), along with a few other criteria.
    One retrospective study showed that researchers using levels of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients both with and without celiac disease. A team of researchers recently set out to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures.
    The research team included Johannes Wolf, David Petroff, Thomas Richter, Marcus KH. Auth, Holm H. Uhlig, Martin W. Laass, Peter Lauenstein, Andreas Krahl, Norman Händel, Jan de Laffolie, Almuthe C. Hauer, Thomas Kehler, Gunter Flemming, Frank Schmidt, Astor Rodriques, Dirk Hasenclever, and Thomas Mothes.
    Their team conducted a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. They then compared results from antibody tests with results from biopsies, follow-up data, and diagnoses made by the pediatric gastroenterologists. In all cases, diagnosis was made for celiac disease, no celiac disease, or no final diagnosis.
    Blinded researchers measured levels of IgA-TTG, IgG-DGL, and endomysium antibodies, while tissue sections were analyzed by local and blinded reference pathologists. The team validated two procedures for diagnosis: total-IgA and IgA-TTG, as well as IgG-DGL with IgA-TTG. Patients whose antibody concentrations for all tests were below 1-fold the ULN were assigned to the no celiac disease category.
    Those whose antibody concentrations for at least one test were above 10-fold the ULN were assigned to the celiac disease category. All other cases were considered to require biopsy analysis.
    The team calculated the ULN values using the cut-off levels suggested by the test kit manufacturers. They conducted HLA-typing for 449 participants. To extrapolate the PPV and NPV to populations with lower rates of celiac disease, they used models that accounted for how specificity values change with prevalence.
    In all, the team found 592 patients with celiac disease, 345 who did not have celiac disease, and 24 with no final diagnosis.
    The TTG-IgA procedure identified celiac disease patients with a PPV of 0.988 and an NPV of 0.934. The TTG-DGL procedure identified celiac disease patients with a PPV of 0.988 and an NPV of 0.958.
    Their extrapolation model estimated that PPV and NPV would remain above 0.95 even at a disease prevalence as low as 4%. Meanwhile, tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG 10-fold or more above the ULN.
    Interestingly, the pathologists disagreed in their analyses of duodenal morphology about 4.2% of the time, a rate comparable to the error rate for serologic tests.
    This study validates the use of the TTG-IgA procedure and the TTG-DGL procedure in lieu of biopsy to diagnose pediatric patients with or without celiac disease.
    Source:
    Gastroenterology. DOI: http://dx.doi.org/10.1053/j.gastro.2017.04.023  
    The researchers are variously affiliated with the Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University and University Hospital, Leipzig, Germany, the Institute for Medical Informatics, Statistics & Epidemiology (IMISE), University of Leipzig, Germany, the Department of Paediatrics, University of Oxford, Oxford, United Kingdom, the Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, the, University Children's Hospital Halle, Germany, the Medical School, Hannover, Germany, Helios Hospital, Department of Paediatrics, Plauen, Germany, the Children's Hospital Prinzessin Margaret, Darmstadt, Germany, the University Children's Hospital Graz, Austria, the Children's Hospital, Justus Liebig University Giessen, Germany, the University Children's Hospital Leipzig, Germany, the Children's Hospital of the Clinical Centre Sankt Georg Leipzig, Germany, the Clinical Trial Centre, University of Leipzig, Germany, the DKD Helios Children's Hospital, German Clinic for Diagnostics, Wiesbaden, Germany, the University Children's Hospital, Technical University Dresden, Germany, and the Alder Hey Children's National Health Service Foundation Trust, Liverpool, United Kingdom.

    Jefferson Adams
    Celiac.com 07/13/2017 - Until recently, duodenal biopsy was considered the gold standard for diagnosing celiac disease, but that is changing.
    A number of studies have shown that celiac disease can be diagnosed using serological tests alone, but many clinicians have yet to embrace this approach.
    In both retrospective and prospective studies, one research team showed that certain IgA-tissue transglutaminase antibodies levels can predict celiac disease in adults 100% of the time.
    After making some adjustments to the analytical method for measuring the antibody, a team of researchers recently set out to to determine whether such serum tests can reliably diagnose celiac disease in large numbers adult patients without the need for small bowel biopsy.
    The research team included GKT Holmes, JM Forsyth, S Knowles, H Seddon, PG Hill, and AS Austin.
    They are variously associated with the Royal Derby Hospital, the Department of Pathology, and the Derby Digestive Diseases Centre at the Royal Derby Hospital in Derby, UK.
    For their study, the team conducted a retrospective analysis in an unselected series of 270 adult patients who underwent small bowel biopsies and the measurement of serum IgA-tissue transglutaminase antibody levels from 2009 to 2014.
    At an IgA-tissue transglutaminase antibody cut-off greater than 45 U/ml (>8×upper limit of normal+2SDs) the positive predictive value for celiac disease in this cohort was 100%; 40% of cases were above this cut-off.
    The team found that they could use IgA-tissue transglutaminase antibody levels to reliably diagnose celiac disease in a high proportion of these adult patients.
    This study adds to the growing body of evidence that supports the diagnosis of celiac disease without a mandatory small bowel biopsy.
    As a realist of these findings, the study team has changed the diagnostic guidelines for their center, and will now make celiac diagnosis based on cut-off levels of IgA-tissue transglutaminase.
    This is exciting news. For many, many years, the biopsy was considered the gold standard for diagnosing celiac disease.
    By eliminating biopsies in favor of IgA-tissue transglutaminase levels, diagnosing celiac disease could become much easier and even cheaper.
    Do you have celiac disease? Did you receive a biopsy for diagnosis? How do you feel about celiac diagnosis without biopsy? Share your thoughts below.
    Source:
    Eur J Gastroenterol Hepatol. 2017 Jun;29(6):640-645. doi: 10.1097/MEG.0000000000000841.

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    And he needs to be super strict in his gluten free diet! SUPER strict, not just low gluten. No cross contamination, NONE.  I am so sorry, there are no short cuts with the testing. It flat out sucks but there you have it.  Welcome to the forum!
    Hi TDZ, My understanding is the same, a full gluten challenge is needed for the DH diagnosis.  The method the use for DH is to take a skin biopsy from next to a lesion, not on it.  They check the biopsy for IgA antibodies. I don't know of any way to shortcut the process and avoid eating gluten to get tested.  There may be a test some  day that doesn't require it, but for now I don't think there are any out there. One thing he might not have tried is avoiding iodine.  Some of the m
    Hello, new here and new to the whole thing! My husband has been battling this rash and assorted digestive issues for years. He was diagnosed with contact dermatitis by the dermatologist, had some steroid injections and various creams over the last couple of years, and then in November he went to the ER and they said eczema and gave him steroid pills. This was after a huge bloom that pretty much hit him from head to toe, where it had been mostly arms and legs before. He finally concluded he
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