|
1
|
Shiha MG, Hadjisavvas N, Sanders DS, Penny HA. Optimising the Diagnosis of Adult Coeliac Disease: Current Evidence and Future Directions. Br J Hosp Med (Lond) 2024; 85:1-21. [PMID: 39347683 DOI: 10.12968/hmed.2024.0362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Coeliac disease is a common autoimmune disorder that affects nearly 1% of the general population. Current diagnostic strategies involve active case finding, serological tests, and endoscopy with biopsies. However, many patients with coeliac disease remain undiagnosed due to a wide gap between clinical guidelines and real-world practice in the diagnosis of adult coeliac disease. This highlights the need for increased education, training, and targeted quality-improvement interventions to optimise the diagnosis of coeliac disease.
Collapse
Affiliation(s)
- Mohamed G Shiha
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | | | - David S Sanders
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Hugo A Penny
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
2
|
Tye‐Din JA. Evolution in coeliac disease diagnosis and management. JGH Open 2024; 8:e13107. [PMID: 38957478 PMCID: PMC11217771 DOI: 10.1002/jgh3.13107] [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] [Received: 03/18/2024] [Revised: 05/04/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
The traditional gut-centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease - well demonstrated in children - are growing for adults. Novel biomarkers such as interleukin-2 that identify the gluten-specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case-finding strategy and enthusiasm for population screening is growing. The gluten-free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly-responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super-sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.
Collapse
Affiliation(s)
- Jason A Tye‐Din
- Immunology DivisionWalter and Eliza Hall InstituteParkvilleVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia
- Department of GastroenterologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Centre for Food & Allergy ResearchThe Murdoch Children's Research InstituteParkvilleVictoriaAustralia
| |
Collapse
|
|
3
|
Syage JA, Mäki M, Leffler DA, Silvester JA, Sealey-Voyksner JA, Wu TT, Murray JA. A Composite Morphometric Duodenal Biopsy Mucosal Scale for Celiac Disease Encompassing Both Morphology and Inflammation. Clin Gastroenterol Hepatol 2024; 22:1238-1244.e3. [PMID: 37952751 DOI: 10.1016/j.cgh.2023.10.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/27/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND & AIMS Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease. Although the field of celiac disease has advanced, there remains no broadly accepted measure of mucosal injury. We assessed whether a composite Vh:Cd and IEL scale (VCIEL) can improve accuracy and statistical precision for assessing histology, compared with individual measures. METHODS The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results. The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IEL were compared with those for VCIEL with regards to clinical significance (effect size) and statistical significance. RESULTS For the ALV003-1021 trial, we observed an effect size and P value (analysis of covariance) of 1.37 and 0.038 for ΔVh:Cd, 1.17 and 0.005 for ΔIEL, and 1.86 and 0.004 for ΔVCIEL. For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76 and 0.057 for ΔVh:Cd, 0.98 and 0.018 for ΔIEL, and 1.14 and 0.007 for ΔVCIEL. Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study. CONCLUSIONS The composite VCIEL scale combining Vh:Cd and IEL values seems to improve accuracy and statistical precision compared with either component alone.
Collapse
Affiliation(s)
| | - Markku Mäki
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Daniel A Leffler
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts
| | - Jocelyn A Silvester
- Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts
| | | | | | | |
Collapse
|
|
4
|
Punia P, Bala K, Verma M, Nandi A, Mahlotra P, Singh S, Garg S, Parmar A, Kumar D. Feasibility of a "No-Biopsy" Approach for the Diagnosis of Celiac Disease in Symptomatic Adults. Cureus 2024; 16:e54578. [PMID: 38523934 PMCID: PMC10957510 DOI: 10.7759/cureus.54578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2024] [Indexed: 03/26/2024] Open
Abstract
Celiac disease (CD) is an immune-mediated enteropathy, caused by hypersensitivity to gluten in genetically predisposed individuals. The worldwide prevalence of CD has been estimated to be approximately 1%. Most guidelines for diagnosis of CD rely on a sequential approach, with serological testing of antibodies against tissue transglutaminase (tTG) as a first-line test, followed by a duodenal biopsy. However, GI biopsy is an invasive procedure with various complications. Hence, this study was planned to ascertain whether it could be possible to have a non-biopsy approach, using only serological markers to establish the diagnosis of CD in adults. MATERIAL AND METHODS It was a retrospective analysis of medical records of all biopsy-diagnosed CD patients with available anti-tTGA antibodies reports from 2019 to 2023. The patients were divided into three groups based on Marsh grading and anti-tTGA antibody levels were compared using various statistical tests. RESULTS A total of 94 biopsy-diagnosed symptomatic CD patients with anti-tTGA antibody reports available formed the study group. Of these, 54 had biopsy findings consistent with Marsh 3 lesion, three had Marsh 2 lesion, and 37 had Marsh 1 lesion. A significant correlation existed between Marsh grading 3 lesion and anti-tTGA antibody levels above the upper limit of normal (ULN) x 10. CONCLUSION Serum levels of anti-tTGA antibodies greater than 10 x ULN can be used to identify symptomatic patients with Marsh grade 3 CD lesions.
Collapse
Affiliation(s)
- Parul Punia
- Microbiology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Kiran Bala
- Microbiology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Mansi Verma
- Microbiology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Ankita Nandi
- Microbiology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Parveen Mahlotra
- Gastroenterology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Sunita Singh
- Pathology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Seema Garg
- Microbiology, BPS Government Medical College for Women, Sonepat, IND
| | - Aparna Parmar
- Microbiology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | - Devender Kumar
- Oral Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| |
Collapse
|
|
5
|
Fowler A, FitzPatrick M, Shanmugarasa A, Ibrahim ASF, Kockelbergh H, Yang HC, Williams-Walker A, Luu Hoang KN, Evans S, Provine N, Klenerman P, Soilleux EJ. An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease. Biomolecules 2023; 13:1707. [PMID: 38136579 PMCID: PMC10742135 DOI: 10.3390/biom13121707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
Coeliac disease (CeD) is a T-cell mediated enteropathy triggered by dietary gluten which remains substantially under-diagnosed around the world. The diagnostic gold-standard requires histological assessment of intestinal biopsies taken at endoscopy while consuming a gluten-containing diet. However, there is a lack of concordance between pathologists in histological assessment, and both endoscopy and gluten challenge are burdensome and unpleasant for patients. Identification of gluten-specific T-cell receptors (TCRs) in the TCR repertoire could provide a less subjective diagnostic test, and potentially remove the need to consume gluten. We review published gluten-specific TCR sequences, and develop an interpretable machine learning model to investigate their diagnostic potential. To investigate this, we sequenced the TCR repertoires of mucosal CD4+ T cells from 20 patients with and without CeD. These data were used as a training dataset to develop the model, then an independently published dataset of 20 patients was used as the testing dataset. We determined that this model has a training accuracy of 100% and testing accuracy of 80% for the diagnosis of CeD, including in patients on a gluten-free diet (GFD). We identified 20 CD4+ TCR sequences with the highest diagnostic potential for CeD. The sequences identified here have the potential to provide an objective diagnostic test for CeD, which does not require the consumption of gluten.
Collapse
Affiliation(s)
- Anna Fowler
- Department of Health Data Science, Institute of Population Health, University of Liverpool, Liverpool L69 3GF, UK
| | - Michael FitzPatrick
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; (M.F.); (P.K.)
| | | | - Amro Sayed Fadel Ibrahim
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| | - Hannah Kockelbergh
- Department of Health Data Science, Institute of Population Health, University of Liverpool, Liverpool L69 3GF, UK
| | - Han-Chieh Yang
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| | - Amelia Williams-Walker
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| | - Kim Ngan Luu Hoang
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| | - Shelley Evans
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| | - Nicholas Provine
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; (M.F.); (P.K.)
| | - Paul Klenerman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; (M.F.); (P.K.)
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Elizabeth J. Soilleux
- Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK; (A.S.F.I.); (H.-C.Y.); (A.W.-W.); (K.N.L.H.); (S.E.); (E.J.S.)
| |
Collapse
|
|
6
|
Ciacci C, Bai JC, Holmes G, Al-Toma A, Biagi F, Carroccio A, Ciccocioppo R, Di Sabatino A, Gingold-Belfer R, Jinga M, Makharia G, Niveloni S, Norman GL, Rostami K, Sanders DS, Smecuol E, Villanacci V, Vivas S, Zingone F. Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study. Lancet Gastroenterol Hepatol 2023; 8:1005-1014. [PMID: 37696284 DOI: 10.1016/s2468-1253(23)00205-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease. METHODS In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data. FINDINGS We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet. INTERPRETATION Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA. FUNDING None.
Collapse
Affiliation(s)
- Carolina Ciacci
- Centre for Coeliac Disease, AOU San Giovanni Di Dio e Ruggi d'Aragona, Salerno, Italy; Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Italy.
| | - Julio Cesar Bai
- Research Institutes, Universidad del Salvador, Buenos Aires, Argentina; Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Geoffrey Holmes
- Department of Gastroenterology, Royal Derby Hospital, Derby, UK
| | - Abdulbaqi Al-Toma
- Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, Netherlands
| | - Federico Biagi
- Department of Internal Medicine and Medical Therapy, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy; Gastroenterology Unit of Pavia Institute, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy
| | - Antonio Carroccio
- Unit of Internal Medicine, Cervello Hospital, University of Palermo, Palermo, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico GB Rossi, University of Verona, Verona, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine and Medical Therapy, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Rachel Gingold-Belfer
- Gastroenterology Division, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mariana Jinga
- Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, Bucharest, Romania
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sonia Niveloni
- Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Gary L Norman
- Research and Development, Headquarters and Technology Centre for Autoimmunity, Werfen, San Diego, CA, USA
| | - Kamran Rostami
- Gastroenterology Unit, MidCentral DHB, Palmerston North, New Zealand
| | - David S Sanders
- Academic Unit of Gastroenterology, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
| | - Edgardo Smecuol
- Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Vincenzo Villanacci
- Institute of Pathology, Spedali Civili University of Brescia, Brescia, Italy
| | - Santiago Vivas
- Gastroenterology Unit, University Hospital of Leon, Leon, Spain
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| |
Collapse
|
|
7
|
Schreiber B, Denholm J, Gilbey J, Schönlieb CB, Soilleux E. Stain normalization gives greater generalizability than stain jittering in neural network training for the classification of coeliac disease in duodenal biopsy whole slide images. J Pathol Inform 2023; 14:100324. [PMID: 37577172 PMCID: PMC10416012 DOI: 10.1016/j.jpi.2023.100324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 08/15/2023] Open
Abstract
Around 1% of the population of the UK and North America have a diagnosis of coeliac disease (CD), due to a damaging immune response to the small intestine. Assessing whether a patient has CD relies primarily on the examination of a duodenal biopsy, an unavoidably subjective process with poor inter-observer concordance. Wei et al. [11] developed a neural network-based method for diagnosing CD using a dataset of duodenal biopsy whole slide images (WSIs). As all training and validation data came from one source, there was no guarantee that their results would generalize to WSIs obtained from different scanners and laboratories. In this study, the effects of applying stain normalization and jittering to the training data were compared. We trained a deep neural network on 331 WSIs obtained with a Ventana scanner (WSIs; CD: n = 190 ; normal: n = 141 ) to classify presence of CD. In order to test the effects of stain processing when validating on WSIs scanned on varying scanners and from varying laboratories, the neural network was validated on 4 datasets: WSIs of slides scanned on a Ventana scanner (WSIs; CD: n = 48 ; normal: n = 35 ), WSIs of the same slides rescanned on a Hamamatsu scanner (WSIs; CD: n = 48 ; normal: n = 35 ), WSIs of the same slides rescanned on an Aperio scanner (WSIs; CD: n = 48 ; normal: n = 35 ), and WSIs of different slides scanned on an Aperio scanner (WSIs; CD: n = 38 ; normal: n = 37 ). Without stain processing, the F1 scores of the neural network were 0.947 , 0.619 , 0.746 , and 0.727 when validating on the Ventana validation WSIs, Hamamatsu and Aperio rescans of the Ventana validation WSIs, and Aperio WSIs from a different source respectively. With stain normalization, the performance of the neural network improved significantly with respective F1 scores 0.982 , 0.943 , 0.903 , and 0.847 . Stain jittering resulted in a better performance than stain normalization when validating on data from the same source F1 score 1.000 , but resulted in poorer performance than stain normalization when validating on WSIs from different scanners (F1 scores 0.939 , 0.814 , and 0.747 ). This study shows the importance of stain processing, in particular stain normalization, when training machine learning models on duodenal biopsy WSIs to ensure generalizability between different scanners and laboratories.
Collapse
Affiliation(s)
- B.A. Schreiber
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
| | - J. Denholm
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
- Lyzeum Ltd., Cambridge, UK
| | - J.D. Gilbey
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
| | - C.-B. Schönlieb
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
- Lyzeum Ltd., Cambridge, UK
| | - E.J. Soilleux
- Department of Pathology, University of Cambridge, Cambridge, UK
- Lyzeum Ltd., Cambridge, UK
| |
Collapse
|
|
8
|
Popp A, Laurikka P, Czika D, Kurppa K. The role of gluten challenge in the diagnosis of celiac disease: a review. Expert Rev Gastroenterol Hepatol 2023; 17:691-700. [PMID: 37243608 DOI: 10.1080/17474124.2023.2219893] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/12/2023] [Accepted: 05/26/2023] [Indexed: 05/29/2023]
Abstract
INTRODUCTION Duodenal biopsy is the gold standard in the diagnosis of celiac disease, with increasing utilization of serology. A gluten challenge may be required, for example, when dietary gluten reduction precedes appropriate diagnostic evaluations. Evidence on the best challenge protocol is currently sparse. Pharmaceutical trials in recent years may have provided new insights into the challenge and advanced the development of novel sensitive histological and immunological methods. AREAS COVERED This review outlines the current perspectives on the use of gluten challenge in the diagnosis of celiac disease and explores future directions in this area. EXPERT OPINION Comprehensive elimination of celiac disease before dietary gluten restriction is essential to avoid diagnostic uncertainties. Gluten challenge continues to have an important role in certain clinical scenarios, although it is important to understand its limitations in the diagnostic evaluation. The evidence so far permits no unequivocal recommendation considering the timing, duration, and amount of gluten used in the challenge. Thus, these decisions should be made on a case-by-case basis. Further studies with more standardized protocols and outcome measures are called for. In the future novel immunological methods may help to shorten or even avoid gluten challenge.
Collapse
Affiliation(s)
- Alina Popp
- Department of Pediatrics, University of Medicine and Pharmacy Carol Davila and National Institute for Mother and Child Health, Bucharest, Romania
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Pilvi Laurikka
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Diana Czika
- Department of Pediatrics, University of Medicine and Pharmacy Carol Davila and National Institute for Mother and Child Health, Bucharest, Romania
| | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent and Maternal Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
- The University Consortium of Seinäjoki, Seinäjoki, Finland
| |
Collapse
|
|
9
|
Shiha MG, Raju SA, Sidhu R, Penny HA. The debate in the diagnosis of coeliac disease - time to go 'no-biopsy'? Curr Opin Gastroenterol 2023; 39:192-199. [PMID: 37144537 DOI: 10.1097/mog.0000000000000929] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
PURPOSE OF REVIEW Duodenal biopsies have been central to making a diagnosis of coeliac disease for the last 70 years. Recent paediatric guidelines have reduced the emphasis on duodenal biopsies with the incorporation of a 'no-biopsy' arm to the diagnostic pathway. This review discusses the no-biopsy approach in adults and highlights advances in alternative (non-biopsy) diagnostic modalities in coeliac disease. RECENT FINDINGS Evidence suggests that a no-biopsy approach for the diagnosis of adult coeliac disease is accurate. However, a number of factors still favour duodenal biopsy sampling in specific patient groups. Moreover, several factors need to be considered if this pathway is implemented into local gastroenterology services. SUMMARY Duodenal biopsies remain an important step in the diagnosis of adult coeliac disease. However, an alternative approach that removes the necessity for biopsies may be an option in selected adults. If further guidelines incorporate this pathway, then efforts should focus on supporting a dialogue between primary and secondary care to facilitate the appropriate implementation of this approach.
Collapse
Affiliation(s)
- Mohamed G Shiha
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
- Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Suneil A Raju
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
- Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Reena Sidhu
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
- Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Hugo A Penny
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
- Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| |
Collapse
|
|
10
|
Garzón-Benavides M, Ruiz-Carnicer Á, Segura V, Fombuena B, García-Fernandez F, Sobrino-Rodriguez S, Gómez-Izquierdo L, Montes-Cano MA, Millan-Domínguez R, Del Carmen Rico M, González-Naranjo C, Bozada-García JM, Coronel-Rodríguez C, Espin B, Díaz J, Comino I, Argüelles-Arias F, Cebolla Á, Romero-Gómez M, Rodriguez-Herrera A, Sousa C, Pizarro-Moreno Á. Clinical utility of urinary gluten immunogenic peptides in the follow-up of patients with coeliac disease. Aliment Pharmacol Ther 2023; 57:993-1003. [PMID: 36890679 DOI: 10.1111/apt.17417] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/04/2022] [Accepted: 01/31/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND Gluten-free diet (GFD) is the only treatment for patients with coeliac disease (CD) and its compliance should be monitored to avoid cumulative damage. AIMS To analyse gluten exposures of coeliac patients on GFD for at least 24 months using different monitoring tools and its impact on duodenal histology at 12-month follow-up and evaluate the interval of determination of urinary gluten immunogenic peptides (u-GIP) for the monitoring of GFD adherence. METHODS Ninety-four patients with CD on a GFD for at least 24 months were prospectively included. Symptoms, serology, CDAT questionnaire, and u-GIP (three samples/visit) were analysed at inclusion, 3, 6, and 12 months. Duodenal biopsy was performed at inclusion and 12 months. RESULTS At inclusion, 25.8% presented duodenal mucosal damage; at 12 months, this percentage reduced by half. This histological improvement was indicated by a reduction in u-GIP but did not correlate with the remaining tools. The determination of u-GIP detected a higher number of transgressions than serology, regardless of histological evolution type. The presence of >4 u-GIP-positive samples out of 12 collected during 12 months predicted histological lesion with a specificity of 93%. Most patients (94%) with negative u-GIP in ≥2 follow-up visits showed the absence of histological lesions (p < 0.05). CONCLUSION This study suggests that the frequency of recurrent gluten exposures, according to serial determination of u-GIP, could be related to the persistence of villous atrophy and that a more regular follow-up every 6 months, instead of annually, provides more useful data about the adequate adherence to GFD and mucosal healing.
Collapse
Affiliation(s)
- Marta Garzón-Benavides
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - Ángela Ruiz-Carnicer
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Verónica Segura
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Blanca Fombuena
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - Francisco García-Fernandez
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - Salvador Sobrino-Rodriguez
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | | | - Marco Antonio Montes-Cano
- Inmunology Service, CIBER of Epidemiology and Public Health, Virgen del Rocío Hospital /IBiS/CSIC/University of Seville, Seville, Spain
| | - Raquel Millan-Domínguez
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - María Del Carmen Rico
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - Carmen González-Naranjo
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | - Juan Manuel Bozada-García
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | | | - Beatriz Espin
- Pediatric, Gastroenterology, Hepatology and Nutrition Section, Virgen del Rocio Children's Hospital, Seville, Spain
| | - Jacobo Díaz
- Clinical Analysis Service, Hospital Universitario INGESA, Ceuta, Spain
| | - Isabel Comino
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Federico Argüelles-Arias
- Digestive Diseases Clinical Unit, Virgen Macarena Hospital, Seville, and University of Seville, Seville, Spain
| | | | - Manuel Romero-Gómez
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| | | | - Carolina Sousa
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Ángeles Pizarro-Moreno
- Digestive Disease Clinical Unit. and CIBERehd, Institute of Biomedicine of Seville (IBiS), SeLiver Group, Virgen del Rocío Hospital/CSIC/US, Seville, Spain
| |
Collapse
|
|
11
|
Faust O, De Michele S, Koh JE, Jahmunah V, Lih OS, Kamath AP, Barua PD, Ciaccio EJ, Lewis SK, Green PH, Bhagat G, Acharya UR. Automated analysis of small intestinal lamina propria to distinguish normal, Celiac Disease, and Non-Celiac Duodenitis biopsy images. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2023; 230:107320. [PMID: 36608429 DOI: 10.1016/j.cmpb.2022.107320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 12/16/2022] [Accepted: 12/18/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND AND OBJECTIVE Celiac Disease (CD) is characterized by gluten intolerance in genetically predisposed individuals. High disease prevalence, absence of a cure, and low diagnosis rates make this disease a public health problem. The diagnosis of CD predominantly relies on recognizing characteristic mucosal alterations of the small intestine, such as villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. However, these changes are not entirely specific to CD and overlap with Non-Celiac Duodenitis (NCD) due to various etiologies. We investigated whether Artificial Intelligence (AI) models could assist in distinguishing normal, CD, and NCD (and unaffected individuals) based on the characteristics of small intestinal lamina propria (LP). METHODS Our method was developed using a dataset comprising high magnification biopsy images of the duodenal LP compartment of CD patients with different clinical stages of CD, those with NCD, and individuals lacking an intestinal inflammatory disorder (controls). A pre-processing step was used to standardize and enhance the acquired images. RESULTS For the normal controls versus CD use case, a Support Vector Machine (SVM) achieved an Accuracy (ACC) of 98.53%. For a second use case, we investigated the ability of the classification algorithm to differentiate between normal controls and NCD. In this use case, the SVM algorithm with linear kernel outperformed all the tested classifiers by achieving 98.55% ACC. CONCLUSIONS To the best of our knowledge, this is the first study that documents automated differentiation between normal, NCD, and CD biopsy images. These findings are a stepping stone toward automated biopsy image analysis that can significantly benefit patients and healthcare providers.
Collapse
Affiliation(s)
| | - Simona De Michele
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA
| | - Joel Ew Koh
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | - V Jahmunah
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | - Oh Shu Lih
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | | | - Prabal Datta Barua
- Cogninet Australia, Sydney, NSW 2010, Australia; School of Management & Enterprise, University of Southern Queensland, Australia; Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Edward J Ciaccio
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Suzanne K Lewis
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Peter H Green
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA; Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - U Rajendra Acharya
- School of Science and Technology, Singapore University of Social Sciences, 463 Clementi Road, 599494, Singapore; Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
| |
Collapse
|
|
12
|
Endoscopy, video capsule endoscopy, and biopsy for automated celiac disease detection: A review. Biocybern Biomed Eng 2022. [DOI: 10.1016/j.bbe.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
13
|
Denholm J, Schreiber B, Evans S, Crook O, Sharma A, Watson J, Bancroft H, Langman G, Gilbey J, Schönlieb CB, Arends M, Soilleux E. Multiple-instance-learning-based detection of coeliac disease in histological whole-slide images. J Pathol Inform 2022; 13:100151. [PMID: 36605111 PMCID: PMC9808019 DOI: 10.1016/j.jpi.2022.100151] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/21/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
We present a multiple-instance-learning-based scheme for detecting coeliac disease, an autoimmune disorder affecting the intestine, in histological whole-slide images (WSIs) of duodenal biopsies. We train our model to detect 2 distinct classes, normal tissue and coeliac disease, on the patch-level, and in turn leverage slide-level classifications. Using 5-fold cross-validation in a training set of 1841 (1163 normal; 680 coeliac disease) WSIs, our model classifies slides as normal with accuracy (96.7±0.6)%, precision (98.0±1.7)%, and recall (96.8±2.5)%, and as coeliac disease with accuracy (96.7±0.5)%, precision (94.9±3.7)%, and recall (96.5±2.9)% where the error bars are the cross-validation standard deviation. We apply our model to 2 test sets: one containing 191 WSIs (126 normal; 65 coeliac) from the same sources as the training data, and another from a completely independent source, containing 34 WSIs (17 normal; 17 coeliac), obtained with a scanner model not represented in the training data. Using the same-source test data, our model classifies slides as normal with accuracy 96.5%, precision 98.4% and recall 96.1%, and positive for coeliac disease with accuracy 96.5%, precision 93.5%, and recall 97.3%. Using the different-source test data the model classifies slides as normal with accuracy 94.1% (32/34), precision 89.5%, and recall 100%, and as positive for coeliac disease with accuracy 94.1%, precision 100%, and recall 88.2%. We discuss generalising our approach to screen for a range of pathologies.
Collapse
Affiliation(s)
- J. Denholm
- Lyzeum Ltd, Salisbury House, Station Road, Cambridge CB1 2LA, Cambridgeshire, UK,Department of Applied Maths and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, Cambridgeshire, UK,Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, Cambridgeshire, UK,Corresponding author.
| | - B.A. Schreiber
- Department of Applied Maths and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, Cambridgeshire, UK,Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, Cambridgeshire, UK
| | - S.C. Evans
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, Cambridgeshire, UK
| | - O.M. Crook
- The Alan Turing Institute, 96 Euston Rd, London NW1 2DB, UK
| | - A. Sharma
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, Cambridgeshire, UK
| | - J.L. Watson
- Oxford Medical School, University of Oxford, S Parks Road, Oxford OX1 3PL, Oxfordshire, UK
| | - H. Bancroft
- Department of Cellular Pathology, Birmingham Heartlands Hospital, University Hospitals Birmingham, 45 Bordesley Green East, Birmingham B9 5SS, West Midlands, UK
| | - G. Langman
- Department of Cellular Pathology, Birmingham Heartlands Hospital, University Hospitals Birmingham, 45 Bordesley Green East, Birmingham B9 5SS, West Midlands, UK
| | - J.D. Gilbey
- Department of Applied Maths and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, Cambridgeshire, UK
| | - C.-B. Schönlieb
- Department of Applied Maths and Theoretical Physics, University of Cambridge, Centre for Mathematical Sciences, Wilberforce Road, Cambridge CB3 0WA, Cambridgeshire, UK
| | - M.J. Arends
- Division of Pathology, University of Edinburgh, Cancer Research UK Edinburgh Centre, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, Lothian, Scotland
| | - E.J. Soilleux
- Lyzeum Ltd, Salisbury House, Station Road, Cambridge CB1 2LA, Cambridgeshire, UK,Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, Cambridgeshire, UK
| |
Collapse
|
|
14
|
Virta J, Hannula M, Lindfors K, Tamminen I, Taavela J, Huhtala H, Kaukinen K, Saavalainen P, Hyttinen J, Kurppa K. Validation of the X-ray microtomography in the assessment of duodenal morphometry and surface area in celiac disease. Front Immunol 2022; 13:945197. [PMID: 36211435 PMCID: PMC9539806 DOI: 10.3389/fimmu.2022.945197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background Duodenal histology remains the diagnostic reference standard in celiac disease. However, traditional methods have suboptimal sensitivity and reproducibility for early mucosal changes and research purposes. We validated a recently introduced micro-CT imaging method for an accurate digital evaluation of duodenal histomorphometry and mucosal surface areas. Methods Endoscopic biopsies from 58 individuals were utilized for the micro-CT imaging, selecting histological changes ranging from normal to severely damaged mucosa. The imaging protocol was optimized for practicability and resolution. The Bland–Altman method was applied to test intra- and interobserver variations in the blinded measurements. Results The 3D micro-CT reconstructions enabled easy and precise digital cutting with optimal orientation and computer-assisted measurement of the surface area. Intraobserver analysis of morphological measurements showed a mean difference of 0.011 with limits of agreement (LA) from -0.397 to 0.375 and a standard deviation (SD) of 0.197. The corresponding figures for interobserver analysis were 0.080, from -0.719 to 0.537 and 0.320, respectively. The intraclass correlation coefficients (ICC) for the intraobserver and interobserver variations were 0.981 and 0.954, respectively. Intraobserver surface area analysis yielded a mean difference of 0.010, LA from -0.764 to 0.785 and an SD of 0.395, and an interobserver analysis mean difference of 0.028, LA from -0.642 to 0.698 and SD of 0.342. The respective ICCs for the intra- and interobserver variations were 0.963 and 0.972. Conclusions Micro-CT showed excellent accuracy and reproducibility in the evaluation of mucosal morphometry and surface areas. The improved sensitivity for histological changes is a powerful tool for the diagnosis of celiac disease and for clinical and pharmacological studies.
Collapse
Affiliation(s)
- Johannes Virta
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Markus Hannula
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Ilmari Tamminen
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Juha Taavela
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Päivi Saavalainen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Jari Hyttinen
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Kalle Kurppa
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- The University Consortium of Seinäjoki and Seinäjoki Central Hospital, Seinäjoki, Finland
- *Correspondence: Kalle Kurppa,
| |
Collapse
|
|
15
|
Tryfon S, Papadopoulou E, Psarros G, Agrafiotis M, Saroglou M. Celiac disease and idiopathic pulmonary hemosiderosis: A literature review of the Lane-Hamilton Syndrome. Postgrad Med 2022; 134:732-742. [PMID: 35912848 DOI: 10.1080/00325481.2022.2109121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Lane-Hamilton syndrome (LHS) presents a medical emergency, with 14% mortality due to Idiopathic Pulmonary Hemosiderosis (IPH) in acute phase. Despite the clinical severity of this entity, there has been no published review in the international literature, resulting in lack of awareness and delayed diagnosis.A rigorous search of international databases yielded a total of 80 LHS cases from January 1971 to August 2020. We analyzed 44 children (8.56±4.72years, 21boys) and 36 adults (33.61±13.41years, 12men), to present the clinical manifestations, radiological and immunological pattern, therapeutic approaches and outcome of LHS. We also elaborated on clinical and laboratory findings' associations to propose diagnostic indexes and clarified differences based on age distribution.Celiac Disease (CD) and IPH diagnosis was made concurrently in 46 patients, whereas in 21 patients the diagnosis of LHS was delayed for 2.5y (3mo-11y). Hemoptysis (n=56, 70%), dyspnea (n=47, 58.8%), anemia (n=72, 90%) and iron deficiency (n=54, 67.5%) were most commonly observed. Medical history revealed recurrent episodes of hemoptysis (n=38) and persistent iron deficiency anemia (n=25) in need of multiple blood transfusions or iron supplementation. Patchy infiltrate opacities to consolidation predominated in children, whereas bilateral diffuse ground glass opacities in adults. Duodenal biopsy was performed in 66 cases (diagnostic 87.8%), BAL in 51 (diagnostic 74.5%) and surgical lung biopsy in 20. Anti-tTG titer was positive in all 24 (54.6%) children and 19 (52.8%) adults that documented this assay. Prednisone or methylprednisolone pulse therapy and GFD were initiated in the acute phase, whereas chronic therapy included GFD, along with long-term prednisone in refractory cases. Three cases with severe respiratory failure or hemodynamic instability were intubated and a further 3 succumbed.A thorough understanding of LHS may reveal further diagnostic indexes and a consensus on therapy guidelines. Screening for CD is essential in all IPH cases for timely recognition and favorable outcome.
Collapse
Affiliation(s)
- Stavros Tryfon
- Pulmonary Department, "G. Papanikolaou" General Hospital, Thessaloniki, Greece
| | | | | | - Michael Agrafiotis
- Respiratory Failure Unit, "G. Papanikolaou" General Hospital, Thessaloniki, Greece
| | - Maria Saroglou
- Pulmonary Department, "G. Papanikolaou" General Hospital, Thessaloniki, Greece
| |
Collapse
|
|
16
|
Tye‐Din JA. Review article: Follow-up of coeliac disease. Aliment Pharmacol Ther 2022; 56 Suppl 1:S49-S63. [PMID: 35815829 PMCID: PMC9542881 DOI: 10.1111/apt.16847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/12/2022] [Accepted: 02/13/2022] [Indexed: 12/09/2022]
Abstract
Coeliac disease is a lifelong immune-mediated enteropathy with systemic features associated with increased morbidity and modestly increased mortality. Treatment with a strict gluten-free diet improves symptoms and mucosal damage but is not curative and low-level gluten intake is common despite strict attempts at adherence. Regular follow-up after diagnosis is considered best-practice however this is executed poorly in the community with the problem compounded by the paucity of data informing optimal approaches. The aim of dietary treatment is to resolve symptoms, reduce complication risk and improve quality of life. It follows that the goals of monitoring are to assess dietary adherence, monitor disease activity, assess symptoms and screen for complications. Mucosal disease remission is regarded a key measure of treatment success as healing is associated with positive health outcomes. However, persistent villous atrophy is common, even after many years of a gluten-free diet. As the clinical significance of asymptomatic enteropathy is uncertain the role for routine follow-up biopsies remains contentious. Symptomatic non-responsive coeliac disease is common and with systematic follow-up a cause is usually found. Effective models of care involving the gastroenterologist, dietitian and primary care doctor will improve the consistency of long-term management and likely translate into better patient outcomes. Identifying suitable treatment targets linked to long-term health is an important goal.
Collapse
Affiliation(s)
- J. A. Tye‐Din
- Immunology DivisionThe Walter and Eliza Hall InstituteParkvilleVictoriaAustralia,Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia,Department of GastroenterologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia,Centre for Food & Allergy ResearchMurdoch Children’s Research InstituteParkvilleVictoriaAustralia
| |
Collapse
|
|
17
|
Anderson RP. Review article: Diagnosis of coeliac disease: a perspective on current and future approaches. Aliment Pharmacol Ther 2022; 56 Suppl 1:S18-S37. [PMID: 35815826 DOI: 10.1111/apt.16840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/09/2022]
Abstract
Diagnostics will play a central role in addressing the ongoing dramatic rise in global prevalence of coeliac disease, and in deploying new non-dietary therapeutics. Clearer understanding of the immunopathogenesis of coeliac disease and the utility of serology has led to partial acceptance of non-biopsy diagnosis in selected cases. Non-biopsy diagnosis may expand further because research methods for measuring gluten-specific CD4+ T cells and the acute recall response to gluten ingestion in patients is now relatively straightforward. This perspective on diagnosis in the context of the immunopathogenesis of coeliac disease sets out to highlight current consensus, limitations of current practices, gluten food challenge for diagnosis and the potential for diagnostics that measure the underlying cause for coeliac disease, gluten-specific immunity.
Collapse
|
|
18
|
Felber J, Bläker H, Fischbach W, Koletzko S, Laaß M, Lachmann N, Lorenz P, Lynen P, Reese I, Scherf K, Schuppan D, Schumann M, Aust D, Baas S, Beisel S, de Laffolie J, Duba E, Holtmeier W, Lange L, Loddenkemper C, Moog G, Rath T, Roeb E, Rubin D, Stein J, Török H, Zopf Y. Aktualisierte S2k-Leitlinie Zöliakie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:790-856. [PMID: 35545109 DOI: 10.1055/a-1741-5946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Jörg Felber
- Medizinische Klinik II - Gastroenterologie, Hepatologie, Endokrinologie, Hämatologie und Onkologie, RoMed Klinikum Rosenheim, Rosenheim, Deutschland
| | - Hendrik Bläker
- Institut für Pathologie, Universitätsklinikum Leipzig AöR, Leipzig, Deutschland
| | | | - Sibylle Koletzko
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU-Klinikum München, München, Deutschland.,Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, 10-719 Olsztyn, Polen
| | - Martin Laaß
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Deutschland
| | - Nils Lachmann
- Institut für Transfusionsmedizin, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Pia Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - Petra Lynen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - Imke Reese
- Ernährungsberatung und -therapie Allergologie, München, Deutschland
| | - Katharina Scherf
- Institute of Applied Biosciences Department of Bioactive and Functional Food Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Deutschland
| | - Detlef Schuppan
- Institut für Translationale Immunologie, Johannes Gutenberg-Universität Mainz, Mainz, Deutschland.,Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Michael Schumann
- Medizinische Klinik I für Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Upper Gastrointestinal Tract Associated Lesions in Patients with Newly Diagnosed Celiac Disease. GASTROENTEROLOGY INSIGHTS 2022. [DOI: 10.3390/gastroent13010009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
(1) Background: Currently available guidelines require upper gastrointestinal (GI) endoscopy with biopsy sampling for adult celiac disease (CD) diagnosis. Based on the pediatric experience, there has been a growing interest if serology-based diagnosis would be possible for adult CD also. Our aim was to analyze the associated upper GI tract lesions in newly diagnosed CD patients, to see if significant associated pathology is detected during index endoscopy, which might impact patient management not related to CD. (2) Methods: We performed a retrospective analysis of newly diagnosed CD cases diagnosed over a period of 7 years (2014–2020). Demographic, clinical, laboratory, endoscopy and histopathology data were collected from the patients’ charts. Diagnosis was set according to ACG Guideline 2013. (3) Results: Altogether 79 patients were recruited for this study purpose, 75.9% female, median age 39 years. All patients had positive CD-specific serology and atrophic mucosal injury in duodenal biopsy samples. Besides villous atrophy, associated endoscopic findings were detected in 42/79 (53.16%) of patients. Most of the gastric lesions were minor endoscopic findings—small sliding hiatal hernias, non-specific chronic gastritis, but we also found two cases of peptic ulcers, one case of metaplastic gastritis, six cases of atrophic gastritis and one subepithelial lesion. Only one patient had changes in the duodenum except CD-related findings—an inflammatory polyp in the duodenal bulb. No malignancies were found. (4) Conclusions: In our cohort, there was a significant number of newly diagnosed CD patients who had associated lesions during the index upper GI endoscopy, but most of them were minor endoscopic findings.
Collapse
|
|
20
|
Kurppa K, Agardh D. Pediatric coeliac disease. COELIAC DISEASE AND GLUTEN-RELATED DISORDERS 2022:23-41. [DOI: 10.1016/b978-0-12-821571-5.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
21
|
Szaflarska-Popławska A. The Role of the Gluten-Free Diet in the Management of Seronegative Enteropathy. Nutrients 2021; 13:nu13114027. [PMID: 34836279 PMCID: PMC8619095 DOI: 10.3390/nu13114027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/04/2021] [Accepted: 11/09/2021] [Indexed: 11/16/2022] Open
Abstract
The differential diagnosis and treatment of seronegative enteropathy, also termed seronegative villous atrophy (SNVA), is a clinical challenge. Although seronegative coeliac disease (CD) is a frequent cause of SNVA, the aetiology can include immune-mediated, inflammatory, infectious, and drug-related forms. As a misdiagnosis of SNVA can result in patients being unnecessarily placed on a lifelong strict gluten-free diet or even given incorrect immunosuppressive therapy, the aim of this paper is to provide an evidence-based and practical approach for the workup and management of SNVA.
Collapse
Affiliation(s)
- Anna Szaflarska-Popławska
- Department of Paediatric Endoscopy and Gastrointestinal Function Testing, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, ul. Jagiellonska 13-15, 85-067 Bydgoszcz, Poland
| |
Collapse
|
|
22
|
Camarero C, De Andrés A, García-Hoz C, Roldán B, Muriel A, León F, Roy G. Assessment of Duodenal Intraepithelial Lymphocyte Composition (Lymphogram) for Accurate and Prompt Diagnosis of Celiac Disease in Pediatric Patients. Clin Transl Gastroenterol 2021; 12:e00426. [PMID: 34757327 PMCID: PMC8585297 DOI: 10.14309/ctg.0000000000000426] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 09/23/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Quantitative and phenotypic analyses of duodenal intraepithelial lymphocytes (IELs) by flow cytometry (IEL lymphogram) confer specificity and enable the diagnosis even in unconventional presentations of celiac disease (CD). To evaluate the validity of the IEL lymphograms in the pediatric population for new insights into their use as biomarkers in the natural history of CD. METHODS We retrospectively included 1,211 children (602 with active CD, 92 on a gluten-free diet, 47 with potential CD, and 470 nonceliac controls) who required duodenal biopsies in this study. The cutoff values for IEL subsets were established to calculate the probability of disease according to the lymphogram. RESULTS A celiac lymphogram (a ≥15% increase in gamma-delta T-cell receptor IELs and a simultaneous ≤6% decrease in CD3 surface-negative [sCD3-]) IELs was strongly associated with the diagnosis of active CD, which was present in 89.7% of the confirmed patients. The remaining 10% of the celiac patients had a partial celiac lymphogram (≥15% increase gamma-delta T-cell receptor IELs or ≤6% decrease in sCD3- IELs), with lower diagnostic certainty. On a gluten-free diet, nearly 20% of the patients were indistinguishable from nonceliac subjects based on the lymphogram. In potential CD, a decrease in sCD3- IELs was a risk marker of progression to villous atrophy and a diagnosis of active CD. DISCUSSION If a biopsy is clinically indicated, the IEL lymphogram adds specificity to the histological findings, reducing diagnostic delays and misdiagnoses. The lymphogram is useful for monitoring the natural progression of the disease and predicting the transition from potential celiac to overt CD.
Collapse
Affiliation(s)
- Cristina Camarero
- Department of Pediatric Gastroenterology, University Hospital Ramón y Cajal, University of Alcal, Madrid, Spain;
| | - Ana De Andrés
- Department of Immunology, University Hospital Ramón y Cajal, IRYCIS Madrid, Spain;
| | - Carlota García-Hoz
- Department of Immunology, University Hospital Ramón y Cajal, IRYCIS Madrid, Spain;
| | - Belén Roldán
- Department of Pediatric Gastroenterology, University Hospital Ramón y Cajal, University of Alcal, Madrid, Spain;
| | - Alfonso Muriel
- Clinical Biostatistic Unit, University Hospital Ramón y Cajal IRYCIS, CIBERESP Nursing and Physiotherapy Department, University of Alcalá, Madrid, Spain;
| | | | - Garbiñe Roy
- Department of Immunology, University Hospital Ramón y Cajal, IRYCIS Madrid, Spain;
| |
Collapse
|
|
23
|
Coto L, Mendia I, Sousa C, Bai JC, Cebolla A. Determination of gluten immunogenic peptides for the management of the treatment adherence of celiac disease: A systematic review. World J Gastroenterol 2021; 27:6306-6321. [PMID: 34712034 PMCID: PMC8515793 DOI: 10.3748/wjg.v27.i37.6306] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/28/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gluten is a complex mixture of proteins with immunogenic peptide sequences triggering the autoimmune activity in patients with celiac disease (CeD). Gluten immunogenic peptides (GIP) are resistant to gastrointestinal digestion and are then excreted via the stool and urine. Most common detection methods applied in the follow-up visits for CeD patients such as serology tests, dietetic interviews, questionnaires, and duodenal biopsy have been proved to be inefficient, invasive, or inaccurate for evaluating gluten-free diet (GFD) compliance. Determination of excreted GIP in stool and urine has been developed as a non-invasive, direct, and specific test for GFD monitoring.
AIM To summarize published literature about the clinical utility of GIP determination in comparison to the tools employed for GFD monitoring.
METHODS PubMed and Web of Science searches were performed using the keywords “gluten immunogenic peptides” or “gluten immunogenic peptide” and a combination of the previous terms with “feces”, “stools”, “urine”, “celiac disease”, “gluten-free diet”, and “adherence” to identify relevant clinical studies published in English and Spanish between 2012 to January 2021. Reference lists from the articles were reviewed to identify additional pertinent articles. Published articles and abstracts reporting the clinical use of GIP determination in stool and/or urine for the follow-up of patients with CeD in comparison with other tools in use were included. Case reports, commentaries, reviews, conference papers, letters, and publications that did not focus on the aims of this review were excluded.
RESULTS Total of 15 publications were found that involved the use of GIP determination in stool and/or urine to monitor the adherence to the GFD in comparison to other tools. Studies included both children and adults diagnosed with CeD and healthy volunteers. Overall, these preliminary studies indicated that this novel technique was highly sensitive for the detection of GFD transgressions and therefore could facilitate the follow-up of patients with CeD. Tools identified in this work included the CeD-specific serology, dietetic questionnaires, symptomatology, and the duodenal biopsy. Review of the literature revealed that the rates of GFD adherence may vary between 30%-93% using either stool or urine GIP determination, 49%-96% by the serology, 59%-94% using the dietetic questionnaires, 56%-95% by the reported symptoms and 44%-76% with the duodenal biopsy. In addition, the association between the different methods and histological abnormalities (Marsh II-III) was found to be 33%-100% for GIP determination (stool and urine), 25%-39% for CeD-specific serology, 3%-50% for dietetic questionnaires, and 22%-28% for the symptomatology.
CONCLUSION Excreted GIP detection is the precise approach for determining voluntary or involuntary gluten consumption in CeD patients preventing future complications arising from gluten exposure.
Collapse
Affiliation(s)
- Laura Coto
- Research and Development, Biomedal, Camas 41900, Seville, Spain
- Human Nutrition and Food Science Doctoral Program, University of Granada, Granada 18011, Spain
| | - Irati Mendia
- Research and Development, Biomedal, Camas 41900, Seville, Spain
- Molecular Biology, Biomedicine and Clinical Research Doctoral Program, University of Seville, Seville 41012, Spain
| | - Carolina Sousa
- Department of Microbiology and Parasitology, University of Seville, Seville 41013, Spain
| | - Julio César Bai
- Department of Gastroenterology, Dr. Carlos Bonorino Udaondo Gastroenterology Hospital, Buenos Aires 1264, Argentina
- Research Institutes, Universidad del Salvador, Buenos Aires 1050, Argentina
| | - Angel Cebolla
- Research and Development, Biomedal, Camas 41900, Seville, Spain
| |
Collapse
|
|
24
|
Taavela J, Viiri K, Välimäki A, Sarin J, Salonoja K, Mäki M, Isola J. Apolipoprotein A4 Defines the Villus-Crypt Border in Duodenal Specimens for Celiac Disease Morphometry. Front Immunol 2021; 12:713854. [PMID: 34394117 PMCID: PMC8358775 DOI: 10.3389/fimmu.2021.713854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 12/18/2022] Open
Abstract
Histological evaluation of the small intestinal mucosa is the cornerstone of celiac disease diagnostics and an important outcome in scientific studies. Gluten-dependent injury can be evaluated either with quantitative morphometry or grouped classifications. A drawback of mucosal readings is the subjective assessment of the border where the crypt epithelium changes to the differentiated villus epithelium. We studied potential immunohistochemical markers for the detection of the villus-crypt border: apolipoprotein A4 (APOA4), Ki-67, glucose transporter 2, keratin 20, cytochrome P450 3A4 and intestinal fatty-acid binding protein. Among these, villus-specific APOA4 was chosen as the best candidate for further studies. Hematoxylin-eosin (H&E)- and APOA4 stained duodenal biopsy specimens from 74 adult patients were evaluated by five observers to determine the villus-to-crypt ratio (VH : CrD). APOA4 delineated the villus to crypt epithelium transition clearly, and the correlation coefficient of VH : CrD values between APOA4 and H&E was excellent (r=0.962). The VH : CrD values were lower in APOA4 staining (p<0.001) and a conversion factor of 0.2 in VH : CrD measurements was observed to make the two methods comparable to each other. In the intraobserver analysis, the doubled standard deviations, representing the error ranges, were 0.528 for H&E and 0.388 for APOA4 staining, and the ICCs were 0.980 and 0.971, respectively. In the interobserver analysis, the average error ranges were 1.017 for H&E and 0.847 for APOA4 staining, and the ICCs were better for APOA4 than for H&E staining in all analyses. In conclusion, the reliability and reproducibility of morphometrical VH : CrD readings are improved with the use of APOA4 staining.
Collapse
Affiliation(s)
- Juha Taavela
- Central Finland Central Hospital, Jyväskylä, Finland.,Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Keijo Viiri
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anna Välimäki
- Fimlab Laboratories Inc, Tampere, Finland.,Jilab Inc, Tampere, Finland
| | | | | | - Markku Mäki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Tampere University Hospital, Tampere, Finland
| | - Jorma Isola
- Jilab Inc, Tampere, Finland.,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| |
Collapse
|
|
25
|
Beig J, Rostami K, Hayman DTS, Hassan S, Gerred S, Ogra R. Is duodenal biopsy always necessary for the diagnosis of coeliac disease in adult patients with high anti-tissue transglutaminase (TTG) antibody titres? Frontline Gastroenterol 2021; 13:287-294. [PMID: 35722610 PMCID: PMC9186042 DOI: 10.1136/flgastro-2020-101728] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 06/08/2021] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE Avoiding duodenal biopsy in adults for coeliac disease (CD) diagnosis is controversial. Some retrospective and prospective studies have shown that CD can be reliably diagnosed in adults with serology rather than duodenal biopsies. This study aimed to check the accuracy of a cut-off value of ≥10 upper limit of normal of anti-tissue transglutaminase antibody (anti-TTG IgA) titres for CD diagnosis in adult patients. METHOD We retrospectively analysed adult patients (≥16 years) who underwent gastroscopy from 2013 to 2018 for positive coeliac serology. The relationship between titres and disease was determined by using linear models, whereas sensitivity and specificity were assessed by receiver operator curve. RESULTS We analysed 144 newly anti-TTG antibody-positive adult patients with a median age of 48.5 years (IQR 32-62); among them, 86 (60%) patients had CD (Marsh III: n=68 and Marsh II and I: n=18) with a higher prevalence in females (n=59 (69%)) and Europeans (n=60 (70%)). Fifty (58%) patients with CD had colonoscopy and five (6%) had imaging; only six patients were diagnosed with additional conditions. An anti-TTG IgA titre cut-off value of 150 U/L was 100% specific for CD in our dataset, with 70% (95% CI: 60% to 88%) sensitivity for this patient group. CONCLUSION Coeliac serology using anti-TTG IgA with titres ≥10× normal value is an excellent predictor of CD, irrespective of age, gender and ethnicity. Duodenal biopsy may not be necessary in selected adult patients with CD, especially younger than 50 years of age without additional gastrointestinal red-flag signs and symptoms.
Collapse
Affiliation(s)
- Junaid Beig
- Gastroenterology and Hepatology, Middlemore Hospital - Counties Manukau DIstrict Health Board (CMDH), Auckland, New Zealand
| | - Kamran Rostami
- Gastroenterology and Hepatology, MidCentral District Health Board, Palmerston North, New Zealand
| | - David T S Hayman
- Molecular Epidemiology and Public Health Laboratory, School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Summer Hassan
- Gastroenterology and Hepatology, Middlemore Hospital - Counties Manukau DIstrict Health Board (CMDH), Auckland, New Zealand
| | - Stephen Gerred
- Gastroenterology and Hepatology, Middlemore Hospital - Counties Manukau DIstrict Health Board (CMDH), Auckland, New Zealand
| | - Ravinder Ogra
- Gastroenterology and Hepatology, Middlemore Hospital - Counties Manukau DIstrict Health Board (CMDH), Auckland, New Zealand
| |
Collapse
|
|
26
|
Lizio MG, Boitor R, Notingher I. Selective-sampling Raman imaging techniques for ex vivo assessment of surgical margins in cancer surgery. Analyst 2021; 146:3799-3809. [PMID: 34042924 DOI: 10.1039/d1an00296a] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
One of the main challenges in cancer surgery is to ensure the complete excision of the tumour while sparing as much healthy tissue as possible. Histopathology, the gold-standard technique used to assess the surgical margins on the excised tissue, is often impractical for intra-operative use because of the time-consuming tissue cryo-sectioning and staining, and availability of histopathologists to assess stained tissue sections. Raman micro-spectroscopy is a powerful technique that can detect microscopic residual tumours on ex vivo tissue samples with accuracy, based entirely on intrinsic chemical differences. However, raster-scanning Raman micro-spectroscopy is a slow imaging technique that typically requires long data acquisition times wich are impractical for intra-operative use. Selective-sampling Raman imaging overcomes these limitations by using information regarding the spatial properties of the tissue to reduce the number of Raman spectra. This paper reviews the latest advances in selective-sampling Raman techniques and applications, mainly based on multimodal optical imaging. We also highlight the latest results of clinical integration of a prototype device for non-melanoma skin cancer. These promising results indicate the potential impact of Raman spectroscopy for providing fast and objective assessment of surgical margins, helping surgeons ensure the complete removal of tumour cells while sparing as much healthy tissue as possible.
Collapse
Affiliation(s)
- Maria Giovanna Lizio
- School of Physics and Astonomy, University of Nottingham, Nottingham, Nottinghamshire, UK.
| | - Radu Boitor
- School of Physics and Astonomy, University of Nottingham, Nottingham, Nottinghamshire, UK.
| | - Ioan Notingher
- School of Physics and Astonomy, University of Nottingham, Nottingham, Nottinghamshire, UK.
| |
Collapse
|
|
27
|
Koh JEW, De Michele S, Sudarshan VK, Jahmunah V, Ciaccio EJ, Ooi CP, Gururajan R, Gururajan R, Oh SL, Lewis SK, Green PH, Bhagat G, Acharya UR. Automated interpretation of biopsy images for the detection of celiac disease using a machine learning approach. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 203:106010. [PMID: 33831693 DOI: 10.1016/j.cmpb.2021.106010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/15/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND AND OBJECTIVES Celiac disease is an autoimmune disease occurring in about 1 in 100 people worldwide. Early diagnosis and efficient treatment are crucial in mitigating the complications that are associated with untreated celiac disease, such as intestinal lymphoma and malignancy, and the subsequent high morbidity. The current diagnostic methods using small intestinal biopsy histopathology, endoscopy, and video capsule endoscopy (VCE) involve manual interpretation of photomicrographs or images, which can be time-consuming and difficult, with inter-observer variability. In this paper, a machine learning technique was developed for the automation of biopsy image analysis to detect and classify villous atrophy based on modified Marsh scores. This is one of the first studies to employ conventional machine learning to automate the use of biopsy images for celiac disease detection and classification. METHODS The Steerable Pyramid Transform (SPT) method was used to obtain sub bands from which various types of entropy and nonlinear features were computed. All extracted features were automatically classified into two-class and multi-class, using six classifiers. RESULTS An accuracy of 88.89%, was achieved for the classification of two-class villous abnormalities based on analysis of Hematoxylin and Eosin (H&E) stained biopsy images. Similarly, an accuracy of 82.92% was achieved for the two-class classification of red-green-blue (RGB) biopsy images. Also, an accuracy of 72% was achieved in the classification of multi-class biopsy images. CONCLUSION The results obtained are promising, and demonstrate the possibility of automating biopsy image interpretation using machine learning. This can assist pathologists in accelerating the diagnostic process without bias, resulting in greater accuracy, and ultimately, earlier access to treatment.
Collapse
Affiliation(s)
- Joel En Wei Koh
- Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore
| | - Simona De Michele
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA
| | - Vidya K Sudarshan
- School of Science and Technology, Singapore University of Social Sciences, Singapore
| | - V Jahmunah
- Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore
| | - Edward J Ciaccio
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Chui Ping Ooi
- School of Science and Technology, Singapore University of Social Sciences, Singapore
| | - Raj Gururajan
- School of Business, University of Southern Queensland Springfield, Australia
| | | | - Shu Lih Oh
- Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore
| | - Suzanne K Lewis
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Peter H Green
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Govind Bhagat
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA
| | - U Rajendra Acharya
- Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore; School of Science and Technology, Singapore University of Social Sciences, Singapore; School of Business, University of Southern Queensland Springfield, Australia; Department of Bioinformatics and Medical Engineering, Asia University, Taiwan; International Research Organization for Advanced Science and Technology (IROAST) Kumamoto University, Kumamoto, Japan.
| |
Collapse
|
|
28
|
Penny HA, Raju SA, Lau MS, Marks LJS, Baggus EMR, Bai JC, Bassotti G, Bontkes HJ, Carroccio A, Danciu M, Derakhshan MH, Ensari A, Ganji A, Green PHR, Johnson MW, Ishaq S, Lebwohl B, Levene A, Maxim R, Mohaghegh Shalmani H, Rostami-Nejad M, Rowlands D, Spiridon IA, Srivastava A, Volta U, Villanacci V, Wild G, Cross SS, Rostami K, Sanders DS. Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut 2021; 70:876-883. [PMID: 33139268 PMCID: PMC8040155 DOI: 10.1136/gutjnl-2020-320913] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/29/2020] [Accepted: 07/18/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.
Collapse
Affiliation(s)
- Hugo A Penny
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Suneil A Raju
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Michelle S Lau
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Lauren JS Marks
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Elisabeth MR Baggus
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Julio C Bai
- Medicine, Gastroenterology Hospital 'Dr C Bonorino Udaondo', Buenos Aires, Argentina
| | - Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
| | - Hetty J Bontkes
- Department Clinical Chemistry, Amsterdam Gastroenterology and Metabolism and Infection and Immunity Institutes, Amsterdam UMC, Amsterdam, The Netherlands
| | - Antonio Carroccio
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Mihai Danciu
- Pathology Department, Grigore T. Popa University of Medicine and Pharmacy Iasi, Iasi, Romania
| | | | - Arzu Ensari
- Department of Pathology, Ankara University Medical School, Ankara, Turkey
| | - Azita Ganji
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Peter H R Green
- Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Matt W Johnson
- Gastroenterology, Luton and Dunstable Hospital NHS Foundation Trust, Luton, UK
| | - Sauid Ishaq
- Department of Gastroenterology, Dudley Group NHS Foundation Trust, Birmingham City University, Birmingham, UK
| | - Benjamin Lebwohl
- Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Adam Levene
- Gastroenterology, Luton and Dunstable Hospital NHS Foundation Trust, Luton, UK
| | - Roxana Maxim
- Gastroenterology Department, Grigore T. Popa University of Medicine and Pharmacy Iasi, Iasi, Romania
| | - Hamid Mohaghegh Shalmani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - David Rowlands
- Department of Gastroenterology, Queen Elizabeth II Hospital, Hertfordshire, UK
| | - Irene A Spiridon
- Pathology Department, Grigore T. Popa University of Medicine and Pharmacy Iasi, Iasi, Romania
| | | | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Graeme Wild
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Simon S Cross
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Kamran Rostami
- Department of Gastroenterology, MidCentral District Health Board, Palmerston North, New Zealand
| | - David S Sanders
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| |
Collapse
|
|
29
|
Sakhuja S, Holtz LR. Progression of pediatric celiac disease from potential celiac disease to celiac disease: a retrospective cohort study. BMC Pediatr 2021; 21:149. [PMID: 33781221 PMCID: PMC8006356 DOI: 10.1186/s12887-021-02625-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/23/2021] [Indexed: 11/17/2022] Open
Abstract
Background A subset of patients with serology suggesting celiac disease have an initially negative biopsy but subsequently develop histopathologic celiac disease. Here we characterize patients with potential celiac disease who progress to celiac disease. Methods We performed a retrospective analysis of children (0–18 years of age) with biopsy-confirmed celiac disease seen at St. Louis Children’s Hospital between 2013 and 2018. Results Three hundred sixteen of 327 (96%) children with biopsy-confirmed celiac disease were diagnosed on initial biopsy. The 11 children with potential celiac disease who progressed to celiac disease had lower anti-tissue transglutaminase (anti-TTG IgA) concentrations (2.4 (1.6–5) X upper limit of normal (ULN) vs. 6.41 (3.4–10.5) X ULN) at time of first biopsy. Their median anti-TTG IgA concentrations rose from 2.4 (1.6–5) X ULN to 3.6 (3.1–9.2) X ULN between biopsies. Conclusions Four percent of biopsy confirmed celiac patients initially had a negative biopsy, but later developed histopathologic celiac disease. This is likely an underestimate as no surveillance algorithm was in place. We recommend repeat assessment in children whose serology suggests celiac disease despite normal small bowel biopsy. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-021-02625-z.
Collapse
Affiliation(s)
- Shruti Sakhuja
- Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid, Campus, Box 8208, St. Louis, MO, 63110, USA
| | - Lori R Holtz
- Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid, Campus, Box 8208, St. Louis, MO, 63110, USA.
| |
Collapse
|
|
30
|
Foers AD, Shoukat MS, Welsh OE, Donovan K, Petry R, Evans SC, FitzPatrick ME, Collins N, Klenerman P, Fowler A, Soilleux EJ. Classification of intestinal T-cell receptor repertoires using machine learning methods can identify patients with coeliac disease regardless of dietary gluten status. J Pathol 2021; 253:279-291. [PMID: 33225446 PMCID: PMC7898595 DOI: 10.1002/path.5592] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/29/2020] [Accepted: 11/12/2020] [Indexed: 12/17/2022]
Abstract
In coeliac disease (CeD), immune-mediated small intestinal damage is precipitated by gluten, leading to variable symptoms and complications, occasionally including aggressive T-cell lymphoma. Diagnosis, based primarily on histopathological examination of duodenal biopsies, is confounded by poor concordance between pathologists and minimal histological abnormality if insufficient gluten is consumed. CeD pathogenesis involves both CD4+ T-cell-mediated gluten recognition and CD8+ and γδ T-cell-mediated inflammation, with a previous study demonstrating a permanent change in γδ T-cell populations in CeD. We leveraged this understanding and explored the diagnostic utility of bulk T-cell receptor (TCR) sequencing in assessing duodenal biopsies in CeD. Genomic DNA extracted from duodenal biopsies underwent sequencing for TCR-δ (TRD) (CeD, n = 11; non-CeD, n = 11) and TCR-γ (TRG) (CeD, n = 33; non-CeD, n = 21). We developed a novel machine learning-based analysis of the TCR repertoire, clustering samples by diagnosis. Leave-one-out cross-validation (LOOCV) was performed to validate the classification algorithm. Using TRD repertoire, 100% (22/22) of duodenal biopsies were correctly classified, with a LOOCV accuracy of 91%. Using TCR-γ (TRG) repertoire, 94.4% (51/54) of duodenal biopsies were correctly classified, with LOOCV of 87%. Duodenal biopsy TRG repertoire analysis permitted accurate classification of biopsies from patients with CeD following a strict gluten-free diet for at least 6 months, who would be misclassified by current tests. This result reflects permanent changes to the duodenal γδ TCR repertoire in CeD, even in the absence of gluten consumption. Our method could complement or replace histopathological diagnosis in CeD and might have particular clinical utility in the diagnostic testing of patients unable to tolerate dietary gluten, and for assessing duodenal biopsies with equivocal features. This approach is generalisable to any TCR/BCR locus and any sequencing platform, with potential to predict diagnosis or prognosis in conditions mediated or modulated by the adaptive immune response. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Andrew D Foers
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - M Saad Shoukat
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Oliver E Welsh
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | | | - Russell Petry
- Department of Pathology, University of Cambridge, Cambridge, UK.,Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Shelley C Evans
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Michael Eb FitzPatrick
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Nadine Collins
- Department of Molecular Pathology, Royal Surrey NHS Foundation Trust, Guildford, UK
| | - Paul Klenerman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Anna Fowler
- Department of Health Data Science, Institute of Population Health, University of Liverpool, Liverpool, UK
| | - Elizabeth J Soilleux
- Department of Pathology, University of Cambridge, Cambridge, UK.,Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| |
Collapse
|
|
31
|
Das P, Vaiphei K, Amarapurkar AD, Sakhuja P, Nada R, Paulose RR, Chaturvedi R, Sekaran A, Kini U, Rastogi A, Kumari N, Pulimood A, Banerjee M, Kinra P, Singh L, Puri A, Pai G, Kochhar R, Dhali GK, Ramakrishna BS, Sood A, Ghoshal UC, Ahuja V, DattaGupta S, Makharia GK, Misra V. Best practices of handling, processing, and interpretation of small intestinal biopsies for the diagnosis and management of celiac disease: A joint consensus of Indian association of pathologists and microbiologists and Indian society of gastroenterology. INDIAN J PATHOL MICR 2021; 64:S8-S31. [PMID: 34135135 DOI: 10.4103/ijpm.ijpm_1405_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.
Collapse
Affiliation(s)
- Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kim Vaiphei
- Department of Pathology, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India
| | - Anjali D Amarapurkar
- Department of Pathology, Lokmanya Tilak Municipal General Hospital Sion Hospital, Mumbai, Maharashtra, India
| | - Puja Sakhuja
- Department of Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Ritambhra Nada
- Department of Pathology, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India
| | - Roopa Rachel Paulose
- Department of Pathology, School of Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Rachana Chaturvedi
- Department of Pathology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, Maharashtra, India
| | - Anuradha Sekaran
- Department of Pathology, Asian Institute of Gastroenterology and AIG Hospitals, Hyderabad, Telangana, India
| | - Usha Kini
- Department of Pathology, St. John's Medical College, Bangalore, Karnataka, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Niraj Kumari
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anna Pulimood
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Mala Banerjee
- Department of Pathology, KPC Medical College and Hospital and Peerless Hospital, Kolkata, West Bengal, India
| | - Prateek Kinra
- Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
| | - Lavleen Singh
- Department of Pathology, Chacha Nehru Bal Chikitsalya, New Delhi, India
| | - AmarenderSingh Puri
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Ganesh Pai
- Department of Gastroenterology, Kuwait Hospital, Sharjah, UAE
| | - Rakesh Kochhar
- Department of Gastroenterology, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India
| | - Gopal Krishna Dhali
- Department of Gastroenterology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
| | - B S Ramakrishna
- Department of Gastroenterology, SRM Institute of Medical Sciences, Chennai, Tamil Nadu, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Uday Chand Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Govind K Makharia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Vatsala Misra
- Department of Pathology, MLN Medical College, Allahabad, Uttar Pradesh, India
| |
Collapse
|
|
32
|
Narang V, Jindal A, Singh A, Varun Mehta BG, Sood N, Sood A. Diagnostic utility of multiple site duodenal biopsies in celiac disease. INDIAN J PATHOL MICR 2021; 64:S73-S77. [PMID: 34135142 DOI: 10.4103/ijpm.ijpm_797_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Celiac Disease involves the small intestine patchily affecting more frequently the proximal small bowel but the histological changes have been observed till terminal ileum. Of late in addition to D2, the duodenal bulb (D1 region) biopsies have been found helpful in identifying a small group of patients with CD. Therefore, multiple site biopsies are recommended as histological changes are not uniform throughout small intestine. Methods During this present 1.5 years prospective study, we evaluated 84 cases of suspected celiac disease with respect to the light microscopy (D1, D2, and D3 biopsy) and serology (anti tTg and or EMA). Histological examination was done according to Modified Marsh grading system. Results Out of 84 cases with raised anti tTg, the segmental biopsies significantly increased the diagnostic accuracy from 39/44 cases (88.6%) to 43/44 cases (97.7%) and 44/44 cases (100%) when D2 alone, D1 + D2 and D1 + D2 + D3 biopsies were evaluated, respectively. Of the suspected cases of celiac disease patients (tTg > 10 ULN and associated weight loss, diarrhea), additional D3 biopsy increased the diagnostic yield by 2.1%, compared to D1, D2 region biopsy and 6.38% compared to standard D2 biopsy alone. Of the 28 cases (tTg > 10 times ULN + EMA positive and associated weight loss, diarrhea), the potential celiac disease (histologically Type 1/Normal) cases reduced from 28.5% (standard D2 region alone) to 21.4% and 17.8% when additional biopsies were taken from D1 region and D3 region, respectively, and additional D3 biopsy increased the diagnostic yield by 10.8% (compared to standard D2 biopsy alone) and 3.7% (compared to D1 and D2 biopsy). Conclusion We believe multiple sites duodenal biopsies including D3 region biopsies might increase the diagnostic accuracy of adult celiac disease in addition to sensitive and specific serologic tests.
Collapse
Affiliation(s)
- Vikarm Narang
- Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Akriti Jindal
- Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Aminder Singh
- Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | | | - Neena Sood
- Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Ajit Sood
- Department of Gastroentrology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| |
Collapse
|
|
33
|
Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease. Gastroenterology 2021; 160:63-75. [PMID: 32950520 DOI: 10.1053/j.gastro.2020.06.098] [Citation(s) in RCA: 180] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/22/2020] [Accepted: 06/06/2020] [Indexed: 12/16/2022]
Abstract
The incidence of celiac disease is increasing, partly because of improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related to environmental factors that may promote loss of tolerance to dietary gluten. Strategies to reduce the development of celiac disease have not been proven successful in randomized trials, but the quantity of early-life gluten exposure has been a major focus of prevention efforts. The criteria for the diagnosis of celiac disease are changing, but in adults, diagnosis still depends on the presence of duodenal villous atrophy while the patient is on a gluten-containing diet, along with findings from serology analysis. Although guidelines in the United States continue to mandate a biopsy at all ages, some children receive a diagnosis of celiac disease without a biopsy. If proven accurate and scalable, assays that detect gluten-HLA tetramer complexes might be used in diagnosis to be made in the context of a gluten-free diet without intestinal biopsy.
Collapse
Affiliation(s)
- Benjamin Lebwohl
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
| | - Alberto Rubio-Tapia
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| |
Collapse
|
|
34
|
Badizadegan K, Vanlandingham DM, Hampton W, Thompson KM. Value of biopsy in a cohort of children with high-titer celiac serologies: observation of dynamic policy differences between Europe and North America. BMC Health Serv Res 2020; 20:962. [PMID: 33081760 PMCID: PMC7576777 DOI: 10.1186/s12913-020-05815-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022] Open
Abstract
Background Healthcare systems implement change at different rates because of differences in incentives, organizational processes, key influencers, and management styles. A comparable set of forces may play out at the national and international levels as demonstrated in significant differences in the diagnostic management of pediatric Celiac Disease (CD) between European and North American practitioners. Methods We use retrospective clinical cohorts of 27,868 serum tissue transglutaminase (tTG) immunoglobulin A levels and 7907 upper gastrointestinal endoscopy pathology reports to create a dataset of 793 pathology reports with matching tTG results between July 1 of 2014 and July 1 of 2018. We use this dataset to characterize histopathological findings in the duodenum, stomach and esophagus of patients as a function of serum tTG levels. In addition, we use the dataset to estimate the local and national cost of endoscopies performed in patients with serum tTG levels greater than 10 times the upper limit of normal. Results Using evidence from a US tertiary care center, we show that in the cohort of pediatric patients with high pre-test probability of CD as determined by serum tTG levels, biopsy provides no additional diagnostic value for CD, and that it counter-intuitively introduces diagnostic uncertainty in a number of patients. We estimate that using the European diagnostic algorithms could avoid between 4891 and 7738 pediatric endoscopies per year in the US for evaluation of CD. Conclusions This study considers the North American and European management guidelines for the diagnosis of pediatric CD and highlights the slow adoption in North America of evidence-based algorithms developed and applied in Europe for triage of endoscopy and biopsy. We suggest that system dynamics influences that help maintain the status quo in North America include a variety of social and economic factors in addition to medical evidence. This work contributes to the growing body of evidence that the dynamics that largely favor maintaining status quo management policies in a variety of systems extend to clinical medicine and potentially influence clinical decisions at the level of individual patients and the population. Supplementary information Supplementary information accompanies this paper at 10.1186/s12913-020-05815-0.
Collapse
Affiliation(s)
| | - David M Vanlandingham
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | - Wesley Hampton
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | | |
Collapse
|
|
35
|
X-ray microtomography is a novel method for accurate evaluation of small-bowel mucosal morphology and surface area. Sci Rep 2020; 10:13164. [PMID: 32753621 PMCID: PMC7403326 DOI: 10.1038/s41598-020-69487-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/06/2020] [Indexed: 12/15/2022] Open
Abstract
The often poorly orientated small-bowel mucosal biopsies taken for the diagnostics of celiac disease and other intestinal disorders are prone to misinterpretation. Furthermore, conventional histopathology has suboptimal sensitivity for early histopathological changes observed in short-term challenge studies. X-ray microtomography (micro-CT) is a promising new method for accurate imaging of human-derived biological samples. Here, we report that micro-CT could be utilized to create virtual reconstructions of endoscopically obtained intestinal biopsies. The formed digital 3D images enabled selection of always optimal cutting angles for accurate measurement of the mucosal damage and revealed diagnostic lesions in cases interpreted as normal with conventional histomorphometry. We also demonstrate that computer-assisted point cloud analysis can be used to calculate biologically meaningful surface areas of the biopsies in different stages of mucosal damage with excellent replicability and correlation with other disease parameters. We expect the improved diagnostic accuracy and capability to measure the surface areas to provide a powerful tool for the diagnostics of intestinal diseases and for future clinical and pharmaceutical trials.
Collapse
|
|
36
|
Dotsenko V, Oittinen M, Taavela J, Popp A, Peräaho M, Staff S, Sarin J, Leon F, Isola J, Mäki M, Viiri K. Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge. Cell Mol Gastroenterol Hepatol 2020; 11:13-32. [PMID: 32745639 PMCID: PMC7593586 DOI: 10.1016/j.jcmgh.2020.07.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Gluten challenge studies are instrumental in understanding the pathophysiology of celiac disease. Our aims in this study were to reveal early gluten-induced transcriptomic changes in duodenal biopsies and to find tools for clinics. METHODS Duodenal biopsies were collected from 15 celiac disease patients on a strict long-term gluten-free diet (GFD) prior to and post a gluten challenge (PGC) and from 6 healthy control individuals (DC). Biopsy RNA was subjected to genome-wide 3' RNA-Seq. Sequencing data was used to determine the differences between the three groups and was compared to sequencing data from the public repositories. The biopsies underwent morphometric analyses. RESULTS In DC vs. GFD group comparisons, 167 differentially expressed genes were identified with 117 genes downregulated and 50 genes upregulated. In PGC vs. GFD group comparisons, 417 differentially expressed genes were identified with 195 genes downregulated and 222 genes upregulated. Celiac disease patients on a GFD were not "healthy". In particular, genes encoding proteins for transporting small molecules were expressed less. In addition to the activation of immune response genes, a gluten challenge induced hyperactive intestinal wnt-signaling and consequent immature crypt gene expression resulting in less differentiated epithelium. Biopsy gene expression in response to a gluten challenge correlated with the extent of the histological damage. Regression models using only four gene transcripts described 97.2% of the mucosal morphology and 98.0% of the inflammatory changes observed. CONCLUSIONS Our gluten challenge trial design provided an opportunity to study the transition from health to disease. The results show that even on a strict GFD, despite being deemed healthy, patients reveal patterns of ongoing disease. Here, a transcriptomic regression model estimating the extent of gluten-induced duodenal mucosal injury is presented.
Collapse
Affiliation(s)
- Valeriia Dotsenko
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland
| | - Mikko Oittinen
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland
| | - Juha Taavela
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland,Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä, Finland
| | - Alina Popp
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland,Pediatric Department, Carol Davila University of Medicine and Pharmacy, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania
| | - Markku Peräaho
- Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä, Finland
| | - Synnöve Staff
- Department of Obstetrics and Gynecology and Tays Cancer Centre, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University, Tampere, Finland
| | - Jani Sarin
- Laboratory of Cancer Biology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland,Jilab Inc, Tampere, Finland
| | | | - Jorma Isola
- Laboratory of Cancer Biology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland,Jilab Inc, Tampere, Finland
| | - Markku Mäki
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland
| | - Keijo Viiri
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University Hospital, Tampere University Tampere, Finland,Correspondence Address correspondence to: Keijo Viiri, PhD, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Arvo Ylpön katu 34, Tampere, FIN-33520, Finland; fax: +35833641369.
| |
Collapse
|
|
37
|
Balaban DV, Jinga M. Digital histology in celiac disease: A practice changer. Artif Intell Gastroenterol 2020; 1:1-4. [DOI: 10.35712/aig.v1.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/18/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023] Open
Abstract
Artificial intelligence (AI) has grown tremendously in the last decades and is undoubtedly the future era in medicine. Concerning digestive diseases, applications of AI include clinical gastroenterology, gastrointestinal endoscopy and imaging, and not least pathological diagnosis. Several gastrointestinal pathologies require histological confirmation for a positive diagnosis. Among them, celiac disease (CD) diagnosis has been in the spotlight over time, but controversy is still ongoing with regard to the so-called celiac-type histology. Despite efforts to improve histological diagnosis in CD, there are still several issues and pitfalls associated with duodenal histology reading. Several papers have assessed the accuracy of AI techniques in detecting CD on duodenal biopsy images and have shown high diagnostic performance over standard histology reading. We discuss the role of computer-assisted histology in improving the assessment of mucosal architectural injury and inflammation in CD patients, both for diagnosis and follow-up.
Collapse
Affiliation(s)
- Daniel Vasile Balaban
- Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| | - Mariana Jinga
- Internal Medicine and Gastroenterology, Carol Davila University of Medicine and Pharmacy, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest 020021, Romania
| |
Collapse
|
|
38
|
Digital histology in celiac disease: A practice changer. Artif Intell Gastroenterol 2020. [DOI: 10.35712/wjg.v1.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
39
|
Tye-Din JA, Skodje GI, Sarna VK, Dzuris JL, Russell AK, Goel G, Wang S, Goldstein KE, Williams LJ, Sollid LM, Lundin KEA, Anderson RP. Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity. United European Gastroenterol J 2020; 8:108-118. [PMID: 32213060 PMCID: PMC7006000 DOI: 10.1177/2050640619874173] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 08/06/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD. OBJECTIVE We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS). METHODS Australian patients with CD (n = 26) and SR-GS (n = 18) on a GFD consumed bread (estimated gluten 6 g). Serum at baseline and at 3 and 4 h was tested for IL-2, IL-8 and IL-10. Separately, Norwegian SR-GS patients (n = 49) had plasma cytokine assessment at baseline and at 2, 4 and 6 h after food bars containing gluten (5.7 g), fructan or placebo in a previous double-blind crossover study. RESULTS Gluten significantly elevated serum IL-2, IL-8 and IL-10 at 3 and 4 h in patients with CD but not SR-GS. The highest median fold-change from baseline at 4 h was for IL-2 (8.06, IQR: 1.52-24.0; P < 0.0001, Wilcoxon test). The two SR-GS cohorts included only one (1.5%) confirmed IL-2 responder, and cytokine responses to fructan and placebo were no different to gluten. Overall, cytokine release after gluten was present in 22 (85%) CD participants, but 2 of the 4 non-responders remained clinically well after 1 y on an unrestricted diet. Hence, cytokine release occurred in 22 (92%) of 24 'verified' CD participants. CONCLUSIONS Gluten challenge with high-sensitivity cytokine assessment differentiates CD from SR-GS in patients on a GFD and identifies patients likely to tolerate gluten reintroduction. Systemic cytokine release indicating early immune activation by gluten in CD individuals cannot be detected in SR-GS individuals.
Collapse
Affiliation(s)
- Jason A Tye-Din
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Australia
- Murdoch Children's Research Institute, Parkville, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Australia
| | - Gry I Skodje
- KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Unit for Clinical Nutrition, Division of Cancer Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Vikas K Sarna
- KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Amy K Russell
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Australia
| | | | | | | | | | - Ludvig M Sollid
- KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Knut EA Lundin
- KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | |
Collapse
|
|
40
|
Penny HA, Baggus EMR, Rej A, Snowden JA, Sanders DS. Non-Responsive Coeliac Disease: A Comprehensive Review from the NHS England National Centre for Refractory Coeliac Disease. Nutrients 2020; 12:E216. [PMID: 31947666 PMCID: PMC7019917 DOI: 10.3390/nu12010216] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 02/06/2023] Open
Abstract
Coeliac disease is a common small intestinal enteropathy which manifests following ingestion of gluten in genetically susceptible individuals. Since gluten was identified as the driving factor in coeliac disease, the gluten-free diet (GFD) has remained the mainstay of treatment. While most individuals will display improvement in symptoms and signs of coeliac disease following institution of the GFD, up to 30% will continue to experience symptoms and/or have persisting intestinal inflammation. These individuals can be classified as having non-responsive coeliac disease (NRCD), which may be associated with dietary indiscretion, slow healing, refractory coeliac disease, and/or an alternative condition. The purpose of this review is to provide an overview of the causes of NRCD in adults, highlight a systematic approach to investigate these patients, and appraise the latest management aspects of this subset of coeliac disease.
Collapse
Affiliation(s)
- Hugo A. Penny
- Academic Unit of Gastroenterology, University of Sheffield, Sheffield S10 2TN, UK; (H.A.P.); (E.M.R.B.); (A.R.)
- Lydia Becker Institute of Inflammation and Immunology, University of Manchester, Manchester M13 9PL, UK
| | - Elisabeth M. R. Baggus
- Academic Unit of Gastroenterology, University of Sheffield, Sheffield S10 2TN, UK; (H.A.P.); (E.M.R.B.); (A.R.)
| | - Anupam Rej
- Academic Unit of Gastroenterology, University of Sheffield, Sheffield S10 2TN, UK; (H.A.P.); (E.M.R.B.); (A.R.)
| | - John A. Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK;
| | - David S. Sanders
- Academic Unit of Gastroenterology, University of Sheffield, Sheffield S10 2TN, UK; (H.A.P.); (E.M.R.B.); (A.R.)
| |
Collapse
|
|
41
|
Molder A, Balaban DV, Jinga M, Molder CC. Current Evidence on Computer-Aided Diagnosis of Celiac Disease: Systematic Review. Front Pharmacol 2020; 11:341. [PMID: 32372947 PMCID: PMC7179080 DOI: 10.3389/fphar.2020.00341] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 03/09/2020] [Indexed: 02/05/2023] Open
Abstract
Celiac disease (CD) is a chronic autoimmune disease that occurs in genetically predisposed individuals in whom the ingestion of gluten leads to damage of the small bowel. It is estimated to affect 1 in 100 people worldwide, but is severely underdiagnosed. Currently available guidelines require CD-specific serology and atrophic histology in duodenal biopsy samples for the diagnosis of adult CD. In pediatric CD, but in recent years in adults also, nonbioptic diagnostic strategies have become increasingly popular. In this setting, in order to increase the diagnostic rate of this pathology, endoscopy itself has been thought of as a case finding strategy by use of digital image processing techniques. Research focused on computer aided decision support used as database video capsule, endoscopy and even biopsy duodenal images. Early automated methods for diagnosis of celiac disease used feature extraction methods like spatial domain features, transform domain features, scale-invariant features and spatio-temporal features. Recent artificial intelligence (AI) techniques using deep learning (DL) methods such as convolutional neural network (CNN), support vector machines (SVM) or Bayesian inference have emerged as a breakthrough computer technology which can be used for computer aided diagnosis of celiac disease. In the current review we summarize methods used in clinical studies for classification of CD from feature extraction methods to AI techniques.
Collapse
Affiliation(s)
- Adriana Molder
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Center of Excellence in Robotics and Autonomous Systems, Military Technical Academy Ferdinand I, Bucharest, Romania
| | - Daniel Vasile Balaban
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Gastroenterology Department, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest, Romania
- *Correspondence: Daniel Vasile Balaban,
| | - Mariana Jinga
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Gastroenterology Department, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest, Romania
| | - Cristian-Constantin Molder
- Center of Excellence in Robotics and Autonomous Systems, Military Technical Academy Ferdinand I, Bucharest, Romania
| |
Collapse
|
|
42
|
Diagnosing Celiac Disease: Towards Wide-Scale Screening and Serology-Based Criteria? Gastroenterol Res Pract 2019; 2019:2916024. [PMID: 31467522 PMCID: PMC6701393 DOI: 10.1155/2019/2916024] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022] Open
Abstract
Celiac disease is one of the most common food-related chronic disorders in children. Unfortunately, this multifaceted disease is challenging to recognize and remains markedly underdiagnosed. Screening of either known at-risk groups or even the whole population could increase the suboptimal diagnostic yield substantially. Many recent guidelines recommend screening of at least selected risk groups, but more wide-scale screening remains controversial. The increasing prevalence of celiac disease and the development of autoantibody assays have also led to a gradual shift in the diagnostics towards less invasive serology-based criteria in a subgroup of symptomatic children. The main open questions concern whether these criteria are applicable to all countries and clinical settings, as well as to adult patients. On the other hand, widening screening and the mistaken practice of initiating a gluten-free diet before the appropriate exclusion of celiac disease increase the number of borderline seropositive cases, which may also challenge the classical histopathological diagnostics. Sophisticated diagnostic methods and a deeper understanding of the natural history of early developing celiac disease may prove useful in these circumstances.
Collapse
|
|
43
|
Diagnostic Accuracy of Point of Care Tests for Diagnosing Celiac Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2019; 53:535-542. [PMID: 29912751 DOI: 10.1097/mcg.0000000000001081] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
GOALS To perform a systematic review and meta-analysis to estimate the overall diagnostic accuracy of point of care tests (POCTs) for diagnosing celiac disease (CD). BACKGROUND Recently, POCTs for CD have been developed and are commercially available. Studies have reported significant variability in their sensitivity (70% to 100%) and specificity (85% to 100%). STUDY We searched MEDLINE, EMBASE databases, and the Cochrane library through June 2017. Positive reference test was defined as villous atrophy along with positive celiac-specific serology and/or clinical improvement after gluten-free diet. Normal duodenal biopsy was defined as negative reference test. Bivariate random-effect model was used to present the summary estimates of sensitivities and specificities along with 95% confidence regions We assessed methodologic quality using the quality assessment of diagnostic accuracy studies-2 tool. RESULTS The pooled sensitivity and specificity of all POCTs (based on tTG or DGP or tTG+Anti-gliadin antibodies) for diagnosing CD were 94.0% [95% confidence interval (CI), 89.9-96.5] and 94.4% (95% CI, 90.9-96.5), respectively. The pooled positive and negative likelihood ratios for POCTs were 16.7 and 0.06, respectively. The pooled sensitivity and specificity for IgA-tTG-based POCTs were 90.5% (95% CI, 82.3-95.1) and 94.8% (95% CI, 92.5-96.4), respectively. CONCLUSIONS The pooled sensitivity and specificity of POCTs in diagnosing CD are high. POCTs may be used to screen for CD, especially in areas with limited access to laboratory-based testing. Further research assessing the diagnostic accuracy of individual POCTs and comparing it with other available POCTs is needed.
Collapse
|
|
44
|
Green PHR, Guandalini S. When Is Celiac Disease Celiac Disease? Gastroenterology 2019; 157:293-294. [PMID: 31260660 DOI: 10.1053/j.gastro.2019.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 06/07/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Peter H R Green
- Celiac Disease Center, Columbia University Medical Center, New York, New York.
| | - Stefano Guandalini
- Celiac Disease Center, University of Chicago, Chicago, Illinois; Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| |
Collapse
|
|
45
|
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal (GI) disorder driven by innate and adaptive immune responses to gluten. Presentation of CD has changed over time, with non-GI symptoms, such as anemia and osteoporosis, presenting more commonly. With improved screening and diagnostic methods, the reported prevalence of CD has increased globally, and there is considerable global variation in diagnostic and treatment practices. The objective of this study was to describe the current state of CD diagnosis and treatment patterns. A targeted review of literature from MEDLINE, Embase, the Cochrane Library, and screening of relevant conference abstracts was performed. The generally recommended diagnostic approach is GI endoscopy with small bowel biopsy; however, in selected patients, biopsy may be avoided and diagnosis based on positive serology and clinical symptoms. Diagnosis often is delayed; the average diagnostic delay after symptom onset is highly variable and can last up to 12 years. Barriers to accurate and timely diagnosis include atypical presentation, lack of physician awareness about current diagnostic criteria, misdiagnosis, and limited access to specialists. Currently, strict adherence to a gluten-free diet (GFD) is the only recommended treatment, which is not successful in all patients. Only one-third of patients are monitored regularly following diagnosis. Unmet needs for CD include improvements in the accuracy and timeliness of diagnosis, and the development of treatments for both refractory CD and GFD nonresponsive CD. Further research should investigate the impact of education about gluten-free eating and the availability of gluten-free foods support adherence and improve outcomes in patients with CD.
Collapse
|
|
46
|
Ensari A, Marsh MN. Diagnosing celiac disease: A critical overview. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2019; 30:389-397. [PMID: 31060993 PMCID: PMC6505646 DOI: 10.5152/tjg.2018.18635] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 12/22/2018] [Indexed: 12/11/2022]
Abstract
The diagnosis of celiac disease (CD) no longer rests on a malabsorptive state or severe mucosal lesions. For the present, diagnosis will always require the gold-standard of a biopsy, interpreted through its progressive phases (Marsh classification). Marsh classification articulated the immunopathological spectrum of gluten-induced mucosal changes in association with the recognition of innate (Marsh I infiltration) and T cell-based adaptive (Marsh II, and the surface re-organisation typifying Marsh III lesions) responses. Through the Marsh classification the diagnostic goalposts were considerably widened thus, over its time-course, permitting countless patients to begin a gluten-free diet but who, on previous criteria, would have been denied such vital treatment. The revisions of this classification failed to provide additional insight in the interpretation of mucosal pathology. Morever, the subclassification of Marsh 3 imposed an enormous amount of extra work on pathologists with no aid in diagnosis, treatment, or prognosis. Therefore, it should now be apparent that if gastroenterologists ignore these sub-classifications in clinical decision-making, then on that basis alone, there is no need whatsoever for pathologists to persist in reporting them. Since new treatments are under critical assessment, we might have to consider use of some other higher level histological techniques sensitive enough to detect the changes sought. A promising alternative would be to hear more voices from imaginative histopathologists or morphologists together with some more insightful approaches, involving molecular-based techniques and stem cell research may be to evaluate mucosal pathology in CD.
Collapse
Affiliation(s)
- Arzu Ensari
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | | |
Collapse
|
|
47
|
Wei JW, Wei JW, Jackson CR, Ren B, Suriawinata AA, Hassanpour S. Automated Detection of Celiac Disease on Duodenal Biopsy Slides: A Deep Learning Approach. J Pathol Inform 2019; 10:7. [PMID: 30984467 PMCID: PMC6437784 DOI: 10.4103/jpi.jpi_87_18] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/31/2019] [Indexed: 12/12/2022] Open
Abstract
CONTEXT Celiac disease (CD) prevalence and diagnosis have increased substantially in recent years. The current gold standard for CD confirmation is visual examination of duodenal mucosal biopsies. An accurate computer-aided biopsy analysis system using deep learning can help pathologists diagnose CD more efficiently. SUBJECTS AND METHODS In this study, we trained a deep learning model to detect CD on duodenal biopsy images. Our model uses a state-of-the-art residual convolutional neural network to evaluate patches of duodenal tissue and then aggregates those predictions for whole-slide classification. We tested the model on an independent set of 212 images and evaluated its classification results against reference standards established by pathologists. RESULTS Our model identified CD, normal tissue, and nonspecific duodenitis with accuracies of 95.3%, 91.0%, and 89.2%, respectively. The area under the receiver operating characteristic curve was >0.95 for all classes. CONCLUSIONS We have developed an automated biopsy analysis system that achieves high performance in detecting CD on biopsy slides. Our system can highlight areas of interest and provide preliminary classification of duodenal biopsies before review by pathologists. This technology has great potential for improving the accuracy and efficiency of CD diagnosis.
Collapse
Affiliation(s)
- Jason W. Wei
- Department of Biomedical Data Science, Dartmouth College, Hanover, New Hampshire, USA
- Department of Computer Science, Dartmouth College, Hanover, New Hampshire, USA
| | - Jerry W. Wei
- Department of Biomedical Data Science, Dartmouth College, Hanover, New Hampshire, USA
| | - Christopher R. Jackson
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Bing Ren
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Arief A. Suriawinata
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Saeed Hassanpour
- Department of Biomedical Data Science, Dartmouth College, Hanover, New Hampshire, USA
- Department of Computer Science, Dartmouth College, Hanover, New Hampshire, USA
- Department of Epidemiology, Dartmouth College, Hanover, New Hampshire, USA
| |
Collapse
|
|
48
|
Abstract
Celiac disease predominantly involves the proximal small bowel, but villus atrophy can be patchy, spare the duodenum, and be present more distally. Video capsule endoscopy is more sensitive than standard endoscopy to detect villus atrophy, and can define extent of disease, though it cannot obtain biopsies. Duodenal biopsy is the gold standard for diagnosis. Video capsule endoscopy assists in special circumstances when biopsy is not possible, and in equivocal diagnosis. Video capsule endoscopy and enteroscopy are recommended for evaluating complicated celiac disease, especially refractory celiac disease type II. Future developments include computer-assisted capsule programs and advanced capsule and enteroscope design.
Collapse
Affiliation(s)
- Suzanne K Lewis
- Division of Digestive Diseases, Celiac Disease Center at Columbia University, Columbia University, 180 Fort Washington Avenue, New York, NY 10032, USA.
| | - Carol E Semrad
- The University of Chicago, 5841 South Maryland Avenue, MC 4080 S401, Chicago, IL 60637, USA
| |
Collapse
|
|
49
|
Lagana SM, Bhagat G. Biopsy Diagnosis of Celiac Disease: The Pathologist's Perspective in Light of Recent Advances. Gastroenterol Clin North Am 2019; 48:39-51. [PMID: 30711210 DOI: 10.1016/j.gtc.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Celiac disease is a common immune-mediated disorder that occurs in individuals with permissive genetics (HLA-DQ2/DQ8 genotype) following exposure to certain wheat proteins. The histopathologic manifestations of small intestinal mucosal injury (villus atrophy, crypt hyperplasia, and intraepithelial lymphocytosis) are well recognized. However, these findings are not specific for celiac disease, because they are observed in other small intestinal disorders. These mimics include common and rare entities, the list of which continues to grow. This article discusses the histopathology and differential diagnosis of celiac disease and provides the pathologist's perspective on biopsy adequacy, evaluation, and reporting in light of current knowledge.
Collapse
Affiliation(s)
- Stephen M Lagana
- Columbia University, New York Presbyterian Hospital, 622 West 168th Street, VC14-209, New York, NY 10032, USA.
| | - Govind Bhagat
- Columbia University, New York Presbyterian Hospital, 622 West 168th Street, VC14-228, New York, NY 10032, USA
| |
Collapse
|
|
50
|
Husby S, Murray JA, Katzka DA. AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease-Changing Utility of Serology and Histologic Measures: Expert Review. Gastroenterology 2019; 156:885-889. [PMID: 30578783 PMCID: PMC6409202 DOI: 10.1053/j.gastro.2018.12.010] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/28/2018] [Accepted: 12/05/2018] [Indexed: 02/08/2023]
Abstract
PURPOSE The purpose of this clinical practice update is to define key modalities in the diagnosis and monitoring of celiac disease (CD) in adults as well as in children and adolescents. METHODS The recommendations outlined in this expert review are based on available published evidence, including cohort and case-control studies of the diagnostic process as well as controlled and descriptive studies of disease management. Best Practice Advice 1: Serology is a crucial component of the detection and diagnosis of CD, particularly tissue transglutaminase-immunoglobulin A (TG2-IgA), IgA testing, and less frequently, endomysial IgA testing. Best Practice Advice 2: Thorough histological analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry is important for diagnosis as well as for differential diagnosis. Best Practice Advice 2a: TG2-IgA, at high levels (> ×10 upper normal limit) is a reliable and accurate test for diagnosing active CD. When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for CD is virtually 100%. In adults, esophagogastroduodenoscopy (EGD) and duodenal biopsies may then be performed for purposes of differential diagnosis. Best Practice Advice 3: IgA deficiency is an infrequent but important explanation for why patients with CD may be negative on IgA isotype testing despite strong suspicion. Measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing in that circumstance is recommended. Best Practice Advice 4: IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency. Best Practice Advice 5: In patients found to have CD first by intestinal biopsies, celiac-specific serology should be undertaken as a confirmatory test before initiation of a gluten-free diet (GFD). Best Practice Advice 6: In patients in whom CD is strongly suspected in the face of negative biopsies, TG2-IgA should still be performed and, if positive, repeat biopsies might be considered either at that time or sometime in the future. Best Practice Advice 7: Reduction or avoidance of gluten before diagnostic testing is discouraged, as it may reduce the sensitivity of both serology and biopsy testing. Best Practice Advice 8: When patients have already started on a GFD before diagnosis, we suggest that the patient go back on a normal diet with 3 slices of wheat bread daily preferably for 1 to 3 months before repeat determination of TG2-IgA. Best Practice Advice 9: Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of CD; especially as very young children before the introduction of celiac-specific serology. MANAGEMENT Best Practice Advice 10: Celiac serology has a guarded role in the detection of continued intestinal injury, in particular as to sensitivity, as negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure. Follow-up serology should be performed 6 and 12 months after diagnosis, and yearly thereafter. Best Practice Advice 11: Patients with persistent or relapsing symptoms, without other obvious explanations for those symptoms, should undergo endoscopic biopsies to determine healing even in the presence of negative TG2-IgA.
Collapse
Affiliation(s)
- Steffen Husby
- Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
| | - Joseph A. Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - David A. Katzka
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|