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Fietz SA, Kalusa M, Jergens AE, Sahoo DK, Stewart T, Heilmann RM. Ultrastructural changes in chronic inflammatory enteropathies-a comparison between dogs and humans. Front Cell Dev Biol 2024; 12:1379714. [PMID: 38872928 PMCID: PMC11173093 DOI: 10.3389/fcell.2024.1379714] [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] [Received: 01/31/2024] [Accepted: 04/24/2024] [Indexed: 06/15/2024] Open
Abstract
Chronic inflammatory enteropathies (CIEs) are an important group of diseases in dogs and involve complex pathogenetic aspects. Endoscopy and histopathology are vital for documenting the disease but are less useful for subclassifying CIEs and predicting the response to treatment. However, healing of the mucosal disease process (deep remission) and ultrastructural evaluation of the mucosa have received little attention in canine CIE. Given that canine CIE shares many similarities with inflammatory bowel diseases (IBDs) in human patients-and presents a good spontaneous disease model for human IBD-this perspective article evaluates the literature on ultrastructural lesions in canine CIE and human IBD and offers future directions for the study of ultrastructural mucosal lesions in canine CIE. Such lesions might have a higher sensitivity of detection than structural changes revealed upon light microscopy and may even precede or remain after the resolution of the clinical signs and histologic lesions.
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Affiliation(s)
- Simone A. Fietz
- Institute of Anatomy, Histology and Embryology, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
| | - Mirjam Kalusa
- Institute of Anatomy, Histology and Embryology, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
| | - Albert E. Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Dipak Kumar Sahoo
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Tracey Stewart
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Romy M. Heilmann
- Department for Small Animals, College of Veterinary Medicine, Leipzig University, Leipzig, Saxony, Germany
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Díaz-Regañón D, Gabriel V, Livania V, Liu D, Ahmed BH, Lincoln A, Wickham H, Ralston A, Merodio MM, Sahoo DK, Zdyrski C, Meyerholz DK, Mochel JP, Allenspach K. Changes of Enterocyte Morphology and Enterocyte: Goblet Cell Ratios in Dogs with Protein-Losing and Non-Protein-Losing Chronic Enteropathies. Vet Sci 2023; 10:417. [PMID: 37505823 PMCID: PMC10383676 DOI: 10.3390/vetsci10070417] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/18/2023] [Accepted: 06/26/2023] [Indexed: 07/29/2023] Open
Abstract
This study aimed to assess the morphometry of enterocytes as well as the goblet cell-to-enterocyte ratio in different intestinal segments of dogs with chronic enteropathies (CE). Histopathological intestinal samples from 97 dogs were included in the study (19 healthy juveniles, 21 healthy adults, 24 dogs with protein-losing enteropathy (PLE), and 33 CE dogs without PLE). Healthy adult small intestinal enterocytes showed progressively reduced epithelial cell height in the aboral direction, while juvenile dogs showed progressively increased epithelial cell height in the aboral direction. CE dogs had increased epithelial cell height in the duodenum, while PLE dogs had decreased epithelial cell heights compared to healthy adult dogs. Both the CE and PLE dogs showed decreased enterocyte width in the duodenal segment, and the ileal and colonic enterocytes of CE dogs were narrower than those of healthy adult dogs. CE dogs had a lower goblet cell-to-enterocyte ratio in the colon segment compared to healthy dogs. This study provides valuable morphometric information on enterocytes during canine chronic enteropathies, highlighting significant morphological enterocyte alterations, particularly in the small intestine, as well as a reduced goblet cell-to-enterocyte ratio in the colon of CE cases compared to healthy adult dogs.
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Affiliation(s)
- David Díaz-Regañón
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain
| | - Vojtech Gabriel
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Vanessa Livania
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Dongjie Liu
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Basant H. Ahmed
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Addison Lincoln
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Hannah Wickham
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | | | - Maria M. Merodio
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
| | - Dipak K. Sahoo
- Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA 50011, USA;
| | - Christopher Zdyrski
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
- 3D Health Solutions Inc., Ames, IA 50010, USA;
| | - David K. Meyerholz
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Jonathan P. Mochel
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
- 3D Health Solutions Inc., Ames, IA 50010, USA;
| | - Karin Allenspach
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (V.G.); (V.L.); (D.L.); (B.H.A.); (A.L.); (H.W.); (M.M.M.); (C.Z.); (J.P.M.)
- 3D Health Solutions Inc., Ames, IA 50010, USA;
- Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA 50011, USA;
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Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study. Nutrients 2022; 14:nu14122487. [PMID: 35745217 PMCID: PMC9230100 DOI: 10.3390/nu14122487] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 02/07/2023] Open
Abstract
Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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Iron Deficiency in Celiac Disease: Prevalence, Health Impact, and Clinical Management. Nutrients 2021; 13:nu13103437. [PMID: 34684433 PMCID: PMC8537360 DOI: 10.3390/nu13103437] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/13/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Iron is an essential nutrient to life and is required for erythropoiesis, oxidative, metabolism, and enzymatic activities. It is a cofactor for mitochondrial respiratory chain enzymes, the citric acid cycle, and DNA synthesis, and it promotes the growth of immune system cells. Thus, iron deficiency (ID) leads to deleterious effects on the overall health of individuals, causing significant morbidity. Iron deficiency anemia (IDA) is the most recognized type of anemia in patients with celiac disease (CD) and may be present in over half of patients at the time of diagnosis. Folate and vitamin B12 malabsorption, nutritional deficiencies, inflammation, blood loss, development of refractory CD, and concomitant Heliobacter pylori infection are other causes of anemia in such patients. The decision to replenish iron stores and the route of administration (oral or intravenous) are controversial due, in part, to questions surrounding the optimal formulation and route of administration. This paper provides an algorithm based on the severity of symptoms; its impact on the health-related quality of life (HRQL); the tolerance and efficiency of oral iron; and other factors that predict a poor response to oral iron, such as the severity of histological damage, poor adherence to GFD, and blood loss due to mucosal lesions.
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Stefanelli G, Viscido A, Longo S, Magistroni M, Latella G. Persistent Iron Deficiency Anemia in Patients with Celiac Disease Despite a Gluten-Free Diet. Nutrients 2020; 12:E2176. [PMID: 32708019 PMCID: PMC7468819 DOI: 10.3390/nu12082176] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 12/12/2022] Open
Abstract
Celiac disease (CD) is an autoimmune disorder characterized by intolerance to dietary gluten in genetically predisposed subjects. Iron deficiency anemia (IDA) is a common sign in CD, being the only abnormality in approximately 40% of celiac patients. A multifactorial etiology leads to IDA in CD. The two main causes are the villous atrophy of the mucosa at the site of iron absorption (the duodenum) and the resulting inflammation, which triggers the mechanism that leads to the anemia of chronic disease. Until now, it has been unclear why some patients with CD continue to have IDA despite a careful gluten-free diet (GFD) and the normalization of villous atrophy. Furthermore, some celiac patients are refractory to oral iron supplementation despite the healing of the mucosa, and they thus require periodic intravenous iron administration. The Marsh classification evaluates the degree of inflammation and villous atrophy, but it does not assess the possible persistence of ultrastructural and molecular alterations in enterocytes. The latter was found in CD in remission after adopting a GFD and could be responsible for the persistently reduced absorption of iron and IDA. Even in non-celiac gluten sensitivity, anemia is present in 18.5-22% of patients and appears to be related to ultrastructural and molecular alterations in intestinal microvilli. It is possible that a genetic component may also play a role in IDA. In this review, we evaluate and discuss the main mechanisms of IDA in CD and the possible causes of its persistence after adopting a GFD, as well as their therapeutic implications.
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Affiliation(s)
| | | | | | | | - Giovanni Latella
- Gastroenterology, Hepatology and Nutrition Division, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (G.S.); (A.V.); (S.L.); (M.M.)
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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.
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Affiliation(s)
- Arzu Ensari
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
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Rostami K, Srivastava A. Coeliac disease novel histological quantification. Comput Biol Med 2018; 106:149. [PMID: 30580816 DOI: 10.1016/j.compbiomed.2018.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Kamran Rostami
- Department of Gastroenterology, MidCentral District Health Board, Palmerston North Hospital, Palmerston North, New Zealand.
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Evolutionary Developments in Interpreting the Gluten-Induced Mucosal Celiac Lesion: An Archimedian Heuristic. Nutrients 2017; 9:nu9030213. [PMID: 28264483 PMCID: PMC5372876 DOI: 10.3390/nu9030213] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/22/2017] [Indexed: 02/07/2023] Open
Abstract
The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process—since it can recover structurally. Rather, the intestinal mucosa manifests a vast hypertrophic response resulting in the formation of large plateaus formed from partially reduced villi and their amalgamation with the now increased height and width of the inter-villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat-topped villi which continues to encourage both the continued use of irrelevant “atrophy” terminologies and a marked failure to perceive what random sections through mosaic plateaus actually look like. While reviewing the extensive 40+ year literature on mucosal analysis, we extracted data on intraepithelial lymphocytes (IEL) counts from 607 biopsies, and applied receiver-operating characteristic (ROC)-curve analysis. From that perspective, it appears that counting IEL/100 enterocyte nuclei in routine haematoxylin and eosin (H&E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut-off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC-curve analysis also revealed the somewhat lesser accuracies of either CD3+ or γδ+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten-induced mucosal pathologies and how they could be optimally interpreted, as well as in promoting the ideal manner for physicians and pathologists to interact in interpreting intestinal mucosae submitted for analysis. Future trends should incorporate 3-D printing and computerised modelling in order to exemplify the subtle micro-anatomical features associated with the crypt-villus interzone. The latter needs precise delineation with use of mRNA in-section assays for brush border enzymes such as alkaline phosphate and esterase. Other additional approaches are needed to facilitate recognition and interpretation of the features of this important inter-zone, such as wells, basins and hypertrophic alterations in the size of inter-villous ridges. The 3-D computerised models could considerably expand our understandings of the microvasculature and its changes—in relation both to crypt hypertrophy, in addition to the partial attrition and subsequent regrowth of villi from the inter-villous ridges during the flattening and recovery processes, respectively.
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Affiliation(s)
- Michael N Marsh
- Department of Gastroenterology, Luton & Dunstable NHS University Hospital Trust and Wolfson College, University of Oxford, Oxford, UK
| | - Kamran Rostami
- Department of Gastroenterology, Milton Keynes NHS University Hospital Trust, Milton Keynes, UK
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Rostami K, Aldulaimi D, Holmes G, Johnson MW, Robert M, Srivastava A, Fléjou JF, Sanders DS, Volta U, Derakhshan MH, Going JJ, Becheanu G, Catassi C, Danciu M, Materacki L, Ghafarzadegan K, Ishaq S, Rostami-Nejad M, Peña AS, Bassotti G, Marsh MN, Villanacci V. Microscopic enteritis: Bucharest consensus. World J Gastroenterol 2015; 21:2593-2604. [PMID: 25759526 PMCID: PMC4351208 DOI: 10.3748/wjg.v21.i9.2593] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 12/29/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
Microscopic enteritis (ME) is an inflammatory condition of the small bowel that leads to gastrointestinal symptoms, nutrient and micronutrient deficiency. It is characterised by microscopic or sub-microscopic abnormalities such as microvillus changes and enterocytic alterations in the absence of definite macroscopic changes using standard modern endoscopy. This work recognises a need to characterize disorders with microscopic and submicroscopic features, currently regarded as functional or non-specific entities, to obtain further understanding of their clinical relevance. The consensus working party reviewed statements about the aetiology, diagnosis and symptoms associated with ME and proposes an algorithm for its investigation and treatment. Following the 5th International Course in Digestive Pathology in Bucharest in November 2012, an international group of 21 interested pathologists and gastroenterologists formed a working party with a view to formulating a consensus statement on ME. A five-step agreement scale (from strong agreement to strong disagreement) was used to score 21 statements, independently. There was strong agreement on all statements about ME histology (95%-100%). Statements concerning diagnosis achieved 85% to 100% agreement. A statement on the management of ME elicited agreement from the lowest rate (60%) up to 100%. The remaining two categories showed general agreement between experts on clinical presentation (75%-95%) and pathogenesis (80%-90%) of ME. There was strong agreement on the histological definition of ME. Weaker agreement on management indicates a need for further investigations, better definitions and clinical trials to produce quality guidelines for management. This ME consensus is a step toward greater recognition of a significant entity affecting symptomatic patients previously labelled as non-specific or functional enteropathy.
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Walker D, Knuchel-Takano A, McCutchan A, Chang YM, Downes C, Miller S, Stevens K, Verheyen K, Phillips A, Miah S, Turmaine M, Hibbert A, Steiner J, Suchodolski J, Mohan K, Eastwood J, Allenspach K, Smith K, Garden O. A Comprehensive Pathological Survey of Duodenal Biopsies from Dogs with Diet-Responsive Chronic Enteropathy. J Vet Intern Med 2013; 27:862-74. [DOI: 10.1111/jvim.12093] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/15/2013] [Accepted: 03/13/2013] [Indexed: 12/19/2022] Open
Affiliation(s)
- D. Walker
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - A. Knuchel-Takano
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - A. McCutchan
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - Y-M. Chang
- Research Office; The Royal Veterinary College; London UK
| | - C. Downes
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - S. Miller
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - K. Stevens
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - K. Verheyen
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - A.D. Phillips
- Institute of Child Health; University College London; Royal Free Hospital; London UK
| | - S. Miah
- Institute of Orthopaedics and Musculoskeletal Science; University College London; Royal National Orthopaedic Hospital; Stanmore UK
| | - M. Turmaine
- Division of Biosciences; Medical Sciences Building; University College London; London UK
| | - A. Hibbert
- Department of Comparative Biomedical Sciences; The Royal Veterinary College; Royal College Street; London UK
| | - J.M. Steiner
- Gastrointestinal Laboratory; College of Veterinary Medicine and Biomedical Sciences; Texas A&M University; College Station TX
| | - J.S. Suchodolski
- Gastrointestinal Laboratory; College of Veterinary Medicine and Biomedical Sciences; Texas A&M University; College Station TX
| | - K. Mohan
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - J. Eastwood
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - K. Allenspach
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
| | - K. Smith
- Department of Pathology and Infectious Diseases; The Royal Veterinary Col-lege; Hatfield UK
| | - O.A. Garden
- Department of Clinical Sciences and Services; The Royal Veterinary College; Hatfield UK
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Adriaanse MPM, Tack GJ, Passos VL, Damoiseaux JGMC, Schreurs MWJ, van Wijck K, Riedl RG, Masclee AAM, Buurman WA, Mulder CJJ, Vreugdenhil ACE. Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies. Aliment Pharmacol Ther 2013; 37:482-90. [PMID: 23289539 DOI: 10.1111/apt.12194] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 07/19/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I-FABP) is a sensitive marker to study enterocyte damage. AIMS To evaluate the severity of enterocyte damage in adult-onset CD and its course upon a gluten-free diet (GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied. METHODS Serum I-FABP levels were determined in 96 biopsy-proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody (IgA-tTG) levels served as controls. I-FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA-tTG. RESULTS I-FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P < 0.001) and correlated with Marsh grade (r = 0.265, P < 0.05) and IgA-tTG (r = 0.403, P < 0.01). Upon a GFD serum levels decreased significantly, however, not within the range observed in controls, despite the common observed normalisation of IgA-tTG levels and Marsh grade. CD patients with elevated I-FABP levels nonresponding to GFD showed persistent histological abnormalities. CONCLUSIONS Enterocyte damage assessed by serum I-FABP correlates with the severity of villous atrophy in coeliac disease at the time of diagnosis. Although enterocyte damage improves upon treatment, substantial enterocyte damage persists despite absence of villous atrophy and low IgA-tTG levels in the majority of cases. Elevated I-FABP levels nonresponding to gluten-free diet are indicative of histological abnormalities and warrant further evaluation.
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Affiliation(s)
- M P M Adriaanse
- Department of Paediatrics & Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, the Netherlands.
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Mones RL, Yankah A, Duelfer D, Bustami R, Mercer G. Disaccharidase deficiency in pediatric patients with celiac disease and intact villi. Scand J Gastroenterol 2011; 46:1429-34. [PMID: 21936724 DOI: 10.3109/00365521.2011.619276] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The "gold standard" for the diagnosis of celiac disease (CD) is the small intestinal biopsy. A significant number of biopsies are inadequate for interpretation. Furthermore, the labeling of a biopsy as a Marsh I or II is somewhat subjective and may vary with the experience of the pathologist. Our hypothesis is that patients with intact villi undergoing biopsies frequently have associated disaccharidase deficiencies (DSD). METHODS We reviewed 220 charts of pediatric patients with CD and selected those with a duodenal biopsy Marsh score of I/II. The disaccharidase (DS) levels of these patients were compared with a randomly selected, age-matched control group. DSD is defined as levels below the lower limits of normal. RESULTS Lactase (mean lactase = 18.8 in the control group vs. 4.2 in the diseased group, p = 0.004); sucrase (mean sucrase = 46.4 in the control group vs. 21.4 in the diseased group, p = 0.001); maltase (mean maltase = 138 in the control group vs. 52.5 in the diseased group, p = 0.001); palatinase (mean palatinase = 9.6 in the control group vs. 3.3 in the diseased group, p < 0.001). CONCLUSION There is a profound deficiency of DS levels in pediatric patients with CD who have intact villi.
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Affiliation(s)
- Richard L Mones
- The Division of Pediatric Gastroenterology and Nutrition of the Goryeb Children's Hospital, Atlantic Health System, Morristown, New Jersey 07960, USA.
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Microscopic enteritis and pathomechanism of malabsorption. AUTOIMMUNITY HIGHLIGHTS 2010; 1:37-8. [PMID: 26000105 PMCID: PMC4389062 DOI: 10.1007/s13317-010-0006-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/28/2010] [Accepted: 03/29/2010] [Indexed: 01/29/2023]
Abstract
Microscopic enteritis (ME) is the stage of microscopic and sub-microscopic changes (microenteropathy) associated with the symptoms of gluten sensitive enteropathy leading to micronutrient deficiencies. It is characterized by subtle mucosal abnormalities without prominent inflammation, villous effacement, erosions or ulcerations on conventional light microscopy. The intraepithelial lymphocytes are usually in normal range <25/100 enterocytes (microenteropathy) or increased (lymphocytic enteritis). ME is the entity behind atypical forms of CD previously known as potential and latent CD. Systemic inflammation predominantly is found to be engaged in pathophysiology of micro-nutrient deficiency even in absence of macroscopic mucosal changes.
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15
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Dickey W. Diagnostic immunology in celiac disease. Expert Rev Clin Immunol 2010; 5:471-9. [PMID: 20477043 DOI: 10.1586/eci.09.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Serum autoantibodies to transglutaminase and endomysium are found in the majority of patients with celiac disease, an autoimmune multisystem disorder affecting approximately 1% of Western and Middle-Eastern populations. Detection of these antibodies plays a crucial role in the diagnosis of celiac disease. The aim of this review is to summarize recent publications in this field, with particular focus on the applications and limitations of celiac autoantibody testing in routine clinical practice.
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Affiliation(s)
- William Dickey
- Department of Gastroenterology, Altnagelvin Hospital, Londonderry, Northern Ireland, BT47 6SB, UK.
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Symposium 1: Joint BAPEN and British Society of Gastroenterology Symposium on ‘Coeliac disease: basics and controversies’ Coeliac disease in the twenty-first century. Proc Nutr Soc 2009; 68:234-41. [DOI: 10.1017/s0029665109001414] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Coeliac disease (CD), traditionally perceived as a rare childhood condition presenting with malabsorption, is instead an autoimmune multisystem disorder usually presenting in adulthood, affecting ⩾1% of the population and linked to the genetic expression of human leucocyte antigens (HLA) DQ2 and DQ8. Presentation occurs most often in the 40–60 years age-group, but potentially at any age. Symptoms attributable to the gut or to malabsorption may be mild, non-specific or absent; under one-third of patients have diarrhoea and almost half are overweight. Histological diagnosis no longer requires small intestine villous atrophy. The Marsh classification recognizes increased intraepithelial lymphocytes and crypt hyperplasia with intact villi as part of the gluten enteropathy spectrum, while some individuals have more subtle abnormalities identified only on electron microscopy. Serological testing for CD autoantibodies (to endomysium and tissue transglutaminase) has revolutionized diagnosis, shifting the process towards primary care. However, a substantial number of patients with CD are seronegative, particularly those without villous atrophy. The autoantibody to endomysium may be produced before histological change. The immune response to transglutaminase is crucial to the disease process. An exciting new development is the link between antibodies to organ-specific transglutaminases and clinical presentation; transglutaminases 2 (gut), 3 (skin) and 6 (nervous system). Negative testing for CD does not preclude its development later and HLA testing may allow ‘once and for all’ exclusion. In conclusion, an increasing proportion of patients with CD do not meet the ‘classic’ picture of malabsorption, positive serological testing and villous atrophy. Insisting on all these criteria for diagnosis will result in under diagnosis.
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Rostami K, Villanacci V. Microscopic enteritis: novel prospect in coeliac disease clinical and immuno-histogenesis. Evolution in diagnostic and treatment strategies. Dig Liver Dis 2009; 41:245-52. [PMID: 18657490 DOI: 10.1016/j.dld.2008.06.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2008] [Revised: 06/11/2008] [Accepted: 06/12/2008] [Indexed: 12/11/2022]
Abstract
The diagnosis of coeliac disease has traditionally depended on symptoms and intestinal biopsies; nowadays, the diagnosis has been expanded to include an array of serological markers and subtle microscopic lesions. The most important advance in classifying mucosal lesions in coeliac disease was forwarded by Marsh (1992), who provided the biological explanation of how the small bowel reacts to a variety of environmental antigenic challenges including gluten. In the modified version of this classification (Arnhem 1998-1999) autoantibodies have integrated into Marsh's histopathological scheme. As a large part of the coeliac 'iceberg' remains unrecognised, the difficulties in diagnosis continue to challenge clinicians and researchers. Advances in immuno-histochemistry and discovery of the other sensitive markers have acquainted us with so-called Microscopic enteritis, the distinctive subtle abnormalities behind the atypical gluten sensitivity symptoms that often remain unrecognised. Current diagnostic pathways do not always include facilities for looking for this common histological feature in atypical cases. This is essential since improving of the detection rate has been shown to be directly proportional to recognition of cases with milder or minimal mucosal abnormalities. In this revision, we will define and characterise microscopic enteritis as the entity behind a wide range of unexplained gastrointestinal symptoms. Screening for this subtle and distinctive presentation in small bowel pathology will open a new prospect in recognising the most common but unrecognised atypical forms of symptomatic gluten related enteropathies.
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Affiliation(s)
- K Rostami
- School of Medicine, University of Birmingham, UK.
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18
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Carroccio A, Brusca I, Iacono G, Alessio MG, Sonzogni A, Di Prima L, Barrale M, Ottomano C, Ambrosiano G, Teresi S, D'Angelo A, Pirrone G, Cefalù B, Scalici C, La Chiusa SM. IgA anti-actin antibodies ELISA in coeliac disease: a multicentre study. Dig Liver Dis 2007; 39:818-23. [PMID: 17652043 DOI: 10.1016/j.dld.2007.06.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2007] [Revised: 05/25/2007] [Accepted: 06/05/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND Previous studies have demonstrated that serum anti-actin antibodies are a reliable marker of intestinal damage severity in coeliac disease. AIMS To validate in a multicentre study the clinical usefulness of serum IgA anti-actin antibody ELISA and its possible use in monitoring intestinal mucosa lesions during gluten-free diet. PATIENTS AND METHODS Four centres recruited 205 newly diagnosed coeliac disease patients with villous atrophy, 80 healthy controls and 81 "disease" controls. Twelve coeliac disease patients on gluten-free diet but with persistent symptoms underwent serum IgA anti-actin antibody assay and intestinal histology evaluation. IgA anti-actin antibody ELISA was performed with a commercial kit. All coeliac disease patients underwent intestinal histology study. RESULTS IgA anti-actin antibodies showed a sensitivity of 80% and a specificity of 85% in the diagnosis of coeliac disease patients with villous atrophy. The area under the receiving operator curve for anti-actin antibodies was 0.873 [95% C.I. 0.805-0.899]. Serum anti-actin antibodies values were significantly higher in coeliac disease patients than in healthy or "disease" controls (P<0.0001). Serum anti-actin antibodies were positive in 41 of the 60 coeliac disease patients with mild intestinal histology lesions (69%) and in 123 of the 145 with severe lesions (85.3%) (P<0.05). There was a significant inverse correlation between anti-actin antibody values and the villi/crypts ratio (r=-0.423; P<0.0001). In the 12 coeliac disease patients on gluten-free diet who underwent re-evaluation as they were persistently symptomatic, intestinal histology showed three cases with persistent villous atrophy: all of these were positive for serum anti-actin antibodies ELISA, whereas both serum anti-tTG and EmAs were negative. The other nine patients showed normal intestinal villi and were negative for serum anti-actin antibodies. CONCLUSIONS Anti-actin antibodies are a reliable marker of severe intestinal mucosa damage in coeliac disease patients and a simple ELISA technique offers an accurate method for their determination. These antibodies seem to be a very reliable marker of persistent intestinal damage in coeliac disease patients.
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Affiliation(s)
- A Carroccio
- Internal Medicine, University Hospital, Palermo, via del Vespro 141, 90127 Palermo, Italy.
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19
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Abstract
Coeliac disease is the manifestation of an immune hypersensitivity reaction towards gluten and related proteins, in genetically predisposed people. Although the precise pathogenesis of this condition remains to be fully elucidated, it is probably multifactorial in origin. The diagnosis of coeliac disease has traditionally depended on intestinal biopsies alone; nowadays, the diagnosis has been expanded to include an array of serological markers. This review is intended to offer pathologists an update of the relevant history and immunopathology pertaining to coeliac disease and also to offer recommendations on the ongoing responsibilities of the pathologist in the diagnosis and reporting of coeliac disease.
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Affiliation(s)
- B C Dickson
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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20
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Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther 2006; 24:47-54. [PMID: 16803602 DOI: 10.1111/j.1365-2036.2006.02967.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND With the appreciation of the high prevalence of coeliac disease there is increasing use of serology in screening asymptomatic people and testing those with suggestive features. AIM To compare the sensitivities and specificities of the endomysial antibody and the tissue transglutaminase antibody tests. METHODS Using electronic databases a search was made for relevant papers using the terms tissue transglutaminase and endomysial antibody. RESULTS Both the endomysial antibody and tissue transglutaminase antibody have very high sensitivities (93% for both) and specificities (>99% and >98% respectively) for the diagnosis of typical coeliac disease with villous atrophy. Human recombinant tissue transglutaminase performs much better than guinea pig tissue transglutaminase. Review of studies comparing endomysial antibody with human recombinant tissue transglutaminase antibody shows that endomysial antibody more often has a higher specificity and human recombinant tissue transglutaminase antibody more often has a higher sensitivity. CONCLUSION The human recombinant tissue transglutaminase antibody is the preferred test for screening asymptomatic people and for excluding coeliac disease in symptomatic individuals with a low pretest probability (i.e. <25%) for coeliac disease. Furthermore, it has a number of practical and financial advantages. If the pretest probability is >25%, biopsy is preferred as the post-test probability of coeliac disease with a negative test is still >2%.
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Affiliation(s)
- N R Lewis
- Department of Gastroenterology, Lincoln County Hospital, Lincoln, UK
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Schedel J, Rockmann F, Bongartz T, Woenckhaus M, Schölmerich J, Kullmann F. Association of Crohn's disease and latent celiac disease: a case report and review of the literature. Int J Colorectal Dis 2005; 20:376-80. [PMID: 15578194 DOI: 10.1007/s00384-004-0661-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND Crohn's disease is a chronic inflammatory disease of the intestine potentially affecting all parts of the intestine with predilection sites in the terminal ileum and proximal colon. Its prevalence in Western Europe is 20-40/100,000 with equal affection of both sexes and familiar accumulation. Histopathologically, it is characterized by a discontinuous, segmental manifestation and implication of all intestinal layers. Celiac disease, on the other hand, is defined by histologically proven villous atrophy associated with hyperplasia of crypts, lymphocytic infiltration and clinical improvement after a gluten-free diet. CASE REPORT We report the case of a 52-year-old man presenting with long-term diarrhea and loss of weight associated with Crohn's disease. After interventional therapy for an unstable coronary artery syndrome and medical therapy for hyperthyroidism, the diarrhea stopped only after maintaining a gluten-free diet. A latent form of celiac disease (clinical symptoms, improvement after gluten-free diet, detection of anti-gliadin IgA antibodies, negative histology) was diagnosed. CONCLUSION To our knowledge, this is the first report on the association of Crohn's disease and the latent form of celiac disease in the same patient. Whereas in most cases, Crohn's disease develops secondary to a pre-existing celiac disease, in our patient, latent celiac disease was diagnosed years after the onset of and therapy for Crohn's disease.
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Affiliation(s)
- Jörg Schedel
- Department of Internal Medicine I, University Hospital of Regensburg, 93042 Regensburg, Germany.
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22
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Abstract
PURPOSE OF REVIEW This article aims to summarize recent critical research in celiac disease. RECENT FINDINGS The crucial epitopes that confer toxicity to gliadin and related prolamins continue to be defined, as do methods of assessing their toxicity. New approaches to making the gluten-free diet more palatable are being studied. SUMMARY The position of proline residues is critical to the toxicity of cereal proteins to patients with celiac disease. Other genetic factors, apart from HLA status, remain elusive. Exciting advances in altering the toxicity of cereal proteins are being made.
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Affiliation(s)
- G Robins
- Department of Academic Medicine, St. James's University Hospital, Leeds, United Kingdom.
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23
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Clemente MG, Musu MP, Troncone R, Volta U, Congia M, Ciacci C, Neri E, Not T, Maggiore G, Strisciuglio P, Corazza GR, Gasbarrini G, Cicotto L, Sole G, Fasano A, De Virgiliis S. Enterocyte actin autoantibody detection: a new diagnostic tool in celiac disease diagnosis: results of a multicenter study. Am J Gastroenterol 2004; 99:1551-6. [PMID: 15307876 DOI: 10.1111/j.1572-0241.2004.30296.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study describes a new method to detect autoantibodies against actin filaments (AAA) as a serological marker of intestinal villous atrophy (IVA) in celiac disease (CD), and reports the results of an Italian double-blind multicenter study. METHODS IgA-AAA were analyzed by immunofluorescence using a newly developed method based on intestinal epithelial cells cultured in presence of colchicine. IgA-AAA were blindly evaluated prospectively in 223 antiendomysial antibody (AEA) and/or antitransglutaminase antibody (TGA) positive subjects and in 78 AEA and TGA negative subjects. IgA-AAA positive patients underwent an intestinal biopsy to confirm the diagnosis. Moreover, IgA-AAA were retrospectively investigated in 84 biopsy-proven CD patients and in 2,000 new consecutively collected serum samples from AEA and TGA negative nonbiopsied subjects. RESULTS IgA-AAA were positive in 98.2% of the CD patients with flat mucosa, in 89% with subtotal villous atrophy, and in 30% with partial villous atrophy. IgA-AAA were present in none of the AEA and TGA negative nonbiopsied controls. In AEA and/or TGA positive CD patients IgA-AAA positivity significantly correlated with IVA (p < 0.000 in the prospective study, p = 0.005 in the retrospective study). In the prospective study, the values of sensitivity, specificity, the positive predictive value, the negative predictive value, and the efficiency of the IgA-AAA test to identify patients with IVA were, respectively, 83.9%, 95.1%, 97.8%, 69.2%, and 87.0%. Furthermore, a significant correlation (p < 0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56). CONCLUSIONS The results of this multicenter study show that the new method for IgA-AAA detection could represent a practical diagnostic tool in AEA and/or TGA positive subjects, which would be especially useful when IVA shows a patchy distribution, when the histological picture is difficult to interpret, or when a biopsy could represent a life-threatening risk.
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Affiliation(s)
- M G Clemente
- Department of Biomedical Sciences and Biotechnologies, Second Pediatrics Clinic, Cagliari University, Italy
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25
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Affiliation(s)
- K Rostami
- Department of Gastroenterology, Good Hope Hospital NHS Trust, Rectory Rd, Sutton Coldfield, West Midlands B75 7RR, UK.
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