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Li MH, Ruan GC, Zhou WX, Li XQ, Zhang SY, Chen Y, Bai XY, Yang H, Zhang YJ, Zhao PY, Li J, Li JN. Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital. World J Gastroenterol 2024; 30:2523-2537. [PMID: 38817655 PMCID: PMC11135415 DOI: 10.3748/wjg.v30.i19.2523] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/20/2024] [Accepted: 04/11/2024] [Indexed: 05/20/2024] Open
Abstract
BACKGROUND Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM To improve overall understanding of this disease's diagnosis and prognosis. METHODS We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin's lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.
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Affiliation(s)
- Mu-Han Li
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Ge-Chong Ruan
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Wei-Xun Zhou
- Department of Pathology, Chinese Academy of Medical Scinences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Xiao-Qing Li
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Sheng-Yu Zhang
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Yang Chen
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Xiao-Yin Bai
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Hong Yang
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Yu-Jie Zhang
- Department of Pathology, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Peng-Yu Zhao
- Affairs Office, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital (West campus), Beijing 100032, China
| | - Ji Li
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
| | - Jing-Nan Li
- Department of Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing 100730, China
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Besa E, Tembo MJ, Mulenga C, Mweetwa M, Choudhry N, Chandwe K, Storer C, Head R, Amadi B, Haritunians T, McGovern D, Kwenda G, Peiris M, Kelly P. Potential determinants of low circulating glucagon-like peptide 2 concentrations in Zambian children with non-responsive stunting. Exp Physiol 2023; 108:568-580. [PMID: 36744850 PMCID: PMC10103869 DOI: 10.1113/ep090492] [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: 01/23/2023] [Accepted: 01/19/2023] [Indexed: 02/07/2023]
Abstract
NEW FINDINGS What is the central question of this study? Non-responsive stunting is characterised by a progressive decline of circulating glucagon-like peptide 2: what are the possible causes of this decline? What is the main finding and its importance? In contrast with the established loss of Paneth and goblet cells in environmental enteropathy, there was no evidence of a parallel loss of enteroendocrine cells as seen by positive tissue staining for chromogranin A. Transcriptomic and genomic analyses showed evidence of genetic transcripts that could account for some of the variability seen in circulating glucagon-like peptide 2 values. ABSTRACT Nutrient sensing determines digestive and hormonal responses following nutrient ingestion. We have previously reported decreased levels of glucagon-like peptide 2 (GLP-2) in children with stunting. Here we demonstrate the presence of enteroendocrine cells in stunted children and explore potential pathways that may be involved in reduced circulating levels of GLP-2. At the time of performing diagnostic endoscopies for non-responsive stunted children, intestinal biopsies were collected for immunofluorescence staining of enteroendocrine cells and transcriptomic analysis. Circulating levels of GLP-2 were also measured and correlated with transcriptomic data. An exploratory genome-wide association study (GWAS) was conducted on DNA samples (n = 158) to assess genetic contribution to GLP-2 variability. Intestinal tissue sections collected from non-responsive stunted children stained positive for chromogranin A (88/89), alongside G-protein-coupled receptors G-protein receptor 119 (75/87), free fatty acid receptor 3 (76/89) and taste 1 receptor 1 (39/45). Transcriptomic analysis found three pathways correlated with circulating GLP-2: sugar metabolism, epithelial transport, and barrier function, which likely reflect downstream events following receptor-ligand interaction. GWAS analysis revealed potential genetic contributions to GLP-2 half-life and receptor binding. Enteroendocrine cell loss was not identified in stunted Zambian children as has been observed for goblet and Paneth cells. Transcriptomic analysis suggests that GLP-2 has pleiotrophic actions on the intestinal mucosa in malnutrition, but further work is needed to dissect pathways leading to perturbations in nutrient sensing.
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Affiliation(s)
- Ellen Besa
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Mizinga Jacqueline Tembo
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Chola Mulenga
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Monica Mweetwa
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Naheed Choudhry
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Kanta Chandwe
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Chad Storer
- Genome Technology Access Center at McDonnell Genome InstituteWashington University in St LouisSt LouisMOUSA
| | - Richard Head
- Genome Technology Access Center at McDonnell Genome InstituteWashington University in St LouisSt LouisMOUSA
| | - Beatrice Amadi
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
| | - Talin Haritunians
- Cedars‐Sinai Medical CenterInflammatory Bowel and Immunobiology Research InstituteLos AngelesCAUSA
| | - Dermot McGovern
- Cedars‐Sinai Medical CenterInflammatory Bowel and Immunobiology Research InstituteLos AngelesCAUSA
| | - Geoffrey Kwenda
- Department of Biomedical Sciences, School of Health SciencesUniversity of ZambiaLusakaZambia
| | - Madusha Peiris
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Paul Kelly
- Tropical Gastroenterology and Nutrition Group, School of MedicineUniversity of ZambiaLusakaZambia
- Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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van Wanrooij RLJ, Neefjes-Borst EA, Bontkes HJ, Schreurs MWJ, Langerak AW, Mulder CJJ, Bouma G. Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center. Clin Transl Gastroenterol 2021; 12:e00387. [PMID: 34333499 PMCID: PMC8323799 DOI: 10.14309/ctg.0000000000000387] [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: 02/02/2021] [Accepted: 06/28/2021] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center. METHODS Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10). RESULTS Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23-73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation. DISCUSSION Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.
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Affiliation(s)
- Roy L J van Wanrooij
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Institute, Amsterdam, the Netherlands
| | | | - Hetty J Bontkes
- Laboratory Medical Immunology, Department of Clinical Chemistry, Amsterdam UMC, AGEM Research Institute, AI & I Institute, Amsterdam, the Netherlands
| | - Marco W J Schreurs
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Anton W Langerak
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Institute, Amsterdam, the Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Institute, Amsterdam, the Netherlands
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Iaquinto G, Panico L, Luongo G, Tenneriello V, Iaquinto S, Giardullo N, Rotondi Aufiero V, Mazzarella G, Rispoli R, Lucariello A, Perna A, De Luca A. Adult autoimmune enteropathy in autoimmune hepatitis patient. Case report and literature review. Clin Res Hepatol Gastroenterol 2021; 45:101673. [PMID: 33744411 DOI: 10.1016/j.clinre.2021.101673] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 01/25/2021] [Accepted: 03/02/2021] [Indexed: 02/04/2023]
Abstract
Autoimmune enteropathy (AIE) is a rare disease characterized by prolonged diarrhea, vomiting and weight loss; although it is mainly a rare pediatric disease, over the years a number of adults have also been found to be affected. In this study, we present a case report of a 73-year-old woman with a history of autoimmune hepatitis, antinuclear (ANA) and positive anti-enterocyte antibodies (AEA), who has suffered two months of intractable diarrhea, nausea, anorexia and severe weight loss. The histological examination of the endoscopic duodenal mucosa biopsies revealed severe shortening and flattening of the villi, resulting in mucosal atrophy. The immunohistochemical study revealed a polymorphic lymphoid population, exhibiting a B cell (CD20+) phenotype in follicles and a T cell phenotype (CD3+) in the diffuse component within the lamina propria. Our patient had a complete recovery after two weeks of taking prednisone and following a gluten-rich diet. To our knowledge this is the first case of autoimmune enteropathy in adults with ANA and AEA 7 years after a diagnosis of autoimmune hepatitis. To date, the patient is still in clinical remission on a low dose of orally administered predinisone without any additional immunosuppression.
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Affiliation(s)
- Gaetano Iaquinto
- Division of Gastroenterology, Department of Internal Medicine, S. Rita Hospital, Atripalda, Avellino, Italy.
| | - Luigi Panico
- Department of Pathology, AORN dei Colli, Monaldi Hospital, Naples, Italy
| | - Gelsomina Luongo
- Department of Pathology, San G. Moscati Hospital, Avellino, Italy
| | | | | | - Nicola Giardullo
- Division of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | | | | | - Raffaella Rispoli
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Angela Lucariello
- Department of Sport Sciences and Wellness, University of Naples "Parthenope", Naples, Italy
| | - Angelica Perna
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
| | - Antonio De Luca
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania "Luigi Vanvitelli", Naples, Italy
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Chong A, Kashani A, Ansstas M, Jamil L, Guindi M. Seronegative autoimmune enteropathy with duodenal sparing and colonic clues in an adult female. Clin J Gastroenterol 2021; 14:546-550. [PMID: 33630282 DOI: 10.1007/s12328-020-01336-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 12/29/2020] [Indexed: 10/22/2022]
Abstract
Autoimmune enteropathy (AIE) is a rare immune disorder of the gut seldom found in adults and characterized by uncontrollable diarrhea resulting in malabsorption. While AIE is known to be pan-enteric, virtually all cases have presented with altered duodenal histology following known patterns with or without macroscopic change. We describe a unique case of seronegative AIE lacking typical duodenal manifestations in a 43-year-old female. To our knowledge, this is the first report of AIE lacking usual duodenal histologic changes, which resulted in missed diagnosis for years. Ultimately, crypt epithelial apoptosis, mononuclear inflammation of the lamina propria, and goblet cell loss of intestinal mucosa besides the duodenum clinched the diagnosis of AIE. Colonic histologic abnormalities consistent with AIE in the setting of diarrhea with malnutrition despite duodenal sparing should prompt suspicion for AIE given the pan-enteric nature of this disease.
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Affiliation(s)
- Albert Chong
- Keck School of Medicine of the University of Southern California, 1975 Zonal Avenue, Keith Administration 100B, Los Angeles, CA, 90089, USA
| | - Amir Kashani
- Division of Gastroenterology, Hepatology, and Nutrition, University of Utah School of Medicine, 300 North 1900 East SOM 4R118, Salt Lake City, UT, 84132, USA
| | - Michael Ansstas
- Division of Digestive and Liver Disease, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA
| | - Laith Jamil
- Section of Gastroenterology and Hepatology, Beaumont Hospital-Royal Oak, Administrative Building West, 3711 W 13 Mile Rd, Royal Oak, MI, 48073, USA
| | - Maha Guindi
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
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Acute Flare of Adult-Onset Autoimmune Enteropathy Associated With Cyclophosphamide. ACG Case Rep J 2021; 8:e00541. [PMID: 33634202 PMCID: PMC7901791 DOI: 10.14309/crj.0000000000000541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 10/04/2020] [Indexed: 01/01/2023] Open
Abstract
This is a case of adult-onset autoimmune enteropathy (AIE) in a 46-year-old man with multiple autoimmune conditions who presented with worsening disease process after receiving cyclophosphamide. We describe the investigations and management of this patient over a 6-year timeline. The diagnosis and management of AIE is challenging given the heterogeneity in clinicopathologic findings and a small number of adult case reports. We describe the current diagnostic criteria, review the literature on treatment options and outcomes, and discuss the evidence for cyclophosphamide in the treatment of AIE. Adult-onset AIE should be considered in the differential diagnosis of refractory diarrhea and weight loss.
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Neuroendocrine Cells Are Commonly Absent in the Intestinal Crypts in Autoimmune Enteropathy. Am J Surg Pathol 2020; 44:1130-1136. [PMID: 32590456 DOI: 10.1097/pas.0000000000001516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The absence of neuroendocrine (NE) cells in the intestinal mucosa in autoimmune enteropathy (AIE) has been occasionally reported. However, the status of NE cells has not been studied in detail in AIE. Small bowel and colonic biopsies were retrospectively retrieved from 18 AIE patients (26 baseline [18 small bowel and 8 colon]; and 15 follow-up [11 duodenum and 4 colon] biopsies in 11 patients). Thirty-three common variable immunodeficiency (CVID) patients (30 small bowel and 16 colon), 15 inflammatory bowel disease patients (5 duodenum and 10 colon), 13 immunoglobulinA deficiency patients (13 duodenum and 5 colon), and 10 normal controls (5 colon and 5 duodenum) were selected as control groups. Histologic features (villous atrophy, intraepithelial lymphocytosis, acute inflammation, crypt apoptosis, and absence or presence of goblet cells, Paneth cells and plasma cells) were recorded. Chromogranin immunostain was performed and chromogranin-positive NE cells were counted per 10 consecutive, well-oriented crypts. On the basis of the number of chromogranin-positive NE cells, cases were graded as being absent (≤3 NE cells), markedly decreased (≤15), and intact (>15). The NE cell status correlated with histologic features. The median age of 18 AIE patients was 38.5 years (range: 11 to 74 y) and 14 patients were male. Fourteen of 18 (78%) patients showed loss (absent or markedly decreased) of NE cells in the small bowel and/or colon in the baseline biopsies including 12 (of 18) small bowel and 6 (of 8) colon biopsies. Follow-up biopsy was available in 11 patients. Six of 7 (85%) patients who showed loss of NE cells in the baseline biopsies regained NE cells in the follow-up biopsies, and 1 patient continued to show loss of NE cells. Four patients who showed intact NE cells in the baseline remained unchanged in the follow-up. Among the control groups, 3 of 33 (9%) CVID patients showed loss of NE cells. NE cells were not lost in the biopsies of all 15 and 13 patients with inflammatory bowel disease and immunoglobulinA deficiency, respectively, or the 10 normal controls. In all 41 biopsies (26 baseline plus 15 follow-up) with AIE, NE cell loss was significantly associated with increased crypt apoptosis and loss of goblet cells (P=0.001, both) but not with other histologic findings. In conclusion, our study suggests that NE cells may also be the target cells in AIE and commonly lost in the intestinal crypts in AIE, and consequently loss of NE cells can be used as an adjunct histologic feature for diagnosis of AIE.
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Jamee M, Zaki-Dizaji M, Lo B, Abolhassani H, Aghamahdi F, Mosavian M, Nademi Z, Mohammadi H, Jadidi-Niaragh F, Rojas M, Anaya JM, Azizi G. Clinical, Immunological, and Genetic Features in Patients with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-like Syndrome. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 8:2747-2760.e7. [PMID: 32428713 DOI: 10.1016/j.jaip.2020.04.070] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 04/06/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immunity caused by mutations in the forkhead box P3 (FOXP3) gene. OBJECTIVE In this study, we conducted a systematic review of patients with IPEX and IPEX-like syndrome to delineate differences in these 2 major groups. METHODS The literature search was performed in PubMed, Web of Science, and Scopus databases, and demographic, clinical, immunologic, and molecular data were compared between the IPEX and IPEX-like groups. RESULTS A total of 459 patients were reported in 148 eligible articles. Major clinical differences between patients with IPEX and IPEX-like syndrome were observed in rates of pneumonia (11% vs 31%, P < .001), bronchiectasis (0.3% vs 14%, P < .001), diarrhea (56% vs 42%, P = .020), and organomegaly (10% vs 23%, P = .001), respectively. Eosinophilia (95% vs 100%), low regulatory T-cell count (68% vs 50%), and elevated IgE (87% vs 61%) were the most prominent laboratory findings in patients with IPEX and IPEX-like syndrome, respectively. In the IPEX group, a lower mortality rate was observed among patients receiving hematopoietic stem cell transplantation (HSCT) (24%) compared with other patients (43%), P = .008; however, in the IPEX-like group, it was not significant (P = .189). CONCLUSIONS Patients with IPEX syndrome generally suffer from enteropathy, autoimmunity, dermatitis, eosinophilia, and elevated serum IgE. Despite similarities in their clinical presentations, patients with IPEX-like syndrome are more likely to present common variable immunodeficiency-like phenotype such as respiratory tract infections, bronchiectasis, and organomegaly. HSCT is currently the only curative therapy for both IPEX and IPEX-like syndrome and may result in favorable outcome.
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Affiliation(s)
- Mahnaz Jamee
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran; Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Bernice Lo
- Sidra Medicine, Division of Translational Medicine, Research Branch, Doha, Qatar
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Fatemeh Aghamahdi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mehdi Mosavian
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Zohreh Nademi
- Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle, United Kingdom
| | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Manuel Rojas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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Abstract
The enteroendocrine system is located in the gastrointestinal (GI) tract, and makes up the largest endocrine system in the human body. Despite that, its roles and functions remain incompletely understood. Gut regulatory peptides are the main products of enteroendocrine cells, and play an integral role in the digestion and absorption of nutrients through their effect on intestinal secretions and gut motility. Several peptides, such as cholecystokinin, polypeptide YY and glucagon-like peptide-1, have traditionally been reported to suppress appetite following food intake, so-called satiety hormones. In this review, we propose that, in the healthy individual, this system to regulate appetite does not play a dominant role in normal food intake regulation, and that there is insufficient evidence to wholly link postprandial endogenous gut peptides with appetite-related behaviours. Instead, or additionally, top-down, hedonic drive and neurocognitive factors may have more of an impact on food intake. In GI disease however, supraphysiological levels of these hormones may have more of an impact on appetite regulation as well as contributing to other unpleasant abdominal symptoms, potentially as part of an innate response to injury. Further work is required to better understand the mechanisms involved in appetite control and unlock the therapeutic potential offered by the enteroendocrine system in GI disease and obesity.
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Ahmed Z, Imdad A, Connelly JA, Acra S. Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy. Dig Dis Sci 2019; 64:643-654. [PMID: 30415406 PMCID: PMC8260026 DOI: 10.1007/s10620-018-5364-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.
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Affiliation(s)
- Zunirah Ahmed
- School of Medicine, University of Alabama, Montgomery Campus, 2055 E South Blvd Ste 202, Montgomery, AL, 36116, USA
| | - Aamer Imdad
- Division of Pediatric Gastroenterology, SUNY Upstate Medical University, 725 Irving Street, Suite 501, Syracuse, NY, 13210, USA
| | - James A Connelly
- Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, 2100 Children's Way, Nashville, TN, 37212, USA
| | - Sari Acra
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2100 Children's Way, Nashville, TN, 37212, USA.
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Eriguchi Y, Nakamura K, Yokoi Y, Sugimoto R, Takahashi S, Hashimoto D, Teshima T, Ayabe T, Selsted ME, Ouellette AJ. Essential role of IFN-γ in T cell-associated intestinal inflammation. JCI Insight 2018; 3:121886. [PMID: 30232288 DOI: 10.1172/jci.insight.121886] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 08/14/2018] [Indexed: 12/11/2022] Open
Abstract
Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell-mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7-dependent mechanism. IFN-γ mediated these effects, because IFN-γ receptor-null enteroids were unaffected by activated T cells. In mice, administration of IFN-γ induced enteropathy with crypt hyperplasia, villus shortening, Paneth cell depletion, and modified ISC marker expression. IFN-γ exacerbated radiation enteritis, which was ameliorated by treatment with a selective JAK1/2 inhibitor. Thus, IFN-γ induced Paneth cell death and impaired regeneration of small intestinal epithelium in vivo, suggesting that IFN-γ may be a useful target for treating defective mucosal regeneration in enteric inflammation.
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Affiliation(s)
- Yoshihiro Eriguchi
- Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Kiminori Nakamura
- Department of Cell Biological Science, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Yuki Yokoi
- Department of Cell Biological Science, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Rina Sugimoto
- Department of Cell Biological Science, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Shuichiro Takahashi
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Daigo Hashimoto
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Tokiyoshi Ayabe
- Department of Cell Biological Science, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Michael E Selsted
- Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - André J Ouellette
- Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Abstract
Autoimmune enteropathy (AIE) is rare but damaging. The lack of consistent objective findings makes diagnosis a challenge. A 45-year-old male developed noninfectious diarrhea with significant weight loss and electrolyte abnormalities. Computed tomography delineated enteritis. Colonoscopy and esophagogastroduodenoscopy showed villous atrophy, chronic inflammation, and ulceration of the terminal ileum and cecum. Pathology showed cryptitis with apoptosis and abscesses throughout the small and large bowel and absent goblet cells. Steroids rapidly improved symptoms. Anti-enterocyte antibody serologies were negative. Management can be challenging, and, in this case, the patient initially improved with budesonide and infliximab but required alternative anti-tumor necrosis factor therapy after relapsing. This is an unusual presentation of seronegative AIE, which should be considered in cases of persistent severe diarrhea.
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13
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Uncontrolled IL-17 Production by Intraepithelial Lymphocytes in a Case of non-IPEX Autoimmune Enteropathy. Clin Transl Gastroenterol 2016; 7:e182. [PMID: 27415620 PMCID: PMC5543485 DOI: 10.1038/ctg.2016.41] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 06/01/2016] [Indexed: 12/19/2022] Open
Abstract
Objectives: To provide a functional and phenotypic characterization of immune cells infiltrating small intestinal mucosa during non-IPEX autoimmune enteropathy (AIE), as to gain insights on the pathogenesis of this clinical condition. Methods: Duodenal biopsies from a patient with AIE at baseline and following drug-induced remission were analyzed by immunohistochemistry, immunofluorescence, and flow cytometry, and results were compared with those obtained from patients with active celiac disease, ileal Crohn’s disease and healthy controls. Lamina propria (LP) and intraepithelial (IELs) lymphocytes from AIE and controls were analyzed for mechanisms regulating cytokine production. Foxp3 expression and suppressive functions of LP regulatory T cells (Tregs) were analyzed. Results: The quantitative deficit of Foxp3 expression in Tregs in AIE associates with unrestrained IL-17 production by IELs. Interleukin (IL)-17-producing IELs were rare in the uninflamed duodenum and in the ileum of Crohn’s disease patients, and disappeared upon drug-induced AIE remission. IL-17 upregulation in CD4+IELs and CD4+LP T cells had different requirements for pro-inflammatory cytokines. Moreover, transforming growth factor-β (TGF-β) selectively enhanced IL-17 production by CD8+IELs. Intriguingly, although Foxp3lowTregs in AIE were poorly suppressive, they could upregulate GARP-LAP/TGF-β surface expression and enhanced IL-17 production selectively by CD8+IELs. Finally, phosphorylated Smad2/3 was detectable in duodenal CD8+ lymphocytes in active AIE in situ, indicating that they received signals from the TGF-β receptor in vivo. Conclusions: AIE is characterized by the appearance of unconventional IL-17-producing IELs, which could be generated locally by pro-inflammatory cytokines and TGF-β. These results suggest that Foxp3+Tregs and Treg-derived TGF-β regulate IL-17 production by IELs in the small intestine and in AIE.
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14
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Abstract
Tropical sprue (TS) is a malabsorption syndrome of presumed infectious aetiology that affects residents of (or visitors to) the tropics. The histological changes of TS are similar to those of coeliac disease, with increased intraepithelial lymphocytes being central to both. Unlike in coeliac disease, however, a completely flat small bowel biopsy is uncommon in TS. TS typically involves the terminal ileum, whereas coeliac disease does not. Small intestinal bacterial overgrowth (SIBO) has been defined as an increase in number and/or a change in the type of bacteria in the upper gut. Conditions that predispose to SIBO are largely those that decrease or interfere with small bowel motility. The mucosal histology is variable, and may include modest villous blunting accompanied by increased lamina propria and epithelial inflammation. Autoimmune enteropathy (AE) is a family of rare diseases that share common themes such as immunodeficiency states and autoantibodies. AE cases typically have marked villous atrophy similar to that in fully developed coeliac disease, but they lack the intense surface epithelial lymphocytosis. Apoptosis and lymphocyte infiltration at the base of the crypts, crypt abscesses and cryptitis are also seen. Patients with anti-goblet cell antibodies can have a lack of goblet cells, endocrine cells, and Paneth cells.
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15
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Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol 2014; 38:1319-29. [PMID: 25188868 DOI: 10.1097/pas.0000000000000317] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Autoimmune enteropathy (AIE) is a rare disorder characterized by severe diarrhea and small intestinal mucosal atrophy resulting from immune-mediated injury. It remains a challenging diagnosis because of its clinicopathologic variability. To better understand its histopathologic features, we describe the gastrointestinal biopsy findings of 25 patients, including children and adults. The most common finding on small intestinal biopsy (13/25 cases, 52%) was villous blunting, expansion of the lamina propria by mixed but predominantly mononuclear inflammation, and neutrophilic cryptitis with or without crypt microabscesses. In 5 cases (20%), the duodenum exhibited changes indistinguishable from celiac disease, with villous blunting and intraepithelial lymphocytosis. Increased crypt apoptosis with minimal inflammation, resembling acute graft-versus-host disease, was observed in 4 cases (16%). The remaining 3 cases (12%) exhibited a mixture of 2 or more of the above patterns. Mucosal abnormalities outside the small intestine were present in all 24 cases with available biopsies (100%), with the stomach most commonly affected (19/22 cases, 86%), followed by the colon (14/22, 64%) and esophagus (5/18, 28%). Findings in non-small intestinal sites were variable and included mixed active and chronic inflammation, chronic inflammation alone, intraepithelial lymphocytosis, and increased apoptosis resembling acute graft-versus-host disease. In summary, AIE most commonly presents as an active enteritis with villous blunting and expansion of the lamina propria by mixed inflammation. Mucosal abnormalities are frequently seen elsewhere in the gut. AIE may thus be better regarded as a pan-gastrointestinal autoimmune disorder, and biopsies from sites other than the small intestine may greatly facilitate its diagnosis.
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16
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Harrison E, Lal S, McLaughlin JT. Enteroendocrine cells in gastrointestinal pathophysiology. Curr Opin Pharmacol 2013; 13:941-5. [PMID: 24206752 DOI: 10.1016/j.coph.2013.09.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 09/08/2013] [Accepted: 09/09/2013] [Indexed: 01/15/2023]
Abstract
Enteroendocrine cells in the gastrointestinal tract play an important role in the regulation of appetite and digestive responses through the secretion of peptides. Their involvement in gastrointestinal diseases has been acknowledged, but relatively few studies have sought to clearly define their role in the pathogenesis or as therapeutic targets. Recent, but still limited, work has identified new roles for EEC in GI diseases.
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Affiliation(s)
- Elizabeth Harrison
- Institute of Inflammation and Repair, Faculty of Medical and Human Sciences and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
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17
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Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (or autoimmune polyendocrine syndrome type 1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene. It causes a loss in central immune tolerance, failure to eliminate autoreactive T cells in the thymus, and their escape to the periphery. APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine and nonendocrine autoimmune diseases. Although it depends on the series, approximately 25% of APECED patients are affected by gastrointestinal (GI) manifestations, mainly autoimmune-related disorders like autoimmune hepatitis, atrophic gastritis with or without pernicious anemia (Biermer disease), intestinal infections, and malabsorption. In contrast to the major organ-specific autoimmune symptoms of APECED, the GI symptoms and their underlying pathogenesis are poorly understood. Yet isolated case reports and small series depict severe intestinal involvement in children, leading to malabsorption, multiple deficiencies, growth impairment, and possible death. Moreover, very few systematic studies of GI function with intestinal biopsies have been performed. GI symptoms may be the first manifestation of APECED, yet they may have various causes; effective treatment will therefore vary. We provide here an updated review of GI manifestations in APECED, including principles of diagnosis and therapy.
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Affiliation(s)
- Nicolas Kluger
- Departments of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, University of Helsinki, and Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland.
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18
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Murray JA, Rubio-Tapia A. Diarrhoea due to small bowel diseases. Best Pract Res Clin Gastroenterol 2012; 26:581-600. [PMID: 23384804 PMCID: PMC3621726 DOI: 10.1016/j.bpg.2012.11.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 11/14/2012] [Indexed: 01/31/2023]
Abstract
Small intestinal diseases are a common, though often overlooked cause of diarrhoeal illness. Fully 1% of the Caucasian population are affected by coeliac disease and a substantial portion of children living in poverty in the developing world are affected by environmental enteropathy. These are but two examples of the many diseases that cause mucosal injury to the primary digestive and absorptive organ in our body. While diarrhoea may be a common, though not universally seen symptom of small bowel mucosal disease, the consequent malabsorption can lead to substantial malnutrition and nutrient deficiencies. The small intestine, unlike the colon, has been relatively inaccessible, and systematic evaluation is often necessary to identify and treat small intestinal mucosal diseases that lead to diarrhoea. Immunodeficiency states, including HIV enteropathy, adult autoimmune enteropathy, drug-associated enteropathy, and tropical sprue continue to occur and require specific therapy. All patients with severe diarrhoea or diarrhoea associated with features suggestive of malabsorption may have a disease of the small intestinal mucosa that requires careful evaluation and targeted management.
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Affiliation(s)
- Joseph A. Murray
- Corresponding author. Tel.: +1 507 255 5713; fax: +1 507 255 6318.
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19
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Bishu S, Arsenescu V, Lee EY, Vargas HD, de Villiers WJS, Arsenescu R. Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review. BMC Gastroenterol 2011; 11:131. [PMID: 22126605 PMCID: PMC3287162 DOI: 10.1186/1471-230x-11-131] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 11/29/2011] [Indexed: 01/26/2023] Open
Abstract
Background Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE. Case Presentation We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement. Conclusions AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE.
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Affiliation(s)
- Shrinivas Bishu
- Department of Internal Medicine, University of Kentucky Medical Center, 800 Rose Street, Lexington, Kentucky 40536, USA.
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20
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Moran GW, Leslie FC, Levison SE, Worthington J, McLaughlin JT. Enteroendocrine cells: neglected players in gastrointestinal disorders? Therap Adv Gastroenterol 2011; 1:51-60. [PMID: 21180514 DOI: 10.1177/1756283x08093943] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Enteroendocrine cells (EEC) form the basis of the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility. Their key purpose is to act as sensors of luminal contents, either in a classical endocrine fashion, or by a paracrine effect on proximate cells, notably vagal afferent fibres. They also play a pivotal role in the control of food intake, and emerging data add roles in mucosal immunity and repair. We propose that EEC are fundamental in several gastrointestinal pathologies, notably Post-infectious Irritable Bowel Syndrome, infectious enteritis, and possibly inflammatory bowel disease. Further work is needed to fully illustrate the importance, detailed biology and therapeutic potential of these frequently overlooked cells.
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Affiliation(s)
- Gordon W Moran
- Department of Gastroenterology, University Hospital of North Staffordshire, Stoke-on-Trent, UK
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21
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Gonzalez G, Castro FP, Berho M, Petras R. Autoimmune enteropathy associated with cessation of interferon-alpha therapy in chronic hepatitis C. Dig Dis Sci 2010; 55:1490-1493. [PMID: 19639409 DOI: 10.1007/s10620-009-0877-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2009] [Accepted: 06/08/2009] [Indexed: 12/09/2022]
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Montalto M, D'Onofrio F, Santoro L, Gallo A, Gasbarrini A, Gasbarrini G. Autoimmune enteropathy in children and adults. Scand J Gastroenterol 2010; 44:1029-36. [PMID: 19255930 DOI: 10.1080/00365520902783691] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Autoimmune enteropathy is a rare disorder characterized by severe and protracted diarrhea, weight loss from malabsorption and immune-mediated damage to the intestinal mucosa, generally occurring in infants and young children, although some cases of adult onset have been reported in the literature. Pathogenetic mechanisms involve immunological disorders, in which the presence of antienterocyte autoantibodies, although detected since first description, seems now to be secondary. As occurs frequently in autoimmunity, subjects with autoimmune enteropathy may be affected by other autoimmune disorders, sometimes leading to particular forms, i.e. the IPEX syndrome and the APECED syndrome. The prognosis of autoimmune enteropathy patients depends on the severity of digestive symptoms (including fecal output), on the severity and extension of histological lesions along the gastrointestinal apparatus, and on the presence of extra-intestinal involvement. Management of autoimmune enteropathy patients is based on nutritional support and adequate hydration to ensure optimal growth and development, together with immunosuppressive therapy. Recently, biological agents have been introduced, with apparent beneficial effects.
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Affiliation(s)
- Massimo Montalto
- Institute of Internal Medicine, Catholic University, Rome, Italy.
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23
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Ohsie S, Gerney G, Gui D, Kahana D, Martín MG, Cortina G. A paucity of colonic enteroendocrine and/or enterochromaffin cells characterizes a subset of patients with chronic unexplained diarrhea/malabsorption. Hum Pathol 2009; 40:1006-14. [PMID: 19297006 PMCID: PMC7595368 DOI: 10.1016/j.humpath.2008.12.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 12/24/2008] [Accepted: 12/30/2008] [Indexed: 01/01/2023]
Abstract
A generalized absence of enteroendocrine cells characterizes 2 diarrheal/malabsorptive diseases, namely, enteroendocrine cell dysgenesis and autoimmune polyglandular syndrome 1. However, it is not routine for pathologists to examine mucosal biopsies for enteroendocrine cells in cases of chronic diarrheal illness. Our primary aim was to prospectively examine colonic mucosa for loss of enteroendocrine cells using chromogranin A immunohistochemistry for diagnostic purposes. Our secondary aim was to investigate enterochromaffin cells as a subset of enteroendocrine cells, using serotonin (5HT) immunohistochemistry; we hypothesized that other causes of diarrhea due to loss of enteroendocrine cell subsets are missed by evaluating enteroendocrine cells alone. Our approach was limited to patients with chronic unexplained diarrhea partly selected by referring physicians who considered the patients problematic. Seven problematic patients with reduced enteroendocrine or enterochromaffin cells were collected over a 9-month period and placed in group A. Three group A patients demonstrated reduced enteroendocrine cells relative to controls, and they were later diagnosed as having enteroendocrine cell dysgenesis (n = 1) and autoimmune polyglandular syndrome 1 (n = 2). Four group A patients had reduced enterochromaffin cells but normal enteroendocrine cells. These 4 patients had conditions such as congenital diarrhea, mild graft-versus-host disease, acquired childhood chronic diarrhea, and diarrhea post lung transplant. The reduced enterochromaffin cells in the graft-versus-host disease patient inspired a third aim, that is, to investigate whether a loss of enterochromaffin cells would be a generalized defect seen in patients with mild colonic graft-versus-host disease (group B). However, no loss of enterochromaffin cells was detected in group B. Two methods of enumerating endocrine cells were used and demonstrated 67% agreement.
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Affiliation(s)
- Steven Ohsie
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Garrett Gerney
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Dorina Gui
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Doron Kahana
- Division of Gastroenterology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Martín G. Martín
- Division of Gastroenterology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Galen Cortina
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095, USA
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Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, Brousse N. Digestive histopathological presentation of IPEX syndrome. Mod Pathol 2009; 22:95-102. [PMID: 18820676 DOI: 10.1038/modpathol.2008.161] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) syndrome is a well recognized and particularly severe form of autoimmune enteropathy. It has an X-linked recessive transmission, and is caused by mutations in the FOXP3 gene. We studied the intestinal morphological changes characterizing IPEX syndrome in a series of 12 children with a molecularly confirmed diagnosis. Histological examination of duodenal, gastric and colonic biopsies were retrospectively reviewed and compared by two independent experienced pathologists. In parallel, the presence of circulating anti-enterocyte antibodies was analysed using an indirect immunofluorescence technique and a quantitative radioligand assay against the 75-kDa autoantigen. The morphology of the inflammatory gut lesions could be categorized into three different entities, namely graft-vs-host disease-like changes (9/12 patients), a coeliac disease-like pattern (2/12) and an enteropathy with a complete depletion of goblet cells (1/12). Our results do not suggest any phenotype-genotype correlation. Circulating antibodies were detected in all 12 patients, with an anti-brush border pattern (11/12) and anti-goblet cell antibodies (1/12), as well as by a radioligand assay. The histological presentation of autoimmune enteropathy is rather variable. However, a graft-vs-host disease-like pattern associated with positive anti-enterocyte antibodies is the most frequent intestinal presentation of IPEX syndrome, and constitutes a very valuable tool for pathologists to suspect this diagnosis.
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Akram S, Murray JA, Pardi DS, Alexander GL, Schaffner JA, Russo PA, Abraham SC. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol 2007; 5:1282-90; quiz 1245. [PMID: 17683994 PMCID: PMC2128725 DOI: 10.1016/j.cgh.2007.05.013] [Citation(s) in RCA: 162] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Autoimmune enteropathy is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. It is rarely observed in adults, with only 11 cases reported to date. METHODS Fifteen adults with autoimmune enteropathy were identified at the Mayo Clinic, Rochester, from May 2001-June 2006. The demographic, clinical, and treatment data were abstracted from their records. RESULTS The study population was 87% white, 47% female, with median age of 55 years (interquartile range, 42-67 years). All patients had protracted diarrhea, weight loss, and malnutrition. Celiac disease was excluded by lack of response to gluten-free diet or absence of the celiac disease susceptibility HLA genotypes. Fourteen patients were tested for gut epithelial cell antibodies, and 93% were positive for anti-enterocyte and/or anti-goblet cell antibodies. Predisposition to autoimmune diseases was noted in 80%, as indicated by a variety of circulating autoantibodies. Small intestinal histopathologic findings included subtotal villous atrophy and lymphoplasmacytic infiltration in the lamina propria with relatively few surface intraepithelial lymphocytes. T-cell receptor gene rearrangement studies were negative in all cases. Immunosuppressive therapy was required in 93% of cases. Clinical improvement was noted in 60% after 1-8 weeks of steroid therapy. CONCLUSIONS Autoimmune enteropathy is a heterogeneous disease and should be considered in the differential diagnosis of malabsorption and small bowel villous atrophy. The presence of gut epithelial cell antibodies can help confirm the diagnosis. No single agent is unequivocally effective in inducing remission, and immunosuppressive therapy is required in most cases.
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Affiliation(s)
- Salma Akram
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Joseph A. Murray
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Darrell S. Pardi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Glenn L. Alexander
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - John A. Schaffner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Pierre A. Russo
- Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Susan C. Abraham
- Division of Anatomic Pathology, Department of Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
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Cortina G, Smart CN, Farmer DG, Bhuta S, Treem WR, Hill ID, Martín MG. Enteroendocrine cell dysgenesis and malabsorption, a histopathologic and immunohistochemical characterization. Hum Pathol 2007; 38:570-80. [PMID: 17258790 DOI: 10.1016/j.humpath.2006.10.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Revised: 09/24/2006] [Accepted: 10/11/2006] [Indexed: 01/03/2023]
Abstract
Enteroendocrine cell dysgenesis was observed in 3 patients with intestinal failure of unknown cause. Enteroendocrine cell dysgenesis is a congenitally acquired life-threatening malabsorptive condition with a unique clinical phenotype paired with a histologically identifiable disease pattern. Two cases were first presented at the Ninth International Small Bowel Transplantation Symposium, Brussels 2005, and were subsequently published (N Engl J Med 2006;355:270). We now present the histopathologic and immunohistochemical findings of the gastric antrum, small bowel, and colon in greater detail. The clinical phenotype of the patients was unusual in that the affected patients demonstrated profound malabsorption of all nutrients, except water, from birth. The small intestine in each patient demonstrated almost no abnormality, except a near absence of endocrine cells in the mucosa. The colon appeared similarly affected. Known causes of congenital malabsorption, inflammatory, and infectious causes of diarrhea were excluded. The defect is secondary to point mutations in NEUROG3, which result in an arrest of endocrine cell development in the small intestine and colon. This work describes the pathologic characterization of enteroendocrine cell dysgenesis using routine techniques. The pattern of injury is distinct from other histopathologically assessed congenital malabsorptive conditions such as microvillus inclusion disease, tufting enteropathy, and abetalipoproteinemia. It is also easily distinguished from inflammatory conditions such as food allergy, gluten-sensitive enteropathy, autoimmune enteropathy, IPEX (immune dysfunction, polyendocrinopathy, enteropathy, and X-linked inheritance), and inflammatory bowel disease. The histopathology of disease is similar to what has been found transiently in a single patient with autoimmune polyglandular syndrome type I.
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Affiliation(s)
- Galen Cortina
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
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Abstract
PURPOSE OF REVIEW To review recently published studies presenting novel and relevant information on antimicrobial peptides in gastrointestinal infections. RECENT FINDINGS Defensins and cathelicidins are important antimicrobial peptides expressed by the gastrointestinal epithelium. Their localization and regulation have been the focus of current research establishing the relevance of these peptides both in counteracting an attack by pathogens as well as in controlling the endogenous bacterial flora. In the small intestine, Paneth cell alpha-defensins maintain a low level of microorganisms and regulate the composition of the bacterial flora. In contrast, a constitutive beta-defensin can be found in nearly all gastrointestinal tissues. Other relevant beta-defensins as well as human cathelicidin are inducible by inflammation or infections. Thus Helicobacter pylori enhances defensin expression in the gastric mucosa and Campylobacter jejuni and Salmonella provoke a similar response in the colon. Other pathogenic bacteria may suppress the antimicrobial peptide response as an escape strategy. Notably, the therapeutic induction of cathelicidins alleviates experimental shigellosis, suggesting a future role of endogenous antibiotics in medical therapy. SUMMARY These recent findings together with a better understanding of underlying mechanisms involved in the regulation and biology of antimicrobial peptides will open up new therapeutic avenues to battle infections.
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Abstract
PURPOSE OF REVIEW To review recently published studies presenting novel and relevant information on Paneth cells and their function. RECENT FINDINGS Paneth cells are secretory epithelial cells which are predominantly found in the small-intestinal crypts of Lieberkühn. Their most abundant products are alpha-defensins, which are endogenous antibiotics with activity against gram-negative and gram-positive bacteria, fungi, viruses and protozoa. The differentiation from stem-cell progenitors to Paneth cells is regulated by Wnt signalling via a complex gene programme, terminally including defensins. A disturbance of Paneth-cell differentiation and function may predispose to intestinal infections and appears to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. SUMMARY It is conceivable that these recent findings together with a better understanding of underlying mechanisms involved in the regulation and biology of Paneth cells will open up new therapeutic avenues for preventing infection as well as for causally treating inflammatory bowel diseases.
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Affiliation(s)
- Jan Wehkamp
- Robert Bosch Hospital and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
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Volk EE. Association between thymoma and autoimmune enteropathy in adults. Hum Pathol 2006; 37:1368; author reply 1368-9. [PMID: 16996380 DOI: 10.1016/j.humpath.2006.06.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Accepted: 06/20/2006] [Indexed: 11/26/2022]
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