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1
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Sienkiewicz M, Sroka K, Binienda A, Jurk D, Fichna J. A new face of old cells: An overview about the role of senescence and telomeres in inflammatory bowel diseases. Ageing Res Rev 2023; 91:102083. [PMID: 37802318 DOI: 10.1016/j.arr.2023.102083] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/01/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023]
Abstract
Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.
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Affiliation(s)
- Michał Sienkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Kamila Sroka
- Department of Family Medicine and Public Health, University of Opole, Opole, Poland
| | - Agata Binienda
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Diana Jurk
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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2
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Truta B, Wohler E, Sobreira N, Datta LW, Brant SR. Role of telomere shortening in anticipation of inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2020; 11:69-78. [PMID: 32953227 PMCID: PMC7475772 DOI: 10.4292/wjgpt.v11.i4.69] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/25/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism. AIM To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms. METHODS We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance. RESULTS Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance. CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.
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Affiliation(s)
- Brindusa Truta
- Steven R Brant, Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21210, United States
| | - Elizabeth Wohler
- McKusick-Nathan Institute of Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
| | - Nara Sobreira
- McKusick-Nathan Institute of Genetics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
| | - Lisa W. Datta
- Steven R Brant, Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21210, United States
| | - Steven R. Brant
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers-Robert Wood Johnson Medical School, NJ, 08901, United States
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3
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Park SH, Hwang SW, Ye BD, Noh S, Park JC, Kim JY, Kim J, Ham NS, Oh EH, Yang DH, Byeon JS, Myung SJ, Yang SK. Concordance regarding disease type and phenotypic characteristics among patients with familial inflammatory bowel disease. J Gastroenterol Hepatol 2020; 35:988-993. [PMID: 31674059 DOI: 10.1111/jgh.14913] [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: 08/29/2019] [Revised: 10/03/2019] [Accepted: 10/13/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS The phenotypic concordance among familial cases of inflammatory bowel disease (IBD) has been rarely reported. Thus, the present study aimed to evaluate the concordance regarding disease type and phenotypic features in a large cohort of Korean patients with IBD. METHODS A total of 6647 patients with IBD who visited the Asan Medical Center between June 1989 and September 2016 were enrolled in the study. When at least two familial cases existed in our cohort, they were included in the concordance analysis (κ index). The concordance between younger and older members for IBD type [Crohn's disease (CD) and ulcerative colitis (UC)] and phenotypic characteristics such as disease extent and location, disease behavior, the use of medication, and need for surgery were evaluated. RESULTS A positive family history of IBD was noted in 216 patients with CD (7.0%) and in 238 patients with UC (6.7%). Of all patients, 167 consanguineous pairs in 146 families were identified. The crude concordance rate for IBD type was 82.6% with a κ index of 0.656 [95% confidence interval (CI): 0.545-0.768, good concordance]. There was mild concordance for disease location in CD (κ = 0.256; 95% CI: 0.007-0.505) and for the use of antitumor necrosis factor agents in UC (κ = 0.354; 95% CI: -0.049-0.757). The concordance for IBD type and several phenotypes in first-degree relative pairs was better than that in the entire pairs. CONCLUSIONS Disease type and phenotypic characteristics of patients with familial IBD may be anticipated.
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Affiliation(s)
- Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Soomin Noh
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jae Cheol Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jin Yong Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jeongseok Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Nam Seok Ham
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Eun Hye Oh
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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4
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Banerjee R, Pal P, Hutfless S, Ganesh BG, Reddy DN. Familial aggregation of inflammatory bowel disease in India: prevalence, risks and impact on disease behavior. Intest Res 2019; 17:486-495. [PMID: 31370386 PMCID: PMC6821951 DOI: 10.5217/ir.2018.00174] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 06/14/2019] [Indexed: 01/06/2023] Open
Abstract
Background/Aims Information about familial aggregation of inflammatory bowel disease (IBD) in Asia is limited. We aimed to analyze the prevalence and risk of familial IBD in an Indian cohort and compare familial and sporadic cases. Methods Familial IBD cases were identified from a large prospectively maintained IBD registry. The prevalence of IBD in first- and seconddegree relatives of index cases was evaluated. The disease behavior was compared to that of sporadic cases. Results Total 3,553 patients (ulcerative colitis [UC], 2,053; Crohn’s disease [CD], 1,500) were included. Familial IBD was noted in 4.13% of CD and 4.34% of UC patients. Family history was commoner in pediatric group (< 18 years) (P= 0.0002; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.6–4.8). Majority had paternal transmission (UC, 67.42%; CD, 70.97%). Concordance of disease type was higher in UC (79.7%) compared to CD (37.1%). Familial IBD was associated with higher cumulative relapse rate (CD, P< 0.001; UC, P< 0.001), higher cumulative rate of surgery (CD, P< 0.001; UC, P< 0.001) and higher rate of biologic use (CD, P= 0.010; UC, P= 0.015). Pan-colitis was higher in familial UC (P= 0.003; OR, 1.935; 95% CI, 1.248–3.000). Fistulizing disease was commoner in familial CD (P= 0.041; OR, 2.044; 95% CI, 1.030–4.056). Conclusions The prevalence of familial IBD in India appears comparable to rest of Asia but lower than the West. It is associated with a younger age of onset, higher incidence of pan-colitis in UC and fistulizing complications in CD. Familial IBD has higher cumulative relapse, surgery and biologic use rates. Hence, family history of IBD could have important prognostic implications.
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Affiliation(s)
- Rupa Banerjee
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Susan Hutfless
- Division of Gastroenterology and Hepatology, Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
| | - B Girish Ganesh
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
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5
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Ghersin I, Khteeb N, Katz LH, Daher S, Shamir R, Assa A. Trends in the epidemiology of inflammatory bowel disease among Jewish Israeli adolescents: a population-based study. Aliment Pharmacol Ther 2019; 49:556-563. [PMID: 30687945 DOI: 10.1111/apt.15160] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/08/2018] [Accepted: 01/05/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND The incidence and prevalence trends of inflammatory bowel disease (IBD) vary between developed and developing countries. AIM To investigate the prevalence and associated sociodemographic factors of IBD in Israeli Jewish adolescents METHODS: The files of the army medical corps were reviewed for adolescents recruited in 2002-2016 with confirmed IBD. Covariate data included birth date, patient and parental country of birth, number of children in the household, age at diagnosis, and socioeconomic status. Findings were compared with the remaining recruits without IBD. RESULTS Of the 1,144,213 adolescents recruited, 2372 (0.2%) had IBD (Crohn's disease, 68%). Median age of the cohort was 17.1 years (interquartile range, 16.9-17.3). Over the study period, the annual point prevalence per 100,000 examinees significantly increased: total IBD, 58 to 373; Crohn's disease, 42 to 425; ulcerative colitis, 16 to 128. Mean age at IBD diagnosis decreased from 15.0 ± 2.8 years in 2002-2008 to 14.3 ± 3.1 years in 2009-2016 (P < 0.0001). Significance was maintained on separate analyses of Crohn's disease and ulcerative colitis. Both diseases were significantly less prevalent in subjects from families with at least one parent born in a developing country and ≥3 children. There was a significant association of lower socioeconomic status with lower prevalence of Crohn's disease (odds ratio 0.41, 95% confidence interval, 0.31-0.54) and ulcerative colitis (odds ratio 0.25, 95% confidence interval, 0.15-0.42). CONCLUSIONS The point prevalence of Crohn's disease and ulcerative colitis in Israeli Jewish adolescents increased six-fold and eight-fold, respectively, over 15 years along with a decrease in age at diagnosis.
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Affiliation(s)
- Itai Ghersin
- Israel Defense Forces, Medical Corps, Ramat Gan, Israel.,Department of Internal Medicine, Rambam Health Care Campus, Haifa, Israel
| | - Neron Khteeb
- Israel Defense Forces, Medical Corps, Ramat Gan, Israel
| | - Lior H Katz
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Saleh Daher
- Israel Defense Forces, Medical Corps, Ramat Gan, Israel
| | - Raanan Shamir
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Amit Assa
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
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6
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Schiff ER, Frampton M, Semplici F, Bloom SL, McCartney SA, Vega R, Lovat LB, Wood E, Hart AL, Crespi D, Furman MA, Mann S, Murray CD, Segal AW, Levine AP. A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population. Dig Dis Sci 2018; 63:3049-3057. [PMID: 30178286 PMCID: PMC6182437 DOI: 10.1007/s10620-018-5219-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/18/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS The inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease. METHODS A total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed. RESULTS The 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn's disease. CONCLUSIONS This study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.
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Affiliation(s)
- Elena R. Schiff
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Matthew Frampton
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Francesca Semplici
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Stuart L. Bloom
- Department of Gastroenterology, University College London Hospital, London, UK
| | - Sara A. McCartney
- Department of Gastroenterology, University College London Hospital, London, UK
| | - Roser Vega
- Department of Gastroenterology, University College London Hospital, London, UK
| | - Laurence B. Lovat
- Department of Gastroenterology, University College London Hospital, London, UK ,Research Department of Tissue and Energy, Division of Surgery and Interventional Science, University College London, London, UK
| | - Eleanor Wood
- Gastroenterology Department, Homerton University Hospital, London, UK
| | - Ailsa L. Hart
- Gastroenterology Department, St Mark’s Hospital, London, UK
| | - Daniel Crespi
- Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK
| | - Mark A. Furman
- Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK
| | - Steven Mann
- Gastroenterology Department, Barnet General Hospital, London, UK
| | | | - Anthony W. Segal
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Adam P. Levine
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
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7
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Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 2017; 31:14-23. [PMID: 29333063 PMCID: PMC5759609 DOI: 10.20524/aog.2017.0208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Familial aggregation in inflammatory bowel disease (IBD) has been established for several decades, reflecting shared genetic and environmental susceptibility. A positive family history remains the strongest recognizable risk factor for the development of IBD and is reported in around 8-12% of IBD patients. Crohn’s disease shows a more frequent familial pattern than ulcerative colitis. The risk of developing IBD in first-degree relatives of an affected proband is increased 4- to 8-fold. The risk for twins and children born from couples who both have IBD is also substantially higher; a cumulative effect of the number of family members affected has been described, with the highest incidence being described for families with three or more affected members. Herein, we review the available evidence regarding familial IBD, and briefly discuss the variation of IBD across different races and ethnicities, hoping to provide a useful update and a practical guide that can serve clinicians as a guide for counseling.
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Affiliation(s)
- Maria Pia Costa Santos
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Catarina Gomes
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Joana Torres
- Gastroenterology Division, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
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8
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Abstract
Inflammatory bowel disease (IBD) includes 2 chronic idiopathic inflammatory diseases: ulcerative colitis and Crohn disease. The incidence and prevalence of IBD is increasing worldwide. It can affect people of all ages, including children and geriatric populations, and can impact all aspects of life. In this article, diagnosis and treatment of IBD in adults, pediatric, pregnant, and elderly populations are explored from the perspective of a primary care physician.
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Affiliation(s)
- Tomoko Sairenji
- Department of Family Medicine, University of Washington, 1959 Northeast Pacific Street E-304, Seattle, WA 98195-6390, USA.
| | - Kimberly L Collins
- Department of Family Medicine, University of Washington, 331 NE Thornton Place, Seattle, WA 98125, USA
| | - David V Evans
- Department of Family Medicine, University of Washington, 1959 Northeast Pacific Street E-304, Seattle, WA 98195-6390, USA
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Coughlan A, Wylde R, Lafferty L, Quinn S, Broderick A, Bourke B, Hussey S. A rising incidence and poorer male outcomes characterise early onset paediatric inflammatory bowel disease. Aliment Pharmacol Ther 2017; 45:1534-1541. [PMID: 28449214 DOI: 10.1111/apt.14070] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 05/11/2016] [Accepted: 03/10/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND The incidence of paediatric inflammatory bowel disease diagnosed before age 10 years is reportedly increasing, but national data are limited. AIM To characterise the epidemiology, phenotype and clinical outcomes of children diagnosed with inflammatory bowel disease before age 10 years, and compare with data from children diagnosed aged 10-16 years. METHODS A review of all Irish cases of early onset inflammatory bowel disease (diagnosis <10 years, EO-IBD) presenting between January 2000 and December 2014 was undertaken and compared to a cohort of later onset paediatric inflammatory bowel disease patients (diagnosis between 10 and 16 years, LO-IBD). Diagnostic investigations, phenotype, treatments, and long-term clinical and surgical outcomes were analysed. RESULTS One hundred and ninety children (99 male) with EO-IBD were identified; 92 (48%) CD, 77 (41%) UC and 21 (11%) IBDU. The incidence of EO-IBD increased by 0.6 per 100 000 per year (0.8-3.2 per 100 000 per year), with a significant increase in UC by 0.06 per 100 000 per year (P=.02). Males with CD had more upper GI disease (L4a; 48% vs 21%; P=.007), more extensive disease distribution (L3±L4; 31% vs 11%; P=.05) and more severe disease activity at presentation (52% vs 31%; P=.05) than females. Fewer patients with early onset than later onset Crohn's disease had ileocolonic disease (L3; 10% vs 20%; P<.001). More relapses were observed in the first year post-diagnosis in early onset than later onset IBD (1.02 vs 0.5 mean relapses; P<.001). CONCLUSIONS EO-IBD is increasing in incidence. Males have more extensive and severe disease phenotypes, and younger patients have higher relapse rates than older children. Further research to explain these findings is warranted.
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Affiliation(s)
- A Coughlan
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,National Children's Research Centre, OLCHC, Crumlin, Dublin, Ireland
| | - R Wylde
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,Leiden University Medical Centre, Leiden, The Netherlands
| | - L Lafferty
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland
| | - S Quinn
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland
| | - A Broderick
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,Academic Centre for Paediatric Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - B Bourke
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,National Children's Research Centre, OLCHC, Crumlin, Dublin, Ireland.,Academic Centre for Paediatric Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - S Hussey
- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,National Children's Research Centre, OLCHC, Crumlin, Dublin, Ireland.,Academic Centre for Paediatric Research, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.,Department of Paediatrics, Royal College of Surgeons of Ireland, Dublin, Ireland
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- National Centre for Paediatric Gastroenterology (NCPG), OLCHC, Crumlin, Dublin, Ireland.,National Children's Research Centre, OLCHC, Crumlin, Dublin, Ireland
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10
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Moller FT, Andersen V, Wohlfahrt J, Jess T. Familial risk of inflammatory bowel disease: a population-based cohort study 1977-2011. Am J Gastroenterol 2015; 110:564-71. [PMID: 25803400 DOI: 10.1038/ajg.2015.50] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 01/01/2015] [Accepted: 02/03/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Estimates of familial risk of inflammatory bowel diseases (IBDs), Crohn's disease (CD), and ulcerative colitis (UC) are needed for counseling of patients and could be used to target future prevention. We aimed to provide comprehensive population-based estimates of familial risk of IBD. METHODS The study encompassed the entire Danish population during 1977-2011 (N=8,295,773; 200 million person-years). From national registries, we obtained information on diagnosis date of IBD (N=45,780) and family ties. Using Poisson regression, we estimated incidence rate ratios (IRRs) of IBD in relatives of IBD cases compared with individuals with relatives of the same type without IBD. RESULTS The risk of CD was significantly increased in first-degree (IRR, 7.77; 95% confidence interval (CI), 7.05-8.56), second-degree (IRR, 2.44; 95% CI, 2.01-2.96), and third-degree relatives (IRR, 1.88; 95% CI, 1.30-2.71) to patients with CD, and was less pronounced in relatives to UC cases. Likewise, the risk of UC was increased in first-degree (IRR, 4.08; 95% CI, 3.81-4.38), second-degree (IRR, 1.85; 95% CI, 1.60-2.13), and third-degree relatives (IRR, 1.51; 95% CI, 1.07-2.12) of UC cases, and less pronounced in relatives of CD cases. IRRs increased with two or more IBD-affected relatives and were modified by age, with the highest family-related IRR observed in early life. CONCLUSIONS The risk of IBD is significantly increased in first -, second-, and third-degree relatives of IBD-affected cases, with up to 12% of all IBD cases being family cases. The risk is particularly pronounced in young individuals.
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Affiliation(s)
- Frederik Trier Moller
- 1] Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark [2] Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark [3] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Vibeke Andersen
- 1] Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark [2] Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark
| | - Jan Wohlfahrt
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Tine Jess
- 1] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark [2] Department of Clinical Epidemiology, University of Aalborg, Aalborg, Denmark
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11
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Wędrychowicz A, Tomasik P, Pieczarkowski S, Kowalska-Duplaga K, Grzenda-Adamek Z, Fyderek K. Clinical value of serum eosinophilic cationic protein assessment in children with inflammatory bowel disease. Arch Med Sci 2014; 10:1142-6. [PMID: 25624851 PMCID: PMC4296054 DOI: 10.5114/aoms.2013.34415] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 07/14/2012] [Accepted: 09/04/2012] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION Eosinophils contribute to the pathogenesis of inflammatory bowel disease (IBD) in the intestine. Eosinophilic cationic protein (ECP) is one of the most important eosinophilic specific mediators released during activation. The aim of the study was to evaluate the clinical value of serum ECP determination in children with active and inactive IBD and its correlation with disease activity. MATERIAL AND METHODS There were 125 children with IBD (63 with Crohn's disease - CD, 44 with ulcerative colitis - UC, 18 indeterminate colitis - IC) enrolled in the study. Among them 83 children were in the active phase of the disease, while the remaining 42 were in remission. The control group consisted of 56 healthy children. The ECP was assessed three times in children with active IBD, at baseline and after 2 and 6 weeks of treatment and once in children with inactive IBD and controls using fluoroenzymeimmunoassays. RESULTS We found elevated ECP at baseline in the total active IBD group when compared to the inactive IBD and control groups, decreasing during treatment. Serum ECP was also elevated in the active UC and CD groups when compared to the inactive UC and CD groups, and correlated with clinical UC and CD activity (R = 0.57 and R = 0.52, p < 0.05, respectively) and duration of the clinical manifestation in UC (R = 0.62, p < 0.05) but not with the disease location in the gastrointestinal tract, or endoscopic and histopathological activity. CONCLUSIONS Evaluation of serum ECP in children with IBD may be useful in disease activity assessment at onset and during the treatment.
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Affiliation(s)
- Andrzej Wędrychowicz
- Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
| | - Przemysław Tomasik
- Department of Clinical Biochemistry, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
| | - Stanisław Pieczarkowski
- Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
| | - Kinga Kowalska-Duplaga
- Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
| | - Zofia Grzenda-Adamek
- Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
| | - Krzysztof Fyderek
- Department of Pediatrics, Gastroenterology and Nutrition, Polish-American Children's Hospital, Jagiellonian University Medical College, Krakow, Poland
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Childers RE, Eluri S, Vazquez C, Weise RM, Bayless TM, Hutfless S. Family history of inflammatory bowel disease among patients with ulcerative colitis: a systematic review and meta-analysis. J Crohns Colitis 2014; 8:1480-97. [PMID: 24974207 DOI: 10.1016/j.crohns.2014.05.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 05/03/2014] [Accepted: 05/31/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Despite numerous shared susceptibility loci between Crohn's disease and ulcerative colitis, the prevalence of family history among ulcerative colitis patients is not well-established and considered to be less prevalent. A systemic review and meta-analysis were conducted to estimate the prevalence of family history of inflammatory bowel disease in ulcerative colitis patients, and its effect on disease outcomes. METHODS PubMED was searched to identify studies reporting the prevalence of family history of inflammatory bowel disease among ulcerative colitis patients. Definitions of family history, study type, and subtypes of family history prevalence were abstracted, as were disease outcomes including age at ulcerative colitis diagnosis, disease location, surgery and extraintestinal manifestations. Pooled prevalence estimates were calculated using random effects models. RESULTS Seventy-one studies (86,824 patients) were included. The prevalence of a family history of inflammatory bowel disease in ulcerative colitis patients was 12% (95% confidence interval [CI] 11 to 13%; range 0-39%). Family history of ulcerative colitis (9%; 22 studies) was more prevalent than Crohn's disease (2%; 18 studies). Patients younger than 18years of age at time of diagnosis had a greater family history of inflammatory bowel disease (prevalence 15%, 95% CI: 11-20%; 13 studies). There were no differences in disease location, need for surgery, or extraintestinal manifestations among those with a family history, although very few studies reported on these outcomes. CONCLUSIONS Overall, 12% of ulcerative colitis patients have a family history of inflammatory bowel disease, and were more likely to have a family history of ulcerative colitis than Crohn's disease. Pediatric-onset ulcerative colitis patients were more likely to have a family history of inflammatory bowel disease.
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Affiliation(s)
- Ryan E Childers
- Division of Gastroenterology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
| | - Swathi Eluri
- Department of Medicine, Johns Hopkins University, 601 North Caroline Street, Baltimore, MD 21287, USA
| | - Christine Vazquez
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University, 600N Wolfe St, Baltimore, MD 21287, USA
| | | | - Theodore M Bayless
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University, 600N Wolfe St, Baltimore, MD 21287, USA
| | - Susan Hutfless
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University, 600N Wolfe St, Baltimore, MD 21287, USA
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13
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Cabré E, Mañosa M, García-Sánchez V, Gutiérrez A, Ricart E, Esteve M, Guardiola J, Aguas M, Merino O, Ponferrada A, Gisbert JP, Garcia-Planella E, Ceña G, Cabriada JL, Montoro M, Domènech E. Phenotypic concordance in familial inflammatory bowel disease (IBD). Results of a nationwide IBD Spanish database. J Crohns Colitis 2014; 8:654-61. [PMID: 24388046 DOI: 10.1016/j.crohns.2013.12.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 12/06/2013] [Accepted: 12/10/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Disease outcome has been found to be poorer in familial inflammatory bowel disease (IBD) than in sporadic forms, but assessment of phenotypic concordance in familial IBD provided controversial results. We assessed the concordance for disease type and phenotypic features in IBD families. METHODS Patients with familial IBD were identified from the IBD Spanish database ENEIDA. Families in whom at least two members were in the database were selected for concordance analysis (κ index). Concordance for type of IBD [Crohn's disease (CD) vs. ulcerative colitis (UC)], as well as for disease extent, localization and behaviour, perianal disease, extraintestinal manifestations, and indicators of severe disease (i.e., need for immunosuppressors, biological agents, and surgery) for those pairs concordant for IBD type, were analyzed. RESULTS 798 out of 11,905 IBD patients (7%) in ENEIDA had familial history of IBD. Complete data of 107 families (231 patients and 144 consanguineous pairs) were available for concordance analyses. The youngest members of the pairs were diagnosed with IBD at a significantly younger age (p<0.001) than the oldest ones. Seventy-six percent of pairs matched up for the IBD type (κ=0.58; 95%CI: 0.42-0.73, moderate concordance). There was no relevant concordance for any of the phenotypic items assessed in both diseases. CONCLUSIONS Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type.
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Affiliation(s)
- Eduard Cabré
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
| | - Míriam Mañosa
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | - Elena Ricart
- Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Maria Esteve
- Hospital Universitari Mútua de Terrassa, Terrassa, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jordi Guardiola
- Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain
| | - Mariam Aguas
- Hospital Universitari La Fe, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | - Javier P Gisbert
- Hospital Universitario de La Princesa, IP, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | | | | | - Eugeni Domènech
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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El-Salhy M, Wendelbo IH, Gundersen D, Hatlebakk JG, Hausken T. Evaluation of the usefulness of colonoscopy with mucosal biopsies in the follow-up of TNBS-induced colitis in rats. Mol Med Rep 2013; 8:446-50. [PMID: 23778962 DOI: 10.3892/mmr.2013.1528] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 05/29/2013] [Indexed: 11/05/2022] Open
Abstract
Animal models are required for research regarding the pathogenesis and efficacy of anti-inflammatory agents in inflammatory bowel disease (IBD). Trinitrobenzene sulfonic acid (TNBS)-induced colitis closely mimics Crohn's disease. The present study was undertaken in order to determine the reliability of following the inflammatory course of TNBS-induced colitis using colonoscopy together with biopsy samples obtained during the examination. In this study we used 20 adult male Wistar rats, with a mean weight of 201.9 g. The rats were divided into two groups, control and TNBS, with ten rats in each group. Following the induction of TNBS colitis, the rats underwent colonoscopy with mucosal biopsies. At the end of the experiment, the rats were sacrificed and whole-wall colonic samples were obtained. The degree of inflammation was assessed endoscopically, macroscopically and microscopically. There was no significant change in the body weight of the control group but significant weight loss was observed in the TNBS group. Examination of the control group did not reveal any inflammation. Severe colitis was observed in the TNBS-induced colitis rats, as assessed endoscopically, macroscopically and microscopically. The endoscopic inflammation score obtained through colonoscopy examinations correlated with that obtained macroscopically, and those obtained microscopically from the whole-wall colon and biopsy samples collected during the colonoscopy. Moreover, the inflammation scores obtained from the whole-wall colon and biopsy samples collected during colonoscopy correlated markedly. In conclusion, colonoscopy is a reliable method for following up the course of inflammation in experimentally induced colitis. Although biopsy samples collected during colonoscopies may be used to assess the degree of inflammation, whole-wall samples are superior in this regard.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, Stord, Norway.
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15
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Chen RR, Han ZY, Li JG, Shi YQ, Zhou XM, Wang JB, Cai XQ, Wang XC, Han Y, Fan DM. Cytotoxic T-lymphocyte antigen 4 gene +49A/G polymorphism significantly associated with susceptibility to primary biliary cirrhosis: a meta-analysis. J Dig Dis 2011; 12:428-35. [PMID: 22118691 DOI: 10.1111/j.1751-2980.2011.00537.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate comprehensively the association of cytotoxic T-lymphocyte antigen 4 (CTLA-4) +49A/G polymorphism with susceptibility to primary biliary cirrhosis (PBC). METHODS PubMed was used to search for the relevant published articles. The risk of PBC association with the CTLA-4+49A/G polymorphism was estimated for each study in a random-effects model. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each study. Risks to PBC were estimated by stratified analysis in patients with different ethnicity and antimitochondrial antibody (AMA) status, as well as histological stages. RESULTS A total of 12 articles were included in the study. An association between PBC and CTLA-4 G allele was found, overall OR = 1.20, 95% CI 1.03-1.41 (P = 0.02). However, stratification by ethnicity indicated a significant association between the G allele and PBC in Asians (OR = 1.36, 95% CI 1.12-1.65, P = 0.002), but not in Caucasians (OR = 1.15, 95% CI 0.95-1.39, P = 0.15). Moreover, AMA positive patients carrying G allele were more susceptible to PBC compared with AMA negative patients (OR = 1.23, 95% CI 1.06-1.43, P = 0.007; OR = 0.98, 95% CI 0.71-1.34, P = 0.88, respectively). CONCLUSIONS Polymorphism in exon 1 of CTLA-4 gene at position 49 may act as a candidate of susceptibility locus to PBC. However, larger studies with participants of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.
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Affiliation(s)
- Rui Rui Chen
- Institute of Digestive Diseases, Xijing Hospital, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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Nunes T, Fiorino G, Danese S, Sans M. Familial aggregation in inflammatory bowel disease: Is it genes or environment? World J Gastroenterol 2011; 17:2715-22. [PMID: 21734779 PMCID: PMC3123468 DOI: 10.3748/wjg.v17.i22.2715] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 09/18/2010] [Accepted: 09/25/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) develops in genetically susceptible individuals due to the influence of environmental factors, leading to an abnormal recognition of microbiota antigens by the innate immune system which triggers an exaggerated immune response and subsequent bowel tissue damage. IBD has been more frequently found in families, an observation that could be due to either genetic, environmental or both types of factors present in these families. In addition to expanding our knowledge on IBD pathogenesis, defining the specific contribution to familial IBD of each one of these factors might have also clinical usefulness. We review the available evidence on familial IBD pathogenesis.
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Lee JJ, Essers JB, Kugathasan S, Escher JC, Lettre G, Butler JL, Stephens MC, Ramoni MF, Grand RJ, Hirschhorn J. Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study. Ann Hum Genet 2010; 74:489-97. [PMID: 20846217 DOI: 10.1111/j.1469-1809.2010.00606.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951 subjects (317 CD patient-parent trios) for 64 polymorphisms within 14 CD-susceptibility and 23 stature-associated loci. Patient height-for-age Z-score < -1.64 was used to dichotomize probands into growth-impaired and nongrowth-impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height-for-age Z-score < -1.64) and a stature-related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57-6.51], p = 0.0007). In addition, there was nominal over-transmission of two CD-susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth-impaired CD children (OR = 2.36, CI [1.26-4.41] p = 0.0056 and OR = 2.45, CI [1.22-4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD.
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Bengtson MB, Solberg C, Aamodt G, Jahnsen J, Moum B, Sauar J, Vatn MH. Clustering in time of familial IBD separates ulcerative colitis from Crohn's disease. Inflamm Bowel Dis 2009; 15:1867-74. [PMID: 19434721 DOI: 10.1002/ibd.20978] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Accepted: 03/25/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND The aim was to compare clustering of time at diagnosis and phenotype of inflammatory bowel disease (IBD) between affected parents and children and to explore generational differences in age at diagnosis (AAD) as well as the concordance of clinical characteristics. METHODS Eighty-four affected pairs from 45 families were included from 5 counties in southeastern Norway between August 2003 and December 2006; 43 were sib-sib pairs and 39 parent-child pairs. Clinical data were obtained by phone interviews and by hospital records. RESULTS The difference in median AAD was 17.0 years (P < 0.001) and 2.0 years (P = 0.29) in parent-child and sib-sib pairs, respectively. When the time interval between diagnosis in parent and child was split into 2 groups, below and above 5 years, 64% of pairs with ulcerative colitis (UC) offspring were diagnosed within 5 years, compared to 24% of pairs with Crohn's disease (CD) offspring (odds ratio [OR] = 5.7, 95% confidence interval [CI]: 1.4, 23.8). Concordance for smoking habits was low in 26 pairs with mixed disease (κ = 0.15), whereas patients with CD tended to be current smokers. CONCLUSIONS Most of the children acquire their disease at an earlier time in life compared to their parents, suggesting genetic anticipation. The time interval between diagnosis of the parents and offspring was lower when the offspring developed UC compared to CD, which might reflect the influence of shared environment on the generational difference in AAD in UC families. This study confirmed the effect of smoking habits on IBD phenotype.
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Bengtson MB, Solberg C, Aamodt G, Sauar J, Jahnsen J, Moum B, Lygren I, Vatn MH. Familial aggregation in Crohn's disease and ulcerative colitis in a Norwegian population-based cohort followed for ten years. J Crohns Colitis 2009; 3:92-9. [PMID: 21172251 DOI: 10.1016/j.crohns.2008.11.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2008] [Revised: 11/02/2008] [Accepted: 11/03/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS To explore the change in risk among 1st degree relatives of ulcerative colitis (UC) and Crohn's disease (CD) for development of concordant disease in an incidence cohort followed for ten years. Furthermore, we wanted to compare familial and sporadic cases regarding clinical characteristics and the course of the disease. METHODS This population-based study included 421 patients with UC and 197 with CD enrolled from 1990 to 1994. Clinical characteristics and the number of 1st degree relatives of the patients were recorded continuously during ten years. RESULTS Age at diagnosis in CD patients (OR=0.95, 95% CI: 0.93-0.98) and cumulative relapse rate in UC patients (OR=4.91, 95% CI=1.16, 20.75) were significantly associated to familial clustering. Based on the calculated population prevalence of CD (262/100000) and UC (505/100000), the age-adjusted risk for development of concordant disease was 25.9 and 8.6 among siblings and parents of CD, respectively. In UC, the corresponding risks were 8.6 and 1.5. In the course of ten years the increase in risk was observed only among siblings (28%) and parents (97%) of UC, in contrast to no increase in CD. Moreover, the concordance for UC was high in three generations. CONCLUSIONS Our study confirmed the importance of genetic influence on the development of CD. Within an observation period of ten years, the increased concordance and relapse rate in familial UC, might point to a larger genetic component in UC than previously suggested.
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Biank V, Broeckel U, Kugathasan S. Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis 2007; 13:1430-8. [PMID: 17600381 DOI: 10.1002/ibd.20213] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.
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Affiliation(s)
- Vincent Biank
- Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Henriksen M, Jahnsen J, Lygren I, Vatn MH, Moum B. Are there any differences in phenotype or disease course between familial and sporadic cases of inflammatory bowel disease? Results of a population-based follow-up study. Am J Gastroenterol 2007; 102:1955-63. [PMID: 17573793 DOI: 10.1111/j.1572-0241.2007.01368.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The influence of familial IBD on phenotype and course of disease in patients with CD and UC has not been studied in population-based cohorts. AIM To compare phenotype and course of disease between IBD patients with a first-degree relative with IBD and sporadic cases in a population-based cohort followed prospectively for 5 yr. METHODS Family history of IBD was registered at diagnosis and after 1 and 5 yr. Phenotype and course of disease were compared between sporadic and familial cases. RESULTS Data for 200 patients with CD and 454 with UC were sufficient for analysis. A first-degree relative with IBD was registered in 14.5% of CD patients and 10.1% of UC patients. The concordance for type of disease was 82% and 70% for CD and UC, respectively. No differences between familial and sporadic cases as regards localization and behavior of disease in CD patients or disease extent in UC patients were observed. In CD patients with colonic involvement, those in the familial group were significantly younger at diagnosis than the sporadic cases. No difference in disease severity in CD patients was observed between the familial and sporadic groups. In UC patients relapse was more frequent in familial cases, but no difference was observed in the need for surgery or medical treatment. CONCLUSIONS A family history of IBD does not seem to influence phenotype or to be an important prognostic factor for disease course in IBD patients.
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Affiliation(s)
- Magne Henriksen
- Department of Internal Medicine, Østfold Hospital Moss, Moss, Norway
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Heetun ZS, Byrnes C, Neary P, O'Morain C. Review article: Reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26:513-533. [PMID: 17661756 DOI: 10.1111/j.1365-2036.2007.03397.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) affects mainly the young population. The effect of IBD and its treatment on fertility and pregnancy is therefore an important clinical consideration. AIM To review the best management of IBD in the reproductive and pregnant population. METHODS A MEDLINE and an EMBASE search were performed using mainly the search phrases 'pregnancy AND IBD,''sulphasalazine AND male fertility,''abdominal surgery AND female fertility,''AZA AND placenta' and 'infliximab AND pregnancy.' No language or date restrictions were placed. References of review articles were examined. RESULTS Overall male and female fertility are not affected by IBD. Sulphasalzine reduces male fertility. No other drugs used in IBD affect significantly fertility in humans. The risk of pregnancy-related complications and the disease behaviour during pregnancy depends mainly on disease activity at time of conception. Proactive treatment for maintenance of disease remission during gestation is recommended. Except for methotrexate, drugs used in IBD appear safe in pregnancy. Breast feeding should be encouraged. CONCLUSION The management of IBD in the young and pregnant population remains controversial because the literature comes mostly from retrospective studies. Further studies particularly large prospective trials are needed to guide clinicians in decision making.
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Affiliation(s)
- Z S Heetun
- Department of Gastroenterology, Adelaide and Meath Hospital, Trinity College, Tallaght, Dublin 24, Ireland.
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Halme L, Paavola-Sakki P, Turunen U, Lappalainen M, Farkkila M, Kontula K. Family and twin studies in inflammatory bowel disease. World J Gastroenterol 2006; 12:3668-72. [PMID: 16773682 PMCID: PMC4087458 DOI: 10.3748/wjg.v12.i23.3668] [Citation(s) in RCA: 192] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Studies examining the inheritance of inflammatory bowel disease (IBD) within different family groups have been the basis for recent molecular advances in the genetics of IBD. The derived heritability in Crohn’s disease (CD) is higher than in many other complex diseases. The risk of IBD is highest in first-degree relatives of a CD proband, but first-degree relatives of a proband suffering from ulcerative colitis (UC) and more distant relatives are also at increased risk. Disease concordance rates in IBD have been examined in multiplex families and in three large European twin studies.
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Affiliation(s)
- Leena Halme
- Department of Transplantation and Liver Surgery, Helsinki University Hospital, Finland.
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Abstract
The recent molecular advances in the understanding of the genetics of inflammatory bowel disease (IBD) have their grounding in studies examining IBD within different family groups and populations. The risk of IBD is highest in first-degree relatives of an IBD proband but more distant relatives are also at increased risk. The risk is higher for relatives of a CD proband. The risks of developing IBD for 'high-risk' relatives might be as great as 1 in 3 but in general first-degree relatives have a 1 in 10-20 risk. Three recent systematic studies have identified a total of 326 European twin pairs to examine disease concordance rates. The derived heritability in Crohn's disease is greater than for many complex diseases and is currently under detailed examination. Strong concordance has been shown, in particular for disease type and disease location, in multiplex families and twin studies. More than 75% children are diagnosed with IBD at a younger age than their parents but true genetic anticipation appears unlikely.
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Affiliation(s)
- R K Russell
- Department of Medical Sciences, Gastrointestinal Unit, University of Edinburgh, Edinburgh EH4 2XU, UK.
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Abstract
In parallel with overall population trends, the incidence of paediatric ulcerative colitis (UC) has remained stable, whereas that of paediatric Crohn's disease (CD) has increased in recent decades. Still rare among preschool children, the incidence of both UC and CD rises steadily from middle childhood through adolescence. There is an unexplained preponderance of males with early-onset CD, and an equal gender distribution in paediatric UC. Observations on the familiality of paediatric inflammatory bowel disease (IBD) suggest that genetic susceptibility is particularly important to disease pathogenesis in young patients. In comparison to adult-onset disease, childhood UC is usually extensive but the anatomic localization of paediatric CD varies, as in adults. UC manifests uniformly as bloody diarrhea whereas the symptomatology of paediatric CD is much more diverse. Linear growth impairment frequently complicates chronic intestinal inflammation in paediatric CD. Key contributing factors have been defined; better immunomodulatory therapy and emerging biologic agents will potentially reduce its prevalence.
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Affiliation(s)
- Anne M Griffiths
- IBD Program, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, Ont. M5G 1X8, Canada.
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Weinstein TA, Levine M, Pettei MJ, Gold DM, Kessler BH, Levine JJ. Age and family history at presentation of pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2003; 37:609-13. [PMID: 14581806 DOI: 10.1097/00005176-200311000-00020] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Young children are thought to be a unique subset of pediatric patients with inflammatory bowel disease (IBD). The authors' objective was to evaluate the differences in initial clinical presentation of young and older children with IBD and to determine whether a positive family history of IBD is associated with the age of presentation. METHODS The authors reviewed the records of all patients with new diagnoses of Crohn disease (CD) and ulcerative colitis (UC) who presented between July 1996 and July 1999. Initial evaluation included assessment of growth parameters and laboratory values (hemoglobin concentration, platelet count, erythrocyte sedimentation rate, and serum albumin). Inquiry regarding a family history of IBD was made in every patient. RESULTS There were 153 patients with new diagnoses (82 with CD and 71 with UC), with a mean age of 11.9 years (range, 16 months-18 years). The children with CD had a higher sedimentation rate and platelet count and a lower mean hemoglobin concentration and serum albumin at presentation than did children with UC. Body mass index (BMI) was significantly lower in patients with newly diagnosed CD than in those with UC. The only significant laboratory differences between patients younger than 11 years and those 11 years or older was a higher mean platelet count in patients with CD who were younger than 11 years. Of the younger patients with CD, 41.7% had a positive family history of IBD, which was significantly greater that that found in the older patients with CD. CONCLUSIONS Except for higher platelet counts, a lower BMI, and a higher frequency of positive family history in young children with CD, there were no significant differences in the presentation of young children with IBD compared with older children.
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Affiliation(s)
- Toba A Weinstein
- Division of Pediatric Gastroenterology, Schneider Children's Hospital, North Shore-Long Island Jewish Health System, Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
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Tamboli CP, Cortot A, Colombel JF. What are the major arguments in favour of the genetic susceptibility for inflammatory bowel disease? Eur J Gastroenterol Hepatol 2003; 15:587-92. [PMID: 12840667 DOI: 10.1097/00042737-200306000-00002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Epidemiological data, notably concordance rates in twin pairs and familial aggregation, have provided strong evidence for the importance of the genetic contribution in inflammatory bowel diseases. Genome wide scanning has been remarkably successful in identifying a number of susceptibility loci. The identification of the IBD1 gene on chromosome 16 as NOD2/CARD15 definitely establishes that a significant proportion of Crohn's disease has an underlying genetic cause. In addition, our knowledge of the clinical impact of other genes in modelling disease phenotypes has increased in parallel. These results have led to great optimism that important clinical applications will result from genetic research in the near future.
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Affiliation(s)
- Cyrus P Tamboli
- Department of Hepato-Gastroenterology, Hôpital Claude Huriez, Lille, France
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28
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Abstract
The strongest currently recognized risk factor for Crohn's disease (CD) development is having a relative with the disease. In this study, 1,000 patients with CD, seen directly by the investigator during a period of more than 20 years, were consecutively evaluated for a family history of CD. There were 140 patients who reported a relative with CD. Of these, all 87 first-degree relatives were confirmed to have CD (36 men and 51 women). Siblings, particularly women, were most commonly affected in comparison with parents or children. There were 65 with a single affected first-degree relative and 22 with multiple affected first-degree relatives. In this series, the tendency to have a female sibling with CD was further increased in those with multiple affected first-degree relatives. Although the age of diagnosis of children was less than the age of diagnosis in the respective parents, there were almost identical numbers of mother-child and father-child pairs. These findings in a population with prolonged follow-up by the same physician may reflect a bias toward case ascertainment rather than the previously reported phenomena in recruited populations of genetic anticipation and genomic imprinting. Patients with multiple first-degree relatives were older with more extensive disease in both ileal and colonic sites compared with those with only a single first-degree relative and more frequent colonic disease. Future studies are needed to further explore the role of both genetic and environmental factors in the pathogenesis and phenotypic expression of familial CD.
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Affiliation(s)
- Hugh J Freeman
- Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC
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30
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Faybush EM, Blanchard JF, Rawsthorne P, Bernstein CN. Generational differences in the age at diagnosis with Ibd: genetic anticipation, bias, or temporal effects. Am J Gastroenterol 2002; 97:636-40. [PMID: 11922559 DOI: 10.1111/j.1572-0241.2002.05542.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Previous cross-sectional research has demonstrated generational differences in age at diagnosis (AAD) in inflammatory bowel disease (IBD). This observation has at times been ascribed to genetic anticipation, but could also be due to biases related to case ascertainment or follow-up or to temporal changes in IBD epidemiology. We aimed to explore this issue using a population-based database. METHODS In 1995 we used the comprehensive administrative databases in the province of Manitoba, Canada to establish a population-based IBD Research Registry that includes clinical and demographic information for persons. We contacted those subjects within our Research Registry who reported having any family members with IBD and their family members for verification of diagnosis and AAD. Differences in AAD between familial pairs were calculated. In addition, to assess whether duration of follow-up accounted for generational differences in AAD, we computed the mean AAD for subjects with and without family histories of IBD based on age at the time of interview (i.e., < 45 and > or = 45 yr of age). RESULTS Of the 2445 persons with IBD in the Research Registry, 548 reported positive family histories, and 315 of these (58%) were reached by telephone. There were 169 Crohn's disease and 146 ulcerative colitis subjects with positive family histories. The mean AADs for the parents, aunts/uncles, and grandparents were significantly greater than the mean AADs for the children, nieces/nephews, and grandchildren, respectively. There was a doubling of the mean AAD when comparing the grandparent/grandchild cases with the parent/child or aunt/uncle-niece/nephew cases. No statistically significant difference in anticipation was observed, whether or not the older generation was male or female or had Crohn's disease or ulcerative colitis. The AAD was substantially greater for those interviewed at > or = 45 yr of age for subjects with and without family histories. However, there was no substantial difference in mean AAD between familial and nonfamilial subjects. CONCLUSION The present study has demonstrated that there is a tendency for children to be younger than their parents at the time of diagnosis of familial IBD, and that this difference in mean AAD is almost doubled for grandparent/grandchild pairs. However, we conclude that these differences are most likely due to a bias based on length of follow-up or recent multigenerational temporal changes in the risk of IBD, or both.
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Affiliation(s)
- E M Faybush
- Department of Medicine, University of Manitoba, Winnipeg, Canada
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Annese V, Andreoli A, Astegiano M, Campieri M, Caprilli R, Cucchiara S, D'Incà R, Giaccari S, Iaquinto G, Lombardi G, Napolitano G, Pera A, Riegler G, Valpiani D, Andriulli A. Clinical features in familial cases of Crohn's disease and ulcerative colitis in Italy: a GISC study. Italian Study Group for the Disease of Colon and Rectum. Am J Gastroenterol 2001; 96:2939-45. [PMID: 11693330 DOI: 10.1111/j.1572-0241.2001.04685.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (< 1 yr or > or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.
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Affiliation(s)
- V Annese
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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32
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Abstract
This article reviews basic molecular genetics and summarizes recent work in the genetics of Crohn's disease. Family studies are summarized, and candidate genes are described. The current state of knowledge and the implications of possible inheritance of Crohn's disease for patient care are discussed.
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Affiliation(s)
- J M Church
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Ohio 44195, USA
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Peeters M, Cortot A, Vermeire S, Colombel JF. Familial and sporadic inflammatory bowel disease: different entities? Inflamm Bowel Dis 2000; 6:314-20. [PMID: 11149564 DOI: 10.1002/ibd.3780060409] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The strongest risk factor for developing inflammatory bowel disease (IBD) is having a relative with the disease. Familial IBD may be one homogeneous subgroup, phenotypically different from sporadic IBD. Several observations support a role for familiarity in disease site and behavior, particularly in Crohn's disease (CD), but published findings do not all concur. Early disease onset is often found in children with IBD who have a parent with the disease. Genetic anticipation may explain this finding but other explanations and/or observational biasis are more likely. Location and type may differ between familial and sporadic CD cases: family studies report many cases involving both small bowel and colon, and few cases of colonic disease alone, although such features may be secondary to early age at onset. Most studies found no effect of positive family history on severity and course of CD. In ulcerative colitis (UC), phenotypic differences between familial and sporadic cases appear to be limited, but little data are available for analysis. No difference has been found between familial and sporadic IBD as far as disease markers such as pANCA, ASCA, or intestinal permeability are concerned. In conclusion, the only message available for clinical practice is that the relative risk of IBD in first-degree relatives is increased by a factor of 10-15 compared with the general population. Families should not receive genetic counseling/information about age at onset and disease severity.
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Affiliation(s)
- M Peeters
- Department of Gastroenterology, University of Leuven, Belgium
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Walker-Smith JA. Chronic inflammatory bowel disease in children: a complex problem in management. Postgrad Med J 2000; 76:469-72. [PMID: 10908372 PMCID: PMC1741682 DOI: 10.1136/pmj.76.898.469] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- J A Walker-Smith
- University Department of Paediatric Gastroenterology, Royal Free and University College Medical School, Hampstead, London, UK
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