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Jyotsna, Sarkar B, Yadav M, Deka A, Markandey M, Sanyal P, Nagarajan P, Gaikward N, Ahuja V, Mohanty D, Basak S, Gokhale RS. A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis. eLife 2024; 12:RP93273. [PMID: 39137024 PMCID: PMC11321761 DOI: 10.7554/elife.93273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024] Open
Abstract
Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.
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Affiliation(s)
- Jyotsna
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Binayak Sarkar
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Mohit Yadav
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Alvina Deka
- System Immunology Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Manasvini Markandey
- Department of GastroEnterology, All India Institute of Medical SciencesNew DelhiIndia
| | | | - Perumal Nagarajan
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
| | | | - Vineet Ahuja
- Department of GastroEnterology, All India Institute of Medical SciencesNew DelhiIndia
| | - Debasisa Mohanty
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Soumen Basak
- System Immunology Laboratory, National Institute of ImmunologyNew DelhiIndia
| | - Rajesh S Gokhale
- Immunometabolism Laboratory, National Institute of ImmunologyNew DelhiIndia
- Department of Biology, Indian Institute of Science Education and ResearchPashanIndia
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Beheshti Maal A, Shahrbaf MA, Sadri B, Hossein-Khannazer N, Mansournia MA, Vosough M. Prevalence of Hepatobiliary Manifestations in Inflammatory Bowel Disease: A GRADE Assessed Systematic Review and Meta-Analysis of more than 1.7 Million Patients. J Crohns Colitis 2024; 18:360-374. [PMID: 37695111 DOI: 10.1093/ecco-jcc/jjad157] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 08/21/2023] [Accepted: 09/08/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal manifestations, such as hepatobiliary complications. This meta-analysis aims to assess the prevalence of different hepatic manifestations in IBD patients. METHODS For this systematic review and meta-analysis, PubMed, Scopus, Web of Science, and Embase were searched until July 20, 2022, by specifying keywords for IBD, hepatic manifestations, and study type. Full texts of cohort studies in English that examined the prevalence of different hepatic manifestations were included in this study. The primary outcome was the overall prevalence of hepatic manifestations in IBD patients. For the statistical analysis, a proportion by random effect model meta-analysis was performed. The registration number for the protocol of this study in PROSPERO is CRD42022369595. RESULTS From the 4421 articles retrieved from the primary search, 118 met the inclusion criteria and were included in the final analysis. After a pooled analysis of 1 729 128 patients, the overall prevalence of hepatic manifestations was 3.49% (95% confidence interval [CI]: 3.31-3.68%; I2: 99.55%). The pooled prevalence of non-alcoholic fatty liver disease in 228 216 patients was 26.1% [95% CI: 22.1-30.2%; I2: 99.018%]. After pooled analysis of 9642 patients, the prevalence of primary sclerosing cholangitis was 1.67% [95% CI: 1.47-1.88%; I2: 99.10%]. The pooled prevalence of biliary stones was 4.1% [95% CI: 3.6-4.7%; I2: 97.43%]. Autoimmune hepatitis (0.51% [95% CI: 0.26-0.75%]; I2: 85.36%) and portal vein thrombosis (0.21% [95% CI: 0.08-0.33%]; I2: 97.95%) are considered as rare manifestations. CONCLUSION This study summarizes the prevalence and importance of different hepatic manifestations in IBD patients. These findings are crucial for the management of extraintestinal manifestations, especially hepatic manifestations, in IBD patients.
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Affiliation(s)
- Alireza Beheshti Maal
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Shahrbaf
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Bahareh Sadri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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3
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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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Stratmann K, Aydolmus S, Gu W, Heling D, Spengler U, Terjung B, Strassburg CP, Vollenberg R, Blumenstein I, Trebicka J. Hepatobiliary manifestations in patients with ulcerative colitis: a retrospective analysis. Front Med (Lausanne) 2024; 10:1273797. [PMID: 38249970 PMCID: PMC10796802 DOI: 10.3389/fmed.2023.1273797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 12/18/2023] [Indexed: 01/23/2024] Open
Abstract
Background Inflammatory bowel diseases (IBDs) are often associated with altered liver function tests (LFTs). There is little data on the relationship between abnormal LFT and IBD. Our study aimed to evaluate the prevalence and etiology of elevated LFT in patients with ulcerative colitis (UC) and to determine whether there is an association with clinical and demographic parameters. Methods The clinical records of the Gastroenterology Outpatients Clinic at a single center were reviewed and screened for patients with UC from 2005 to 2014. In total, 263 patients were included. Patients with Crohn's disease (CD), colitis indeterminate, and colitis of other origins were excluded. Abnormal LFT and liver injuries were analyzed. Results A cohort of 182 patients was analyzed (114 males, 68 females; mean age = 50.2 ± 16.1 years). 58 patients had already been diagnosed with a hepatobiliary disorder. Patients with a known hepatobiliary disorder suffered from UC for a significantly longer duration. Elevated LFT in patients without known hepatobiliary disorders was 69.4%. Liver injury was found in 21.8%. A transient increase in abnormal LFT was shown in 59 patients (68.6%), a persistent increase was found in 27 patients (31.4%). Treatment with thiopurines was a risk factor for persistent elevated LFT (p = 0.029), steroids had a protective impact (p = 0.037). Conclusion This study clearly highlights the importance of screening for hepatobiliary disorders and abnormal LFT in patients with UC, as the prevalence of hepatobiliary disorders and abnormal LFT is detected very often among this patient group.
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Affiliation(s)
- Katharina Stratmann
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
| | - Songül Aydolmus
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Wenyi Gu
- Department of Internal Medicine B, University Clinic Münster, Münster, Germany
| | - Dominik Heling
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany
| | - Birgit Terjung
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany
| | | | - Richard Vollenberg
- Department of Internal Medicine B, University Clinic Münster, Münster, Germany
| | - Irina Blumenstein
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
| | - Jonel Trebicka
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany
- Department of Internal Medicine B, University Clinic Münster, Münster, Germany
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Erdenebileg S, Son YJ, Kim M, Oidovsambuu S, Cha KH, Kwon J, Jung DS, Nho CW. Saposhnikovia divaricata root and its major components ameliorate inflammation and altered gut microbial diversity and compositions in DSS-induced colitis. Integr Med Res 2023; 12:100998. [PMID: 38024289 PMCID: PMC10630121 DOI: 10.1016/j.imr.2023.100998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Background The root of Saposhnikovia divaricata (Turcz.) Schischk is a well-known traditional medicinal plant, containing various bioactive compounds with anti-inflammatory, antioxidant, and analgesic properties. However, no scientific studies have validated its clinical use as an anti-inflammatory agent against inflammatory bowel disease (IBD). This study aimed to investigate whether the root extract of S. divaricata ameliorates IBD and induces gut microbial alteration, using a RAW 264.7 cell line and a DSS-induced colitis mouse model. Methods To investigate the anti-inflammatory effects and alleviation of IBD, using a methanol extract of Saposhnikovia divaricata (Turcz.) Schischk. root (MESD), RAW 264.7, murine macrophages and a dextran sodium sulfate (DSS)-induced colitis mouse model were employed. 16S rRNA gene sequencing was conducted to determine the alterations in the gut microbiota of mice with DSS-induced colitis. Results MESD significantly decreased nitric oxide (NO) and inflammatory cytokine levels in lipopolysaccharide (LPS)-induced RAW 264.7 cells in vitro. Oral administration of MESD reduced the expression of inflammatory cytokines in the colons of mice with DSS-induced colitis. Additionally, MESD inhibited the abundance of Clostridium sensu stricto 1 and enhanced the predicted functional pathways, including l-glutamate degradation VIII (to propanoic acid). Seven compounds with anti-inflammatory properties were isolated from the MESD. Among them, 3'-O-acetylhamaudol and 3'-O-angeloylhamaudol exhibited strong anti-inflammatory effects in vitro. Conclusion Overall, MESD may be a potential natural product for the treatment of IBD by lowering inflammatory cytokine levels and altering gut microbiota composition.
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Affiliation(s)
- Saruul Erdenebileg
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Daejeon, South Korea
| | - Yang-Ju Son
- Department of Food and Nutrition, Chung-Ang University, Anseong, South Korea
| | - Myungsuk Kim
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
| | - Sarangerel Oidovsambuu
- Natural Product Chemistry Laboratory, Institute of Chemistry and Chemical Technology, Mongolian Academy of Sciences, Ulaanbaatar, Mongolia
| | - Kwang Hyun Cha
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
| | - Jaeyoung Kwon
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
| | - Da Seul Jung
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
| | - Chu Won Nho
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung, South Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Daejeon, South Korea
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Vestergaard MV, Allin KH, Poulsen GJ, Lee JC, Jess T. Characterizing the pre-clinical phase of inflammatory bowel disease. Cell Rep Med 2023; 4:101263. [PMID: 37939713 PMCID: PMC10694632 DOI: 10.1016/j.xcrm.2023.101263] [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: 03/08/2023] [Revised: 07/21/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023]
Abstract
Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.
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Affiliation(s)
- Marie Vibeke Vestergaard
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Kristine H Allin
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Gry J Poulsen
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - James C Lee
- Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK; Institute of Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London, London, UK
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.
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Nagata T, Funakoshi S, Morihara D, Shakado S, Yokoyama K, Takata K, Tanaka T, Fukunaga A, Yamauchi R, Fukuda H, Matsuoka H, Imakiire S, Sakisaka H, Matsuoka S, Kuno N, Abe K, Ishibashi H, Ashizuka S, Hirai F. Malnutrition and inflammation status in nonobese patients with inflammatory bowel disease are associated with nonalcoholic fatty liver disease: a retrospective study. Intest Res 2023; 21:471-480. [PMID: 37559192 PMCID: PMC10626015 DOI: 10.5217/ir.2023.00035] [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: 03/23/2023] [Revised: 06/19/2023] [Accepted: 07/03/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND/AIMS The frequency and details of nonalcoholic fatty liver disease (NAFLD) complications in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to clarify characteristics of NAFLD in patients with IBD. METHODS We retrospectively identified and enrolled patients with IBD diagnosed with or without NAFLD by undergoing abdominal computed tomography (CT) at our institution between 2005 and 2020. The primary endpoint was the complication rate of NAFLD in patients with IBD. Secondary endpoints were the clinical characteristics of nonobese patients with IBD and comorbid NAFLD and their association with nutritional and inflammatory parameters. RESULTS Twenty-one (21.9%) of 96 eligible patients with IBD also had NAFLD. In nonobese patients (defined as patients with a body mass index <25 kg/m2), C-reactive protein (CRP; P<0.001) and alanine aminotransferase (P=0.018) levels were higher and the albumin level (P=0.005) and prognostic nutritional index (PNI; P=0.002) values were lower in patients with NAFLD than in those without NAFLD. The PNI value was positively correlated (P<0.001) and the CRP level was negatively correlated (P=0.001) with the hepatosplenic ratio. However, in the NAFLD combined group, PNI (P<0.05) and CRP values (P<0.001) were improved over time after CT imaging by continuing IBD treatment. CONCLUSIONS Worsening nutritional and inflammatory status in IBD patients is associated with complications of NAFLD. Diagnosis of NAFLD in IBD patients using CT imaging might be useful not only for early detection of NAFLD but also in assessing the need for therapeutic intervention for IBD.
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Affiliation(s)
- Takahiro Nagata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Sadahiro Funakoshi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Daisuke Morihara
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hiroki Matsuoka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - So Imakiire
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hideto Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Satoshi Matsuoka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Nobuaki Kuno
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Koichi Abe
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Hideki Ishibashi
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Shinya Ashizuka
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
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8
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Rodriguez-Duque JC, Calleja JL, Iruzubieta P, Hernández-Conde M, Rivas-Rivas C, Vera MI, Garcia MJ, Pascual M, Castro B, García-Blanco A, García-Nieto E, Olmo SCD, Cagigal ML, Lopez-Montejo L, Fernández-Lamas T, Rasines L, Fortea JI, Vaque JP, Frias Y, Rivero M, Arias-Loste MT, Crespo J. Increased risk of MAFLD and Liver Fibrosis in Inflammatory Bowel Disease Independent of Classic Metabolic Risk Factors. Clin Gastroenterol Hepatol 2023; 21:406-414.e7. [PMID: 35124272 DOI: 10.1016/j.cgh.2022.01.039] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is conflicting evidence regarding the prevalence of and risk factors for metabolic-associated fatty liver disease (MAFLD) in patients with inflammatory bowel disease (IBD). We aimed to determine MAFLD prevalence and risk factors in IBD patients. METHODS Cross-sectional, case-control study included all consecutive IBD patients treated at 2 different university hospitals. Controls were subjects randomly selected from the general population and matched by age, sex, type 2 diabetes status, and body mass index in a 1:2 ratio. MAFLD was confirmed by controlled attenuation parameter. Liver biopsies were collected when MAFLD with significant liver fibrosis was suspected. In addition, age- and fibrosis stage-paired non-IBD patients with biopsy-proven MAFLD served as a secondary control group. RESULTS Eight hundred thirty-one IBD patients and 1718 controls were included. The prevalence of MAFLD and advanced liver fibrosis (transient elastography ≥9.7 kPa) was 42.00% and 9.50%, respectively, in IBD patients and 32.77% and 2.31%, respectively, in the general population (P < .001). A diagnosis of IBD was an independent predictor of MAFLD (adjusted odds ratio, 1.99; P < .001) and an independent risk factor for advanced liver fibrosis (adjusted odds ratio, 5.55; P < .001). Liver biopsies were obtained from 40 IBD patients; MAFLD was confirmed in all cases, and fibrosis of any degree was confirmed in 25 of 40 cases (62.5%). Body mass index and type 2 diabetes prevalence were significantly lower in IBD-MAFLD patients than in severity-paired patients with biopsy-proven MAFLD. CONCLUSIONS MAFLD and liver fibrosis are particularly prevalent in IBD patients, regardless of the influence of classic metabolic risk factors.
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Affiliation(s)
- Juan Carlos Rodriguez-Duque
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - José Luis Calleja
- Gastroenterology and Hepatology Department, University Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Paula Iruzubieta
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Marta Hernández-Conde
- Gastroenterology and Hepatology Department, University Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Coral Rivas-Rivas
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - María Isabel Vera
- Gastroenterology and Hepatology Department, University Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Maria Jose Garcia
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Marta Pascual
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Beatriz Castro
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Agustín García-Blanco
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Enrique García-Nieto
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Soraya Curiel-Del Olmo
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - María Luisa Cagigal
- Pathology Department, University Hospital Marqués de Valdecilla, Santander, Spain
| | - Lorena Lopez-Montejo
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Tatiana Fernández-Lamas
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Laura Rasines
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - José Ignacio Fortea
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - José Pedro Vaque
- Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain; Molecular Biology Department, University of Cantabria, Santander, Spain
| | - Yza Frias
- Gastroenterology and Hepatology Department, University Hospital Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Montserrat Rivero
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Javier Crespo
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Santander, Spain; Group of Clinical and Translational Research in Digestive Diseases Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain.
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9
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Cheng Y, McLean R, Sewell JL, Huang C, Khalili M. Inflammatory bowel disease type influences development of elevated liver enzymes. JGH Open 2022; 6:846-853. [PMID: 36514498 PMCID: PMC9730719 DOI: 10.1002/jgh3.12831] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 09/15/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022]
Abstract
Background and Aim Up to a third of patients with inflammatory bowel disease (IBD) have elevated liver enzymes (ELE). We evaluated the incidence, predictors, and outcomes associated with ELE in a diverse and vulnerable IBD cohort. Methods We retrospectively evaluated 336 IBD patients receiving care at the San Francisco safety net gastroenterology clinics between June 1996 and December 2019. Baseline characteristics were captured at first visit, then patients were followed until last clinic activity or death. Testing and etiology, pattern of ELE defined as transient (<1 month) or persistent (≥1 month), were assessed. Multivariate modeling evaluated predictors of ELE at baseline, new ELE at follow-up, and pattern of ELE. Results Baseline median age was 40.3 years, 62% male, 46% White (13% Black, 19% Asian, and 18% Latino), and 59% had ulcerative colitis (UC). Among those without known liver disease (n = 14), 51.6% (166 of 322; 52 at baseline, 114 during follow-up) had ELE. In multivariate logistic regression, 5-aminosalicylic acid use (odds ratio [OR] 2.2, 95% confidence interval [CI]: 1.07-4.4, P = 0.03) and higher body mass index (OR 1.08, 95% CI: 1.02-1.14, P = 0.01) were associated with baseline ELE. In multivariate Cox regression, UC (vs. Crohn's disease [CD]) had a 34% lower risk of developing new ELE during follow-up (hazard ratio [HR] 0.66, 95% CI: 0.46-0.95, P = 0.02). Mortality rate was higher for patients with ELE (0% normal vs 2.3% transient ELE vs 6.5% persistent ELE, P < 0.001). Conclusion ELE is prevalent in IBD, especially in CD, and associated with higher rates of mortality. Identification and management of ELE particularly when persistent are important to IBD outcomes.
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Affiliation(s)
- Yao‐Wen Cheng
- Department of Medicine, Division of GastroenterologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Richard McLean
- Department of Medicine, Division of GastroenterologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Justin L Sewell
- Department of Medicine, Division of GastroenterologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Chiung‐Yu Huang
- Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Mandana Khalili
- Department of Medicine, Division of GastroenterologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA
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10
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Islam J, Agista AZ, Watanabe K, Nochi T, Aso H, Ohsaki Y, Koseki T, Komai M, Shirakawa H. Fermented rice bran supplementation attenuates chronic colitis-associated extraintestinal manifestations in female C57BL/6N mice. J Nutr Biochem 2022; 99:108855. [PMID: 34517096 DOI: 10.1016/j.jnutbio.2021.108855] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/04/2021] [Accepted: 08/10/2021] [Indexed: 12/17/2022]
Abstract
Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti-colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups-control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM.
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Affiliation(s)
- Jahidul Islam
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan.
| | - Afifah Zahra Agista
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Kouichi Watanabe
- International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; Laboratory of Functional Morphology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Tomonori Nochi
- International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; Laboratory of Functional Morphology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Hisashi Aso
- International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; Laboratory of Functional Morphology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Yusuke Ohsaki
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Takuya Koseki
- Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata, Japan
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; International Education and Research Center for Food and Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
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11
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Brown BC, Knowles DA. Welch-weighted Egger regression reduces false positives due to correlated pleiotropy in Mendelian randomization. Am J Hum Genet 2021; 108:2319-2335. [PMID: 34861175 DOI: 10.1016/j.ajhg.2021.10.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/19/2021] [Indexed: 02/01/2023] Open
Abstract
Modern population-scale biobanks contain simultaneous measurements of many phenotypes, providing unprecedented opportunity to study the relationship between biomarkers and disease. However, inferring causal effects from observational data is notoriously challenging. Mendelian randomization (MR) has recently received increased attention as a class of methods for estimating causal effects using genetic associations. However, standard methods result in pervasive false positives when two traits share a heritable, unobserved common cause. This is the problem of correlated pleiotropy. Here, we introduce a flexible framework for simulating traits with a common genetic confounder that generalizes recently proposed models, as well as a simple approach we call Welch-weighted Egger regression (WWER) for estimating causal effects. We show in comprehensive simulations that our method substantially reduces false positives due to correlated pleiotropy while being fast enough to apply to hundreds of phenotypes. We apply our method first to a subset of the UK Biobank consisting of blood traits and inflammatory disease, and then to a broader set of 411 heritable phenotypes. We detect many effects with strong literature support, as well as numerous behavioral effects that appear to stem from physician advice given to people at high risk for disease. We conclude that WWER is a powerful tool for exploratory data analysis in ever-growing databases of genotypes and phenotypes.
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Affiliation(s)
- Brielin C Brown
- Data Science Institute, Columbia University, New York, NY 10027, USA; New York Genome Center, New York, NY 10013, USA.
| | - David A Knowles
- Data Science Institute, Columbia University, New York, NY 10027, USA; New York Genome Center, New York, NY 10013, USA; Department of Computer Science, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Columbia University, New York, NY 10027, USA.
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12
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Bernstein CN, Nugent Z, Shaffer S, Singh H, Marrie RA. Comorbidity before and after a diagnosis of inflammatory bowel disease. Aliment Pharmacol Ther 2021; 54:637-651. [PMID: 34156724 DOI: 10.1111/apt.16444] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/12/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Comorbidity is an important predictor of how disease course in inflammatory bowel (IBD) evolves. AIMS To determine pre-diagnosis relative rates (RR) and post-diagnosis hazard ratios (HR) of component diseases of the Charlson Comorbidity Index (CCI) in a cohort study of persons with IBD. METHODS The University of Manitoba IBD Epidemiology Database includes all Manitobans with IBD from 1 April 1984 through 31 March 2018 and matched controls. All outpatient physician claims and hospital discharge abstracts were searched for diagnostic codes for CCI component diseases. Some diseases were collapsed into one group such that we assessed 12 conditions. We report the RR of these conditions prior to IBD and the incidence of these diagnoses after IBD. Using Cox proportional hazards regression we report post-diagnosis HR. Confidence intervals were adjusted for Bonferroni correction. RESULTS The RR of cardiovascular diseases, peripheral vascular diseases, chronic pulmonary diseases, connective tissue disease/rheumatic diseases, renal disease, liver diseases, peptic ulcer disease, and cancer were all increased prior to diagnoses of IBD compared to controls. All comorbidities were increased post IBD diagnosis. The increased HR for dementia in persons with Crohn's disease was a concerning novel finding. The increased association with paraplegia/hemiplegia was unexpected. For all comorbidities, except diabetes, the age at diagnosis was younger in IBD than controls. CONCLUSIONS Persons with IBD have a higher comorbidity burden than persons without IBD. Optimal care plans for persons with IBD should include an assessment for other comorbidities that include just about every other organ system.
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Affiliation(s)
- Charles N Bernstein
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
| | - Zoann Nugent
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada.,Cancercare Manitoba, Winnipeg, MB, Canada
| | - Seth Shaffer
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
| | - Harminder Singh
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada.,Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Ruth Ann Marrie
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.,University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada.,Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
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13
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Hyun CK. Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22179139. [PMID: 34502047 PMCID: PMC8430512 DOI: 10.3390/ijms22179139] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023] Open
Abstract
Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
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Affiliation(s)
- Chang-Kee Hyun
- School of Life Science, Handong Global University, Pohang 37554, Gyungbuk, Korea
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14
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Vermeire S, Hébuterne X, Tilg H, De Hertogh G, Gineste P, Steens JM. Induction and Long-term Follow-up With ABX464 for Moderate-to-severe Ulcerative Colitis: Results of Phase IIa Trial. Gastroenterology 2021; 160:2595-2598.e3. [PMID: 33662385 DOI: 10.1053/j.gastro.2021.02.054] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 01/21/2023]
Affiliation(s)
- Séverine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium.
| | - Xavier Hébuterne
- Department of Gastroenterology and Clinical Nutrition, CHU of Nice, University Côte d'Azur, Nice, France
| | - Herbert Tilg
- Department of Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Gert De Hertogh
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Abivax, Paris, France
| | - Paul Gineste
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Abivax, Paris, France
| | - Jean-Marc Steens
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium; Abivax, Paris, France
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15
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Evaluation of Nonalcoholic Fatty Liver Disease in Pediatric Patients With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2021; 72:574-578. [PMID: 33346578 DOI: 10.1097/mpg.0000000000003023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Adult studies demonstrate the co-existence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) without traditional risk factors. Data in children with IBD are lacking. Here, we sought to establish the prevalence of NAFLD in a single-center pediatric IBD cohort, and identify potential risk factors. After institutional review board approval, we enrolled children with IBD who underwent routine abdominal magnetic resonance enterography. Proton density fat fraction (PDFF) was then estimated on magnetic resonance enterography. A total of 83 patients with IBD were identified and PDFF maps completed. Five (6%) were found to have PDFF >5%, meeting criteria for NAFLD. Compared to the patients with IBD without NAFLD, none of the evaluated risk factors including age, sex, diagnosis, time since diagnosis, medication, median alanine aminotransferase, and weight status were statistically significant. Our findings demonstrate the occult nature of NAFLD in pediatric IBD. The prevalence is not at variance with what is expected in general teenage populations.
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16
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El-Shabrawi MHF, Tarek S, Abou-Zekri M, Meshaal S, Enayet A, Mogahed EA. Hepatobiliary manifestations in children with inflammatory bowel disease: A single-center experience in a low/middle income country. World J Gastrointest Pharmacol Ther 2020; 11:48-58. [PMID: 32844043 PMCID: PMC7416377 DOI: 10.4292/wjgpt.v11.i3.48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 05/28/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There has been a worldwide increase in the reported incidence of inflammatory bowel disease (IBD) in children over the past 2-3 decades. The hepatobiliary (HB) manifestations of IBD have been well-studied in children in industrialized and developed countries but are infrequently reported in low- and middle-income countries (LMIC) such as Egypt.
AIM To determine the prevalence of the HB manifestations in a cohort of Egyptian children with IBD.
METHODS This cross-sectional observational study was carried out over a period of 6 mo (between June 2013 to December 2013) at the Paediatric Hepatology and Gastroenterology Units of Cairo University Children's Hospital, which is the largest paediatric tertiary care centre in the country.
RESULTS The study included 48 patients with confirmed IBD based upon clinical, laboratory, endoscopic and histopathological features, 29 (60.4%) were male. Twenty-four patients (50%) had ulcerative colitis (UC), 11 (22.9%) had Crohn's disease (CD) and 13 (27.1%) had unclassified-IBD (IBD-U), which was formerly known as indeterminate colitis. The mean age of the patients at the time of presentation was 8.14 (± SD 4.02) years and the mean age at the time of study enrolment was 10.16 (± SD 4.19) years. All patients were screened for HB manifestations by physical examination, liver function tests, imaging and liver biopsy when indicated. HB disorders were confirmed in 13 patients (27.1%). Transaminases were elevated in 3 patients (6.3%). Two patients (4.2%) had elevated biliary enzymes (one was diagnosed as primary sclerosing cholangitis (PSC) and the other was diagnosed with PSC/autoimmune hepatitis overlap syndrome and the third patient had hepatitis C virus infection. Ten patients (20.8%) had bright echogenic liver on ultrasound suggesting fatty infiltration as a sequel of malnutrition or medication toxicity.
CONCLUSION The commonest HB disorders in Egyptian children with IBD were abnormal liver function tests, fatty infiltration and PSC. These HB manifestations in paediatric patients in LMIC may be relatively more common than in industrialized countries. Therefore, IBD patients in LMIC should be meticulously screened for liver disease to allow prompt diagnosis and management.
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Affiliation(s)
- Mortada HF El-Shabrawi
- Department of Paediatrics, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Sara Tarek
- Department of Paediatrics, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Maha Abou-Zekri
- Department of Paediatrics, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Safa Meshaal
- Department of Clinical Pathology, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Afaf Enayet
- Department of Paediatrics, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
| | - Engy Adel Mogahed
- Department of Paediatrics, Kasr Alainy School of Medicine, Cairo University, Cairo 11562, Egypt
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17
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Ghattamaneni NKR, Panchal SK, Brown L. An improved rat model for chronic inflammatory bowel disease. Pharmacol Rep 2018; 71:149-155. [PMID: 30550995 DOI: 10.1016/j.pharep.2018.10.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/13/2018] [Accepted: 10/10/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an important cause of chronic disability in humans. METHODS We characterized a model of chronic IBD in young male Wistar rats by administering dextran sodium sulfate (DSS: 0%, 0.25%, 0.5%, or 1% in drinking water) for six weeks, with 0.5% DSS for twelve weeks, following DSS cessation or together with treatment with sulfasalazine for the last 6 weeks. We measured gastrointestinal characteristics including stool consistency, blood in stools, small intestine and colon length, intestinal transit and permeability, and gut microbiota, as well as extra-intestinal parameters including oral glucose tolerance, systolic blood pressure, fat and lean mass, and left ventricular stiffness. RESULTS At 6 weeks, 0.25-1% DSS produced gastrointestinal changes as diarrhea and blood in stools. At 12 weeks, 0.5% DSS produced chronic and sustained gastrointestinal changes, with marked infiltration of inflammatory cells throughout the gastrointestinal tract and crypt distortion. Firmicutes increased and Bacteroidetes and Actinobacteria decreased in DSS-treated rats. Changes were reversed by DSS cessation or sulfasalazine treatment. Gastrointestinal permeability and extra-intestinal parameters did not change, so DSS changes were limited to the gastrointestinal tract. CONCLUSION Chronic 0.5% DSS produces selective and reversible gastrointestinal changes, providing an improved chronic model in rats that mimics human IBD for testing new interventions.
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Affiliation(s)
- Naga K R Ghattamaneni
- School of Health and Wellbeing, University of Southern Queensland, Toowoomba, QLD, Australia; Functional Foods Research Group, University of Southern Queensland, Toowoomba, QLD, Australia
| | - Sunil K Panchal
- Functional Foods Research Group, University of Southern Queensland, Toowoomba, QLD, Australia
| | - Lindsay Brown
- School of Health and Wellbeing, University of Southern Queensland, Toowoomba, QLD, Australia; Functional Foods Research Group, University of Southern Queensland, Toowoomba, QLD, Australia.
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18
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Principi M, Iannone A, Losurdo G, Mangia M, Shahini E, Albano F, Rizzi SF, La Fortezza RF, Lovero R, Contaldo A, Barone M, Leandro G, Ierardi E, Di Leo A. Nonalcoholic Fatty Liver Disease in Inflammatory Bowel Disease: Prevalence and Risk Factors. Inflamm Bowel Dis 2018; 24:1589-1596. [PMID: 29688336 DOI: 10.1093/ibd/izy051] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is common in inflammatory bowel diseases (IBD). Herein, NAFLD prevalence and risk factors in a large IBD cohort were evaluated and compared to that of a non-IBD sample. METHODS Crohn's disease/ulcerative colitis outpatients referred to IBD service of our Gastroenterology Unit were enrolled. Subjects affected by functional and motor gastrointestinal disorders, in whom IBD was ruled out, referred to general outpatient service in the same area, were considered as nonIBD group. Exclusion criteria were based on previous diagnosis of nonNAFLD chronic liver diseases and secondary causes of fat liver overload. Characteristics of IBD and liver status were collected. Risk factors for metabolic syndrome were analyzed. Ultrasonographic presence and degree of steatosis were assessed. Data were examined by univariate and multivariate analyses. RESULTS For this study 465 IBD and 189 non-IBD subjects were consecutively enrolled. NAFLD was found in 28.0% and 20.1% in IBD and non-IBD subjects, respectively (P = 0.04). IBD patients with NAFLD were younger than non-IBD ones. There was no significant difference in steatosis grade and association between NAFLD and IBD behavior, extension, activity, and drugs. In the IBD group, multivariate analysis demonstrated that NAFLD was independently associated to metabolic syndrome (OR=2.24, 95%CI 1.77-28.81), diabetes (OR=1.71, 95%CI 1.43-12.25), fasting blood glucose (OR=1.36, 95%CI 1.13-1.68), and abdominal circumference (OR=1.68, 95%CI 1.15-14.52). CONCLUSIONS NAFLD is more common and occurs at a younger age in IBD than in nonIBD subjects. However, further investigation is required to ascertain possible NAFLD pathogenic IBD-related factors other than conventional/metabolic ones. 10.1093/ibd/izy051_video1izy051.video15774874877001.
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Affiliation(s)
- Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Andrea Iannone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Michela Mangia
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Endrit Shahini
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Francesca Albano
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Salvatore Fabio Rizzi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Rosa Federica La Fortezza
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Rosa Lovero
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Antonella Contaldo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Gioacchino Leandro
- National Institute of Gastroenterology, "S De Bellis" Research Hospital, Castellana Grotte, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, AOU Policlinico, University of Bari, Italy
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Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases. Int J Colorectal Dis 2018; 33:927-936. [PMID: 29748708 PMCID: PMC6002455 DOI: 10.1007/s00384-018-3069-8] [Citation(s) in RCA: 30] [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] [Accepted: 04/29/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn's disease (CD) and ulcerative colitis (UC). METHODS Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls. RESULTS IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (> 5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance. CONCLUSIONS Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.
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Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. J Pediatr Gastroenterol Nutr 2017; 64:639-652. [PMID: 27984347 DOI: 10.1097/mpg.0000000000001492] [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] [Indexed: 02/06/2023]
Abstract
Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.
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Chao CY, Battat R, Al Khoury A, Restellini S, Sebastiani G, Bessissow T. Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: A review article. World J Gastroenterol 2016; 22:7727-7734. [PMID: 27678354 PMCID: PMC5016371 DOI: 10.3748/wjg.v22.i34.7727] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/19/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Emerging data have highlighted the co-existence of non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease; both of which are increasingly prevalent disorders with significant complications and impact on future health burden. Cross-section observational studies have shown widely variable prevalence rates of co-existing disease, largely due to differences in disease definition and diagnostic tools utilised in the studies. Age, obesity, insulin resistance and other metabolic conditions are common risks factors in observational studies. However, other studies have also suggested a more dominant role of inflammatory bowel disease related factors such as disease activity, duration, steroid use and prior surgical intervention, in the development of NAFLD. This suggests a potentially more complex pathogenesis and relationship between the two diseases which may be contributed by factors including altered intestinal permeability, gut dysbiosis and chronic inflammatory response. Commonly used immunomodulation agents pose potential hepatic toxicity, however no definitive evidence exist linking them to the development of hepatic steatosis, nor are there any data on the impact of therapy and prognosis in patient with co-existent diseases. Further studies are required to assess the impact and establish appropriate screening and management strategies in order to allow early identification, intervention and improve patient outcomes.
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Incidence and Predictors of Nonalcoholic Fatty Liver Disease by Serum Biomarkers in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:1937-44. [PMID: 27379445 DOI: 10.1097/mib.0000000000000832] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) are at high risk for non-alcoholic fatty liver disease (NAFLD). Longitudinal data on incident NAFLD are lacking. We employed non-invasive methods to study incidence and predictors of NAFLD. METHODS This was a retrospective study of IBD patients without known liver disease followed at IBD clinic of McGill University. NAFLD was defined as Hepatic Steatosis Index (HSI) ≥36 and absence of alcohol intake. Advanced liver fibrosis was diagnosed by FIB-4 ≥2.67. Active IBD was defined as partial Mayo score ≥3 for ulcerative colitis, Harvey Bradshaw Index ≥ 5 or flare during follow-up. Kaplan-Meier and Cox regression analyses were used to investigate incidence and predictors of NAFLD development. RESULTS Three hundred twenty-one consecutive patients (median age 33.7 yr, 47% males) were observed for a median of 3.2 years (interquartile range 1.5-6). Over 1181.2 persons-year (PY), 108 (33.6%) patients developed NAFLD, accounting for an incidence rate of 9.1/100 PY (95% confidence interval [CI], 7.4-10.9). 7 (2.2%) patients developed advanced liver fibrosis, accounting for an incidence rate of 0.5/100 PY (95% CI, 0.2-1.1). Development of NAFLD was predicted by disease activity (adjusted hazard ratio [aHR] = 1.58; 95% CI, 1.08-2.33, P = 0.02), disease duration (aHR = 1.12; 95% CI, 1.03-1.23, P = 0.01), and prior surgery for IBD (aHR = 1.34; 95% CI, 1.04-1.74, P = 0.02). CONCLUSIONS NAFLD is a frequent comorbidity in patients with IBD. These patients can also develop advanced liver fibrosis. Disease activity, duration of IBD and prior surgery are predictors of NAFLD development. This should represent one more incentive to achieve and maintain early clinical remission. Further prospective studies are of interest.
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PNPLA3 148M Carriers with Inflammatory Bowel Diseases Have Higher Susceptibility to Hepatic Steatosis and Higher Liver Enzymes. Inflamm Bowel Dis 2016; 22:134-40. [PMID: 26355465 PMCID: PMC4894778 DOI: 10.1097/mib.0000000000000569] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract and encompass Crohn's disease and ulcerative colitis. IBD are often associated with extraintestinal manifestations affecting multiple organs including the liver. Increased levels of serum aminotransferases, possibly related to nonalcoholic fatty liver disease, constitute one of the most frequently described IBD-related liver diseases. The PNPLA3 I148M substitution is a major common genetic determinant of hepatic fat content and progression to chronic liver disease. The aim of this study was to investigate whether carriers of PNPLA3 148M allele with IBD have higher risk of liver steatosis and increase in transaminases levels. METHODS The PNPLA3 I148M (rs738409) genotype was performed by Taqman assays in 158 individuals from Southern Italy (namely, Catanzaro cohort) and in 207 individuals from Northern Italy (namely, Milan cohort) with a definite diagnosis of IBD. Demographic and clinical data and also alanine transaminase levels were collected for both cohorts. The Catanzaro cohort underwent liver evaluation by sonography and liver stiffness and controlled attenuation parameter measurements by transient elastography. RESULTS Here, we show for the first time that carriers of the PNPLA3 148M allele with IBD have a greater risk of hepatic steatosis (odds ratio, 2.9, and confidence interval, 1.1-7.8), higher controlled attenuation parameter values (P = 0.029), and increased circulating alanine transaminase (P = 0.035) in the Catanzaro cohort. We further confirm the higher alanine transaminase levels in the Milan cohort (P < 0.001). CONCLUSIONS Our results show that PNPLA3 148M carriers with IBD have higher susceptibility to hepatic steatosis and liver damage.
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Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment. Eur J Gastroenterol Hepatol 2015; 27:698-704. [PMID: 25923946 DOI: 10.1097/meg.0000000000000350] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown. METHODS The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities. RESULTS Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31). CONCLUSION This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.
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Samsel A, Seneff S. Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies. Surg Neurol Int 2015; 6:45. [PMID: 25883837 PMCID: PMC4392553 DOI: 10.4103/2152-7806.153876] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 01/21/2015] [Indexed: 12/20/2022] Open
Abstract
Manganese (Mn) is an often overlooked but important nutrient, required in small amounts for multiple essential functions in the body. A recent study on cows fed genetically modified Roundup(®)-Ready feed revealed a severe depletion of serum Mn. Glyphosate, the active ingredient in Roundup(®), has also been shown to severely deplete Mn levels in plants. Here, we investigate the impact of Mn on physiology, and its association with gut dysbiosis as well as neuropathologies such as autism, Alzheimer's disease (AD), depression, anxiety syndrome, Parkinson's disease (PD), and prion diseases. Glutamate overexpression in the brain in association with autism, AD, and other neurological diseases can be explained by Mn deficiency. Mn superoxide dismutase protects mitochondria from oxidative damage, and mitochondrial dysfunction is a key feature of autism and Alzheimer's. Chondroitin sulfate synthesis depends on Mn, and its deficiency leads to osteoporosis and osteomalacia. Lactobacillus, depleted in autism, depend critically on Mn for antioxidant protection. Lactobacillus probiotics can treat anxiety, which is a comorbidity of autism and chronic fatigue syndrome. Reduced gut Lactobacillus leads to overgrowth of the pathogen, Salmonella, which is resistant to glyphosate toxicity, and Mn plays a role here as well. Sperm motility depends on Mn, and this may partially explain increased rates of infertility and birth defects. We further reason that, under conditions of adequate Mn in the diet, glyphosate, through its disruption of bile acid homeostasis, ironically promotes toxic accumulation of Mn in the brainstem, leading to conditions such as PD and prion diseases.
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Affiliation(s)
- Anthony Samsel
- Research Scientist and Consultant, Deerfield, NH 03037, USA
| | - Stephanie Seneff
- Spoken Language Systems Group, Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA 02139, USA
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