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Sinha A, Roy S. Exploring the drug repurposing potential of lisinopril against TNBS-induced colitis in Wistar rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04212-w. [PMID: 40328912 DOI: 10.1007/s00210-025-04212-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with a multifactorial etiology. Given the limitations and adverse effects of current therapies, there is a need for novel therapeutic approaches. Drug repurposing presents a promising opportunity to utilize medications with known safety and pharmacological profiles for alternative colitis treatment. Emerging evidence suggests the renin-angiotensin system (RAS) plays a significant role in the colitis pathophysiology. Angiotensin-converting enzyme (ACE) inhibitors may offer therapeutic potential by modulating pro-inflammatory cytokines and reducing oxidative stress. This study aims to evaluate the efficacy of lisinopril (LIS) in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in Wistar rats. Colitis was induced in Wistar rats via a single intracolonic TNBS dose (100 mg/kg). Treatment groups received oral interventions for 5 days: 5-aminosalicylic acid (5-ASA; 25.5 mg/kg), LIS (10 mg/kg), or LIS (20 mg/kg). Efficacy was evaluated using the disease activity score rate (DASR), colon/body weight ratio (CBWR), and colon length, diameter, and pH. Colonic tissue was analyzed macroscopically and histopathologically. Inflammatory biomarkers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), oxidative stress markers glutathione (GSH), and malondialdehyde (MDA), as well as C-reactive protein (CRP) and complete blood count (CBC), were measured. LIS significantly reduced colitis severity, decreasing DASR and CBWR, while restoring colon dimensions and pH. LIS showed potent anti-colitic effects by suppressing TNF-α and IL-6 levels, reducing MDA, and increasing GSH. LIS restored RBC and WBC levels while normalizing CRP and hemoglobin levels. Histopathological and macroscopic analyses confirmed colonic protection with minimal detrimental effects on the stomach and liver. LIS, particularly at 20 mg/kg, exhibited dose-dependent anti-inflammatory, antioxidant, and tissue-protective effects, showing promise as a therapeutic agent for colitis treatment.
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Affiliation(s)
- Akshit Sinha
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida, 201313, India
| | - Supriya Roy
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Sector 125, Noida, 201313, India.
- Amity Institute of Pharmacy, Amity University Uttar Pradesh Lucknow Campus, Lucknow, 226028, Uttar Pradesh, India.
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Gong Y, He Y, Wan M, Chen H. Risk Factors for Gallstones in Crohn's Disease: A Systematic Review and Meta-Analysis. Dig Dis Sci 2024; 69:4187-4202. [PMID: 39322804 DOI: 10.1007/s10620-024-08597-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 08/15/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Crohn's disease (CD) have an increased risk of gallstone disease. We aimed to systematically evaluate the prevalence rate and relevant risk factors of gallstones in CD patients. METHODS A comprehensive search of PubMed, Embase, and Web of Science databases from inception to September 10, 2023, identified studies investigating risk factors for gallstone development among CD patients. Gender, age, body mass index, disease duration, disease site, stenosis, prior surgery, hospitalization times, corticosteroids, immunomodulators, and total parenteral nutrition (TPN) were assessed as potential risk factors. Odds ratios (OR) and confidence intervals (CI) were calculated. RESULT Among 1184 articles, 11 observational studies (3588 patients) were included. The prevalence of CD patients with gallstones was approximately 14.7%. Factors significantly associated with increased gallstone risk included Age ≥ 40 years old (OR 3.06, 95% CI 2.09- 4.48), disease duration > 15 years (OR 3.01, 95% CI 2.06-4.42), lifetime surgery(OR 2.50, 95% CI 1.99-3.12), disease located in ileocolon (OR 1.38, 95% CI 1.04-1.83) and ileocecal(OR 1.93, 95% CI 1.16-3.21), multiple hospitalizations(OR 4.26, 95% CI 2.43-7.46), corticosteroid treatments(OR 2.65, 95% CI 1.52-4.63), immunomodulator therapy(OR 1.94, 95% CI 1.12-3.38), and TPN use(OR 2.66, 95% CI 1.29-5.51). Sex, stenosis, overweight, or low weight did not significantly increase the risk of gallstone developing. CONCLUSION Age, long disease duration, specific disease locations (ileocolon, ileocecal), surgery, number of hospitalizations, corticosteroids, immunomodulator therapy, and TPN were identified as factors that increased the risk of gallstones in CD patients. About 14.7% of CD patients experience gallstones, so raising awareness and implementing prevention are needed. REGISTRATION PROSPERO (CRD42023449299).
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Affiliation(s)
- Yan Gong
- School of Medicine, Southeast University, Nanjing, China
- Department of Gastroenterology, Zhongda Hospital of Southeast University, HuNan Street, GuLou District, Nanjing, China
| | - Yishu He
- School of Medicine, Southeast University, Nanjing, China
- Department of Gastroenterology, Zhongda Hospital of Southeast University, HuNan Street, GuLou District, Nanjing, China
| | - Mengting Wan
- School of Medicine, Southeast University, Nanjing, China
- Department of Gastroenterology, Zhongda Hospital of Southeast University, HuNan Street, GuLou District, Nanjing, China
| | - Hong Chen
- School of Medicine, Southeast University, Nanjing, China.
- Department of Gastroenterology, Zhongda Hospital of Southeast University, HuNan Street, GuLou District, Nanjing, China.
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Bhat MA, Roy S, Dhaneshwar S, Kumar S, Saxena SK. Desloratadine via its anti-inflammatory and antioxidative properties ameliorates TNBS-induced experimental colitis in rats. Immunopharmacol Immunotoxicol 2024:1-14. [PMID: 38816915 DOI: 10.1080/08923973.2024.2360043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 05/18/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Intestinal mucosal immune cells, notably mast cells, are pivotal in ulcerative colitis (UC) pathophysiology. Its activation elevates tissue concentrations of histamine. Inhibiting colonic histamine release could be an effective therapeutic strategy for treating UC. Experimental model like 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats mimic human IBD, aiding treatment investigations. Drug repurposing is a promising strategy to explore new indications for established drugs. Desloratadine (DES) is second-generation antihistamine utilized for managing allergies by blocking histamine action in the body. It also has reported anti-inflammatory and antioxidant actions. OBJECTIVE DES was investigated for its repurposing potential in UC by preclinical screening in TNBS-induced colitis in Wistar rats. METHODS Therapeutic efficacy of DES was evaluated both individually and in combination with standard drug 5-aminosalicylicacid (5-ASA). Rats were orally administered DES (10 mg/kg), 5-ASA (25 mg/kg), and DES + 5-ASA (5 mg + 12.15 mg) following the induction of colitis. Parameters including disease activity score rate (DASR), colon/body weight ratio (CBWR), colon length, diameter, pH, histological injury, and scoring were evaluated. Inflammatory biomarkers such as IL-1β, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. RESULTS Significant protective effects of DES, especially in combination with 5-ASA, against TNBS-induced inflammation were observed as evidenced by reduced DASR, CBWR, and improved colon morphology. Drugs significantly lowered plasma and colon histamine and, cytokines levels. GSH restoration, and decreased MDA content were also observed. CONCLUSION DES and DES + 5-ASA demonstrated potential in alleviating colonic inflammation associated with TNBS-induced colitis in rats. The effect can be attributed to its antihistamine, anticytokine, and antioxidative properties.
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Affiliation(s)
- Mohammad Aadil Bhat
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
| | - Supriya Roy
- Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India
| | - Suneela Dhaneshwar
- Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
| | - Swatantra Kumar
- Centre for Advanced Research (CFAR), Faculty of Medicine, King George's Medical University (KGMU), Uttar Pradesh, Lucknow, India
| | - Shailendra K Saxena
- Centre for Advanced Research (CFAR), Faculty of Medicine, King George's Medical University (KGMU), Uttar Pradesh, Lucknow, India
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Ozturk NB, Fiel MI, Schiano TD. Identification and clinical significance of nodular regenerative hyperplasia in primary sclerosing cholangitis. JGH Open 2022; 6:607-611. [PMID: 36091322 PMCID: PMC9446399 DOI: 10.1002/jgh3.12795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/27/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIM Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts. PSC is frequently associated with inflammatory bowel disease (IBD). Nodular regenerative hyperplasia (NRH) can occur in IBD with the use or even in the absence of thiopurine treatment. We aimed to study the significance of the presence of NRH and obliterative portal venopathy (OPV), both causes of non-cirrhotic portal hypertension (NCPH), in patients having PSC. METHODS Patients with PSC and concurrent NRH on liver biopsy were identified from the digital pathology database covering the period 2003-2019. Evaluation of liver biopsy and the original diagnoses were confirmed on review based on standard histological features diagnostic for NRH and OPV. Clinical and laboratory data were obtained from electronic medical records. RESULTS Thirty-one patients (21 male, 10 female; median age at biopsy 40.1 years) were included in the study. Twelve (38.7%) patients had OPV in addition to NRH on the liver biopsy. Nineteen (61.2%) patients had IBD including 11 with Crohn's disease (CD), 7 with ulcerative colitis (UC), and 1 with indeterminate colitis. Thirteen (41.9%) patients had evidence of portal hypertension, 10 (32.2%) with esophageal varices, 4 (12.9%) with history of variceal bleeding, 6 (19.3%) with ascites, and 14 (12.9%) with splenomegaly. Eleven (35.4%) patients had a cirrhotic-appearing liver on imaging. Twelve (38.7%) patients had a history of prior or current thiopurine use. CONCLUSIONS The current study suggests that NRH with or without OPV independently occurs in patients having PSC and may lead to NCPH, even in the absence of concurrent IBD and/or thiopurine therapy.
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Affiliation(s)
- Nazli Begum Ozturk
- Division of Liver Diseases and Recanati‐Miller Transplantation InstituteIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Maria Isabel Fiel
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Thomas D. Schiano
- Division of Liver Diseases and Recanati‐Miller Transplantation InstituteIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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Patel A, Perl A. Redox Control of Integrin-Mediated Hepatic Inflammation in Systemic Autoimmunity. Antioxid Redox Signal 2022; 36:367-388. [PMID: 34036799 PMCID: PMC8982133 DOI: 10.1089/ars.2021.0068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/20/2022]
Abstract
Significance: Systemic autoimmunity affects 3%-5% of the population worldwide. Systemic lupus erythematosus (SLE) is a prototypical form of such condition, which affects 20-150 of 100,000 people globally. Liver dysfunction, defined by increased immune cell infiltration into the hepatic parenchyma, is an understudied manifestation that affects up to 20% of SLE patients. Autoimmunity in SLE involves proinflammatory lineage specification in the immune system that occurs with oxidative stress and profound changes in cellular metabolism. As the primary metabolic organ of the body, the liver is uniquely capable to encounter oxidative stress through first-pass derivatization and filtering of waste products. Recent Advances: The traffic of immune cells from their development through recirculation in the liver is guided by cell adhesion molecules (CAMs) and integrins, cell surface proteins that tightly anchor cells together. The surface expression of CAMs and integrins is regulated via endocytic traffic that is sensitive to oxidative stress. Reactive oxygen species (ROS) that elicit oxidative stress in the liver may originate from the mitochondria, the cytosol, or the cell membrane. Critical Issues: While hepatic ROS production is a source of vulnerability, it also modulates the development and function of the immune system. In turn, the liver employs antioxidant defense mechanisms to protect itself from damage that can be harnessed to serve as therapeutic mechanisms against autoimmunity, inflammation, and development of hepatocellular carcinoma. Future Directions: This review is aimed at delineating redox control of integrin signaling in the liver and checkpoints of regulatory impact that can be targeted for treatment of inflammation in systemic autoimmunity. Antioxid. Redox Signal. 36, 367-388.
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Affiliation(s)
- Akshay Patel
- Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Microbiology and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Andras Perl
- Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Microbiology and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
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Mazza S, Soro S, Verga MC, Elvo B, Ferretti F, Cereatti F, Drago A, Grassia R. Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders. World J Hepatol 2021; 13:1828-1849. [PMID: 35069993 PMCID: PMC8727201 DOI: 10.4254/wjh.v13.i12.1828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/16/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Sara Soro
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Maria Chiara Verga
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Biagio Elvo
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Francesca Ferretti
- Gastroenterology Unit, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan 20157, Italy
| | - Fabrizio Cereatti
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Andrea Drago
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Roberto Grassia
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
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Seo KI, Kang SB. [Hepatobiliary Manifestation of Inflammatory Bowel Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 73:248-259. [PMID: 31132831 DOI: 10.4166/kjg.2019.73.5.248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/05/2019] [Accepted: 05/12/2019] [Indexed: 12/13/2022]
Abstract
The hepatobiliary system is one of the most common sites of extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The progression of IBD can lead to a primary hepatobiliary manifestation and can occur secondary to multiple drugs or accompanying viral infections. Primary sclerosing cholangitis is the representative hepatobiliary manifestation of IBD, particularly in ulcerative colitis. Although most agents used in the treatment of IBD are potentially hepatotoxic, the risk of serious hepatitis or liver failure is low. The prevalence of HBV and HCV in IBD is similar to the general population, but the clinical concern is HBV reactivation associated with immunosuppressive therapy. Patients undergoing cytotoxic chemotherapy or immunosuppressive therapy with a moderate to high risk of HBV reactivation require prophylactic antiviral therapy. On the other hand, HCV has little risk of reactivation. Patients with IBD are more likely to have nonalcoholic fatty liver disease than the general population and tend to occur at younger ages. IBD and cholelithiasis are closely related, especially in Crohn's disease.
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Affiliation(s)
- Kwang Il Seo
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Sang-Bum Kang
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
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Drug-Induced Gastrointestinal and Hepatic Disease Associated with Biologics and Nonbiologic Disease-Modifying Antirheumatic Drugs. Rheum Dis Clin North Am 2018; 44:29-43. [DOI: 10.1016/j.rdc.2017.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Protective effects of tranilast on experimental colitis in rats. Biomed Pharmacother 2017; 90:842-849. [DOI: 10.1016/j.biopha.2017.04.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/05/2017] [Accepted: 04/10/2017] [Indexed: 01/27/2023] Open
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Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int 2017; 37:475-489. [PMID: 27712010 DOI: 10.1111/liv.13265] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases-associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4-associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug-induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work-up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.
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Affiliation(s)
- Sophie Restellini
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
| | - Olivier Chazouillères
- Division d'Hépatologie, Centre de Référence des Maladies Inflammatoires des Voies Biliaires, et Université de Sorbonne, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Jean-Louis Frossard
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
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