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Tonutti A, Pugliese N, Ceribelli A, Isailovic N, De Santis M, Colapietro F, De Nicola S, Polverini D, Selmi C, Aghemo A. The autoimmune landscape of Porto-sinusoidal vascular disorder: What the rheumatologist needs to know. Semin Arthritis Rheum 2024; 67:152467. [PMID: 38805899 DOI: 10.1016/j.semarthrit.2024.152467] [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] [Received: 02/22/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/30/2024]
Abstract
Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions of the portal venules and sinusoids with clinical manifestations ranging from non-specific abnormalities in serum liver enzymes to clinically overt portal hypertension and related complications. Several reports have documented cases of PSVD in patients with systemic autoimmune conditions, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. It is of note that these diseases share specific pathophysiological features with PSVD, including endothelial dysfunction, vascular inflammation, and molecular signatures. This narrative review aims to summarize the current knowledge on the association between PSVD and systemic autoimmune diseases, emphasizing the importance of promptly recognizing this condition in the rheumatological practice, and highlighting the key aspects where further research is necessary from both pathogenic and clinical perspectives.
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Affiliation(s)
- Antonio Tonutti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Angela Ceribelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Natasa Isailovic
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Maria De Santis
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Stella De Nicola
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Davide Polverini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Carlo Selmi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
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Pugliese N, Giuli L, Mastrorocco E, Santopaolo F, Marcozzi G, Bezzio C, Dal Buono A, Gabbiadini R, Gasbarrini A, Ponziani FR, Armuzzi A, Aghemo A. Exploring the link: Porto-sinusoidal vascular disorder and inflammatory bowel disease - A comprehensive narrative review. Dig Liver Dis 2024; 56:964-970. [PMID: 38044225 DOI: 10.1016/j.dld.2023.11.021] [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: 10/23/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 12/05/2023]
Abstract
Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions involving the portal venules and sinusoids, independent of the presence of portal hypertension (PH), and for which liver biopsy is essential for diagnosis. PSVD has been shown to be common in patients with immune-mediated diseases, including inflammatory bowel disease (IBD). The association between PSVD and the use of thiopurines and thioguanine in patients with IBD has been well established. In addition, research suggests an association between PSVD and IBD, even in cases where patients haven't been exposed to specific medications, probably related to changes in intestinal permeability. The identification and management of patients with known IBD and PSVD is a challenge for gastroenterologists. This narrative review aims to summarize the currently available data on the association between IBD and PSVD and provide practical suggestions for the management of this group of patients.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Lucia Giuli
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome 00168, Italy
| | | | - Francesco Santopaolo
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome 00168, Italy
| | - Giacomo Marcozzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
| | - Cristina Bezzio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; IBD Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Arianna Dal Buono
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; IBD Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Roberto Gabbiadini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; IBD Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Antonio Gasbarrini
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome 00168, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome 00168, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; IBD Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy.
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Baumert LS, Shih A, Chung RT. Management of liver disease and portal hypertension in common variable immunodeficiency (CVID). JHEP Rep 2023; 5:100882. [PMID: 37869072 PMCID: PMC10585302 DOI: 10.1016/j.jhepr.2023.100882] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/30/2023] [Accepted: 07/22/2023] [Indexed: 10/24/2023] Open
Abstract
Patients with common variable immunodeficiency (CVID) frequently develop liver disease and associated complications, which represent an increasingly prevalent unmet medical need. The main hepatic manifestation of CVID is nodular regenerative hyperplasia (NRH), resulting in non-cirrhotic portal hypertension (NCPH). Liver disease is often underdiagnosed, leading to poor outcomes and decreased survival. The increasing numbers of patients with CVID who are diagnosed late with progressive liver disease underscores the importance of appropriate clinical management and treatment of liver complications. At the same time, specific guidelines for the clinical management of CVID-related liver disease are still lacking. Here, we review the epidemiology of CVID-related liver disease, reveal new insights into NRH and NCPH biology and highlight recently uncovered opportunities for NCPH diagnostics in CVID. Finally, we focus on current management of liver disease, portal hypertension and its complications - the key challenge in patients with CVID. Specifically, we review recent data regarding the role of transjugular intrahepatic portosystemic shunt and liver transplantation in clinical management. The role for anticoagulants and immunosuppressants targeting the pathogenesis of NRH will also be discussed. We propose an updated algorithm for the diagnostic work-up and treatment of NCPH in CVID. Finally, we consider future needs and therapeutic opportunities for CVID-related liver disease.
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Affiliation(s)
- Lukas S. Baumert
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Faculty of Medicine, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Angela Shih
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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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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Núñez F P, Quera R, Bay C, Castro F, Mezzano G. Drug-Induced Liver Injury Used in the Treatment of Inflammatory Bowel Disease. J Crohns Colitis 2022; 16:1168-1176. [PMID: 35044449 DOI: 10.1093/ecco-jcc/jjac013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 12/28/2022]
Abstract
Therapeutic options for the management of inflammatory bowel disease [IBD] have been expanding in recent decades. New biological and small molecule therapies have been incorporated into the pharmacological arsenal, allowing a more personalized management, and seeking increasingly strict remission goals. However, the fear of developing adverse events represents one of the most important limitations in deciding its use by patients and by a multidisciplinary team. Despite the risk of hepatotoxicity of thiopurines and methotrexate, these drugs are still used either as monotherapy or as combined therapy with anti-tumour necrosis factor [anti-TNF] biological agents. Although drug-induced liver injury [DILI] appears to be less frequent with anti-TNF agents, newer biologics and small molecules, liver tests should be considered in the follow-up of these patients, especially regarding future combined therapy of biologics or of these drugs with small molecules. The objective of this review is to show data on the risk of developing DILI in patients with IBD who are undergoing treatment with traditional therapy or new drugs, whether biological or small molecules.
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Affiliation(s)
- Paulina Núñez F
- Inflammatory Bowel Disease Program, Santiago, Chile
- Gastroenterology, Digestive Disease Center, Universidad de los Andes, Santiago, Chile
- Gastroenterology, Universidad de Chile, Facultad Medicina Occidente-Hospital San Juan De Dios, Santiago, Chile
| | - Rodrigo Quera
- Inflammatory Bowel Disease Program, Santiago, Chile
- Gastroenterology, Digestive Disease Center, Universidad de los Andes, Santiago, Chile
| | - Constanza Bay
- Pediatrics Department, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Fabiola Castro
- Gastroenterology, Digestive Disease Center, Universidad de los Andes, Santiago, Chile
| | - Gabriel Mezzano
- Gastroenterology, Digestive Disease Center, Universidad de los Andes, Santiago, Chile
- Gastroenterology, Hospital del Salvador, Providencia, Chile
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Le Joncour A, Saadoun D. Systemic Diseases Affecting Liver Vessels. VASCULAR DISORDERS OF THE LIVER 2022:329-343. [DOI: 10.1007/978-3-030-82988-9_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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The prevalence of nodular regenerative hyperplasia of the liver in long-term thiopurine-treated inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 2021; 33:e102-e107. [PMID: 33136726 DOI: 10.1097/meg.0000000000001980] [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
INTRODUCTION Nodular regenerative hyperplasia (NRH) has been associated with thiopurine therapy in patients with inflammatory bowel disease (IBD), but prevalence and prognosis of NRH remain unclear. This study is a cross-sectional search for NRH in IBD patients with long-term azathioprine or 6-mercaptopurine treatment. MATERIAL AND METHODS Thirty-three IBD patients with continuous azathioprine/6-mercaptopurine treatment for at least 5 years were included. Laboratory tests, thiopurine metabolite levels, liver histology, MRI were examined for NRH and signs of portal hypertension. RESULTS NRH was not observed in this cohort of 33 patients. Nevertheless, some possibly related signs of vascular changes were found by MRI in three patients. Also, splenomegaly, which may be associated with portal hypertension, was found in one patient. No high thiopurine dose neither high metabolite levels were found in these patients. CONCLUSION No NRH was found in this group of IBD patients with long-term azathioprine/6-mercaptopurine treatment. Larger multicenter studies are needed to determine the prevalence of NRH in thiopurine-treated IBD patients.
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Losurdo G, Brescia IV, Lillo C, Mezzapesa M, Barone M, Principi M, Ierardi E, Di Leo A, Rendina M. Liver involvement in inflammatory bowel disease: What should the clinician know? World J Hepatol 2021; 13:1534-1551. [PMID: 34904028 PMCID: PMC8637677 DOI: 10.4254/wjh.v13.i11.1534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/06/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) may show a wide range of extraintestinal manifestations. In this context, liver involvement is a focal point for both an adequate management of the disease and its prognosis, due to possible serious comorbidity. The association between IBD and primary sclerosing cholangitis is the most known example. This association is relevant because it implies an increased risk of both colorectal cancer and cholangiocarcinoma. Additionally, drugs such as thiopurines or biologic agents can cause drug-induced liver damage; therefore, this event should be considered when planning IBD treatment. Additionally, particular consideration should be given to the evidence that IBD patients may have concomitant chronic viral hepatitis, such as hepatitis B and hepatitis C. Chronic immunosuppressive regimens may cause a hepatitis flare or reactivation of a healthy carrier state, therefore careful monitoring of these patients is necessary. Finally, the spread of obesity has involved even IBD patients, thus increasing the risk of non-alcoholic fatty liver disease, which has already proven to be more common in IBD patients than in the non-IBD population. This phenomenon is considered an emerging issue, as it will become the leading cause of liver cirrhosis.
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Affiliation(s)
- Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy.
| | - Irene Vita Brescia
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Chiara Lillo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Martino Mezzapesa
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Maria Rendina
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
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Nguyen ALH, Sparrow MP. Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules. Dig Dis Sci 2021; 66:3250-3262. [PMID: 33073334 DOI: 10.1007/s10620-020-06662-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/06/2020] [Indexed: 12/09/2022]
Abstract
In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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Affiliation(s)
- Anke L H Nguyen
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.,Monash University, Melbourne, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia. .,Monash University, Melbourne, Australia.
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Özcan HN, Karçaaltıncaba M, Seber T, Yalçın B, Oğuz B, Akyüz C, Haliloğlu M. Hepatocyte-specific contrast-enhanced MRI findings of focal nodular hyperplasia-like nodules in the liver following chemotherapy in pediatric cancer patients. ACTA ACUST UNITED AC 2021; 26:370-376. [PMID: 32490830 DOI: 10.5152/dir.2019.19398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE We aimed to assess the MRI findings and follow-up of multiple focal nodular hyperplasia (FNH)- like lesions in pediatric cancer patients diagnosed by imaging findings. METHODS We retrospectively analyzed clinical data and MRI examinations of 16 pediatric patients, who had been scanned using gadoxetate disodium (n=13) and gadobenate dimeglumine (n=3). Hepatic nodules were reviewed according to their number, size, contour, T1- and T2-weighted signal intensities, arterial, portal, delayed and hepatobiliary phase enhancement patterns. Follow-up images were evaluated for nodule size, number, and appearance. RESULTS All 16 patients received chemotherapy in due course. Time interval between the initial diagnosis of cancer and detection of the hepatic nodule was 2-14 years. Three patients had a single lesion, 13 patients had multiple nodules. The median size of the largest nodules was 19.5 mm (range, 8-41 mm). Among 16 patients that received hepatocyte-specific agents, FNH-like nodules appeared hyperintense in 11 and isointense in 5 on the hepatobiliary phase. During follow-up, increased number and size of the nodules were seen in 4 patients. The nodules showed growth between 6-15 mm. CONCLUSION Liver MRI using hepatocyte-specific agents is a significant imaging method for the diagnosis of FNH-like lesions, which can occur in a variety of diseases. Lesions can increase in size and number in pediatric patients.
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Affiliation(s)
- H Nursun Özcan
- Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey
| | | | - Turgut Seber
- Department of Radiology, Kayseri City Hospital, Kayseri, Turkey
| | - Bilgehan Yalçın
- Department of Pediatrics, Division of Pediatric Oncology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Berna Oğuz
- Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Canan Akyüz
- Department of Pediatrics, Division of Pediatric Oncology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Mithat Haliloğlu
- Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey
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Bury MI, Fuller NJ, Clemons TD, Sturm RM, Morrison CD, Lisy‐Snow DC, Nolan BG, Tarczynski C, Ayello EMT, Boyce A, Muckian B, Ahmad N, Hunter CJ, Karver MR, Stupp SI, Sharma AK. Self‐Assembling Nanofibers Inhibit Inflammation in a Murine Model of Crohn's‐Disease‐Like Ileitis. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202000274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Matthew I. Bury
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Natalie J. Fuller
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Tristan D. Clemons
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Department of Chemistry Northwestern University 2145 Sheridan Road Evanston IL 60208 USA
| | - Renea M. Sturm
- Department of Urology University of California Los Angeles 200 Medical Plaza Driveway #140 Los Angeles CA 90095 USA
| | - Christopher D. Morrison
- Department of Urology Northwestern University Feinberg School of Medicine 676 North St. Clair Suite 2300 Chicago IL 60611 USA
| | - Devon C. Lisy‐Snow
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Bonnie G. Nolan
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Christopher Tarczynski
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
| | - Emily M. T. Ayello
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
| | - Amber Boyce
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Bridget Muckian
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Nida Ahmad
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Catherine J. Hunter
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Lurie Children's Hospital of Chicago 255 East Superior Street Chicago IL 60611 USA
| | - Mark R. Karver
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
| | - Samuel I. Stupp
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Department of Chemistry Northwestern University 2145 Sheridan Road Evanston IL 60208 USA
- McCormick School of Engineering Department of Biomedical Engineering Northwestern University 2145 Sheridan Road Evanston IL 60208 USA
- Department of Materials Science and Engineering Northwestern University 2145 Sheridan Road Evanston IL 60208 USA
- Feinberg School of Medicine Department of Medicine Northwestern University 420 E Superior Street Chicago IL 60611 USA
| | - Arun K. Sharma
- Simpson Querrey Institute (SQI) Northwestern University 303 East Superior Street Chicago IL 60611 USA
- Department of Urology Northwestern University Feinberg School of Medicine 676 North St. Clair Suite 2300 Chicago IL 60611 USA
- McCormick School of Engineering Department of Biomedical Engineering Northwestern University 2145 Sheridan Road Evanston IL 60208 USA
- Stanley Manne Children's Research Institute (SMCRI) 303 East Superior Street Chicago IL 60611 USA
- Center for Advanced Regenerative Engineering (CARE) 2145 Sheridan Road Evanston IL 60208 USA
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Larrey D, Meunier L, Valla D, Hillaire S, Hernandez-Gea V, Dutheil D, Plessier A, Bureau C. Drug induced liver injury and vascular liver disease. Clin Res Hepatol Gastroenterol 2020; 44:471-479. [PMID: 32371005 DOI: 10.1016/j.clinre.2020.03.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/03/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Dominique Larrey
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.
| | - Lucy Meunier
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Dominique Valla
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Sophie Hillaire
- Department of Internal Medicine, Foch Hospital, 40, rue Worth, 92150 Suresnes, France
| | - Virginia Hernandez-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd). Health Care Provider of the European Reference Network onRare Liver Disorders (ERN-Liver), Spain
| | - Danielle Dutheil
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Association of patients with vascular liver diseases (AMVF), Department of Hepatology, Beaujon Hospital, 100, boulevard du Général Leclerc, 92118 Clichy, France
| | - Aurélie Plessier
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Christophe Bureau
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Gastroenterology and Hepatology, Rangueil Hospital, University Hospital of Toulouse, 1, avenue du Professeur Jean-Poulhès, 31400 Toulouse, France
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Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:1324-1335.e2. [PMID: 32059920 DOI: 10.1016/j.cgh.2020.02.009] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/17/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBDs) can be kept low by respecting contraindications. Patients with IBD frequently develop serious infections resulting from the disease itself or its treatment. At the time of diagnosis, patients' vaccination calendars should be updated according to IBD guidelines-live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein-Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on the carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with the lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended.
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Unusual intestinal and extra intestinal findings in Crohn's disease seen on abdominal computed tomography and magnetic resonance enterography. Clin Imaging 2020; 59:30-38. [PMID: 31715515 DOI: 10.1016/j.clinimag.2019.04.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/09/2019] [Accepted: 04/22/2019] [Indexed: 01/16/2023]
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Luber RP, Honap S, Cunningham G, Irving PM. Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases? Front Med (Lausanne) 2019; 6:279. [PMID: 31850357 PMCID: PMC6892750 DOI: 10.3389/fmed.2019.00279] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/14/2019] [Indexed: 12/21/2022] Open
Abstract
Thiopurines are a cheap, effective treatment option in the management of inflammatory bowel disease (IBD). However, with the growing choice of targeted therapies available, as well as the well-documented toxicities of thiopurines, the role of thiopurines has been questioned. Nevertheless, given their inexpense in an era of spiraling healthcare costs, thiopurines remain an attractive option in the right patients. In the age of personalized medicine, being able to predict patients who will respond as well as those that will develop toxicity to a treatment is vital to tailoring therapy. This review will summarize the available literature with respect to predictors of response and toxicity to thiopurines in order to guide management in IBD. Specifically, toxicities addressed will include myelotoxicity, hepatotoxicity, pancreatitis, alopecia, gastrointestinal and flu-like symptoms, and complications associated with Epstein-Barr virus. While more work needs to be done to further our ability to predict both response to and side effects from therapies, pharmacogenomic research shows significant promise in its ability to personalize our use of thiopurines.
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Affiliation(s)
- Raphael P Luber
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Sailish Honap
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Georgina Cunningham
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Peter M Irving
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
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16
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Sun Y, Lan X, Shao C, Wang T, Yang Z. Clinical features of idiopathic portal hypertension in China: A retrospective study of 338 patients and literature review. J Gastroenterol Hepatol 2019; 34:1417-1423. [PMID: 30462857 DOI: 10.1111/jgh.14552] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 11/03/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Idiopathic portal hypertension (IPH) refers to a relatively rare condition characterized by intrahepatic portal hypertension in the absence of underlying disease such as liver cirrhosis. METHODS We retrospectively reviewed 338 patients with IPH that were diagnosed at the pathological consultation center of our hospital. RESULTS The ratio of male to female patients was 1:1. Mean age at onset was 35.1 ± 16.5 years; male patients on average were 12 years younger than female patients at onset. The median duration from onset to IPH diagnosis was 12 months. In 50 patients, medication use may have been an etiological factor. The most common clinical manifestations were splenomegaly (91.3%) and hypersplenism (68.9%); 57.0% patients presented varicosis, while 25.1% patients had a history of variceal bleeding. Nodular regenerative hyperplasia was found in 22.2% liver biopsies. Among patients for whom laboratory data were available, 65.0%, 50.3%, and 71.4% patients presented leukopenia, anemia, and thrombocytopenia due to hypersplenism. Liver function was mostly in the compensated stage. Female patients showed worse leukopenia and anemia, while male patients were more likely to have abnormal serum transaminase and bilirubin levels. Sixty-seven patients received surgical or interventional treatment. CONCLUSIONS High-quality liver biopsy, detailed clinical information, and expert pathologist are necessary for diagnosis of IPH. IPH can occur concurrently with other liver disease such as hepatitis and drug-induced liver injury. Medication appears to be an important etiological factor for IPH in China. Management approach was largely focused on treatment of portal hypertension and its complications.
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Affiliation(s)
- Yongliang Sun
- Department of General Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Xu Lan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chen Shao
- Department of Pathology, Beijing You'an Hospital affiliated with Capital Medical University, Beijing, China
| | - Tailing Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Zhiying Yang
- Department of General Surgery, China-Japan Friendship Hospital, Beijing, China
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Abstract
Crohn's disease and ulcerative colitis affect an increasing number of patients, and utilization of immune suppressant and biologic therapies is also increasing. These agents are linked to adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. Areas covered: This review provides an updated discussion on adverse events associated with immunomodulator, anti-TNF-α, anti-integrin, and anti-IL 12/IL-23 antibody therapies. In addition, we review the risk profile of the currently widely available infliximab biosimilar medication. Expert commentary: Providers should engage in risk-benefit discussion with information specific to each medication discussed, and consider individualized risk factors when selecting therapeutic agents. Drug monitoring and shared decision-making results in more personalized medical management of inflammatory bowel disease.
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Affiliation(s)
- Sandra M Quezada
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland School of Medicine , Baltimore , MD , USA
| | - Leon P McLean
- b Department of Medicine , Geisel School of Medicine at Dartmouth , Hanover , NH , USA.,c Granite State Gastrointestinal Consultants , Derry , NH , USA
| | - Raymond K Cross
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland School of Medicine , Baltimore , MD , USA
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18
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Abstract
Various medications used to treat inflammatory bowel diseases have been implicated to cause hepatotoxicity. These include sulfasalazine, 5-aminosalicylic acids, fluoroquinolones, metronidazole, thiopurines, methotrexate, anti-tumor necrosis factor agents, and alpha-4 integrin inhibitors. Various types of liver injury have been reported in association with these medications including hypersensitivity reaction, hepatocellular or cholestatic disease, nodular regenerative hyperplasia, liver fibrosis/cirrhosis, portal hypertension and autoimmune liver injury. The revised Roussel Uclaf Causality Assessment Method (RUCAM) provides a scoring system to determine the likelihood of whether a drug caused liver injury. Unfortunately some of the reported liver injuries in association with these treatments have not undergone RUCAM assessment. Therefore, although some of the reports used in this review article show an association between a medication and the reported liver injury, they may not necessarily show causation. In this article, we address methods of monitoring to detect these injuries. We also discuss the prognosis and recommended management plans when liver injury occurs.
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19
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Bermejo F, Aguas M, Chaparro M, Domènech E, Echarri A, García-Planella E, Guerra I, Gisbert JP, López-Sanromán A. Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:205-221. [PMID: 29357999 DOI: 10.1016/j.gastrohep.2017.11.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 11/26/2017] [Indexed: 12/17/2022]
Abstract
Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.
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Affiliation(s)
- Fernando Bermejo
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España.
| | - Mariam Aguas
- Servicio de Digestivo, Hospital Universitari La Fe, Valencia, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Chaparro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
| | - Eugeni Domènech
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicio de Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, España
| | - Ana Echarri
- Servicio de Digestivo, Complejo Hospitalario Universitario de Ferrol, Ferrol, España
| | | | - Iván Guerra
- Servicio de Digestivo, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, España
| | - Javier P Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Servicios de Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, España
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20
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Tran-Minh ML, Sousa P, Maillet M, Allez M, Gornet JM. Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease. World J Hepatol 2017; 9:613-626. [PMID: 28539989 PMCID: PMC5424291 DOI: 10.4254/wjh.v9.i13.613] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/01/2017] [Accepted: 04/24/2017] [Indexed: 02/06/2023] Open
Abstract
The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.
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Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy. Inflamm Bowel Dis 2017; 23:448-452. [PMID: 28151736 DOI: 10.1097/mib.0000000000001036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination. METHODS An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist. RESULTS Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670). CONCLUSIONS The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.
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22
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Fraser AG. Editorial: can we get more clinical benefit from thiopurine metabolite testing? Aliment Pharmacol Ther 2017; 45:857-858. [PMID: 28211629 DOI: 10.1111/apt.13942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- A G Fraser
- Department of Medicine, University of Auckland, Auckland, New Zealand
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Suárez Ferrer C, Llop Herrera E, Calvo Moya M, Vera Mendoza MI, González Partida I, González Lama Y, Matallana Royo V, Calleja Panero JL, Abreu García L. Idiopathic portal hypertension regarding thiopurine treatment in patients with inflammatory bowel disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:79-83. [PMID: 26838489 DOI: 10.17235/reed.2015.3954/2015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
INTRODUCTION The possibility of developing idiopathic portal hypertension has been described with thiopurine treatment despite compromises the prognosis of these patients, the fact its true prevalence is unknown. MATERIAL AND METHODS A cross-sectional study was conducted in a cohort of inflammatory bowel disease (IBD) patients followed at our unit, to determine the prevalence of diagnosis of idiopathic portal hypertension (IPH) and its relationship with thiopurine treatment. RESULTS At the time of the analysis, 927/1,419 patients were under treatment with thiopurine drugs (65%). A total of 4 patients with IBD type Crohn's disease with idiopathic portal hypertension probably related to the thiopurine treatment were identified (incidence of 4.3 cases per 1,000). Seventy-five percent of patients started with signs or symptoms of portal hypertension. Only one patient was asymptomatic but the diagnosis of IPH because of isolated thrombocytopenia is suspected. However, note that all patients had thrombocytopenia previously. Abdominal ultrasound with fibroscan, hepatic vein catheterization and liver biopsy were performed on all of them as part of the etiology of portal hypertension. In the abdominal ultrasound, indirect portal hypertension data were observed in all patients (as splenomegaly) cirrhosis was also ruled out. The fibroscan data showed significant liver fibrosis (F2-F3). CONCLUSION Idiopathic portal hypertension following thiopurine treatment in IBD patients is a rare occurrence, but it must be borne in mind in the differential diagnosis for early diagnosis, especially in patients undergoing thiopurine treatment over a long period. The presence of thrombocytopenia is often the only predictor of its development in the preclinical stage.
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Affiliation(s)
| | - Elba Llop Herrera
- GASTROENTEROLOGIA , Hospital Universitario Puerta de Hierro Majadahonda. Madrid, ESPAÑA
| | - Marta Calvo Moya
- GASTROENTEROLOGIA , Hospital Universitario Puerta de Hierro Majadahonda. Madrid, españa
| | | | | | - Yago González Lama
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, España
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Mantzaris GJ. Thiopurines and Methotrexate Use in IBD Patients in a Biologic Era. ACTA ACUST UNITED AC 2017; 15:84-104. [DOI: 10.1007/s11938-017-0128-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Abstract
OBJECTIVE The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. BACKGROUND Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. METHODS Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. RESULTS Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. CONCLUSIONS Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.
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Heimgartner B, Dawson H, De Gottardi A, Wiest R, Niess JH. Successful Treatment of Small Intestinal Bleeding in a Crohn's Patient with Noncirrhotic Portal Hypertension by Transjugular Portosystemic Shunt Placement and Infliximab Treatment. Case Rep Gastroenterol 2016; 10:589-595. [PMID: 27920646 PMCID: PMC5121555 DOI: 10.1159/000450541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 08/31/2016] [Indexed: 01/21/2023] Open
Abstract
Small intestinal bleeding in Crohn's disease patients with noncirrhotic portal hypertension and partial portal and superior mesenteric vein thrombosis is a life-threatening event. Here, a case is reported in which treatment with azathioprine may have resulted in nodular regenerative hyperplasia, portal hypertension and portal vein thrombosis. The 56-year-old patient with Crohn's disease developed nodular regenerative hyperplasia under treatment with azathioprine. He was admitted with severe bleeding. Gastroscopy showed small esophageal varices without bleeding stigmata. Blood was detected in the terminal ileum. CT scan revealed a partial portal vein thrombosis with extension to the superior mesenteric vein, thickening of the jejunal wall and splenomegaly. Because intestinal bleeding could not be controlled by conservative treatment, the thrombus was aspirated and a transjugular intrahepatic portosystemic shunt (TIPS) was placed. Switching the immunosuppressive medication to infliximab controlled Crohn's disease activity. Bleeding was stopped, hemoglobin normalized, and thrombocytopenia and bowel movements improved. In summary, small intestinal bleeding in a Crohn's patient with nodular regenerative hyperplasia, portal hypertension and portal vein thrombosis can be efficiently treated by TIPS. TIPS placement together with infliximab treatment led to the improvement of the blood panel and remission in this patient.
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Affiliation(s)
- Benjamin Heimgartner
- Division of Gastroenterology, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland
| | - Heather Dawson
- Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Andrea De Gottardi
- Division of Hepatology, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland
| | - Reiner Wiest
- Division of Gastroenterology, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland
| | - Jan Hendrik Niess
- Division of Gastroenterology, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland; Departments of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
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Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2733-2747. [PMID: 27760078 DOI: 10.1097/mib.0000000000000923] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.
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28
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Meijer B, Mulder CJJ, Peters GJ, van Bodegraven AA, de Boer NKH. Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review. World J Gastroenterol 2016; 22:9012-9021. [PMID: 27833392 PMCID: PMC5083806 DOI: 10.3748/wjg.v22.i40.9012] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/20/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease (IBD) patients, irrespective of the (hepato-) toxicity profile.
METHODS A systematic literature search of the MEDLINE database using PubMed was performed using the keywords “thioguanine”, “6-TG”, “thioguanine”, “inflammatory bowel disease”, “IBD”, “Crohn’s disease”, “Ulcerative colitis” and “effectiveness” in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were cross-checked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed.
RESULTS A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospective manner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients (225 patients with Crohn’s disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance (n = 321) or de novo thioguanine administration (n = 32) were included for analysis, of which 228 (65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years (median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg (range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients (20%).
CONCLUSION The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.
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The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease. Inflamm Bowel Dis 2016; 22:2112-20. [PMID: 27482972 DOI: 10.1097/mib.0000000000000869] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. METHODS A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. RESULTS One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. CONCLUSIONS The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.
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Chen JH, Andrews JM, Kariyawasam V, Moran N, Gounder P, Collins G, Walsh AJ, Connor S, Lee TWT, Koh CE, Chang J, Paramsothy S, Tattersall S, Lemberg DA, Radford-Smith G, Lawrance IC, McLachlan A, Moore GT, Corte C, Katelaris P, Leong RW. Review article: acute severe ulcerative colitis - evidence-based consensus statements. Aliment Pharmacol Ther 2016; 44:127-144. [PMID: 27226344 DOI: 10.1111/apt.13670] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 12/18/2015] [Accepted: 04/27/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of ulcerative colitis. AIM To develop consensus statements based on a systematic review of the literature of the management of ASUC to improve patient outcome. METHODS Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre-determined by ≥80% votes in 'complete agreement' or 'agreement with minor reservation'. RESULTS Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres. CONCLUSION These evidenced-based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up-to-date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.
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Affiliation(s)
- J-H Chen
- Concord Hospital, Sydney, NSW, Australia
| | - J M Andrews
- Royal Adelaide Hospital, Adelaide, SA, Australia
| | | | - N Moran
- Concord Hospital, Sydney, NSW, Australia
| | - P Gounder
- Concord Hospital, Sydney, NSW, Australia
| | - G Collins
- Concord Hospital, Sydney, NSW, Australia
| | - A J Walsh
- St. Vincent Hospital, Sydney, NSW, Australia
| | - S Connor
- Liverpool Hospital, Sydney, NSW, Australia
| | - T W T Lee
- Wollongong Hospital, Wollongong, NSW, Australia
| | - C E Koh
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - J Chang
- Concord Hospital, Sydney, NSW, Australia
| | | | - S Tattersall
- Royal North Shore Hospital, Sydney, NSW, Australia
| | - D A Lemberg
- Sydney Children's Hospital, Sydney, NSW, Australia
| | - G Radford-Smith
- Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - I C Lawrance
- Saint John of God Hospital, Perth, WA, Australia
| | | | - G T Moore
- Monash Medical Centre, Melbourne, Vic., Australia
| | - C Corte
- Concord Hospital, Sydney, NSW, Australia
| | | | - R W Leong
- Concord Hospital, Sydney, NSW, Australia
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31
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Marzano C, Cazals-Hatem D, Rautou PE, Valla DC. The significance of nonobstructive sinusoidal dilatation of the liver: Impaired portal perfusion or inflammatory reaction syndrome. Hepatology 2015; 62:956-63. [PMID: 25684451 DOI: 10.1002/hep.27747] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 02/08/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Sinusoidal dilatation found in the absence of an impaired sinusoidal blood outflow has been so far of unclear significance. Sinusoidal dilatation may actually be a nonspecific feature of impaired portal venous blood inflow, whatever the cause, or a feature of severe systemic inflammatory reaction syndrome, whatever the cause. Sinusoidal dilatation is mainly located in the centrilobular area even in the absence of an outflow block. A predominantly periportal location is specifically found in oral contraceptive users, associated with an inflammatory condition. There is strong evidence for the association of sinusoidal dilatation and oxaliplatin-based chemotherapy but not for estroprogestative steroids or thiopurine derivatives. Exposure to anabolic androgen steroids appears to cause sinusoidal changes different from a mere sinusoidal dilatation. CONCLUSION There is evidence of activation of the interleukin-6 and vascular endothelial growth factor pathways in sinusoidal dilatation, but the mechanisms linking the activation of these pathways with the microvascular changes must be identified.
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Affiliation(s)
- Chiara Marzano
- Dipartimento di Medicina Clinica, UOC di Gastroenterologia, Umberto I Policlinico di Roma, Sapienza Università di Roma, Rome, Italy
| | - Dominique Cazals-Hatem
- DHU UNITY, Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Hôpital Beaujon, HUPNVS, APHP, Clichy-la-Garenne, France
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- CRI Paris-Montmartre, UMR 1149, Université Paris Diderot, PRES SPC, Hôpital Bichat, Paris, France
| | - Pierre-Emmanuel Rautou
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- Inserm, U970, Paris Cardiovascular Research Center-PARCC, Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France
| | - Dominique-Charles Valla
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- CRI Paris-Montmartre, UMR 1149, Université Paris Diderot, PRES SPC, Hôpital Bichat, Paris, France
- Inserm U1149, Hôpital Bichat, Paris, France
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Goldberg R, Irving PM. Toxicity and response to thiopurines in patients with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9:891-900. [PMID: 25915575 DOI: 10.1586/17474124.2015.1039987] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.
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Affiliation(s)
- Rimma Goldberg
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
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Jharap B, van Asseldonk DP, de Boer NKH, Bedossa P, Diebold J, Jonker AM, Leteurtre E, Verheij J, Wendum D, Wrba F, Zondervan PE, Colombel JF, Reinisch W, Mulder CJJ, Bloemena E, van Bodegraven AA. Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement. PLoS One 2015; 10:e0120299. [PMID: 26054009 PMCID: PMC4459699 DOI: 10.1371/journal.pone.0120299] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Accepted: 01/28/2015] [Indexed: 12/17/2022] Open
Abstract
Background and Aims Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH. Methods Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index. Results After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45). Conclusions The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.
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Affiliation(s)
- Bindia Jharap
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands
- * E-mail:
| | - Dirk P. van Asseldonk
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands
| | - Nanne K. H. de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands
| | - Pierre Bedossa
- Department of Pathology, Beaujon Hospital, Paris, France
| | - Joachim Diebold
- Department of Pathology, Cantonal Hospital, Lucerne, Switzerland
| | - A. Mieke Jonker
- Department of Pathology, Refaja Hospital, Stadskanaal, the Netherlands
| | | | - Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
| | | | - Fritz Wrba
- Department of Pathology, University Medical Center Vienna, Vienna, Austria
| | | | - Jean-Frédéric Colombel
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Walter Reinisch
- Department of Gastroenterology and Hepatology, University Medical Center Vienna, Vienna, Austria
| | - Chris J. J. Mulder
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands
| | - Elisabeth Bloemena
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Adriaan A. van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands
- Department of Internal Medicine, Gastroenterology and Geriatrics, ORBIS Medical Center, Sittard-Geleen, the Netherlands
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Konidari A, Anagnostopoulos A, Bonnett LJ, Pirmohamed M, El-Matary W. Thiopurine monitoring in children with inflammatory bowel disease: a systematic review. Br J Clin Pharmacol 2015; 78:467-76. [PMID: 24592889 DOI: 10.1111/bcp.12365] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 02/14/2014] [Indexed: 12/13/2022] Open
Abstract
AIMS The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). METHODS Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC. RESULTS Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6-thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6-methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non-compliance. CONCLUSION Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow-up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non-compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.
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Affiliation(s)
- Anastasia Konidari
- Department of Clinical and Molecular Pharmacology, Wolfson Centre for Personalised Medicine, Institute for Translational Medicine, University of Liverpool, Liverpool, UK
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Affiliation(s)
- Edouard Louis
- Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium
| | - Peter Irving
- Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, London, UK
| | - Laurent Beaugerie
- Department of Gastroenterology, Hôpital St-Antoine and UPMC Univ Paris 06, Paris, France
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Goel A, Elias JE, Eapen CE, Ramakrishna B, Elias E. Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)-Newer Insights into Pathogenesis and Emerging Newer Treatment Options. J Clin Exp Hepatol 2014; 4:247-56. [PMID: 25755567 PMCID: PMC4284211 DOI: 10.1016/j.jceh.2014.07.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 07/05/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic microangiopathy of portal venules results in idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH). Recent data suggest a role for vasoactive factors of portal venous origin in the pathogenesis of this 'pure' vasculopathy of the liver. Enteropathies (often silent), are an important 'driver' of this disease. NCIPH is under-recognized and often mis-labeled as cryptogenic cirrhosis. Liver biopsy is needed to prove the diagnosis of NCIPH. In these patients, with advancing disease and increased porto-systemic shunting, the portal venous vasoactive factors bypass the liver filter and contribute to the development of pulmonary vascular endothelial disorders-porto-pulmonary hypertension and hepato-pulmonary syndrome as well as mesangiocapillary glomerulonephritis. Prognosis in NCIPH patients is determined by presence, recognition and management of associated disorders. With better understanding of the pathogenesis of NCIPH, newer treatment options are being explored. Imbalance in ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13): vWF (von-Willebrand factor) ratio is documented in NCIPH patients and may have a pathogenic role. Therapeutic interventions to correct this imbalance may prove to be important in the management of NCIPH.
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Key Words
- ADAMTS 13
- CVID, common variable immunodeficiency
- HPS, hepato-pulmonary syndrome
- HVPG, hepatic venous pressure gradient
- IBD, inflammatory bowel disease
- NCIPH, non-cirrhotic intrahepatic portal hypertension
- NRH, nodular regenerative hyperplasia
- OPV, obliterative portal venopathy
- PPH, porto-pulmonary hypertension
- PVT, portal vein thrombosis
- SOS, sinusoidal obstruction syndrome
- endothelial dysfunction
- primary haemostasis
- tTG, Tissue transglutaminase
- von-Willebrand factor (vWF)
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Affiliation(s)
- Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | | | | | | | - Elwyn Elias
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India,Liver Unit, University Hospital Birmingham, Birmingham, UK,Address for correspondence: Elwyn Elias, Emeritus Professor, Liver Unit, University Hospital Birmingham, Birmingham, UK.
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Konidari A, Matary WE. Use of thiopurines in inflammatory bowel disease: Safety issues. World J Gastrointest Pharmacol Ther 2014; 5:63-76. [PMID: 24868487 PMCID: PMC4023326 DOI: 10.4292/wjgpt.v5.i2.63] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 02/19/2014] [Indexed: 02/06/2023] Open
Abstract
Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Inter-individual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.
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Abstract
Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.
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Affiliation(s)
- Leon P McLean
- Department of Medicine, Division of Gastroenterology and Hepatology University of Maryland, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA
| | - Raymond K Cross
- Department of Medicine, Division of Gastroenterology and Hepatology University of Maryland, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA
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Min MX, Weinberg DI, McCabe RP. Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use. J Clin Pharm Ther 2014; 39:107-11. [DOI: 10.1111/jcpt.12125] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 12/05/2013] [Indexed: 12/14/2022]
Affiliation(s)
- M. X. Min
- Abbott Northwestern Hospital; Minneapolis MN USA
| | | | - R. P. McCabe
- Minnesota Gastroenterology PA; Minneapolis MN USA
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40
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Musumba CO. Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol Ther 2013; 38:1025-37. [PMID: 24099468 DOI: 10.1111/apt.12490] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 06/18/2013] [Accepted: 08/27/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear. AIMS To summarise the data on the association between NRH and thiopurine therapy in patients with IBD. METHODS A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included. RESULTS Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naïve IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH. CONCLUSIONS The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.
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Affiliation(s)
- C O Musumba
- Department of Gastroenterology and Hepatology, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
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41
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Abstract
Diseases of the liver and the biliary tract are commonly observed in patients with inflammatory bowel diseases (IBD). Besides primary sclerosing cholangitis (PSC), drug-induced hepatotoxicity and non-alcoholic fatty liver disease (NAFLD) are the most frequent liver complications in IBD. PSC is a chronic inflammatory and commonly progressive disorder of unknown etiology associated with fibrosis and stricture development in the intrahepatic and extrahepatic biliary tree. Interestingly, this form of liver disease is mainly associated with ulcerative colitis. Development of PSC is highly relevant for IBD patients as cholestasis-associated problems increase over time resulting in biliary strictures, cholangitis, cholangiocarcinoma and importantly these patients also have a higher risk to develop colon cancer. Another major aspect regarding IBD and liver disease refers to drug-induced hepatotoxicity. Clinically, most relevant is liver toxicity caused by immunosuppressants such as azathioprine. Azathioprine and its derivate 6-mercaptopurine can cause a spectrum of liver injuries ranging from asymptomatic elevated liver enzymes to cholestasis and nodular regenerative hyperplasia. The third common IBD-associated liver disease is NAFLD, and first studies suggest that NAFLD might appear in IBD patients independent of classical risk factors such as obesity or insulin resistance. Overall, liver complications are observed in 10-20% of IBD patients, and therefore physicians have to be familiar with these complications to improve and to optimize patient care.
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Affiliation(s)
- V Wieser
- Department of Internal Medicine I, Gastroenterology, Endocrinology and Metabolism, Innsbruck Medical University, Innsbruck, Austria
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Kinnucan JA, Hanauer SB. Reassessing the risks and benefits of thiopurines in Crohn's disease. Clin Gastroenterol Hepatol 2013; 11:395-7. [PMID: 23333707 DOI: 10.1016/j.cgh.2012.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 12/12/2012] [Accepted: 12/13/2012] [Indexed: 02/07/2023]
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Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2012; 35:15-36. [PMID: 22050052 DOI: 10.1111/j.1365-2036.2011.04905.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter-individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. AIM To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic-based therapeutic recommendations. METHODS We conducted a query on PubMed database using 'inflammatory bowel disease', 'thiopurine', 'azathioprine', '6-mercaptopurine', 'TPMT', 'pharmacogenetics', 'TDM', and selected relevant articles, especially clinical studies. RESULTS Thiopurine metabolism - key enzyme: thiopurine S-methyltransferase (TPMT) - modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6-TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S-transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. CONCLUSIONS Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.
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Affiliation(s)
- L Chouchana
- Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Biochimie, Pharmacogénétique et Oncologie Moléculaire, Paris, France
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