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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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Jena A, Neelam PB, Telaprolu H, Mangipudi UK, Dutta U, Sebastian S, Sharma V. Effectiveness and safety of thioguanine as a maintenance therapy of inflammatory bowel disease: Systematic review, meta-analysis and meta-regression. Clin Res Hepatol Gastroenterol 2023; 47:102155. [PMID: 37301255 DOI: 10.1016/j.clinre.2023.102155] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/28/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Thiopurines are an important therapy for the maintenance of remission in inflammatory bowel disease (IBD). However, the use of thioguanine has been limited by concerns regarding its toxicity. We performed a systematic review to evaluate its effectiveness and safety in IBD. METHODS Electronic databases were searched to identify studies reporting clinical responses and/or adverse events of thioguanine therapy in IBD. We calculated the pooled clinical response and clinical remission rates of thioguanine in IBD. Subgroup analyses were done for the dosage of thioguanine and the type of studies (prospective or retrospective). Meta-Regression was used to analyze the impact of dose on clinical efficacy and occurrence of nodular regenerative hyperplasia. RESULTS A total of 32 studies were included. The pooled clinical response rate of thioguanine therapy in IBD was 0.66 (95% C.I. 0.62 - 0.70; I2 = 16%). The pooled clinical response rate with low-dose was similar to high-dose thioguanine therapy [0.65 (95% C.I. 0.59 - 0.70; I2 = 24%) and 0.68 (95% C.I. 0.61 - 0.75; I2 = 18%) respectively]. The pooled remission maintenance rate was 0.71 (95% C.I. 0.58 - 0.81; I2 = 86%). The pooled rates of occurrence of nodular regenerative hyperplasia, liver function tests abnormalities and cytopenia were 0.04 (95% C.I. 0.02 - 0.08; I2 = 75%), 0.11 (95% C.I. 0.08 - 0.16; I2 = 72%) and 0.06 (95% C.I. 0.04 - 0.09; I2 = 62%) respectively. Meta-regression suggested that the risk of nodular regenerative hyperplasia is related to the dose of thioguanine. CONCLUSION TG is an efficacious and well-tolerated drug in most patients with IBD. Nodular regenerative hyperplasia, cytopenias, and liver function abnormalities occur in a small subset. Future studies should look into TG as primary therapy in IBD.
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Affiliation(s)
- Anuraag Jena
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pardhu B Neelam
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Harshavardhan Telaprolu
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Uday Kiran Mangipudi
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Usha Dutta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shaji Sebastian
- IBD Unit, Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Little R, Kamath BM, Ricciuto A. Liver Disease in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:129-149. [DOI: 10.1007/978-3-031-14744-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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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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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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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Biemans VBC, Savelkoul E, Gabriëls RY, Simsek M, Dijkstra G, Pierik MJ, West RL, de Boer NK, Hoentjen F. A comparative analysis of tioguanine versus low-dose thiopurines combined with allopurinol in inflammatory bowel disease patients. Aliment Pharmacol Ther 2020; 51:1076-1086. [PMID: 32339331 PMCID: PMC7318327 DOI: 10.1111/apt.15730] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/02/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Both tioguanine and low-dose thiopurines combined with allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to adverse events. AIM To compare the safety of tioguanine and LDTA in IBD patients. METHODS Inflammatory bowel disease patients who failed conventional thiopurines due to adverse events and initiated LDTA in standard care were identified in the prospective ICC Registry. IBD patients who failed conventional thiopurines due to adverse events and initiated tioguanine were enrolled in three university hospitals. Patients on concomitant biologicals were excluded. The primary outcome was discontinuation of therapy due to adverse events. Secondary outcomes included: safety outcomes and surgery-, biological- and corticosteroid-free clinical remission (physician global assessment = 0) after 104 weeks. Both multiple logistic regression and propensity score matching were used to correct for confounders. RESULTS In total, 182 IBD patients treated with tioguanine (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91-104). Of these, 19% (tioguanine: 20%, LDTA: 18%) of patients discontinued therapy due to adverse events. After adjusting for confounders, there were no differences in terms of discontinuation rate due to adverse events (OR 0.50, 95% CI 0.15-1.68, P = 0.26), adverse events (OR 0.89, 95% CI 0.44-1.81, P = 0.75), infections (OR 1.05, 95% CI 0.40-2.73, P = 0.93), hospitalisations (OR 2.00, 95% CI 0.64-6.23, P = 0.23) or clinical remission (OR 0.74, 95%CI 0.33-1.68, P = 0.48). All results are comparable with the propensity score matched cohort. CONCLUSION Nineteen percent of IBD patients with prior failure to conventional thiopurines due to adverse events discontinued therapy with tioguanine or LDTA due to adverse events. Either therapy may be considered before escalating to biological therapy.
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Affiliation(s)
- Vince B. C. Biemans
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands,Department of Gastroenterology and HepatologyMaastricht University Medical CentreMaastrichtThe Netherlands
| | - Edo Savelkoul
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands
| | | | - Melek Simsek
- Amsterdam University Medical CentreVrije UniversiteitAmsterdamThe Netherlands,Amsterdam Gastroenterology & Metabolism research instituteAmsterdamThe Netherlands
| | - Gerard Dijkstra
- University Medical Centre GroningenGroningenThe Netherlands,University of GroningenGroningenthe Netherlands
| | - Marieke J. Pierik
- Department of Gastroenterology and HepatologyMaastricht University Medical CentreMaastrichtThe Netherlands
| | | | - Nanne K.H. de Boer
- Amsterdam University Medical CentreVrije UniversiteitAmsterdamThe Netherlands,Amsterdam Gastroenterology & Metabolism research instituteAmsterdamThe Netherlands
| | - Frank Hoentjen
- Department of Gastroenterology and HepatologyRadboud University Medical CentreNijmegenThe Netherlands
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Bayoumy AB, Simsek M, Seinen ML, Mulder CJJ, Ansari A, Peters GJ, De Boer NK. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol 2020; 16:111-123. [PMID: 32090622 DOI: 10.1080/17425255.2020.1719996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022]
Abstract
Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.
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Affiliation(s)
- Ahmed B Bayoumy
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Melek Simsek
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
| | - Margien L Seinen
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Chris J J Mulder
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Azhar Ansari
- Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK
| | - Godefridus J Peters
- Amsterdam UMC, VU University Medical Center, Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Nanne K De Boer
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
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Cannella R, Minervini MI, Rachakonda V, Bollino G, Furlan A. Liver stiffness measurement in patients with nodular regenerative hyperplasia undergoing magnetic resonance elastography. Abdom Radiol (NY) 2020; 45:373-383. [PMID: 31834457 DOI: 10.1007/s00261-019-02367-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Nodular regenerative hyperplasia (NRH) may mimic cirrhosis at imaging. We aim to investigate the effect of NRH on liver stiffness measurement (LSM) obtained with magnetic resonance elastography (MRE). METHODS This retrospective, Institutional Review Board-approved study included 37 subjects with NRH (Group 1) and no or minimal fibrosis (F0-F1), a control group (Group 2) made of 30 subjects with non-advanced fibrosis (F0-F2), and a control group (Group 3) made of 30 subjects with advanced fibrosis (F3-F4), all with available MRE. LSM was measured in each subject along with assessment of hepatic morphological features of cirrhosis and signs of portal hypertension. The significance of the difference in mean LSM between Group 1 and 2 and between Group 1 and 3 was evaluated using the Mann-Whitney U test. The difference in distribution of imaging features among groups was assessed using the Pearson χ2 or Fisher exact test. RESULTS The mean ± SD LSM in Group 1 (3.56 ± 1.10 kPa) was significantly higher compared to Group 2 (2.91 ± 0.52 kPa, P = 0.019) and significantly lower compared to Group 3 (7.18 ± 2.08 kPa, P < 0.001). Twelve (32%) patients with NRH had LSM ≥ 4.11 kPa, and 6 (16%) patients had LSM ≥ 4.71 kPa. Surface nodularity (P = 0.032) and caudate lobe hypertrophy (P = 0.004) were more commonly visualized in Group 1 than in Group 2. At least one feature of portal hypertension was observed in 16 (43%) NRH subjects. CONCLUSION NRH may increase the LSM obtained with MRE and may represent a confounding factor when using liver stiffness for the non-invasive diagnosis of fibrosis.
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Affiliation(s)
- Roberto Cannella
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
- Section of Radiology - BiND, University Hospital "Paolo Giaccone", Via del Vespro 129, 90127, Palermo, Italy
| | - Marta I Minervini
- Division of Transplantation Pathology UPMC Montefiore, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Vikrant Rachakonda
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gideon Bollino
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Alessandro Furlan
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
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Can we differentiate HIV-associated obliterative portopathy from liver cirrhosis using MRI? Eur Radiol 2019; 30:213-223. [PMID: 31410601 DOI: 10.1007/s00330-019-06391-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/18/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
AIM To describe the magnetic resonance imaging (MRI) features of HIV-associated obliterative portopathy (HIV-OP) and determine the most indicative appearance of this condition on MRI by using a retrospective case-control study. METHODS MRI examinations of 24 patients with HIV-OP (16 men, 8 women; mean age = 48 ± 6.6 [SD] years; age range, 35-71 years) were analyzed by two blinded observers and compared with those obtained in 18 HIV-infected patients with hepatic cirrhosis (14 men, 4 women; mean age = 51 ± 3.4 [SD] years; age range, 35-60 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. Comparisons were performed using uni- and multivariate analyses. RESULTS Regular liver contours had the highest accuracy for the diagnosis of HIV-OP (83%, 35 of 42; 95% confidence interval [CI], 69-93%) and was the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio, 51; 95%CI, 4.96-1272%) (p < 0.0001). At multivariate analysis, the width of segment 4 in millimeters (OR = 1.23 [95%CI, 1.05-1.44%]; p = 0.011) and the presence of regular liver contours (OR = 7.69 [95%CI, 1.48-39.92%]; p = 0.015) were the variables independently associated with the diagnosis of HIV-OP. CONCLUSIONS Regular liver contours are the most discriminating independent variable for the diagnosis of HIV-OP but have limited accuracy. Familiarity with this finding may help differentiate HIV-OP from cirrhosis in HIV-infected patients. KEY POINTS • Regular liver contour is the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio = 51) with 83% accuracy. • At multivariate analysis, the width of segment 4 in millimeters and the presence of regular liver contours are the variables independently associated with the diagnosis of HIV-OP. • MRI helps diagnose HIV-OP in the presence of several categorical findings, which are more frequently observed in HIV-OP patients than in HIV patients with cirrhosis.
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Toksvang LN, Schmidt MS, Arup S, Larsen RH, Frandsen TL, Schmiegelow K, Rank CU. Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: A systematic review. PLoS One 2019; 14:e0212157. [PMID: 31125338 PMCID: PMC6534292 DOI: 10.1371/journal.pone.0212157] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
Background The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity. Objectives To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established. Data sources Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018. Methods We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included. Results and conclusions We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.
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Affiliation(s)
- Linea Natalie Toksvang
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Magnus Strøh Schmidt
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sofie Arup
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Rikke Hebo Larsen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Leth Frandsen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kjeld Schmiegelow
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Institute of Clinical Medicine, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
| | - Cecilie Utke Rank
- Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Paediatric Oncology Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Jackson B, De Cruz P. Algorithms to facilitate shared decision-making for the management of mild-to-moderate ulcerative colitis. Expert Rev Gastroenterol Hepatol 2018; 12:1079-1100. [PMID: 30284911 DOI: 10.1080/17474124.2018.1530109] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Nonadherence has been a key barrier to the efficacy of medical treatments in ulcerative colitis (UC). Engaging patients in their IBD care via shared decision-making (SDM) to facilitate self-management may improve adherence to therapy. Areas covered: This review aims to summarize the most recent trial evidence from 2012 to 2017 for mild-to-moderate UC in order to develop clinical algorithms that guide SDM to facilitate self-management. A structured literature search via multiple electronic databases was performed using the search terms 'ulcerative colitis,' 'treatment,' 'management,' 'medication,' 'maintenance,' 'remission,' '5-ASA,' and 'inflammatory bowel disease. Expert commentary: Novel formulations of existing oral and topical medications have expanded the treatment options available for the induction and maintenance therapy for mild-to-moderate UC. Daily dosing of 5-ASA therapy is equivalent to twice daily dosing. The combination therapies of oral plus topical 5-ASA therapy and 5-ASA plus corticosteroid therapy are more effective than monotherapy. Budesonide MMX now plays a role in the management of mild-to-moderate UC. This review collates the evidence on drug efficacy and safety, adherence and tolerability, and noninvasive monitoring of mild-to-moderate UC into SDM-orientated algorithms to facilitate self-management.
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Affiliation(s)
- Belinda Jackson
- a Department of Gastroenterology , The Austin Hospital , Melbourne , Australia.,b Department of Medicine, Austin Academic Centre , University of Melbourne , Melbourne , Australia
| | - Peter De Cruz
- a Department of Gastroenterology , The Austin Hospital , Melbourne , Australia.,b Department of Medicine, Austin Academic Centre , University of Melbourne , Melbourne , Australia
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Neupane R, Gaudana R, Boddu SHS. Imaging Techniques in the Diagnosis and Management of Ocular Tumors: Prospects and Challenges. AAPS JOURNAL 2018; 20:97. [PMID: 30187172 DOI: 10.1208/s12248-018-0259-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 08/23/2018] [Indexed: 12/23/2022]
Abstract
Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. This review focuses on five most commonly used imaging modalities, i.e., positron emission tomography-computed tomography (PET/CT), single photon emission computed tomography (SPECT), optical coherence tomography (OCT), ultrasound (US), and magnetic resonance imaging (MRI). The principal of imaging modalities is briefly explained, along with their role in the diagnosis and management of the most common ocular tumors such as retinoblastoma and uveal melanoma. Further, the diagnostic features of ocular tumors corresponding to each imaging modality and possibilities of utilizing imaging techniques in the process of ocular drug development are included in this review.
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Affiliation(s)
- Rabin Neupane
- College of Pharmacy and Pharmaceutical Sciences, The University of Toledo Health Science Campus, Toledo, OH, 43614, USA
| | - Ripal Gaudana
- Principal Scientist, Par Pharmaceuticals, 1 Ram Ridge Rd, Spring Valley, New York, 10977, USA
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P.O. Box 346, Ajman, United Arab Emirates.
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Movva R, Haywood A, Khan SA, Florin TH, Oancea I. Critical assessment of thioguanine treatment for inflammatory bowel diseases: Is it time to rehabilitate this treatment? J Dig Dis 2017; 18:529-536. [PMID: 28834232 DOI: 10.1111/1751-2980.12536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 08/10/2017] [Accepted: 08/17/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The potential therapeutic effect of thioguanine in the management of inflammatory bowel disease (IBD) is hindered due to association with vascular hepatotoxicity. The study aimed to assess the evidence for efficacy of thioguanine in IBD management and the association with nodular regenerative hyperplasia (NRH) and other thioguanine-related hepatotoxicities. METHODS Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for literature search. Due to the lack of randomized controlled trials (RCTs), the search was extended to observational studies. Quality of the included studies were graded A to C based on evaluation tools used to determine efficacy (subjective and objective grading tools) and nodular regenerative hyperplasia safety (liver biopsy and imaging tools). RESULTS Two hundred and ninety studies were identified, but following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines only 13 studies were evaluated for efficacy and safety of thioguanine. Outcome measures were consistent across the included studies. Thioguanine appeared efficacious and well-tolerated in patients who were intolerant/non-responsive to existing immunomodulators. There was a trend toward a positive association between dose of thioguanine and NRH but not with other adverse events such as liver biochemical abnormalities or with portal hypertension. CONCLUSIONS The evidence to support thioguanine treatment is limited to observational studies. While encouraging, there is a need for prospective RCTs to determine the role of thioguanine in the management of IBD.
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Affiliation(s)
- Ramya Movva
- School of Pharmacy, Menzies Health Institute, Griffith University, Gold Coast, Queensland, Australia.,Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.,Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Alison Haywood
- School of Pharmacy, Menzies Health Institute, Griffith University, Gold Coast, Queensland, Australia.,Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia
| | - Sohil A Khan
- School of Pharmacy, Menzies Health Institute, Griffith University, Gold Coast, Queensland, Australia.,Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia
| | - Timothy Hj Florin
- Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.,Translational Research Institute, Woolloongabba, Queensland, Australia.,School of Medicine-University of Queensland, St Lucia, Queensland, Australia
| | - Iulia Oancea
- Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.,Translational Research Institute, Woolloongabba, Queensland, Australia.,School of Medicine-University of Queensland, St Lucia, Queensland, Australia
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15
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Ward MG, Patel KV, Kariyawasam VC, Goel R, Warner B, Elliott TR, Blaker PA, Irving PM, Marinaki AM, Sanderson JD. Thioguanine in inflammatory bowel disease: Long-term efficacy and safety. United European Gastroenterol J 2017; 5:563-570. [PMID: 28588888 PMCID: PMC5446138 DOI: 10.1177/2050640616663438] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 07/17/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators. METHODS This is a retrospective, single-centre study of IBD patients treated with TG from 2001-2013. Response was defined as clinical remission (Harvey-Bradshaw Index < 5 for Crohn's disease (CD), Simple Clinical Colitis Activity Index < 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI). RESULTS 54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20-40 mg/d)) as monotherapy (n = 36) or concomitantly with anti-TNF (n = 18) for a median inter-quartile range of 16 (5-37) months (126 patient-years of follow-up). 32 (59%) patients responded to TG at 6 months and 23 (43%) at 12 months. Pancreatitis did not recur amongst the 19 patients with prior thiopurine-induced pancreatitis. 16 (30%) patients ceased TG due to intolerance or toxicity (four serious); NRH was not observed. 6-thioguanine nucleotide concentrations did not correlate with efficacy nor with toxicity. CONCLUSIONS TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur.
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Affiliation(s)
- Mark G Ward
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Kamal V Patel
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Viraj C Kariyawasam
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Rishi Goel
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Ben Warner
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Tim R Elliott
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Paul A Blaker
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
| | - Peter M Irving
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
| | - Anthony M Marinaki
- Purine Research Laboratory, Viapath, Guy’s and St. Thomas’ Hospital, London, UK
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy’s and St. Thomas’ Hospital, NHS Foundation Trust, London, UK
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
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16
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Taylor KM, Ward MG, Blaker PA, Sparrow MP. Is there a role for thioguanine therapy in IBD in 2017 and beyond? Expert Rev Gastroenterol Hepatol 2017; 11:473-486. [PMID: 28276819 DOI: 10.1080/17474124.2017.1294062] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.
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Affiliation(s)
- Kirstin M Taylor
- a Department of Gastroenterology , Alfred Hospital and Monash University , Melbourne , Australia
| | - Mark G Ward
- a Department of Gastroenterology , Alfred Hospital and Monash University , Melbourne , Australia
| | - Paul A Blaker
- b Department of Gastroenterology , The Tunbridge Wells Hospital , Tunbridge Wells , UK
| | - Miles P Sparrow
- a Department of Gastroenterology , Alfred Hospital and Monash University , Melbourne , Australia
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17
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Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. J Pediatr Gastroenterol Nutr 2017; 64:639-652. [PMID: 27984347 DOI: 10.1097/mpg.0000000000001492] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.
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18
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Coskun M, Steenholdt C, de Boer NK, Nielsen OH. Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease. Clin Pharmacokinet 2016; 55:257-74. [PMID: 26255287 DOI: 10.1007/s40262-015-0316-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.
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Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. .,Department of Biology and Biotech Research and Innovation Centre (BRIC), The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.
| | - Casper Steenholdt
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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19
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Meijer B, Mulder CJJ, van Bodegraven AA, de Boer NKH. How I treat my inflammatory bowel disease-patients with thiopurines? World J Gastrointest Pharmacol Ther 2016; 7:524-530. [PMID: 27867685 PMCID: PMC5095571 DOI: 10.4292/wjgpt.v7.i4.524] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/12/2016] [Accepted: 10/09/2016] [Indexed: 02/06/2023] Open
Abstract
Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease (IBD). Thiopurines used in IBD are azathioprine (2.0-2.5 mg/kg), mercaptopurine (1.0-1.5 mg/kg) and thioguanine (0.2-0.3 mg/kg). However, mainly due to numerous adverse events associated with thiopurine use, almost 50% of the patients have to discontinue conventional thiopurine treatment. Extensive monitoring and the application of several treatment strategies, such as split-dose administration, co-administration with allopurinol or dose reduction/increase, may increase the chance of successful therapy. With this review, we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands. We provide clinical information concerning safety issues, indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.
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20
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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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van Gils T, van de Donk T, Bouma G, van Delft F, Neefjes-Borst EA, Mulder CJJ. The first cases of collagenous sprue successfully treated with thioguanine. BMJ Open Gastroenterol 2016; 3:e000099. [PMID: 27486523 PMCID: PMC4947710 DOI: 10.1136/bmjgast-2016-000099] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 05/10/2016] [Accepted: 05/12/2016] [Indexed: 01/28/2023] Open
Abstract
Objective Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. Design We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre. Evaluation of small bowel biopsies was performed by an expert pathologist. Results None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype. Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably. Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient. In the third patient, the thickened basement membrane was only very focally recognised. The thickened membrane persisted in the last patient, probably because of the short time of follow-up. Conclusions CS should be separated from coeliac disease. Based on the lack of typical HLA phenotyping and the absence of coeliac-specific antibodies, there seems to be no relation with coeliac disease in these 4 cases. A promising treatment option might be 6-TG with or without budesonide. Research in a larger cohort is needed to standardise treatment for CS.
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Affiliation(s)
- Tom van Gils
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Tine van de Donk
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Foke van Delft
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | | | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
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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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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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Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis 2015; 21:445-52. [PMID: 25248004 DOI: 10.1097/mib.0000000000000197] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. METHODS A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. RESULTS Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. CONCLUSIONS Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.
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Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study. Inflamm Bowel Dis 2014; 20:2239-46. [PMID: 25230165 DOI: 10.1097/mib.0000000000000206] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Thioguanine (TG) is a treatment for inflammatory bowel disease, but association with nodular regenerative hyperplasia has restricted its use. We conjectured that splitting a therapeutic daily dose of TG would be efficacious and should avoid liver toxicity. METHODS We report on 62 patients with severe inflammatory bowel disease not responding to prednisolone, conventional thiopurines, biologics, or calcineurin inhibitors. Patients were prescribed oral split-daily TG to avoid individual doses >0.3 mg/kg. Data on concomitant medication, clinical efficacy measured by Harvey-Bradshaw Index for Crohn's, or Simple Clinical Colitis Score for ulcerative/indeterminate colitis (UC), and some paired endoscopies were available. Safety was followed clinically and with bloods at 2 centers. All patients at the U.K. center had a liver biopsy or magnetic resonance imaging after 6 months. Twenty-one patients had serial ultrasounds at the Australian center. RESULTS At 6 months, 19/21 of patients with Crohn's disease and 27/38 with ulcerative colitis had improved clinical activity. At study end, 53% of patients maintained improved clinical activity of steroids. Median duration of TG was 8 (0.3-45) months, median dose was 0.6 (0.3-1) mg/kg per day. Previous thiopurine-related adverse reactions were not encountered. Twenty-nine patients withdrew because of loss to follow-up, medical adverse events, or surgery. Possible early nodular regenerative hyperplasia was found on liver biopsy in 1 patient who was heterozygote deficient for thiopurine methyltransferase; the TG dose was lowered. TG was discontinued in a patient with nodular regenerative hyperplasia and concomitant antiphospholipid syndrome. There was 1 successful term pregnancy; cord blood and breast milk TG were low. CONCLUSIONS Split-dose TG seemed well tolerated and efficacious in this retrospective study of patients with difficult inflammatory bowel disease.
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Abstract
Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.
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Affiliation(s)
- Hanh D Vo
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital at Downstate, SUNY-Downstate Medical Center, Brooklyn, NY
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Davids M, Zöllner FG, Ruttorf M, Nees F, Flor H, Schumann G, Schad LR. Fully-automated quality assurance in multi-center studies using MRI phantom measurements. Magn Reson Imaging 2014; 32:771-80. [DOI: 10.1016/j.mri.2014.01.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 01/20/2014] [Accepted: 01/24/2014] [Indexed: 11/27/2022]
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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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Wang YX, Deng M. Medical imaging in new drug clinical development. J Thorac Dis 2012; 2:245-52. [PMID: 22263053 DOI: 10.3978/j.issn.2072-1439.2010.11.10] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 11/28/2010] [Indexed: 11/14/2022]
Abstract
Medical imaging can help answer key questions that arise during the drug development process. The role of medical imaging in new drug clinical trials includes identification of likely responders; detection and diagnosis of lesions and evaluation of their severity; and therapy monitoring and follow-up. Nuclear imaging techniques such as PET can be used to monitor drug pharmacokinetics and distribution and study specific molecular endpoints. In assessing drug efficacy, imaging biomarkers and imaging surrogate endpoints can be more objective and faster to measure than clinical outcomes, and allow small group sizes, quick results and good statistical power. Imaging also has important role in drug safety monitoring, particularly when there is no other suitable biomarkers available. Despite the long history of radiological sciences, its application to the drug development process is relatively recent. This review highlights the processes, opportunities, and challenges of medical imaging in new drug development.
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Affiliation(s)
- Yi-Xiang Wang
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
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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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Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World J Gastroenterol 2011; 17:4166-73. [PMID: 22072847 PMCID: PMC3208360 DOI: 10.3748/wjg.v17.i37.4166] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 06/20/2011] [Accepted: 06/27/2011] [Indexed: 02/06/2023] Open
Abstract
The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine, are efficacious in the arsenal of inflammatory bowel disease (IBD) therapy. Previous reports indicate that 6-thioguanine nucleotide (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Due to their complex metabolism, there is wide individual variation in patient response therein, both in achieving therapeutic drug levels as well as in developing adverse reactions. Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects. In this report, we will review different approaches to administer the thiopurine medications, including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine; co-administration of thiopurine with allopurinol; co-administration of thiopurine with anti-tumor necrosis factor α; 6-TGN administration; desensitization trials; and split dosing of 6-MP.
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Biologic and clinical features of benign solid and cystic lesions of the liver. Clin Gastroenterol Hepatol 2011; 9:547-62.e1-4. [PMID: 21397723 DOI: 10.1016/j.cgh.2011.03.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Revised: 02/24/2011] [Accepted: 03/02/2011] [Indexed: 02/07/2023]
Abstract
The widespread use of imaging analyses, either routinely or to evaluate symptomatic patients, has increased the detection of liver lesions (tumors and cysts) in otherwise healthy individuals. Although some of these incidentally discovered masses are malignant, most are benign and must be included in the differential diagnosis. The management of benign hepatic tumors ranges from conservative to aggressive, depending on the nature of the lesions. New imaging modalities, increased experience of radiologists, improved definition of radiologic characteristics, and a better understanding of the clinical features of these lesions have increased the accuracy of diagnoses and reduced the need for invasive diagnostic tests. These advances have led to constant adjustments in management approaches to benign hepatic lesions. We review the biologic and clinical features of some common hepatic lesions, to guide diagnosis and management strategies.
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López-Martín C, Chaparro M, Espinosa L, Bejerano A, Maté J, Gisbert JP. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 34:385-92. [PMID: 21616565 DOI: 10.1016/j.gastrohep.2011.03.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Revised: 03/02/2011] [Accepted: 03/09/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND Thiopurine immunomodulators are the most commonly used immunosuppressants in inflammatory bowel disease. AIMS To evaluate the incidence of adverse events (AE) in patients with inflammatory bowel disease treated with azathioprine (AZA) or 6-mercaptopurine (MP) in our hospital, the features of these effects, the distribution of socio-demographic factors, and the possible predisposing factors. METHODS We included 377 patients with inflammatory bowel disease who were diagnosed through 2008 and who received AZA or MP during the course of their disease. We collected retrospective demographic, clinical, and laboratory data about their disease and detailed information on any AE. RESULTS Fifty-one patients had some form of AE with AZA or MP (13.5%) and 11% discontinued therapy because of toxicity. Statistically significant association with Crohn's disease was found (P = .008). Myelotoxicity occurred in 18 patients (4.8%) with a mean time of laboratory abnormalities appearing after 16 months. Nine patients had hepatotoxicity secondary to these drugs (2.4%); one of them developed nodular regenerative hyperplasia and portal hypertension. Ten patients had acute pancreatitis (2.7%) with a mean time occurrence of 27 days and a statistically significant association with Crohn's disease (P = .03) and smoking (P = .01). Fifteen patients had gastrointestinal intolerance (4%) but 5 were able to continue with medication given in divided doses or switching to MP. CONCLUSIONS Thiopurine immunomodulators have a significant percentage of AE (13.5%), which, although usually mild, forced us to follow up all cases and sometimes even suspend treatment.
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Affiliation(s)
- Cristina López-Martín
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
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Kverka M, Rossmann P, Tlaskalova-Hogenova H, Klimesova K, Jharap B, de Boer NK, Vos RM, van Bodegraven AA, Lukas M, Mulder CJ. Safety and efficacy of the immunosuppressive agent 6-tioguanine in murine model of acute and chronic colitis. BMC Gastroenterol 2011; 11:47. [PMID: 21545711 PMCID: PMC3097145 DOI: 10.1186/1471-230x-11-47] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Accepted: 05/05/2011] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD. METHODS We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry. RESULTS 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice. CONCLUSIONS Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.
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Affiliation(s)
- Miloslav Kverka
- Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
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Hofmaenner D, Kovari H, Weber A, Weishaupt D, Speck RF. Nodular regenerative hyperplasia of the liver associated with didanosine persists for years even after its interruption. BMJ Case Rep 2011; 2011:bcr.03.2011.3928. [PMID: 22696691 DOI: 10.1136/bcr.03.2011.3928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago.
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van Asseldonk DP, Sanderson J, de Boer NKH, Sparrow MP, Lémann M, Ansari A, Almer SH, Florin THJ, Gearry RB, Mulder CJ, Mantzaris G, van Bodegraven AA. Difficulties and possibilities with thiopurine therapy in inflammatory bowel disease--proceedings of the first Thiopurine Task Force meeting. Dig Liver Dis 2011; 43:270-6. [PMID: 20934926 DOI: 10.1016/j.dld.2010.09.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 07/10/2010] [Accepted: 09/01/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND Thiopurines, such as azathioprine and mercaptopurine, are of pivotal importance in the treatment of inflammatory bowel disease. Although these drugs have been used for several decades, still many questions remain unanswered. AIM To provide an overview of clinically and scientifically challenging topics concerning thiopurine therapy in inflammatory bowel disease treatment. METHODS The first meeting of the Thiopurine Task Force Interest Group was held during the 2009 United European Gastroenterology Week in London (GASTRO2009). The topics of this meeting were of particular clinical and scientific interest. Additional literature was identified by performing a Pubmed search using the search terms 'inflammatory bowel disease', 'azathioprine', '6-mercaptopurine' and 'thioguanine'. RESULTS The following topics were discussed: therapeutic drug monitoring; the synergy of thiopurines with aminosalicylates and allopurinol; serious adverse events such as opportunistic infections, hepatotoxicity, carcinogenicity and pancreatitis; prolongation of thiopurines during clinical remission; indications for thiopurines in the postoperative setting; and the potential use of thioguanine. Specific interesting and clinically relevant topics for potential future research are provided. CONCLUSIONS Thiopurines remain central to inflammatory bowel disease treatment, although future studies are required to substantiate a more personalised medicine approach to their use.
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Affiliation(s)
- Dirk P van Asseldonk
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
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van Asseldonk DP, Jharap B, Kuik DJ, de Boer NKH, Westerveld BD, Russel MGVM, Kubben FJGM, van Bodegraven AA, Mulder CJ. Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis. Dig Liver Dis 2011; 43:110-5. [PMID: 20739231 DOI: 10.1016/j.dld.2010.07.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Revised: 06/22/2010] [Accepted: 07/23/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. AIM To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. METHODS A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. RESULTS Forty-six patients were included and median treatment duration was 22 months (range 0.3-72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03-0.48). When performed, ultrasonography (n = 21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n = 12) predominantly revealed no abnormalities (n = 4) or non-specific regeneration (n = 4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P = 0.180). CONCLUSIONS Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy.
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Affiliation(s)
- Dirk P van Asseldonk
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
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Seksik P, Mary JY, Beaugerie L, Lémann M, Colombel JF, Vernier-Massouille G, Cosnes J. Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine. Inflamm Bowel Dis 2011; 17:565-72. [PMID: 20848502 DOI: 10.1002/ibd.21330] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) is a rare hepatic disorder that may lead to severe portal hypertension. Cases of NRH have been reported in patients receiving thiopurines for inflammatory bowel disease (IBD). Since azathioprine (AZA) is used more and more frequently as a maintenance treatment in IBD, the risk of NRH must be known. The objective of this study was to evaluate the prevalence of NRH and its predictive factors in IBD patients treated with AZA. MATERIALS AND METHODS From the same tertiary referral center, 1888 consecutive IBD patients treated with AZA were studied. Clinical diagnosis of NRH was proven by liver biopsy in all cases except one. The cumulative risk of NRH was estimated with the Kaplan-Meier method. Factors associated with NRH were tested independently with the log-rank method and multivariate proportional hazards model with time-dependent covariates. RESULTS Fifteen patients developed NRH in a median treatment duration of 52.4 months (SE 1.6). The cumulative incidence of NRH was 1.28±0.45% at 10 years. Only two variables were independently associated with NRH occurrence: male gender (P=0.0001, hazard ratio [HR] 8.5, 95% confidence interval [CI] 1.9-37.9) and small bowel resection≥50 cm (P<0.0001, HR 6.6, 95% CI 2.2-20.0), either prior to or after AZA initiation. CONCLUSIONS The risk of developing NRH during AZA treatment is low. This study suggests that male patients with small bowel resection≥50 cm constitute the group with the higher risk of developing NRH while treated with AZA.
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Affiliation(s)
- Philippe Seksik
- Pierre & Marie Curie University, Faculté de médecine, AP-HP, Department of Gastroenterology and Nutrition, Hôpital Saint-Antoine, Paris, France.
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Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease. J Crohns Colitis 2011; 5:48-53. [PMID: 21272804 DOI: 10.1016/j.crohns.2010.08.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Revised: 08/02/2010] [Accepted: 08/02/2010] [Indexed: 02/08/2023]
Abstract
Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno-occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6-mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease.
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[Nodular regenerative hyperplasia: azathioprine-induced hepatotoxicity in a patient with Crohn's disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2010; 34:16-9. [PMID: 21168244 DOI: 10.1016/j.gastrohep.2010.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Revised: 10/04/2010] [Accepted: 10/06/2010] [Indexed: 01/13/2023]
Abstract
We report the case of a 53-year-old man with Crohn's disease who developed azathioprine-induced nodular regenerative hyperplasia of the liver. The diagnosis was suspected when abnormalities in liver function tests were observed and transabdominal ultrasonography and upper gastrointestinal endoscopy showed signs of portal hypertension. The final diagnosis was established by liver biopsy, showing the characteristic alterations in liver architecture. Outcome was favorable after treatment discontinuation, with complete normalization of liver function tests within a year. The present article describes the incidence and the main clinical characteristics of this adverse effect to thiopurines.
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Abstract
IMPORTANCE OF THE FIELD traditional immunosuppressants, including azathioprine, remain the mainstay of therapy in steroid dependent/refractory patients with inflammatory bowel diseases (IBD). The main limitations of its use are its side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity. Major complications occur in patients with low thiopurine-S-methyltransferase (TPMT) enzyme activity; however, the clinical relevance of these tests remains conflictive. AREAS COVERED IN THIS REVIEW in this review, the authors aim to summarize the new data regarding the relationship between the pharmacology of thiopurines and pathogenesis of adverse events. WHAT THE READER WILL GAIN readers will gain an understanding of the metabolism of thiopurines, side effect profile, pharmacological background of side effects, importance of metabolite monitoring, clinical relevance of inherited differences in drug metabolism and other conditions (e.g., concomitant use of allopurinol) which can modify enzyme activity. By gaining an understanding of the pharmacology and metabolism of thiopurines, clinicians will be able to optimize thiopurine therapy in IBD. TAKE HOME MESSAGE TPMT testing and metabolite monitoring are still not considered the standard of care, and clinicians will continue to choose the approach that best suits their clinical practice and patient needs. Regardless of what strategy is chosen, patients need to be carefully monitored and well informed about the potential risks.
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Affiliation(s)
- Pal Miheller
- Semmelweis University, 2nd Department of Medicine, Budapest, Koranyi, Hungary
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de Boer NKH, van Asseldonk DP, van Bodegraven A. ECCO consensus: evidence-based use of 6-thioguanine therapy in Crohn's disease? J Crohns Colitis 2010; 4:484-5. [PMID: 21122549 DOI: 10.1016/j.crohns.2010.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 07/12/2010] [Indexed: 02/08/2023]
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Morris JM, Oien KA, McMahon M, Forrest EH, Morris J, Stanley AJ, Campbell S. Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series. Eur J Gastroenterol Hepatol 2010; 22:1001-1005. [PMID: 20075739 DOI: 10.1097/meg.0b013e3283360021] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIMS Nodular regenerative hyperplasia (NRH) is a rarely identified liver disorder. It is characterized histologically by nodular hepatocyte regeneration without significant fibrosis, and clinically by portal hypertension and abnormal liver function tests (LFTs). Survival data in an unselected cohort after diagnosis of NRH have not been previously described. This study aims to identify a regional cohort with NRH, to determine survival after diagnosis and to assess the relative frequency of associated conditions. METHODS Patients were identified retrospectively from liver biopsy reports within pathology databases, over a 13-year period from Glasgow, Scotland, UK. Case notes were retrieved, clinical information extracted and survival was determined. RESULTS Forty-two patients were identified (19 males). Common presenting features were abnormal LFTs (predominantly cholestatic) (76%) and portal hypertension (9.5%). None had severe liver dysfunction (Child-Pugh score A: 81%, B: 19%, C: 0%). Varices were detected in 26%, and portal hypertension was detected in 31%. There were five (12%) variceal bleeds, one fatal. The patients were subdivided into four groups according to associated clinical conditions: malignancy (29%), prothrombotic (21%), rheumatological (24%) and idiopathic/other (26%). Mean survival was 8.1 years, although survival was highly variable, and was associated with age and associated disease, but not with portal hypertension or varices. No patients in the rheumatological subgroup died. CONCLUSION NRH is usually associated with malignant, prothrombotic or rheumatological conditions. Survival is highly variable and related to age and the underlying disease process, but not to portal hypertension overall. Liver function remains well preserved.
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Affiliation(s)
- Jude M Morris
- Department of Gastroenterology, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, UK.
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Abstract
BACKGROUND The only way to diagnose nodular regenerative hyperplasia (NRH) is liver biopsy. AIM To evaluate in a prospective study the performance of noninvasive liver investigations in patients with NRH. METHODS All consecutive patients with NRH who were being followed up in our unit from 2004 to 2007 were included. All biopsy specimens were reanalysed independently to confirm the diagnosis of NRH (classified as certain or probable) and to assess portal or sinusoidal associated fibrosis. All patients had liver stiffness (using FibroScan) and FibroTest measurements. Magnetic resonance imaging (MRI) was performed using two contrast agents (gadolinium-chelate and ferucarbotran). RESULTS Thirty patients were included (mean age: 53 years). Median liver stiffness value was 7.9 kPa (range: 3.5-16.8), with 63% of the patients having more than 7.1 kPa. No relationship was found between NRH with or without portal hypertension and liver stiffness or Fibrotest. No correlation was found between liver stiffness and portal and/or sinusoidal fibrosis. In patients studied with MRI, 55% had portal hypertension and 9% a diffuse fine-nodular loss of iron uptake after ferucarbotran injection. CONCLUSION Liver stiffness and FibroTest values may be increased in NRH patients, with no correlation with portal hypertension or portal and sinusoidal fibrosis. Contrast-enhanced MRI is disappointing in NRH.
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Rogler G. Gastrointestinal and liver adverse effects of drugs used for treating IBD. Best Pract Res Clin Gastroenterol 2010; 24:157-65. [PMID: 20227029 DOI: 10.1016/j.bpg.2009.10.011] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Accepted: 10/01/2009] [Indexed: 01/31/2023]
Abstract
Drugs used for treating inflammatory bowel disease are known to have a number of gastrointestinal and liver adverse effects. 5-ASA products are relatively safe and have few adverse events. In contrast sulfasalazine has side effects in 11-40% of treated patients including fatigue, nausea, abdominal pain and diarrhoea. Glucocorticoids can induce or propagate peptic ulcers and upper GI bleeding especially in combination with NSAIDs. Thioguanins may have severe gastrointestinal side effects including gastrointestinal complaints (in up to 12%), hepatotoxicity (up to 4%) and pancreatitis (1%). Nodular regenerative hyperplasia (NRH) is an important potential side effect of thiopurine therapy especially in men with Crohn's disease after ileocecal resection. NRH may ultimately lead to portal hypertension. A major concern of methotrexate therapy in IBD besides myelosuppression and pulmonary fibrosis is hepatotoxicity. 5mg of folic acid substitution per week potentially decreases gastrointestinal side effects by 80% without interfering with the efficacy of methotrexate. Besides renal dysfunction, tremor, hirsutism, hypertension and gum hyperplasia cyclosporine is known to have a number of gastrointestinal side effects that occur with less frequency such as diarrhoea (up to 8%) nausea and vomiting (up to 10%) and hepatotoxicity in 1-4%. Rare gastrointestinal adverse events are gastritis and peptic ulcers. Paying attention to these potential deleterious side effects is mandatory for physicians treating IBD patients.
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Affiliation(s)
- Gerhard Rogler
- Division of Gastroenterology and Hepatology, Department of Visceral Medicine, University Hospital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland.
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O'Connor A, Qasim A, O'Moráin CA. The long-term risk of continuous immunosuppression using thioguanides in inflammatory bowel disease. Ther Adv Chronic Dis 2010; 1:7-16. [PMID: 23251725 PMCID: PMC3513853 DOI: 10.1177/2040622310368736] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The efficacy of thiopurine treatment in the induction, and especially maintenance, of remission in inflammatory bowel disease is well proven; however, it is associated with side effects in both medium and long-term use. The potential harmful effects may be anticipated and minimised by due diligence prior to commencing these drugs followed by close monitoring of haematological and biochemical parameters once started. Careful clinical examination and history taking are also essential. Affected patients are expected to lead lives that include travel, employment and pregnancy - the implications of continued thiopurine therapy in such patients are discussed.
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Affiliation(s)
- Anthony O'Connor
- Dr Asghar Qasim Prof. Colm A. O'Moráin Department of Gastroenterology, Adelaide and Meath Hospital incorporating the National Children's Hospital/Trinity College Dublin, Belgard Road, Tallaght, Dublin 24, Ireland
| | - Asghar Qasim
- Dr Asghar Qasim Prof. Colm A. O'Moráin Department of Gastroenterology, Adelaide and Meath Hospital incorporating the National Children's Hospital/Trinity College Dublin, Belgard Road, Tallaght, Dublin 24, Ireland
| | - Colm A. O'Moráin
- Dr Asghar Qasim Prof. Colm A. O'Moráin Department of Gastroenterology, Adelaide and Meath Hospital incorporating the National Children's Hospital/Trinity College Dublin, Belgard Road, Tallaght, Dublin 24, Ireland
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Nahon S, Cadranel JF, Chazouilleres O, Biour M, Jouannaud V, Marteau P. Liver and inflammatory bowel disease. ACTA ACUST UNITED AC 2009; 33:370-81. [DOI: 10.1016/j.gcb.2009.02.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Revised: 12/22/2008] [Accepted: 02/16/2009] [Indexed: 02/07/2023]
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6-Thioguanine therapy in Crohn's disease--observational data in Swedish patients. Dig Liver Dis 2009; 41:194-200. [PMID: 18799369 DOI: 10.1016/j.dld.2008.07.314] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Revised: 06/17/2008] [Accepted: 07/23/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Adverse events (AE) leading to discontinuation or dose-reduction of thiopurine therapy (TP) occur in 9-28% of patients with inflammatory bowel disease. 6-Thioguanine (6-TG) has been proposed as an alternative treatment in patients intolerant for azathioprine (AZA), but some concerns have been raised about drug safety. METHODS We evaluated in a prospective manner the tolerance and efficacy of 6-TG in 23 Crohn's disease (CD) patients (13 men, median age 41 (19-65) years) with prior intolerance (n=18) or resistance (n=5) to AZA and/or 6-mercaptopurine (6-MP). In addition, eight patients had tried mycophenolate mofetil. Seventeen patients (74%) had undergone intestinal resection, often several times. RESULTS Patients were treated with a median daily dose of 40 mg 6-TG (range 20-60) for 259 (15-2272) days. Seven of 13 patients (54%) with active disease went into remission after 8 (4-26) weeks. Sixteen patients (70%) experienced AE that lead to discontinuation (n=10) after 85 (15-451) days or dose reduction (n=6) after 78 (10-853) days. Ten of 18 patients (56%) with prior TP-intolerance discontinued 6-TG treatment due to AE compared to none of five patients with TP-resistance (p=0.046). Of 13 patients that tolerated 6-TG, eight discontinued the drug due to therapeutic failure (n=5) or safety concerns (n=3). Eight patients (35%) continued treatment beyond 12 months. There was no significant difference in maximum thioguanine nucleotide levels between patients with AE leading to discontinuation/dose reduction and patients without AE, 652 (99-2488) vs. 551 (392-1574) pmol/8 x 10(8) RBC; p=0.80. CONCLUSIONS In this cohort of CD patients with severe disease failing traditional thiopurine treatment, a small fraction (22%) had long-term benefit of 6-TG-treatment. 6-TG therapy seems to offer a limited therapeutic gain for patients intolerant to both AZA and 6-MP and other treatment options should be considered.
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Robinson PJA. The effects of cancer chemotherapy on liver imaging. Eur Radiol 2009; 19:1752-62. [PMID: 19238392 DOI: 10.1007/s00330-009-1333-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Accepted: 01/24/2009] [Indexed: 12/28/2022]
Abstract
Chemotherapy changes the appearance of liver tumours and may also affect the liver parenchyma. Tumours respond with changes in size, outline, and internal architecture. The accuracy of liver CT for detecting metastases is reduced after chemotherapy. Histologic studies have shown that some metastases which become invisible on follow-up CT are completely sterile at later resection, but most 'disappearing' lesions still contain active tumour. Hepatic steatosis becomes much more common after chemotherapy. Diffuse fatty change may conceal metastases on US and CT, whilst focal steatosis may mimic tumour. Chemical-shift MRI will distinguish fat from tumour. Fatty change is usually reversible, unless the liver receives a 'second hit' of damage from other causes. Sinusoidal obstructive syndrome (SOS), nodular regenerative hyperplasia, veno-occlusive disease and peliosis are manifestations of microvascular injury which can result from chemotherapy. SOS, the most common of these, is undetectable on US and CT, but can be shown on SPIO-enhanced MRI. Although SOS causes no symptoms in most patients, it may cause increased bleeding from the friable liver at surgery, and greater risk of peri-operative adverse events. Rarer complications of chemotherapy include pseudo-cirrhosis and sclerosing cholangitis.
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