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Abstract
Hepatobiliary disorders are commonly encountered in patients with inflammatory bowel disease (IBD). Although primary sclerosing cholangitis is the stereotypical hepatobiliary disorder associated with IBD, other diseases, including autoimmune hepatitis and nonalcoholic fatty liver disease, also are encountered in this population. Several agents used for treatment of IBD may cause drug-induced liver injury, although severe hepatotoxicity occurs infrequently. Furthermore, reactivation of hepatitis B virus infection may occur in patients with IBD treated with systemic corticosteroids and biologic agents.
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Affiliation(s)
- Mahmoud Mahfouz
- Department of Internal Medicine, Mount Sinai Medical Center, 4300 Alton Road, Suite 301, Miami Beach, FL 33140, USA
| | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA.
| | - Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA
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Biswas S, Gogna S, Patel P. A Fatal Case of Intra-Abdominal Hemorrhage Following Diagnostic Blind Percutaneous Liver Biopsy in a Patient With Peliosis Hepatis. Gastroenterology Res 2017; 10:318-321. [PMID: 29118875 PMCID: PMC5667700 DOI: 10.14740/gr873e] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 07/03/2017] [Indexed: 12/17/2022] Open
Abstract
Peliosis hepatis (PH) is a rare vascular condition of the liver characterized by the presence of cystic blood filled cavities distributed randomly throughout the liver parenchyma. We describe a case of a 42-year-old previously healthy male patient, airlifted to us in a state of hemorrhagic shock after undergoing percutaneous diagnostic liver biopsy for lesions seen on CT scan. Repeat CT scan with IV contrast on presentation in our hospital showed intraperitoneal bleeding. Hepatic angiography failed to identify any specific bleeding source. A diagnostic laparoscopy was performed and approximate 9 L of hemoperitoneum was evacuated. The postoperative course was complicated with rapid hemodynamic deterioration, associated with acute hepatic failure progressively leading to multiorgan failure and death in spite of aggressive intensive care support. We suggest that PH should be considered as differential diagnosis of hypervascular hepatic lesions. It potentially can cause fatal acute non-traumatic liver hemorrhage.
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Affiliation(s)
- Saptarshi Biswas
- Department of Trauma and Acute Care Surgery, Forbes Hospital, Allegheny Health Network, PA 15146, USA
| | - Shekhar Gogna
- Department of General Surgery, Westchester University Medical Center, Valhalla, NY, USA
| | - Prem Patel
- Department of General Surgery, Westchester University Medical Center, Valhalla, NY, USA
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Alessandrino F, Tirumani SH, Krajewski KM, Shinagare AB, Jagannathan JP, Ramaiya NH, Di Salvo DN. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol 2017; 72:521-533. [PMID: 28476244 DOI: 10.1016/j.crad.2017.04.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/28/2017] [Accepted: 04/03/2017] [Indexed: 12/13/2022]
Abstract
The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions.
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Affiliation(s)
- F Alessandrino
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
| | - S H Tirumani
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - K M Krajewski
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - A B Shinagare
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - J P Jagannathan
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - N H Ramaiya
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - D N Di Salvo
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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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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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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Han NY, Park BJ, Sung DJ, Kim MJ, Cho SB, Lee CH, Jang YJ, Kim SY, Kim DS, Um SH, Won NH, Yang KS. Chemotherapy-induced focal hepatopathy in patients with gastrointestinal malignancy: gadoxetic acid--enhanced and diffusion-weighted MR imaging with clinical-pathologic correlation. Radiology 2014; 271:416-25. [PMID: 24475862 DOI: 10.1148/radiol.13131810] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE To retrospectively evaluate findings of chemotherapy-induced focal hepatopathy (CIFH) on gadoxetic acid-enhanced magnetic resonance (MR) and diffusion-weighted (DW) images and to determine imaging features that are most helpful in differentiating CIFH from metastasis. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, and informed consent was waived. MR images, including DW images and gadoxetic acid-enhanced images, from 12 patients (four men, eight women; age range, 25-64 years) with 15 CIFHs were reviewed independently and in consensus by two radiologists and were compared with those obtained in 20 control patients (12 men, eight women; age range, 32-84 years) with 30 hepatic metastasis who were matched for tumor size, primary organ, and chemotherapy regimen. Interobserver agreement was assessed with κ statistics, and univariate analysis was performed for comparisons. For quantitative analyses, apparent diffusion coefficients (ADCs) and lesion-to-liver contrast ratios (CRs) were measured. Histopathologic examinations were performed for CIFHs. RESULTS Histopathologic examination revealed that the development of CIFHs was attributable to accentuated manifestations of sinusoidal obstruction syndrome. Interobserver agreement was excellent (κ > 0.85). An ill-defined margin on hepatobiliary phase (HBP) images was the most discriminating independent variable in the differentiation of CIFH from metastasis (odds ratio, 16; P = .009). ADC and CR values in CIFH group were significantly higher than those in metastasis group (P < .001 and P = .041). CONCLUSION CIFH should be considered a mimicker of metastasis in patients with gastrointestinal malignancy during chemotherapy. CIFH can be differentiated from metastasis on the basis of gadoxetic acid-enhanced MR and DW imaging findings; an ill-defined margin on HBP images was especially characteristic.
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Affiliation(s)
- Na Yeon Han
- From the Departments of Radiology (H.N.Y., B.J.P., D.J.S., M.J.K., S.B.C.), Surgery (D.S.K.), Internal Medicine (S.H.U.), and Pathology (N.H.W.), College of Medicine, and Department of Biostatistics (K.S.Y.), Korea University, Anam Hospital, 126-1 5-Ka, Anam-Dong, Sungbuk-ku, Seoul 136-705, Republic of Korea; Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea (C.H.L.); Department of Radiology, Kyungpook National University Hospital, Daegu, Republic of Korea (Y.J.J.); and Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea (S.Y.K.)
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Sommacale D, Palladino E, Tamby EL, Diebold MD, Kianmanesh AR. Spontaneous hepatic rupture in a patient with peliosis hepatis: A report of one case. Int J Surg Case Rep 2013; 4:508-10. [PMID: 23562904 DOI: 10.1016/j.ijscr.2013.01.030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 01/17/2013] [Accepted: 01/21/2013] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Liver rupture is a serious event that is most commonly due to blunt abdominal trauma. We present a case of peliosis hepatis in a patient admitted for acute pyelonephritis who developed hemoperitoneum due to spontaneous hepatic rupture from this rare liver condition. PRESENTATION OF CASE We report a 44 year-old woman who presented to our hospital with acute pyelonephrititis and hemoperitoneum due to spontaneous hepatic rupture from peliosis hepatis. Physicians should be aware of this rare condition in patients who present with non-traumatic hepatic rupture with hemoperitoneum. DISCUSSION PH should be considered in all patients with known risk factors who present with typical morphological changes or a hepatic mass, especially when the cause of sudden intraperitoneal hemorrhage is obscure. CONCLUSION Peliosis hepatis is most often asymptomatic and an incidental finding at autopsy. In symptomatic patients, surgery should be reserved for those patients whose hemorrhage is-life-threatening. Familiarity with the imaging characteristics can help in earlier diagnosis of peliosis hepatis.
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Affiliation(s)
- Daniele Sommacale
- Department of General, Digestive and Endocrine Surgery, Reims University Hospital, France
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Xiong WJ, Hu LJ, Jian YC, He Y, Zhou W, Guo XL, Zheng YX. Focal peliosis hepatis in a colon cancer patient resembling metastatic liver tumor. World J Gastroenterol 2012; 18:5999-6002. [PMID: 23139621 PMCID: PMC3491612 DOI: 10.3748/wjg.v18.i41.5999] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Revised: 08/13/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
Peliosis hepatis (PH) is a rare benign condition characterized by the presence of multiple, randomly distributed, blood filled cystic areas of variable size within the liver parenchyma. PH is difficult to recognize and may be mistaken for neoplasm, metastases or multiple abscesses. A 75-year-old female with a previous history of colon cancer was admitted when a liver mass in the right liver lobe was found 11 mo after surgery during the follow-up period. Computed tomography and magnetic resonance imaging scan of the abdomen were performed. The initial possible diagnosis was metastatic hepatocellular carcinoma. The patient underwent excision of the hepatic segment where the nodule was located. The pathological diagnosis of the surgical specimen was PH. PH should be considered in the differential diagnosis of new liver lesions in patients whose clinical settings do not clearly favor metastasization. Clinicians and radiologists must recognize these lesions to minimize the probability of misdiagnosis and inappropriate treatment.
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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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Choi SK, Jin JS, Cho SG, Choi SJ, Kim CS, Choe YM, Lee KY. Spontaneous liver rupture in a patient with peliosis hepatis: A case report. World J Gastroenterol 2009; 15:5493-7. [PMID: 19916182 PMCID: PMC2778108 DOI: 10.3748/wjg.15.5493] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Peliosis hepatis is a rare pathological entity and may cause fatal hepatic hemorrhage and liver failure. Here, we present a young male patient with aplastic anemia, who had received long-term treatment with oxymetholone. The patient suffered from sudden onset of intra-abdominal hemorrhage with profuse hemoperitoneum. The patient was treated successfully with a right hemihepatectomy and is in good health after 13 postoperative months. We suggest that peliosis hepatis be considered in patients with hepatic parenchymal hematoma, especially in patients under prolonged synthetic anabolic steroid medication. The possibility of a potentially life-threatening complication of massive intra-abdominal bleeding should also be considered.
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Vora A, Mitchell CD, Lennard L, Eden TOB, Kinsey SE, Lilleyman J, Richards SM. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 2006; 368:1339-48. [PMID: 17046466 DOI: 10.1016/s0140-6736(06)69558-5] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND 6-mercaptopurine has been a standard component of long-term continuing treatment for childhood lymphoblastic leukaemia, whereas 6-thioguanine has been mainly used for intensification courses. Since preliminary data have shown that 6-thioguanine is more effective than 6-mercaptopurine, we compared the efficacy and toxicity of the two drugs for childhood lymphoblastic leukaemia. METHODS Consecutive children with lymphoblastic leukaemia diagnosed in the UK and Ireland between April, 1997, and June, 2002, were randomly assigned either 6-thioguanine (750 patients) or 6-mercaptopurine (748 patients) during interim maintenance and continuing therapy. All patients received 6-thioguanine during intensification courses. We analysed event-free and overall survival on an intention-to-treat basis. We obtained toxicity data using an adverse-event reporting system, with follow-up questionnaires to seek detailed information for specific toxicities. This trial is registered with the International Standard Randomised Controlled Number 26727615 with the name ALL97. FINDINGS After a median follow up of 6 years, there was no difference in event-free or overall survival between the two treatment groups. Although 6-thioguanine conferred a significantly lower risk of isolated CNS relapse than did 6-mercaptopurine (odds ratio [OR] 0.53, 95% CI 0.30-0.92, p=0.02), the benefit was offset by an increased risk of death in remission (2.22, 1.20-4.14, p=0.01), mainly due to infections during continuing therapy. Additionally, 95 patients developed veno-occlusive disease of the liver. Of these, 82 were randomly assigned 6-thioguanine, representing 11% of all 6-thioguanine recipients. On long-term follow-up, about 5% of 6-thioguanine recipients have evidence of non-cirrhotic portal hypertension due to periportal liver fibrosis or nodular regenerative hyperplasia. INTERPRETATION Compared with 6-mercaptopurine, 6-thioguanine causes excess toxicity without an overall benefit. 6-mercaptopurine should remain the thiopurine of choice for continuing therapy of childhood lymphoblastic leukaemia.
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Affiliation(s)
- Ajay Vora
- Department of Paediatric Haematology, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
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Abstract
The selection of an antineoplastic regimen for an oncology patient is based first on the availability of effective drugs and then on a balancing of potential treatment-related toxicities with the patient's clinical condition and associated comorbidities. Liver function abnormalities are commonly observed in this patient population and identifying their etiology is often difficult. Immunosuppression, paraneoplastic phenomena, infectious diseases, metastases, and poly-pharmacy may cloud the picture. While criteria for standardizing liver injury have been established, dose modifications often rely on empiric clinical judgment. Therefore, a comprehensive understanding of hepatotoxic manifestations for the most common chemotherapeutic agents is essential. We herein review the hepatotoxicity of commonly used antineoplastic agents and regimens.
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Affiliation(s)
- Justin Floyd
- Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Missouri-Columbia/Ellis Fischel Cancer Center, Columbia, MO 65203, USA
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Samyn M, Hadzic N, Davenport M, Verma A, Karani J, Portmann B, Mieli-Vergani G. Peliosis hepatis in childhood: case report and review of the literature. J Pediatr Gastroenterol Nutr 2004; 39:431-4. [PMID: 15448437 DOI: 10.1097/00005176-200410000-00024] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- M Samyn
- Department of Child Health, King's College Hospital, Denmark Hill, London, United Kingdom.
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Geller SA, Dubinsky MC, Poordad FF, Vasiliauskas EA, Cohen AH, Abreu MT, Tran T, Martin P, Vierling JM, Targan SR. Early Hepatic Nodular Hyperplasia and Submicroscopic Fibrosis Associated With 6-Thioguanine Therapy in Inflammatory Bowel Disease. Am J Surg Pathol 2004; 28:1204-11. [PMID: 15316320 DOI: 10.1097/01.pas.0000128665.12063.97] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.
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Affiliation(s)
- Stephen A Geller
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Shastri S, Dubinsky MC, Fred Poordad F, Vasiliauskas EA, Geller SA. Early Nodular Hyperplasia of the Liver Occurring With Inflammatory Bowel Diseases in Association With Thioguanine Therapy. Arch Pathol Lab Med 2004; 128:49-53. [PMID: 14692812 DOI: 10.5858/2004-128-49-enhotl] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Context.—Nodular hyperplasia (also referred to as nodular regenerative hyperplasia and nodular regenerative hyperplasia of the liver) is a sequel to therapy with thioguanine in patients with hematologic malignancies. Recently, 6-thioguanine has been used to treat patients with inflammatory bowel disease who have been resistant to other forms of therapy.
Objective.—To study liver biopsies from 3 patients with inflammatory bowel disease who had received thioguanine for more than a year, and who had elevated serum liver enzyme values and underwent percutaneous liver biopsy.
Design.—Percutaneous liver biopsies and histologic examinations were performed, including staining with the reticulin silver impregnation method.
Results.—All 3 patients had foci of nodular regenerative hyperplasia, which was best seen with the reticulin silver impregnation method.
Conclusions.—Thioguanine-treated inflammatory bowel disease patients are at risk for the development of nodular hyperplasia. Reticulin-stained histologic sections are necessary to recognize this change. Further studies are needed to determine the frequency and significance of this change.
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Affiliation(s)
- Sunita Shastri
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Stoneham S, Lennard L, Coen P, Lilleyman J, Saha V. Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 123:100-2. [PMID: 14510948 DOI: 10.1046/j.1365-2141.2003.04578.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The case records of 99 consecutive children with acute lymphoblastic leukaemia who received either 6-thioguanine (6-TG) or 6-mercaptopurine (6-MP) as maintenance therapy for at least 1 year were reviewed for hepatic veno-occlusive disease (VOD). Overall, 12% of those on 6-TG developed VOD (all boys). Isolated persistent thrombocytopenia appeared to be the earliest indicator of incipient VOD. Multivariate analysis identified male sex and 6-TG as risk factors. In all cases, VOD was mild and reversible on withdrawing 6-TG or replacing it with 6-MP. The data implicate a sex-linked polymorphic variation in xenobiotic pathways of thiopurine metabolism in the pathogenesis of VOD.
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Affiliation(s)
- Sara Stoneham
- Cancer Research UK, Children's Cancer Group, Bart's and The London, Queen Mary School of Medicine and Dentistry, London, UK.
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Bonaz B, Boitard J, Marteau P, Lémann M, Coffin B, Flourié B, Belaiche J, Cadiot G, Metman EH, Cortot A, Colombel JF. Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine. Aliment Pharmacol Ther 2003; 18:401-8. [PMID: 12940925 DOI: 10.1046/j.1365-2036.2003.01683.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases. AIMS : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP. METHODS An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy. RESULTS Forty-nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13-21 days after TG was started. No haematological side-effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG. CONCLUSIONS TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.
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Affiliation(s)
- B Bonaz
- Département d'Hépato-Gastroentérologie, CHU de Grenoble, France.
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Dubinsky MC, Feldman EJ, Abreu MT, Targan SR, Vasiliauskas EA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol 2003; 98:1058-63. [PMID: 12809828 DOI: 10.1111/j.1572-0241.2003.07413.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy. METHODS IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation. RESULTS 6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10-40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up. CONCLUSIONS These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.
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Affiliation(s)
- Marla C Dubinsky
- Department of Medicine, Division of Gastroenterology, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA
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Abstract
6-Thioguanine (6-TG) is a thiopurine analogue that is closely related to 6-mercaptopurine (6-MP) and azathioprine (AZA). These agents have potent cytotoxic and immunomodulatory effects and are useful in the treatment of a variety of conditions, including inflammatory bowel disease. Both 6-MP and AZA are widely used and are known to cause hepatotoxicity in a proportion of patients. 6-Thioguanine is being increasingly used in the treatment of inflammatory bowel disease but has not been reported to cause liver injury in this context. We describe a case of significant elevation of serum transaminases in a patient treated with 6-TG for a flare of Crohn's disease. We believe the temporal association of the abnormal liver enzymes in this patient, in the absence of other offending agents, argues strongly in favor of 6-TG as a cause of liver enzyme abnormalities. This case highlights the need to monitor liver enzymes in patients treated with 6-TG and identifies the need for additional research focused on the mechanism of thiopurine-induced hepatic injury.
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Affiliation(s)
- Stephen J Rulyak
- Division of Gastroenterology, University of Washington, Seattle, Washington 98195, USA
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Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002; 122:904-15. [PMID: 11910342 DOI: 10.1053/gast.2002.32420] [Citation(s) in RCA: 352] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT. METHODS Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information. RESULTS Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation. CONCLUSIONS Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.
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Affiliation(s)
- Marla C Dubinsky
- Division of Gastroenterology and Genetics, Department of Medicine and Pediatrics, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA.
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Abstract
After assessment of tumor histology, the next important factor to consider in the selection of a chemotherapy regime is organ function. Patients who are to receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate, and which drug doses should be modified. Following therapy abnormalities of liver function tests may be due to the therapy rather than to progressive disease, and this distinction is of critical importance. Furthermore, not all abnormalities in liver function are due to the tumor or its treatment, and other processes, such as hepatitis, must be kept in mind. This article reviews the hepatic toxicity of chemotherapeutic agents, and suggests dose modifications based upon liver function abnormalities. Emphasis is placed on agents known to be hepatotoxic, and those agents with hepatic metabolism.
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Affiliation(s)
- P D King
- Gastroenterology and Hepatology, Department of Internal Medicine, University of Missouri-Columbia, Columbia, MO 65203, USA
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Jacquemin E, Pariente D, Fabre M, Huault G, Valayer J, Bernard O. Peliosis hepatis with initial presentation as acute hepatic failure and intraperitoneal hemorrhage in children. J Hepatol 1999; 30:1146-50. [PMID: 10406195 DOI: 10.1016/s0168-8278(99)80271-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Peliosis hepatis, a condition characterized by the presence of blood-filled lacunar spaces in the liver, usually has a chronic presentation pattern and is mainly reported in adult patients in association with chronic wasting disorders and after administration of various drugs. The present report concerns two previously healthy young children in whom peliosis hepatis initially presented as acute hepatic failure and who had Escherichia coli pyelonephritis. Both patients had active intraperitoneal hemorrhage from the peliotic liver lesions, and liver ultrasonography showed multiple hypoechoic areas of different sizes, which in this context should suggest the diagnosis. One child died from hypovolemic shock and the other recovered. This study indicates that acute peliosis hepatis can be a serious life-threatening disease in children.
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Affiliation(s)
- E Jacquemin
- Department of Pediatrics, Unit of Hepatology, Bicêtre Hospital, Le Kremlin Bicêtre, France
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Affiliation(s)
- R A Gatenby
- Department of Diagnostic Imaging, Temple University Hospital, Philadelphia, PA 19140
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Tinel M, Berson A, Pessayre D, Letteron P, Cattoni MP, Horsmans Y, Larrey D. Pharmacogenetics of human erythrocyte thiopurine methyltransferase activity in a French population. Br J Clin Pharmacol 1991; 32:729-34. [PMID: 1768566 PMCID: PMC1368554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
1. A genetic polymorphism in human erythrocyte thiopurine methyltransferase activity (RBC TPMT) resulting in a trimodal phenotypic distribution has been demonstrated both in a North American population and in British children. 2. We studied whether such a polymorphism may be also present in a white French population by testing RBC TPMT activity in 303 randomly selected blood donors. 3. We found a large inter-individual variation in RBC TPMT activity which ranged from 2 to 40 nmol ml-1 packed RBC h-1, with a mean value of 15.4 +/- 7.0 nmol ml-1 packed RBC h-1. The enzyme activity was not significantly influenced by the sex and age of the subjects. 4. In our population sample, we found no subject with undetectable enzyme activity. However, the probit plot of the log RBC TPMT activity showed a highly significant change in slope at a TPMT activity of 7.5 nmol ml-1 packed RBC h-1. Thirty four subjects (11% of our population) had TPMT activities below 7.5 nmol ml-1 packed RBC h-1. 5. These data are consistent with the view that the genetic polymorphism of TPMT activity described in populations from North America and the United Kingdom is also present in a French population, with about 89% of subjects exhibiting a high activity and 11% an intermediate activity.
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Affiliation(s)
- M Tinel
- Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France
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de Sousa JM, Portmann B, Williams R. Nodular regenerative hyperplasia of the liver and the Budd-Chiari syndrome. Case report, review of the literature and reappraisal of pathogenesis. J Hepatol 1991; 12:28-35. [PMID: 2007773 DOI: 10.1016/0168-8278(91)90904-p] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We report a case of nodular regenerative hyperplasia (NRH) of the liver associated with the Budd-Chiari syndrome in a patient whose clinical and radiological presentation suggested a diagnosis of multiple liver tumours. Based on both our study and a review of the literature, it appears that, in a number of cases of NRH associated with various clinical conditions, blood stasis at the sinusoidal level is the common denominator. We postulate that, in this situation, the prolonged exposure of hepatocytes to blood-borne hepatotrophic substances, such as hepatopoietins, glucagon and insulin, in combination with functional loss due to pressure injury within the congested areas, may be one of the mechanisms leading to the development of NRH.
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Affiliation(s)
- J M de Sousa
- Liver Unit, King's College Hospital, London, United Kingdom
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Abstract
Hepatic injury secondary to arsenic poisoning has been known long but is poorly documented. A case of a patient with hepatic injury following severe arsenic poisoning is reported. Histological study of the liver demonstrated acute venoocclusive disease and perisinusoidal fibrosis. This case indicates that arsenic poisoning causes veno-occlusive disease in humans. It also suggests that hepatic damage in arsenic poisoning is secondary to vascular endothelial injury and supports the hypothesis that different patterns of hepatic vascular injury might proceed from a common mechanism.
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