Liver Veno-Occlusive Disease (VOD) in a patient given 6-thioguanine for Crohn's disease.
A routine laboratory investigation of ascitic fluid showed < 500 leukocytes/[micro]L and < 250 polymorphonuclear leukocytes (PMNs)/[micro]L. The ascitic fluid total protein level was 2.1 g/dl and serum-ascites albumin gradient (SAAG) was > 1.1 g/dL. No neoplastic cells were found. A transjugular liver biopsy was then performed, showing marked centrilobular hemorrhage with hepatocyte necrosis. There was mild ductular reaction, with no evidence of centrilobular vein thrombosis. The histologic diagnosis confirmed veno-occlusive disease (VOD) (Figure 1B). Screening for thrombophilia was also done, showing low levels of serum protein C and protein S. There was no mutation of JAK-2 V617F. The patient was then treated with a hyposodic diet, mild hydric restriction, enoxaparin, spironolactone, lactulose and omeprazole. He was discharged two weeks later, and after 3 months a complete regression of ascites and hepatomegaly occurred, and echography of the liver was unremarkable (Figure 2A and 2B).
Although VOD was known among complications of 6-TG in childhood, this case-report emphasises the occurrence of VOD in adults with Crohn's disease, as first described by Kane et al. in 2004 (1). The thiopurine drugs were developed more than 50 years ago, and 6-MP was first used as a drug in 1952 (2). Since then, 6-MP and 6-TG have been widely used to treat acute lymphoblastic leukemia in children. VOD mimicking Budd-Chiari like disease was then described as a frequent complication of 6-TG in pediatric patients given the drug for lymphoblastic leukaemia. Later on, in 1976, Griner et al. described the cases of two adult male patients with acute leukaemia developing a fatal Budd-Chiari-like disease while receiving 6-TG (3). Since patients were given 6-TG plus cytosine arabinoside, authors were unable to ascribe this complication solely to 6-TG (3). VOD exclusively related to 6-TG was first described by Gill et al., who observed a clinically reversible liver VOD developing in a young man with acute lymphocytic leukemia after 10 month administration of 6-TG (4). Furthermore, sinusoidal obstruction was also reported in a patient with psoriasis treated with 6-TG and other cytotoxic therapy (5). In 2006, a European 6-TG Working Party established that 6-TG should be considered a rescue drug in stringently defined indications in inflammatory bowel diseases (IBD). The indication for administration of 6-TG should only include its use for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Moreover, 6-TG must be withdrawn in case of overt or histologically proven hepatotoxicity (6). Although Ansari et al (7) found no nodular regenerative hyperplasia (NRH) in the liver of patients given 6TG, Dubinsky et al. (8) described NHR as a common finding in 6-TG-treated patients with inflammatory bowel disease in the absence of VOD. By contrast, in our case report we showed histological pattern of VOD and, in accord with Gisbert et al. (9), would suggest that 6-TG should not be administered out of a clinical trial setting. Given that the proportion of patients with Crohn's disease achieving an improvement of symptoms during 6-TG treatment is similar to that after methotrexate (10) or infliximab (6), these drugs should therefore be considered as second line therapy in patients intolerant or resistant to azathioprine and 6-mercaptopurine.
AGATA SALERNO MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. MARCO VACANTE, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. DONATELLA POLLINA, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. BENEDETTA STANCANELLI, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. SILVIA MARTINI, MD, SSCVD Insufficienza Epatica e Trapianto, Azienda Ospedaliera Citta della Salute e della Scienza--Molinette, C.so Bramante 88, 10126 Turin, Italy. EZIO DAVID, MD, SCDU II Anatomia Patologica, Azienda Ospedaliera Citta della Salute e della Scienza--Molinette, C.so Bramante 88, 10126 Turin, Italy. LORENZO MALATINO, MD, PROFESSOR OF MEDICINE Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
CORRESSPONDENCE: MARCO VACANTE, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
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(3.) Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases. Ann Intern Med. 1976;85:578-82.
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(7.) Ansari A, Elliott T, Fong F, Arenas-Hernandez M, Rottenberg G, Portmann B, et al. Further experience with the use of 6-thioguanine in patients with Crohn's disease.Inflamm Bowel Dis. 2008;14:1399-405.
(8.) Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003;125:298-303.
(9.) Gisbert JP, Gonzalez-Lama Y, Mate J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518-27.
(10.) Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995;332:292-7.
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|Title Annotation:||Case Report|
|Author:||Salerno, Agata; Vacante, Marco; Pollina, Donatella; Stancanelli, Benedetta; Martini, Silvia; David,|
|Publication:||British Journal of Medical Practitioners|
|Article Type:||Clinical report|
|Date:||Jun 1, 2014|
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