ORIGINAL ARTICLE The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease Dirk P. van Asseldonk, MD, PhD,* Bindia Jharap, MD, PhD,* Joanne Verheij, MD, PhD, † Gijsbert den Hartog, MD, PhD, ‡ Dik B. Westerveld, MD, PhD, § Marco C. Becx, MD, k Maurice G. Russel, MD, PhD, ¶ Leopold G. Engels, MD, PhD,** Dirk J. de Jong, MD, PhD, †† Birgit I. Witte, PhD, ‡‡ Chris J. Mulder, MD, PhD,* Carin M. van Nieuwkerk, MD, PhD,* Elisabeth Bloemena, MD, PhD, §§ Nanne K. H. de Boer, MD, PhD,* and Ad A. van Bodegraven, MD, PhD* , ** 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 ¼ 0.02), elevated gamma- glutamyl transferase (P ¼ 0.01) and alkaline phosphatase (P ¼ 0.01) levels, a higher mean corpuscular volume (P ¼ 0.02), and a lower platelet or leukocyte count (P , 0.01 and P ¼ 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. (Inflamm Bowel Dis 2016;22:2112–2120) Key Words: thioguanine, liver biopsy, drug-induced liver injury, nodular regenerative hyperplasia, inflammatory bowel disease P urine analogs such as azathioprine (AZA) and mercaptopurine (MP) have proven their effectiveness in inflammatory bowel disease (IBD) therapy both in induction (lately primarily advo- cated in combination with tumor necrosis factor (TNF)-a inhibi- tors) and in maintenance of clinical remission. 1 Their use is hampered by a substantial risk of adverse events or nonresponse, usually related to the complex metabolism of these drugs with production of undesired metabolites. 2,3 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org). Received for publication March 27, 2016; Accepted April 9, 2016. From the *Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; † Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands; ‡ Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands; § Department of Gastroenterology and Hepatology, Isala Klinieken, Zwolle, the Netherlands; k Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, the Netherlands; ¶ Department of Gastroenterology and Hepatology, Medical Spectrum Twente, Enschede, the Netherlands; **Department of Internal Medicine, Gastroenterology and Geriatrics, Atrium-Orbis Medical Center, Heerlen-Sittard-Geleen, the Netherlands; †† Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands; Departments of ‡‡ Epidemiology and Biostatistics, and §§ Pathology, VU University Medical Center, Amsterdam, the Netherlands. C. J. Mulder received an unrestricted research grant from HLW pharma, a company interested in drug rediscovery, including thioguanine. This money was used to employ a PhD student to perform research. There was no study sponsor; this was an investigator-initiated study as part of the PhD theses of D. P. van Asseldonk and B. Jharap. The remaining authors have no conflict of interest to disclose. Address correspondence to: Dirk P. van Asseldonk, MD, PhD, Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands (e-mail: d_van_asseldonk@hotmail.com). Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000869 Published online 2 August 2016. 2112 | www.ibdjournal.org Inflamm Bowel Dis  Volume 22, Number 9, September 2016 Copyright © 2016 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited. 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