Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy.
Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination.



An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist.



Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670).



The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.
*Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; †Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia; ‡Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; and §Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen, Sittard-Geleen, the Netherlands.
Margien L
ML
Seinen
Dirk P
DP
van Asseldonk
Nanne K
NK
de Boer
Gerd
G
Bouma
Carin M
CM
van Nieuwkerk
Chris J
CJ
Mulder
Elisabeth
E
Bloemena
Adriaan A
AA
van Bodegraven
D000328:Adult; D000493:Allopurinol / Q000008:administration & dosage / Q000009:adverse effects*; D000963:Antimetabolites / Q000008:administration & dosage / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D020518:Focal Nodular Hyperplasia / Q000139:chemically induced / Q000453:epidemiology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008099:Liver / Q000473:pathology; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence
D000963:Antimetabolites; D000493:Allopurinol; D015122:Mercaptopurine