Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity

Abstract

In a recent study by Breen et al., a possible causal role of the key enzyme thiopurine methyltransferase (TPMT) in inducing nodular regenerative hyperplasia (NRH) during azathioprine (AZA) treatment in liver transplant patients was considered.1 Both patients who developed this histological liver abnormality had one mutant TPMT allele, probably leading to an impaired ability to methylate AZA-generated metabolites and subsequently to an overproduction of the pharmacologically active end metabolites 6-thioguaninenucleotides (6-TGN).2 We believe that NRH may not be caused by the TPMT activity itself but is attributable to the generated 6-TGN concentrations. Recently, the use of the thiopurine 6-thioguanine (6-TG) in inflammatory bowel disease (IBD) patients has been discarded due to its presumed role in inducing NRH.3 A major pharmacokinetic difference between AZA and 6-TG is that during 6-TG administration (40 to 80 mg), much higher 6-TGN levels (>1,000 pmol/108 per red blood cell [RBC]) are achieved than during AZA treatment (normally between 100 and 500 pmol/108 RBC).2 These relatively high 6-TGN levels may explain the alleged elevated risk of developing NRH during 6-TG therapy. Our liver histological data concerning the use of low-dose 6-TG for treating IBD patients intolerant or refractory to AZA therapy support this hypothesis (Table 1). At our hospital, a liver biopsy is routinely performed in patients who use 6-TG for at least one year. In addition, 6-TGN levels are regularly monitored. The fact that we have not encountered one case of NRH may well be explained by the relatively low 6-TGN levels (mean 442 pmol/108 RBC) achieved as a consequence of the prescribed 6-TG dosages (approximately 0.3 mg/kg). The induction of NRH during thiopurine treatment in general may be 6-TGN dependent. This hypothesis explains the relatively low but well-documented incidence of NRH during AZA treatment as high 6-TGN levels are merely found in those patients with impaired TPMT activity (approximately 10% of the population) and would also provide an answer for the high incidence of NRH during high-dose 6-TG treatment. We therefore consider low-dose 6-TG (0.3 mg/kg) as a therapeutic alternative, but until more long-term toxicity data are available, 6-TG use should preferably be restricted to trials with a regular performance of liver biopsies. TPMT, thiopurine methyltransferase; NRH, nodular regenerative hyperplasia; AZA, azathioprine; 6-TGN, 6-thioguaninenucleotides; 6-TG, 6-thioguanine; IBD, inflammatory bowel disease; RBC, red blood cell. Nanne K. H. de Boer*, Chris J.J. Mulder*, Adriaan A. van Bodegraven*, * Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.