The prevalence of nodular regenerative hyperplasia of the liver in long-term thiopurine-treated inflammatory bowel disease patients

Gilissen, Lennard P L; Tajzai, Rudaba; Romberg, Marielle; Pierik, Marieke; Stronkhorst, Arnold; Steenhuisen, Karin; Bodegraven, A. van; Daniels, Alette; Wong, Dennis R.

doi:10.1097/meg.0000000000001980

Cited by 5 publications

(2 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absolute risk seems limited when applying the relatively low doses as advocated in treatment of IBD patients, with dose adaptation if 6-TGN concentrations are exceeding 1000 pmol/8x10 8 red blood cells (RBC). [24][25][26][27][28] Despite its simple metabolism, TG may also induce myelotoxicity, even when prescribed in the suggested low dose for IBD. [29,30] In current guidelines, dose adaptations of 50-80% of the registered TG dose are recommended for intermediate TPMT metabolisers, while a 10-fold reduction (0-10%) is advised for poor metabolisers.…”

Section: Introductionmentioning

confidence: 99%

Implications of tioguanine dosing in IBD patients with a TPMT deficiency

Deben

Derijks

Bosch

et al. 2023

Preprint

View full text Add to dashboard Cite

Purpose: Tioguanine is metabolised by less enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. Methods: In this retrospective cohort study, all determined TPMT genotypes (2016 – 2021) were evaluated for aberrant metabolism (i.e. intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMTgenotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. Results: TPMT genotypes were determined in 485 patients of whom 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Conclusions: Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.

show abstract

Section: Introductionmentioning

confidence: 99%

Implications of tioguanine dosing in IBD patients with a TPMT deficiency

Deben

Derijks

Bosch

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Whether TG is associated with a higher risk of (long term) hepatotoxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, compared to conventional thiopurines is still debated. The absolute risk seems limited when applying the relatively low doses as advocated in treatment of IBD patients, with dose adaptation if 6-TGN concentrations are exceeding 1000 pmol/8 × 10 8 red blood cells (RBC) [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency

Deben,

Derijks,

van den Bosch

et al. 2023

Metabolites

View full text Add to dashboard Cite

Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016–2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.

show abstract