Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation

Thomas, Fabienne; Maillard, Maud; Launay, Manon; Tron, Camille; Étienne-Grimaldi, Marie-Christine; Gautier-Veyret, Élodie; Haufroid, Vincent; Pallet, Nicolas; Royer, Bernard; Narjoz, Céline; Schmitt, Antonin

doi:10.1016/j.annonc.2021.02.020

Cited by 12 publications

(6 citation statements)

References 3 publications

(4 reference statements)

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“…In our study, only one patient was sampled for uracil measurement while under continuous infusion of 5-FU (uracilemia 75.3 ng/mL). This case is in line with the observations of Thomas et al 35 who reported 17 cases sampled for uracil measurement after fluoropyrimidine exposure. Due to their similar chemical structure, the competition between uracil and 5-FU for DPD-mediated metabolism is likely to explain these falsely positive chromatographic results.…”

Section: Discussionsupporting

confidence: 92%

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients

et al. 2023

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Background: Dihydropyrimidine dehydrogenase (DPD) deficiency screening is a pre-therapeutic standard to prevent severe fluoropyrimidine-related toxicity. Although several screening methods exist, the accuracy of their results remains debatable. In France, the uracilemia measurement is considered the standard in DPD deficiency screening. The objective of this study was to describe the hyperuracilemia (⩾16 ng/mL) rate and investigate the influence of hepatic and renal impairment in uracilemia measurements since the guidelines were implemented. Patients and methods: Using a cohort of 1138 patients screened between 18 October 2018 and 18 October 2021, basic demographic characteristics, date of blood sampling, and potential biological confounders including liver function tests [aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin] and estimated glomerular filtration rate (eGFR) were collected. The second same-patient uracilemia analysis was also performed. Temporal change was graphically represented while potential confounders were stratified to show linearity when suspected. Results: Hyperuracilemia was diagnosed in 12.7% ( n = 150) samples with 6.7%, 5.4%, 0.5%, and 0.08% between 16 and 20 ng/mL, 20 and 50 ng/mL, 50 and 150 ng/mL, and >150 ng/mL, respectively. The median uracilemia concentration was 9.4 ng/mL (range: 1.2 and 172.3 ng/mL) and the monthly hyperuracilemia rate decreased steadily from >30% to around 9%. Older age, normalized AST, γGT, ALP results, bilirubin levels, and decreased eGFR were linearly associated with higher plasma uracil concentrations (all p < 0.001). In the adjusted multivariate linear model, AST, eGFR, and ALP remained associated with uracilemia ( p < 0.05). When measured twice in 39 patients, the median uracilemia rate of change was −2.5%, which subsequently changed the diagnosis in nine patients (23.1%). Conclusions: Better respect of pre-analytical conditions may explain the steady decrease in monthly hyperuracilemia rates over the 3 years. Elevated AST, ALP levels, and reduced eGFR could induce a false increase in uracilemia and second uracilemia measurements modified the first DPD deficiency diagnosis in almost 25% of the patients.

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Section: Discussionsupporting

confidence: 92%

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients

et al. 2023

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“…Our first problematic was to ensure that this deficiency was a real one. Indeed, recent papers have shown that uracilemia may be artificially increased due to non-controlled pre-analytical conditions, renal or hepatic impairment (19)(20)(21)(22). However, no prior organ dysfunction was evidenced in our patient.…”

Section: Discussionmentioning

confidence: 56%

Case report: 5-Fluorouracil treatment in patient with an important partial DPD deficiency

Schmitt

Royer²,

Boidot

et al. 2023

Front. Oncol.

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Esophageal cancer is a cancer with poor prognosis and the standard 1st line treatment for metastatic or recurrent EC is systemic chemotherapy with doublet chemotherapy based on platinum and 5-fluorouracil (5-FU). However, 5-FU could be a source of severe treatment-related toxicities due to deficiency of dihydropyrimidine dehydrogenase (DPD). In this case report, a 74-year-old man with metastatic esophageal cancer was found to have partial DPD deficiency based on uracilemia measurements (about 90 ng/mL). Despite this, 5-FU was safely administered thanks to therapeutic drug monitoring (TDM). The case report highlights the importance of TDM in administering 5-FU to patients with partial DPD deficiency, as it allows individualized dosing and prevents severe toxicity.

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“…For instance, performing the blood pretreatment within 1 hour instead of 1.5 hours may decrease this intra‐individual variability. Additionally, various factors such as renal 35 or hepatic functions, 36 tumour lysis syndrome 37 or samples being drawn during FP treatment 38 have been shown to interfere with endogenous concentrations of U. Importantly, we showed that the non‐respect of pre‐analytical practices increased the risk of misclassifying patients (from 17% to 34%).…”

Section: Discussionmentioning

confidence: 82%

Quantitative impact of pre‐analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency

Maillard

Launay

Royer

et al. 2022

Brit J Clinical Pharma

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Aims Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre‐analytical recommendations for determining U and dihydrouracil (UH2) concentrations, as they are essential in reliable DPD‐deficiency testing. Methods U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long‐term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter‐occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD‐deficiency testing. Results Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0–99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD‐deficient) based on the analysis of their two samples. For those having at least one non‐compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. Conclusion Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre‐analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.

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Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation

Cited by 12 publications

References 3 publications

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients

Case report: 5-Fluorouracil treatment in patient with an important partial DPD deficiency

Quantitative impact of pre‐analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency

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