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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

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...

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Autores principales: Callon, Sidonie, Brugel, Mathias, Botsen, Damien, Royer, Bernard, Slimano, Florian, Feliu, Catherine, Gozalo, Claire, Konecki, Céline, Devie, Bruno, Carlier, Claire, Daire, Viktor, Laurés, Nicolas, Perrier, Marine, Djerada, Zoubir, Bouché, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837271/
https://www.ncbi.nlm.nih.gov/pubmed/36643657
http://dx.doi.org/10.1177/17588359221148536
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author Callon, Sidonie
Brugel, Mathias
Botsen, Damien
Royer, Bernard
Slimano, Florian
Feliu, Catherine
Gozalo, Claire
Konecki, Céline
Devie, Bruno
Carlier, Claire
Daire, Viktor
Laurés, Nicolas
Perrier, Marine
Djerada, Zoubir
Bouché, Olivier
author_facet Callon, Sidonie
Brugel, Mathias
Botsen, Damien
Royer, Bernard
Slimano, Florian
Feliu, Catherine
Gozalo, Claire
Konecki, Céline
Devie, Bruno
Carlier, Claire
Daire, Viktor
Laurés, Nicolas
Perrier, Marine
Djerada, Zoubir
Bouché, Olivier
author_sort Callon, Sidonie
collection PubMed
description 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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spelling pubmed-98372712023-01-14 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 Callon, Sidonie Brugel, Mathias Botsen, Damien Royer, Bernard Slimano, Florian Feliu, Catherine Gozalo, Claire Konecki, Céline Devie, Bruno Carlier, Claire Daire, Viktor Laurés, Nicolas Perrier, Marine Djerada, Zoubir Bouché, Olivier Ther Adv Med Oncol Original Research 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. SAGE Publications 2023-01-10 /pmc/articles/PMC9837271/ /pubmed/36643657 http://dx.doi.org/10.1177/17588359221148536 Text en © The Author(s), 2023. https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Research
Callon, Sidonie
Brugel, Mathias
Botsen, Damien
Royer, Bernard
Slimano, Florian
Feliu, Catherine
Gozalo, Claire
Konecki, Céline
Devie, Bruno
Carlier, Claire
Daire, Viktor
Laurés, Nicolas
Perrier, Marine
Djerada, Zoubir
Bouché, Olivier
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837271/
https://www.ncbi.nlm.nih.gov/pubmed/36643657
http://dx.doi.org/10.1177/17588359221148536
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