RESUMO
BACKGROUND: Inhaled corticosteroids (ICS) are the recommended long-term control therapy for asthma in children. However, concern exists regarding potential adrenal suppression with chronic ICS use. Our pilot study reported that hair cortisol in children was 50% lower during ICS therapy than prior to therapy, suggestive of adrenal suppression. OBJECTIVE: To evaluate hair cortisol concentration (HCC) as a potential biomarker for possible adrenal suppression from ICS use in children with asthma. METHODS: A retrospective observational study was performed at asthma clinics in Vancouver, Winnipeg, and Toronto, Canada. Children (nâ¯=â¯586) were recruited from July 2012 to December 2014 inclusive of those without asthma, with asthma not using ICS, and with asthma using ICS. The most recent three-month HCC was measured by enzyme immunoassay and compared among the groups. Quantile regression analysis was performed to identify factors potentially affecting HCC. RESULTS: The median HCC was not significantly different among the children: No ICS (nâ¯=â¯47, 6.7â¯ng/g, interquartile range (IQR) 3.7-9.8â¯ng/g), ICS Treated (nâ¯=â¯360, 6.5â¯ng/g, IQR 3.8-14.3â¯ng/g), and Controls (nâ¯=â¯53, 5.8â¯ng/g, IQR 4.6-16.7â¯ng/g). 5.6% of the children using ICS had hair cortisol <2.0â¯ng/g compared to none in the control groups (Pâ¯<â¯.05, comparing ICS Treated (20/360) to all Controls combined (0/100)) and only half had been exposed to systemic corticosteroids. Age, sex, BMI, and intranasal corticosteroid use were significantly associated with HCC. CONCLUSIONS: Results suggest HCC may be a potential biomarker for adrenal suppression as a population of children using ICS with HCCâ¯<â¯2.0â¯ng/g was identified compared to none in the control groups. Further research is needed to determine if those children have or are at risk of adrenal suppression or insufficiency.
Assuntos
Corticosteroides/efeitos adversos , Glândulas Suprarrenais/efeitos dos fármacos , Insuficiência Adrenal/induzido quimicamente , Anti-Inflamatórios/efeitos adversos , Asma/tratamento farmacológico , Cabelo/metabolismo , Hidrocortisona/metabolismo , Administração Intranasal , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Glândulas Suprarrenais/metabolismo , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/metabolismo , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Asma/metabolismo , Biomarcadores/metabolismo , Canadá/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Ambulatório Hospitalar , Projetos Piloto , Análise de Regressão , Estudos Retrospectivos , RiscoRESUMO
AIMS: The importance of polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD. MATERIALS & METHODS: The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed. RESULTS: None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic polymorphisms (IVS5+18G>A, IVS6+139G>A and IVS9-51T>G) and a synonymous mutation (c.1236G>A), which was observed five- out of eight-times in patients with severe adverse effects. CONCLUSION: The association of a haplotype containing no nonsynonymous or splice-site polymorphisms indicates that additional important genetic variation may be located in noncoding gene regions. Furthermore, a comparison with other studies suggests that the relative importance of particular DPYD mutations (IVS14+1G>A and c.2846A>T) for predicting severe 5-FU toxicity differs geographically across Europe.