Table_1_Assessment of Distinct Electrophysiological Parameters in Rectal Biopsies for the Choice of the Best Diagnosis/Prognosis Biomarkers for Cystic Fibrosis.docx

Most cases of Cystic Fibrosis (CF) are diagnosed early in life. However, people with atypical CF forms pose diagnosis dilemmas, requiring laboratory support for diagnosis confirmation/exclusion. Ex vivo analysis of fresh rectal biopsies by Ussing chamber has been the best discriminant biomarker for CF diagnosis/prognosis so far. Here we aimed to evaluate different electrophysiological parameters from Ussing chamber analysis of rectal biopsies from people with CF (PwCF) to establish the one with highest correlations with clinical features as the best CF diagnosis/prognosis biomarker. We analyzed measurements of CFTR-mediated Cl– secretion in rectal biopsies from 143 individuals (∼592 biopsies), the largest cohort so far analyzed by this approach. New parameters were analyzed and compared with the previous biomarker, i.e., the IBMX (I)/Forskolin (F)/Carbachol (C)-stimulated short-circuit current (I’sc–I/F/C). Correlations with clinical features showed that the best parameter corresponded to voltage measurements of the I/F + (I/F/CCH) response (VI/F+I/F/C), with higher correlations vs. I’sc–I/F/C for: sweat chloride (59 vs. 52%), fecal elastase (69 vs. 55%) and lung function, measured by FEV1 (27 vs. 20%). Altogether data show that VI/F+I/F/C is the most sensitive, reproducible, and robust predictive biomarker for CF diagnosis/prognosis effectively discriminating classical, atypical CF and non-CF groups.

绝大多数囊性纤维化（Cystic Fibrosis, CF）病例可在生命早期得到确诊。然而，非典型CF患者的诊断仍存在困境，需借助实验室检测手段以明确或排除诊断。迄今为止，通过尤斯灌流室（Ussing chamber）对新鲜直肠活检组织进行离体分析，仍是用于CF诊断与预后评估的最优鉴别生物标志物。本研究旨在对囊性纤维化患者（People with CF, PwCF）直肠活检组织的尤斯灌流室电生理检测参数进行评估，筛选出与临床特征相关性最高的指标，作为最优的CF诊断与预后生物标志物。本研究共纳入143名受试者的约592份直肠活检组织，分析其中CFTR介导的氯离子分泌相关指标，这是目前采用该方法开展的规模最大的队列研究。本研究对全新检测参数进行了分析，并与既往采用的生物标志物——即异丁基甲基黄嘌呤（IBMX）、福司柯林（Forskolin）、卡巴胆碱（Carbachol）联合刺激下的短路电流（short-circuit current, I’sc–I/F/C）——进行了对比。与临床特征的相关性分析结果显示，最优指标为I/F联合(I/F/CCH)刺激下的电压检测参数（VI/F+I/F/C），其与各项临床特征的相关性均优于I’sc–I/F/C：汗液氯离子浓度（59% vs 52%）、粪便弹性蛋白酶水平（69% vs 55%）以及以一秒用力呼气容积（FEV1）衡量的肺功能（27% vs 20%）。综合以上研究数据表明，VI/F+I/F/C是用于CF诊断与预后评估的最灵敏、可重复性最佳且稳定性最强的预测性生物标志物，可有效区分典型CF、非典型CF以及非CF人群。