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Abstract：
BACKGROUND: APRI and FIB-4 scores are used to exclude clinically significant fibrosis (defined as stage ≥ F2) in patients with chronic viral hepatitis. However, the cut-offs for these scores (generated by Youden indices) vary between different patient cohorts. This study aimed to evaluate whether serum dithiothreitol-oxidizing capacity (DOC), i.e., a surrogate test of quiescin sulfhydryl oxidase-1, which is a matrix remodeling enzyme, could be used to non-invasively identify significant fibrosis in patients with various chronic liver diseases (CLDs).
METHODS: Diagnostic performance of DOC was compared with APRI and FIB-4 for identifying significant fibrosis. ROC curve analyses were undertaken in: a) two chronic hepatitis B (CHB) cohorts, independently established from hospitals in Wenzhou (n = 208) and Hefei (n = 120); b) a MASLD cohort from Wenzhou hospital (n = 122); and c) a cohort with multiple CLD etiologies (except CHB and MASLD; n = 102), which was identified from patients in both hospitals. Cut-offs were calculated using the Youden index. All CLD patients (n = 552) were then stratified by age for ROC curve analyses and cut-off calculations.
RESULTS: Stratified by CLD etiology or age, ROC curve analyses consistently showed that the DOC test was superior to APRI and FIB-4 for discriminating between clinically significant fibrosis and no fibrosis, when APRI and FIB-4 showed poor/modest diagnostic performance (P < 0.05, P < 0.01 and P < 0.001 in 3, 1 and 3 cohort comparisons, respectively). Conversely, the DOC test was equivalent to APRI and FIB-4 when all tests showed moderate/adequate diagnostic performances (P > 0.05 in 11 cohort comparisons). DOC had a significant advantage over APRI or FIB-4 scores for establishing a uniform cut-off independently of age and CLD etiology (coefficients of variation of DOC, APRI and FIB-4 cut-offs were 1.7%, 22.9% and 47.6% in cohorts stratified by CLD etiology, 2.0%, 26.7% and 29.5% in cohorts stratified by age, respectively). The uniform cut-off was 2.13, yielded from all patients examined. Surprisingly, the uniform cut-off was the same as the DOC upper limit of normal with a specificity of 99%, estimated from 275 healthy control individuals. Hence, the uniform cut-off should possess a high negative predictive value for excluding significant fibrosis in primary care settings. A high DOC cut-off with 97.5% specificity could be used for detecting significant fibrosis (≥ F2) with an acceptable positive predictive value (87.1%).
CONCLUSIONS: This proof-of-concept study suggests that the DOC test may efficiently rule out and rule in significant liver fibrosis, thereby reducing the numbers of unnecessary liver biopsies. Moreover, the DOC test may be helpful for clinicians to exclude significant liver fibrosis in the general population.
METHODS: Diagnostic performance of DOC was compared with APRI and FIB-4 for identifying significant fibrosis. ROC curve analyses were undertaken in: a) two chronic hepatitis B (CHB) cohorts, independently established from hospitals in Wenzhou (n = 208) and Hefei (n = 120); b) a MASLD cohort from Wenzhou hospital (n = 122); and c) a cohort with multiple CLD etiologies (except CHB and MASLD; n = 102), which was identified from patients in both hospitals. Cut-offs were calculated using the Youden index. All CLD patients (n = 552) were then stratified by age for ROC curve analyses and cut-off calculations.
RESULTS: Stratified by CLD etiology or age, ROC curve analyses consistently showed that the DOC test was superior to APRI and FIB-4 for discriminating between clinically significant fibrosis and no fibrosis, when APRI and FIB-4 showed poor/modest diagnostic performance (P < 0.05, P < 0.01 and P < 0.001 in 3, 1 and 3 cohort comparisons, respectively). Conversely, the DOC test was equivalent to APRI and FIB-4 when all tests showed moderate/adequate diagnostic performances (P > 0.05 in 11 cohort comparisons). DOC had a significant advantage over APRI or FIB-4 scores for establishing a uniform cut-off independently of age and CLD etiology (coefficients of variation of DOC, APRI and FIB-4 cut-offs were 1.7%, 22.9% and 47.6% in cohorts stratified by CLD etiology, 2.0%, 26.7% and 29.5% in cohorts stratified by age, respectively). The uniform cut-off was 2.13, yielded from all patients examined. Surprisingly, the uniform cut-off was the same as the DOC upper limit of normal with a specificity of 99%, estimated from 275 healthy control individuals. Hence, the uniform cut-off should possess a high negative predictive value for excluding significant fibrosis in primary care settings. A high DOC cut-off with 97.5% specificity could be used for detecting significant fibrosis (≥ F2) with an acceptable positive predictive value (87.1%).
CONCLUSIONS: This proof-of-concept study suggests that the DOC test may efficiently rule out and rule in significant liver fibrosis, thereby reducing the numbers of unnecessary liver biopsies. Moreover, the DOC test may be helpful for clinicians to exclude significant liver fibrosis in the general population.
摘要：
背景：APRI和FIB-4评分用于排除慢性病毒性肝炎患者的临床显着纤维化（定义为阶段≥F2）。然而,这些评分的截止值(由Youden指数生成)在不同的患者队列中有所不同.本研究旨在评估血清二硫苏糖醇氧化能力(DOC)即，隔离素巯基氧化酶-1的替代测试，这是一种基质重塑酶，可用于非侵入性识别各种慢性肝病（CLDs）患者的显着纤维化。
方法：将DOC的诊断性能与APRI和FIB-4进行比较，以确定明显的纤维化。ROC曲线分析进行：a）两个慢性乙型肝炎（CHB）队列，从温州（n=208）和合肥（n=120）的医院独立建立；b）温州医院的MASLD队列（n=122）；c）具有多种CLD病因的队列（CHB和MASLD除外；n=102），这是从两家医院的病人身上发现的。截止日期是使用Youden指数计算的。然后将所有CLD患者(n=552)按年龄分层以进行ROC曲线分析和截止计算。
结果：按CLD病因或年龄分层，ROC曲线分析一致显示，DOC检验优于APRI和FIB-4区分临床显著纤维化和无纤维化。当APRI和FIB-4显示较差/中等的诊断性能时（在3、1和3个队列比较中，P<0.05，P<0.01和P<0.001，分别)。相反，当所有测试均显示中等/足够的诊断表现时,DOC检验与APRI和FIB-4相当(11个队列比较P>0.05).与APRI或FIB-4评分相比，DOC具有显着的优势，可以独立于年龄和CLD病因（DOC的变异系数，APRI和FIB-4截止率为1.7%，在按CLD病因分层的队列中，分别为22.9%和47.6%，2.0%,按年龄分层的队列分别为26.7%和29.5%，分别)。从所有检查的患者中得出的统一截止值为2.13。令人惊讶的是,统一的截断值与正常的DOC上限相同，特异性为99%，从275名健康对照个体中估计。因此，在初级保健机构中,统一的截止值对于排除显著纤维化应具有较高的阴性预测值.具有97.5%特异性的高DOC截止值可用于检测具有可接受的阳性预测值(87.1%)的显著纤维化(≥F2)。
结论：这项概念验证研究表明，DOC测试可以有效地排除和排除严重的肝纤维化，从而减少不必要的肝活检的数量。此外，DOC试验可能有助于临床医生排除普通人群中的显著肝纤维化.
方法：将DOC的诊断性能与APRI和FIB-4进行比较，以确定明显的纤维化。ROC曲线分析进行：a）两个慢性乙型肝炎（CHB）队列，从温州（n=208）和合肥（n=120）的医院独立建立；b）温州医院的MASLD队列（n=122）；c）具有多种CLD病因的队列（CHB和MASLD除外；n=102），这是从两家医院的病人身上发现的。截止日期是使用Youden指数计算的。然后将所有CLD患者(n=552)按年龄分层以进行ROC曲线分析和截止计算。
结果：按CLD病因或年龄分层，ROC曲线分析一致显示，DOC检验优于APRI和FIB-4区分临床显著纤维化和无纤维化。当APRI和FIB-4显示较差/中等的诊断性能时（在3、1和3个队列比较中，P<0.05，P<0.01和P<0.001，分别)。相反，当所有测试均显示中等/足够的诊断表现时,DOC检验与APRI和FIB-4相当(11个队列比较P>0.05).与APRI或FIB-4评分相比，DOC具有显着的优势，可以独立于年龄和CLD病因（DOC的变异系数，APRI和FIB-4截止率为1.7%，在按CLD病因分层的队列中，分别为22.9%和47.6%，2.0%,按年龄分层的队列分别为26.7%和29.5%，分别)。从所有检查的患者中得出的统一截止值为2.13。令人惊讶的是,统一的截断值与正常的DOC上限相同，特异性为99%，从275名健康对照个体中估计。因此，在初级保健机构中,统一的截止值对于排除显著纤维化应具有较高的阴性预测值.具有97.5%特异性的高DOC截止值可用于检测具有可接受的阳性预测值(87.1%)的显著纤维化(≥F2)。
结论：这项概念验证研究表明，DOC测试可以有效地排除和排除严重的肝纤维化，从而减少不必要的肝活检的数量。此外，DOC试验可能有助于临床医生排除普通人群中的显著肝纤维化.
