背景:评估慢性丙型肝炎(CHC)患者时,肝纤维化的存在和严重程度是重要的预后变量。尽管肝活检仍是参考标准,非侵入性血清学标志物,如四个因素(FIB-4)得分和Forns指数,也可用于肝纤维化分期。
目的:为了确定FIB-4评分和Forns指数在慢性丙型肝炎(CHC)病毒患者肝纤维化分期中的诊断准确性,使用肝活检作为参考标准(主要目标)。比较这些测试对CHC患者肝纤维化分期的诊断准确性,并探索异质性的潜在来源(次要目标)。
方法:我们使用标准Cochrane搜索方法进行诊断准确性研究(搜索日期:2022年4月13日)。
方法:我们包括评估FIB-4评分表现的诊断性横断面或病例对照研究,Forns指数,或者两者兼而有之,针对肝活检,在CHC参与者的肝纤维化评估中。我们没有语言限制。我们排除了以下研究:参与者除CHC外还有肝病的原因;参与者已成功接受CHC治疗;或指数测试和肝活检之间的间隔超过六个月。
方法:两位综述作者独立提取数据。我们使用双变量模型进行荟萃分析,并计算汇总估计值。我们评估了两种测试在三个目标条件下的表现:显着纤维化或更差(METAVIR分期≥F2);严重纤维化或更差(METAVIR分期≥F3);和肝硬化(METAVIR分期F4)。我们将荟萃分析限制在原始验证截止值(FIB-4为1.45和3.25;Forns指数为4.2和6.9)周围的特定范围内(FIB-4为+/-0.15;Forns指数为+/-0.3)的研究。我们计算了每个指数测试/截止/目标条件组合将收到不确定结果(即高于排除阈值但低于规则阈值)的人的百分比。
结果:我们纳入了来自28个国家的84项研究(共有107,583名参与者),在2002年至2021年之间发表的定性综合报告。在84项研究中,82(98%)是基于队列抽样的横断面诊断准确性研究,其余两项(2%)为病例对照研究.所有研究均在转诊中心进行。我们的主要荟萃分析包括62项研究(100,605名参与者)。总的来说,两项研究(2%)的偏倚风险较低,23项研究(27%)有不清楚的偏倚风险,59项研究(73%)存在高偏倚风险.我们判断13项研究(15%)在参与者选择方面存在适用性问题。FIB-4评分FIB-4评分的下限(1.45)旨在排除患有至少严重纤维化(≥F3)的人。39个研究队列(86,907名参与者)的总敏感度为81.1%(95%置信区间(CI)75.6%至85.6%),特异性为62.3%(95%CI57.4%至66.9%),负似然比(LR-)为0.30(95%CI0.24至0.38)。FIB-4评分的高临界值(3.25)旨在统治至少患有严重纤维化(≥F3)的人。24个研究队列(81,350名参与者)的总敏感度为41.4%(95%CI33.0%至50.4%),特异性为92.6%(95%CI89.5%至94.9%),正似然比(LR+)为5.6(95%CI4.4至7.1)。使用FIB-4评分评估严重纤维化,并同时应用两种截止值,30.9%的人会得到不确定的结果,需要进一步调查。当用于评估主要审查文本中的显着纤维化(≥F2)和肝硬化(F4)时,我们报告了FIB-4评分的摘要准确性估计。Forns指数Forns指数的下限(4.2)旨在排除至少有明显纤维化(≥F2)的人。17个研究队列(4354名参与者)的总敏感度为84.7%(95%CI为77.9%至89.7%),特异性为47.9%(95%CI38.6%至57.3%),LR为0.32(95%CI0.25至0.41)。Forns指数的高临界值(6.9)旨在统治至少有明显纤维化(≥F2)的人。12个研究队列(3245名参与者)的总敏感度为34.1%(95%CI26.4%至42.8%),特异性为97.3%(95%CI92.9%至99.0%),LR+为12.5(95%CI5.7至27.2)。使用Forns指数评估显着纤维化,并同时应用两种截止值,44.8%的人会得到不确定的结果,需要进一步调查。我们报告了在正文中用于评估严重纤维化(≥F3)和肝硬化(F4)时Forns指数的摘要准确性估计。比较FIB-4与Forns指数没有足够的研究来荟萃分析Forns指数诊断严重纤维化和肝硬化的性能。因此,对于这些目标条件,无法比较两次测试的性能。为了诊断显著的纤维化,更糟的是,使用高截止值时,它们的性能没有显着差异。当使用低/排除临界值时,Forns指数的表现略优于FIB-4(相对灵敏度1.12,95%CI1.00至1.25;P=0.0573;相对特异性0.69,95%CI0.57至0.84;P=0.002)。
结论:FIB-4评分和Forns指数均可用于CHC患者的初步评估。FIB-4评分的低临界值(1.45)可用于排除至少严重纤维化(≥F3)和肝硬化(F4)的人。Forns指数的高临界值(6.9)可用于诊断至少有明显纤维化(≥F2)的人。我们认为大多数纳入研究的偏倚风险不明确或高。整体证据质量较低或很低,需要更多高质量的研究。我们的审查仅收集了转诊中心的数据。因此,当把我们的结果推广到初级保健人群时,假阳性的概率可能会更高,假阴性的概率可能会更低。撒哈拉以南非洲需要更多的研究,因为这些测试在这种资源贫乏的环境中可能是有价值的。
BACKGROUND: The presence and severity of liver fibrosis are important prognostic variables when evaluating people with chronic hepatitis C (CHC). Although liver biopsy remains the reference standard, non-invasive serological markers, such as the four factors (FIB-4) score and the Forns index, can also be used to stage liver fibrosis.
OBJECTIVE: To determine the diagnostic accuracy of the FIB-4 score and Forns index in staging liver fibrosis in people with chronic hepatitis C (CHC) virus, using liver biopsy as the reference standard (primary objective). To compare the diagnostic accuracy of these tests for staging liver fibrosis in people with CHC and explore potential sources of heterogeneity (secondary objectives).
METHODS: We used standard Cochrane search methods for diagnostic accuracy studies (search date: 13 April 2022).
METHODS: We included diagnostic cross-sectional or case-control studies that evaluated the performance of the FIB-4 score, the Forns index, or both, against liver biopsy, in the assessment of liver fibrosis in participants with CHC. We imposed no language restrictions. We excluded studies in which: participants had causes of liver disease besides CHC; participants had successfully been treated for CHC; or the interval between the index test and liver biopsy exceeded six months.
METHODS: Two review authors independently extracted data. We performed meta-analyses using the bivariate model and calculated summary estimates. We evaluated the performance of both tests for three target conditions: significant fibrosis or worse (METAVIR stage ≥ F2); severe fibrosis or worse (METAVIR stage ≥ F3); and cirrhosis (METAVIR stage F4). We restricted the meta-analysis to studies reporting cut-offs in a specified range (+/-0.15 for FIB-4; +/-0.3 for Forns index) around the original validated cut-offs (1.45 and 3.25 for FIB-4; 4.2 and 6.9 for Forns index). We calculated the percentage of people who would receive an indeterminate result (i.e. above the rule-out threshold but below the rule-in threshold) for each index test/cut-off/target condition combination.
RESULTS: We included 84 studies (with a total of 107,583 participants) from 28 countries, published between 2002 and 2021, in the qualitative synthesis. Of the 84 studies, 82 (98%) were cross-sectional diagnostic accuracy studies with cohort-based sampling, and the remaining two (2%) were case-control studies. All studies were conducted in referral centres. Our main meta-analysis included 62 studies (100,605 participants). Overall, two studies (2%) had low risk of bias, 23 studies (27%) had unclear risk of bias, and 59 studies (73%) had high risk of bias. We judged 13 studies (15%) to have applicability concerns regarding participant selection. FIB-4 score The FIB-4 score\'s low cut-off (1.45) is designed to rule out people with at least severe fibrosis (≥ F3). Thirty-nine study cohorts (86,907 participants) yielded a summary sensitivity of 81.1% (95% confidence interval (CI) 75.6% to 85.6%), specificity of 62.3% (95% CI 57.4% to 66.9%), and negative likelihood ratio (LR-) of 0.30 (95% CI 0.24 to 0.38). The FIB-4 score\'s high cut-off (3.25) is designed to rule in people with at least severe fibrosis (≥ F3). Twenty-four study cohorts (81,350 participants) yielded a summary sensitivity of 41.4% (95% CI 33.0% to 50.4%), specificity of 92.6% (95% CI 89.5% to 94.9%), and positive likelihood ratio (LR+) of 5.6 (95% CI 4.4 to 7.1). Using the FIB-4 score to assess severe fibrosis and applying both cut-offs together, 30.9% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the FIB-4 score when used for assessing significant fibrosis (≥ F2) and cirrhosis (F4) in the main review text. Forns index The Forns index\'s low cut-off (4.2) is designed to rule out people with at least significant fibrosis (≥ F2). Seventeen study cohorts (4354 participants) yielded a summary sensitivity of 84.7% (95% CI 77.9% to 89.7%), specificity of 47.9% (95% CI 38.6% to 57.3%), and LR- of 0.32 (95% CI 0.25 to 0.41). The Forns index\'s high cut-off (6.9) is designed to rule in people with at least significant fibrosis (≥ F2). Twelve study cohorts (3245 participants) yielded a summary sensitivity of 34.1% (95% CI 26.4% to 42.8%), specificity of 97.3% (95% CI 92.9% to 99.0%), and LR+ of 12.5 (95% CI 5.7 to 27.2). Using the Forns index to assess significant fibrosis and applying both cut-offs together, 44.8% of people would obtain an indeterminate result, requiring further investigations. We report the summary accuracy estimates for the Forns index when used for assessing severe fibrosis (≥ F3) and cirrhosis (F4) in the main text. Comparing FIB-4 to Forns index There were insufficient studies to meta-analyse the performance of the Forns index for diagnosing severe fibrosis and cirrhosis. Therefore, comparisons of the two tests\' performance were not possible for these target conditions. For diagnosing significant fibrosis and worse, there were no significant differences in their performance when using the high cut-off. The Forns index performed slightly better than FIB-4 when using the low/rule-out cut-off (relative sensitivity 1.12, 95% CI 1.00 to 1.25; P = 0.0573; relative specificity 0.69, 95% CI 0.57 to 0.84; P = 0.002).
CONCLUSIONS: Both the FIB-4 score and the Forns index may be considered for the initial assessment of people with CHC. The FIB-4 score\'s low cut-off (1.45) can be used to rule out people with at least severe fibrosis (≥ F3) and cirrhosis (F4). The Forns index\'s high cut-off (6.9) can be used to diagnose people with at least significant fibrosis (≥ F2). We judged most of the included studies to be at unclear or high risk of bias. The overall quality of the body of evidence was low or very low, and more high-quality studies are needed. Our review only captured data from referral centres. Therefore, when generalising our results to a primary care population, the probability of false positives will likely be higher and false negatives will likely be lower. More research is needed in sub-Saharan Africa, since these tests may be of value in such resource-poor settings.