服用阿司匹林与降低肝纤维化指标成年人美国之间的关联

StephenW

Aspirin use is associated with lower indices of liver fibrosis among adults in the United States

    Z. Gordon Jiang1,*, L. Feldbrügge1, E. B. Tapper1, Y. Popov1, T. Ghaziani1, N. Afdhal1, S. C. Robson1 andK. J. Mukamal2

Article first published online: 7 JAN 2016

DOI: 10.1111/apt.13515

© 2016 John Wiley & Sons Ltd

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Alimentary Pharmacology & Therapeutics

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    1    Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    2    Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

* Correspondence to:
Dr Z. Gordon Jiang, Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
E-mail: [email protected]


Summary
Background

Recent animal studies have shown that platelets directly activate hepatic stellate cells to promote liver fibrosis, whereas anti-platelet agents decrease liver fibrosis. It is unknown whether platelet inhibition by aspirin prevents liver fibrosis in humans.
Aim

To examine the association between aspirin use and liver fibrosis among adults with suspected chronic liver disease.
Methods

We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey III. We identified 1856 individuals with suspected chronic liver disease (CLD). The degree of liver fibrosis was determined using four validated fibrosis indices and a composite index.
Results

The use of aspirin was associated with a significantly lower composite liver fibrosis index calculated from FIB4, APRI, Forns and NFS [0.24 standard deviation (s.d.) units lower; 95% CI −0.42 to −0.06, P = 0.009]. The association of aspirin with lower fibrosis scores was significantly larger among those with suspected CLD compared to those without (−0.23 vs. −0.03 s.d. units; P interaction = 0.05). The negative association between aspirin use and lower fibrosis index was consistent across all four fibrosis indices (P = 0.002–0.08) in individuals with chronic viral hepatitis, suspected alcoholic liver disease and NASH. In comparison, no negative associations with liver fibrosis were seen with ibuprofen in parallel analyses.
Conclusions

The use of aspirin was associated with significantly lower indices of liver fibrosis among US adults with suspected chronic liver diseases. Aspirin and other anti-platelet drugs warrant further investigation for the prevention and treatment of liver fibrosis.

Introduction

Fibrosis, a common response to chronic liver injury, is characterised by the excessive accumulation of extracellular matrix.[1] Fibrosis in the liver may lead to cirrhosis, a devastating condition affecting at least 400 000 Americans.[2, 3] Therapeutic strategies for liver fibrosis and cirrhosis are presently limited to the treatment of its underlying cause and the mitigation of cirrhotic complications. Unfortunately, direct anti-fibrotic therapy is unavailable.[4, 5]

The platelet is a promising target for the development of anti-fibrotic therapeutics. Platelet activation and degranulation are essential components of the physiological response to tissue injury, which in turn activates wound closure and repair.[6] However, during chronic inflammation, sustained platelet activation can drive dysregulated fibrotic response. Pre-clinical evidence supports a role for anti-platelet therapy. For example, a recent study of a chronic hepatitis B mouse model demonstrated reduced severity of liver fibrosis following treatment with aspirin or clopidogrel.[7] We recently established a murine model of biliary fibrosis, with which we demonstrated that in chronic liver injury, platelets drive liver fibrosis by the direct activation of hepatic stellate cells. Importantly, we showed that both low-dose aspirin and antibodies against platelet-derived growth factor B protected against fibrosis.[8]

Based on these observations, we hypothesised that regular use of aspirin might protect against liver fibrosis in humans. To test this hypothesis, we analysed the association between aspirin use and liver fibrosis indices among a nationally representative sample of US adults using data from the National Health and Nutritional Examination Survey III (NHANES III). To ensure specificity, we primarily focused upon the associations among individuals at risk for liver fibrosis and tested relationships with ibuprofen (which lacks major anti-platelet activity) and among individuals at low fibrosis risk in sensitivity analyses.

StephenW

服用阿司匹林与降低肝纤维化指标成年人美国之间的关联

    Z.戈登Jiang1，* L。Feldbrügge1，EB Tapper1，Y. Popov1，T Ghaziani1，N. Afdhal1，S​​C Robson1和K。 J. Mukamal2

文章首次在网上公布：2016年1月7日

DOI：10.1111 / apt.13515

©2016年约翰·威利父子有限公司

问题
封面图片卷。 43第4期
消化系统药理学和治疗

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    胃肠病学和肝病，内科，贝斯以色列女执事医疗中心，哈佛大学医学院，波士顿，MA，USA的1部
    全科医学及基层医疗，贝斯以色列女执事医疗中心，哈佛大学医学院，波士顿，MA，USA第2分部

*通讯作者：
Z.戈登江医生，胃肠病学和肝病，内科，贝斯以色列女执事医疗中心，波士顿，MA 0​​2115，USA的分部。
电子信箱：[email protected]


概要
背景

最近的动物研究表明，血小板直接激活的肝星状细胞，促进肝纤维化，而抗血小板剂减少肝纤维化。它是未知的血小板抑制由阿司匹林是否能预防肝纤维化的人类。
目的

为了研究成人疑似慢性肝病患者中使用阿司匹林和肝纤维化的关系。
方法

我们进行使用从全国健康和营养调查III数据的横截面分析。我们确定了1856年的个人疑似慢性肝病（CLD）。肝纤维化的程度被使用四个验证纤维化指数和一个综合指数来确定。
结果

使用阿司匹林与从FIB4，APRI，Forns和NFS [0.24标准偏差（SD）为单位计算下一个显著低级复合肝纤维化指数相关联; 95％CI为-0.42至-0.06，P = 0.009]。阿司匹林与低级纤维化评分的关联是在那些怀疑CLD相比那些没有显著较大（-0.23 -0.03对比的sd单元，P相互作用= 0.05）。服用阿司匹林与降低纤维化指标之间的负相关关系是在所有四个纤维化指标（P = 0.002-0.08）与慢性病毒性肝炎，疑似酒精性肝病和NASH的个体相一致。相比之下，肝纤维化无负面联想被视为与并行分析布洛芬。
结论

使用阿司匹林与肝纤维化之间的美国成年人怀疑慢性肝病显著降低指数相关。阿司匹林等抗血小板药物值得进一步研究肝纤维化的预防和治疗。

介绍

纤维化，慢性肝损伤的共同响应，特点是细胞外基质的过度积累。[1]纤维化的肝脏可能会导致肝硬化，一场毁灭性的条件已造成至少40万美国人。[2，3]治疗策略肝纤维化和肝硬化是目前限制其根本原因的治疗和肝硬化并发症的缓解作用。不幸的是，直接抗纤维化治疗不可用。[4，5]

血小板是一个有希望的目标的抗纤维化治疗剂的开发。血小板活化和脱颗粒是生理响应组织损伤，从而激活伤口闭合和修复必要成分。[6]然而，在慢性炎症，持续血小板活化可以驱动失调纤维化反应。临床前证据支持抗血小板治疗的作用。例如，最近的一个慢性乙型肝炎小鼠模型的研究表明肝纤维化的减少程度以下阿司匹林或氯吡格雷治疗。[7]最近，我们建立了胆纤维化小鼠模型，与我们表明，在慢性肝损伤，血小板通过直接激活的肝星状细胞的驱动肝纤维化。重要的是，我们表明，两种低剂量的阿司匹林和抗血小板衍生生长因子B免受纤维化。[8]

根据这些意见，我们假设，经常服用阿司匹林可能防止在人类肝纤维化。为了检验这一假设，我们分析使用阿司匹林和肝纤维化指标之间的关联使用来自全国健康和营养检查调查III（NHANES III）数据的美国成年人全国代表性样本中。以确保特异性，我们主要集中在个人之间的关联的风险肝纤维化和测试与布洛芬的关系（其缺乏主要抗血小板活性）和个人之间在低纤维化风险中的敏感性分析。

StephenW

Discussion

Among the pleiotropic effects of aspirin, its anti-platelet activity has been widely exploited for the prevention and treatment of coronary artery disease. We recently observed in animal models that platelet activation directly promotes liver fibrosis, whereas aspirin prevents progression of liver fibrosis.[8] Here, we report an association between aspirin use and lower indices of liver fibrosis in NHANES III, a nationally representative sample of US adults. Furthermore, this protective association was most pronounced among those with suspected chronic liver disease. These findings suggest a potential benefit of aspirin in inhibiting liver fibrosis.

Our findings confirm and extend the literature on anti-platelet effects and liver fibrosis. Recently, Poujol-Robert and colleagues reported that patients taking daily low-dose aspirin had reduced progression of liver fibrosis in the setting of hepatitis C recurrence following liver transplantation.[31] Our data extend these insights in three ways. First, we observed consistent inverse associations with aspirin use among all four indices of liver fibrosis. Second, this association appears to be specific to aspirin, but not ibuprofen, a nonsteroidal anti-inflammatory drug with significantly less anti-platelet effect. Finally, we observed statistically significant effect modification, in that individuals with viral hepatitis, suspected alcoholic liver disease or NASH had much stronger associations between aspirin use and lower fibrosis scores. This effect modification argues for causality, as confounders alone are unlikely to have produced this interaction.

The magnitude of aspirin's effect could be sizable. While the precision of our estimates in some analyses was limited by study design and very few individuals with advanced liver fibrosis, individuals on aspirin had almost a quarter of one s.d. decrease in the composite fibrosis index. Taking FIB4 score as an example, the decrease in FIB4 was 0.47 in viral hepatitis, 0.30 in alcoholic liver disease and 0.21 in NASH. This difference was sizable considering the FIB4 cutoff points for F0-1 and F3-4 fibrosis were 1.45 and 3.25 for viral hepatitis and 1.3 and 2.67 for NASH respectively.[12, 19] Although small, there was also a significant effect of aspirin on fibrosis scores for individuals with no risk factors of chronic liver disease, perhaps reflecting the presence of subjects with chronic liver diseases that were not captured by our selection criteria.

We did not find a dose effect in the association between aspirin use and its improvement in liver fibrosis indices. This is likely attributable to the mechanism of platelet inhibition by aspirin, which is both irreversible and lasts 8–9 days, the life span of a platelet, thus masking any true dose effect.[32] This lack of dose effect has been noted in studies of aspirin's protective effect against coronary artery disease and colon cancer, and may not negate true causality.[33, 34]

Our data must be interpreted conservatively, as cross-sectional observational studies are subject to confounding, especially confounding by indication. To address this, we employed comprehensive multivariate analysis for known confounders. In addition, we included a parallel analysis of ibuprofen, which has a half-life of less than 2 h and reversibly inhibits cyclooxygenase 1 (COX-1), hence lacks a long-lasting anti-platelet effect.[32, 35] The use of ibuprofen captured some of the background differences between aspirin users and non-users since their uses and contraindications share some similarities.

This study has several strengths and weaknesses. This is the first study to our knowledge that directly examined the effect of aspirin on liver fibrosis. The large sample size as well as a nationally representative design in NHANES III allows us to detect a small effect size that should be generalisable to the US population. The limitation of our study largely results from the observational design. First, the documentation of aspirin use in NHANES III was limited to the month prior to the entry of study, whereas the protection against liver fibrosis likely requires long-term use. However, it is worth noting that using ‘recent use’ as a proxy for ‘long-term use’ likely introduces random misclassification. Since random misclassification tends to bias towards the null, the fact that we observed a significant signal in aspirin use, but not in ibuprofen use, suggests that the real impact of long-term aspirin use could be even larger. Future studies are clearly needed to clarify the duration and dose of aspirin necessary to achieve potential benefit for liver fibrosis. Secondly, because liver biopsy data were not available in NHANES, validated surrogate non-invasive markers of liver fibrosis were employed, a strategy used by other investigators.[36, 37] A particular concern relates to aspirin use and platelet count, a component of all four fibrosis indices. The direct effect of aspirin on platelet count is not established despite extensive clinical trials on aspirin. The only study that addressed this question was a small placebo-controlled study by Erhart et al. in 1999, where they observed no differences under physiological conditions without repeated phlebotomy.[38]

Here, we report a consistent association between aspirin use and reduced liver fibrosis indices in a nationally representative cohort of US adults. This protective association was significantly more robust among those with suspected chronic liver diseases. Our observations support the emerging experimental and clinical evidence for a critical pathological link between platelet activation and liver fibrosis. Clinical equipoise is emerging that may justify prospective randomised trials of aspirin, and potentially other anti-platelet drugs to determine their ability to delay or diminish the progression of liver fibrosis in patients with various forms of chronic liver diseases.

StephenW

讨论

间阿司匹林的多效作用，其抗血小板活性已被广泛开发用于冠状动脉病的预防和治疗。我们最近在动物模型中的血小板活化，直接促进肝纤维化的观察，而阿司匹林可以防止肝纤维化的进展。[8]在这里，我们报告使用阿司匹林和降低肝纤维化指标的NHANES III，美国具有全国代表性的样本之间的关联成人。此外，该保护协会被大多数的那些怀疑慢性肝病明显。这些研究结果表明阿司匹林的潜在的好处在抑制肝纤维化。

我们的研究结果确认和延长文献的抗血小板作用和肝纤维化。近日，Poujol，罗伯特和他的同事报道，患者服用肝纤维化的每日小剂量阿司匹林减少了进展丙型肝炎复发的肝移植设置。[31]我们的数据有三种方式扩展这些见解。首先，我们观察到一致的负相关肝纤维化的四个指数中阿司匹林的使用。第二，这种关联似乎是特定于阿司匹林，但不是布洛芬，非类固醇抗炎药与显著较少抗血小板作用。最后，我们观察到统计学上显著的效果修改，在个人与病毒性肝炎，疑似酒精性肝病或纳什在服用阿司匹林与降低纤维化评分之间更强的关联。这种效应修正主张因果关系，因为单独的混杂因素是不太可能产生这种相互作用。

阿司匹林的效果的大小可能是相当大的。虽然我们在一些分析估计的精度是由研究设计和极少数个人拥有先进的肝纤维化的限制，对阿司匹林个人有一个SD的近四分之一减少在复合纤维化指标。服用FIB4得分作为一个例子，在FIB4的降低为0.47病毒性肝炎，0.30酒精性肝病和0.21在NASH。这种差异是相当大的考虑FIB4截止点为F0-1和F3-4纤维化分别为1.45和3.25病毒性肝炎和1.3和2.67纳什分别。[12，19]虽小，也有阿司匹林显著影响纤维化评分为慢性肝病的风险因素，这也许反映出的受试者的慢性肝脏疾病不是由我们的选择标准捕获的存在个体。

我们没有发现服用阿司匹林和肝纤维化指标的改善之间的关联的剂量效应。这可能归因于血小板抑制由阿司匹林的机制，这是既不可逆的，持续8-9天，血小板的寿命，从而掩盖任何真实剂量效应。[32]这种缺乏剂量效应已记录在阿司匹林的抗冠状动脉疾病和结肠癌，并且可能不能否定真正的因果关系的保护作用的研究[33，34]

我们的数据必须保守地解释，因为横断面观察性研究受到混杂，适应症尤其是混杂的。为了解决这个问题，我们采用综合多变量分析对已知的混杂因素。此外，我们包括布洛芬的平行分析，其具有小于2小时的半衰期和可逆地抑制环氧合酶-1（COX-1），因此，缺乏持久的抗血小板作用。[32，35]使用布洛芬捕获一些阿司匹林用户和非用户之间的背景的差异，因为它们的用途和禁忌分享一些相似之处。

这项研究有几个优点和缺点。这是第一次研究我们的知识直接检查阿司匹林对肝纤维化的影响。大样本量以及具有全国代表性的设计NHANES III使我们能够检测应适于推广到美国人口小的影响大小。我们研究的局限性主要是起因于观察的设计。首先，在NHANES III使用阿司匹林的文档被限制在之前研究的条目的月份，而防止肝纤维化可能需要长期使用。不过，值得注意的是，将“最近使用的”作为“长期使用”代理可能引入随机错误分类。由于随机的误判往往会偏向空，我们观察到使用阿司匹林一个显著的信号，但事实不是布洛芬使用，建议长期使用阿司匹林的实际影响可能会更大。未来的研究显然需要澄清的持续时间和必要阿司匹林的剂量，以实现肝纤维化的潜在益处。其次，由于肝活检的数据都不在NHANES可用，有效的肝纤维化的替代非侵入性指标被雇用，使用其他研究者的战略。[36，37]特别值得关注的涉及到使用阿司匹林和血小板计数的一个组成部分所有四个纤维化指标。是不成立的，尽管阿司匹林广泛的临床试验阿司匹林对血小板计数的直接影响。强调该问题的唯一研究是由尔哈特等小型安慰剂对照研究。在1999年，他们观察到的生理条件下没有区别无需反复放血。[38]

在这里，我们报告中的美国成年人具有全国代表性的人群服用阿司匹林与降低肝纤维化指标之间的一致的关联。这种保护协会是显著在那些疑似慢性肝病更稳健。我们的观察支持新兴的实验和临床证据的血小板活化和肝纤维化之间的重要病理环节。临床均势正在出现，这种可证明阿司匹林前瞻性随机试验，和潜在的其它抗血小板药物，以确定其延迟或减少肝纤维化的进展患者各种形式的慢性肝脏疾病的能力。

StephenW

全文:
http://onlinelibrary.wiley.com/doi/10.1111/apt.13515/full

请注意：
阿司匹林可引起出血。服用阿司匹林之前，请咨询你的医生。