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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. 作者: StephenW 时间: 2016-1-19 09:47
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，SC Robson1和K。 J. Mukamal2
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.作者: StephenW 时间: 2016-1-19 09:49