PLoS Med：早期的肝功能改变或可预测致命性感染

近日，来自德国耶拿大学医院的研究者揭示，通过新型技术检测到的早期肝功能改变可以帮助研究者识别急性感染（败血症的发生），这对于开发新型的疾病疗法可以提供重要的指导建议。相关研究成果刊登于国际杂志PLoS Medicine上。

几乎一半的严重败血症的病人会由于突发状况而死亡，由于其诊断太晚而不能及时对病人施救。这项研究中，研究者通过对动物模型进行研究发现，败血症早期发生的肝功能异常以及急性免疫过程所涉及的PI3K信号路径在肝脏功能障碍中扮演着重要的角色，研究者同时发现肝脏功能的解毒作用可以受到败血症的影响。

研究者对48个败血症病人的临床研究结果支持了其在动物模型实验中所得到的结果，揭示了肝功能的检测可以帮助诊断早期败血症的发生，并且为临床治疗提供了一定帮助。由于许多药物在肝脏中可以被分解，因此这就也建议研究者给予急性败血症病人特定的药物或许也可以损伤病人的肝脏。

研究者解释道，肝脏的功能障碍在败血症小鼠模型中或许只是早期的症状，PI3K信号路径或许扮演着重要角色，肝脏生物转化的所有过程在败血症患者中都会受到影响，而且伴随着预后不良的情况。

这些研究发现或许为诊断肝脏功能异常及药物疗法提供意见，研究者最后表示，未来需要进行大量的临床工作来进行验证。

编译自：Early Changes in Liver Function Could Indicate Life-Threatening Infection

doi:10.1371/journal.pmed.1001338
PMC:
PMID:

Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Peter Recknagel1,2#, Falk A. Gonnert1#, Martin Westermann3, Sandro Lambeck1, Amelie Lupp4, Alain Rudiger2, Alex Dyson2, Jane E. Carré2, Andreas Kortgen1, Christoph Krafft5, Jürgen Popp5, Christoph Sponholz1, Valentin Fuhrmann6, Ingrid Hilger7, Ralf A. Claus1, Niels C. Riedemann1, Reinhard Wetzker8, Mervyn Singer2, Michael Trauner6¶, Michael Bauer1¶*

Background Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice.