Early changes in liver function detected by novel techniques can identify severe infection (sepsis) hours after onset and so could have important implications for the treatment of patients who are critically ill, according to a groundbreaking study by European researchers published in this week's PLOS Medicine.
Almost half of all people who develop severe sepsis die as this life-threatening condition often develops quickly and is often diagnosed too late to save the patient's life.
In this study, the authors from Austria, Germany, and the UK, led by Peter Recknagel from Jena University Hospital in Germany, used experimental laboratory work in cell cultures, genetically modified mice and rats, and studies carried out in critically ill patients to shed light on the mechanisms behind severe sepsis.
They found that in animal models, liver dysfunction is an early sign of sepsis and that a process known as PI3K signalling (which is involved in several immune processes) plays a crucial role in the development of liver dysfunction. The authors also found that all aspects of detoxification by the liver are affected during sepsis, a finding which suggests that clinical outcomes are linked to the severity of these liver changes.
The clinical information included in the study from 48 patients with severe sepsis also supports the finding from the animal models and suggests that liver function tests might help in the early diagnosis of sepsis and also provide information about possible clinical outcomes. As many medicines are broken down in the liver, these findings suggest that giving certain drugs to patients with severe sepsis may further damage the liver.
The authors explain their findings: "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."
They continue: "Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids."
The authors conclude; "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."
In an accompanying Perspective, John Marshall, a critical care expert from the University of Toronto (uninvolved in the study), says: "The hybrid translational model embodied in the work reported here by Bauer and colleagues not only provides a valuable new insight into the pathogenesis of liver derangements in sepsis, but even more importantly, establishes a model that should be welcomed and embraced by scientists working in the field."
Research Article:
Funding: This study was supported by the German Federal Ministry of Education and Research within the ''Center for Sepsis Control and Care'' (grant 01 EO 1002, Project D1.2; to MB). This work was further supported by grants P18613 and P19118 of the Austrian Science Foundation (to MT). Some of the studies were performed at UCLH/UCL, which receives a proportion of its funding from the UK Department of Health's NIHR Biomedical Research Centre's funding scheme. MS, AD, and JEC received funding from the UK Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors declare that a patent has been filed regarding the use of bile acids for the diagnosis of sepsis (MB). MS is a member of the Editorial Board of PLOS Medicine. The authors declare that no other competing interests exist.
Citation: Recknagel P, Gonnert FA, Westermann M, Lambeck S, Lupp A, et al. (2012) Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis. PLoS Med 9(11): e1001338. doi:10.1371/journal.pmed.1001338
IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER (THIS LINK WILL BECOME LIVE WHEN THE EMBARGO LIFTS):
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001338
CONTACT:
Michael Bauer
Integrated Research and Treatment Center
Center for Sepsis Control and Care
Jena University Hospital, Jena, Germany,
Michael.Bauer@med.uni-jena.de
Perspective:
Funding: No specific funding was received for writing this article.
Competing Interests: The author has declared that no competing interests exist.
Citation: Marshall JC (2012) New Translational Research Provides Insights into Liver Dysfunction in Sepsis. PLoS Med 9(11): e1001341. doi:10.1371/journal.pmed.1001341
IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER (THIS LINK WILL BECOME LIVE WHEN THE EMBARGO LIFTS):
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001341
CONTACT:
John C. Marshall
Departments of Surgery and Critical Care Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute
St. Michael's Hospital, University of Toronto
Toronto, Ontario, Canada
marshallj@smh.ca
Journal
PLoS Medicine