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Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis.
- Source :
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PLoS medicine [PLoS Med] 2012; Vol. 9 (11), pp. e1001338. Date of Electronic Publication: 2012 Nov 13. - Publication Year :
- 2012
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Abstract
- 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.<br />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).<br />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. Please see later in the article for the Editors' Summary.
- Subjects :
- Animals
Bile Acids and Salts blood
Biomarkers blood
Blotting, Western
Cholestasis microbiology
Cholestasis physiopathology
Coinfection microbiology
Coinfection physiopathology
Feces chemistry
Gene Expression Regulation
Genome-Wide Association Study
Humans
Liver physiopathology
Liver Diseases microbiology
Liver Diseases physiopathology
Liver Function Tests
Male
Mice
Mice, Inbred C57BL
Microscopy, Electron, Scanning
Peritonitis microbiology
Phosphatidylinositol 3-Kinase genetics
Phosphatidylinositol 3-Kinase metabolism
Rats
Rats, Wistar
Sepsis microbiology
Signal Transduction
Spectrum Analysis, Raman
Xenobiotics metabolism
Peritonitis physiopathology
Sepsis physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1549-1676
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PLoS medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23152722
- Full Text :
- https://doi.org/10.1371/journal.pmed.1001338