Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis.
<h4>Background</h4>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.<h4>Methods and fin...
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Medicine |
| Online Access: | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001338&type=printable |
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| author | Peter Recknagel Falk A Gonnert Martin Westermann Sandro Lambeck Amelie Lupp Alain Rudiger Alex Dyson Jane E Carré Andreas Kortgen Christoph Krafft Jürgen Popp Christoph Sponholz Valentin Fuhrmann Ingrid Hilger Ralf A Claus Niels C Riedemann Reinhard Wetzker Mervyn Singer Michael Trauner Michael Bauer |
| author_facet | Peter Recknagel Falk A Gonnert Martin Westermann Sandro Lambeck Amelie Lupp Alain Rudiger Alex Dyson Jane E Carré Andreas Kortgen Christoph Krafft Jürgen Popp Christoph Sponholz Valentin Fuhrmann Ingrid Hilger Ralf A Claus Niels C Riedemann Reinhard Wetzker Mervyn Singer Michael Trauner Michael Bauer |
| author_sort | Peter Recknagel |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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).<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-cf339bafd25349caa950811263c7ea3a |
| institution | Kabale University |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-cf339bafd25349caa950811263c7ea3a2025-08-20T03:46:12ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762012-01-01911e100133810.1371/journal.pmed.1001338Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis.Peter RecknagelFalk A GonnertMartin WestermannSandro LambeckAmelie LuppAlain RudigerAlex DysonJane E CarréAndreas KortgenChristoph KrafftJürgen PoppChristoph SponholzValentin FuhrmannIngrid HilgerRalf A ClausNiels C RiedemannReinhard WetzkerMervyn SingerMichael TraunerMichael Bauer<h4>Background</h4>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.<h4>Methods and findings</h4>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).<h4>Conclusions</h4>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.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001338&type=printable |
| spellingShingle | Peter Recknagel Falk A Gonnert Martin Westermann Sandro Lambeck Amelie Lupp Alain Rudiger Alex Dyson Jane E Carré Andreas Kortgen Christoph Krafft Jürgen Popp Christoph Sponholz Valentin Fuhrmann Ingrid Hilger Ralf A Claus Niels C Riedemann Reinhard Wetzker Mervyn Singer Michael Trauner Michael Bauer Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. PLoS Medicine |
| title | Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. |
| title_full | Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. |
| title_fullStr | Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. |
| title_full_unstemmed | Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. |
| title_short | Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. |
| title_sort | liver dysfunction and phosphatidylinositol 3 kinase signalling in early sepsis experimental studies in rodent models of peritonitis |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1001338&type=printable |
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