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Mechanisms of Disease: mechanisms and clinical implications of cholestasis in sepsis

Abstract

Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated cholestasis. Recent advances in the understanding of intrahepatic cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation.

Key Points

  • Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis, predominantly associated with Gram-negative bacteria

  • Cholestasis in sepsis results from either a functional defect in bile formation at the hepatocellular level or an impairment in bile secretion at the level of the small or large bile ducts caused by proinflammatory cytokines and nitric oxide

  • The clinical presentation of sepsis-associated liver injury varies according to the severity of the bacterial infection

  • Functional hepatocellular cholestasis (sepsis-associated cholestasis) predominates in patients with sepsis, whereas ischemic liver injury (shock liver) and, occasionally, progressive sclerosing cholangitis can be found in patients with septic shock or major trauma with systemic inflammatory response syndrome

  • Treatment is focused mainly on eradicating the underlying infection and managing the sepsis

  • Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation

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Figure 1: Hepatic cytokine production in sepsis and extrahepatic bacterial infections.
Figure 2: Hepatobiliary transport systems in hepatocytes and cholangiocytes.
Figure 3: Overview of hepatocellular, ductular and ductal levels of cholestasis in extrahepatic bacterial infections and sepsis.
Figure 4: Hepatocellular mechanisms of sepsis-associated cholestasis.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft SFB542 TP C1 (to A Geier) and by grant P18613-B05 from the Austrian Science Fund, grant 10266 from the Jubilee Funds of the Austrian National Bank and a GEN-AU grant from the Austrian Ministry for Science (to M Trauner).

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Correspondence to Michael Trauner.

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Geier, A., Fickert, P. & Trauner, M. Mechanisms of Disease: mechanisms and clinical implications of cholestasis in sepsis. Nat Rev Gastroenterol Hepatol 3, 574–585 (2006). https://doi.org/10.1038/ncpgasthep0602

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