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REVIEW

URRENT C OPINION

The liver in sepsis: patterns of response and injury
Michael Bauer a, Adrian T. Press a, and Michael Trauner b

Purpose of review Sepsis elicits profound changes in the concentrations of plasma proteins synthesized by liver parenchymal cells referred to as acute-phase proteins. Mechanisms controlling this orchestrated response include release of cytokines that induce acute-phase proteins, while other ‘house-keeping’ genes are downregulated. Recent findings Although some acute-phase proteins help to control damage, functions of many other acute-phase reactants remain obscure. Changes in acute-phase gene expression are primarily subject to transcriptional regulation and can be comprehensively monitored by array techniques. Emerging evidence from such strategies implies that in addition to a ‘common host response’ also highly specific pathways are induced in specific disease contexts. Applying a systems biology approach to the integrated response of the hepatocyte to infection would suggest that the reprogramming of metabolic functions occurs in parallel with a severitydependent disruption of phase I and II biotransformation and canalicular transport, that is, excretory failure. Although traditionally bilirubin serves to monitor excretion, emerging evidence suggests that bile acids indicate liver dysfunction with higher sensitivity and specificity. Summary Sepsis induces reprogramming of the hepatic transcriptome. This includes induction of adaptive acutephase proteins but also repression of phase I, II metabolism and transport with important implications for monitoring and pharmacotherapy. Keywords acute phase, biotransformation, cholestasis, stress response, transcriptomics

INTRODUCTION
Liver dysfunction and jaundice are redoubtable manifestations of critical illness. Extrahepatic bacterial infection and sepsis account for approximately 20% of jaundice cases only surpassed by malignant compression of the bile duct as cause [1]. As the liver plays a pivotal role in metabolic and immunological homeostasis, alterations in its function can acutely promote – in an ill-defined manner – progression of multiple organ failure. In a large Austrian multicentric cohort, early increase of plasma bilirubin (>2 mg/dl), noted in approximately 10% of critically ill intensive care patients of whom many were septic, was a strong independent risk factor for subsequent mortality [2], a pattern that has been confirmed in the year reviewed [3]. Furthermore, prolonged hepatic dysfunction impairs neutrophil phagocytic activity, burst, and killing but also the interplay with the adaptive immune system [4 ]. Thus, preexisting liver disease is a risk factor for the progression of bacterial infections to sepsis, for example, in community-acquired pneumonia with increased odds ratios for hospitalization, ICU admission, and death [5]. Vice versa,
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development of jaundice as a manifestation of sepsis was only observed with the widespread establishment of ICUs in the 1960s related at least in part to prototypical therapeutic ICU interventions, such as multiple transfusions, parenteral nutrition, and potentially hepatotoxic medications [6]. As a consequence, patients with septic complications in the presence of chronic liver disease, most notably cirrhosis, have a poor prognosis.

PATTERNS OF RESPONSE TO INFECTION: ACUTE PHASE AND BEYOND
Sepsis elicits profound changes in the plasma proteome. Many of the proteins affected are
a Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany and bDivision of Gastroenterology and Hepatology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria

Correspondence to Michael Bauer, Jena University Hospital, Erlanger Allee 101, D-07747 Jena, Germany. Tel: +49 3641 9323111; e-mail: michael.bauer@med.uni-jena.de Curr Opin Crit Care 2013, 19:123–127 DOI:10.1097/MCC.0b013e32835eba6d

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phosphatidylinositol-3-kinase (PI3K) is essential for intracellular trafficking and has been shown to selectively regulate ATP-dependent canalicular transporters in health and disease. augmenter of liver regeneration (ALR) protein. such as biotransformation and hepatobiliary transport. an important factor to promote liver regeneration. or metabolome of cells or tissues in an integrative manner. maintains hepatocellular viability and having an important role in parenchymal/ nonparenchymal cross-talk is inducible both by endotoxin and microbial sepsis [9 ]. was applied to study associated changes in the liver. Unauthorized reproduction of this article is prohibited. & & & && predominantly synthesized in liver parenchymal cells and named acute-phase proteins. 1). promising candidates to describe patterns of response to sepsis and infection.co-criticalcare. A model developed by Rudiger et al. hepatic induction of cholesterol biosynthesis was identified as a remote. including systemic inflammatory response syndrome (SIRS) and sepsis. This approach might be extended beyond protein-coding transcripts to identify regulatory micro-RNAs and long noncoding RNAs [12 ]. && ‘OMICS-TECHNOLOGIES’ AND APPROACHES OF SYSTEMS BIOLOGY Modern ‘highly parallel’ techniques allow assessing thousands of biomolecules simultaneously and can describe the genome. Moreover.Gastrointestinal system KEY POINTS  An increasing number of highly specific pathways induced in the liver in response to certain pathogens have been identified in addition to well known ‘common host response’ genes. These strategies can also be applied to assess gene expression patterns as they relate to outcome. Within the year of review. interleukin-6 (IL-6). altered handling of bile acids was observed to perform superiorly as a biomarker compared to the clinical standard. for example. induction of S-nitrosated alpha-1-acid glycoprotein [7 ] as well as angiopoetin-2 [8] was shown to confer protection in true microbial sepsis. PI3K signaling that had received considerable attention in the context of bile acidmediated apoptosis was also observed to affect hepatic phase I and II metabolism of bile acids.  This pattern of response seems to reflect an early and commonplace event that is underestimated based on conventional laboratory parameters. The shift in gene expression patterns due to sepsis is reflected in a large group of proteins that are conserved across pathogens and sites of infection. The primarily transcriptional control and the complex regulatory interplay of various mediators render gene expression profiling techniques. affect subsets of acute-phase genes and can either synergistically enhance or inhibit their respective effects acting on a transcriptional and. [15] predicting mortality that occurred between day 2 and 3 in septic peritonitis as early as 6 h after infection. posttranscriptional level. Furthermore. for instance. differences in the response to surgery per se (SIRS) and sepsis were monitored by array and identified significant differences regarding kinetics/resolution of the response as well as regarding specific effector functions [13 ]. This response reflects a highly regulated process as part of a more generalized reprogramming of signaling events across the body primarily under the influence of cytokines released in response to pathogenassociated molecular patterns. bilirubin. but there are in addition specific response patterns. Applying a similar transcriptomic and metabolomic approach across tissues. such as microarray and next generation sequencing. With regard to the physiological regulation of hepatobiliary transport and bile secretion. several groups have applied these ‘omics’-techniques to assess the response of the liver in the context of complex diseases and syndromes. pathogen-specific adaptive response to pneumococcal disease [14 ]. transcriptome. several promising candidates have been unraveled. Although some acute-phase proteins have been shown to control damage and to participate in tissue repair. even against multidrug-resistant bacteria. ‘house keeping functions’. which is paralleled by impaired innate immunity & & 124 www. a lack of hepatic c-Met and gp130 are associated with a substantially attenuated acute-phase response. In the clinical setting. and xenobiotics. measurements of acute-phase proteins are primarily of diagnostic or prognostic value.com Volume 19  Number 2  April 2013 Copyright © Lippincott Williams & Wilkins. bilirubin [16 ] (Fig. These mediators.  In parallel. understanding of this highly conserved adaptive mechanism might help to unravel novel therapeutic avenues. From a pathophysiological point of view. proteome. to a lesser extent. the role of many acutephase reactants remains speculative. A failure of hepatobiliary transport processes was observed in animals predicted to die due to septic peritonitis and resulted in hepatocellular retention of bile acids. . Within the year of review. in 2002 [11]. are downregulated. Since the pioneering work of Cobb et al. These signaling events may result in an upregulation (as in the case of C-reactive protein) or downregulation of proteins (as in the case of albumin). and antibacterial defense during cholestatic conditions [10 ]. Vice versa.

As a consequence. Influx of polymorphonuclear neutrophils (PMNs) represents a prominent feature of sepsisassociated tissue injury. the hepatobiliary excretory machinery appears exceptionally sensitive to inflammation [17]. a novel protective role for nonmyeloid cell MyD88 has been reported in septic peritonitis. PI3Kgamma serves as a molecular switch for liver failure in sepsis and is a potential target structure for novel therapy for liver dysfunction (xenobiotics. Inhalation of H2 allowed to safely apply hyperoxia (a therapeutic option that is hampered by its toxic side-effects). which results in increased hepatotoxicity in sepsis. This well described mechanism of hepatic inflammatory injury seems to be subject to alterations depending on the hormonal milieu [19] and contributes to the sexual dimorphism characterized by a higher susceptibility of male individuals for and protection against sepsisassociated liver injury by female hormones [20. in the development of hepatic dysfunction [29. wherein the proteins of the excretory apparatus (e. most notably the energy-dependent canalicular ATPbinding cassette (ABC) transporters required for normal bile secretion [27] underlying sepsis-associated cholestasis [28]. Gaseous mediators of cellular function beyond nitric oxide may include not only carbon monoxide and hydrogen sulphide but also molecular hydrogen & at low concentrations presumably preventing oxidative stress. endotoxin) of Gram-negative bacteria trigger Toll-like receptor (TLR)-dependent release of cytokines and other inflammatory mediators by Kupffer and other primarily nonparenchymal cells. Liver failure and potential underlying signaling events in sepsis.Liver in sepsis: patterns of response and injury Bauer et al. These factors impair the downstream expression and functional integrity of hepatocellular transport proteins. MECHANISMS AND MANIFESTATION OF HEPATIC PARENCHYMAL INJURY Of the varied liver partial functions. Interest continues in the role of preexisting liver disease.30]. Many of these concepts have been derived based on the use of endotoxininduced systemic inflammation or even shock www. Unlike in models of ischemia and reperfusion. potentially perpetuating hepatic excretory dysfunction [25. thereby increasing survival in the cecal ligation and puncture model substantially [23]. such as bile duct obstruction or alcoholic liver disease. including peroxynitrite [18]. Interestingly. Overexpressed PI3Kgamma is associated with downregulation of cytochromes and other enzymes involved in biotransformation. enzymes involved in biotransformation). Further. xenobiotics may accumulate in hepatocytes. Interest continues in assessing the role of gaseous mediators of microcirculatory and mitochondrial dysfunction in sepsis-associated liver injury. Sinusoid Physiologic state Sepsis induced dysfunction Sepsis Phase I and II metabolism PI3K-γ PI3K-γ Phase I and II metabolism PI3K-γ PI3K-γ inhibition ? PI3K-γ Canaliculi FIGURE 1. Indeed. PI3Kgamma-related signaling also causes internalization of the basolateral actin-rich brush borders. Mrp2) are located. Pathogen-associated molecular patterns (PAMPs) including lipopolysaccharides (LPSs. Interest continues in the role of nitric oxide as perpetuator of injury in particular in the presence of oxidative stress with the potential formation of reactive oxygen and nitrogen species. PI3Kgamma.com 125 1070-5295 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins.21]. To put it in a nut shell..26]. whereas myeloid MyD88 had the expected pro-inflammatory effect [22 ]. Unauthorized reproduction of this article is prohibited. the morphology as well as the physiology may be recovered by the inhibition of PI3Kgamma. .co-criticalcare. H2S seems to contribute to liver injury in sepsis acting in part via its vasoactive properties that differentially affect sinusoidal and extrasinusoidal vessels [24].g.

[32 ]. also referred to as phase III of biotransformation. Thus. functions of many other acute-phase reactants remain obscure. Volume 19  Number 2  April 2013 126 www. Although traditionally bilirubin has been used to monitor the excretory system. The aforementioned hepatobiliary transport processes involved in bile formation. Underlying mechanisms controlling this orchestrated response include the remote or paracrine release of mediators. phase I. A study by Vanwijngaerden et al. Similarly. Although some of these proteins have been shown to minimize tissue damage or to participate in hemostasis and repair. Changes in acute-phase protein gene expression are primarily subject to transcriptional regulation and can be comprehensively monitored by array or sequencing techniques. In this light. Consistently. glucuronic acid. that in turn affect subsets of acute-phase genes. altered biotransformation of endogenous substrates. The role of neutrophils as perpetrators of injury must be revisited and extended by a potential beneficial role as a contributor to bacterial clearance. Progress has been made during the year of review regarding understanding of potential mechanisms of liver dysfunction in the critically ill septic host. sulfonates. Emerging evidence from such strategies implies that in addition to a ‘common host response’ also highly specific pathways are induced in specific disease contexts. These authors observed a significant contribution of neutrophils and their DNA-based neutrophil extracellular traps or NETs to the overall phagocytic and bacterial clearing function of the liver. may be a critical yet underappreciated aspect of perpetuated liver damage in the postacute phase of sepsis in which patients often receive a multitude of different drugs daily. [36] that appeared in the year of review would indicate that hyperbilirubinemia in these patients indeed reflects cholestasis as it is associated with a disrupted expression pattern && & of the export machinery and a concomitant increase in serum bile acid levels. CONCLUSION Severe infections elicit profound changes in the concentrations of plasma proteins synthesized by liver parenchymal cells and referred to as acute-phase proteins. Apart from their fundamental role in the metabolism of endogenous compounds. and III of biotransformation are critical determinants of hepatic drug clearance [33]. glutathione. This is achieved by cytochrome P450dependent phase I (intramolecular) modifications that allow conjugation with various compounds. Acknowledgements None. oxidative stress. Applying a systems biology approach to the integrated response of the hepatocyte to infection and tissue injury would suggest that the reprogramming of metabolic functions occurs in parallel with a severity-dependent disruption of phase I and II biotransformation and canalicular transport. that is. typically require prior processing to improve solubility of hydrophobic or amphiphilic substrates including bile acids. In contrast. in phase II of the biotransformation process.com Copyright © Lippincott Williams & Wilkins. Thus. it is becoming increasingly clear that this diagnostic approach underestimates the problem and ignores the pathophysiologically important bile acids that indicate liver dysfunction with higher sensitivity and specificity. most notably bile acids and xenobiotics. excretory failure. there is emerging evidence that models of endotoxemia are not exactly modeling the mechanism of injury of sepsisinduced liver dysfunction. II.co-criticalcare. an adaptive role for influx of PMNs was described by McDonald et al. liver dysfunction with impaired phase I. Conflicts of interest The authors have no conflicts of interest to declare. Similarly. Recent evidence would suggest that amounts of endotoxin that induce significant cholestasis also induce injury/demise of hepatocytes (reflected in increases in transaminases) and of bile duct epithelia (reflected by increased alkaline phosphatase and gamma-glutamyl-transferase). caution is indicated regarding the use of statins that are currently discussed as adjunct therapies for sepsis-associated liver failure [34 ] as their pharmacokinetics are dramatically altered in the septic host [35]. such as IL-6. . Unauthorized reproduction of this article is prohibited.Gastrointestinal system associated with high doses of endotoxin by far exceeding those amounts observed in liver disease or sepsis. cholestasis is even more pronounced in polymicrobial sepsis in the absence of significant amounts of cytokines. II metabolism and transport reflects an early and poor prognostic event in the critically ill with important implications for monitoring and pharmacotherapy in the ICU. and ensuing conventional liver cell injury [31] casting doubt on the suitability of endotoxin models to unravel pathogenesis of sepsis-induced cholestasis. or amino acids. for example. the concept of a biphasic hepatic injury that heavily depends on an early oxidative stress mediated by Kupffer cells and followed by a secondary phase of neutrophil-dependent damage holds true for endotoxemia but oversimplifies the pathophysiology of hepatocellular dysfunction and the role of effector cells of innate immunity in true microbial sepsis.

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