Bench-to-beside review: Acute-on-chronic liver failure - linking the gut, liver and systemic circulation

Len Verbeke 0 Frederik Nevens 0 Wim Laleman 0 0 Department of Liver and Biliopancreatic Disorders, University Hospital Gasthuisberg, K.U. Leuven , Herestraat 49, B-3000 Leuven , Belgium The concept of acute-on-chronic liver failure (ACLF) was introduced recently to describe a subset of patients with chronic liver disease presenting with profound deterioration of liver function and rapidly evolving multi-organ failure. ACLF is frequently accompanied by the development of severe inflammatory response syndrome and has a high mortality. To date, treatment options are limited and exclusively supportive. Over the last few years, some insights have been generated in the pathophysiology of ACLF. A key role for the interaction of innate immune dysfunction, enhanced bacterial translocation from the gut, and circulatory dysfunction has been proposed. In this respect, therapeutic strategies have been examined, with variable success, in experimental studies in animals and humans. This review focuses on potentially relevant pathophysiological elements in the development of ACLF and points out promising treatment modalities in ACLF. - prevalence varies between 39% and 92% [3,4]. In Asia, mostly hepatitis B reactivation or the intake of hepatotoxic drugs is reported in the literature [5,6]. On the Indian subcontinent, a high incidence of hepatitis E superinfection was proposed in the etiology of ACLF [7]. The definition of ACLF is a matter of ongoing debate. In 2008, the Asian Pacific Association for the Study of the Liver proposed a consensus guideline defining the concept of ACLF [8]. In that paper, liver failure was defined as the development of jaundice and coagulopathy, complicated by ascites or encephalopathy or both within a time frame of 4 weeks. Remarkably, in this expert consensus definition, the precipitating event leading to ACLF was obligatory hepatic in origin. Thus, this definition excluded liver failure elicited by infection or gastrointestinal bleeding. Alternatively, in the recent literature in the West, ACLF is regarded more as a systemic complication of chronic liver disease since its clinical presentation is almost invariably accompanied by hemodynamic alterations, kidney failure, multi-organ failure, and inflammatory changes mimicking severe inflammatory response syndrome (SIRS) [2,3]. ACLF differs from chronic hepatic decompensation (CHD) in two key elements. First, the development of liver failure and end-organ dysfunction in ACLF is much faster than in CHD. In the literature, this period ranges from 2 to 12weeks [2,3,8,9]. Second (and maybe of more importance), in ACLF, there is still a chance of recovery of liver function. This is illustrated by clinical data in our prospective clinical cohort study, in which 54% of patients with ACLF survived hospitalization, and transplant-free survival rates in time matched those of comparable patients with CHD [3]. The high prevalence and mortality rates associated with ACLF make it an important health-care issue and, owing to the use of the MELD (Model for End-Stage Liver Disease) scoring system, renew interest in liver transplantation. In reported literature, short-term mortality rates vary from 46% to 89% [10]. Mortality in ACLF is closely related to the development of SIRS in patients, irrespective of the severity of liver disease [3,11]. Figure 1. Schematic representation of the presumed pathophysiology of acute-on-chronic liver failure. An acute insult launches a liverdriven cascade of bacterial translocation from the gut, an inappropriate response from the innate immune system, and subsequent intra- and extrahepatic circulatory dysfunction, ultimately leading to multi-organ failure. Pathophysiology of acute-on-chronic liver failure Three main mechanisms are currently proposed as key elements in the development of ACLF: immune dysfunction, intestinal bacterial translocation, and circulatory dysfunction (Figure 1). We will discuss each of these elements separately and point out important interactions in the context of ACLF. Innate immune dysfunction The innate immune system and Kupffer cells The innate immune system serves as a first-line defense mechanism against bacteria and toxins. It generates a non-pathogen-specific inflammatory response after stimulation with highly conserved antigens, such as lipopolysaccharides (LPSs). The main effector cells of the innate immune system are phagocytic cells, such as macrophages, neutrophils, and monocytes. The main cellular components of the innate immune system within the liver are the Kupffer cells. The liver is extremely important in innate immunity since Kupffer cells represent 80% to 90% of the tissue macrophages in the human body [12]. The strategic location of Kupffer cells within the lumen of the liver sinusoids and the anatomical location of the liver as a first-line station for bacteria and toxins derived from the gut further stress the importance of the liver as a strategic immunological organ. Classic mechanism of Kupffer cell activation Several basic scientific data support the concept of innate immune dysfunction on the cellular and molecular level in ACLF. The main orchestrator of immune dysfunction in liver disease has proven to be the Kupffer cell (Figure2). Kupffer cells in healthy liver exert many roles: they intervene in hemoglobin degradation, phagocytize bacteria and damaged cells, serve as antigen-presenting cells, and eliminate toxins such as ethanol [12,13]. Importantly, they interact intensively with other cells such as immune cells, sinusoidal endothelial cells, hepatocytes, and stellate cells, especially once they are activated. Kupffer cells are activated by many different stimuli through Toll-like receptors (TLRs). This form of Kupffer cell activation is considered the classic pathway of Kupffer cell activation into so-called M1 proinflammatory macrophages [14]. TLRs recognize multiple highly conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pathways (DAMPs). The most common pathway of Kupffer cell activation is through activation by LPS or Gram-negative bacterial endotoxin [13,15-21]. LPS binds to the acute-phase protein LPS-binding protein, enhancing interaction with the TLR4-CD14-MD2 receptor complex [22]. This interaction results in the recruitment of the adaptor molecules MyD88 and TRIF, which activate further downstream signaling cascades. The MyD88 signaling pathway is shared by all 13 members of the TLR family except for TLR3 [21]. Gram-positive bacteria interact with Kupffer cells through recognition of peptidoglycans and lipoproteins by the TLR2-TLR6 heterodimer complex [21,23]. Various other ligands such as viral RNA and necrotic cells have been identified interacting with specific members of the TLR family. The role of complement receptors binding C3a and C5a has also been established in Kupffer cell activation [12]. Recently, a new mechanism of Kupffer cell activation by hydrogen p (...truncated)