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Pathogenesis of Acute‐on‐Chronic Liver Failure in Patients With Infection

Clinical Liver Disease2019Vol. 14(3), pp. 103–106

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Watch a video presentation of this article Acute-on-chronic liver failure (ACLF) can develop in patients with cirrhosis both at the compensated and decompensated stages of liver disease (Fig. 1). The clinical symptoms of ACLF include acute liver decompensation, organ failure (or multiorgan failure), and increased short-term mortality.1 The triggers for ACLF could be different events including infections, gastrointestinal bleeding, alcohol binge, large-volume paracentesis, transjugular intrahepatic portosystemic shunt, and surgery, although the precipitating factor cannot be identified in some cases of ACLF.2 Most studies found infection as the most frequent cause of ACLF. The CANONIC study reported bacterial infection in 32.6% of 303 cases, whereas Shi et al. found 27.9% of 404 cases of ACLS linked to bacterial infection.3, 11 In the latter study from Asia, hepatitis B virus exacerbation caused ACLD in 35.8% of reported ACLS cases.3 Infection and ACLS is a dangerous combination for clinical outcomes for several reasons. In patients with ACLS caused by different etiologies, the presence of bacterial infection was associated with significantly lower 90-day survival compared with ACLF with no infection.4 Furthermore, the probability of acquiring infections in ACLS is increased in the presence of cirrhosis.5 Perhaps this is not unexpected given that cirrhosis is associated with nonspecific, low-level immunosuppression.6 Key elements of immune responses are impaired in patients with cirrhosis, including antigen presentation capacity of monocytes and decreased phagocytic function of macrophages that is pivotal for antibacterial immune defense. In addition, dysfunction of neutrophil leukocytes has been reported with reduced bacterial killing and migration activity in cirrhosis.6 All of these are combined with defects in the adaptive immune system with decreased T cell proliferation capacity and decreased levels of humoral immune components such as opsonins and complement factors.6 The combination of these impaired immune cell functions results in dysfunctional immune response to infections and pathogens. Pathogens that trigger ACLF can include bacterial, fungal, and viral pathogens that are mostly exogenous but can also be host derived from gut microbial translocation, the oral cavity, or skin sources (Fig. 2). The most common types of infections are spontaneous bacterial peritonitis (SBP), urinary tract infection (UTI), Clostridium difficile (C diff), and nosocomial infections. Infections, inflammation, and immune responses play an integral role in ACLF (Fig. 3). Immune and molecular recognition of infection is triggered by pathogen-derived signals, also referred to as pathogen-associated molecular patterns (PAMPs), through recognition by pattern recognition receptors such as Toll-like receptors (TLRs), intracellular helicase receptors, and nucleotide oligomerization domain–like receptors (NLRs). Activation of these receptors triggers innate immune responses in forms of proinflammatory cytokines and type I interferons. Induction of these innate immune host defense mechanisms in healthy individuals usually resolves the initial infection. In the setting of cirrhosis-related immune dysfunction, the host response to PAMPs is not always effective, resulting in systemic and/or prolonged infections. Infection and related sepsis are the most common causes of ACLF. Furthermore, increased levels of proinflammatory cytokines and chemokines contribute to organ dysfunction and multiorgan failure syndrome that dramatically increase mortality in ACLF. The systemic inflammatory response syndrome (SIRS) is defined as two or more of the following criteria: fever >38°C or 90 beats per minute, respiratory rate >20 breaths per minute or arterial CO2 tension 12,000 or 10% immature forms. SIRS is a clinical response to infection or a nonspecific insult such as ACLF. In ACLF, organ failure and mortality have a direct relationship. Plasma inflammatory cytokine levels, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, IL-10, and IL-1ra, are all significantly increased in ACLF compared with normal controls or patients with cirrhosis with no ACLF.7 A recent study identified that an increase in circulating levels of vascular cell adhesion molecule 1, vascular endothelial growth factor A, fractalkine, macrophage inflammatory protein 1α, eotaxin, and IL-10 with reduction in RANTES (regulated upon activation, normal T cell expressed, and secreted), granulocyte-macrophage colony-stimulating factor, and IL-1ß correlated with ACLF.7 Recent studies suggest that neutrophil leukocytes may play an important role not only in infection but also in ACLF. In a mouse model, abnormal neutrophil extracellular trap formation was reported in sepsis after acute alcohol binge drinking in mice.8 In severe bacterial infection, neutrophil recruitment through emergency granulopoiesis is a host defense mechanism to fight infection.9 Increased numbers of circulating neutrophils but reduced lymphocytes and monocyte counts were reported in patients with ACLF, indicating impaired immune balance.7 In persistent inflammatory states combined with sepsis, such as ACLF, the immune system is often debilitated by impaired and delayed adaptive immune responses in combination with persistent inflammation and immunosuppression (Fig. 4). Recent clinical trials attempted to ameliorate neutrophil functions by testing granulocyte-colony stimulating factor (G-CSF) in ACLF. Initial reports indicate a benefit of G-CSF administration in patients with ACLF.10 It remains, however, to be evaluated whether this approach will provide specific benefits in infection-related ACLF. In summary, infections trigger inflammation and ACLF via TLR and NLR sensor/receptors. ACLF is associated with intense systemic inflammation indicated by increased circulating cytokine levels. Inflammatory cytokines mediate many of the clinical symptoms of ACLF and contribute to SIRS and multiorgan dysfunction syndrome (MODS). Infection and cytokines induce emergency granulocytopoiesis characterized by neutrophilia and decreased frequencies of T cells, B cells, natural killer cells, and antigen-presenting cells. Preexisting immune dysfunction associated with cirrhosis compromises resolution of infections and complicates the clinical picture of ACLF.

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