Acute-on-Chronic Liver Failure Arroyo, Vicente; Moreau, Richard; Jalan, Rajiv
The New England journal of medicine,
05/2020, Volume:
382, Issue:
22
Journal Article
Peer reviewed
Acute decompensation in patients with chronic liver disease is called acute-on-chronic liver failure. Usually, systemic inflammation from infection or an acute hepatic injury precipitates liver ...dysfunction and extrahepatic organ failures, with increased mortality.
Abstract The gut is open to the outer environment, harbours the microbiome containing several fold more genetic material than the human genome and produces a myriad of metabolites as well as ...hormones/peptides. The liver is at the nexus between this vast source of nutrients, toxins and hormones and the remaining human body. Not surprisingly, this liver-gut-axis has hence, been demonstrated in experimental models and in-vitro systems to contribute to the pathogenesis of most liver diseases such as alcoholic and non-alcoholic fatty liver disease (NAFLD), -steatohepatitis (NASH), cholestatic liver diseases, hepatocellular carcinoma, acute-on-chronic liver failure, progression to fibrosis/cirrhosis and complications of cirrhosis. Therapeutic approaches can be grouped into modulation of the microbiota, the bile acid pool and/or its signaling, gut-lumen adsorptive strategies, bariatric procedures, incretins and miscellaneous (e.g.prokinetics). However, in order to proof these concepts investigations in humans are key and thus, this article will highlight the most recent human studies and clinical trials targeting the liver-gut-axis. A list of ongoing (not yet published) trials is presented in table 1. Moreover, we will take the liberty to encourage clinical trials on concepts that are so far not yet established.
The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and ...immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan ...dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
Summary Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is ...associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality.
Renal dysfunction occurs in 25% to 50% of patients with cirrhosis admitted to the hospital with an acute episode of hepatic decompensation and may be due to underlying chronic kidney disease, an ...acute deterioration, or both. An acute deterioration in renal function in cirrhotic patients is now collectively referred to as acute kidney injury (AKI), which has been subclassified into different grades of severity that identify prognostic groups. Acute-on-chronic liver failure is characterized by acute hepatic and/or extrahepatic organ failure driven by a dysregulated immune response and systemic inflammatory response. AKI is also one of the defining features of ACLF and a major component in grading the severity of acute-on-chronic liver failure. As such, the pattern of AKI now observed in patients admitted to the hospital with acutely decompensated liver disease is likely to be one of inflammatory kidney injury including acute tubular injury (referred in this review as non–hepatorenal syndrome HRS-AKI) rather than HRS. As the management and supportive treatment of non–HRS-AKI potentially differ from those of HRS, then from the nephrology perspective, it is important to distinguish between non–HRS-AKI and HRS-AKI when reviewing patients with acute-on-chronic liver failure and AKI, so that appropriate and early management can be instituted.
Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal ...dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.
Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and ...characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.Patients407 patients with ACLF and 235 patients with acute decompensation (AD).Results152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%).ConclusionBacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.
Cirrhosis is a major cause of mortality worldwide. Exponential rises in prevalence have been observed secondary to increases in obesity and alcohol consumption. Multiple lines of evidence implicate ...gut-derived bacteria and bacterial ligands as a central driver of pathogenesis. Recent developments in culture-independent techniques have facilitated a more accurate description of microbiome composition in cirrhosis and led to the description of measures of dysbiosis shown to be associated with disease. More importantly, metagenomic studies are adding to an understanding of the functional contribution of the microbiota and may prove to be a more clinically relevant biomarker than phylogenetic studies. Much like other dysbiotic states such as inflammatory bowel disease, the microbiota in cirrhosis is characterized by a low microbial and genetic diversity. Therapeutic strategies to diminish this process are currently limited to selective intestinal decontamination with antibiotics. This review summarizes the available data and develops a framework for the use of current and future treatment strategies to diminish the consequences of dysbiosis in cirrhosis. Interventional strategies to bind bacterial products in the gut lumen and blood, and modulate the magnitude of host sensing mechanisms remain an unmet clinical need. A greater understanding of the host-microbiota interaction in cirrhosis is of key importance to inform future interventional strategies to diminish the currently escalating burden of the disease.
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