Acute-on-Chronic Liver Failure: Pathophysiological Basis of Therapeutic Options

Abstract

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short- and long-term prognosis. This review focusses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver-support strategies to enhance the recovery process.

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

“…Many toxic compounds, such as copper, iron, ammonia, and bile acids, are likely to accumulate in circulation, resulting in severe inflammation and tissue injury and leading to progression of ACLF. 1 We hypothesized that iron balance is dysregulated in patients with ACLF. At the discovery phase, a relative protein expression profile analysis was performed and we identified 416 circulating proteins; 35 were more than 2-fold up-regulated and 54 were more than 2-fold down-regulated.…”

“…1 ACLF often leads to mortality in 50%-90%, mainly owing to ongoing hepatic dysfunction and multiorgan failure (MOF). [1][2][3] Various small molecules, toxic metabolites, heavy metals, and phenols are reported to accumulate in ACLF.…”

“…1 ACLF often leads to mortality in 50%-90%, mainly owing to ongoing hepatic dysfunction and multiorgan failure (MOF). [1][2][3] Various small molecules, toxic metabolites, heavy metals, and phenols are reported to accumulate in ACLF. 4 Abbreviations: ACLF, acute-on-chronic liver failure; ACLF-MOF, acute-on-chronic liver failure with multiorgan failure; ALT, alanine aminotransferase; APC, allophycocanin; ATG, autophagy-related gene; AUROC, area under the receiver operating characteristic curve; BAX, B-cell lymphoma 2-associated X protein; CA-AM, acetomethoxy derivate of calcein; CHOP, CAAT/enhancer-binding protein homologous protein; CI, confidence interval; CLD, chronic liver disease; CP, ceruloplasmin; CTP, Child-Turcotte-Pugh; DMT1, divalent metal transporter 1; DCYTB, duodenal cytochrome B; ELISA, enzyme-linked immunosorbent assay; ER, endoplasmic reticulum; GRP78, 78-kDa glucose-regulated protein; HBV, hepatitis B virus; HE, hepatic encephalopathy; HFE, hemochromatosis factor; HLA, human leukocyte antigen; IQR, interquartile range; IRE1, inositol-requiring enzyme 1; iTRAQ, isobaric tags for relative and absolute quantitation; LC, liver cirrhosis; LIP, labile iron pool; MELD, Model for End-Stage Liver Disease; MOF, multiorgan failure; MS, mass spectrometry; PBMCs, peripheral blood mononuclear cells; PCR, polymerase chain reaction; PE, phycoerythrin; PERK, PKR-like ER-resident kinase; %SAT, percentage transferrin saturation; RR, relative risk; SOFA, sequential organ failure assessment; Tf, transferrin; TfR, transferrin receptor; TFR2, transferrin receptor 2; TNF, tumor necrosis factor; TRF2, telomeric repeatbinding factor 2; XBP1, X-box protein 1.…”

“…From the 1 Departments of Research and 3 Hepatology, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India; 2 Institute of Bioinformatics, International Technology Park, Bangalore, India; Departments of 4 Biological Chemistry, 5 Pathology, and 6 Oncology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; and 7 Department of Pathology, ILBS, New Delhi, India.…”

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014

“…Liver dialysis and replacement therapy in ACLF The hepatocellular injury in ACLF is driven to a large extent by a ''cytokine burst,'' with elevated levels of multitude of cytokines, small molecular weight toxins, vasoactive substances that are known to accumulate secondary to the failing liver [122]. There is an additional challenge of the injury due to endotoxin and metabolites released from gut bacteria.…”