Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions

Laleman, Wim; Verbeke, Len; Meersseman, Philippe; Wauters, Joost; Pelt, Jos van; Cassiman, David; Wilmer, Alexander; Verslype, Chris; Nevens, Frederik

doi:10.1586/egh.11.47

Cited by 87 publications

(92 citation statements)

References 100 publications

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“…Multi-organ failure often ensues in the ACLF syndrome following the hepatic decompensation. 34 Liver insufficiency is typically associated with a decreased detoxification function as manifested by hyperbilirubinemia (with clinical jaundice), encephalopathy and reduction of synthetic function leading to hypoalbuminemia and a decrease in prothrombin time. In this specific setting, the lack of liver detoxification and metabolic and regulatory functions leads to lifethreatening complications, which in the context of ACLF typically involve systemic hemodynamic dysfunction, renal insufficiency, cerebral failure (hepatic encephalopathy) and increased susceptibility to infections.…”

Section: Clinical Features and Prognosis Of Hev-related Aclfmentioning

confidence: 99%

“…In this specific setting, the lack of liver detoxification and metabolic and regulatory functions leads to lifethreatening complications, which in the context of ACLF typically involve systemic hemodynamic dysfunction, renal insufficiency, cerebral failure (hepatic encephalopathy) and increased susceptibility to infections. 34 In a large prospective study on ACLF, Garg et al have described the clinical, biochemical and etiological profiles of 91 ACLF patients. 31 The median ages of these patients was 36 years and most were males.…”

Section: Clinical Features and Prognosis Of Hev-related Aclfmentioning

confidence: 99%

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Hepatitis E and Acute-on-Chronic Liver Failure

Kumar

Saraswat

2013

Journal of Clinical and Experimental Hepatology

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Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis (AVH) globally. It causes large scale epidemics of AVH across the low-and middle income countries in Asia and Africa, and also causes sporadic cases of AVH in the same geographical region. AVH due to HEV is usually an acute, self-limiting illness, similar in clinical presentation to AVH caused by hepatitis A virus (HAV). When HEV causes AVH in patients of chronic liver disease it may worsen rapidly to a syndrome called acute-on-chronic liver failure (ACLF) leading to very high mortality. Acute deterioration of liver function in a patient with compensated chronic liver disease is the characteristic feature of ACLF. The typical disease course of patients with ACLF is the appearance of organ failure, which progresses to multi-organ failure and death. Many publications have reported HEV as one of the leading causes for ACLF from Asia and Africa, where HEV is endemic. The mortality rate of HEV-related ACLF (HEV-ACLF) ranges from 0% to 67% with a median being 34%. These patients require admission in the intensive care unit and they benefit from a team approach of clinicians with expertise in both hepatology and critical care. The goals of treatment are to prevent further deterioration in liver function, reverse precipitating factors, and support failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. One preliminary report suggests that ribavirin may be an effective and safe drug for treatment of HEV-ACLF however this requires validation in large trials. ( J CLIN EXP HEPATOL 2013;3:225-230)

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Section: Clinical Features and Prognosis Of Hev-related Aclfmentioning

confidence: 99%

Section: Clinical Features and Prognosis Of Hev-related Aclfmentioning

confidence: 99%

Hepatitis E and Acute-on-Chronic Liver Failure

Kumar

Saraswat

2013

Journal of Clinical and Experimental Hepatology

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“…In a patient with cirrhosis, liver failure occurs when a critical threshold of hepatocellular function is crossed due to progression of liver disease. 70,71 Any attrition of liver function due to ATD-induced hepatotoxicity in a patient with wellcompensated or previously decompensated chronic liver disease may result in severe, acute deterioration, resulting in a clinical picture suggestive of acute or acute-onchronic liver failure (ALF or ACLF) (Figure 1). With this background in mind, one needs to be circumspect in making recommendations regarding the prescription of ATT in liver cirrhosis (Table 3).…”

Section: Chronic Hepatitis C Virus Infectionmentioning

confidence: 99%

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Dhiman

Saraswat

Rajekar

et al. 2012

Journal of Clinical and Experimental Hepatology

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Tuberculosis remains one of the 'Captains of the Men of Death' even today, particularly in the developing world. Its frequency is increased 14-fold in patients with chronic liver diseases (CLD) and liver cirrhosis, more so in those with decompensated disease, probably due to the cirrhosis-associated immune dysfunction syndrome, and case-fatality rates are high. The diagnosis of tuberculosis, particularly the interpretation of the Mantoux test, is also fraught with difficulties in CLD, especially after previous BCG vaccination. However, the greatest challenge in the patient with CLD or liver cirrhosis and tuberculosis is managing their therapy since the best first-line anti-tuberculosis drugs are hepatotoxic and baseline liver function is often deranged. Frequency of hepatotoxicity is increased in those with liver cirrhosis, chronic hepatitis B and chronic hepatitis C, possibly related to increased viral loads and may be decreased following antiviral therapy. If hepatotoxicity develops in those with liver cirrhosis, particularly decompensated cirrhosis, the risk of severe liver failure is markedly increased. Currently, there are no established guidelines for anti-tuberculosis therapy (ATT) in CLD and liver cirrhosis although the need for such guidelines is self-evident. It is proposed that ATT should include no more than 2 hepatotoxic drugs (RIF and INH) in patients with CLD or liver cirrhosis and stable liver function [ChildTurcotte-Pugh (CTP) #7], only a single hepatotoxic drug (RIF or INH) in those with advanced liver dysfunction and no hepatotoxic drugs with very advanced liver dysfunction (CTP $11). A standard protocol should be followed for monitoring ATT-related hepatotoxicity and for stop rules and reintroduction rules in all these patients, on the lines proposed here. It is hoped that these proposals will introduce uniformity and result in streamlining the management of these difficult patients. ( J CLIN EXP HEPATOL 2012;2:260-270)

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“…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.…”

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confidence: 99%

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

et al. 2015

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Acute-on-chronic liver failure (ACLF) is an ailment with high incidence of multiorgan failure (MOF) and consequent mortality. Dysregulated iron homeostasis and macrophage dysfunction are linked to increased incidence of MOF. We investigated whether a panel of circulating iron-regulating proteins are associated with development of MOF and can predict 15-or 30-day mortality in ACLF patients. One hundred twenty patients with ACLF, 20 patients with compensated cirrhosis, and 20 healthy controls were studied. Relative protein expression profiling was performed in the derivative cohort and confirmed in the validation cohort. A panel of iron regulators and indices were determined. Multiparametric flow cytometry for quantitation of labile iron pool (LIP) was performed. Validation studies confirmed lower serum transferrin (Tf) and ceruloplasmin levels in ACLF and ACLF-MOF, compared to patients with cirrhosis and controls (P < 0.01). Serum iron and ferritin levels were markedly elevated (P < 0.001; P < 0.05) and hepcidin levels were lower (P < 0.001) in ACLF patients with MOF than those without and other groups (P < 0.001). Percentage Tf saturation (%SAT) was higher in ACLF-MOF (39.2%; P < 0.001) and correlated with poor outcome (hazard ratio: 6.970; P < 0.01). Intracellular LIP indices were significantly elevated in the subsets of circulating macrophages in ACLF-MOF, compared to other groups (P < 0.01). Whereas expression of iron-regulatory genes was markedly down-regulated, genes related to endoplasmic reticulum stress, apoptosis, and inflammation were up-regulated in ACLF patients, compared to patients with cirrhosis. Severe dysregulation of autophagy mechanisms was also observed in the former. Conclusions: Iron metabolism and transport are severely deranged in ACLF patients and more so in those with MOF. %SAT, circulating hepcidin, and LIP in macrophages correlate with disease severity and %SAT could be used for early prognostication in ACLF patients. (HEPATOLOGY 2015;61:1306-1320

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Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions

Cited by 87 publications

References 100 publications

Hepatitis E and Acute-on-Chronic Liver Failure

Hepatitis E and Acute-on-Chronic Liver Failure

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

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

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