==== Front
Crit Care
Critical Care
1364-8535
1466-609X
BioMed Central London

37393351
4540
10.1186/s13054-023-04540-4
Review
Acute-on-chronic liver failure: far to go—a review
Luo Jinjin 1
Li Jiaqi 12
Li Peng 1
Liang Xi 3
Hassan Hozeifa Mohamed 3
Moreau Richard richard.moreau@inserm.fr

456
Li Jun lijun2009@zju.edu.cn

1
1 grid.13402.34 0000 0004 1759 700X State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003 China
2 grid.506977.a 0000 0004 1757 7957 Department of Gastroenterology, Zhejiang Provincial People’s Hospital, People’s Hospital Affiliated of Hangzhou Medical College, Hangzhou, China
3 grid.452858.6 0000 0005 0368 2155 Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
4 grid.490732.b 0000 0004 7597 9559 European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
5 grid.7429.8 0000000121866389 Centre de Recherche Surl’Inflammation (CRI), Institut National de La Santé Et de La Recherche Médicale (INSERM) & Université Paris-Cité, Paris, France
6 grid.411599.1 0000 0000 8595 4540 Service d’Hépatologie, Assistance Publique–Hôpitaux de Paris (APHP), Hôpital Beaujon, Clichy, France
1 7 2023
1 7 2023
2023
27 25915 5 2023
22 6 2023
© The Author(s) 2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Acute-on-chronic liver failure (ACLF) has been recognized as a severe clinical syndrome based on the acute deterioration of chronic liver disease and is characterized by organ failure and high short-term mortality. Heterogeneous definitions and diagnostic criteria for the clinical condition have been proposed in different geographic regions due to the differences in aetiologies and precipitating events. Several predictive and prognostic scores have been developed and validated to guide clinical management. The specific pathophysiology of ACLF remains uncertain and is mainly associated with an intense systemic inflammatory response and immune-metabolism disorder based on current evidence. For ACLF patients, standardization of the treatment paradigm is required for different disease stages that may provide targeted treatment strategies for individual needs.

Keywords

Acute-on-chronic liver failure
Organ failure
Prognosis
Systemic inflammatory response
Immune-metabolism disorder
Clinical management
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81830073 Li Jun National Provincial special support program for high-level personnel recruitmentTen-thousand Talents Program Li Jun State’s Key Project of Research and Development Plan of China2022YFC2304801 Li Jun Zhejiang Public Welfare ProjectLGF21H200006 Li Jun issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2023
==== Body
pmcIntroduction

Acute-on-chronic liver failure (ACLF) is a life-threatening clinical syndrome that develops in patients with acute deterioration of chronic liver disease [1]. In Western countries, alcohol-related cirrhosis is the most common cause of chronic liver disease, with bacterial infections being the most important precipitant of ACLF. In contrast, in the Asia–Pacific region, hepatitis B virus (HBV) infection is the most common aetiology of liver disease, and HBV reactivation is the most frequent ACLF trigger/hepatic event [2]. The definitions of ACLF currently vary worldwide, but despite these differences, patients with ACLF uniformly have a high risk of short-term mortality with multiorgan failure [1]. New results have been published suggesting the existence of a unique pathophysiology of patients with HBV-ACLF [3]. Meanwhile, the current evolution of ACLF clinical management involves the emergence of potential therapeutic strategies. This review provides an updated summary of the diagnostic criteria and prognostic scores proposed by different scientific societies, the underlying pathophysiology of ACLF and its treatment.

Definitions

In the past decade, several definitions of ACLF have been proposed by international consortia (summarized in Table 1). The main controversies involve the type of precipitating events (intrahepatic or extrahepatic), the stage of underlying chronic liver disease leading to ACLF (chronic hepatitis or cirrhosis) and whether the definition should include extrahepatic organ failures (OFs).Table 1 Definitions, diagnostic criteria and stratification of ACLF proposed by each of the four major international scientific consortia

Characteristics	European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium	Chinese Group on the Study of Severe Hepatitis B (COSSH)	Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC)	North American Consortium for the Study of End-stage Liver Disease (NACSELD)	
Study type	Multicentre, prospective, observational study	Multicentre, prospective, observational study	Expert consensus report	Multicentre, prospective, observational study	
Main aetiology	Alcohol, HCV	HBV	HBV	Alcohol	
Precipitating events	Intrahepatic (alcoholic hepatitis), extrahepatic (infection, variceal haemorrhage), or both	Intrahepatic (HBV reactivation), extrahepatic (bacterial infection) or both	Intrahepatic	Intrahepatic, extrahepatic or both	
Population	Compensated and decompensated cirrhosis	HBV-related chronic liver disease	Chronic liver disease

Compensated cirrhosis

	Compensated and decompensated cirrhosis	
Criteria of Organ failure	Liver: total bilirubin ≥ 12 mg/dL;

Kidney: creatinine ≥ 2 mg/dL or use of RRT;

Coagulation: INR ≥ 2.5;

Brain: West Haven grade 3–4 HE or use of mechanical ventilation due to HE;

Circulation: Use of vasopressors;

Respiration: PaO2/FiO2 ≤ 200 or SpO2/FiO2 ≤ 214,

or use of mechanical ventilation not due to HE

	Liver: Total bilirubin ≥ 12 mg/dL;

Kidney: Creatinine ≥ 2 mg/dL or use of RRT;

Coagulation: INR ≥ 2.5;

Brain: West Haven grade 3–4 HE or use of mechanical ventilation due to HE;

Circulation: Use of vasopressors;

Respiration: PaO2/FiO2 ≤ 200 or SpO2/FiO2 ≤ 214,

or use of mechanical ventilation not due to HE

	Liver: Total bilirubin ≥ 5 mg/dL;

Brain: clinical HE

	Kidney: Use of dialysis or other form of RRT;

Brain: HE Grade 3–4 in West Haven classification;

Circulation: MAP < 60 mmHg or reduction of 40 mmHg in

SBP from baseline, in spite of fluid resuscitation and adequate cardiac output;

Respiration: Use of mechanical ventilation

	
Criteria for the presence of ACLF and ACLF stratification	ACLF is divided into 3 grades of increasing severity

Grade 1 includes 3 subgroups:

(1) single kidney failure; (2) single liver, coagulation, circulatory or respiratory failure with either kidney dysfunction, brain dysfunction, or both;

(3) single brain failure and kidney dysfunction;

Grade 2: 2 organ failures;

Grade 3: 3 or more organ failures

	ACLF is divided into 3 grades of increasing severity

Grade 1 includes 4 subgroups:

(1) single kidney failure; (2) single liver failure and either INR ≥ 1.5, kidney dysfunction, brain dysfunction, or any combination of these alterations;

(3) single coagulation, circulatory or respiratory failure with either kidney dysfunction, brain dysfunction, or both;

(4) brain failure alone plus kidney dysfunction;

Grade 2: 2 organ failures;

Grade 3: 3 or more organ failures

	Acute hepatic insult manifesting as jaundice (total bilirubin levels of 5 mg/dl or more) and coagulopathy (INR ≥ 1.5, or prothrombin activity < 40%) complicated within 4 weeks by clinical ascites, HE, or both

The severity of ACLF is assessed using the AARC score

Grade 1: 5–7 scores,

Grade 2: 8–10 scores,

Grade 3: 11–15 scores

	Patients are stratified according to the number of organ failures 2, 3, or all 4 organ failures	
Prevalence of ACLF grade	Grade 1: 49%

Grade 2: 35%

Grade 3: 16%

	Grade 1: 61%

Grade 2: 33%

Grade 3: 6%

	/	2 Organ failures: 43%

3 Organ failures: 41%

4 Organ failures: 16%

	
Main organ failures	Kidney, Liver	Liver, Coagulation	Liver, Coagulation	Brain	
Short-term mortality rate of ACLF	By 28 days:

Grade 1: 22%

Grade 2: 32%

Grade 3: 77%

	By 28 days:

Grade 1: 23%

Grade 2: 61%

Grade 3: 93%

	By 28 days:

Grade 1: 13%

Grade 2: 45%

Grade 3: 86%

	By 30 days:

2 Organ failures: 49%

3 Organ failures: 64%

4 Organ failures: 77%

	
ACLF acute-on-chronic liver failure; FiO2 fraction of inspired oxygen; HBV hepatitis B virus; HCV hepatitis C virus; HE hepatic encephalopathy; INR international normalized ratio; MAP mean arterial pressure; PaO2 partial pressure of arterial oxygen; RRT renal replacement therapy; SBP systolic blood pressure; SpO2 pulse oximetric saturation

European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) ACLF

To define ACLF as a distinct syndrome, a multicentre, prospective and observational (chronic liver failure consortium acute-on-chronic liver failure in cirrhosis) CANONIC study, involving 1343 patients nonelectively hospitalized for acute decompensation of cirrhosis with or without prior decompensation, was performed in Europe to determine the characteristics of patients with OFs; a ≥ 15% mortality rate at 28 days was observed [4]. The EASL-CLIF ACLF definition includes both intra- and extra-hepatic precipitating events and emphasizes the importance of extrahepatic OFs rather than liver failure alone. The diagnosis of organ failure is based on the CLIF-C OF scoring system as a modified sequential organ failure assessment (SOFA) score, which assesses six organ systems (liver, kidney, brain, coagulation, circulation and respiration) [5]. The criteria comprise three grades with increasing severity. Patients with ACLF have a single kidney failure (ACLF grade 1/ACLF-1); a single nonkidney organ failure if it is associated with kidney or brain dysfunction (ACLF-1); or more than 2 OFs (ACLF-2 or 3) on the basis of the type and number of OF(s).

Chinese Group on the Study of Severe Hepatitis B (COSSH) ACLF

To clarify the characteristics of ACLF in the HBV population, a definition was proposed by the prospective and observational COSSH study based on data from 1322 patients nonelectively hospitalized with cirrhosis or severe liver injury due to chronic hepatitis B. The COSSH study found that patients with HBV-ACLF had significantly worse clinical characteristics, and the short-term mortality of patients with noncirrhotic HBV-ACLF was significantly higher than that of patients with non-HBV-ACLF. Regardless of the presence of cirrhosis, patients with a total bilirubin (TB) ≥ 12 mg/dL and an international normalized ratio (INR) ≥ 1.5 had a higher short-term mortality [6]. Three ACLF grades were also proposed to more easily categorize patients with ACLF based on criteria that were similar to the European definition; however, patients with single liver failure and an INR of ≥ 1.5 were additionally diagnosed with ACLF grade 1. The COSSH-ACLF criteria exhibited higher diagnostic sensitivity and prognostic accuracy and bridged the gap in the EASL-CLIF criteria for HBV-ACLF diagnosis.

Asian Pacific Association for the Study of the Liver (APASL) ACLF

Based on expert opinion, a definition was published by the APASL ACLF Research Consortium (AARC) in 2009. ACLF was defined as a syndrome of acute liver function damage on the basis of known or unknown chronic liver disease (TB ≥ 5 mg/dl and INR ≥ 1.5 or prothrombin activity ≤ 40%) accompanied by ascites and/or hepatic encephalopathy within 4 weeks. The features of “high 28-day fatality rate” and “reversibility of the ACLF syndrome” were added as parts of the definition in subsequent updates in 2014 and 2019 [7–9]. The definition mainly includes patients with compensated liver disease and excludes patients with prior decompensation. Primary intrahepatic insults are considered the only precipitating events; extrahepatic insults, such as bacterial infection, are considered to be complications but not precipitating events of ACLF. Liver failure is essential in diagnosing ACLF, whereas extrahepatic OFs are not required to make the diagnosis and are considered to be manifestations that are concurrent with the development of ACLF.

North American Consortium for the Study of End-stage Liver Disease (NACSELD) ACLF

The NACSELD proposed a definition of ACLF in 2014, based on the analysis of the NACSELD database, which included 507 patients with acutely decompensated cirrhosis with infection [10]. Four organ systems (circulation, respiration, kidney, brain) were assessed, and the presence of ≥ 2 OFs was defined as ACLF. The definition did not include changes in liver function and coagulation, which are the typical pathophysiological manifestations of ACLF.

Prediction and prognosis

The accuracy and sensitivity of predictive and prognostic scores are important to make decisions regarding intensive care strategies and predict outcomes in patients with ACLF. The populations, variables, formulas and applications of commonly used scores developed by the abovementioned consortia are summarized in Table 2 [4–6, 11–15].Table 2 Predictive and prognostic scores developed by different consortia

Scores	Population	Variable	Formula	Application	
Prognostic scores					
CLIF-C ACLFs	Acutely decompensated cirrhosis	CLIF‐OFs (TB, creatinine, use of RRT, HE, endotracheal intubation for HE, INR, MAP, Use of vasopressors, PaO2, SpO2, FiO2), age, WBC	10 × [0.33 × CLIF-OFs) + 0.04 × age + 0.63 × ln (WBC, 109/L) − 2]	Individual estimates of mortality	
COSSH-ACLFs	Acute deterioration of HBV-related chronic liver disease	HBV-SOFAs (creatinine, HE, MAP, Use of vasopressors, PaO2, SpO2, FiO2), INR, age, TB	0.741 × INR + 0.523 × HBV-SOFAs + 0.026 × age + 0.003 × TB (μmol/L)	/	
COSSH-ACLF IIs	Acute deterioration of HBV-related chronic liver disease	INR, HE, neutrophil, TB, serum urea, age	1.649 × ln(INR) + 0.457 × HE score (0/I-II/III-IV: 1/2/3 points) + 0.425 × ln(neutrophil, 109/L) + 0.396 × ln(TB, umol/L) + 0.576 × ln(serum urea, mmol/L) + 0.033 × age	Individual estimates of mortality;

Risk stratification: 28-/90-day Mortality:

Low-risk (< 7.4): 8%/19%;

Intermediate-risk (7.4–8.4): 50%/66%;

High-risk (≥ 8.4): 76%/88%

	
AARC-ACLFs	Acute deterioration of chronic liver disease	TB, creatinine, serum lactate, INR, HE	TB (< 15/15–25/ > 25 mg/dl; 1/2/3 points) + HE (0/I-II/III-IV; 1/2/3 points) + INR (< 1.8/1.8–2.5/ > 2.5; 1/2/3 points) + Lactate (< 1.5/1.5–2.5/ > 2.5 mmol/L;1/2/3 points) + creatinine (< 0.7/0.7–1.5/ > 1.5 mg/dl; 1/2/3 points)	Risk stratification: 28-day Mortality:

Grade-I (5–7): 13%;

Grade-II (8–10): 45%;

Grade-III (11–15): 86%

	
Predictive scores					
CLIF-C ACLF-Ds	Acutely decompensated cirrhosis without ACLF	Age, ascites, WBC, albumin, TB, creatinine	0.03 × Age + 0.45 × Ascites + 0.26 × ln(WBC)–(0.37 × Albumin) + 0.57 × ln(TB) + 1.72 × ln(Creatinine) + 3 × 10	Predicting the onset of ACLF, but showed a similar accuracy to other scores	
COSSH-onset- ACLFs	Acute deterioration of HBV-related chronic liver disease without ACLF	ALT, TB, INR, serum ferritin	0.101 × ln(ALT) + 0.819 × ln(TB) + 2.820 × ln(INR) + 0.016 × ln(ferritin)	Predicting the onset of HBV-ACLF at 7/14/28 days after admission;

Risk stratification for progression to ACLF at 7/14/28 days:

Low-risk (< 6.3): 2.5%/3.2%/3.7%;

High-risk (≥ 6.3): 42.6%/49.2%/50%

	
ACLF acute-on-chronic liver failure; AARC Asian Pacific Association for the Study of the Liver ACLF Research Consortium; HBV hepatitis B virus; CLIF-C Chronic Liver Failure-Consortium; COSSH Chinese Group on the Study of Severe Hepatitis B; HE hepatic encephalopathy; INR international normalized ratio; MAP mean arterial pressure; NACSELD; North American Consortium for the Study of End-stage Liver Disease; OF organ failure; RRT renal replacement therapy; SOFA sequential organ failure assessment; TB total bilirubin; WBC white blood cell

Pathophysiology

Systemic inflammation

Studies have indicated that the intense systemic inflammatory response is the main cause of acute deterioration that leads to ACLF in patients with alcohol-related liver disease (ALD) and in those with chronic hepatitis C [16, 17]. ALD-ACLF patients have higher levels of inflammatory response indicators, such as the WBC count and C-reactive protein, which are closely related to prognosis. The levels of proinflammatory factors such as interleukin (IL)-6 and IL-8 and anti-inflammatory factors such as IL-10 in the blood are also significantly increased in these patients [4, 5, 16, 18]. Systemic inflammation can be induced by the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [19, 20]. Bacterial infection, the primary precipitant of ACLF, can cause high levels of circulating PAMPs, which can be recognized by pattern-recognition receptors (PRRs). PRR engagement can drive intracellular signalling cascades (such as JAK2/STAT1, NF-κβ, etc.), ultimately leading to the transcription and synthesis of inflammatory mediators, an imbalance in anti-inflammatory and proinflammatory regulation, and the production of a cytokine storm [20]. Systemic inflammation can also occur in the absence of infection, a process known as sterile inflammation. In this case, the release of numerous DAMPs from dying or damaged hepatocytes (in the context of alcohol-related hepatitis or HBV activity) activates specific PRRs, triggering the release of inflammatory cytokines, which leads to an inflammatory response and ultimately ACLF (Fig. 1) [21, 22].Fig. 1 Pathophysiology of ACLF. Chronic liver diseases related to alcohol and HBV under precipitating events (bacterial infection and HBV reactivation) induce a dramatic immune-inflammatory response and metabolism disorder and eventually develop into multiple organ failures. The systemic inflammatory response plays an important role in the development of ALD-ACLF. The released PAMPs and DAMPs from bacteria and necrotic cells activate immune cells and result in the increased release of inflammatory mediators and even a cytokine storm. Activation of the innate-immune system and exhaustion of the adaptive immune system are the core mechanisms of HBV-ACLF. Alterations in metabolic pathways regulate glycolysis, proteolysis and lipolysis in the context of immune-inflammatory disorder and liver failure. Glucose is used to rapidly produce ATP through glycolysis and enters the pentose phosphate pathway and glucuronic acid pathway, whereas mitochondrial oxidative phosphorylation is suppressed; mitochondrial β-oxidation of fatty acids is inhibited; and increased generation and accumulation of amino acids are metabolized through specific metabolic pathways. ACLF, acute-on-chronic liver failure; ATP, adenosine triphosphate; HBV, hepatitis B virus; CoA, coenzyme A; DAMPs, damage-associated molecular patterns; ETC, electron transport chain; HMGB1, high mobility group box 1; IL, interleukin; LPS, lipopolysaccharide; MDSC, myeloid-derived suppressor cell; m-TOR, mammalian target of rapamycin; NETs, neutrophil extracellular traps; NO, nitric oxide; PAMPs, pathogen-associated molecular patterns; PPAR, peroxisome proliferator-activated receptors; PRRs, pattern-recognition receptors; ROS, reactive oxygen species; TCA, tricarboxylic acid; TNF-α, tumour necrosis factor-α

Immune-metabolism disorder

ACLF is often associated with immunodeficiency [23, 24]. Liver cirrhosis, in which liver fibres and fibrous septa replace the normal endothelial reticulum structure of the liver, leads to a decrease in the Kupffer cell number and a reduction in innate-immune protein molecules and PRRs [24], which greatly increases the risk of bacterial infection, systemic inflammatory response, and sepsis. In addition, studies involving HBV-ACLF patients showed that during chronic HBV infection, the number of myeloid dendritic cells and plasmacytoid dendritic cells in the host does not change significantly, but their functions are significantly altered compared with those in healthy controls [25–28]. HBV proteins, such as hepatitis B e antigen, can affect the ability of Kupffer cells to express Toll-like receptors, inhibit the proliferation of specific T lymphocytes and the secretion of interferon-γ and IL-10 [29]. A large number of mutations in HBV surface antigen-encoding genes were found in HBV-ACLF patients, which are associated with HBV-immune escape [30]. Circulating neutrophil and monocyte counts were higher while lymphocyte counts were lower in ACLF patients than in patients without ACLF [31, 32]. Neutrophils in patients with decompensated cirrhosis and ACLF displayed impaired phagocytosis, reactive oxygen species production, and bactericidal activity but an increased capacity to form neutrophil extracellular traps [33–35]. The function of the monocyte-macrophage system is significantly inhibited in ACLF patients, with a decrease in proinflammatory factor secretion, killing bacteria, oxidative burst, and phagocytosis [36, 37]. During the progression of HBV-related liver diseases, the percentage of CD163+CD206+ macrophages increases, and the macrophage polarization gradually changes from classically activated to alternatively activated [38]. Myeloid-derived suppressor cells are expanded in patients with ACLF and attenuate antimicrobial innate-immune responses by suppressing T cell function [39, 40]. Studies have also shown that HBV reactivation can lead to a significant increase in HBV-specific CD4+ and CD8+ T lymphocytes and cause liver damage [41, 42]. The human leukocyte antigen class II-restricted CD4+ T cell pathway plays an important role in the immunopathogenesis of HBV-ACLF [43]. During the evolving disease course from chronic hepatitis B or liver cirrhosis to ACLF, significantly increased expression of interferon-related, monocyte-related, neutrophil-related and dendritic cell-related gene modules, and significantly decreased expression of T cell-related, B cell-related and natural killer cell-related gene modules were observed. HBV reactivation causes immune dysregulation, including activation of the innate-immune system and exhaustion of the adaptive immune system, which are the core mechanisms of HBV-ACLF (Fig. 1) [3].

The liver is the main metabolic organ that regulates the homeostasis of lipids and cholesterol, processes amino acids, and stores glucose. Recent advances indicating prevailing metabolic alterations in the disease progression of ACLF have led to new directions in our understanding of the pathophysiology of advanced liver disease. Metabolic dysregulations, such as altered serum lysophosphatidylcholine and high-density lipoprotein cholesterol levels, are associated with increased severity and mortality of decompensated liver disease that reflect hepatocyte death [44–46]. Prominent metabolic pathway alterations (including lipid metabolism, autophagy and oxygen homoeostasis) across all stages of ACLF development were observed, which highlighted the importance of immune-metabolism disorder as a potential mechanism of ACLF [3]. Meanwhile, studies using high-throughput blood metabolomics in ACLF revealed profound alterations in major metabolic pathways; in particular, a significant decrease in mitochondrial fatty acid β-oxidation leads to decreased oxidative phosphorylation and ATP production [47, 48]. During this process, blood amino acids, along with glucose, fuel the synthesis of protein and nucleotide in the activated innate-immune system, which may contribute to the deterioration of the disease [48, 49]. Moreover, mitochondrial dysfunction governs immunometabolism in leukocytes from patients with acute decompensation of cirrhosis and ACLF, and bioenergetic failure is an emerging factor in the pathophysiology (Fig. 1) [50]. Prognostic scores based on metabolites reflecting systemic inflammation, mitochondrial dysfunction and sympathetic system activation also showed good accuracy in short-term mortality assessments [51].

Clinical treatment

Treatment principle

Patients with ACLF should be managed in an intensive care unit by a team with expertise in critical care and liver transplantation. The main principles of treatment are to remove the precipitating cause, support failing organ(s), and perform liver transplantation in selected patients (Fig. 2). General management includes the rapid restoration of metabolic and haemodynamic stability and provision of nutritional support and agents to protect hepatocytes and promote regeneration. Vital signs and organ function should be monitored frequently, and early organ-specific supportive care should be provided with care overseen by experts in the management of liver failure [52–54].Fig. 2 Schematic diagram showing a paradigm for ACLF management. In the chronic liver disease stage, standardization of management protocols for the treatment of precipitating events is needed to close the “switch” of acute deterioration. Once patients develop to the acutely decompensated stage, different populations could be diagnosed using different criteria depending on the phenotype specificity of ACLF. Non-ACLF patients should be predicted the risk of progression to ACLF to prevent the onset of ACLF with intense intervention, while ACLF patients should be assessed for different prognostic stratifications by scores. Patients with ACLF who can derive a high survival benefit from LT by evaluation should be prioritized for liver transplantation, making efficient use of the limited donor organs and reducing the risk of futile transplantation. ACLF, acute-on-chronic liver failure; ALD, alcohol-related liver disease; HBV, hepatitis B virus; CLIF-C ACLFs, chronic liver failure consortium ACLF score; COSSH, Chinese Group on the Study of Severe Hepatitis B; COSSH- ACLF IIs, COSSH- ACLF II score; COSSH-onset-ACLFs, COSSH-onset-ACLF score; G-CSF, granulocyte colony-stimulating; SDC, stable decompensated cirrhosis; UDC, unstable decompensated cirrhosis

Treating acute precipitants

Hepatitis B virus reactivation

The most common precipitating disorder of patients with HBV-ACLF is HBV reactivation (more than 60% of cases) [6, 55]. Early and rapid reduction of HBV DNA levels could suppress hepatocellular necrosis and cytokine release, which slows or reverses the progression of the disease [56]. Studies have indicated that nucleoside analogues could significantly reduce HBV DNA levels in patients with HBV-ACLF, and the reduction in HBV DNA levels within 2 weeks is related to survival improvement [56, 57]. All patients with HBV infection at presentation should be treated with nucleoside analogues immediately. Potent antiviral drugs, such as tenofovir, tenofovir alafenamide or entecavir, should be used [9].

Infection

The prevalence of infection in ACLF patients is approximately 50% and rises to more than 70% in ACLF-3 [58]. Bacterial infections are more common than fungal infections [58]. Studies have suggested that bacterial infections are associated with a worse clinical course and high short-term mortality in patients with ACLF [10, 58, 59]. Early identification of bacterial infections is important for the management of ACLF. A comprehensive examination for signs and symptoms of infection, including cytological and microbiological examinations of blood and ascites and imaging examinations of suspected sites, should be systematically performed in all patients at admission before starting antimicrobial therapy. An effective antibiotic treatment is strongly associated with an improvement in survival. Thus, empirical high-dose broad-spectrum antibiotic therapy, which relies on the organism isolated, suspected site of infection and local epidemiological patterns, should be started in ACLF patients with possible infection [60, 61]. Empirical antifungal therapy in patients without risk factors for invasive fungal infections is not recommended [52].

Alcohol-related hepatitis

Alcohol-related hepatitis is a major precipitating event of ACLF worldwide. Corticosteroids are the first-line treatment for severe alcoholic hepatitis. The response to corticosteroids can be assessed by dynamically calculating the Lille score, and the probability of response is negatively correlated with the number of OFs at baseline (52% for 1 OF, 42% for 2 OFs and 8% for 3 OFs) [53, 62–64]. Moreover, patients who responded to the treatment exhibited a higher short-term survival rate [64, 65]. However, considering the high risk of bacterial infections in patients with ALD-ACLF [52] and HBV reactivation in patients with HBV-ACLF [66], the benefit of corticosteroids should be carefully evaluated before use [55].

Acute variceal haemorrhage

For patients with cirrhosis, acute variceal haemorrhage is a common precipitating event. Standard medical treatment for this life-threatening precipitant is the combination of a vasoconstrictor (including terlipressin, somatostatin or analogues such as octreotide, maintained for 2–5 days) and endoscopic therapy (endoscopic variceal ligation or endoscopic sclerotherapy) with antibiotic prophylactic therapy [53, 67]. In addition, preemptive transjugular intrahepatic portosystemic shunts might also improve the survival of ACLF patients with acute variceal haemorrhage; however, further studies are still needed to validate their role in outcomes in patients with ACLF [68].

Organ failure support

The artificial liver support system (ALSS) has been recognized as a promising alternative therapy to LT in patients with ACLF by replacement of the dysfunctional liver since it can remove toxins, modulate haemodynamics, clear cytokines, and improve metabolism and consciousness [69–73]. To date, various ALSSs have been tried as treatments for ACLF [73–75]. Albumin dialysis with the molecular adsorbent recirculation system and fractionated plasma separation and adsorption, the most commonly used ALSS models for the treatment of ALD-ACLF in Europe, have shown beneficial effects for improving hepatic and renal functions [76–79]. Recently, a retrospective study and a meta-analysis showed that the use of an ALSS could improve short-term survival (14 and 28 days) in patients with ACLF and multiple OFs [80, 81]. However, two large randomized clinical trials demonstrated no improvement in short-term survival in ACLF patients treated with albumin dialysis compared with standard medical therapy [76, 78]. Other studies on plasma exchange, haemofiltration, and haemoperfusion have shown benefits for the short-term survival of HBV-ACLF and have considered these models as bridges to LT [70, 73, 82]. The clinical utility of these systems for survival benefit was different among studies, and further prospective randomized clinical trials are still needed.

Principles of treatment for extrahepatic OFs of ACLF are summarized in Table 3. Recommendations are based on current clinical guidelines and recent reviews on the management of critically ill patients with or without cirrhosis [53, 55, 83, 84].Table 3 Principles of treatment for extrahepatic organ failures of ACLF

Type of organ failure	What should be done	What should be avoided	
Coagulation	Perform the test of blood cell count and coagulation status;

Administer fibrinogen and/or platelets in patients with hypofibrinogenemia (< 1 g/L) and/or thrombocytopenia (< 20 × 109/L) with invasive procedures;

Prophylaxis for deep-vein thrombosis in patients without severe coagulopathy

	Avoid correction of INR with fresh frozen plasma for patients without bleeding or a planned procedure	
Kidneys	Assess the severity of acute kidney injury (AKI) with modified KDIGO criteria of the International Club of Ascites;

20% albumin (1 g/kg for 48 h) for patients with AKI stage 2–3;

For patients with type-1 hepatorenal syndrome: 20% albumin (1 g/kg for 48 h and then 20–40 g/day) + terlipressin (2 mg/24 h) or norepinephrine (0.5 mg/hour, when terlipressin is not available);

RRT serves as a bridge to LT

	Avoid nephrotoxic drugs, e.g., NSAIDs;

Avoid unnecessary RRT or early initiation of RRT

	
Respiration	Assess respiratory status (calculating the PaO2/FiO2 or SpO2/FiO2 and performing imaging examination);

Oxygen inhalation and lung protective ventilation strategy;

Endotracheal intubation for patients with West-Heaven grade 3–4 HE to facilitate airway management, prevent aspiration, and control ventilation;

PPIs are suggested to be used in patients on a ventilator

	Avoid delay in intubation even if with normal blood oxygen level	
Circulation	Assess haemodynamic state at admission;

Maintain mean arterial pressure  > 65 mmHg;

Norepinephrine is the first choice of vasopressor, epinephrine and terlipressin serve as additional agents;

Administer crystalloids and 5% albumin as resuscitation fluid;

Administer 20% albumin for patients with spontaneous bacterial peritonitis, large volume paracentesis or AKI

	Avoid using starches formulations;

Limit saline solutions in patients with ascites or anasarca

	
Brain	Evaluation of the mental status, care of the airway, treatment of the precipitating factors, and empiric HE therapy should be performed simultaneously;

Use lactulose and enemas to clear the bowel;

Use short-acting sedative agents

	Avoid deep sedation;

Avoid using benzodiazepines;

Ventilation in patients without altered mental status should not be considered as brain failure

	
Recommendations are based on current clinical guidelines and recent reviews on the management of critically ill patients with or without cirrhosis. ACLF acute-on-chronic liver failure; AKI acute kidney injury; HE hepatic encephalopathy; INR international normalized ratio; KDIGO kidney disease improving global outcomes; LT liver transplantation; NSAIDs nonsteroidal anti-inflammatory drugs; PPIs proton pump inhibitors; RRT renal replacement therapy

Liver transplantation

LT is an effective therapy for ACLF. The results of an international collaborative study in Europe showed that the 1-year post-LT survival was 81% in 234 ACLF patients, providing clear evidence of a survival benefit from LT [85]. Data from other studies based on multicentre cohorts or national registries also confirmed that LT could markedly improve survival in selected patients, even in those with ACLF-3, with a 1-year survival over 80% [86, 87]. However, the prioritization for LT in these specific populations remains unclear. Current organ allocation around the world is based on a prognostic model, called the MELD score, although studies have shown that the MELD score is not sensitive or accurate enough to predict survival in patients with ACLF since the impact of extrahepatic OF is not reflected in the score [88, 89]. The criteria and prognostic scores, which were developed specifically for patients with ACLF, such as the COSSH-ACLF score and CLIF-C ACLF score, should be used to assess the prognosis and to determine the prioritization and ideal timing for LT in patients with ACLF [6, 13, 85, 90, 91]. Researchers from Europe have proposed the worldwide adoption of new organ allocation policies for patients with ACLF and have designed a global study, referred to as the CHANCE study, to solve these issues [92]. In addition, dynamic assessment of the disease severity after hospitalization may be helpful to optimize patients for LT listing and transplantation. The CANONIC study showed that the high risk of early death in patients with ACLF-2 or ACLF-3 made it necessary to consider LT, and the futility of LT may be considered for patients with 4 or more OFs or a CLIC-C ACLF score > 64 (at days 3–7) if they have other contraindications for LT [90]. The COSSH study currently also assessed the outcomes of patients with HBV-ACLF who underwent LT and proposed a net survival benefit-based priority for LT of HBV-ACLF to decrease the risk of futile LT. The COSSH-ACLF II score identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with a COSSH-ACLF II score of 7–10 derived a higher net survival benefit from LT [93].

Future perspectives

Despite improvements in understanding of how patients with ACLF might progress from underlying chronic liver disease to death, controversies in many fields still exist and require further scientific exploration.

With the increasing prevalence of risk factors for the development of chronic liver disease, such as alcohol addiction, drug abuse and obesity, ACLF is expected to become more prevalent in the coming years [1]. However, given regional limitations, any definitions of ACLF now proposed may be considered only transitional definitions, both in the East and in the West. The multiple definitions have also accounted for substantial confusion among multidisciplinary teams caring for ACLF patients. A uniform definition of ACLF applicable in all parts of the world should be based on global, prospectively collected and validated data, which can provide a sufficient theoretical basis for standardized clinical management. Patients with chronic liver disease (with or without cirrhosis), with any type of precipitating event (intrahepatic or extrahepatic), and extrahepatic OFs should be included for data collection to ultimately arrive at a comprehensive definition of ACLF. More efforts are also required to develop and validate more accurate prognostic scores that can accommodate various aetiologies and phenotypes around the world. In addition, the unmet medical needs of diagnosing patients who have a high risk of progression to ACLF (pre-ACLF) at admission are eagerly awaited to be addressed in future studies. Using advanced approaches such as transcriptomics, proteomics and metabolomics, biomarkers including inflammatory markers, cell-death markers and functional characteristics of immune cells would also help accurately identify pre-ACLF patients to refine clinical prognostic models and provide novel therapeutic targets [94].

To delve deeper into the pathogenesis of ACLF, future work should not only decipher the respective contributions of each immune cell type and their interactions and increase our understanding of dynamic changes in inflammatory, immune and metabolic status during the natural history of ACLF but also generate tractable therapeutic targets through recent advances in single-cell genomics technologies and the rapidly evolving fields of spatial transcriptomic and proteomic profiling [95, 96]. Reliable ACLF animal models are needed to uncover detailed features of the disease pathogenesis. Inflammation-induced ACLF models, in which chronic injury is induced by carbon tetrachloride, bile duct ligation or porcine serum and acute injury is induced by D-galactosamine/lipopolysaccharide, have a high short-term mortality rate after acute insult and rarely lead to the development of portal hypertension, ascites, and multiple OFs [97–102]. Currently, a bacteria-induced ACLF model has been developed using Klebsiella pneumoniae, which provided the survival window to understand the pathophysiology of liver failure in response to infection [103]. A porcine serum-induced liver cirrhosis-based ACLF animal model verified immune-metabolism disorder as the core-axis mechanism in the clinical pathophysiology, which positively contributed to the interpretation of disease pathogenesis [104]. Nevertheless, establishing an HBV-based ACLF model is an arduous task because of the extremely narrow host range of HBV, which mostly infects humans. The application of sophisticated technologies has led to the generation of dual humanized transgenic mice that are susceptible to chronic HBV infection and ultimately generate liver cirrhosis [105]. This model could serve as a potential resource for HBV-ACLF modeling with a suitable secondary trigger.

Several interventions targeting immune regulation and metabolic balance are receiving attention as potential treatments for ACLF. Glucocorticoids can suppress excessive immune responses and have been tried in the treatment of ACLF. However, due to the side effects of glucocorticoids and the rapid changes in the immune status of ACLF patients, only some ACLF patients can benefit from glucocorticoids. Therefore, it is difficult to determine the optimal timing for glucocorticoids in patients with ACLF. Granulocyte-colony stimulating factor (G-CSF), which can induce the mobilization of bone mesenchymal stem cells, has been studied to reduce the short-term mortality of ACLF [106]. A meta-analysis demonstrated that G-CSF significantly reduced short-term mortality and the incidence of complications [107]. However, this result was not validated in a recent multicentre randomized clinical trial, which enrolled 176 patients with ACLF from 18 European centres; the interim analysis showed no benefit of G-CSF on 90- or 360-day LT-free survival, overall survival or disease severity scores [108]. Based on current data, the use of G-CSF is debatable. G-CSF may be beneficial in early stages of ACLF before the onset of sepsis and extrahepatic OFs [109] but may not be recommended as a part of routine management for patients in late stages of ACLF [52]. Stem cell therapies, including human allogeneic liver-derived progenitor cell, mesenchymal stem cell (MSC) or multipotent MSC and bone mesenchymal stem cell therapies, are emerging as alternatives because of the shortage of liver donors and the high cost of LT. A clinical phase II study that involved 24 patients suggested that the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells to treat patients with ACLF is safe [110]. Other studies have demonstrated that the transplantation of MSCs improved liver function and short-term survival in HBV-ACLF, and the procedure appeared to be safe during the observational time [111, 112]. However, these studies were preliminary, with small sample sizes and limited follow-up periods. Further studies are required to confirm the safety and assess the efficacy before widespread use in clinical practice.

Conclusions

ACLF has been recognized as a severe clinical syndrome based on the acute deterioration of chronic liver disease, and it is characterized by organ failure and high short-term mortality. The specific pathophysiology of ACLF remains unclear, but it is likely related to systemic inflammation and immune-metabolism disorder. Current therapeutic management of ACLF relies on supportive therapy for organ failure and liver transplantation. ACLF is still a major challenge in the field of hepatology, and future studies are needed to clarify its pathogenesis and achieve precise management through spatiotemporal multi-omics.

Abbreviations

ACLF Acute-on-chronic liver failure

AARC Asian Pacific Association for the Study of the Liver ACLF Research Consortium

ALD Alcohol-related liver disease

ALSS Artificial liver support system

APASL Asian Pacific Association for the Study of the Liver

AUROC Area under the receiver operating characteristic curve

CANONIC Chronic liver failure (CLIF) consortium acute-on-chronic liver failure in cirrhosis

C-index Concordance index

COSSH Chinese Group on the Study of Severe Hepatitis B

DAMPs Damage-associated molecular patterns

EASL-CLIF European Association for the Study of the Liver-Chronic Liver Failure

G-CSF Granulocyte-colony stimulating factor

HBV Hepatitis B virus

HE Hepatic encephalopathy

INR International normalized ratio

IL Interleukin

LT Liver transplantation

MELD Model for end-stage liver disease

MSC Mesenchymal stromal cell

NACSELD North American Consortium for the Study of End-stage Liver Disease

OFs Organ failures

PRRs Pattern-recognition receptors

PAMPs Pathogen-associated molecular patterns

SOFA Sequential organ failure assessment

TB Total bilirubin

WBC White blood cell

Acknowledgements

Not applicable.

Author contributions

All authors participated in the drafting of the manuscript and were involved in critical revision of the manuscript for important intellectual content.

Funding

This study was supported by the National Natural Science Foundation of China (81830073,82272426), the National Special Support Program for High-level Personnel Recruitment (Ten-thousand Talents Program), National Key Research and Development Program of China (2022YFC2304800, 2022YFA1104100), and Zhejiang Public Welfare Project (LGF21H200006, LY21H030007).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jinjin Luo, Jiaqi Li, Peng Li and Xi Liang have contributed equally to this work.
==== Refs
References

1. Mezzano G Juanola A Cardenas A Mezey E Hamilton JP Pose E Global burden of disease: acute-on-chronic liver failure, a systematic review and meta-analysis Gut 2022 71 1 148 155 10.1136/gutjnl-2020-322161 33436495
2. Asrani SK Devarbhavi H Eaton J Kamath PS Burden of liver diseases in the world J Hepatol 2019 70 1 151 171 10.1016/j.jhep.2018.09.014 30266282
3. Li J Liang X Jiang J Yang L Xin J Shi D PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF Gut 2022 71 1 163 175 10.1136/gutjnl-2020-323395 33431576
4. Moreau R Jalan R Gines P Pavesi M Angeli P Cordoba J Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis Gastroenterology 2013 144 7 1426 37.e9 10.1053/j.gastro.2013.02.042 23474284
5. Jalan R Saliba F Pavesi M Amoros A Moreau R Gines P Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure J Hepatol 2014 61 5 1038 1047 10.1016/j.jhep.2014.06.012 24950482
6. Wu T Li J Shao L Xin J Jiang L Zhou Q Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure Gut 2018 67 12 2181 2191 10.1136/gutjnl-2017-314641 28928275
7. Sarin SK Kumar A Almeida JA Chawla YK Fan ST Garg H Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL) Hep Intl 2009 3 1 269 282 10.1007/s12072-008-9106-x
8. Sarin SK Kedarisetty CK Abbas Z Amarapurkar D Bihari C Chan AC Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL) 2014 Hepatol Int 2014 8 4 453 471 10.1007/s12072-014-9580-2 26202751
9. Sarin SK Choudhury A Sharma MK Maiwall R Al Mahtab M Rahman S Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update Hepatol Int 2019 13 4 353 390 10.1007/s12072-019-09946-3 31172417
10. Bajaj JS O'Leary JG Reddy KR Wong F Biggins SW Patton H Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures Hepatology 2014 60 1 250 256 10.1002/hep.27077 24677131
11. Trebicka J Fernandez J Papp M Caraceni P Laleman W Gambino C The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology J Hepatol 2020 73 4 842 854 10.1016/j.jhep.2020.06.013 32673741
12. Luo J Liang X Xin J Li J Li P Zhou Q Predicting the onset of hepatitis B virus-related acute-on-chronic liver failure Clin Gastroenterol Hepatol 2023 21 3 681 693 10.1016/j.cgh.2022.03.016 35337983
13. Li J Liang X You S Feng T Zhou X Zhu B Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure J Hepatol 2021 75 5 1104 1115 10.1016/j.jhep.2021.05.026 34090929
14. Choudhury A Jindal A Maiwall R Sharma MK Sharma BC Pamecha V Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models Hepatol Int 2017 11 5 461 471 10.1007/s12072-017-9816-z 28856540
15. O'Leary JG Reddy KR Garcia-Tsao G Biggins SW Wong F Fallon MB NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis Hepatology 2018 67 6 2367 2374 10.1002/hep.29773 29315693
16. Claria J Stauber RE Coenraad MJ Moreau R Jalan R Pavesi M Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure Hepatology 2016 64 4 1249 1264 10.1002/hep.28740 27483394
17. Laleman W Claria J Van der Merwe S Moreau R Trebicka J Systemic inflammation and acute-on-chronic liver failure: too much Not Enough Can J Gastroenterol Hepatol 2018 2018 1027152 30155448
18. Xin J Ding W Hao S Chen X Zhang J Jiang L Serum macrophage inflammatory protein 3alpha levels predict the severity of HBV-related acute-on-chronic liver failure Gut 2016 65 2 355 357 10.1136/gutjnl-2015-309916 26041751
19. Jalan R D'Amico G Trebicka J Moreau R Angeli P Arroyo V New clinical and pathophysiological perspectives defining the trajectory of cirrhosis J Hepatol 2021 75 Suppl 1 S14 S26 10.1016/j.jhep.2021.01.018 34039485
20. Bernardi M Moreau R Angeli P Schnabl B Arroyo V Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis J Hepatol 2015 63 5 1272 1284 10.1016/j.jhep.2015.07.004 26192220
21. Lucey MR Mathurin P Morgan TR Alcoholic hepatitis N Engl J Med 2009 360 26 2758 2769 10.1056/NEJMra0805786 19553649
22. Zhao RH Shi Y Zhao H Wu W Sheng JF Acute-on-chronic liver failure in chronic hepatitis B: an update Expert Rev Gastroenterol Hepatol 2018 12 4 341 350 10.1080/17474124.2018.1426459 29334786
23. Jenne CN Kubes P Immune surveillance by the liver Nat Immunol 2013 14 10 996 1006 10.1038/ni.2691 24048121
24. Albillos A Lario M Alvarez-Mon M Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance J Hepatol 2014 61 6 1385 1396 10.1016/j.jhep.2014.08.010 25135860
25. Beckebaum S Cicinnati VR Dworacki G Muller-Berghaus J Stolz D Harnaha J Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection Clin Immunol 2002 104 2 138 150 10.1006/clim.2002.5245 12165275
26. Martinet J Dufeu-Duchesne T Bruder Costa J Larrat S Marlu A Leroy V Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection Gastroenterology 2012 143 6 1586 96.e8 10.1053/j.gastro.2012.08.046 22960656
27. Tavakoli S Mederacke I Herzog-Hauff S Glebe D Grun S Strand D Peripheral blood dendritic cells are phenotypically and functionally intact in chronic hepatitis B virus (HBV) infection Clin Exp Immunol 2008 151 1 61 70 10.1111/j.1365-2249.2007.03547.x 18031557
28. van der Molen RG Sprengers D Binda RS de Jong EC Niesters HG Kusters JG Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B Hepatology 2004 40 3 738 746 10.1002/hep.20366 15349914
29. Park JJ Wong DK Wahed AS Lee WM Feld JJ Terrault N Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B Gastroenterology 2016 150 3 684 95.e5 10.1053/j.gastro.2015.11.050 26684441
30. Gao S Joshi SS Osiowy C Chen Y Coffin CS Duan ZP Chronic hepatitis B carriers with acute on chronic liver failure show increased HBV surface gene mutations, including immune escape variants Virol J 2017 14 1 203 10.1186/s12985-017-0870-x 29065883
31. Wu W Yan H Zhao H Sun W Yang Q Sheng J Characteristics of systemic inflammation in hepatitis B-precipitated ACLF: differentiate it from No-ACLF Liver Int 2018 38 2 248 257 10.1111/liv.13504 28646630
32. Weiss E de la Grange P Defaye M Lozano JJ Aguilar F Hegde P Characterization of blood immune cells in patients with decompensated cirrhosis including ACLF Front Immunol 2020 11 619039 10.3389/fimmu.2020.619039 33613548
33. Boussif A Rolas L Weiss E Bouriche H Moreau R Perianin A Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis J Hepatol 2016 64 5 1041 1048 10.1016/j.jhep.2015.12.005 26719020
34. Rolas L Boussif A Weiss E Letteron P Haddad O El-Benna J NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation Gut 2018 67 8 1505 1516 10.1136/gutjnl-2016-313443 28601846
35. Wu W Sun S Wang Y Zhao R Ren H Li Z Circulating neutrophil dysfunction in HBV-related acute-on-chronic liver failure Front Immunol 2021 12 620365 10.3389/fimmu.2021.620365 33717119
36. O'Brien AJ Fullerton JN Massey KA Auld G Sewell G James S Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2 Nat Med 2014 20 5 518 523 10.1038/nm.3516 24728410
37. Vergis N Khamri W Beale K Sadiq F Aletrari MO Moore C Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase Gut 2017 66 3 519 529 10.1136/gutjnl-2015-310378 26860769
38. Liang J Long Z Zhang Y Wang J Chen X Liu X Chloride intercellular channel 3 suppression-mediated macrophage polarization: a potential indicator of poor prognosis of hepatitis B virus-related acute-on-chronic liver failure Immunol Cell Biol 2022 100 5 323 337 10.1111/imcb.12542 35238065
39. Bernsmeier C Triantafyllou E Brenig R Lebosse FJ Singanayagam A Patel VC CD14(+) CD15(−) HLA-DR(−) myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure Gut 2018 67 6 1155 1167 10.1136/gutjnl-2017-314184 28592438
40. Zeng Y Li Y Xu Z Gan W Lu L Huang X Myeloid-derived suppressor cells expansion is closely associated with disease severity and progression in HBV-related acute-on-chronic liver failure J Med Virol 2019 91 8 1510 1518 10.1002/jmv.25466 30905084
41. Jung MC Pape GR Immunology of hepatitis B infection Lancet Infect Dis 2002 2 1 43 50 10.1016/S1473-3099(01)00172-4 11892495
42. Kao JH Chen DS Global control of hepatitis B virus infection Lancet Infect Dis 2002 2 7 395 403 10.1016/S1473-3099(02)00315-8 12127351
43. Tan W Xia J Dan Y Li M Lin S Pan X Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure Gut 2018 67 4 757 766 28130311
44. McPhail MJW Shawcross DL Lewis MR Coltart I Want EJ Antoniades CG Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis J Hepatol 2016 64 5 1058 1067 10.1016/j.jhep.2016.01.003 26795831
45. Trieb M Rainer F Stadlbauer V Douschan P Horvath A Binder L HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure J Hepatol 2020 73 1 113 120 10.1016/j.jhep.2020.01.026 32061870
46. Juanola A Graupera I Elia C Piano S Sole C Carol M Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis J Hepatol 2022 76 1 107 114 10.1016/j.jhep.2021.08.031 34530063
47. Claria J Curto A Moreau R Colsch B Lopez-Vicario C Lozano JJ Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis J Hepatol 2021 75 5 1116 1127 10.1016/j.jhep.2021.06.043 34245803
48. Moreau R Claria J Aguilar F Fenaille F Lozano JJ Junot C Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF J Hepatol 2020 72 4 688 701 10.1016/j.jhep.2019.11.009 31778751
49. Zaccherini G Aguilar F Caraceni P Claria J Lozano JJ Fenaille F Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF J Hepatol 2021 74 5 1117 1131 10.1016/j.jhep.2020.11.035 33276029
50. Zhang IW Curto A Lopez-Vicario C Casulleras M Duran-Guell M Flores-Costa R Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure J Hepatol 2022 76 1 93 106 10.1016/j.jhep.2021.08.009 34450236
51. Weiss E de la Pena-Ramirez C Aguilar F Lozano JJ Sanchez-Garrido C Sierra P Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET) Gut 2023 10.1136/gutjnl-2022-328708 36788016
52. Bajaj JS O'Leary JG Lai JC Wong F Long MD Wong RJ Acute-on-chronic liver failure clinical guidelines Am J Gastroenterol 2022 117 2 225 252 10.14309/ajg.0000000000001595 35006099
53. Arroyo V Moreau R Jalan R Acute-on-chronic liver failure N Engl J Med 2020 382 22 2137 2145 10.1056/NEJMra1914900 32459924
54. Bernal W Karvellas C Saliba F Saner FH Meersseman P Intensive care management of acute-on-chronic liver failure J Hepatol 2021 75 Suppl 1 S163 S177 10.1016/j.jhep.2020.10.024 34039487
55. Zaccherini G Weiss E Moreau R Acute-on-chronic liver failure: definitions, pathophysiology and principles of treatment JHEP Rep 2021 3 1 100176 10.1016/j.jhepr.2020.100176 33205036
56. Wang J Ma K Han M Guo W Huang J Yang D Nucleoside analogs prevent disease progression in HBV-related acute-on-chronic liver failure: validation of the TPPM model Hepatol Int 2014 8 1 64 71 10.1007/s12072-013-9485-5 26202407
57. Garg H Sarin SK Kumar M Garg V Sharma BC Kumar A Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure Hepatology 2011 53 3 774 780 10.1002/hep.24109 21294143
58. Fernandez J Acevedo J Wiest R Gustot T Amoros A Deulofeu C Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis Gut 2018 67 10 1870 1880 10.1136/gutjnl-2017-314240 28847867
59. Shi Y Yang Y Hu Y Wu W Yang Q Zheng M Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults Hepatology 2015 62 1 232 242 10.1002/hep.27795 25800029
60. Fernandez J Prado V Trebicka J Amoros A Gustot T Wiest R Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe J Hepatol 2019 70 3 398 411 10.1016/j.jhep.2018.10.027 30391380
61. Wong F Piano S Singh V Bartoletti M Maiwall R Alessandria C Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure J Hepatol 2021 74 2 330 339 10.1016/j.jhep.2020.07.046 32781201
62. European Association for the Study of the Liver Electronic address EEE, European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis J Hepatol 2018 69 2 406 460 10.1016/j.jhep.2018.03.024 29653741
63. Gustot T Jalan R Acute-on-chronic liver failure in patients with alcohol-related liver disease J Hepatol 2019 70 2 319 327 10.1016/j.jhep.2018.12.008 30658733
64. Serste T Cornillie A Njimi H Pavesi M Arroyo V Putignano A The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis J Hepatol 2018 69 2 318 324 10.1016/j.jhep.2018.02.022 29524528
65. Forrest EH Atkinson SR Richardson P Masson S Ryder S Thursz MR Prevalent acute-on-chronic liver failure and response to corticosteroids in alcoholic hepatitis J Hepatol 2018 69 5 1200 1201 10.1016/j.jhep.2018.06.019 30150133
66. Zhong Z Liao W Dai L Feng X Su G Gao Y Average corticosteroid dose and risk for HBV reactivation and hepatitis flare in patients with resolved hepatitis B infection Ann Rheum Dis 2022 81 4 584 591 10.1136/annrheumdis-2021-221650 34933869
67. Garcia-Tsao G Bosch J Management of varices and variceal hemorrhage in cirrhosis N Engl J Med 2010 362 9 823 832 10.1056/NEJMra0901512 20200386
68. Trebicka J Gu W Ibanez-Samaniego L Hernandez-Gea V Pitarch C Garcia E Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS J Hepatol 2020 73 5 1082 1091 10.1016/j.jhep.2020.04.024 32339602
69. Carpentier B Gautier A Legallais C Artificial and bioartificial liver devices: present and future Gut 2009 58 12 1690 1702 10.1136/gut.2008.175380 19923348
70. Larsen FS Artificial liver support in acute and acute-on-chronic liver failure Curr Opin Crit Care 2019 25 2 187 191 10.1097/MCC.0000000000000584 30672818
71. MacDonald AJ Karvellas CJ Emerging role of extracorporeal support in acute and acute-on-chronic liver failure: recent developments Semin Respir Crit Care Med 2018 39 5 625 634 10.1055/s-0038-1675334 30485892
72. Struecker B Raschzok N Sauer IM Liver support strategies: cutting-edge technologies Nat Rev Gastroenterol Hepatol 2014 11 3 166 176 10.1038/nrgastro.2013.204 24166083
73. Yang L Wu T Li J Xin J Shi D Jiang J Artificial liver treatment improves survival in patients with hepatitis B virus-related acute-on-chronic liver failure: a case-control matched analysis Hepatol Res 2020 50 6 656 670 10.1111/hepr.13497 32134538
74. Hassanein TI Schade RR Hepburn IS Acute-on-chronic liver failure: extracorporeal liver assist devices Curr Opin Crit Care 2011 17 2 195 203 10.1097/MCC.0b013e328344b3aa 21346566
75. Karvellas CJ Subramanian RM Current evidence for extracorporeal liver support systems in acute liver failure and acute-on-chronic liver failure Crit Care Clin 2016 32 3 439 451 10.1016/j.ccc.2016.03.003 27339682
76. Banares R Nevens F Larsen FS Jalan R Albillos A Dollinger M Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial Hepatology 2013 57 3 1153 1162 10.1002/hep.26185 23213075
77. Hassanein TI Tofteng F Brown RS Jr McGuire B Lynch P Mehta R Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis Hepatology 2007 46 6 1853 1862 10.1002/hep.21930 17975845
78. Kribben A Gerken G Haag S Herget-Rosenthal S Treichel U Betz C Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure Gastroenterology 2012 142 4 782 9.e3 10.1053/j.gastro.2011.12.056 22248661
79. Krisper P Haditsch B Stauber R Jung A Stadlbauer V Trauner M In vivo quantification of liver dialysis: comparison of albumin dialysis and fractionated plasma separation J Hepatol 2005 43 3 451 457 10.1016/j.jhep.2005.02.038 16023249
80. Gerth HU Pohlen M Tholking G Pavenstadt H Brand M Husing-Kabar A Molecular adsorbent recirculating system can reduce short-term mortality among patients with acute-on-chronic liver failure—a retrospective analysis Crit Care Med 2017 45 10 1616 1624 10.1097/CCM.0000000000002562 28640024
81. Shen Y Wang XL Wang B Shao JG Liu YM Qin Y Survival benefits with artificial liver support system for acute-on-chronic liver failure: a time series-based meta-analysis Medicine 2016 95 3 e2506 10.1097/MD.0000000000002506 26817889
82. Chen JJ Huang JR Yang Q Xu XW Liu XL Hao SR Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-on-chronic liver failure: a nationwide prospective multicenter study in China Hepatobiliary Pancreat Dis Int 2016 15 3 275 281 10.1016/S1499-3872(16)60084-X 27298103
83. Gines P Fernandez J Durand F Saliba F Management of critically-ill cirrhotic patients J Hepatol 2012 56 Suppl 1 S13 24 10.1016/S0168-8278(12)60003-8 22300462
84. Nadim MK Durand F Kellum JA Levitsky J O'Leary JG Karvellas CJ Management of the critically ill patient with cirrhosis: a multidisciplinary perspective J Hepatol 2016 64 3 717 735 10.1016/j.jhep.2015.10.019 26519602
85. Belli LS Duvoux C Artzner T Bernal W Conti S Cortesi PA Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS) J Hepatol 2021 75 3 610 622 10.1016/j.jhep.2021.03.030 33951535
86. Artru F Louvet A Ruiz I Levesque E Labreuche J Ursic-Bedoya J Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3 J Hepatol 2017 67 4 708 715 10.1016/j.jhep.2017.06.009 28645736
87. Thuluvath PJ Thuluvath AJ Hanish S Savva Y Liver transplantation in patients with multiple organ failures: feasibility and outcomes J Hepatol 2018 69 5 1047 1056 10.1016/j.jhep.2018.07.007 30071241
88. Hernaez R Liu Y Kramer JR Rana A El-Serag HB Kanwal F Model for end-stage liver disease-sodium underestimates 90-day mortality risk in patients with acute-on-chronic liver failure J Hepatol 2020 73 6 1425 1433 10.1016/j.jhep.2020.06.005 32531416
89. Sundaram V Shah P Mahmud N Lindenmeyer CC Klein AS Wong RJ Patients with severe acute-on-chronic liver failure are disadvantaged by model for end-stage liver disease-based organ allocation policy Aliment Pharmacol Ther 2020 52 7 1204 1213 32725664
90. Gustot T Fernandez J Garcia E Morando F Caraceni P Alessandria C Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis Hepatology 2015 62 1 243 252 10.1002/hep.27849 25877702
91. Zhang X Ying Y Zhou P Liu X Li R Tao Y A Stepwise evaluation of hepatitis B virus-related acute-on-chronic liver failure to optimize the indication for urgent liver transplantation Dig Dis Sci 2021 66 1 284 295 10.1007/s10620-020-06149-x 32140946
92. Arroyo V Angeli P Moreau R Jalan R Claria J Trebicka J The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis J Hepatol 2021 74 3 670 685 10.1016/j.jhep.2020.11.048 33301825
93. Li P Liang X Luo J Li J Xin J Jiang J Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study Lancet Reg Health West Pac 2023 32 100638 10.1016/j.lanwpc.2022.100638 36793753
94. Bajaj JS Reddy KR O'Leary JG Vargas HE Lai JC Kamath PS Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute-on-chronic liver failure and death in patients with cirrhosis Gastroenterology 2020 159 5 1715 30.e12 10.1053/j.gastro.2020.07.019 32687928
95. Hwang WL Jagadeesh KA Guo JA Hoffman HI Yadollahpour P Reeves JW Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment Nat Genet 2022 54 8 1178 1191 10.1038/s41588-022-01134-8 35902743
96. Guilliams M Bonnardel J Haest B Vanderborght B Wagner C Remmerie A Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches Cell 2022 185 2 379 96.e38 10.1016/j.cell.2021.12.018 35021063
97. Harry D Anand R Holt S Davies S Marley R Fernando B Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat Hepatology 1999 30 5 1198 1205 10.1002/hep.510300515 10534341
98. Carl DE Ghosh SS Gehr TW Abbate A Toldo S Sanyal AJ A model of acute kidney injury in mice with cirrhosis and infection Liver Int 2016 36 6 865 873 10.1111/liv.13023 26583566
99. Ni S Li S Yang N Tang X Zhang S Hu D Deregulation of regulatory T cells in acute-on-chronic liver failure: a rat model Mediators Inflamm 2017 2017 1390458 10.1155/2017/1390458 28194045
100. Tripathi DM Vilaseca M Lafoz E Garcia-Caldero H Viegas Haute G Fernandez-Iglesias A Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension Gastroenterology 2018 155 5 1564 1577 10.1053/j.gastro.2018.07.022 30055171
101. Engelmann C Sheikh M Sharma S Kondo T Loeffler-Wirth H Zheng YB Toll-like receptor 4 is a therapeutic target for prevention and treatment of liver failure J Hepatol 2020 73 1 102 112 10.1016/j.jhep.2020.01.011 31987990
102. Engelmann C Habtesion A Hassan M Kerbert AJ Hammerich L Novelli S Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF J Hepatol 2022 77 5 1325 1338 10.1016/j.jhep.2022.07.006 35843375
103. Xiang X Feng D Hwang S Ren T Wang X Trojnar E Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice J Hepatol 2020 72 4 736 745 10.1016/j.jhep.2019.11.013 31786256
104. Hassan HM Cai Q Liang X Xin J Ren K Jiang J Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats Life Sci Alliance 2022 5 3 e202101189 10.26508/lsa.202101189 34853163
105. Yuan L Jiang J Liu X Zhang Y Zhang L Xin J HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation Gut 2019 68 11 2044 2056 10.1136/gutjnl-2018-316091 30700543
106. Garg V Garg H Khan A Trehanpati N Kumar A Sharma BC Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure Gastroenterology 2012 142 3 505 12.e1 10.1053/j.gastro.2011.11.027 22119930
107. Chavez-Tapia NC Mendiola-Pastrana I Ornelas-Arroyo VJ Norena-Herrera C Vidana-Perez D Delgado-Sanchez G Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis Ann Hepatol 2015 14 5 631 641 10.1016/S1665-2681(19)30757-4 26256891
108. Engelmann C Herber A Franke A Bruns T Reuken P Schiefke I Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: a multicenter randomized trial (GRAFT study) J Hepatol 2021 75 6 1346 1354 10.1016/j.jhep.2021.07.033 34364917
109. Jindal A Sarin SK G-CSF in acute-on-chronic liver failure—art of ‘patient selection’ is paramount! J Hepatol 2022 76 2 472 473 10.1016/j.jhep.2021.08.022 34478764
110. Nevens F Gustot T Laterre PF Lasser LL Haralampiev LE Vargas V A phase II study of human allogeneic liver-derived progenitor cell therapy for acute-on-chronic liver failure and acute decompensation JHEP Rep 2021 3 4 100291 10.1016/j.jhepr.2021.100291 34169246
111. Shi M Zhang Z Xu R Lin H Fu J Zou Z Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients Stem Cells Transl Med 2012 1 10 725 731 10.5966/sctm.2012-0034 23197664
112. Lin BL Chen JF Qiu WH Wang KW Xie DY Chen XY Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial Hepatology 2017 66 1 209 219 10.1002/hep.29189 28370357