Definition and classification of acute-on-chronic liver diseases.

Patients with chronic liver diseases (CLDs) develop acute liver injury and/or acute decompensation under the attack of various precipitants and present with significantly elevated alanine aminotransferase and/or total bilirubin levels, liver failure, or acute decompensation of liver cirrhosis, which is called acute-on-CLD (AoCLD). AoCLD accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. AoCLD is complicated by various clinical types, the severity of the disease, and may pose a high risk of death. To date, the definition of AoCLD is still vague, and a consensus concept of the clinical classification is lacking. This review aimed to define the concept and clinical types of AoCLD based on related studies and the literature. ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: Acute–on-chronic liver disease (AoCLD) can be defined as a group of diseases that experience acute liver injury (ALI) or acute decompensation in patients with pre-existing chronic liver disease (CLD). AoCLD can be divided into acute-on-chronic liver failure (ACLF) and non-ACLF according to the degree of ALI and the presence or absence of organ failure. According to the basic state of CLD, ACLF can be classified as type A (on the basis of chronic hepatitis), type B (on the basis of compensatory cirrhosis), and type C (on the basis of decompensated cirrhosis), and non-ACLF can be further classified as chronic hepatitis with acute exacerbation, the active phase of liver cirrhosis, and liver cirrhosis-acute decompensation.

INTRODUCTION

It is estimated that at least 1.5 billion people worldwide suffer from chronic liver diseases (CLDs), and an average of 2 million people die of CLDs each year[1,2]. The latest data from research investigating the global burden of disease released by The Lancet in 2020 show that the disability-adjusted life years caused by CLD in 2019 have increased by 33.0% over the past 30 years, accounting for 1.8% of the global burden. These data indicate that CLD imposes an increasing burden on public health[3], likely because most CLD patients are in a stable state for a long time without obvious symptoms or signs in the early stage. In most cases, CLD patients are often unaware of their disease and are exposed to various liver injury factors until the onset of symptoms, such as nausea, vomiting, abdominal distension, jaundice, etc., and require hospitalization. At this point, the disease progressed to severe hepatitis, decompensated cirrhosis, and even acute-on-chronic liver failure (ACLF) characterized by high short-term mortality[4,5], placing a serious economic burden on the family and society. These patients are collectively referred to as acute-on-CLD (AoCLD) patients[6]. Given such a large group of patients, it is of great importance for clinicians to quickly identify patients at a high risk of death and make corresponding clinical decisions that can improve the prognosis of patients and save medical resources. To date, the definition of AoCLD is still vague, and a consensus concept of the clinical classification is lacking. Therefore, a definitive definition and classification of AoCLD is urgently needed.

DEFINITION OF AOCLD

In the early 1990s, Kohn et al[7], for the first time, proposed the concept of AoCLD and mentioned that “AoCLD may lead to hepatic encephalopathy”. At the end of the 1990s, AoCLD was preliminarily defined as a type of disease with hepatic encephalopathy based on CLD[8,9]. In 2009, the definition of AoCLD was expanded to “acute decompensation occurring on CLD”[10]. With increasing attention to ACLF, some scholars[11] described AoCLD as acute liver injury (ALI) superimposed on CLD and further classified AoCLD into ACLF and non-ACLF. However, other scholars defined AoCLD as ALI on the basis of CLD and patients who did not meet the ACLF criteria[12]. In 2019, Caracuel et al[13] proposed another interpretation of the concept of AoCLD, arguing that AoCLD is a clinical syndrome characterized by decompensated cirrhosis, portal hypertension, and visceral hyperdynamic circulation. Recently, in the Chinese ACLF multicentre prospective cohort study launched by the Chinese ACLF Consortium, AoCLD was redefined as an acute exacerbation of liver cirrhosis and non-cirrhotic CLD, including ACLF and non-ACLF (other unstable CLD)[6,14-16]. The evolution of the definition of AoCLD is listed in Table 1.

Table 1

Evolution of the definition of acute-on-chronic liver diseases

Ref.	Definition of AoCLD	Chronic liver disease status	Clinical features
Kohn et al[7], 1993	A type of disease that may develop into hepatic encephalopathy	Liver cirrhosis	Hepatic encephalopathy
Clemmesen et al[8,9], 1999	A class of diseases of hepatic encephalopathy based on CLD	Liver cirrhosis or non-cirrhosis	Hepatic encephalopathy
Agarwal et al[10], 2009	Acute decompensation occurs on CLD	Liver cirrhosis	Acute decompensation events
Jagadisan et al[11], 2012	Acute liver injury superimposed on the basis of CLD including ACLF and non-ACLF	Liver cirrhosis or non-cirrhosis	Acute liver injury and/or acute decompensation events
Tasneem and Luck[12], 2017	Acute liver injury on the basis of CLD that does not meet the criteria of ACLF	Liver cirrhosis or non-cirrhosis	Acute liver injury
Caracuel et al[13], 2019	A clinical syndrome characterized by decompensated cirrhosis, portal hypertension, and visceral hyperdynamic circulation	Liver cirrhosis	Acute decompensation events
Qiao et al[6], 2021	Acute exacerbations of various CLD (including cirrhosis and non-cirrhosis), including ACLF and non-ACLF	Liver cirrhosis or non-cirrhosis	Acute liver injury and/or acute decompensation events

CLD: Chronic liver disease; AoCLD: Acute-on-chronic-liver disease; ACLF: Acute-on-chronic liver failure.

Considering the evolution of the definition of AoCLD (Table 1), there are two necessary conditions as follows: An underlying disease of CLD and acute exacerbation of the disease in a short period. CLD refers to a cluster of diseases with varying degrees of intrahepatic inflammatory necrosis and/or fibrosis caused by different aetiologies with a history of at least 6 mo. CLDs usually include cirrhosis and non-cirrhotic chronic liver diseases[16], including different forms of chronic hepatitis [chronic hepatitis B (CHB) and chronic hepatitis C], alcohol-associated liver disease, metabolic associated fatty liver disease, autoimmune liver disease, genetic metabolic liver disease and chronic drug-induced liver injury. Acute exacerbation is manifested as the new occurrence of acute inflammatory necrosis in the liver under the attack of different inducements (such as hepatitis virus mutation, overlap virus infection, bacterial infection, excessive alcohol intake, drugs or immune damage), causing further aggravation of the original inflammation and/or fibrosis and leading to liver dysfunction, decompensation, or even liver failure[17-19]. The period of the onset of acute aggravation varies in different basic states of CLD. Upon ALI, acute exacerbation usually presents in patients with chronic hepatitis within 1 wk[20,21], and acute decompensation of liver cirrhosis (LC-AD) usually occurs within 1 mo[6]. Since the definition of ACLF has not been unified in Eastern and Western countries, the time window of the acute exacerbation of ACLF is unclear; however, most studies suggest that ACLF patients display increased mortality at 28 d and that the most adverse outcomes (death or liver transplantation) occur within 3 mo[22-24]. Notably, if ALI occurs in CLD patients without underlying intrahepatic inflammation or fibrosis, AoCLD should not be diagnosed[25].

Thus, AoCLD can be defined as a cluster of diseases in which ALI or acute decompensation occurs in patients with pre-existing CLD, triggered by different precipitants. AoCLD may histologically present with intrahepatic mild to severe inflammatory necrosis and/or advanced fibrosis and clinically manifest as significantly increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and total bilirubin (TBil) levels within 1 wk, acute decompensation of liver cirrhosis, or liver failure within 1 mo.

CLINICAL CLASSIFICATIONS OF AOCLD

Inflammation and/or fibrosis in patients with chronic hepatitis or compensatory cirrhosis can be alleviated or even reversed (for compensatory cirrhosis) if a proper treatment regimen is applied, such as continuous nucleos(t)ide analogue (NUC) treatment for CHB[26,27]. Once patients with cirrhosis develop acute decompensation, the prognosis is poor, and the median survival time is approximately 5 years[28]. A mild ALI imposed on CLD may not lead to liver dysfunction, and liver injury can recover upon active treatment with minimal effects on the quality of life and longevity. However, once massive or submassive hepatic necrosis occurs, ACLF is triggered with a short-term (28-d) mortality rate of more than 15%[19,29]. The prognosis of AoCLD highly differs depending on both the various types of CLD and the degree of ALI. Therefore, AoCLD can be divided into ACLF and non-ACLF according to the degree of ALI; furthermore, according to the basic state of CLD (non-cirrhotic chronic liver diseases, compensatory cirrhosis, or decompensated cirrhosis), non-ACLF can be further divided into chronic hepatitis with acute exacerbation (CHAE), the active phase of liver cirrhosis (LC-A), and liver cirrhosis-acute decompensation (LC-AD) (Figure 1). A brief definition and the diagnostic criteria for each clinical type of AoCLD are shown in Table 2.

Figure 1

Pathogenesis and clinical classification of acute-on-chronic liver diseases. HBV: Hepatitis B virus; HCV: Hepatitis C virus; CMV: Cytomegalovirus; EBV: Epstein–Barr virus; ALD: Alcohol-associated liver disease; MAFLD: Metabolic-associated fatty liver disease; DILI: Drug-Induced liver injury; AILD: Autoimmune liver disease; MLD: Metabolic liver disease; CLD: Chronic liver disease; AoCLD: Acute-On-Chronic-Liver disease; C-LC: Compensatory liver cirrhosis; D-LC: Decompensated liver cirrhosis; CHAE: Chronic hepatitis with acute exacerbation; LC-A: Liver cirrhosis active phase; LC-AD: Liver cirrhosis acute decompensation; ACLF: Acute-on-chronic liver failure; SIRS: Systemic inflammatory response syndrome; GI bleeding: Gastrointestinal bleeding. 1Precipitating factors: Hepatitis virus mutation, hepatotoxic drugs, alcohol, immune injury, overlapping virus infection, etc.

Table 2

Brief definition and diagnostic criteria for each clinical type related to acute-on-chronic liver diseases

Clinical classification	Brief definition	Diagnostic criteria
CLD	It refers to a cluster of diseases with varying degrees of intrahepatic inflammatory necrosis and/or fibrosis caused by different aetiologies with a history of liver dysfunction for over 6 mo[16]	No
Liver cirrhosis	Liver cirrhosis is a consequence of chronic liver inflammation that is followed by diffuse hepatic fibrosis, where in the normal hepatic architecture is replaced by regenerative hepatic nodules[57]. (1) C-LC, patients with cirrhosis without any cirrhosis-related symptoms or complication; and (2) D-LC, patients with cirrhosis with cirrhosis-related complications such as ascites, variceal bleeding, hepatic encephalopathy, or non-obstructive jaundice	Diagnosis of cirrhosis is based on one of the following criteria[56]: (1) Histologically cirrhosis; (2) gastroesophageal varices or digestive tract ectopic varices on the basis of excluding non-cirrhotic portal hypertension; (3) imaging reveals cirrhosis or portal hypertension; and (4) meeting two or more of the four criteria: PLT < 100 × 109/L without any other reasons; ALB < 35g/L, excluding malnutrition or kidney diseases; INR > 1.3 or PT prolonged; APRI > 2
AoCLD	Acute liver injury, acute decompensation or acute liver failure occurs on the basis of CLD in a short period[16]	(1) Increased ALT/AST and TBil levels on the basis of CLD within 1 wk[16]; and (2) acute decompensation of liver cirrhosis, or liver failure on the basis of CLD within 1 mo[16]
ACLF	Acute liver failure or decompensation occurs on the basis of CLD in a short period: (1) Type-A, ACLF occurs on the basis of chronic hepatitis; (2) Type-B, ACLF occurs on the basis of compensated cirrhosis; and (3) Type-C, ACLF occurs on the basis of decompensated cirrhosis	(1) Acute or subacute deterioration of pre-existing chronic liver disease[34]; (2) extreme fatigue with severe digestive symptoms; and (3) TBil ≥ 10 mg/dL or daily rise ≥ 1 mg/dL, and INR ≥ 1.5 (or) PTA ≤ 40%[34]
Non-ACLF
CHAE	Chronic hepatitis acute aggravation in a short period	Intermittent transaminase elevation that exceeds 5 times the ULN or 2 times the baseline level in a short period (usually 1 wk)[44]
LC-A	Cirrhosis changes from the quiescent to the active stage without acute decompensation	(1) Liver fibrosis and liver inflammation simultaneously coexist; (2) a rapid increase in the liver stiffness value and serum liver fibrosis markers in a short period (usually 1 wk)[52,53]; and (3) increase in ALT and TBil and decrease in the albumin level to varying degrees[54]
LC-AD	Occurrence of acute decompensation in cirrhotic patients with/without previous decompensation in a short period (within 1 mo) under the action of acute incentives	Acute decompensated events, including ascites, hepatic encephalopathy, jaundice and gastrointestinal bleeding that occur in cirrhotic patients within 1 mo[14,58,60]

CLD: Chronic liver disease; C-LC: Compensated liver cirrhosis; D-LC: Decompensated liver cirrhosis; PLT: Platelet; ALB: Albumin; INR: International normalized ratio; APRI: Aspartate aminotransferase-to-platelet ratio; AoCLD: Acute-on-chronic-liver disease; ACLF: Acute-on-chronic liver failure; CHAE: Chronic hepatitis with acute exacerbation; LC-A: Liver cirrhosis active phase; LC-AD: Liver cirrhosis acute decompensation; ALT: Alanine Aminotransferase; AST: Aspartate aminotransferase; TBil: Total Bilirubin.

ACLF

ACLF refers to a syndrome that occurs in CLD patients under the action of various ALI factors and is characterized by acute jaundice, coagulatory dysfunction, and rapid disease progression with high mortality[12,30]. The differences in the aetiology of CLD and the induction of acute injury between Eastern and Western countries have led to nonuniform diagnostic criteria for ACLF. The definition of ACLF in Asia focuses on liver failure caused by ALI, while the definition in Europe and America pays more attention to systemic multiorgan failure, considering liver failure an unnecessary condition[31]. In 2015, the World Gastrointestinal Organization proposed consensus definitions of ACLF integrated from the East and the West and proposed the following three clinical types of ACLF based on the different CLDs: Type A (based on chronic hepatitis), type B (based on compensatory cirrhosis), and type C (based on decompensated cirrhosis)[22,32,33]. The Chinese Medical Association summarized the definition of ACLF in the Guidelines for the Diagnosis and Treatment of Liver Failure as follows: Acute liver failure (ALF) occurs on the basis of CLD (with or without cirrhosis), mainly manifesting as jaundice (serum TBil attaining a level over 10 times the upper limit of normal (ULN) value or a daily increase ≥ 17.1 μmol/L) and a bleeding tendency (prothrombin activity ≤ 40% or international normalized ratio ≥ 1.5), accompanied by failure of one or more extrahepatic organs with significantly increased mortality within 28 d and 3 mo after onset[34]. According to the basic status of CLD, ACLF was also classified into three clinical types consistent with those of the World Gastrointestinal Organization.

In the diagnosis of ACLF, attention should be given to discriminating ACLF from ALF or subacute LF (SALF) in which liver failure develops within 2 wk or 26 wk, respectively, in patients without pre-existing chronic liver injury[35]. Therefore, the difference between ACLF and ALF/SALF mainly lies in the presence or absence of underlying chronic liver injury. Hepatitis B virus (HBV) infection is the main cause of ACLF[36]. The diagnosis of HBV-associated ACLF is sometimes difficult due to the complexity of the natural history of HBV infection. According to the European Association for the Study of the Liver, the natural history of chronic HBV infection is divided into five stages, namely, hepatitis B e antigen (HBeAg)-positive chronic HBV infection, HBeAg-positive CHB, HBeAg-negative chronic HBV infection, HBeAg-negative CHB, and hepatitis B surface antigen (HBsAg)-negative stage[37]. The nomenclature is based on the description of the following two main characteristics of the history of HBV infection: infection and hepatitis. In a state of chronic HBV infection, there is limited or no chronic inflammation or fibrosis in the liver[25]. Studies have shown that the survival rate of chronic HBV-infected patients is comparable to that of non-HBV-infected patients[38]. Therefore, ALF/SALF rather than ACLF should be diagnosed once liver failure occurs in patients with chronic HBV infection or CHB whose intrahepatic inflammation and fibrosis have completely disappeared for more than half a year upon NUC treatment[39,40]. In contrast, ACLF should be diagnosed once liver failure occurs in CHB patients with active intrahepatic inflammation and/or fibrosis. However, since most patients with chronic HBV infection lack liver histological evidence, the status of liver inflammatory activity and fibrosis can be judged only indirectly by referring to the levels of serum ALT/AST and liver stiffness (detected by transient elastography)[41,42]. Thus, for patients with chronic HBV infection who do not show obvious signs and symptoms of active hepatitis but may have different degrees of inflammatory activity and fibrosis histologically, the dynamic monitoring of the ALT/AST levels and liver stiffness could facilitate the assessment of liver inflammatory activity and fibrosis, respectively, which is helpful for distinguishing ALF/SALF from ACLF[41,43].

NON-ACLF AOCLD

CHAE

In patients with chronic hepatitis, the presence of various precipitants, such as HBV reactivation, leads to acute exacerbation of liver inflammation and/or focal necrosis of hepatocytes, which is manifested as repeated or continuous increases in the serum ALT and/or AST levels, a decrease in albumin or the albumin/globulin ratio, an increase in the TBil level, and even the presence of abnormal coagulation function[17]. The 2015 edition of the Asia-Pacific Liver Association clinical practice guidelines for hepatitis B define CHAE as an intermittent transaminase elevation that exceeds 5 times the ULN or 2 times the baseline level[44]. CHAE clinically manifests as the activation of chronic hepatitis, which can be classified as mild, moderate, and severe according to the degree of inflammation and fibrosis of liver tissue[45].

Notably, due to the particularity of the natural history of HBV infection, HBV-related ALI occurring in a state of chronic HBV infection can be divided into the following two situations: one situation involves a mild transient liver injury that does not activate HBV or require anti-HBV treatment, and the patient is still in a state of “chronic HBV infection” after recovery from ALI[46,47], while in the other situation, the precipitants persist, leading to severe liver damage and even HBV activation, and anti-HBV treatment is needed to control the disease progression. In this case, “chronic HBV infection” transitions into “chronic hepatitis B”[48]. Therefore, ALI occurring under a chronic HBV infection status should not be diagnosed as CHAE.

LC-A

According to the status of inflammatory activity in liver tissue, liver cirrhosis can be divided into the active and quiescent stages[49,50]. In patients with quiescent cirrhosis, the liver is histologically characterized by pseudolobules and does not show hepatocyte necrosis, lymphocyte infiltration or new fibrogenesis. The presence of acute aggravating factors leads to intrahepatic inflammatory cell infiltration, hepatocyte necrosis and new fibrogenesis, indicating that liver cirrhosis transitioned to the active phase[51]. LC-A is histologically defined as a state of active intrahepatic inflammation and fibrogenesis in patients with cirrhosis and clinically manifests as a sharp increase in serum liver fibrosis markers (laminin, hyaluronic acid, pro-peptide of type III procollagen and collagen IV) or liver stiffness within a short period (usually 1 wk)[52,53] and is accompanied by elevated ALT and TBil levels and decreased albumin[54]. LC-A can occur in both compensatory LC (C-LC) and decompensated LC (D-LC). Due to obvious portal hypertension in patients with D-LC, haemodynamic disorders are very likely to occur, causing hepatic tissue ischaemia and hypoxia, and immunodeficiency renders D-LC patients vulnerable to secondary infections, leading to sepsis and further liver injury; thus, D-LC is rarely in a quiescent state[55]. Therefore, LC-A occurs in patients with C-LC more commonly than in those with D-LC.

LC-AD

In patients with C-LC, the remaining liver cells can maintain liver functions, such as synthesis and catabolism, even in the presence of portal hypertension[56,57]. D-LC is defined as the occurrence of ascites, hepatic encephalopathy, jaundice, or oesophageal-gastric varices bleeding in patients with C-LC[56,58,59]. Both C-LC and D-LC patients may experience acute decompensation in a short period (within 1 mo) under the action of acute inducement, which is called LC-AD[58].

LC-AD is mainly manifested by the following two types of pathophysiological changes: portal hypertension and liver dysfunction. The complications of LC-AD may interact with each other, forming a vicious cycle and promoting the progression of LC-AD[59]. Studies have shown that the prognosis of LC-AD patients with previous decompensation is worse than that of LC-AD patients without previous decompensation[28,60], likely because D-LC patients are more prone to intractable ascites and endotoxaemia than C-LC patients. Under the triple attack of immune injury, ischaemia and hypoxia, and endotoxaemia, patients with liver cirrhosis experience massive/submassive necrosis of the liver tissue, resulting in rapid deterioration, and easily develop ACLF[18,61,62].

CONCLUSION

The present review preliminarily summarized the definition, aetiology and inducement, and clinical types of AoCLD (Figure 1). However, the aetiology and precipitants of AoCLD are complex, and the clinical classification and definition of AoCLD are divergent; in particular, the diagnostic criteria for ACLF are controversial. For individual clinical types of AoCLD, the relevant factors, including the assessment of the degree of the disease and the prognosis, need to be characterized, and the mechanism driving the progression of AoCLD needs to be further clarified. Therefore, a multicentre, prospective cohort study is needed to systematically analyse the clinical characteristics and prognostic factors of the individual clinical types of AoCLD, which could provide an evidence-based definition and characterization of the diseases.