Acute-on-Chronic Liver Failure

Background: Cirrhosis is the end stage of chronic liver disease. Cirrhosis causes portal hypertension, which, in turn, can lead to acute on chronic liver failure (ACLF), which is defined as acute decompensation combined with failure of the liver, coagulation system, kidneys, lungs, and/or circulatory system, or hepatic encephalopathy.

Methods: This review is based on a selective literature search for international publications in the NCBI database using the keywords “liver cirrhosis” and “ACLF.” Valid guidelines (up to June 2024) were also included.

Results: Cirrhosis is present in approximately 1% of all hospital admissions in Germany, and complications of cirrhosis cause an estimated 1 million deaths worldwide each year. ACLF, the most severe form of decompensated liver cirrhosis, bears a 28-day mortality of 45% and affects 35% of all patients hospitalized for decompensated cirrhosis. Its precipitating factors are infection, alcohol overuse, bleeding, and drug-induced encephalopathy (benzodiazepines or opioids). No drugs or other treatments for ACLF have been approved; only its etiology and precipitating factors are amenable to treatment.

Conclusion: Liver transplantation is currently the only curative option for ACLF but is not suitable for all patients because of the narrow therapeutic window and the common presence of contraindications. Prospective data are lacking that would aid in the selection of patients for liver transplantation so that post-transplantation survival rates can be improved.

Cite this as:
Trebicka J, Praktiknjo M, Peiffer KH, Pascher A, Schulz MS, Uschner FE: Acute-on-chronic liver failure. Dtsch Arztebl Int 2025; 122: 96–102. DOI: 10.3238/arztebl.m2024.0255

Liver cirrhosis is the end stage of most chronic liver diseases and often remains clinically asymptomatic over a prolonged period of time (1, 2). Only when cirrhosis patients develop complications with signs of acute decompensation, they require hospitalization and their prognosis deteriorates (3). Decompensation and resulting hospitalization are associated with a high mortality of 10.21% (4). According to older, global surveys from the years 1980–2010, up to 1 million deaths per year are attributable to complications of cirrhosis (5). Over the last 15 years, a significant increase in the number of hospitalizations for cirrhosis has been noted in Germany (4). In 2018, 181 688 cirrhosis-related hospitalizations (0.97%) were recorded (4).

Acute-on-chronic liver failure (ACLF) is the term used for a systemic disease which is

• an acute clinical deterioration of cirrhosis with complications (acute decompensation) and
• leads to one are more of altogether six organ failures due to an inflammatory reaction.

ACLF can occur either as a consequence of pre-existing decompensation of liver cirrhosis or as the first event of cirrhotic decompensation.

According to a recently published meta-analysis of data from the years 2013–2020, the global prevalence rate of ACLF was 35% among 184 041 hospital admissions of patients with decompensated cirrhosis and a markedly increased 28-day in-hospital mortality rate of 45% and a 90-day mortality rate of 58% (6). In Germany, the rate of complications that are associated with the development of ACLF has also increased in hospitalized patients with liver cirrhosis; for example, the rate of infections increased from 9.77% in 2005 to 15.61% in 2018) (4).

The purpose of this review is to provide an overview of the pathogenesis, diagnosis and treatment of acute hepatic decompensation of liver cirrhosis and ACLF.

Methods

The contributing authors independently carried out selective searches of the literature for pertinent studies in the PubMed database (1 June 2024). Peer-reviewed studies on “decompensated liver cirrhosis” and “ACLF” were eligible for inclusion in our review.

Acute and non-acute decompensation of liver cirrhosis

In contrast to earlier assumptions, affected patients show two different clinical courses::

• a slowly progressive clinical deterioration with gradual onset of complications referred to as non-acute decompensation; this form can often be managed on an outpatient basis;
• an acute form requiring hospitalization, the acute decompensation of liver cirrhosis (3); in some cases, this form can also manifest as primary ACLF.

The most common hepatic decompensation events are ascites (60.3%), variceal hemorrhage (17.3%), hepatic encephalopathy (24.6%), and infection (21.8%) (7). Patients with spontaneous bacterial peritonitis or hepatorenal syndrome (Figure 1) have an especially poor prognosis (8, 9). The pathophysiological mechanisms responsible for the development of acute decompensation are the underlying portal hypertension and the persistent systemic inflammation in the presence of functional immunosuppression. The latter also increases susceptibility to infection and the risk of secondary complications (10, 11).

Figure 1

Course of liver cirrhosis and decompensation events

The increase in intrahepatic resistance caused by cirrhosis gives rise to portal hypertension which, in turn, leads to an increase in pressure and venous pooling in the splanchnic vascular system. This increase in pressure can be measured indirectly by interventionally assessing the hepatovenous pressure gradient (HVPG) or with non-invasive methods (liver and spleen elastography); it can also be assumed based on clinical findings, such as esophageal varices. Clinically significant portal hypertension (CSPH) is defined as an invasively measures HVPG ≥ 10 mm Hg. The risk of decompensation events increases significantly if HVPG is ≥ 12 mm Hg. For example, a prospective study on patients with compensated cirrhosis showed that from an HVPG ≥ 12 mm Hg the risk of a first decompensation event was 57% over a 3-year period (12, 13). According to the current recommendations, CSPH is unlikely to be present if the non-invasively measured liver stiffness is = 15 kPa in combination with a platelet count ≥ 150 000/µL (negative predictive value >90%). However, in the presence of liver stiffness ≥ 25 kPa and liver cirrhosis etiologically associated with virus hepatitis, alcohol use or metabolic dysfunction (body mass index of over 30 kg/m²), CSPH can be assumed, eliminating the need for invasive diagnostic testing (13). Further clinical consequences are described in eBox 1.

eBox 1

Clinical consequences of portal hypertension

In addition to portal hypertension, progressive systemic inflammation is a key predisposing factor for the development of acute decompensation or ACLF. A number of studies have provided evidence of a variety of pro-inflammatory biomarkers which are associated with the development of ACLF. For example, pro-inflammatory cytokines and markers of inflammasome activation were found in significantly higher concentrations in patients who developed ACLF compared to patients without ACLF (14). The degree of systemic inflammation correlates both with the number of organ failures and with the prognosis and severity of the disease (15) (eBox 2).

eBox 2

Progressive systemic inflammation as a key contributor to acute-on-chronic liver failure

Management of decompensated liver cirrhosis

The current treatment options for non-acute and acute hepatic decompensation consist of three pillars:

• Etiological treatment
• Lowering of portal pressure
• Prophylaxis or treatment of complications.

In many patients, it is possible to provide etiological treatment. This applies mainly to viral hepatitis, which can be treated with antiviral therapy, and liver diseases associated with alcohol use or metabolic dysfunction which can be treated by alcohol cessation or lifestyle modification and weight reduction. Portal pressure can be decreased by pharmacotherapy with non-selective beta-blockers (NSBBs), preferably carvedilol (15, 16) as well as interventionally by placement of a transjugular intrahepatic portosystemic shunt. NSBBs are already established treatments for the primary and secondary prophylaxis of variceal bleeding; in addition, they can be used to reduce the risk and the frequency of decompensation events (16). In a multicenter, placebo-controlled trial, the risk for the primary endpoint (decompensation of liver cirrhosis or death) was significantly reduced by the use of beta-blockers (hazard ratio 0.51, 95% confidence interval [0.26; 0.97]) (16). TIPS are placed to treat complications of liver cirrhosis, mainly after variceal hemorrhage or in cases of recurrent or refractory ascites (17). While it was initially assumed that TIPS was a palliative treatment option only, recent study data indicate that the currently used polytetrafluoroethylene (PTFE)-coated stents with smaller diameters may significantly improve patient survival with a lower complication rate. (18). For example, a prospective case control study showed that placement of an undilated TIPS with a diameter of 8 mm reduced the hospitalization rate for post-interventional hepatic encephalopathy (23% vs. 51%, p<0.001) (18). Human albumin is another drug treatment option. If administered at regular intervals on an outpatient basis, it could reduce the risk of decompensation events in selected patients (19). In a multicenter, prospective, randomized trial, the outpatient administration of human albumin significantly improved the overall survival rate of treated patients from 66% to 77% and reduced the hazard ratio for mortality by 38% (0.62, [0.4; 0.95]) (19). Which patients benefit most from human albumin administration is the subject of current research (20). Further prophylaxis and treatment options are listed in Table 1.

Table 1

Prophylaxis and treatment of decompensation events

Acute-on-chronic liver failure

Globally, still no consensus on the definition of ACLF has been reached among the regional specialist societies in Europe (EASL), North America (NASCLD), and Asia (APASL). This is largely due to considerable geographical differences, e.g., in the underlying etiology. While hepatitis B-associated ACLF is the most common cause in Asia, it is rather rare in Europe (6). The ACLF definition of the European Association for the Study of the Liver (EASL), which is used in Europa and Germany, defines ACLF along the modified CLIF-SOFA score (Table 2). The severity of ACLF is graded based on the number of organ failures (Figure 2; see eBox 3 for further details).

Figure 2

Schematic representation of organ failure in ACLF and severity grading according to EASL-CLIF criteria

Table 2

Modified CLIF-SOFA score according to EASL-CLIF definition to grade the severity of organ dysfunction or organ failure

eBox 3

Assessment of disease severity in acute-onchronic liver failure

Precipitating events for decompensation and acute-on-chronic liver failure

The European PREDICT study analyzed the precipitating events for decompensation in 1273 patients hospitalized for acute hepatic decompensation and observed the disease course over time. Notably, no precipitating event could be identified in 56.6% of the cases (10, 21).The most common identifiable precipitating events were: 1) proven bacterial infection in 44.06%, 2) severe alcoholic hepatitis in 43.56%, 3) severe gastrointestinal bleeding with shock in 5.94%, and 4) toxic encephalopathy in 5.94% of patients with ACLF (21). Alcohol-associated hepatitis was classified as severe in the presence of rapid-onset jaundice, increased aspartate aminotransferase serum levels, and significant alcohol abuse in the short-term history (22). Toxic encephalopathy is defined as the use of neurotoxic substances, such as barbiturates and opioids, leading to cognitive abnormalities and simulating the clinical picture of hepatic encephalopathy. In clinical practice, consideration should be given to the fact that several precipitating events can be present at the same time. The number precipitating events correlates positively with the severity of ACLF (21). Table 3 provides an overview of the most important precipitating events and the related diagnostic evaluation.

Table 3

Prophylaxis and treatment of decompensation events

A retrospective analysis identified surgical procedures (n = 190) as an independent risk factor for the development of ACLF in the subsequent year (e6). Presurgical placement of a TIPS reduced the risk of postoperative ACLF in high-risk patients (e7, 29).

Management of acute-on-chronic liver failure

Besides liver transplantation, the main pillars of the management of ACLF are the treatment of the precipitating factor and the supportive treatment of the resulting organ failure; thus, most patients are treated in specialized intensive care or observation units.

When considering systemic inflammation as the overarching pathomechanism of decompensation and ACLF, the most important initial treatment is understandably: the immediate initiation of broadband antibiotic treatment if an infection is suspected or the precipitating event for decompensation is still unknown. This approach is supported by the findings of a retrospective study on 635 patients with liver cirrhosis and septic shock which indicate that both inadequate and delayed administration of antibiotics may lead to an increase in mortality (with an odds ratio of 1.1 [1.1; 1.2] for each hour of delay) (23). For this reason, empirical treatment should be initiated if an infection is suspected and the selection of the antimicrobial agent should take the local antimicrobial resistance situation and patient-related risk factors for the presence of resistant pathogens into account (24).

In patients with septic shock or deterioration of ACLF, immediate initiation of treatment with broad-spectrum anti-infective agents, covering all conceivable pathogens, is vital. The German guideline that is currently still valid only makes a recommendation for spontaneous bacterial peritonitis. In patients with community-acquired peritonitis, the use of a cephalosporin would be acceptable; however, in patients with hospital-acquired peritonitis or risk factors, a carbapenem should be used as the first-line treatment (25). This recommendation is supported by evidence from a prospective study on 1175 patients with decompensated liver cirrhosis and proven bacterial infection which showed that hospital-acquired infections were an independent predictor of the development of ACLF (odds ratio 1.63; p = 0.028) and that extensively drug-resistant (XDR) pathogens were significantly more common in patients with ACLF (26). In addition, the finding of multidrug resistance (MDR) is associated with a more severe clinical course and an increased 28-day mortality (21).

If an infection can be ruled out and there is evidence that acute severe alcohol-associated hepatitis is the precipitating event for ACLF, the findings of a recently published randomized controlled clinical trial (RCT) indicate that glucocorticoid therapy improves the prognosis of such patients to a larger extent compared to anakinra treatment, e.g., 90-day survival of 90% versus 70% (27). However, in patients with ACLF grade 3 or with an uncontrolled bacterial infection, corticosteroid therapy is not recommended. The current European guideline recommends a dose of 40 mg prednisolone equivalent per day for 28 days. However, if no response to treatment is noted during the first week, treatment discontinuation should be considered (28).

If variceal hemorrhage is the precipitating event, a pre-emptive or rescue TIPS should be considered, because patients with ACLF are at high risk of rebleeding and rebleeding events are associated with a poorer prognosis. According to data from a multicenter observational study on 2138 persons with liver cirrhosis, covering the years 2011–2015, patients with ACLF had a rebleeding risk of 19.1% with an overall mortality of 47% compared to patients without ACLF who had a rebleeding risk of 10% and a mortality risk of 10% (29). Indications for pre-emptive or rescue TIPS placement include::

• Child B liver cirrhosis (≥ 8 points) and active bleeding noted during endoscopy
• Child C liver cirrhosis (≤ 13 points) or
• a bleed that cannot be stopped endoscopically (rescue).

TIPS placement reduces the rebleeding risk and improves the prognosis in patients with ACLF grade 1 and 2 (29).

The management of the resulting organ failure does not differ significantly from the currently used organ-supporting and intensive care treatment principles. Renal failure is common and in the case of hepatorenal syndrome, the administration of terlipressin in combination with human albumin can improve renal function and in some cases prevent the need for renal replacement therapy (30). According to the German guideline recommendation, treatment with terlipressin should be started with a dose of 2–4 mg per day, either as a repeated bolus or continuous infusion; in the absence of a response, the dose should be increased to a maximum dose of 12 mg per day. Concomitant treatment with albumin is administered at doses of 20–40 g per day (25). According to more recent data, however, terlipressin increases the risk of colonization with MDR bacteria and has no positive effects on pre-existing pulmonary failure (30, 31). While many patients with ACLF are prone to bleeding events, they are also prone to develop thrombosis (32). This situation is further complicated by the fact that the results of the widely used standard coagulation tests do not fully apply and are only of limited help in assessing the risk of bleeding and thrombosis in cirrhosis. Therefore, prophylactic correction of abnormal coagulation tests is not recommended; in the case of a hemorrhage requiring transfusion, preference should be given to individual factors (33).

Various liver support systems, such as MARS, Prometheus and plasma exchange with albumin replacement, are available. Since they eliminate protein-bound and water-soluble substances, they could theoretically be of benefit for patients with ACLF, mainly by eliminating cytokines and other inflammatory molecules. While there are indications of a therapeutic benefit of these methods (34,35), the available evidence is still heterogeneous and it is not recommended to use these methods routinely in ACLF therapy outside of clinical trials (24).

Liver transplantation is currently the only curative treatment option for patients with ACLF. A prospective observational study reported an increase in survival in patients with ACLF grade 2 and 3 from 23% to 95% at day 28 by performing a liver transplant (36). High survival rates of about 80% and above one year after transplantation were also reported from other retrospective studies which also found that the severity of the pre-transplant condition had little influence on the prognosis after transplantation (37, 38). However, the questions which patients with ACLF are eligible for transplantation, what is the best timing for transplantation and which criteria indicate a poor prognosis even after transplantation, have not yet been conclusively answered. Likely negative predictors include multi-organ failure of four or more organ systems and a CLIF-C ACLF score of >64 on days 3–7 (38). ACLF patients should be referred for evaluation to a transplant center without delay to establish whether liver transplantation is a treatment option for them.

A change in the intent of treatment to a palliative approach with discontinuation of organ support may be considered in patients not eligible for liver transplantation with organ failure of four or more organ systems or a CLIF-C ACLF score > 70 points after 3–7 days of maximum organ support (38).

Conclusion

The primary goal of the management of decompensated liver cirrhosis is to treat the underlying condition and the precipitating factors. A center experienced in hepatology should be involved in the management of ACLF. Patients usually require observation in intermediate care or intensive care units und may need organ-supporting treatment or potentially liver transplantation.

Conflict of interest
JT received third-party funding from DFG, H2020 and BMBF as well as lecture fees and consulting fees (advisory board) from Versantis, Gore, Boehringer-Ingelheim, Falk, Grifols, Genfit, and CSL Behring. He is a member of DGIM, EASL, DGVS, GASL, and AASLD.

MP received third-party funding from BONFOR, DFG and the Ernst-und-Berta Grimmke Foundation. He received lecture fees and consulting fees as well as travel support from Gore, Orphalan, Gilead, Falk, Univar, Ipsen, Roche, AstraZeneca, Boston Scientific, and MicroTech.

K-HP received third-party funding from DFG, LOEWE and the Wilhelm Sander Foundation as well as travel cost reimbursement, lecture fees and consulting fees from Abbvie, Gilead and CytoSorben.

AP received lecture fees as well as reimbursement of travel costs and congress fees from Novartis, Medtronic, Ethicon, Celltrion, Falk, and Takeda.

MSS received lecture fees from Falk and the Professional Association of German Internists (BDI FU received lecture fees from Falk, Gilead, AbbVie, and AstraZeneca.

Manuscript received on 24 June 2024, revised version accepted on
18 December 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. Dr. med. Jonel Trebicka

Medizinische Klinik B

Universitätsklinikum Münster

Albert-Schweitzer-Campus 1

48149 Münster

Germany

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