Acute on Chronic Liver Failure

Etiology

The etiology of ACLF typically involves a precipitating event occurring in the setting of a preexisting liver condition. Hepatic triggers include alcohol-associated hepatitis, drug-induced liver injury, viral hepatitis (A, B, C, D, and E), hypoxic injury, or liver-related procedures, including transjugular intrahepatic portosystemic shunt placement. Extrahepatic causes are primarily bacterial infections and major surgical interventions. Notably, in approximately 40% to 50% of cases, no identifiable precipitating event is found, and these patients are categorized as having an unrecognized trigger for ACLF.[7][8][9]

The precipitating event of ACLF shows geographical variation, similar to the etiology of acute liver failure. In Western countries, acute alcohol-related liver injury and bacterial infections are the most common triggers. In contrast, in Asia, the predominant causes include reactivation of chronic hepatitis B, acute hepatitis A and E infections, in addition to acute alcohol injury and bacterial infections. This variation is partly attributable to differences in the definitions used to diagnose ACLF, particularly the APASL definition used in Asia, which includes only hepatic insults. Initially, infections were considered a consequence of ACLF rather than a trigger. However, the latest guidelines now recognize infections as an important precipitating factor in developing liver failure.[5]

Epidemiology

According to the American Association for the Study of Liver Diseases (AASLD), the 28-day mortality for patients with ACLF ranges from 30% to 50%, depending on the number and severity of organ failures.[10] Compared to other more common causes of hospitalization in the United States, the healthcare burden per patient with ACLF is significantly higher. The mean cost of hospitalization for patients with ACLF is 3 times greater than the cost of patients hospitalized with cirrhosis, and 5 times higher than the cost of patients hospitalized with congestive heart failure.[11][12]

Although outcomes have improved over time, ACLF remains associated with high mortality. The estimated mortality rate decreased from 65% in 2001 to 50% in 2011. According to the European Association for the Study of Liver-Chronic-Liver Failure (EASL-CLIF) Consortium, the current global mortality rate ranges between 30% and 50%. In the United States, data from the North-American Consortium for the Study of End-Stage Liver Disease (NACSELD) show mortality rates of 27%, 49%, 64%, and 77% in infected decompensated patients with 1, 2, 3, or 4 organ failures, respectively.[13][14] Patients discharged following admission for ACLF have an approximately 30% readmission rate within 30 days. The high readmission rate highlights the need for improved post-discharge care and closer monitoring to reduce recurrence and improve long-term outcomes.[15][16]

Pathophysiology

The pathophysiology of ACLF is based on the understanding that an acute precipitating event in a patient with a chronic liver condition causes hepatocellular injury, triggering a cascade of inflammatory cytokines and resulting in further hepatic injury, particularly impaired hepatocyte regeneration. The resulting immune dysfunction and hepatic decompensation increase the patient's vulnerability to infections, ultimately contributing to multiple organ failure and high mortality.

Systemic inflammation, characterized by elevated leukocytosis, cytokines, and chemokines (including interleukin-6 and interleukin-8), is commonly observed in patients with ACLF. This inflammatory response is typically absent in patients with compensated cirrhosis without ACLF. Bacteria-induced pathogen-associated molecular patterns (PAMPS) and virulence factors activate transcription factors that drive cytokine expression in the inflammatory cascade. In addition, endogenous inducers of inflammation, known as damage-associated molecular patterns (DAMPs)—released from injured or necrotic hepatocytes—also activate inflammatory pathways. These DAMPs interact with Toll-like receptors (TLRs) to amplify the immune response. This immunopathology plays a role in causing tissue and organ damage, ultimately leading to multiple organ failure in patients with ACLF.[17]

History and Physical

A thorough history is essential to identify potential precipitating factors for acute hepatic decompensation. Information should be gathered from the patient’s medical records, the patient, or their family. This includes a known history of chronic liver disease and the degree of fibrosis or cirrhosis, any prior episodes of hepatic decompensation, and the presence of other relevant chronic health conditions. Determining the timeline and nature of presenting symptoms, such as systemic features, fluid overload, gastrointestinal bleeding, abdominal pain, and altered mental status is also important. Inquiries should be made regarding toxic habits or high-risk behaviors, such as alcohol use or intravenous drug use.

Any recent changes in medications or ingestion of potentially hepatotoxic substances, including herbal remedies, sedatives, or analgesics, should be noted. Recent travel history and any recent surgical procedures, particularly transjugular intrahepatic portosystemic shunt placement, are also relevant. On physical examination, findings may include hypotension, altered mental status, jaundice, asterixis, fever (which may suggest an infectious etiology), right upper quadrant pain or tenderness, nausea, and other signs indicative of liver failure.[18]

Evaluation

Patients with ACLF typically present with features of acute hepatic decompensation. Common laboratory abnormalities include a prolonged international normalized ratio of 1.5 or greater, elevated bilirubin and aminotransferases, thrombocytopenia with anemia, hypoglycemia, elevated ammonia levels, and evidence of acute kidney injury (AKI), often reflected by increased serum creatinine and electrolyte imbalances.[19][20][21][22] Among extrahepatic organ failures, the kidney is the most commonly affected in the ACLF. Therefore, it is essential to differentiate the underlying etiologies of AKI, which may include prerenal AKI, hepatorenal syndrome, acute tubular injury, and cholemic nephropathy.[23]

Imaging studies may be necessary to support clinical examination findings and assess for infection or organ failure. Based on clinical suspicion, imaging of the brain, chest, abdomen, and pelvis should be considered. Abdominal imaging is essential to evaluate for portal hypertension, hepatocellular carcinoma, vascular thrombosis, lymphadenopathy, and splenomegaly. An abdominal sonogram with Doppler is particularly useful in patients with renal dysfunction or suspected vascular thrombosis. Brain imaging with computed tomography or magnetic resonance imaging can help rule out structural causes of altered mental status. In contrast, chest imaging is valuable in identifying pulmonary edema, pneumonia, or other thoracic complications. 

The grading and classification of ACLF vary across major hepatology societies, reflecting differences in pathophysiological focus and regional disease patterns. The 3 major ACLF grading systems include EASL-CLIF, NACSELD, and APAS (AARC score). Each system uses different clinical parameters and serves distinct purposes in patient care, depending on regional practices and patient profiles (see Table. Comparison of ACLF Grading Systems). Understanding these distinctions is essential for accurate diagnosis, risk stratification, and management of ACLF.  

Table. Comparison of ACLF Grading Systems

AARC, American Association for Respiratory Care; ACLF, acute-on-chronic liver failure; APASL, Asian Pacific Association for the Study of the Liver; EASL-CLIF, European Association for the Study of the Liver—Chronic Liver Failure Consortium; INR, International Normalized Ratio; NACSELD, North American Consortium for the Study of End-Stage Liver Disease 

While the NACSELD system focuses exclusively on extrahepatic organ failures, its “grading” is effectively based on the number of organ failures. The APASL approach centers on liver injury and employs a numerical score to risk-stratify patients and predict survival, particularly in the context of liver transplantation. In contrast, the EASL-CLIF system captures a broader spectrum of patients and provides detailed risk stratification across varying severities of organ failure.[5]

Treatment / Management

Managing ACLF involves preventing precipitating factors that lead to acute hepatic decompensation, providing supportive care, and initiating specific therapies early. Management also includes preventing and managing complications, assessment of prognosis, and evaluation for liver support, including possible need for liver transplantation. All patients should be hospitalized, preferably at a center with the necessary facilities and expertise for liver transplantation.[24][25]

Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation

While managing ACLF, it is essential to maintain a high index of suspicion for infection. Clinicians should evaluate for potential sources of infection and initiate appropriate treatment as early as possible; early intervention is key to improving outcomes. Sustained viral suppression of hepatitis B and C should be a priority to prevent ongoing liver injury and further hepatic decompensation. Antiviral therapy plays a crucial role in managing the underlying chronic liver disease and reducing the risk of ACLF progression.[26] In patients diagnosed with spontaneous bacterial peritonitis, intravenous albumin should be administered to prevent the development of accelerated renal dysfunction, a hallmark of hepatorenal physiology. However, current evidence does not support the use of intravenous albumin in other types of bacterial infections.[27](B3)

Further, for patients with severe acute alcohol-associated hepatitis, prognostic scoring tools such as the Maddrey Discriminant Function and Model for End-Stage Liver Disease score should be used to guide treatment decisions. These scores help determine the severity of the disease and the need for specific therapies. Preventing AKI is also a critical component of management in this setting.[28] In patients with septic shock, a personalized and carefully monitored approach should be applied. These patients should be stabilized and evaluated for liver transplantation after recovery, as many progress to grade 3 ACLF and have poor survival without transplant intervention.[29](B3)

Supportive Care

• Assess hemodynamic stability and determine the need for intravenous fluid while maintaining acid-base balance and correcting electrolyte abnormalities. Vasopressors should be used to maintain a mean arterial pressure of 75 mm Hg or greater to ensure adequate renal and cerebral perfusion. Serum lactate, a component of the AARC score for ACLF, is an important prognostic marker.
• Monitor hematocrit closely, as patients often have coagulopathy and impaired platelet function, placing them at risk for bleeding. Blood products such as platelets and fresh frozen plasma should be administered in cases of active bleeding.
• Evaluate for hepatic encephalopathy and protect the airway in patients showing signs of neurologic deterioration. Intubation may be necessary in cases of advanced encephalopathy, and protocols should be followed to prevent cerebral edema.
• Ensure adequate nutrition by providing 1 to 1.5 grams of protein per kilogram of body weight per day. Monitor for hypoglycemia and aim to maintain blood glucose levels between 160 and 200 mg/dL.
• Discontinue all home medications unless they are deemed essential to continue during hospitalization. Particular attention should be paid to potentially hepatotoxic drugs, sedatives, and nephrotoxic agents, which may worsen liver or kidney function in the setting of ACLF.

Specific Treatment when Etiology is Known   

• Patients with hepatitis A- or E-associated ACLF should receive supportive care, as there are currently no effective antiviral therapies for these infections. Management focuses on monitoring for complications and maintaining organ support.[30][31]
• For patients with acute hepatitis C or reactivation of chronic hepatitis C, appropriate antiviral therapy should be initiated. The choice of regimen depends on prior treatment history and the patient’s overall clinical status.
• Patients experiencing acute hepatitis B or reactivation of chronic hepatitis B should be started on nucleos(t)ide analogs. Early antiviral intervention can help reduce viral load and improve outcomes.
• In cases where ACLF is triggered by acute decompensation of Wilson disease or hepatic vein thrombosis (such as Budd-Chiari syndrome), liver transplantation should be considered promptly. These conditions carry a poor prognosis with medical therapy alone.

Management of Complications

Every effort should be made to prevent the progression to multiple organ dysfunction, as it significantly worsens the prognosis in ACLF. Early recognition and aggressive management of complications are key to improving patient outcomes. 

• Kidney failure may result from hypovolemia, acute tubular necrosis, or hepatorenal syndrome.
• Vasopressor therapy with norepinephrine or dopamine is indicated in severe hypotension.
• Renal replacement therapy may serve as a bridge to liver transplantation, with continuous renal replacement therapy preferred over intermittent hemodialysis in critically ill individuals.
• Sepsis, including aspiration pneumonia, should be promptly treated with a broad-spectrum antibiotic.
• Blood, sputum, and urine surveillance cultures are recommended for all patients with ACLF to guide therapy.

Metabolic disturbances are common and require targeted management.

• Hypoglycemia, due to impaired glycogen storage and gluconeogenesis, should be treated with continuous infusions of 10% or 20% glucose.[10]
• Hypophosphatemia, related to adensine triphosphate depletion from hepatocyte necrosis, requires aggressive phosphate repletion.
• Alkalosis may occur from hyperventilation, while acidemia with a pH below 7.3 is associated with 95% mortality in acetaminophen overdose if transplantation is not performed.[10] 
• Hypoxemia may develop due to aspiration, ARDS, or pulmonary hemorrhage.
• Patients with encephalopathy beyond grade 2 should be intubated to protect the airway. Seizure-like activity can be managed with phenytoin or benzodiazepines.

Encephalopathy is a hallmark of ACLF and should be closely monitored. In patients with grade 3 encephalopathy or higher, head computed tomography imaging is recommended to assess for cerebral edema or intracranial bleeding.

• Coagulopathy is frequently present but does not often lead to spontaneous bleeding.
• Routine correction is unnecessary unless there is active bleeding or a planned invasive procedure.
• If clinically indicated, transfusion of platelets, fresh frozen plasma, or cryoprecipitate may be used.
• Recombinant factor VII should be used cautiously due to the risk of thrombosis.
• Intravenous vitamin K may be administered slowly if nutritional deficiency or prolonged cholestasis is suspected.

Liver Support and Transplantation

Grading ACLF during the hospital stay helps physicians assess whether a patient will likely recover or require a liver transplant. Although liver transplantation remains the only definitive treatment for ACLF, no standardized selection criteria currently exist.[10][32] Moreover, active infections disqualify nearly half of the patients from transplant eligibility. Among those listed, only 10% to 25% receive a transplant, while 50% to 75% die while waiting.[33]

Extracorporeal liver-assist devices have been used in clinical trials in patients as a potential treatment for ACLF. These devices aim to support detoxification and restore synthetic liver functions. Bioartificial liver support systems have been developed, including porcine hepatocyte-based tumor hepatocyte system, Vitalal Therapies ELAD, and Alliqua HepatAssist 2000. However, results from recent multicenter trials have not demonstrated a survival benefit. Newer extracorporeal systems are currently under investigation.[34] The role of plasma exchange in ACLF remains controversial, with a recent meta-analysis showing no significant survival advantage.[35](A1)

Differential Diagnosis

ACLF is a distinct clinical syndrome and should be carefully differentiated from other liver-related and systemic conditions, including:

• Acute decompensation of cirrhosis 
• Nonacute decompensation of cirrhosis 
• Acute liver failure due to multiple etiologies (eg, drug-induced liver injury, acute viral hepatitis)
• Sepsis and multiple organ dysfunction syndrome (note that under the EASL-CLIF definition, a diagnosis of ACLF does not require elevated bilirubin or INR. Therefore, a high degree of clinical suspicion and thorough understanding of the diagnostic criteria are critical)
• Acute hepatitis from various etiologies (drug-induced liver injury, ischemic hepatitis, reactivation hepatitis B virus)

Prognosis

The CLIF Organ Failure score is a valuable tool for predicting mortality in patients with ACLF. Mortality risk increases proportionally with the number of organ failures. A CLIF score above 64 warrants immediate evaluation for liver transplantation. Importantly, the underlying etiology of the precipitating event does not significantly influence prognosis. 

Infections are the most common etiology of ACLF and are associated with poorer outcomes, as infected patients are often delisted from transplant consideration. Among all organ failures, respiratory failure is linked to the highest mortality. ACLF is a dynamic syndrome that can improve, worsen, or follow a protracted course, offering a potential window for liver transplantation in appropriate candidates. Close clinical progression and organ function monitoring are essential to guide timely intervention.

Complications

Major complications of ACLF include the following:

• AKI
• Hepatic encephalopathy
• Sepsis (bacterial and fungal)
• Circulatory failure or vasoplegic shock
• Respiratory failure
• Gastrointestinal hemorrhage 
• Coagulation failure and bleeding manifestations