What are the common causes of acute on chronic liver failure in patients with a history of chronic liver disease, such as cirrhosis?

Common Causes of Acute-on-Chronic Liver Failure

Bacterial infections and sepsis are the most frequently identified precipitants of ACLF, followed by active alcohol use and severe alcohol-associated hepatitis, though notably 40-50% of ACLF cases have no identifiable precipitating event. 1, 2

Identified Precipitating Events

Infection-Related Causes

• Bacterial infections with sepsis represent the leading identifiable precipitant of ACLF 1
• Infections can be either proven microbial infections with sepsis or clinically apparent septic states 1
• Nosocomial and multidrug-resistant organism (MDRO) infections are particularly associated with poor outcomes 1
• Fungal infections also serve as precipitants, though less commonly than bacterial causes 1

Alcohol-Related Causes

• Active alcoholism and severe alcohol-associated hepatitis are major precipitants, particularly in patients with underlying alcoholic cirrhosis 1, 3, 2
• Alcohol-related cirrhosis is especially prone to developing ACLF 3

Hepatic Insults

• Viral hepatitis reactivation, particularly hepatitis B virus (HBV) in untreated patients 3, 2
• Drug-induced liver injury (direct hepatotoxic factors) 1, 4
• Acute hepatitis superimposed on chronic liver disease 1

Portal Hypertension Complications

• Gastrointestinal hemorrhage, particularly variceal bleeding 1, 4
• This represents an indirect hepatotoxic precipitant through hemodynamic stress 4

Other Precipitants

• Major surgery in patients with cirrhosis 1
• Acute kidney injury and electrolyte disorders 1
• Dehydration and volume depletion 1

The "No Identifiable Precipitant" Phenomenon

A critical clinical reality is that 40-50% of ACLF cases develop without any clinically apparent precipitating event. 1, 3, 2 This suggests that:

• An excessive systemic inflammatory response can trigger ACLF through pathogen- or danger/damage-associated molecular patterns even without obvious external insults 3
• The syndrome may develop through exaggerated inflammatory responses and systemic oxidative stress independent of identifiable triggers 3
• Clinicians should not delay ACLF diagnosis or management while searching for a precipitant that may not exist 1

Pathophysiologic Framework

The European Association for the Study of the Liver emphasizes that ACLF precipitants can be categorized as: 1

• Intrahepatic insults: Direct liver injury (drugs, viral reactivation, alcohol-associated hepatitis)
• Extrahepatic insults: Systemic infections, bleeding, surgery
• No apparent insult: Spontaneous development through dysregulated inflammatory responses

Clinical Implications for Evaluation

When evaluating a patient with suspected ACLF, systematically assess for: 1, 5

• Infection markers: Elevated C-reactive protein (CRP) and white blood cell counts, though these lack sufficient standalone predictive accuracy 5
• Recent alcohol consumption: Detailed history of drinking patterns in the preceding weeks
• Medication review: All prescription, over-the-counter, and herbal supplements for hepatotoxic agents
• Viral hepatitis status: HBV DNA levels if chronic hepatitis B, check for reactivation
• Recent procedures or bleeding: Endoscopy findings, hemoglobin trends
• Signs of infection: Fever, leukocytosis, positive cultures, though absence does not exclude ACLF

The absence of an identifiable precipitant should never delay aggressive management, as nearly half of patients will have no clear trigger despite thorough evaluation. 1, 2