What are the precipitants to Acute-on-Chronic Liver Failure (ACLF) in a patient with cirrhosis, excluding drugs, and what is the primary precipitating event for Acute Liver Failure (ALF) versus ACLF?

Precipitants of ACLF vs ALF

The main precipitants of ACLF in cirrhosis patients (excluding drugs) are bacterial infections, severe alcoholic hepatitis, gastrointestinal hemorrhage with shock, and hepatitis B virus flares, while the number one precipitating event for ALF is acetaminophen toxicity compared to bacterial infections for ACLF. 1

Precipitants to ACLF in Cirrhosis (Excluding Drugs)

Four Major Non-Drug Precipitants of ACLF:

1. Bacterial Infections

   • Most common precipitant of ACLF worldwide (prevalence of 48%) 1
   • Particularly significant in patients with alcohol-associated cirrhosis
   • Common infections include spontaneous bacterial peritonitis, urinary tract infections, and skin/soft tissue infections 1

2. Severe Alcoholic Hepatitis

   • Second most common single precipitant after bacterial infections 1
   • Often occurs in combination with bacterial infections, creating a particularly high-risk scenario 1

3. Gastrointestinal Hemorrhage with Hemodynamic Instability

   • Less common as a single precipitant (only about 2% of cases) but significant 1
   • Particularly dangerous when combined with other precipitants

4. Hepatitis B Virus Flares/Reactivation

   • Particularly important in Asian populations
   • In China, HBV flares and bacterial infections are the main precipitants of ACLF 1

Additional Important Non-Drug Precipitant:

• Hepatitis E Virus Infection - Recognized as a significant precipitant in the PREDICT study 1, 2

Primary Precipitating Events: ALF vs ACLF

ALF (Acute Liver Failure)

• Number 1 precipitant: Drug-induced liver injury, particularly acetaminophen toxicity
• Occurs in patients without pre-existing liver disease
• Rapid onset of severe liver dysfunction leading to coagulopathy and encephalopathy

ACLF (Acute-on-Chronic Liver Failure)

• Number 1 precipitant: Bacterial infections 1
• Occurs in patients with underlying cirrhosis
• The PREDICT study confirmed that proven bacterial infections and severe alcoholic hepatitis accounted for almost all (96-97%) cases of ACLF, either alone or in combination 2

Clinical Implications

• The number of precipitants present simultaneously is a major determinant of short-term outcomes in ACLF patients 1
• Patients with two or more precipitants have a significantly higher risk of death at 90 days than those with only one or no identifiable precipitant 1
• Early identification and treatment of bacterial infections is critical, as adequate first-line antibiotic treatment is associated with lower ACLF development rates and reduced 90-day mortality 2
• Systematic workup should be performed in every patient with ACLF to identify common precipitants and their potential combinations 1

Pitfalls and Caveats

• In approximately 35% of ACLF cases, the systematic workup fails to identify a precipitant 1
• ACLF precipitants may vary geographically (e.g., HBV flares are more common in Asia than Western countries) 1
• The clinical presentation of infection in cirrhosis can be subtle - fever is often absent, and traditional markers of infection may be altered by the underlying liver disease 1
• Biomarkers like C-reactive protein, procalcitonin, and lactate may be elevated in cirrhosis patients with or without infection 1

Understanding these precipitants is crucial for early identification, prompt treatment, and improved outcomes in patients with ACLF, which carries a 28-day mortality rate of 20% or more compared to 5% or less in patients with decompensated cirrhosis without ACLF 1.