What is the differential diagnosis of Acute-on-Chronic Liver Failure (ACLF)?

Differential Diagnosis of Acute-on-Chronic Liver Failure (ACLF)

The differential diagnosis of ACLF primarily involves distinguishing between precipitating factors (hepatic vs. non-hepatic insults), identifying the specific organ failures present, and excluding mimics such as acute liver failure, stable decompensated cirrhosis, and acute tubular necrosis. 1

Primary Diagnostic Framework

When evaluating a patient with suspected ACLF, the differential diagnosis must address three key questions:

1. Is This Actually ACLF or a Mimic?

ACLF must be distinguished from:

• Acute liver failure (ALF) - occurs without pre-existing chronic liver disease, whereas ACLF requires underlying chronic liver disease with or without cirrhosis 1, 2
• Stable decompensated cirrhosis - patients with complications who do not develop organ failures or who are discharged without readmission during 3-month follow-up 2
• Unstable decompensated cirrhosis - patients with liver-related complications requiring readmission but not meeting ACLF organ failure criteria 2
• Acute decompensation without organ failure - acute worsening (ascites, encephalopathy, GI bleeding, jaundice, infections) but without meeting organ failure thresholds 1

2. What Is the Precipitating Factor?

The differential of precipitating events divides into hepatic and non-hepatic insults:

Type I ACLF: Non-Hepatic Precipitants (60% of cases) 3

• Infections/sepsis (most common, 47% of Type I cases) - bacterial infections including spontaneous bacterial peritonitis, pneumonia, urinary tract infections, and bloodstream infections 1, 3
• Gastrointestinal bleeding - variceal or non-variceal hemorrhage causing hemodynamic instability 1, 4
• Surgery or trauma - major surgical procedures or traumatic injury 1
• Hemodynamic derangements - shock states from any cause 1

Type II ACLF: Hepatic Precipitants (40% of cases) 3

• Acute alcoholic hepatitis (most common hepatic precipitant, 29% of all ACLF cases) - active alcohol consumption in patients with underlying alcoholic liver disease 3, 4
• Acute viral hepatitis superimposed on chronic liver disease:
  • Hepatitis E virus (HEV) superinfection 3
  • Hepatitis A virus (HAV) superinfection 3
  • Hepatitis B virus (HBV) reactivation or flare 1, 5
• Drug-induced liver injury (DILI) - hepatotoxic medications or herbal supplements 1
• Autoimmune hepatitis flare - may require transjugular liver biopsy for diagnosis 1, 6
• Ischemic hepatitis - though bilirubin is usually <3 mg/dL despite marked transaminase elevation 6

Critical caveat: In 40-50% of ACLF cases, no identifiable precipitating event can be found despite thorough investigation 7, 8, 4

3. Which Organ Failures Are Present?

The differential diagnosis of specific organ dysfunctions in ACLF includes:

Renal Failure Differential 1

• Hepatorenal syndrome-AKI (HRS-AKI) - functional renal failure meeting ICA criteria: Stage 2+ AKI, no response to volume expansion with albumin 1 g/kg × 2 days, absence of shock, no nephrotoxic drugs, no proteinuria >500 mg/day, no microhematuria >50 RBC/hpf, normal renal ultrasound 1
• Prerenal azotemia (PRA) - accounts for 50% of AKI in cirrhosis, responds to volume expansion 1
• Acute tubular necrosis (ATN) - accounts for 35% of AKI in cirrhosis, evidenced by urinary casts, hematuria, proteinuria 1, 2
• Acute glomerulonephritis - rare, identified by urinalysis showing hematuria and proteinuria 1
• Acute interstitial nephritis - rare, may be drug-related 1

Key diagnostic approach: Urinalysis and urine microscopy differentiate functional (HRS-AKI, PRA) from structural (ATN, glomerulonephritis) causes 1

Hepatic Failure Differential

• Progressive cirrhosis - bilirubin 6-12 mg/dL indicates liver failure by CLIF-SOFA criteria 1, 5
• Massive hepatic necrosis - HBV flare causing marked transaminase elevation and coagulopathy 1
• Wilson's disease with hemolysis - markedly elevated bilirubin with predominant indirect fraction, requires urgent transplant evaluation 6, 5

Cerebral Failure Differential

• Hepatic encephalopathy Grade III-IV - defines cerebral failure in ACLF 1, 5
• Structural brain lesions - must be excluded with imaging if focal neurologic signs present 1
• Metabolic encephalopathy - from uremia, hypoglycemia, or electrolyte disturbances 1
• Septic encephalopathy - associated with systemic infection 4

Coagulation Failure Differential

• Liver synthetic dysfunction - INR ≥2.5 or platelets ≤20,000/mm³ defines coagulation failure 1, 5
• Disseminated intravascular coagulation (DIC) - may complicate sepsis in ACLF 4
• Hemolysis - particularly in Wilson's disease presenting as acute liver failure 6

Circulatory Failure Differential

• Distributive shock - most common in ACLF, requiring vasopressor support 1, 5
• Hypovolemic shock - from GI bleeding 1
• Septic shock - from bacterial infections 4
• Cardiogenic shock - rare but must be excluded 1

Respiratory Failure Differential

• Hepatopulmonary syndrome - PaO₂/FiO₂ ≤200 or SpO₂/FiO₂ ≤214 defines respiratory failure 1, 5
• Aspiration pneumonia - risk increased with hepatic encephalopathy 5
• Fluid overload/pulmonary edema - particularly with aggressive albumin administration 9
• Pleural effusion (hepatic hydrothorax) - occurs in 5.5% of ACLF patients 9
• Acute respiratory distress syndrome (ARDS) - may complicate sepsis 4

ACLF Grade Differential

Once ACLF is confirmed, grading determines prognosis and management:

• ACLF Grade 1a - single kidney failure (creatinine ≥2 mg/dL) 1, 5
• ACLF Grade 1b - single non-kidney organ failure with creatinine 1.5-1.9 mg/dL and/or hepatic encephalopathy Grade 1-2 1, 5
• ACLF Grade 2 - two organ failures, 28-day mortality 32% 1
• ACLF Grade 3 - three or more organ failures, 28-day mortality 78% 1, 5

Common Diagnostic Pitfalls

• Failing to recognize non-hepatic precipitants - infections and sepsis are the most common triggers but may be subtle; always obtain blood cultures, urinalysis, diagnostic paracentesis, and chest imaging 1, 3
• Misclassifying stable decompensated cirrhosis as ACLF - ACLF requires organ failure by CLIF-SOFA criteria, not just decompensation events 1, 2
• Overlooking HBV reactivation - check HBV DNA in all patients with known or newly diagnosed hepatitis B 5
• Assuming all AKI is HRS-AKI - urinalysis is mandatory to differentiate functional from structural renal disease 1
• Missing Wilson's disease - consider in younger patients with hemolysis, marked indirect hyperbilirubinemia, and coagulopathy 6, 5
• Attributing respiratory failure solely to ACLF - fluid overload from excessive albumin administration is a preventable cause; ACLF Grade 3 patients are at highest risk 9
• Not recognizing autoimmune hepatitis flare - may require transjugular liver biopsy in the setting of severe coagulopathy 6