What are the diagnostic criteria for acute liver failure?

Acute Liver Failure Diagnostic Criteria

Acute liver failure (ALF) is diagnosed by the presence of coagulopathy (INR ≥1.5) and any degree of hepatic encephalopathy occurring within 26 weeks of symptom onset in patients without pre-existing cirrhosis. 1, 2, 3

Core Diagnostic Requirements

The diagnosis requires both of the following components:

• Coagulopathy: Prothrombin time with INR ≥1.5 1, 2, 4
• Hepatic encephalopathy: Any degree of mental status alteration, from subtle changes to coma 1, 3
• Timeframe: Symptoms develop within 26 weeks of onset (typically jaundice) 2, 3
• No pre-existing cirrhosis: This distinguishes ALF from acute-on-chronic liver failure 1, 3

Fulminant vs. Non-Fulminant Classification

ALF is further classified based on the rapidity of encephalopathy development:

• Fulminant liver failure: Hepatic encephalopathy occurs within 8 weeks of jaundice onset 3
• Non-fulminant: Encephalopathy develops between 8-26 weeks 3

Severity Assessment Using CLIF-SOFA Score

Once ALF is diagnosed, assess organ dysfunction severity using the CLIF-SOFA system, which evaluates six organ systems 5, 6:

Liver Component

• Bilirubin <20 mmol/L (<1.2 mg/dL): 0 points 5
• Bilirubin 20-34 mmol/L (1.2-2.0 mg/dL): 1 point 5
• Bilirubin 34-102 mmol/L (2.0-6.0 mg/dL): 2 points 5
• Bilirubin 102-204 mmol/L (6.0-12.0 mg/dL): 3 points 5
• Bilirubin >204 mmol/L (>12.0 mg/dL): 4 points 5

Coagulation Component

• INR <1.1: 0 points 5
• INR 1.1-<1.25: 1 point 5
• INR 1.25-<1.5: 2 points 5
• INR 1.5-<2.5: 3 points 5
• INR ≥2.5: 4 points 5

Cerebral Component (Hepatic Encephalopathy)

• Grade 0: 0 points 5
• Grade I-II: 1-2 points 5
• Grade III-IV: 3-4 points 5, 7

Renal Component

• Creatinine <1.2 mg/dL: 0 points 5
• Creatinine 1.2-1.9 mg/dL: 1 point 5
• Creatinine 2.0-3.4 mg/dL: 2-3 points 5
• Creatinine ≥3.5 mg/dL or renal replacement therapy: 4 points 5

Circulatory Component

• Mean arterial pressure ≥70 mmHg without vasopressors: 0 points 5
• MAP <70 mmHg or vasopressor requirement: 1-4 points based on dose 5

Respiratory Component

• PaO2/FiO2 >400 or SpO2/FiO2 >512: 0 points 5
• PaO2/FiO2 ≤200 or SpO2/FiO2 ≤214: 3-4 points 5, 7

King's College Criteria for Transplant Evaluation

These criteria identify patients unlikely to survive without liver transplantation 5:

For Acetaminophen-Induced ALF

Any one of the following:

• Arterial pH <7.3 after fluid resuscitation 5
• Arterial lactate >3.5 mmol/L after fluid resuscitation 5

OR all three of:

• Prothrombin time >100 seconds 5
• Creatinine >3.4 mg/dL 5
• Hepatic encephalopathy grade III-IV 5

For Non-Acetaminophen ALF

Any one of:

• Prothrombin time >100 seconds 5

OR three or more of:

• Age <10 or >40 years 5
• Etiology: non-A, non-B hepatitis, halothane hepatitis, or idiosyncratic drug reaction 5
• Jaundice duration >7 days before encephalopathy onset 5
• Prothrombin time >50 seconds 5
• Bilirubin >17 mg/dL 5

Etiologic Workup

Identifying the cause is critical as many etiologies have specific treatments 8, 3:

Drug-Induced Liver Injury (Most Common in US)

• History of hepatotoxic drug exposure (check LiverTox database) 8
• ALT >5× ULN or ALT >3× ULN with bilirubin >2× ULN 8
• Hepatocellular pattern: R-value >5 (where R = [ALT/ULN] ÷ [ALP/ULN]) 8

Viral Hepatitis

• Hepatitis B: Elevated HBV DNA, positive HBsAg, may have positive anti-HBc IgM 8
• Hepatitis A: AST/ALT >400 IU/mL, bilirubin >3 mg/dL, positive anti-HAV IgM 8
• Hepatitis E: AST/ALT >400 IU/mL, positive anti-HEV IgM, detectable HEV RNA 8
• Herpes simplex: AST/ALT >1,000 IU/mL, positive HSV IgM or PCR 8

Wilson's Disease (Critical Not to Miss)

• High bilirubin >10 mg/dL (predominantly indirect) 8, 5
• Coombs-negative hemolysis 8, 5
• Mild-moderate transaminase elevation (<500 IU/mL) 8
• AST/ALT ratio >2.2 8
• Low alkaline phosphatase 8
• ALP/total bilirubin ratio <4 8
• Low ceruloplasmin <20 mg/dL 8
• 24-hour urinary copper >100 μg (usually >500 μg) 8
• These patients require urgent transplant evaluation 5

Autoimmune Hepatitis

• Elevated AST/ALT, hypergammaglobulinemia, elevated IgG 8
• Positive ANA, anti-smooth muscle antibody (>1:80) in type 1 8
• Positive anti-LKM-1 in type 2 8
• History of medication non-adherence or postpartum period 8
• Transjugular liver biopsy may be necessary with severe coagulopathy 5

Ischemic Hepatitis

• Very high AST/ALT (usually >1,000 IU/mL) 8
• Bilirubin usually <3 mg/dL 8
• Marked INR elevation that improves rapidly 8
• Confirm vascular patency on ultrasound 8

Critical Management Pitfalls

Do not transfuse blood products prophylactically based on INR alone. Despite elevated INR, patients with ALF often have rebalanced hemostasis and may even be hypercoagulable 2, 4. Transfuse fresh frozen plasma, cryoprecipitate, or platelets only for clinically significant bleeding or before invasive procedures 2.

Transfer to a liver transplant center immediately upon diagnosis. Do not wait for clinical deterioration 5, 3, 9. Patients meeting King's College criteria or with ACLF grade 2-3 are transplant candidates 5.

Monitor for renal dysfunction. Creatinine >132-170 mmol/L (>1.5-1.9 mg/dL) indicates associated renal compromise and worsens prognosis 5.