1. Clinical & Laboratory Diagnostic Framework

ALF is defined by acute hepatocellular injury with coagulopathy (INR ≥1.5) and any degree of hepatic encephalopathy (HE) in patients without prior chronic liver disease. Early recognition via focused history, exam, and labs is paramount.

Diagnostic Triad

• Acute onset of liver injury, typically with markedly elevated aminotransferases (AST/ALT).
• Severe synthetic dysfunction, defined as an INR ≥1.5 that is not responsive to vitamin K administration.
• Presence of any grade of hepatic encephalopathy (HE), ranging from mild confusion to coma (West-Haven Grade I–IV).

Initial Laboratory Panel

• Liver Function Tests: AST, ALT (often >1,000 IU/L in acetaminophen-induced ALF), total and direct bilirubin.
• Coagulation Studies: PT/INR, fibrinogen (a level <100 mg/dL signals severe synthetic failure), and D-dimer.
• Metabolic and Renal Function: Serum ammonia (levels >150 µmol/L predict a high risk of cerebral edema), electrolytes, BUN, and creatinine to detect acute kidney injury (AKI).
• Etiologic Workup:
  • Viral Serologies: Hepatitis A, B, C, E (especially in pregnant patients), and Herpes Simplex Virus (HSV).
  • Toxicology Screen: Serum acetaminophen level (mandatory in all patients), and a broader screen for other potential hepatotoxins.
  • Autoimmune Markers: Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and quantitative immunoglobulins (IgG).
  • Specialized Tests: Consider Wilson disease (serum ceruloplasmin, Kayser-Fleischer rings on exam) in patients under 40 years old.

2. Imaging Evaluation

Imaging plays a crucial role in excluding vascular or biliary etiologies that can mimic ALF and helps identify potential complications of severe liver disease or hepatic encephalopathy.

Abdominal Ultrasound with Doppler

This is the initial imaging modality of choice. It is used to assess:

• Vascular Patency: Doppler flow in the hepatic artery, portal vein, and hepatic veins is essential to rule out acute Budd–Chiari syndrome or portal vein thrombosis.
• Biliary Tree: Evaluates for biliary obstruction from stones or strictures, which can cause severe liver injury but is not true ALF.

CT / MRI

• Contrast-Enhanced Studies: Useful for clarifying vascular anatomy or identifying focal lesions when ultrasound is inconclusive.
• MRI: Offers superior soft-tissue detail of the liver parenchyma but is often limited by the patient’s clinical instability and inability to remain still.

Neuroimaging (Noncontrast Head CT)

This is not a routine test but is indicated for any patient with an acute worsening of HE or new focal neurologic deficits. Its primary purpose is to exclude intracranial hemorrhage or ischemic stroke before attributing the change in mental status solely to cerebral edema from ALF.

3. Role of Liver Biopsy

Liver biopsy is reserved for select cases of ALF where the etiology remains indeterminate after a comprehensive noninvasive workup. The procedure carries a significant bleeding risk due to coagulopathy.

Indications

• Etiology remains unclear after extensive laboratory and imaging evaluation.
• High suspicion for autoimmune hepatitis (AIH) or an infiltrative disease (e.g., malignancy) where histologic confirmation would directly alter management.

Transjugular Technique

This is the preferred approach in ALF. Access is gained via the internal jugular vein, allowing the biopsy needle to be passed into the hepatic veins. This technique significantly reduces the risk of intraperitoneal hemorrhage compared to a percutaneous approach. A sample containing at least 11 portal tracts is considered adequate for diagnosis.

Impact on Management

• Confirms Autoimmune Hepatitis: The presence of interface hepatitis on histology would prompt the initiation of corticosteroids.
• Identifies Other Causes: Can reveal unexpected diagnoses like lymphoma, metastatic cancer, or other infiltrative processes.

4. Severity Classification Systems

Grading the severity of hepatic encephalopathy and using validated prognostic scores are essential for predicting outcomes, guiding ICU triage, and determining the urgency of referral for liver transplantation.

West-Haven Criteria for Hepatic Encephalopathy (HE)

• Grade I: Mild confusion, euphoria or anxiety, shortened attention span.
• Grade II: Lethargy, disorientation, obvious personality change, asterixis present.
• Grade III: Somnolent but arousable, gross disorientation, incoherent speech.
• Grade IV: Coma, unresponsive to pain.

Prognostic Scoring Systems

The King’s College Criteria (KCC) and the Model for End-Stage Liver Disease (MELD) score are the two most widely used systems to predict spontaneous survival and identify candidates for urgent transplantation.

5. Integration into Management Pathway

A structured approach that integrates diagnostic findings with severity stratification is critical for timely and appropriate management, including ICU admission, monitoring frequency, and transplant evaluation.