How is acute liver failure diagnosed, including the required clinical criteria, laboratory tests, imaging studies, and initial management steps?

Diagnosis of Acute Liver Failure

Acute liver failure is diagnosed when a patient without preexisting cirrhosis presents with coagulation abnormality (INR ≥1.5) and any degree of mental alteration (encephalopathy) within 26 weeks of illness onset. 1

Diagnostic Criteria

The diagnosis requires three essential components 1:

• Coagulopathy: Prothrombin time prolonged by 4-6 seconds or more, resulting in INR ≥1.5 1
• Hepatic encephalopathy: Any degree of altered sensorium or mental status change 1
• Absence of preexisting cirrhosis: No history or stigmata of chronic liver disease 1

Important exception: Patients with Wilson disease, vertically-acquired hepatitis B, or autoimmune hepatitis may be included despite possible cirrhosis if their disease has been recognized for ≤26 weeks 1

Initial Clinical Assessment

History Taking

Obtain detailed information on 1:

• Toxic exposures: Acetaminophen ingestion (dose and timing), prescription medications, over-the-counter drugs, herbal supplements, dietary supplements 1, 2
• Viral exposures: Recent travel, sick contacts, sexual history, injection drug use 1
• Autoimmune symptoms: Joint pain, rash, prior autoimmune conditions 1
• Family history: Wilson disease, autoimmune hepatitis (particularly in patients <40 years) 1
• Recent pregnancy: Third trimester complications 1
• Cardiovascular events: Hypotension, cardiac arrest, heart failure 1

Physical Examination

Document specific findings 1:

• Mental status: Grade encephalopathy carefully (subtle confusion to coma) 1
• Jaundice: Often but not always present at presentation 1
• Liver size: Inability to palpate or percuss liver suggests massive hepatocyte loss; enlarged liver suggests viral hepatitis, malignant infiltration, heart failure, or Budd-Chiari syndrome 1
• Stigmata of chronic liver disease: Should be absent (spider angiomata, palmar erythema, gynecomastia suggest underlying cirrhosis) 1
• Right upper quadrant tenderness: Variably present 1
• Ascites and hepatomegaly: Suggest Budd-Chiari syndrome 1

Mandatory Laboratory Evaluation

Immediate Tests Required 1

Coagulation and hematology:

• Prothrombin time/INR (diagnostic threshold)
• Complete blood count
• Blood type and screen

Chemistry panel:

• Sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
• Glucose (hypoglycemia common)
• Creatinine, blood urea nitrogen
• AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin

Arterial studies:

• Arterial blood gas
• Arterial lactate (prognostic value)
• Arterial ammonia (if possible; venous acceptable)

Toxicology:

• Acetaminophen level (even without history of ingestion)
• Comprehensive toxicology screen

Etiology-specific serologies:

• Anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV, anti-HCV 1
• Ceruloplasmin level (if age <40 years or Wilson disease suspected) 1
• Autoimmune markers: ANA, ASMA, immunoglobulin levels 1
• Pregnancy test (all females of childbearing age) 1

Additional tests when indicated:

• HIV status (transplant implications) 1
• Amylase and lipase (if clinically indicated) 1
• Uric acid and bilirubin-to-alkaline phosphatase ratio (Wilson disease) 1

Imaging Studies

Initial Imaging 1

• Doppler ultrasonography: Assess hepatic vasculature, exclude Budd-Chiari syndrome (hepatic vein thrombosis), evaluate liver size and echogenicity 1
• CT abdomen with contrast or MR venography: If Budd-Chiari syndrome suspected based on clinical presentation (abdominal pain, ascites, hepatomegaly) 1
• Echocardiography: Evaluate for cardiac dysfunction in suspected ischemic hepatitis ("shock liver") 1

Advanced Diagnostic Procedures

Transjugular liver biopsy 2:

• Consider when etiology remains unclear after routine evaluation
• Particularly useful for suspected autoimmune hepatitis (look for interface hepatitis, plasma cell infiltration, hepatocyte rosettes) 1
• Safer than percutaneous approach given coagulopathy

Initial Management Steps

Immediate Actions Upon Diagnosis

Once ALF is diagnosed (INR ≥1.5 + altered mentation), hospital admission is mandatory 1:

1. ICU transfer: Early transfer preferred as condition may progress hour-by-hour 1
2. Contact transplant center immediately: The "transplantation window" is often narrow 2
3. Continuous monitoring: Liver, kidney, brain, lung, coagulation, and circulation 1

Etiology-Specific Antidotes

Administer immediately when indicated 2:

• Acetaminophen toxicity: N-acetylcysteine 140 mg/kg orally/NG tube, then 70 mg/kg every 4 hours for 17 doses (even if >48 hours post-ingestion) 2
• Herpes simplex virus: Acyclovir (place on transplant list immediately) 2
• Mushroom poisoning: Penicillin G and silymarin 30-40 mg/kg/day for 3-4 days 2
• Autoimmune hepatitis: Prednisone 40-60 mg/day (while listing for transplant) 1, 2
• Acute fatty liver of pregnancy/HELLP: Expeditious delivery with obstetrical consultation 1, 2

Supportive Care Priorities

Hemodynamic management 2:

• Maintain mean arterial pressure ≥50-60 mmHg
• Aggressive fluid resuscitation (prefer albumin over crystalloid)
• Vasopressors if needed: epinephrine, norepinephrine, or dopamine (NOT vasopressin)

Metabolic management 2:

• Monitor glucose every 2 hours; continuous dextrose infusions for hypoglycemia
• Maintain serum sodium 140-145 mmol/L
• Supplement phosphate, magnesium, potassium as needed

Coagulation management 2:

• Administer vitamin K
• Reserve fresh frozen plasma for active bleeding or invasive procedures only
• Avoid prophylactic correction of INR (rebalanced hemostasis exists) 3

Neurological management 2:

• Position head elevated 30 degrees
• Intubate if Glasgow Coma Score <8
• Control seizures with phenytoin (avoid benzodiazepines)
• Consider lactulose for ammonia reduction

Renal support 2:

• Avoid nephrotoxic agents
• Use continuous renal replacement therapy (not intermittent hemodialysis) if dialysis needed

Infection prevention 2:

• H2 blockers or proton pump inhibitors for stress ulcer prophylaxis
• Screen aggressively for infections (common precipitants)

Prognostic Assessment and Transplant Listing

King's College Criteria 1, 2

For acetaminophen-induced ALF, poor prognosis indicated by:

• pH <7.3 after resuscitation, OR
• All three: INR >6.5, creatinine >300 μmol/L, grade 3-4 encephalopathy
• Lactate >3.5 mmol/L at 4 hours or >3.0 mmol/L at 12 hours after resuscitation

For non-acetaminophen ALF, poor prognosis indicated by:

• INR >6.5, OR
• Any three of: age <10 or >40 years, non-A/non-B hepatitis, drug reaction, jaundice >7 days before encephalopathy, INR >3.5, bilirubin >300 μmol/L

Additional Prognostic Markers 1

• Ammonia >100-150 μmol/L: Increased risk of intracranial hypertension 1
• Factor V <20%: Poor prognosis (Clichy-Villejuif criteria) 1
• Vasopressor requirement: Independent poor prognostic factor 1
• Grade 3-4 encephalopathy: 33% short-term survival without transplant 1

List for transplantation early when prognostic indicators suggest high mortality risk, as post-transplant survival reaches 80-90% even with multiple organ failures 2

Common Diagnostic Pitfalls

• Malignant infiltration can mimic ALF; consider in patients with cancer history or massive hepatomegaly 2
• Acute-on-chronic liver failure has different management; look carefully for stigmata of cirrhosis 1
• Acetaminophen toxicity may occur without clear history; always check levels 1
• Wilson disease should be considered in all patients <40 years without obvious etiology 1
• Pregnancy-related ALF (HELLP, acute fatty liver) requires immediate delivery, not transplant 1
• INR elevation does not necessarily indicate bleeding risk due to rebalanced hemostasis 3