What is acute liver failure?

Acute Liver Failure: Clinical Overview

Definition and Diagnostic Criteria

Acute liver failure (ALF) is a rare, life-threatening syndrome defined by the rapid development of severe hepatic dysfunction—specifically coagulopathy (INR ≥1.5) and any degree of hepatic encephalopathy—in patients without pre-existing cirrhosis, with illness duration ≤26 weeks. 1

• The syndrome represents a rapid loss of liver function resulting in multiple organ system failure 2, 3
• Hospital admission is mandatory when prothrombin time is prolonged by 4-6 seconds or more (INR ≥1.5) with any evidence of altered sensorium 1
• ALF is potentially reversible with appropriate management, though mortality remains high (30-100%) without intervention 4
• Approximately 60% of ALF patients in the US require liver transplantation or die without it 3

Etiology

Common Causes

• Acetaminophen toxicity is the most common cause in developed countries 1
• Viral hepatitis (hepatitis A, B, E) represents a significant proportion of cases 5, 6
• Drug-induced liver injury from prescription medications, herbs, and dietary supplements 5, 1
• Autoimmune hepatitis can present as ALF and requires specific treatment 5, 1
• Acute ischemic injury ("shock liver") following cardiac arrest or severe hypotension 5
• Wilson disease presents as uniformly fatal ALF without transplantation 1
• Budd-Chiari syndrome (hepatic vein thrombosis) with abdominal pain, ascites, and hepatomegaly 5
• Acute fatty liver of pregnancy/HELLP syndrome in third trimester 5, 1
• Herpes simplex virus and varicella zoster, particularly in pregnancy 5, 1
• Mushroom poisoning (Amanita species) 1
• Indeterminate etiology accounts for 20-30% of cases despite thorough evaluation 5, 6

Critical Pitfall

• Malignant infiltration (breast cancer, small cell lung cancer, lymphoma, melanoma) can mimic ALF and must be excluded in patients with previous cancer history or massive hepatomegaly through imaging and liver biopsy 5, 1

Clinical Presentation and Organ System Failures

Hepatic Manifestations

• Liver failure indicated by rapidly rising bilirubin (≥6 mg/dl) and worsening coagulopathy (INR ≥1.5) 7
• Marked aminotransferase elevation, though levels correlate poorly with prognosis 1
• Jaundice and detoxification disorders 6

Neurological Complications

• Hepatic encephalopathy ranging from subtle mental status changes (Grade I) to coma (Grade IV) 7, 1
• Cerebral edema is a life-threatening complication, though less frequent than in the past 8
• Intracranial hypertension can lead to brain herniation and death 2, 4

Renal Dysfunction

• Kidney failure with rising serum creatinine (≥2 mg/dl) is a critical indicator 7
• Development of hepatorenal syndrome represents severe kidney system failure 7
• Acute kidney injury commonly complicates ALF 2

Circulatory Failure

• Hypotension with mean arterial pressure <70 mmHg requiring vasopressor support 7
• Hyperdynamic circulation with decreased systemic vascular resistance 5

Respiratory Failure

• Hypoxemia with decreasing PaO2/FiO2 ratio (≤300) requiring supplemental oxygen 7
• May require mechanical ventilation for airway protection 1

Coagulation Abnormalities

• Prolonged INR despite vitamin K administration 1
• Thrombocytopenia, particularly in HELLP syndrome 5
• Increased bleeding risk with invasive procedures 1

Metabolic Derangements

• Hypoglycemia requiring continuous glucose monitoring and infusions 1
• Electrolyte abnormalities including hyponatremia, hypokalemia, hypophosphatemia 1
• Lactic acidosis indicating poor tissue perfusion 1

Systemic Inflammation

• Elevated white blood cell count and C-reactive protein levels 7
• Systemic inflammatory response syndrome (SIRS) often precedes multi-organ failure 3

Initial Assessment and Diagnostic Workup

Immediate Laboratory Evaluation

• Prothrombin time/INR to assess coagulopathy 1
• Comprehensive metabolic panel including sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, glucose 1
• Liver function tests: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin 1
• Arterial blood gases and lactate to assess acid-base status and tissue perfusion 1
• Complete blood count with differential 1
• Acetaminophen level (essential in all cases, even without history of ingestion) 1
• Toxicology screen for drugs and substances 1
• Viral hepatitis serologies: hepatitis A IgM, hepatitis B surface antigen and core antibody, hepatitis E antibody 1
• Renal function tests: creatinine, BUN, eGFR 1

Etiology-Specific Testing

• Autoimmune markers: ANA, anti-smooth muscle antibody, immunoglobulins if autoimmune hepatitis suspected 5, 1
• Ceruloplasmin and 24-hour urine copper if Wilson disease suspected 1
• Pregnancy test in women of childbearing age 5
• HSV/VZV PCR if viral infection suspected 5, 1
• Imaging studies (ultrasound with Doppler, CT, MRI) to evaluate hepatic vasculature and exclude Budd-Chiari syndrome 5

Advanced Diagnostic Procedures

• Transjugular liver biopsy should be considered when etiology remains unclear after routine evaluation, particularly to diagnose autoimmune hepatitis or malignant infiltration 5, 1

History and Physical Examination

• Detailed medication history including prescription drugs, over-the-counter medications, herbal supplements, and dietary products 1
• Exposure history to viral infections, toxins, mushrooms 1
• Alcohol consumption history 7
• Mental status assessment with frequent monitoring for progression of encephalopathy 1
• Search for stigmata of chronic liver disease to exclude underlying cirrhosis 1

Management Principles

General Supportive Care

Early transfer to a liver transplant center is essential to achieve the best chance of transplant-free survival or to undergo emergency liver transplantation if required. 2

Hemodynamic Support

• Fluid resuscitation with careful attention to maintaining adequate intravascular volume 1
• Balanced crystalloids (lactated Ringer's) or albumin preferred over saline for resuscitation 5
• Pulmonary artery catheterization should be considered in hemodynamically unstable patients 1
• Vasopressor support with epinephrine, norepinephrine, or dopamine (not vasopressin) if mean arterial pressure cannot be maintained at 50-60 mmHg with fluids alone 1
• Bedside transthoracic echocardiography to assess cardiac function and volume status 5

Neurological Management

• Frequent mental status monitoring with transfer to ICU if level of consciousness declines 1
• Head elevation at 30 degrees and minimizing stimulation 1
• Intubation for airway protection in Grade III-IV encephalopathy 1
• Seizure control with phenytoin, avoiding benzodiazepines when possible 1
• Lactulose administration may be considered to reduce ammonia levels, though evidence for improved outcomes is limited 1
• Non-invasive intracranial pressure monitoring techniques now preferred over invasive monitoring 8

Metabolic Management

• Continuous glucose infusions to manage hypoglycemia 1
• Monitor and supplement phosphate, magnesium, and potassium levels as needed 1
• Early enteral feeding with moderate protein intake (approximately 60 grams per day) 1
• Parenteral nutrition if enteral feeding contraindicated, despite increased risk of fungal infection 1

Renal Support

• Continuous renal replacement therapy (CRRT) preferred over intermittent hemodialysis for acute kidney injury 1, 2
• Early commencement of CRRT to control hyperammonaemia is now considered an important standard of care 2
• Avoid nephrotoxic agents 1

Coagulation Management

• Vitamin K administration for all ALF patients 1
• Fresh frozen plasma (FFP) reserved for invasive procedures or active bleeding, not for INR correction alone 1
• Platelet transfusion for counts <10,000/mm³ or before invasive procedures 1
• Recombinant activated factor VII may be considered for invasive procedures 1

Infection Prevention

• Prophylaxis for stress ulceration with H2 blockers or proton pump inhibitors 1
• Early empiric antibiotics reasonable in patients at high risk of infection 5
• Surveillance cultures and prompt treatment of documented infections 2

Etiology-Specific Treatments

Acetaminophen Toxicity

• N-acetylcysteine (NAC) should be administered immediately at 140 mg/kg orally or via nasogastric tube, followed by 70 mg/kg every 4 hours for 17 doses, even if >48 hours since ingestion 1
• NAC improves outcomes even in non-acetaminophen ALF 2

Viral Hepatitis

• Hepatitis A and B: supportive care only, as no virus-specific treatment proven effective for ALF 1
• Herpes simplex virus/varicella zoster: immediate acyclovir treatment and urgent transplant listing 1
• Hepatitis B reactivation prevention: nucleoside analogs before and for 6 months after chemotherapy/immunosuppression 1

Autoimmune Hepatitis

• Liver biopsy should be considered to establish diagnosis 5, 1
• Corticosteroids (prednisone 40-60 mg/day) for confirmed autoimmune hepatitis 5, 1
• Transplant listing even while administering corticosteroids 5, 1

Wilson Disease

• Uniformly fatal without transplantation 1
• Albumin dialysis, continuous hemofiltration, plasmapheresis, or plasma exchange to acutely lower serum copper and limit hemolysis 1
• Penicillamine not recommended due to hypersensitivity risk 1

Acute Fatty Liver of Pregnancy/HELLP Syndrome

• Consultation with obstetrical services and expeditious delivery 5, 1
• Recovery typically rapid after delivery with supportive care only 1
• Postpartum transplantation occasionally necessary 5

Drug-Induced Hepatotoxicity

• Discontinue all non-essential medications 1
• Detailed medication history including herbs and dietary supplements 1

Mushroom Poisoning

• Consider penicillin G and silymarin 1
• Urgent transplant listing as often the only lifesaving option 1

Acute Ischemic Injury

• Cardiovascular support is the treatment of choice 5
• Transplantation seldom indicated 5

Budd-Chiari Syndrome

• Liver transplantation indicated for hepatic failure, provided underlying malignancy excluded 5

Liver Support Systems

• Plasma exchange may have a role in the sickest ALF patients and can stabilize patients as a bridge to transplantation 1, 2, 8
• Molecular Adsorbents Recirculating System (MARS) may be efficacious as alternative to plasmapheresis 1
• Other blood purification modalities still lack supporting evidence 2
• Bioartificial liver devices with porcine hepatocytes show promise but require further research 1

Liver Transplantation

Urgent hepatic transplantation is indicated in ALF where prognostic indicators suggest high likelihood of death, with post-transplant survival rates of 80-90%. 1

Poor Prognostic Indicators

• Idiosyncratic drug injury 1
• Non-hepatitis A viral infections 1
• Autoimmune hepatitis 1
• Mushroom poisoning 1
• Wilson disease 1
• Budd-Chiari syndrome 1
• Indeterminate cause 1

Transplant Evaluation

• Early listing for patients meeting criteria 1
• Current prognostic models have good accuracy to identify patients who will die without transplantation but cannot identify those in whom transplantation is futile 8

Clinical Grading and Prognostic Systems

ACLF Grading System

• ACLF Grade 1: single kidney failure or single non-kidney organ failure with mild kidney dysfunction and/or grade 1-2 hepatic encephalopathy 7
• ACLF Grade 2-3: multiple organ failures with 28-day mortality ≥20% 5, 7

CLIF-SOFA Score Components

• Bilirubin levels 7
• Creatinine levels 7
• Hepatic encephalopathy grade 7
• Coagulation (INR) 7
• Circulatory (MAP) 7
• Respiratory (PaO2/FiO2) 7

Critical Pitfalls to Avoid

• Failing to recognize early signs of infection can precipitate rapid deterioration 7
• Overlooking alcohol consumption can trigger acute deterioration even with moderate intake 7
• Administering systemic corticosteroids for general ALF treatment is ineffective except in autoimmune hepatitis 1
• Using aminotransferase levels to predict prognosis correlates poorly with outcomes 1
• Delaying transfer to a transplant center reduces chances of optimal outcome 2
• Overresuscitation with fluids without hemodynamic monitoring can worsen outcomes 5

Monitoring and Follow-up

• Daily liver function tests (bilirubin, INR, albumin) 7
• Regular renal function monitoring (creatinine, urine output) 7
• Frequent neurological assessment for encephalopathy progression 7
• Serial lactate measurements to assess tissue perfusion 1
• Continuous glucose monitoring to prevent hypoglycemia 1