What are the causes of Acute Liver Failure (ALF) in patients with and without a history of liver disease?

Causes of Acute Liver Failure

Acetaminophen (paracetamol) toxicity is the most common cause of acute liver failure in Western countries, accounting for approximately 50% of all ALF cases in the United States and 22% of emergency liver transplantation indications in France. 1, 2

Major Etiologic Categories

Drug-Induced Hepatotoxicity

Acetaminophen hepatotoxicity:

• Represents the single most frequent cause of severe ALF requiring emergency transplantation in industrialized nations 1, 2
• Can occur from intentional overdose or unintentional therapeutic misadventure 1
• Transplant-free survival rate is 50%, which is better than most other drug-induced causes 1, 2

Idiosyncratic drug reactions (non-acetaminophen):

• Account for 9.4% of ALF cases collectively 1
• Include antimicrobial agents (such as ampicillin-clavulanic acid), antiepileptic drugs, and statins 1
• Have transplant-free survival rate <25%, significantly worse than acetaminophen-induced ALF 1, 3
• Most idiosyncratic reactions occur within the first 6 months after drug initiation 1
• Medications used continuously for more than 1-2 years are unlikely to cause de novo liver damage 1

Herbal preparations and nutritional supplements:

• Increasingly recognized as causes of liver injury 1
• Should be specifically inquired about in medication history 1

Viral Hepatitis

Hepatitis A and B:

• Account for 14.6% of ALF cases collectively (hepatitis B 8%, hepatitis A 4% in the United States) 1
• Transplant-free survival rate is 50% 1, 3
• Hepatitis C alone does not appear to cause ALF 1
• Acute hepatitis D may occasionally be diagnosed in hepatitis B positive individuals 1

Hepatitis E:

• Significant cause of liver failure in endemic countries (Russia, Pakistan, Mexico, India) 1
• Tends to be more severe in pregnant women 1
• Should be considered in anyone with recent travel to endemic areas 1
• May be more common than currently recognized, particularly in ambiguous cases 4

Herpes viruses:

• Rarely cause ALF but can occur in immunosuppressed patients, pregnant women (usually third trimester), or healthy individuals 1
• Skin lesions present in only 50% of cases 1
• Varicella zoster has occasionally been implicated 1

Hepatitis B reactivation:

• May occur in the setting of chemotherapy or immunosuppression 1
• Patients positive for HBsAg who begin immunosuppressive therapy should receive prophylactic nucleoside analogs continued for 6 months after completion 1

Toxic Exposures

Mushroom poisoning (Amanita species):

• Accounts for 4.8% of cases when combined with other toxins 1
• Often requires liver transplantation as the only lifesaving option 1

Other toxins:

• Herbal supplements, cocaine, ecstasy collectively account for 4.8% of cases 1

Metabolic and Genetic Disorders

Wilson's disease:

• Accounts for portion of the 28.8% of "other causes" 1
• Considered uniformly fatal without transplantation 5
• Transplant-free survival rate <25% 1

Autoimmune hepatitis:

• Part of the 28.8% "other causes" category 1
• Can remain undiagnosed until initial presentation as ALF 4
• Transplant-free survival rate <25% 1

Other metabolic diseases:

• Contribute to the 28.8% "other causes" category 1

Vascular Causes

Budd-Chiari syndrome:

• Hepatic vein thrombosis leading to ALF 1
• Transplant-free survival rate <25% 1
• Requires verification of vessel patency via Doppler ultrasound 1

Ischemic hepatitis ("shock liver"):

• Results from acute cardiac or circulatory failure 1
• Characterized by AST levels exceeding ALT 1
• Transplant-free survival rate 50% 1

Pregnancy-Related Causes

Acute fatty liver of pregnancy/HELLP syndrome:

• Transplant-free survival rate 50% 1
• Recovery typically rapid after delivery with supportive care 5

Indeterminate Etiology

Unknown causes:

• Account for 25% of ALF cases despite intensive investigation 1, 3
• Represent a significant diagnostic challenge 4

Geographic and Population Variations

Western countries (Europe, North and Latin America):

• Acetaminophen toxicity is the predominant cause 1
• Bacterial infections and active alcohol intake are major precipitating events in patients with underlying cirrhosis 1

Eastern countries (Asia, Pacific region):

• Hepatitis B exacerbation is the leading cause 1
• Followed by alcohol and bacterial infections 1

Critical Diagnostic Pitfall

A medication that has been used continuously for more than 1-2 years is unlikely to cause de novo idiosyncratic liver damage, so focus investigation on recently initiated drugs (within 6 months). 1 However, always obtain serum acetaminophen levels in all ALF patients regardless of history, as unintentional therapeutic misadventure is common and acetaminophen toxicity is highly treatable with N-acetylcysteine. 1, 2