What is acute liver injury?

What is Acute Liver Injury?

Acute liver injury is a syndrome of hepatocellular damage characterized by elevated aminotransferases (ALT ≥3× ULN with bilirubin >2 mg/dL, or ALT ≥5× ULN, or ALP ≥2× ULN) in patients without preexisting liver disease, but crucially lacking the coagulopathy (INR ≥1.5) and hepatic encephalopathy that define acute liver failure. 1, 2

Key Distinguishing Features

Acute liver injury represents a broader, less severe category than acute liver failure:

• Preserved synthetic function – patients maintain adequate coagulation (INR <1.5) and mental status (no encephalopathy), distinguishing it from acute liver failure 2
• Potential for resolution – most cases resolve with removal of the offending agent and supportive care, without progression to failure 2
• Aminotransferase elevation alone is insufficient – the magnitude of ALT/AST elevation does not define failure; a patient can have markedly elevated enzymes (>1000 IU/L) yet still have only acute liver injury if coagulopathy and encephalopathy are absent 2

Diagnostic Criteria

The American Association for the Study of Liver Diseases defines acute liver injury by any of the following 1:

• ALT ≥5× upper limit of normal (ULN)
• Alkaline phosphatase (ALP) ≥2× ULN
• ALT ≥3× ULN with simultaneous total bilirubin >2 mg/dL

Critical caveat: In patients with abnormal baseline liver tests, replace the laboratory ULN with the mean baseline values obtained prior to exposure to the suspect agent 1

Pattern Classification Using R Value

The R value stratifies injury patterns and narrows the differential diagnosis 1:

R = (ALT/ULN) ÷ (ALP/ULN)

• R ≥5 = Hepatocellular pattern (predominant ALT elevation) 1
• R ≤2 = Cholestatic pattern (predominant ALP elevation) 1
• R >2 and <5 = Mixed hepatocellular-cholestatic pattern 1

The R value must be calculated at the peak of the acute injury episode to accurately reflect maximal enzyme perturbation 1. This classification, established by the Council of International Organizations of Medical Sciences in 1990, remains the international standard 1.

Severity Grading

Acute liver injury severity is graded as follows 1:

• Grade 1: Elevated ALT/ALP meeting injury criteria but bilirubin <2× ULN
• Grade 2: Elevated ALT/ALP with bilirubin ≥2× ULN, or symptomatic hepatitis
• Grade 3: Elevated ALT/ALP, bilirubin ≥2× ULN, plus INR ≥1.5, ascites/encephalopathy, or other organ failure due to liver injury
• Grade 4: Death or transplantation due to liver injury

Clinical Presentations and Histological Patterns

Acute liver injury manifests with various histological patterns 1:

• Hepatocellular necrosis
• Cholestatic/mixed injury
• Microvesicular steatosis
• Toxicant-associated steatohepatitis (TASH)

In autoimmune hepatitis presenting acutely, the characteristic pattern is panacinar hepatitis (parenchymal collapse) or pericentral (zone 3) necrosis, which closely resembles drug-induced or toxic injury 3. Additional features include portal lymphoid follicles, plasma cell-enriched infiltrates, and central perivenulitis 3.

Common Etiologies

The differential diagnosis for acute liver injury includes 1, 4:

• Drug-induced liver injury (DILI) – prescription medications, herbal supplements, dietary supplements
• Viral hepatitis – hepatitis A, B, E; rarely herpes simplex or varicella zoster
• Autoimmune hepatitis – may present with acute onset
• Acetaminophen toxicity – even at therapeutic doses in susceptible individuals
• Ischemic hepatopathy ("shock liver") – following hypotension, cardiac arrest, or severe heart failure 3
• Acute fatty liver of pregnancy/HELLP syndrome – third trimester presentations 3
• Budd-Chiari syndrome – hepatic vein thrombosis 3
• Mushroom poisoning (Amanita phalloides) 5
• Wilson disease – typically in young patients 5

Management Approach

For acute liver injury without failure criteria 2:

• Outpatient monitoring is often appropriate with serial laboratory assessment
• Remove the offending agent immediately (medication, toxin, supplement)
• Monitor every 1-2 weeks initially until complete resolution of abnormal liver parameters
• If abnormalities persist beyond 12 months, consider progression to chronic liver disease and escalate evaluation

Contrast with acute liver failure management: ALF requires immediate ICU-level care, early transplant center contact, and multi-organ failure monitoring 2.

Critical Pitfalls to Avoid

• Do not confuse acute liver injury with acute liver failure – the presence of coagulopathy (INR ≥1.5) and encephalopathy defines failure, not aminotransferase levels alone 2
• Do not diagnose acute liver injury in patients with known cirrhosis or chronic liver disease – these patients have acute-on-chronic liver failure (ACLF), which has different management and prognosis 2
• Isolated GGT elevation is not a marker of cellular damage but rather enzyme induction and should not be used for classification 1
• Injury pattern may shift over time – due to differences in clearance kinetics of ALT and ALP, an initially hepatocellular pattern may evolve to cholestatic/mixed 1
• Certain presentations are deceptive – Wilson disease can present with severe liver failure despite relatively modest aminotransferase elevations 2