What is the initial workup for suspected drug-induced liver injury (DILI)?

Initial Workup for Suspected Drug-Induced Liver Injury

The initial workup for suspected DILI requires immediate comprehensive laboratory assessment including ALT, AST, alkaline phosphatase, total and direct bilirubin, and INR, combined with urgent exclusion of alternative causes of liver injury through viral hepatitis serologies, autoimmune markers, and hepatobiliary imaging. 1

Immediate Laboratory Assessment

Core Liver Function Tests

• Obtain ALT, AST, alkaline phosphatase, total bilirubin, and direct bilirubin to characterize the pattern of injury (hepatocellular vs. cholestatic) and assess severity 1
• Measure INR and albumin to evaluate synthetic liver function and screen for hepatic decompensation 2
• Calculate the R-value using the formula: (ALT/ULN) ÷ (ALP/ULN) to classify injury pattern: R>5 indicates hepatocellular, R<2 indicates cholestatic, and R=2-5 indicates mixed pattern 3

Critical Severity Markers

• Direct bilirubin measurement is essential to differentiate true hepatocellular injury from Gilbert's syndrome or hemolysis, particularly when total bilirubin is elevated 1
• Assess for Hy's Law criteria (ALT ≥3× ULN with concurrent total bilirubin ≥2× ULN without significant ALP elevation), which predicts >10% risk of severe or fatal DILI 1, 2

Exclusion of Alternative Diagnoses

Viral Hepatitis Screening

• Obtain hepatitis A IgM, hepatitis B surface antigen, hepatitis B core IgM, and hepatitis C antibody with reflex RNA to exclude acute viral hepatitis 4, 3
• Test for hepatitis E in appropriate clinical contexts (recent travel, immunosuppression) 3
• Consider EBV and CMV serologies if clinical presentation suggests viral syndrome 3

Autoimmune and Metabolic Workup

• Measure ANA, anti-smooth muscle antibody, and immunoglobulins to exclude autoimmune hepatitis, particularly if considering immunosuppressive therapy 4, 3
• Obtain ceruloplasmin and 24-hour urine copper in patients under 40 years to exclude Wilson's disease 3
• Check iron studies (ferritin, transferrin saturation) to exclude hemochromatosis 3

Imaging Studies

• Perform right upper quadrant ultrasound with Doppler to exclude biliary obstruction, hepatic vein thrombosis (Budd-Chiari), and portal vein thrombosis 4, 3
• Consider CT or MRCP if ultrasound is inadequate or biliary pathology remains suspected 3

Detailed Medication History

Comprehensive Drug Exposure Assessment

• Document all prescription medications with exact start dates, doses, and temporal relationship to liver injury onset (typical onset: 5-90 days for most drugs) 5, 3
• Specifically inquire about herbal and dietary supplements, which represent a significant component of DILI in the United States and are often not volunteered by patients 4, 5
• Ask about over-the-counter medications including acetaminophen, NSAIDs, and any recent antibiotic courses 5, 3
• Obtain occupational and recreational drug exposure history, including anabolic steroids and illicit substances 4

Temporal Relationship Documentation

• Hepatocellular DILI typically occurs 2-24 weeks after drug initiation, with occurrence unlikely after 52 weeks or sooner than 4 days 1
• Cholestatic DILI typically occurs 2-12 weeks after drug start but may occur after one year 1

Clinical Assessment for Severity and Complications

Symptom Evaluation

• Assess for liver-related symptoms: severe fatigue, nausea, vomiting, right upper quadrant pain, jaundice, dark urine, pale stools 1
• Screen for immunologic symptoms: rash, fever, arthralgias, eosinophilia >5% 1
• Evaluate for signs of hepatic decompensation: altered mental status (encephalopathy), ascites, coagulopathy, progressive jaundice 2

Physical Examination Findings

• Look for jaundice, hepatomegaly, right upper quadrant tenderness, and stigmata of chronic liver disease 4, 3
• Assess for signs of systemic hypersensitivity: rash, lymphadenopathy, fever 5

Repeat Testing Timeline

Hepatocellular Pattern

• Repeat blood tests within 2-5 days if hepatocellular DILI is suspected (ALT/AST predominant elevation) 1, 2
• The specific interval should be determined based on clinical condition, with more frequent monitoring if symptoms are present or bilirubin is elevated 1

Cholestatic Pattern

• Repeat blood tests within 7-10 days if cholestatic DILI is suspected (ALP predominant elevation), as cholestatic injury typically has slower onset and resolution 1

Common Pitfalls to Avoid

• Do not assume normal baseline liver tests exclude chronic liver disease; patients with NASH or cirrhosis may have near-normal transaminases 1
• Do not overlook Gilbert's syndrome or hemolysis as causes of isolated hyperbilirubinemia; always measure direct bilirubin 1
• Do not delay drug discontinuation while awaiting complete workup if severe DILI is suspected, as delayed discontinuation can result in irreversible liver failure and death 1, 2
• Do not attribute liver injury to drugs without excluding viral hepatitis, autoimmune hepatitis, and biliary obstruction, as misdiagnosis is common 4, 6