How is Drug-Induced Liver Injury (DILI) diagnosed?

How is Drug-Induced Liver Injury (DILI) Diagnosed?

DILI is diagnosed by excluding alternative causes of liver injury through a systematic evaluation of liver biochemistry patterns, comprehensive medication history (including herbals and supplements), viral hepatitis and autoimmune serologies, and imaging studies—there is no specific diagnostic biomarker for DILI. 1

Core Diagnostic Principle

DILI remains fundamentally a diagnosis of exclusion because no laboratory test, biopsy finding, or imaging study can definitively confirm DILI. 2, 3, 4 The diagnosis requires establishing a temporal relationship between drug exposure and liver injury while systematically ruling out competing etiologies. 1

Step 1: Recognize Biochemical Patterns Suggesting DILI

Calculate the R Value to Classify Injury Pattern

• R value = (ALT/ALT ULN) ÷ (ALP/ALP ULN) 1
• R ≥5: Hepatocellular injury (suggests viral hepatitis, autoimmune hepatitis, ischemic injury as alternatives) 1
• R ≤2: Cholestatic injury (suggests biliary obstruction, infiltrative disease, sepsis as alternatives) 1
• R >2 but <5: Mixed injury pattern 1

Key Biochemical Thresholds That Trigger DILI Evaluation

• ALT ≥3× ULN plus total bilirubin ≥2× ULN (especially if ALP ≤2× ULN) in patients with normal baseline—this constitutes "Hy's Law" criteria indicating potentially severe hepatocellular DILI 1
• ALT elevation ≥5× ULN is uncommon in most chronic liver diseases and should prompt DILI investigation 1
• ALP or total bilirubin ≥2× ULN is atypical for conditions like NASH and warrants investigation for DILI or biliary disease 1

Step 2: Obtain Comprehensive Drug/Supplement Exposure History

This is the single most critical diagnostic step. 1

Specific Elements to Document:

• All prescription medications with start dates and doses 1
• Over-the-counter medications including NSAIDs and acetaminophen 1, 5
• Herbal and dietary supplements (ashwagandha is an increasingly recognized cause of cholestatic liver injury) 6
• Complementary and alternative medicines 1
• Nutritional supplements 1
• Alcohol consumption (quantify standard drinks per week) 1
• Illicit substances 1
• Recent viral infections or vaccinations (including COVID-19) 1

Assess Temporal Relationship:

• Most idiosyncratic DILI occurs 5-90 days after drug initiation, though latency varies widely by agent 5
• Some drugs (particularly in oncology) can cause delayed hepatotoxicity months after discontinuation 1

Step 3: Systematically Exclude Alternative Etiologies

First-Line Testing (Most Common Causes):

• Viral hepatitis serologies: Hepatitis A IgM, Hepatitis B surface antigen and core antibody, Hepatitis C antibody, Hepatitis E (if available) 1
• Autoimmune hepatitis markers: ANA, SMA, immunoglobulin G levels 1
• Serum creatine kinase (to exclude muscle injury/rhabdomyolysis as cause of transaminase elevation) 1
• Cross-sectional imaging (CT or MRI preferred over ultrasound): Assess for biliary obstruction, gallstones, hepatic metastases, infiltrative disease 1

Additional Testing Based on Clinical Context:

• Anti-LKM1, anti-SLA, ANCA if autoimmune hepatitis suspected 1
• Hepatitis B DNA if isolated hepatitis B core antibody positive (to exclude reactivation) 1
• Ceruloplasmin and 24-hour urine copper if Wilson disease possible 1
• Iron studies if hemochromatosis suspected 1
• Alpha-1 antitrypsin level if deficiency suspected 1
• HIV testing in appropriate clinical contexts 1

Imaging Considerations:

• CT or MRI is superior to ultrasound for evaluating tumor progression, biliary obstruction, and hepatic metastases 1
• Imaging helps distinguish DILI from disease progression in oncology patients or biliary complications in patients with metabolic syndrome 1

Step 4: Consider Liver Biopsy in Select Cases

Liver biopsy is not routinely required but may be valuable when: 1

• Liver biochemistries fail to resolve or worsen despite drug discontinuation 1
• Other testing is unremarkable and diagnosis remains uncertain 1
• Need to exclude infiltrative malignancy, opportunistic infections (HSV, CMV, EBV), or other specific disorders 1

Biopsy findings are not diagnostic of DILI but can help exclude competing diagnoses and provide mechanistic insights. 1

Step 5: Apply Structured Causality Assessment

RUCAM (Roussel Uclaf Causality Assessment Method):

• Most commonly used structured instrument 1
• Scores across seven domains: temporal relationship, dechallenge response, risk factors, concomitant medications, alternative causes, previous hepatotoxicity reports, and rechallenge 1
• Critical limitation: Not validated for patients with pre-existing liver disease or in clinical trial settings 1

Key Causality Considerations:

• Drug-specific "signatures": Characteristic latency periods, injury patterns, and extrahepatic manifestations for specific drugs (available on LiverTox website: livertox.nih.gov) 4
• Dechallenge response: Improvement after drug discontinuation supports DILI diagnosis, though resolution may be delayed up to 1 year with cholestatic injury 5
• Rechallenge: Recurrence of liver injury upon re-exposure strongly supports DILI but is rarely performed due to safety concerns 1

Special Populations and Pitfalls

In Patients with Pre-existing Liver Disease:

• NASH patients: ALT fluctuations >50% from baseline or ALT ≥5× ULN are atypical for disease progression alone 1
• Cholestatic liver disease (PBC/PSC): Establish new baseline if ALT decreases >50% during treatment; use adjusted thresholds for DILI signals 1
• Gilbert's syndrome: Confirm by calculating conjugated bilirubin <20-30% of total bilirubin; genetic testing if uncertain 1

In Oncology Patients:

• Hepatic metastases are the most common alternative cause of liver test elevations 1
• Timing of elevations (within weeks of drug start) and lack of imaging evidence of tumor progression favor DILI over malignancy 1
• Many oncology patients have multiple competing causes requiring particularly thorough evaluation 1

Common Diagnostic Pitfalls:

• Failure to inquire about herbal/dietary supplements (increasingly common cause) 6
• Attributing cholestatic pattern solely to disease progression without considering cholestatic DILI 1
• Missing non-adherence to concomitant medications (e.g., ursodeoxycholic acid in PBC/PSC patients) that can cause liver test fluctuations 1
• Overlooking acetaminophen toxicity in patients taking combination products 1, 5

Monitoring After Suspected DILI Diagnosis

• Initial frequency: Monitor liver tests 2-3 times weekly initially 1
• Clinical monitoring: Observe for hepatic decompensation signs (ascites, encephalopathy, coagulopathy) 1
• Continue monitoring until resolution or stabilization, regardless of whether suspected drug was discontinued 1
• INR prolongation: Repeat within 2-5 days to confirm and assess trajectory; attempt vitamin K supplementation before attributing to DILI 1