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2025 PACUPrep BCCCP Preparatory Course Drug-Induced Liver Injury Diagnostics and Classification of Drug-Induced Liver Injury

Lesson 37, Topic 2

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Diagnostics and Classification of Drug-Induced Liver Injury

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Learning Objective

Apply diagnostic and classification criteria to assess a patient with drug-induced liver injury (DILI) and guide initial management.

Describe key clinical features and timing patterns that distinguish intrinsic from idiosyncratic DILI.
Interpret essential laboratory tests—including R-value and Hy’s Law—and exclusion studies to confirm DILI.
Use causality tools and severity scores (RUCAM, MELD, King’s College) to stratify risk and guide disposition.

1. Clinical Manifestations and Temporal Patterns

Drug-induced liver injury (DILI) spans a wide clinical spectrum, from asymptomatic, mild enzyme elevations to fulminant acute liver failure. Recognizing the latency of onset and key symptom clusters is critical for accelerating diagnosis and initiating appropriate management.

A. Onset Latency

Intrinsic (Dose-Dependent): Predictable injury occurring within hours to days following a toxic dose or overdose. The classic example is acetaminophen toxicity.
Idiosyncratic (Unpredictable): The more common form of DILI, typically developing 5 to 90 days after initiating a new medication. Immune-mediated cases may have a longer latency period.

B. Symptoms and Signs

Early/Nonspecific: Fatigue, anorexia, nausea, and right upper quadrant (RUQ) discomfort are common initial complaints.
Progressive/Cholestatic: The development of jaundice (icterus), pruritus (itching), dark urine, and pale (acholic) stools signals more significant liver dysfunction.
Severe (Acute Liver Failure): The presence of ascites, coagulopathy (INR >1.5), and hepatic encephalopathy (graded I–IV by West Haven criteria) indicates a life-threatening course.

Risk for DILI is modified by factors such as advanced age, female sex, polypharmacy, and the presence of pre-existing liver disease.

Case Vignette

A 62-year-old woman started on isoniazid for latent tuberculosis presents at week 8 with new-onset fatigue and RUQ pain. Her labs reveal an AST of 420 U/L and an ALT of 395 U/L. The 8-week latency and hepatocellular pattern are highly suggestive of idiosyncratic DILI. The isoniazid is held immediately, and further workup is initiated.

2. Laboratory Evaluation

A structured laboratory approach is essential to categorize the pattern of injury, identify high-risk features, and systematically rule out other causes of liver disease.

Key Laboratory Assessments in Suspected DILI
Parameter	Diagnostic Criteria	Clinical Significance
Hepatocellular Pattern	ALT or AST ≥5× ULN	Indicates primary injury to hepatocytes.
Cholestatic Pattern	Alkaline Phosphatase (ALP) ≥2× ULN	Indicates injury to bile ducts/canaliculi. Often associated with prolonged course.
Mixed Pattern	ALT ≥3× ULN and ALP ≥2× ULN	Features of both hepatocellular and cholestatic injury.
R-value Calculation	R = (ALT/ULN) ÷ (ALP/ULN)	Quantifies pattern: ≥5 Hepatocellular; 2–5 Mixed; ≤2 Cholestatic.
Hy’s Law	ALT/AST ≥3× ULN and Total Bilirubin >2.5 mg/dL	A critical prognostic marker predicting a 10–50% risk of mortality or need for liver transplant.
Synthetic Function	INR and Albumin	An INR >1.5 is a key marker of acute liver failure. Low albumin suggests chronicity.

Exclusion Studies

To confirm a DILI diagnosis, other potential causes must be excluded:

Viral Hepatitis: HAV IgM, HBsAg, HBcAb IgM, HCV Ab (± RNA), HEV IgM (if clinically/geographically indicated).
Autoimmune Hepatitis: ANA, ASMA, and quantitative IgG levels.
Other Conditions: Imaging to rule out biliary obstruction (see Section 3); ceruloplasmin for Wilson’s disease or α1-antitrypsin phenotype if clinical suspicion is high.

3. Imaging and Liver Biopsy

Noninvasive imaging is crucial for excluding biliary or vascular etiologies, while liver biopsy is reserved for cases with diagnostic uncertainty or a protracted clinical course.

A. Imaging Modalities

First-Line: A right upper quadrant (RUQ) ultrasound with Doppler is the initial test of choice. It effectively rules out biliary obstruction, Budd-Chiari syndrome, and provides information on liver parenchyma and the presence of ascites.
Second-Line: If suspicion for obstruction remains high despite a negative ultrasound, a CT abdomen or Magnetic Resonance Cholangiopancreatography (MRCP) may be warranted.

B. Liver Biopsy

A liver biopsy is not required in most DILI cases but is invaluable in specific scenarios:

The diagnosis remains uncertain after a thorough noninvasive workup.
There are prominent autoimmune features, and corticosteroid therapy is being considered.
The injury is protracted (persists >3 months) to assess for chronicity and fibrosis.

Clinical Pearl: Biopsy Timing +

If a biopsy is planned, it is often best to perform it after the suspect drug has been withdrawn for a period. This allows acute, nonspecific necrotic changes to resolve, potentially revealing a more specific underlying histologic pattern. Critically, any significant coagulopathy (e.g., INR >1.5) must be corrected or have resolved before attempting a percutaneous biopsy.

4. Causality Assessment Tools

Structured scoring systems like the Roussel Uclaf Causality Assessment Method (RUCAM) provide a standardized framework to support—but not replace—expert clinical judgment in attributing DILI to a specific medication.

RUCAM Scoring Domains

Time to Onset: Points awarded based on the latency between drug start and liver injury.
Course of Injury: Points for improvement in liver enzymes after drug withdrawal.
Risk Factors: Considers age and alcohol use.
Concomitant Drugs: Evaluates the role of other potentially hepatotoxic medications.
Exclusion of Other Causes: Points awarded for a thorough workup ruling out alternative diagnoses.
Known Hepatotoxicity: Based on prior published evidence for the suspect agent.
Response to Rechallenge: (Rarely performed) Points for recurrence of injury if the drug is restarted.
Total Score Interpretation:
- ≤0: Excluded
- 1–2: Unlikely
- 3–5: Possible
- 6–8: Probable
- ≥9: Highly Probable

While RUCAM is the most widely used tool, it has limitations, especially in cases of polypharmacy or with herbal and dietary supplements. Its main value is in promoting a systematic and comprehensive assessment.

5. Severity Scoring and Prognostication

Once DILI is diagnosed, validated scoring systems are used to stratify the risk of poor outcomes and identify patients who require intensive care or urgent evaluation for liver transplantation.

A. MELD Score

The Model for End-Stage Liver Disease (MELD) score incorporates serum bilirubin, INR, and creatinine (with sodium often included as MELD-Na) to predict 3-month mortality. It is a dynamic score used to prioritize patients on the liver transplant list.

B. King’s College Criteria for Non-Acetaminophen ALF

These criteria are highly specific for identifying patients with non-acetaminophen acute liver failure (ALF) who are unlikely to survive without a transplant. Referral to a transplant center is mandated if criteria are met.

Figure 1: King’s College Criteria. Meeting either the primary INR criterion or any three of the five secondary criteria indicates a very poor prognosis and necessitates immediate consultation with a liver transplant center.

Key Point: Role of N-acetylcysteine (NAC) +

While NAC is the specific antidote for acetaminophen overdose, studies have shown that early administration of intravenous NAC also improves transplant-free survival in patients with early-stage, non-acetaminophen acute liver failure. Its use should be strongly considered in any patient with DILI-related ALF.

6. Clinical Decision Points

A systematic approach using defined thresholds streamlines critical decisions regarding drug cessation, appropriate level of care, and the need for advanced diagnostics or therapies. Multidisciplinary collaboration is paramount.

Figure 2: DILI Clinical Decision Pathway. This flowchart outlines key management steps based on laboratory thresholds and clinical signs, emphasizing prompt action for high-risk features.

References

Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug-, herbal-, and dietary supplement-induced liver injury. Hepatology. 2023;77(3):1036–1065.
Chalasani NP, Maddur H, Russo MW, et al. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116(5):878–898.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs. Part I: application to DILI (RUCAM). J Clin Epidemiol. 1993;46(11):1323–1330.
Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early-stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856–864.e1.
Hosack T, Damry D, Biswas S. Drug-induced liver injury: a comprehensive review. Ther Adv Gastroenterol. 2023;16:1–13.
Björnsson ES, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42(3):481–489.
Chalasani N, Fontana RJ, Bonkovsky HL, Lee WM, Stolz A, Talwalkar J, et al. Prospective study of DILI causes, clinical features, and outcomes in the United States. Gastroenterology. 2008;135(6):1924–1934.e4.
Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–669.

2025 PACUPrep BCCCP Preparatory Course

Pulmonary

Participants 432

Diagnostics and Classification of Drug-Induced Liver Injury

Diagnostics and Classification of Drug-Induced Liver Injury

Learning Objective

1. Clinical Manifestations and Temporal Patterns

A. Onset Latency

B. Symptoms and Signs

Case Vignette

2. Laboratory Evaluation

Exclusion Studies

3. Imaging and Liver Biopsy

A. Imaging Modalities

B. Liver Biopsy

4. Causality Assessment Tools

RUCAM Scoring Domains

5. Severity Scoring and Prognostication

A. MELD Score

B. King’s College Criteria for Non-Acetaminophen ALF

6. Clinical Decision Points

References