Drug-Induced Liver Injury (DILI)

📋 Key Information Summary

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Definition: Drug-induced liver injury (DILI) is liver damage caused by medications, herbal products, or dietary supplements, presenting as acute hepatocellular, cholestatic, or mixed injury.
Classification by pattern: Hepatocellular (ALT >5× ULN, R ≥5), cholestatic (ALP elevation, R ≤2), or mixed (R 2–5); pattern guides differential diagnosis and prognosis.
Intrinsic vs idiosyncratic: Intrinsic DILI (e.g., paracetamol) is dose-dependent, predictable, and reproducible; idiosyncratic DILI is unpredictable and may be immune-mediated or metabolic.
Hy's Law: ALT >3× ULN with total bilirubin >2× ULN (without obstruction) predicts ~10% mortality — treat as a medical emergency requiring urgent specialist review.
Commonest culprit in Australia: Amoxicillin-clavulanate is the most frequently implicated drug; other common causes include flucloxacillin, nitrofurantoin, methotrexate, statins, and herbal/dietary supplements.
Diagnosis: DILI is a clinical diagnosis of exclusion; use the RUCAM (Roussel Uclaf Causality Assessment Method) to quantify causality; temporal relationship and dechallenge are key.
Immediate management: Withdraw the suspected agent promptly; exclude viral hepatitis, autoimmune hepatitis, biliary obstruction, and metabolic causes.
N-acetylcysteine (NAC): Consider IV NAC in non-paracetamol DILI with coagulopathy or early acute liver failure (ALF); evidence supports improved transplant-free survival in early-stage ALF.
Transplant referral: Refer urgently to a liver transplant centre if INR is rising, encephalopathy develops, or King's College criteria are met.
Avoid rechallenge: Re-exposure to the causative agent is contraindicated and may cause more severe or fatal injury.
ATSI considerations: Aboriginal and Torres Strait Islander peoples have higher rates of herbal/alternative medicine use, limited specialist access in remote areas, and higher background rates of chronic liver disease — requiring culturally safe, proactive screening and telehealth-enabled care.
Reporting: Report suspected DILI to the TGA via the Adverse Medicine Events Line (1300 134 237) and document in the patient's My Health Record.

Introduction & Australian Epidemiology

Drug-induced liver injury (DILI) encompasses a spectrum of hepatic dysfunction caused by prescription medications, over-the-counter drugs, herbal preparations, and dietary supplements. It is a leading cause of acute liver failure (ALF) in Australia and the most common reason for post-market withdrawal of medications worldwide.

In Australia, DILI accounts for approximately 10–15% of all cases of acute hepatitis presenting to tertiary centres. The annual incidence is estimated at 14–19 per 100,000 population, though this is likely under-reported due to diagnostic challenges and the self-limiting nature of mild cases. Amoxicillin-clavulanate is the commonest single agent implicated, consistent with its high prescribing frequency in primary care.

Paracetamol remains the most common cause of ALF in Australia, responsible for nearly 50% of all ALF referrals to transplant centres. Idiosyncratic DILI from antibiotics, anti-tuberculosis agents, and herbal products comprises the majority of non-paracetamol cases. Aboriginal and Torres Strait Islander peoples are disproportionately affected, with higher rates of traditional medicine use and reduced access to specialist hepatology services in remote and very remote communities.

⚠️

Under-reporting: DILI is frequently misdiagnosed as viral hepatitis or excluded from differential. A high index of suspicion is required, particularly when liver biochemistry deranges after commencement of a new drug or supplement.

Drug-Induced Liver Injury (DILI) clinical infographic — pathophysiology, clinical clues, diagnosis, imaging, and management — Tap or click image to enlarge — Drug-Induced Liver Injury (DILI): pathophysiology, clinical clues, diagnosis, imaging, and management.

Classification

DILI is classified by biochemical pattern, mechanism, chronology, and clinical course. Correct classification guides the differential diagnosis, investigation pathway, and prognosis.

Biochemical Pattern (R Value)

The R value (ratio of ALT/ULN to ALP/ULN) determines the injury pattern at presentation:

Pattern	R Value	Key Features	Common Culprits
Hepatocellular	R ≥5	ALT >5× ULN; ALP normal or mildly elevated; higher mortality risk	Paracetamol, isoniazid, nitrofurantoin, statins, methotrexate, herbal supplements
Cholestatic	R ≤2	ALP >2× ULN dominant; ALT mildly elevated; jaundice, pruritus common	Amoxicillin-clavulanate, flucloxacillin, erythromycin, anabolic steroids
Mixed	R 2–5	Both ALT and ALP significantly elevated; intermediate prognosis	Sulfonamides, phenytoin, carbamazepine, diclofenac

Mechanism: Intrinsic vs Idiosyncratic

Predictable

Intrinsic (Direct) DILI

Dose-dependent, reproducible, predictable; occurs in most/all individuals at sufficient dose; direct hepatotoxicity or via reactive metabolite.

Example: Paracetamol (NAPQI toxicity), carbon tetrachloride

Unpredictable

Idiosyncratic — Immune-Mediated

Not dose-dependent; latency days to weeks; may have fever, rash, eosinophilia; positive rechallenge causes rapid recurrence; HLA associations identified.

Example: Amoxicillin-clavulanate, flucloxacillin (HLA-B*57:01), nitrofurantoin

Unpredictable

Idiosyncratic — Metabolic

Host-dependent metabolic activation of drug or metabolite; no immune features; longer latency (weeks–months); depends on individual enzyme polymorphisms.

Example: Isoniazid, valproate, methotrexate

Hy's Law — Critical Prognostic Indicator

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Hy's Law (named after Dr Hyman Zimmerman): Hepatocellular injury with ALT >3× ULN AND total bilirubin >2× ULN (without biliary obstruction or Gilbert syndrome) indicates severe hepatocyte necrosis with a mortality rate of approximately 10–50%. This is the single most important predictor of fatal DILI in clinical practice.

Signals impending acute liver failure in up to 10–50% of affected patients
Requires immediate discontinuation of all suspect drugs
Urgent hepatology referral and consideration of liver transplant centre notification
Serial monitoring of INR, bilirubin, and hepatic encephalopathy grade

Chronological Classification

Type	Latency	Course After Withdrawal
Acute	1–8 weeks	Resolution in days–weeks (most common)
Sub-acute	8–26 weeks	Slower resolution; may mimic autoimmune hepatitis
Chronic	>26 weeks	Persistent abnormality; vanishing bile duct syndrome, autoimmune-like (e.g., nitrofurantoin, minocycline)

Common Culprits & Diagnosis

Commonly Implicated Agents in Australia

The following agents account for the majority of DILI notifications to Australian hepatology registries:

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Amoxicillin-Clavulanate

Augmentin® · Augmentin Duo® · β-lactam/β-lactamase inhibitor

Pattern Cholestatic (most common); mixed; hepatocellular

Latency 1–6 weeks (up to 12 weeks if cholestatic)

Risk factors Age >65, prolonged courses (>14 days), male sex

HLA association HLA-A*02:01 and HLA-DRB1*15:01 (cholestatic pattern)

PBS status ✔ PBS General Benefit

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Flucloxacillin

Staphlex® · Floxapen® · Penicillinase-resistant penicillin

Pattern Cholestatic

Latency 1–8 weeks; may persist months (vanishing bile duct syndrome)

HLA association HLA-B*57:01 — strongly associated; consider pre-prescription testing

PBS status ✔ PBS General Benefit

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Nitrofurantoin

Macrobid® · Macrodantin® · Urinary antiseptic

Pattern Hepatocellular (acute); chronic hepatitis-like with prolonged use

Latency Acute: 2–6 weeks; Chronic: months–years of prophylactic use

Special notes Chronic use may mimic autoimmune hepatitis; ANA/ASMA positive; granulomas on biopsy

PBS status ✔ PBS General Benefit

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Isoniazid

Various generics · Anti-tuberculosis agent

Pattern Hepatocellular; may be severe

Latency 1–6 months (risk increases with age >35, alcohol, hepatitis B/C)

Monitoring Baseline LFTs; repeat at 1, 2, 3 months then as clinically indicated; cease if ALT >5× ULN

PBS status ✔ PBS General Benefit

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Methotrexate

Methoblastin® · Antimetabolite / DMARD

Pattern Hepatocellular; fibrosis → cirrhosis with cumulative dose

Risk factors Alcohol, obesity, diabetes, hepatitis B/C, psoriasis (higher doses)

Monitoring LFTs every 1–3 months; ELF score or FibroScan if cumulative >1.5 g; liver biopsy if ELF >9.1

PBS status ✔ PBS General Benefit

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Statins (HMG-CoA reductase inhibitors)

Atorvastatin, rosuvastatin, simvastatin, pravastatin

Pattern Hepatocellular (mild ALT elevation common; severe DILI rare)

Key point Mild ALT <3× ULN: continue statin; ALT ≥3× ULN: withhold and investigate

PBS status ✔ PBS General Benefit

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Herbal & Dietary Supplements

Green tea extract, kava, comfrey, black cohosh, turmeric (high-dose), bodybuilding supplements

Pattern Hepatocellular or mixed; may be severe

Key point Now the 2nd most common cause of DILI in Western countries; patients often do not volunteer use — ask directly

TGA regulation Many sold as "complementary medicines" (AUST L) with less rigorous safety monitoring than prescription drugs

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Minocycline

Minomycin® · Tetracycline antibiotic

Pattern Hepatocellular; autoimmune hepatitis-like with chronic use

Latency Months to years (prophylactic acne therapy)

PBS status ✔ PBS General Benefit

Diagnostic Approach

DILI is a diagnosis of exclusion. No single test is diagnostic. The systematic approach involves:

Establish Liver Injury

Confirm abnormal LFTs on ≥2 occasions. Determine biochemical pattern (hepatocellular, cholestatic, mixed) using the R value.

Temporal Relationship

Map LFT onset to drug commencement. Typical latency: 5–90 days. Rule out drugs started >1 year ago (except methotrexate, nitrofurantoin chronic use).

Exclude Alternative Causes

Viral hepatitis (A, B, C, E), autoimmune hepatitis, biliary obstruction (ultrasound), haemochromatosis, Wilson disease, Budd-Chiari, sepsis, shock liver.

Apply RUCAM Score

Quantitative causality assessment (see below). Score ≥6 = probable; ≥8 = highly probable.

Withdrawal & Dechallenge

Cease suspect drug. Improvement in LFTs within days–weeks supports causality. Do NOT perform deliberate rechallenge.

RUCAM Causality Assessment

The Roussel Uclaf Causality Assessment Method (RUCAM) is the internationally validated scoring system for DILI causality. It incorporates seven domains scored to yield a total of −4 to +14 points:

Domain	Score Range	Key Considerations
Time to onset	+1 to +2	First exposure; latency consistent with known drug
Course after cessation	0 to +3	Decrease in ALT/ALP by ≥50% within 8 days = highly suggestive
Risk factors	0 to +2	Age ≥55, alcohol, pregnancy
Concomitant drugs	0 to +3	No other cause = +3; time suggestive = +2
Non-drug causes	−3 to +2	Exclusion of viral, biliary, autoimmune, ischaemic causes
Previous information	0 to +2	Published DILI for this drug; labelled reaction
Rechallenge	0 to +3	Positive rechallenge +3 (NOT recommended deliberately)

Total Score	Causality
≤0	Excluded
1–2	Unlikely
3–5	Possible
6–8	Probable
≥9	Highly probable

⚠️

Never deliberately rechallenge a patient with the suspected causative agent. Rechallenge may cause more rapid, severe, or fatal liver injury. Unintentional rechallenge data should be used cautiously in RUCAM scoring and reported to the TGA.

Baseline Investigations

Essential Liver function tests (ALT, ALP, GGT, bilirubin, albumin, INR) MBS Item 66500 (hepatic function panel); available at all pathology labs Australia-wide

Essential Viral hepatitis serology (HAV IgM, HBsAg, HBc IgM, HCV Ab, HEV IgM) MBS Item 69430/69433; HEV increasingly tested in ALF workup

Essential Right upper quadrant ultrasound Exclude biliary obstruction, Budd-Chiari; MBS Item 55006

Available Autoimmune screen (ANA, ASMA, IgG, anti-LKM) Rule out autoimmune hepatitis; MBS Item 69496 (immunoglobulins)

Available Iron studies, caeruloplasmin, copper Exclude haemochromatosis and Wilson disease, especially in younger patients

Available Drug levels where applicable Paracetamol level (if timing uncertain), valproate, phenytoin levels

Consider referral Liver biopsy Not routinely required; consider if diagnostic uncertainty, chronic DILI, or autoimmune hepatitis-like pattern; specialist procedure

Management

Immediate Management Principles

Withdraw the Suspected Agent

Cease the implicated drug immediately. This is the single most important intervention. Document the drug name, dose, dates of use, and LFT trend in the patient's record and My Health Record.

Exclude Alternative Diagnoses

Confirm viral hepatitis serology negative (including HEV); exclude biliary obstruction on imaging; check autoimmune markers; review for ischaemic hepatitis, sepsis, or haemodynamic causes.

Supportive Care

IV fluids, electrolyte correction, nutritional support. Monitor for coagulopathy (INR), hypoglycaemia, and hepatic encephalopathy. Avoid hepatotoxic drugs. Cessation of alcohol.

Serial Monitoring

LFTs, INR, and clinical assessment daily in severe cases. Improvement in ALT after withdrawal supports DILI diagnosis; worsening despite cessation raises concern for ALF.

Report to TGA

Report all suspected DILI via the Adverse Medicine Events Line (1300 134 237) or the TGA online form. Include RUCAM score if calculated.

N-Acetylcysteine (NAC) in Non-Paracetamol DILI

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Evidence for NAC: While NAC is the established antidote for paracetamol overdose, emerging evidence supports its use in non-paracetamol acute liver failure (ALF). The landmark US ALF Study Group trial (Lee et al., Hepatology 2009) demonstrated improved transplant-free survival with IV NAC in early-stage (Grade I–II encephalopathy) non-paracetamol ALF.

Indicated in DILI with evidence of ALF: coagulopathy (INR ≥1.5), any grade of encephalopathy, or rapidly rising bilirubin
Greatest benefit in early-stage ALF (Grade I–II hepatic encephalopathy)
No established benefit in mild–moderate DILI without ALF features

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N-Acetylcysteine (NAC) — IV Protocol

Parvolex® · Acetylcysteine · Mucolytic / Antidote

Indication Non-paracetamol DILI with ALF features (coagulopathy, encephalopathy)

Dose — Loading 150 mg/kg IV in 200 mL 5% dextrose over 60 minutes

Dose — Second infusion 50 mg/kg in 500 mL over 4 hours

Dose — Third infusion 100 mg/kg in 1000 mL over 16 hours

Duration Typically 72-hour protocol; may continue until INR improving and encephalopathy resolving

Paediatric Same mg/kg dosing; adjust volumes by weight; consult paediatric hepatologist

Renal adjustment No dose adjustment required; monitor fluid balance in renal impairment

Hepatic adjustment No dose adjustment; monitor for anaphylactoid reactions

PBS status ✔ PBS General Benefit

Transplant Centre Referral

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Urgent liver transplant referral criteria (King's College Criteria adapted):

INR ≥6.5 (regardless of encephalopathy grade)
Any three of: age <10 or >40; non-paracetamol aetiology; jaundice-to-encephalopathy interval >7 days; INR ≥3.5; serum bilirubin ≥300 µmol/L
Progressive hepatic encephalopathy (Grade II or above)
Hy's Law criteria with worsening trajectory despite drug withdrawal
Lactate >3.5 mmol/L after fluid resuscitation

Australian transplant centres: Royal Prince Alfred Hospital (Sydney), Austin Hospital (Melbourne), Princess Alexandra Hospital (Brisbane), Sir Charles Gairdner Hospital (Perth), Flinders Medical Centre (Adelaide).

Severity Grading & Disposition

Mild

ALT <5× ULN, no jaundice

Cease drug; monitor LFTs weekly in GP; expect resolution in 1–4 weeks.

Setting: GP monitoring; specialist referral if not improving at 2 weeks

Moderate

ALT ≥5× ULN or jaundice (bilirubin >2× ULN)

Cease drug; exclude alternatives; hepatology referral; assess Hy's Law; consider NAC if ALF features.

Setting: Specialist outpatient or admission for monitoring

Severe / ALF

Coagulopathy + encephalopathy

Immediate NAC; ICU-level monitoring; urgent transplant centre referral; King's College criteria assessment.

Setting: Tertiary hospital with ICU and liver transplant access

Monitoring After Withdrawal

Serial LFT monitoring is essential to confirm improvement and exclude chronicity:

Days 1–7: LFTs, INR, bilirubin daily or second-daily in severe cases
Weeks 2–4: LFTs weekly; expect ≥50% decline in ALT by 8 days in most cases
Months 1–6: LFTs monthly until normalised; if persistent elevation, investigate for chronic DILI, autoimmune hepatitis, or vanishing bile duct syndrome
Document the causative drug in the patient's allergy/adverse drug reaction list and My Health Record

Special Populations

🤰 Pregnancy

Acute fatty liver of pregnancy (AFLP): Must be excluded; presents in third trimester with hepatocellular injury, coagulopathy, and hypoglycaemia. Delivery is definitive treatment.

HELLP syndrome: Distinguish from DILI by presence of haemolysis, elevated liver enzymes, low platelets. Obstetric emergency.

Paracetamol: NAC is safe in pregnancy; standard dosing applies.

Avoid liver biopsy in pregnancy unless critical; coordinate with obstetric and hepatology teams.

👶 Paediatrics

Incidence: Lower overall but amoxicillin-clavulanate and valproate are common culprits; paracetamol dosing errors are a major cause of ALF in children.

NAC dosing: Weight-based IV NAC protocol is identical to adults on a mg/kg basis. Consult paediatric hepatologist for all cases of suspected DILI in children.

Wilson disease and metabolic disorders must be excluded in paediatric DILI, especially in children <10 years.

👴 Elderly (≥65 years)

Higher risk: Reduced hepatic blood flow, polypharmacy, lower albumin (increased free drug fraction), and impaired detoxification pathways.

Amoxicillin-clavulanate: Risk of cholestatic DILI increases 4-fold in patients >65. Limit courses to <14 days where possible.

Review all medications at each visit; use deprescribing principles; consider RUCAM scoring for any new liver biochemistry abnormality.

🫘 Renal Impairment

Accumulation risk: Reduced renal clearance may increase exposure to hepatotoxic metabolites (e.g., methotrexate, NSAIDs).

NAC: No dose adjustment required; monitor fluid balance to avoid overload in patients on dialysis or with eGFR <30 mL/min.

Distinguish uraemic liver biochemistry changes from true DILI; consult nephrology for CKD patients with new LFT derangement.

🫁 Pre-existing Liver Disease

Increased vulnerability: Patients with chronic liver disease (NAFLD, viral hepatitis, alcohol-related) have reduced hepatic reserve; even mild DILI may precipitate decompensation.

Drug selection: Avoid known hepatotoxins where alternatives exist; e.g., use flucloxacillin cautiously in patients with pre-existing cholestasis.

Baseline LFTs before commencing any potentially hepatotoxic drug; lower threshold for drug withdrawal.

🛡️ Immunocompromised

Confounding infections: CMV, EBV, HSV hepatitis may mimic DILI; active viral hepatitis screening is essential.

TB treatment: Isoniazid-related DILI is more common in HIV-positive patients; close LFT monitoring required (weekly for first 2 months).

Coordinate with infectious disease specialists; avoid unnecessary empiric antibiotic changes without confirmed DILI diagnosis.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander peoples experience a disproportionate burden of liver disease and face unique challenges in the recognition and management of DILI. Cultural safety, proactive screening, and accessible specialist referral are essential.

Higher background liver disease

ATSI peoples have 2–3× higher rates of chronic liver disease (hepatitis B, NAFLD, alcohol-related). This reduces hepatic reserve and increases vulnerability to DILI. Baseline LFTs should be checked before starting hepatotoxic medications.

Herbal & traditional medicine use

Bush medicines and herbal supplements are widely used and may contain hepatotoxic compounds. Patients may not volunteer this information; ask respectfully and document findings. The TGA lists some complementary medicines as AUST L (low-risk), but safety data are limited.

Remote & very remote access

Specialist hepatology services are concentrated in major cities. Patients in remote NT, QLD, and WA communities may face delays of days–weeks for specialist review. Telehealth (MBS Item 91822) and the RFDS are critical for timely DILI assessment.

Pharmacogenomic considerations

HLA polymorphisms associated with DILI (e.g., HLA-B*57:01 for flucloxacillin) have variable prevalence across populations. Pharmacogenomic testing availability is limited in remote communities; empiric caution is advised.

Culturally safe care

Engage Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers. Provide health education in culturally appropriate formats. Use the Australian Indigenous HealthInfoNet and NACCHO resources. Respect cultural practices while ensuring safety.

Reporting & data gaps

ATSI-specific DILI incidence data are sparse. Ensure ATSI status is recorded in all adverse drug reaction reports. AIHW and RHDAustralia resources provide frameworks for culturally safe liver disease management.

📚 References

1. Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144(7):1419–1425.
2. Danan G, Teschke R. RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2016;17(1):14.
3. 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.
4. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148(7):1340–1352.
5. Lucena MI, Molokhia M, Shen Y, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–347.
6. Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41(7):816–819.
7. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399–1408.
8. Australian Commission on Safety and Quality in Health Care (ACSQHC). National Safety and Quality Health Service Standards. 2nd ed. Sydney: ACSQHC; 2017.
9. Australian Institute of Health and Welfare (AIHW). Aboriginal and Torres Strait Islander Health Performance Framework 2020 summary report. Canberra: AIHW; 2020.
10. Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96–108.
11. Craig DGN, Lee A, Hayes PC, Simpson KJ. Review article: The Royal College of Physicians' Biomarker in Liver Injury (BALI) consensus recommendations. Aliment Pharmacol Ther. 2010;31(8):844–856.
12. Lewis JH. The Art and Science of Diagnosing and Managing Drug-Induced Liver Injury in 2020 and Beyond. Clin Gastroenterol Hepatol. 2020;18(11):2441–2452.
13. Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013;19(19):2864–2882.