Drug-Induced Liver Injury (DILI)
Recognising, managing and reporting hepatotoxicity from prescribed and over-the-counter medicines
Drug-induced liver injury (DILI) is hepatic damage caused by prescribed medicines, over-the-counter drugs, herbal preparations, or dietary supplements. It is the most common cause of acute liver failure in the USA and a leading reason for drug withdrawal from the market. DILI can mimic any pattern of liver disease. Careful evaluation of the timeline, causality, and pattern of injury is essential — and stopping the offending drug is the cornerstone of treatment.
How Does DILI Occur?
DILI occurs through two main mechanisms. Intrinsic (predictable) DILI is dose-dependent, reproducible, and occurs in most people exposed to sufficient quantities — the classic example is paracetamol overdose. Idiosyncratic DILI is unpredictable, dose-independent, and occurs in susceptible individuals due to genetic, immunological, or metabolic factors — most drug-induced liver injuries seen in clinical practice fall into this category. The liver is particularly vulnerable because it receives all absorbed drugs via the portal circulation and is the primary site of drug metabolism, generating reactive toxic metabolites.
Common Culprit Drugs
A wide range of drugs can cause DILI. Antibiotics are the most common class implicated: co-amoxiclav (amoxicillin-clavulanate) is the single most common cause of DILI in the UK and causes a cholestatic or mixed pattern that may appear up to 6 weeks after stopping the drug. Flucloxacillin causes cholestatic hepatitis — often delayed by 1–3 months after stopping. Nitrofurantoin (long-term) can cause chronic hepatitis resembling autoimmune hepatitis. Antituberculosis drugs — isoniazid, rifampicin, pyrazinamide — cause hepatocellular injury and require LFT monitoring. Statins cause mild asymptomatic ALT elevation in up to 3% of patients but rarely cause significant DILI — do not routinely stop statins for mild LFT elevation. Methotrexate causes cumulative dose-dependent hepatic fibrosis — requires liver biopsy after a cumulative dose of 1.5 g. Herbal and traditional medicines (including kava, black cohosh, green tea extract) are increasingly recognised as significant causes of DILI and are frequently under-reported.
Patterns of Liver Injury — R-Ratio
DILI is classified by the pattern of LFT elevation using the R-ratio: R = (ALT ÷ upper limit of normal) ÷ (ALP ÷ upper limit of normal). Hepatocellular pattern (R ≥5): predominantly raised ALT — drugs such as isoniazid, paracetamol, NSAIDs. Cholestatic pattern (R ≤2): predominantly raised ALP and bilirubin — drugs such as co-amoxiclav, flucloxacillin, chlorpromazine. Mixed pattern (2 < R < 5): both ALT and ALP raised — drugs such as carbamazepine, phenytoin. The pattern of injury influences the differential diagnosis, causality assessment, and prognosis. Cholestatic DILI generally has a better prognosis than severe hepatocellular DILI (which can progress to acute liver failure).
Causality Assessment and Diagnosis
There is no specific biomarker or test for DILI — diagnosis requires excluding other causes and establishing a plausible causal relationship. The RUCAM (Roussel Uclaf Causality Assessment Method) scale is the most widely used structured tool for causality assessment — it scores the temporal relationship, course after drug withdrawal (dechallenge), rechallenge response, risk factors, and exclusion of other diagnoses. Key investigations include LFTs, INR, bilirubin, FBC, renal function, hepatitis A IgM, hepatitis B sAg, hepatitis C antibody, autoimmune screen, caeruloplasmin (Wilson's), and abdominal ultrasound. Liver biopsy is occasionally needed to confirm the diagnosis or assess fibrosis in uncertain cases.
Management and Monitoring
The essential first step is stopping the offending drug immediately — most cases of DILI resolve after drug withdrawal. Supportive care and close LFT monitoring until normalisation are the mainstays of management. N-acetylcysteine (NAC) is the specific treatment for paracetamol-induced hepatotoxicity. For suspected immune-mediated DILI (e.g. with features of autoimmune hepatitis), corticosteroids may be considered under specialist guidance. Any patient with rising INR, encephalopathy, or bilirubin above 2× the upper limit of normal alongside coagulopathy (Hy's Law) should be urgently referred to a specialist liver unit — these features predict a risk of acute liver failure. All cases of suspected DILI should be reported to the MHRA Yellow Card scheme. This information has been carefully prepared following evaluation of NICE guidance, BSG DILI guidance, and current hepatology practice.