Can diclofenac (nonsteroidal anti-inflammatory drug (NSAID)) cause liver injury in adults, particularly those with pre-existing liver conditions or risk factors for liver disease?

Can Diclofenac Cause Liver Injury?

Yes, diclofenac causes liver injury and is the most frequently implicated NSAID in drug-induced hepatotoxicity, with meaningful transaminase elevations occurring in approximately 2-4% of patients and severe hepatotoxicity including liver failure, transplantation, and death reported in postmarketing surveillance. 1, 2

Incidence and Severity of Hepatotoxicity

Diclofenac carries a substantially higher hepatotoxic risk compared to other NSAIDs:

• Transaminase elevations >3× ULN occur in approximately 2-4% of patients, with marked elevations (>8× ULN) in about 1% of treated patients 1, 3
• Diclofenac was the most frequently implicated NSAID in the U.S. Drug Induced Liver Injury Network registry, accounting for 16 of 30 NSAID-related severe liver injury cases 2
• Severe hepatic reactions including liver necrosis, fulminant hepatitis, liver failure requiring transplantation, and death have been documented in postmarketing reports 1
• Clinical liver events requiring hospitalization occur in approximately 23 per 100,000 patients treated with diclofenac 3

High-Risk Populations Who Should Never Receive Diclofenac

Patients with cirrhosis and ascites have an absolute contraindication to all NSAIDs including diclofenac due to compounded risks of acute renal failure, hepatorenal syndrome, hyponatremia, and diuretic resistance 4, 5

Patients with advanced liver disease (Child-Pugh B or C) should never receive NSAIDs, as bleeding problems and renal failure become substantially more likely 4

Additional high-risk groups include:

• Patients over 50 years of age have increased risk for NSAID-induced liver injury 4
• Patients with osteoarthritis demonstrate higher rates of transaminase elevations compared to rheumatoid arthritis patients 1
• Patients with fatty liver disease and FIB-4 score >2.67 have an absolute contraindication to NSAIDs 4
• Patients with pre-existing chronic liver disease who develop drug-induced liver injury experience significantly higher frequency of adverse outcomes including mortality 6

Timing and Pattern of Liver Injury

The hepatotoxicity profile of diclofenac has distinct temporal characteristics:

• Most elevations occur within the first 2-6 months of therapy, with 42 of 51 patients developing marked transaminase elevations in the first 2 months 1, 3
• Mean latency to liver injury is 67 days, though severe reactions can occur at any time during treatment 1, 2
• Clinical liver events requiring hospitalization occurred between 9 days and 21 months in prospective trials 3
• Hepatocellular injury is the most common pattern (70% of cases), though cholestatic and mixed patterns also occur 2

Mandatory Monitoring Requirements

Establish baseline liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) before initiating diclofenac, and monitor transaminases within 4-8 weeks after initiating treatment, then every 3 months during long-term therapy. 4, 1

Discontinue diclofenac immediately if transaminases rise to ≥3× ULN. 4

Additional stopping criteria include:

• ALT ≥8× ULN with or without symptoms: Interrupt study drug immediately, repeat tests within 2-5 days, initiate workup for competing etiologies 6
• ALT ≥3× ULN with total bilirubin ≥2× baseline: Interrupt drug immediately, as this represents Hy's Law criteria predicting severe outcomes 6, 1
• If hepatic decompensation occurs, the drug cannot be restarted under any circumstances 6

Clinical Algorithm for Patients with Fatty Liver Disease

For patients with non-alcoholic fatty liver disease, use the FIB-4 score to guide decision-making 4:

• FIB-4 <1.3: Exercise caution and prefer acetaminophen over NSAIDs 4
• FIB-4 1.3-2.67: Strong avoidance of all NSAIDs recommended 4
• FIB-4 >2.67: NSAIDs absolutely contraindicated 4

Mechanism and Risk Factors

Diclofenac hepatotoxicity involves multiple molecular mechanisms:

• Bioactivation by CYP2C9 and CYP3A4 to thiol-reactive quinone imines, formation of protein-reactive acyl glucuronides, and oxidative stress from redox cycling 7
• Mitochondrial injury through protonophoretic activity and opening of the permeability transition pore, with cumulative damage explaining delayed onset 7
• Immune-mediated mechanisms involving T cell sensitization, with autoantibodies detected in 33% of cases 2, 8
• IL-17 and IL-1β involvement in the pathogenesis of acute liver injury 8

Critical Clinical Pitfalls to Avoid

A European case-controlled study demonstrated a 4-fold increased odds ratio of liver injury with diclofenac use, which increased further with female gender, doses ≥150 mg daily, and duration >90 days. 1

Exercise extreme caution when prescribing diclofenac with concomitant hepatotoxic drugs (acetaminophen, antibiotics, anti-epileptics), as this compounds hepatotoxicity risk 1

Severe hepatotoxicity may develop without prodromal symptoms, making regular monitoring essential rather than relying on symptom-based detection 1

Warning Signs Requiring Immediate Discontinuation

Patients must be informed to stop diclofenac immediately and seek medical attention if they develop 1:

• Nausea, fatigue, lethargy, or "flu-like" symptoms
• Jaundice or dark urine
• Right upper quadrant tenderness or abdominal pain
• Pruritus or diarrhea
• Systemic manifestations such as eosinophilia or rash

Alternative Analgesic Recommendation

Given the number of NSAID alternatives available, diclofenac should be reserved only for patients who fail other NSAIDs, and a high level of suspicion for hepatotoxicity must be maintained. 2

For patients with liver disease, acetaminophen (maximum 3 grams per 24 hours) is the safest first-line analgesic, as recommended by the American Association for the Study of Liver Diseases 9