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Diclofenac Induced Hepatotoxicity (DIH) is idiosyncratic (individual variability in susceptibility). It is rare. However it can lead to serious liver injury and death.
Toxicokinetics
Toxicokinetics
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For more information references numbered (4), (5), (14), (35), (36), (37), (38), (39), (40), (41) and (42) (in the above slides) can be found in our website Bibliography
Clinical Symptoms, Signs, Tests and Management
Clinical Symptoms, Signs, Tests and Management
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For more information references numbered (17), (35), (36), (37), (38), (37), (38), (39), (40), (41), (42), (43), (44) and (45) (in the above slides) can be found in our website Bibliography
Prevention and Protection
Prevention and Protection
Do not use (contraindications):
Diclofenac in pre-existing liver disease.
Consult your physician before combining Diclofenac with other potentially Hepatotoxic agents e.g. Paracetamol
Past history of Diclofenac Hepatotoxicity.
High index of suspicion if elevated transaminases associated with Diclofenac use in the preceding 3 months.
Emerging evidence (animal studies) suggests protection against Hepatotoxicity with anti-oxidant Vitamin E. For more information visit https://pharmascope.org/ijrps/article/view/1337/1320 46
Use with caution in the Elderly as the physiological reserve declines as we age e.g. maintaining homeostasis decreases with increased chance of comorbidities
Human Case Studies
Human Case Studies
Below are 4 cases highlighting the timing of onset of clinical manifestations (latency), the patterns of Drug Induced Liver Injury (DILI) Hepatocellular, different severities and outcomes of DIH. For more information on these cases please visit: https://www.ncbi.nlm.nih.gov/books/NBK547953/ 44
NB. R≥5 is labeled as hepatocellular DILI, R<2 is labeled cholestatic DILI, and 2< R <5 is labeled “mixed” DILI. For more information please visit: https://www.mdcalc.com/guidelines/acg/diagnosis-management-idiosyncratic-drug-induced-liver-injury 47
Patient Case 1: Severe acute hepatitis and liver failure due to diclofenac.
Patient Case 1: Severe acute hepatitis and liver failure due to diclofenac.
Lady, early 30s. Diclofenac prescribed for Ankylosing Spondylitis.
Lady, early 30s. Diclofenac prescribed for Ankylosing Spondylitis.
Asymptomatic Elevations in Serum Aminotransferase levels during first month of Diclofenac therapy. Serology tests were normal.
Asymptomatic Elevations in Serum Aminotransferase levels during first month of Diclofenac therapy. Serology tests were normal.
Reduction to normal levels of Aminotransferases achieved upon discontinuation of Diclofenac.
Reduction to normal levels of Aminotransferases achieved upon discontinuation of Diclofenac.
Patient Case 2: Asymptomatic elevations in Serum Aminotransferase levels during long-term Diclofenac therapy.
Patient Case 2: Asymptomatic elevations in Serum Aminotransferase levels during long-term Diclofenac therapy.
Lady, early 40s. Diclofenac (50mg thrice daily) prescribed for Chronic knee pain.
Lady, early 40s. Diclofenac (50mg thrice daily) prescribed for Chronic knee pain.
Elevations in Serum Aminotransferase levels during long-term (5 months) Diclofenac Therapy. Experienced sharp, intermittent right upper quadrant pain and itching of the lower extremities. Serology tests were negative for Hepatitis A,B,C but anti-nuclear antibodies (antibodies that attack healthy proteins within cell nuclei) were positive. She denied fever, nausea, weight loss or jaundice.
Elevations in Serum Aminotransferase levels during long-term (5 months) Diclofenac Therapy. Experienced sharp, intermittent right upper quadrant pain and itching of the lower extremities. Serology tests were negative for Hepatitis A,B,C but anti-nuclear antibodies (antibodies that attack healthy proteins within cell nuclei) were positive. She denied fever, nausea, weight loss or jaundice.
Several months later Liver biopsy revealed Chronic Hepatitis. Discontinuation of Atorvastatin did not resolve symptoms.
Several months later Liver biopsy revealed Chronic Hepatitis. Discontinuation of Atorvastatin did not resolve symptoms.
Relieving of symptoms and return to normal levels of Serum Aminotransferases was achieved upon Diclofenac discontinuation.
Relieving of symptoms and return to normal levels of Serum Aminotransferases was achieved upon Diclofenac discontinuation.
Patient Case 3: Severe Acute Hepatitis and Liver Failure due to Diclofenac.
Patient Case 3: Severe Acute Hepatitis and Liver Failure due to Diclofenac.
Lady in her 60s with Osteoarthritis of the hip. Prescribed a combination of oral Diclofenac 50mg and gastro-protective Misoprostol (Arthrotec) three times daily. Background of fatty liver on CT.
Lady in her 60s with Osteoarthritis of the hip. Prescribed a combination of oral Diclofenac 50mg and gastro-protective Misoprostol (Arthrotec) three times daily. Background of fatty liver on CT.
Following Diclofenac discontinuation initial deterioration was followed by spontaneous recovery: Two months later symptoms and jaundice resolved. Normal Liver tests achieved 4 months after onset.
Following Diclofenac discontinuation initial deterioration was followed by spontaneous recovery: Two months later symptoms and jaundice resolved. Normal Liver tests achieved 4 months after onset.
Spontaneous Recovery: Two months later jaundice resolved. Normal Liver tests achieved after 4 months.
Spontaneous Recovery: Two months later jaundice resolved. Normal Liver tests achieved after 4 months.
Patient Case 4: Acute liver failure due to Diclofenac. A fatal incident.
Patient Case 4: Acute liver failure due to Diclofenac. A fatal incident.
Lady, 65 years prescribed Diclofenac for Osteoarthritis.
Lady, 65 years prescribed Diclofenac for Osteoarthritis.
Replaced Ibuprofen with Diclofenac. Sudden onset of nausea, vomiting and fatigue six weeks after starting Diclofenac 75 mg by mouth twice daily. Serum Aminotransferases were mildly elevated.
Replaced Ibuprofen with Diclofenac. Sudden onset of nausea, vomiting and fatigue six weeks after starting Diclofenac 75 mg by mouth twice daily. Serum Aminotransferases were mildly elevated.
Diclofenac stopped but condition worsened with new-onset jaundice. She was treated with Prednisone (30 mg daily), but continued to worsen.
Diclofenac stopped but condition worsened with new-onset jaundice. She was treated with Prednisone (30 mg daily), but continued to worsen.
There was bilateral pitting oedema, ascites and 'flapping tremor'. She did not drink alcohol and had no history of Liver Disease or risk factors for Viral Hepatitis. Tests for Hepatitis A and B and autoantibodies were negative.
There was bilateral pitting oedema, ascites and 'flapping tremor'. She did not drink alcohol and had no history of Liver Disease or risk factors for Viral Hepatitis. Tests for Hepatitis A and B and autoantibodies were negative.
Hepatic Failure deteriorated and she died.
Hepatic Failure deteriorated and she died.
Liver autopsy showed shrunken, mass necrosis and Cholestasis.
Liver autopsy showed shrunken, mass necrosis and Cholestasis.
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