Hepatotoxicity induced by celecoxib and amlodipine

A 58-year old woman received celecoxib (Celebrex®) for 2 years to treat fibromyalgia. Pathological liver enzyme levels were discovered incidentally. Abdominal sonography showed no cholelithiasis, the bile ducts were normal, and there were no signs of chronic liver disease. At admission the patient was icteric and physical examination revealed no signs of chronic liver disease. Her history confirmed that she was taking celecoxib more or less regularly but no other medication within the last three months. She tested negative for anti-HAV, anti-HCV, HBs-antigen, antimitochondrial antibody and antinuclear antibodies. Laboratory tests showed (upper limit of normal): bilirubin 151 (20) umol/L, ASAT 1032 (37) U/L, ALAT 1058 (40) U/L, alkaline phospatase 1101 (270) U/L, gamma-GT 467 (61) U/L, thromboplastin time 81 (>70) %, albumin 35 (>38) g/L. A percutaneous liver biopsy revealed severe, acute hepatitis with marked, mixed inflammatory infiltrates of the portal fields, and confluent, focal necrosis. After discontinuation of celecoxib, the cholestatic parameters normalised during the following 3 months. The transaminases however returned to normal only after 1 year (Fig. 1).


Introduction
We report two cases with severe hepatotoxicity induced by celecoxib and amlodipine respectively.In both patients the observed liver damage was of the mixed cytolytic/ cholestatic type and was entirely reversible.

Case 1
A 58-year old woman received celecoxib (Celebrex ® ) for 2 years to treat fibromyalgia.Pathological liver enzyme levels were discovered incidentally.Abdominal sonography showed no cholelithiasis, the bile ducts were normal, and there were no signs of chronic liver disease.At admission the patient was icteric and physical examination revealed no signs of chronic liver disease.Her history confirmed that she was taking celecoxib more or less regularly but no other medication within the last three months.She tested negative for anti-HAV, anti-HCV, HBs-antigen, antimitochondrial antibody and antinuclear antibodies.Laboratory tests showed (upper limit of normal): bilirubin 151 (20) umol/L, ASAT 1032 (37) U/L, ALAT 1058 (40) U/L, alka-line phospatase 1101 (270) U/L, gamma-GT 467 (61) U/L, thromboplastin time 81 (>70) %, albumin 35 (>38) g/L.
A percutaneous liver biopsy revealed severe, acute hepatitis with marked, mixed inflammatory infiltrates of the portal fields, and confluent, focal necrosis.After discontinuation of celecoxib, the cholestatic parameters normalised during the following 3 months.The transaminases however returned to normal only after 1 year (Fig. 1).
After discontinuation of amlodipine, the transaminases and parameters of cholestasis decreased markedly within 2 weeks (Fig. 2).However, after developing urosepsis, this multi-morbid patient died as a consequence of pulmonary embolism.

Comment
The two patients discussed in this letter were admitted to the hospital for severe, drug induced hepatitis.We were able to incriminate celexoxib and amlodipine respectively as the responsible drugs.Besides celecoxib [2][3][4] other COX-2 inhibitors have been reported to be associated with hepatotoxicity, culminating in fulminant liver necrosis and death as well as in severe, acute pancreatitis.According to "Swissmedic", three other cases of hepatotoxicity possibly associated with amlodipine had been reported until August 2002.Hepatotoxicity induced by amlodipine is highly unusual [5].
In summary drug induced liver disease should not be underestimated in everyday clinical practice, even if this side effect may not be listed in current reference books as it is in the case of amlodipine [1].What Swiss Medical Weekly has to offer:

Figure 1 a
Figure 1a: values of bilirubin and SGPT after withdrawal of celecoxib (case 1).b: values of bilirubin and SGPT after withdrawal of amlodipine (case 2).
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