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Nefazodone-Induced Liver Failure: Report of Three Cases

Jaime Aranda-Michel, MD; Alison Koehler, MD; Pablo A. Bejarano, MD; John E. Poulos, MD; Bruce A. Luxon, MD; Chaudhary Mobin Khan, MD; Looi C. Ee, MD; William F. Balistreri, MD; and Fredrick L. Weber Jr., MD
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From University of Cincinnati and Children's Hospital Medical Center, Cincinnati, Ohio; and St. Louis University, St. Louis, Missouri.


Ann Intern Med. 1999;130(4_Part_1):285-288. doi:10.7326/0003-4819-130-4-199902160-00013
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Background: Liver failure is a rare but devastating result of drug toxicity.

Objective: To describe three cases of subfulminant liver failure that were probably caused by nefazodone, a new antidepressant that is a synthetically derived phenylpiperazine.

Design: Case series.

Setting: Two university medical centers and a children's hospital.

Patients: Three women 16 to 57 years of age.

Intervention: Two patients underwent liver transplantation; the third was listed for transplantation but subsequently improved.

Measurement: Liver biopsy.

Results: Nefazodone was administered for 14 to 28 weeks before the onset of symptoms. The duration of jaundice before onset of encephalopathy ranged from 4 to 6 weeks. All cases of liver failure had similar histologic appearance, with prominent necrosis in the centrolobular areas (zone 3). One patient had successful liver transplantation, one underwent transplantation but died, and one improved without transplantation. The temporal onset of disease after the start of nefazodone therapy suggested severe hepatocellular injury caused by the drug.

Conclusions: Because nefazodone seems to cause severe hepatocellular injury in an idiosyncratic manner, routine liver chemistries should be performed before starting nefazodone therapy and patients should be monitored regularly. Therapy should be discontinued if liver enzyme concentrations become abnormal.

Figures

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Figure.
A. Patient 1.B. Patient 1.arrowC. Patient 2.arrowD. Patient 3.arrowsE. Patient 3.

Initial biopsy specimen showing submassive centrilobular (zone 3) necrosis with collapse of the hepatic framework and adjacent ductular proliferation with cholestasis. (Hematoxylin-eosin; original magnification, ×200.) Specimen from explanted liver 11 days after transplantation. Areas of confluent necrosis and congestion can be seen, and cirrhotic nodules had developed ( ). (Hematoxylin and eosin; original magnification, ×100.) Specimen from explanted cirrhotic liver with extensive centrilobular necrosis and lobular collapse with cholestasis and ductular proliferation. Ballooning of hepatocytes ( ) is accompanied by lymphocytic infiltrates. (Hematoxylin-eosin; original magnification, ×200.) Initial biopsy specimen with centrilobular hepatocyte ballooning and dropout of hepatocytes with apoptotic bodies ( ). (Hematoxylin-eosin; original magnification, ×200.) Specimen from repeated biopsy 12 days later, showing progression towards bridging fibrosis between central veins and associated bile-duct proliferation. (Hematoxylin-eosin; original magnification, ×200.).

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