Steatohepatitis amiodarone

Amiodarone, 4,4 -diethylaminoethoxyhexestrol, and perhexiline are cationic amphiphilic drugs. They have both a lipophiUc moiety and an amine functimi, which can become protonated and thus become positively charged. This cationic amphiphilic structure interferes with both lysosomal and mitochondrial functiOTi, explaining why the three drugs can cause both phospholipidosis and steatosis or steatohepatitis (Pessayre et al. 2001). 

Fig. 16 Effects of amiodarone, perhexiline, and diethylaminoethoxyhexestrol (DEAEH) on mitochondrial function. After crossing the outer membrane, the uncharged secondary or tertiary amine (A) of amiodarone, perhexiline, or diethylaminoethoxyhexestrol (DEAEH) is protonated in the acidic intermembrane space. The positively charged molecule (AH ) is then electrophoretically pushed by the mitochondrial membrane potential into the matrix. High intramitochondrial concentrations inhibit both B-oxidation (causing steatosis) and oxidative phosphorylation, thus causing the accumulation of electrons in the respiratory chain and increasing the mitochondrial formation of ROS. The latter oxidize fat deposits, causing lipid peroxidation, which, together with ROS-induced cytokine production, could cause steatohepatitis.

Amiodarone has been associated with steatohepadtis with advanced fibrosis, presenting with hepatic decompensation and portal hypertension, with ascites and recurrent hemorrhage from esophageal varices [42 ]. There was marked histological similarity between amiodarone-induced liver disease and alcoholic and non-alcoholic steatohepatitis. 

Raja K, Thung SN, Fiel MI, Chang C. Drug-induced steatohepatitis leading to cirrhosis long-term toxicity of amiodarone use. Semin Liver Dis 2009 29(4) 423-8. 

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