Amiodarone is an antiarrhythmic drug widely prescribed for both supraventricular and ventricular arrhythmias; however, this drug has been associated with a wide range of adverse effects [1], [2] involving multiple organs, including the liver, lungs, thyroid, heart, skin, gastrointestinal tract, and eyes. Amiodarone is highly lipophilic and can accumulate in adipose tissue, resulting in a lengthy half-life of around 100 to 120 days and a very wide distribution throughout the body; thus, amiodarone can exert its effects for an extended period of time even after the drug has been withdrawn. Patients taking amiodarone can experience a range of complications, from mild effects requiring no intervention to severe life-threatening complications requiring drug withdrawal and supportive measures. Therefore, patients on amiodarone should be monitored frequently for prompt identification of adverse effects [3], [4].

Amiodarone-induced liver injury (AILI) can range from asymptomatic elevation of aminotransferases to severe or even fatal hepatitis and cirrhosis. While asymptomatic aminotransferase elevation has been reported to occur in 15% to 25% of patients on amiodarone, the incidence of clinically apparent liver injury is low, and most patients do not require drug cessation due to hepatic side effects [5]. According to a recent meta-analysis, however, the relative risk of developing hepatotoxicity with amiodarone compared to placebo is more than two-fold [6], and liver function tests are recommended at baseline and regularly every 6 months afterward to monitor for developing toxicity [7].

Liver biopsy is not routinely performed to diagnose AILI. Rather, the drug is discontinued based on clinical judgement when liver enzymes are elevated more than twice the baseline [7]. Variable histologic features have been reported in cases where liver biopsy analysis was performed for patients with AILI. In most cases, AILI-association histologic features have been reported to resemble alcohol-associated steatohepatitis, sometimes referred to as “pseudoalcoholic hepatitis,” with features of steatosis, ballooning degeneration with Mallory-Denk bodies, mild lobular inflammation, and centrilobular sinusoidal and portal fibrosis. Various other histologic features such as cholestatic hepatitis, acute hepatitis, granulomatous inflammation, and cirrhosis have also been reported in association with amiodarone use. Notably, studies have also emphasized the significance of lamellated lysosomal inclusions, a unique characteristic and ultrastructural finding used for the diagnosis of AILI. Electron microscopy for high-resolution tissue analysis is not routinely performed with liver biopsy samples; therefore, the diagnosis of AILI relies on analysis of morphologic and clinical features alone.

Because we have only a cursory understanding of the specific effects of amiodarone on liver tissue within the context of AILI, we conducted a retrospective cross-sectional study of biopsy samples from patients on amiodarone who underwent liver biopsy for investigation of liver disease. Our aims were to determine whether ballooned hepatocytes occur within specific regions of the liver and to characterize the predominant histologic features of liver biopsy specimens from patients on amiodarone. We also propose a morphologic criterion for diagnosing AILI that may help clinicians determine an appropriate diagnosis and offer a tailored therapeutic strategy that avoids further drug-associated complications and improves outcomes in patients taking amiodarone.