Drug-Induced Steatohepatitis Leading to Cirrhosis: Long-Term Toxicity of Amiodarone Use

ABSTRACT

Nonalcoholic steatosis/steatohepatitis is the most common cause for abnormal liver chemistries. Apart from metabolic syndrome, drugs may also lead to development of steatohepatitis that may, rarely, progress to cirrhosis and portal hypertension. We discuss a case of amiodarone-induced steatohepatitis with advanced fibrosis, presenting with hepatic decompensation and portal hypertension manifesting as ascites and recurrent esophageal variceal hemorrhage. Amiodarone is a lipophilic drug that concentrates in the liver and usually, over a period of time, leads to toxicity related to drug accumulation. There is marked histological similarity between amiodarone-induced liver disease and alcoholic and nonalcoholic steatohepatitis. The clinical manifestations of amiodarone-induced hepatotoxicity and the mechanism of toxicity are also discussed.

KEYWORDS

Steatohepatitis - cirrhosis - hepatotoxicity - amiodarone - phospholipidosis

REFERENCES

• 1 Babatin M, Lee S S, Pollak P T. Amiodarone hepatotoxicity.  Curr Vasc Pharmacol. 2008;  6(3) 228-236
• 2 Lewis J H, Ranard R C, Caruso A et al.. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.  Hepatology. 1989;  9 679-685
• 3 Stravitz R T, Sanyal A J. Drug-induced steatohepatitis.  Clin Liver Dis. 2003;  7(2) 435-451
• 4 Vorperian V R, Havighurst T C, Miller S, January C T. Adverse effects of low dose amiodarone: a meta-analysis.  J Am Coll Cardiol. 1997;  30(3) 791-798
• 5 Llanos L, Moreu R, Peiró A M et al.. Causality assessment of liver injury after chronic oral amiodarone intake.  Pharmacoepidemiol Drug Saf. 2009;  18(4) 291-300
• 6 Kum L C, Chan W W, Hui H H et al.. Prevalence of amiodarone-related hepatotoxicity in 720 Chinese patients with or without baseline liver dysfunction.  Clin Cardiol. 2006;  29(7) 295-299
• 7 Giannattasio F, Salvio A, Varriale M, Picciotto F P, Di Costanzo G G, Visconti M. Three cases of severe acute hepatitis after parenteral administration of amiodarone: the active ingredient is not the only agent responsible for hepatotoxicity.  Ann Ital Med Int. 2002;  17(3) 180-184
• 8 Rhodes A, Eastwood J B, Smith S A. Early acute hepatitis with parenteral amiodarone: a toxic effect of the vehicle?.  Gut. 1993;  34(4) 565-566
• 9 James P R, Hardman S M. Acute hepatitis complicating parenteral amiodarone does not preclude subsequent oral therapy.  Heart. 1997;  77(6) 583-584
• 10 Fogoros R N, Anderson K P, Winkle R A, Swerdlow C D, Mason J W. Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias.  Circulation. 1983;  68(1) 88-94
• 11 Robinson K, Mulrow J P, Rowland E, McKenna W J. Long-term effects of amiodarone on hepatic function.  Am J Cardiol. 1989;  64(1) 95-96
• 12 Chang C C, Petrelli M, Tomashefski Jr J F, McCullough A J. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature.  Arch Pathol Lab Med. 1999;  123(3) 251-256
• 13 Flaharty K K, Chase S L, Yaghsezian H M, Rubin R. Hepatotoxicity associated with amiodarone therapy.  Pharmacotherapy. 1989;  9(1) 39-44
• 14 Hilleman D, Miller M A, Parker R, Doering P, Pieper J A. Optimal management of amiodarone therapy: efficacy and side effects.  Pharmacotherapy. 1998;  18(6 Pt 2) 138S-145S
• 15 Bach N, Schultz B L, Cohen L B et al.. Amiodarone hepatotoxicity: progression from steatosis to cirrhosis.  Mt Sinai J Med. 1989;  56(4) 293-296
• 16 Brien J F, Jimmo S, Brennan F J, Ford S E, Armstrong P W. Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues.  Can J Physiol Pharmacol. 1987;  65(3) 360-364
• 17 Lewis J H, Mullick F, Ishak K G et al.. Histopathologic analysis of suspected amiodarone hepatotoxicity.  Hum Pathol. 1990;  21(1) 59-67
• 18 Rigas B, Rosenfeld L E, Barwick K W et al.. Amiodarone hepatotoxicity. A clinicopathologic study of five patients.  Ann Intern Med. 1986;  104(3) 348-351
• 19 Puli S R, Fraley M A, Puli V, Kuperman A B, Alpert M A. Hepatic cirrhosis caused by low-dose oral amiodarone therapy.  Am J Med Sci. 2005;  330(5) 257-261
• 20 Jones D B, Mullick F G, Hoofnagle J H, Baranski B. Reye's syndrome-like illness in a patient receiving amiodarone.  Am J Gastroenterol. 1988;  83(9) 967-969
• 21 Guigui B, Perrot S, Berry J P et al.. Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.  Hepatology. 1988;  8(5) 1063-1068
• 22 Pirovino M, Müller O, Zysset T, Honegger U. Amiodarone-induced hepatic phospholipidosis: correlation of morphological and biochemical findings in an animal model.  Hepatology. 1988;  8(3) 591-598
• 23 Kaufmann P, Török M, Hänni A, Roberts P, Gasser R, Krähenbühl S. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity.  Hepatology. 2005;  41(4) 925-935
• 24 Fromenty B, Fisch C, Berson A, Letteron P, Larrey D, Pessayre D. Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II.  J Pharmacol Exp Ther. 1990;  255(3) 1377-1384
• 25 Fromenty B, Fisch C, Labbe G et al.. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.  J Pharmacol Exp Ther. 1990;  255(3) 1371-1376