Introduction. Amiodarone has been used for more than 5 decades for the treatment of various tachyarrhythmias and previously for the treatment of refractory angina. There are multiple well-established side effects of amiodarone. However, amiodarone-induced cirrhosis (AIC) of liver is an underrecognized complication. Methods. A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, identified 37 reported cases of which 30 were used in this analysis. Patients were divided into 2 subsets, survivors versus nonsurvivors, at 5 months. Results. Aspartate aminotransferase was significantly lower ( ) in patients who survived at 5-months (mean 103.33？IU/L) compared to nonsurvivors (mean 216.88？IU/L). There was no statistical difference in the levels of prothrombin time, total bilirubin, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, cumulative dose, and latency period between the two groups. The prevalence of DM, HTN, HLD, CAD, and CHF was similar in the two groups. None of the above-mentioned variables could be identified as a predictor of survival at 5 months. Conclusion. AIC carries a mortality risk of 60% at 5 months once the diagnosis is established. Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC. 1. Introduction Amiodarone has been used since the 1960s for the management of various tachyarrhythmias and in the past for refractory angina. There are multiple reported and well-established side effects of amiodarone therapy such as effects on the thyroid, skin, lungs, nerves, and cornea. The effect of amiodarone on the liver resulting in hepatotoxicity is a recognized complication of amiodarone, but this hepatotoxicity leading to cirrhosis of the liver is unfortunately an underrecognized side effect. Little has been written on amiodarone-induced cirrhosis (AIC) of the liver due to its rarity [1–4]. The purpose of this paper is to review what we know so far about AIC of the liver. 2. Materials and Methods 2.1. Selection of Studies A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, was performed; 37 reported cases were identified (Table 1) of which 30 were used in this analysis. We also searched the reference lists of all reported cases to identify citations that were not identified during the initial search. Data that were extracted for each patient included age, gender, latency period in years, whether ≥200？mg/day amiodarone dosage
References
[1]
J. H. Lewis, R. C. Ranard, A. Caruso et al., “Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients,” Hepatology, vol. 9, no. 5, pp. 679–685, 1989.
[2]
S. R. Puli, M. A. Fraley, V. Puli, A. B. Kuperman, and M. A. Alpert, “Hepatic cirrhosis caused by low-dose oral amiodarone therapy,” American Journal of the Medical Sciences, vol. 330, no. 5, pp. 257–261, 2005.
[3]
B. Guigui, S. Perrot, J. P. Berry et al., “Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease,” Hepatology, vol. 8, no. 5, pp. 1063–1068, 1988.
[4]
J. H. Lewis, F. Mullick, K. G. Ishak et al., “Histopathologic analysis of suspected amiodarone hepatotoxicity,” Human Pathology, vol. 21, no. 1, pp. 59–67, 1990.
[5]
M. Atiq, J. C. Davis, L. W. Lamps, S. S. Beland, and J. E. Rose, “Amiodarone induced liver cirrhosis. Report of two cases,” Journal of Gastrointestinal and Liver Diseases, vol. 18, no. 2, pp. 233–235, 2009.
[6]
B. Rigas, L. E. Rosenfeld, and K. W. Barwick, “Amiodarone hepatotoxicity. A clinicopathologic study of five patients,” Annals of Internal Medicine, vol. 104, no. 3, pp. 348–351, 1986.
[7]
D. Capron-Chivrac, N. Reix, C. Quenum, and J. P. Capron, “Amiodarone hepatopathy. Study of a case and review of the literature,” Gastroenterologie Clinique et Biologique, vol. 9, no. 6-7, pp. 535–539, 1985.
[8]
N. B. Chaabane, O. Hellara, L. Safer et al., “Cirrhosis with increased density of the liver: amiodarone-induced hepatotoxicity,” Tunisie Medicale, vol. 90, no. 6, pp. 487–488, 2012.
[9]
http://livertox.nih.gov/Amiodarone.htm.
[10]
M. Richer and S. Robert, “Fatal hepatotoxicity following oral administration of amiodarone,” Annals of Pharmacotherapy, vol. 29, no. 6, pp. 582–586, 1995.
[11]
N. H. Gilinsky, G. W. Briscoe, and C. S. Kuo, “Fatal amiodarone hepatoxicity,” American Journal of Gastroenterology, vol. 83, no. 2, pp. 161–163, 1988.
[12]
K. Tordjman, I. Katz, M. Brusztyn, and T. Rosenthal, “Amiodarone and the liver,” Annals of Internal Medicine, vol. 102, no. 3, pp. 411–412, 1985.
[13]
J. M. Rene, J. Buenestado, B. Pais, and M. C. Pinol, “Cirrosis causada por amiodarona,” Revista Espanola de Enfermedades Digestivas, vol. 87, no. 5, pp. 399–402, 1995.
[14]
A. Singhal, P. Ghosh, and S. A. Khan, “Low dose amiodarone causing pseudo-alcoholic cirrhosis,” Age and Ageing, vol. 32, no. 2, pp. 224–225, 2003.
[15]
N. Bach, B. L. Schultz, L. B. Cohen et al., “Amiodarone hepatotoxicity: progression from steatosis to cirrhosis,” Mount Sinai Journal of Medicine, vol. 56, no. 4, pp. 293–296, 1989.
[16]
R. Martinez, E. Saperas, J. Vilaseca, P. Tornos, and H. Allende, “Cirrosis hepatica inducida por amiodarona,” Gastroenterologia y Hepatologia, vol. 17, no. 9, pp. 482–484, 1994.
[17]
？. ？oban, S. K？klü, H. Sencer, F. Ekiz, and N. ？rmeci, “Low dose amiodarone associated cirrhosis,” Journal of Gastroenterology and Hepatology, vol. 22, no. 1, pp. 140–141, 2007.
[18]
H. Oikawa, C. Maesawa, R. Sato et al., “Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report,” World Journal of Gastroenterology, vol. 11, no. 34, pp. 5394–5397, 2005.
[19]
A. Lamproye, J. Ramos, D. Larrey, and J. Belaiche, “Pseudo-alcoholic hepatitis and cirrhosis caused by Amiodarone (Cordarone),” Revue Médicale de Liège, vol. 53, pp. 120–124, 1998.
[20]
G. Babany, A. Mallat, and E. S. Zafrani, “Chronic liver disease after low daily doses of amiodarone. Report of three cases,” Journal of Hepatology, vol. 3, no. 2, pp. 228–232, 1986.
[21]
H. M. Rinder, J. C. Love, and R. Wexler, “Amiodarone hepatotoxicity,” The New England Journal of Medicine, vol. 314, no. 5, pp. 318–319, 1986.
[22]
N. A. Shepherd, A. M. Dawson, P. R. Crocker, and D. A. Levison, “Granular cells as a marker of early amiodarone hepatotoxicity: a pathological and analytical study,” Journal of Clinical Pathology, vol. 40, no. 4, pp. 418–423, 1987.
[23]
R. Jeyamalar, R. Pathmanathan, D. Wong, and P. Kannan, “Hepatotoxicity of amiodarone,” Annals of the Academy of Medicine Singapore, vol. 21, no. 6, pp. 838–840, 1992.
[24]
S. Ishida, M. Sugino, T. Hosokawa et al., “Amiodarone-induced liver cirrhosis and parkinsonism: a case report,” Clinical Neuropathology, vol. 29, no. 2, pp. 84–88, 2010.
[25]
R. F. Harrison and E. Elias, “Amiodarone-associated cirrhosis with hepatic and lymph node granulomas,” Histopathology, vol. 22, no. 1, pp. 80–82, 1993.
[26]
K. Raja, S. N. Thung, M. I. Fiel, and C. Chang, “Drug-induced steatohepatitis leading to cirrhosis: long-term toxicity of amiodarone use,” Seminars in Liver Disease, vol. 29, no. 4, pp. 423–428, 2009.
[27]
K. K. Flaharty, S. L. Chase, H. M. Yaghsezian, and R. Rubin, “Hepatotoxicity associated with amiodarone therapy,” Pharmacotherapy, vol. 9, no. 1, pp. 39–44, 1989.
[28]
Y. Snir, N. Pick, K. Riesenberg, I. Yanai-Inbar, H. Zirkin, and F. Schlaeffer, “Fatal hepatic failure due to prolonged amiodarone treatment,” Journal of Clinical Gastroenterology, vol. 20, no. 3, pp. 265–266, 1995.
[29]
C. C. Chang, M. Petrelli, J. F. Tomashefski, and A. J. McCullough, “Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature,” Archives of Pathology and Laboratory Medicine, vol. 123, no. 3, pp. 251–256, 1999.
[30]
P. S. Sung and S. K. Yoon, “Amiodarone hepatotoxicity,” Hepatology, vol. 55, no. 1, pp. 325–326, 2012.
[31]
S. Poucell, J. Ireton, and P. Valencia-Mayoral, “Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies,” Gastroenterology, vol. 86, no. 5 I, pp. 926–936, 1984.
[32]
Z. Salti, P. Cloche, P. Weber, G. Houssemand, and F. Vollmer, “A case of amiodarone-induced cholestatic hepatitis,” Annales de Cardiologie et d'Angeiologie, vol. 38, no. 1, pp. 13–16, 1989.
[33]
S. Chandraprakasam and M. Whitcraft, “Pseudo-alcoholic cirrhosis: an interesting case of amiodarone induced hepatotoxicity,” The Internet Journal of Gastroenterology, vol. 11, no. 1, 2012.
[34]
P. K. Lim, P. N. Trewby, G. C. A. Storey, and D. W. Holt, “Neuropathy and fatal hepatitis in a patient receiving amiodarone,” British Medical Journal, vol. 288, no. 6431, pp. 1638–1639, 1984.
[35]
K. Itostetler, M. Reasor, and B. W. Frazee, “Mechanisms of amiodarone toxicity: inhibition of phospholipase A,” Circulation, vol. 79, p. 240, 1984.
[36]
M. F. Heath, F. R. Costa-Jussa, J. M. Jacobs, and W. Jacobson, “The induction of pulmonary phospholipidosis and the inhibition of lysosomal phospholipases by amiodarone,” British Journal of Experimental Pathology, vol. 66, no. 4, pp. 391–397, 1985.
[37]
R. Luallmann-Rauch and G. H. Reil, “Chlorphentermine-induced lipidosis-like ultrastructural alterations in lungs and adrenal glands of several species,” Toxicology and Applied Pharmacology, vol. 30, pp. 408–421, 1974.
[38]
M. Pirovino, O. Muller, T. Zysset, and U. Honegger, “Amiodarone-induced hepatic phospholipidosis: correlation of morphological and biochemical findings in an animal model,” Hepatology, vol. 8, no. 3, pp. 591–598, 1988.
[39]
P. Yagupsky, E. Gazala, and S. Sofer, “Fatal hepatic failure and encephalopathy associated with amiodarone therapy,” Journal of Pediatrics, vol. 107, no. 6, pp. 967–970, 1985.
[40]
A. Vereckei, E. Fehér, I. Gy？rgy et al., “Possibilities of antioxidant therapy in the prevention of side effects of amiodarone,” Orvosi Hetilap, vol. 132, no. 23, pp. 1265–1268, 1991.
[41]
H. W. M. Breuer, W. Bossek, C. Haferland, M. Schmidt, H. Neumann, and J. Gruszka, “Amiodarone-induced severe hepatitis mediated by immunological mechanisms,” International Journal of Clinical Pharmacology and Therapeutics, vol. 36, no. 6, pp. 350–352, 1998.
[42]
P. Kaufmann, M. T？r？k, A. H？nni, P. Roberts, R. Gasser, and S. Kr？henbühl, “Mechanisms of benzarone and benzbromarone-induced hepatic toxicity,” Hepatology, vol. 41, no. 4, pp. 925–935, 2005.
[43]
B. Fromenty, C. Fisch, G. Labbe et al., “Amiodarone inhibits the mitochondrial β-oxidation and fatty acids and produces microvesicular steatosis of the liver in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 255, no. 3, pp. 1371–1376, 1990.
[44]
B. Fromenty, C. Fisch, A. Berson, P. Letteron, D. Larrey, and D. Pessayre, “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,” Journal of Pharmacology and Experimental Therapeutics, vol. 255, no. 3, pp. 1377–1384, 1990.
[45]
P. T. Pollak, “How toxic is amiodarone to the liver?” Journal of Gastrointestinal and Liver Diseases, vol. 19, no. 1, pp. 11–13, 2010.
[46]
S. H. Yap, P. J. M. Rijntjes, H. J. Moshage, H. Croes, and P. H. K. Jap, “Amiodarone-induced lysosomal inclusions in primary cultures of human hepatocytes,” Gastroenterology, vol. 92, no. 1, pp. 272–273, 1987.
[47]
S. Kojima, S. Kojima, H. Ueno, M. Takeya, and H. Ogawa, “Increased density of the liver and amiodarone associated phospholipidosis,” Cardiol Res Pract, vol. 2009, Article ID 598940, 3 pages, 2009.
[48]
L. Llanos, R. Moreu, A. M. Peiró et al., “Causality assessment of liver injury after chronic oral amiodarone intake,” Pharmacoepidemiology and Drug Safety, vol. 18, no. 4, pp. 291–300, 2009.
[49]
J. Gill, R. C. Heel, and A. Fitton, “Amiodarone. An overview of its pharmacological properties, and review of its therapeutic use in cardiac arrhythmias,” Drugs, vol. 43, no. 1, pp. 69–110, 1992.
[50]
P. C. Adams, M. K. Bennett, and D. W. Holt, “Hepatic effects of amiodarone,” British Journal of Clinical Practice. Supplement, vol. 44, pp. 81–95, 1986.
[51]
J. B. Simon, P. N. Manley, J. F. Brien, and P. W. Armstrong, “Amiodarone hepatotoxicity simulating alcoholic liver disease,” The New England Journal of Medicine, vol. 311, no. 3, pp. 167–172, 1984.
[52]
J. F. Brien, S. Jimmo, and F. J. Brennan, “Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues,” Canadian Journal of Physiology and Pharmacology, vol. 65, no. 3, pp. 360–364, 1987.
[53]
P. Lettéron, A. Sutton, A. Mansouri, B. Fromenty, and D. Pessayre, “Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice,” Hepatology, vol. 38, no. 1, pp. 133–140, 2003.
[54]
N. Gluck, M. Fried, and R. Porat, “Acute amiodarone liver toxicity likely due to Ischemic hepatitis,” Israel Medical Association Journal, vol. 13, no. 12, pp. 748–752, 2011.
[55]
U. Klotz, “Antiarrhythmics: elimination and dosage considerations in hepatic impairment,” Clinical Pharmacokinetics, vol. 46, no. 12, pp. 985–996, 2007.
[56]
D. S. Pratt and M. M. Kaplan, “Evaluation of abnormal liver-enzyme results in asymptomatic patients,” The New England Journal of Medicine, vol. 342, no. 17, pp. 1266–1271, 2000.
[57]
W. Mattar, B. Juliar, I. Gradus-Pizlo, and P. Y. Kwo, “Amiodarone hepatotoxicity in the context of the metabolic syndrome and right-sided heart failure,” Journal of Gastrointestinal and Liver Diseases, vol. 18, no. 4, pp. 419–423, 2009.
[58]
M. Babatin, S. S. Lee, and P. T. Pollak, “Amiodarone hepatotoxicity,” Current Vascular Pharmacology, vol. 6, no. 3, pp. 228–236, 2008.
[59]
J. E. Tisdale, S. L. Follin, A. Ordelova, and C. R. Webb, “Risk factors for the development of specific noncardiovascular adverse effects associated with amiodarone,” Journal of Clinical Pharmacology, vol. 35, no. 4, pp. 351–356, 1995.
[60]
L. C. C. Kum, W. W. L. Chan, H. H. Y. Hui et al., “Prevalence of amiodarone-related hepatotoxicity in 720 Chinese patients with or without baseline liver dysfunction,” Clinical Cardiology, vol. 29, no. 7, pp. 295–299, 2006.
[61]
A. E. R？tz Bravo, J. Drewe, R. G. Schlienger, S. Kr？henbühl, H. Pargger, and W. Ummenhofer, “Hepatotoxicity during rapid intravenous loading with amiodarone: description of three cases and review of the literature,” Critical Care Medicine, vol. 33, no. 1, pp. 128–134, 2005.
[62]
P. T. Pollak and S. L. Shafer, “Use of population modeling to define rational monitoring of amiodarone hepatic effects,” Clinical Pharmacology and Therapeutics, vol. 75, no. 4, pp. 342–351, 2004.
[63]
C. Burgess, A. Blaikie, T. Ingham, G. Robinson, and S. Narasimhan, “Monitoring the use of amiodarone: compliance with guidelines,” Internal Medicine Journal, vol. 36, no. 5, pp. 289–293, 2006.
[64]
P. T. Pollak and Y. D. You, “Monitoring of hepatic function during amiodarone therapy,” American Journal of Cardiology, vol. 91, no. 5, pp. 613–616, 2003.
[65]
P. T. Pollak, A. D. Sharma, and S. G. Carruthers, “Relation of amiodarone hepatic and pulmonary toxicity to serum drug concentrations and superoxide dismutase activity,” American Journal of Cardiology, vol. 65, no. 18, pp. 1185–1191, 1990.
[66]
P. J. Podrid, “Amiodarone: reevaluation of an old drug,” Annals of Internal Medicine, vol. 122, no. 9, pp. 689–700, 1995.
