American Journal of Therapeutics 23, e260–e263 (2016)

Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature Chia-Chi Chen, MSCP1 and Chien-Chih Wu, MSCP1,2*

Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (#200 mg/d) could be tried and should monitor liver function regularly. Keywords: amiodarone, hepatotoxicity, adverse drug reaction

INTRODUCTION Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit (ICU). Its half-life is long and can be administered intravenously or orally with loading dose.1–5 Amiodarone is associated with various adverse effects. The most common adverse effects during long-term therapy include thyroid dysfunction, hepatic toxicities, pulmonary toxicities, and corneal microdeposits. Compared with oral amiodarone, intravenous (IV) amiodarone can lead to phlebitis at the injection site, sweating, heat sensation,


Department of Pharmacy, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan; and 2Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. The authors have no conflicts of interest to declare. *Address for correspondence: Director, Clinical Pharmacy Department, National Taiwan University, 7 Chung Shan South Road, Taipei, Taiwan. E-mail: [email protected]

nausea, and severe hypotension. Long-term administration of amiodarone is associated with 2 different types of liver toxicity. Asymptomatic elevation of transaminase is frequent and is usually transient. Symptomatic liver injury usually associated with IV amiodarone use is rare but potentially fatal.1,5–8 In this study, we describe the case of a patient who suffered from IV amiodarone-related acute hepatotoxicity in the ICU and was successfully treated by oral amiodarone afterward.

CASE REPORT This 57-year-old man had a medical history of diabetes mellitus, hypertension, end-stage renal disease under peritoneal dialysis, congestive heart failure, and chronic hepatitis B. He was admitted because of progressive exertional dyspnea and generalized weakness. Peritoneal dialysis dialysate was adjusted to correct his fluid overload first, and coronary artery catheterization was arranged. Oral amiodarone was prescribed for atrial fibrillation under the cardiologist’s suggestion.

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Acute Hepatotoxicity of Intravenous Amiodarone


Table 1. Clinical course after intravenous and oral amiodarone use.



AST (,37 U/L)

ALT (M , 41 U/L)

T-bil (0.2–1.2 mg/dL)

ALP (60–220 U/L)

GGT (0–52 IU/L)

22 21 0 1 2 3 4 6 9 11 14 18 19 23 53

100 mg, QD PO 100 mg, QD PO 150 mg once IF 1350 mg, QD cIF 100 mg, PO for 1 dose — — — — — — 100 mg, BID PO 100 mg, BID PO 100 mg, BID PO 100 mg, BID PO

— 29 — — 4374 1042 480 186 37 23 20 — 25 26 29

— 77 — — .2500 .2500 2200 1101 419 204 88 — 4 4 17

— — — — 0.77 0.97 0.81 0.82 — 0.74 — — 0.76 — —

— — — — 108 108 — — — — — — — — —

— — — — 85 99 — — — — — — — — —

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransaminase; BID, twice a day; cIF, continuous infusion; D0, the start day of intravenous amiodarone; GGT, gamma-glutamyl transpeptidase; PO, orally; QD, everyday; T-bil, total bilirubin.

Transient ventricular tachycardia (VT) was noted later and he complained of persistent chest tightness. He was transferred to the ICU because of unstable hemodynamics. Mexiletine was added for VT and oral amiodarone was shifted to IV form. Ventricular rate was well controlled under IV amiodarone, and IV form was shifted to oral form after 1 day use. However, tremendous AST/ALT elevation was incidentally found (Table 1) within 24 hours after IV amiodarone use. Amiodarone was discontinued immediately because of its possible hepatotoxicity. Hepatitis B viral load were also checked to rule out hepatitis B flare up. On the following days, AST/ALT improved gradually. The hepatocellular injury was probably because of IV amiodarone. Hepatitis B flare up was not likely because of low viral load (36 IU/mL). Ischemia-related liver injury was ruled out due to no shock event during this period and no other organ damage. Aspirin, clopidogrel, mexiletine, and isosorbide mononitrate were used simultaneously; however, all these agents did not show obvious hepatotoxicity. Short-run VT was noted again later and lidocaine was chosen for VT this time to avoid amiodarone use. After lidocaine use, adverse effects with blurred vision, slurred speech, and general weakness developed, so the dose was tapered. Coronary artery catheterization was performed in the ICU and it revealed severe calcification over 3 vessel territories. For his coronary arterial disease, coronary artery bypass graft

(CABG) was performed. After CABG, unstable hemodynamic status with frequent VT was noted under mexiletine use, so oral amiodarone was rechallenged. Liver enzyme was closely followed up after oral amiodarone use and no significant hepatotoxicity occurred afterward.

DISCUSSION Abnormal liver function is common in ICU, and it is very important to differentiate the cause. The etiologies consist of viral hepatitis, ischemia, autoimmune diseases, and medications.9 The incidence rate of acute hepatotoxicity of IV amiodarone is very rare (,0.01%), and it is often ignored. We reviewed the literature published after 2000 and written in English. Only literature with full text were included. Finally, 8 cases were collected (Table 2).8,10–14 According to the currently available documentation, hepatotoxicity usually occurs within 24 hours after starting IV amiodarone administration, but sometimes after more than 3 days.8 It usually recovers gradually after discontinuing IV amiodarone. The toxicity was caused by hepatocellular injury, rather than cholestasis. Three of these 8 cases resumed oral amiodarone later and were uneventful. The mechanism of hepatotoxicity of IV amiodarone is still unclear. Some reports showed that the toxicity of amiodarone is from mitochondrial damage.15 Because American Journal of Therapeutics (2016) 23(1)

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American Journal of Therapeutics (2016) 23(1)

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransaminase; AF, atrial fibrillation; CAD, coronary artery disease; DCMP, dilated cardiomyopathy; DM, diabetes mellitus; F, female; HF, heart failure; HTN, hypertension; M, male; N/A, not available; T-bil, total bilirubin; VHD, valvular heart disease.

(2) 7d 1881/1048 ,1 d Hypothyroidism, HTN, depression F 2013 Nasser et al14


F 2012 Kickers et al13

5 mo

2005 2012 Maker et al11 Rao et al12

2002 2005 Gregory et al10 Ratz Bravo et al8


(2) .14 d 1212/1056

Junctional ectopic tachycardia AF



(+) (2) (2) (+) (+) (2) N/A 1.52/47 1.05/201 2.51/63 N/A 2.63/194 1099/759 2454/3822 12,795/5975 1901/1590 739/1303 –/4578 ,1 d ,1 d ,1 d ,1 d 5d ,1 d VT AF AF AF AF AF

N/A CAD, HF HTN, DM, hyperlipidemia CAD, VHD, HF Burn Old inferior infarct, DCMP, HF, HTN Down syndrome, congenital heart defect F F F M M M

Year Reference

74 66 73 57 54 44


Underlying disease



T-bil (mg/dL)/ Time to ALP (U/L) recovery AST/ALT (U/L) Age (yr)

Table 2. Case reports summary of intravenous amiodarone-related hepatitis.

6d .14 d .14 d 25 d 28 d 10 d

Chen and Wu Oral amiodarone rechallenge


resuming oral amiodarone did not worsen hepatic injury in some of the cases, Rhodes et al postulated first that the cause of hepatotoxicity may not be amiodarone itself, but other contents in amiodarone infusion.8,14,16,17 Amiodarone is lipophilic. To obtain stable solutions of intravenous amiodarone, the drug is dissolved in a mixture of polysorbate 80 and a small amount of benzyl alcohol.6 Polysorbate 80 has been implicated in the E-ferol syndrome. In the 1980s, unexplained hepatomegaly, splenomegaly, cholestatic jaundice, renal failure, and thrombocytopenia were reported in many lowbirthweight infants. It is so-called E-ferol syndrome because it is associated with the use of an intravenous preparation of vitamin E, E-ferol, which contains polysorbate 80 and polysorbate 20. The liver histology in E-ferol syndrome shows Kupffer cell exfoliation, centrilobular accumulation of cellular debris, and panlobular congestion, especially in the central areas. The polysorbates are thought to be responsible for these changes.18–25 The clinical features of the E-ferol syndrome are similar to those found in liver toxicity due to intravenous amiodarone. This suggests that the hepatic insult may be due to the polysorbate rather than amiodarone.8,14,16,17 Dose may be another important factor to cause hyperacute hepatitis. In cases resuming oral amiodarone uneventfully, the dose of oral form is much less than IV form.8 In this case, the daily dose of IV form is 1500 mg and the daily dose of oral form was just 200 mg. Amiodarone is mainly metabolized by cytochrome P450 enzymes (CYP3A4 and CYP2C8). N-desethylamiodarone, an active metabolite of amiodarone, was considered to be the culprit of hepatotoxicity.15 Besides, amiodarone-related mitochondrial toxicity is also dose dependent.26 Therefore, if high dose of oral amiodarone is given, it is still possible to cause hyperacute hepatitis, which seemed to occur only in IV form. As a result, health care provider should be aware of the possibility of IV amiodarone to cause hyperacute hepatitis. When IV amiodarone was prescribed, closely monitoring liver enzyme is highly suggested. In patients with hepatic injury, IV amiodarone should be stopped immediately and not be reintroduced again. If there is no alternative and amiodarone is still needed clinically, oral form may be used with lower dose (#200 mg/d) by monitoring liver function closely.8,16,27

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American Journal of Therapeutics (2016) 23(1)

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care uni...
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