Case Report

Acute liver injury after intravenous amiodarone^? A case report

Abstract

Acute hepatotoxicity is a rare but potentially fatal complication of amiodarone use. Although oral long-term use of the drug is frequently complicated by an asymptomatic rise in serum aminotransferase concentrations, acute hepato- toxicity during intravenous loading is much less frequent and potentially fatal. We report a case of liver injury after intravenous administration in a patient with atrial fibrillation.

An 82-year-old woman was admitted to the emergency department because of worsening dyspnea and palpitations. Her medical history included hypertension, obesity (body mass index, 31.25 kg/m²), long-standing coronary artery disease managed with medical therapy, and a recent episode of traumatic bone fracture complicated by deep vein thrombosis. No history of alcohol abuse or acetaminophen intake was reported. A recent echocardiography had shown a mildly depressed ejection fraction with left ventricular and biAtrial enlargement. Her medication at hospital admission was carvedilol 6.25 mg twice per day, furosemide 25 mg twice per day, spironolactone 50 mg per day, and warfarin. On physical examination, the temperature was normal, blood pressure was 150/95 mm Hg, the pulse was 120 beats/min arrhythmic, and the percutaneous peripheral oxygen saturation was 97% on air; bilateral rales were found on chest auscultation, whereas the remainder of the examination was normal. The electrocardiogram confirmed the presence of atrial fibrillation at an average rate of 140/min and left axis deviation, but no signs of Ischemic injury. Blood tests, including markers of cholestasis

and hepatic cytolysis, were normal.

A rhythm-control strategy was chosen according to current guidelines, and the patient was started on the amiodarone regimen protocol approved at our institution [1]. After the initial loading dose (150 mg over 10 minutes), amiodarone was administered at 45 mg/h to deliver approximately 1250 mg in the first 24 hours. At the control blood tests performed 18 hours after starting amiodarone, a marked increase in aminotrans-

^? No sources of support in the form of equipment, drugs, or grants.

ferase was found (aspartate aminotransferase, 2735 U/L; alanine aminotransferase, 1614 U/L) together with prolonga- tion of the prothrombin time (International normalized ratio INR, 4.47), whereas the markers of cholestasis were unaffected. Emergency ultrasound showed no biliary ductal dilatation with normal appearance of the liver.

Amiodarone infusion and warfarin administration were stopped immediately; nonetheless, the patient received a transfusion of fresh frozen plasma because of further lengthening of the prothrombin time at subsequent controls (INR, 5.47). Upon getting in touch with the toxicologic department and notwithstanding the absence of a history of acetaminophen uptake, it was decided to start infusion of N-acetilcysteine according to the following schedule: 15 mg/kg in 90 minutes followed by a continuous infusion of

300 mg/kg per day until aminotransferase values were below 200 U/L.

Over the following days, the patient received a Combination therapy of digoxin and carvedilol for heart Rate control. Aminotransferase values dropped steadily and got back to normal after 9 days. The patient was discharged without complications.

Amiodarone is a class III antiarrhythmic agent widely used in clinical practise owing to its efficacy in suppressing both supraventricular and ventricular arrhythmias; neverthe- less, its use is associated with frequent adverse effects that differ according to the route and time of administration. In an acute setting, given the large volume of distribution of the drug, intravenous administration is necessary to achieve therapeutic Blood concentrations in short time.

Although oral long-term use of the drug is frequently complicated by an asymptomatic rise in serum amino- transferase concentrations (up to 25% of patients), with only less than 3% developing symptomatic hepatitis, acute hepatotoxicity during intravenous loading is much less frequent. In our case, the causality link between intravenous amiodarone exposure and acute liver injury has been inferred from the fulfilment of the major characteristics constituting the drug signature of amiodar- one-induced acute hepatotoxicity: liver test abnormalities occurring within 24 hours after starting amiodarone administration; predominant increase of aminotransferases over cholestatic markers (which actually did not change); and lengthening of the prothrombin time (favored by concomitant warfarin administration) [2]. No history of

0735-6757/$ - see front matter (C) 2011

843.e6 Case Report

alcohol abuse or acetaminophen intake was reported. Neither severe congestive heart failure nor severe hypotension being able to explain a congestive or shock hepatopathy was observed. Among the patient’s medica- tions taken before hospital admission, only carvedilol has been reported to rarely induce elevated aminotransferases [3]. Nonetheless, given the timing of the event and the previous long-term exposure to carvedilol, this was considered an unlikely cause of liver toxicity, and the drug was not stopped.

For acute amiodarone-induced hepatotoxicity, liver injury is rapidly reversible after discontinuation of amiodarone infusion, although fatal outcomes have been reported [4]. Treatment is mainly supportive. A recent study has shown evidence in favor of the use of N-acetylcysteine in acute liver injury beyond Acetaminophen intoxication; this might pave the way for more widespread use of this compound in this clinical scenario [5]. Characteristically, liver injury does not recur upon reintroduction of amiodarone by the oral route; yet in this case, it was decided for a rate-control strategy not including the readministration of the drug.

To conclude, acute intravenous amiodarone-induced hepatotoxicity is a rare but potentially fatal complication whose frequency is expected to increase with the ever wider use of the intravenous route of administration. Emergency physicians and cardiologists should be aware of it and check for its occurrence by performing serial liver tests.

Andrea Verhovez Fabrizio Elia MD high dependency unit

S. Giovanni Bosco Hospital P.za Donatore del Sangue 3. 10154, Torino, Italy E-mail addresses: [email protected]

[email protected]

Alessandra Riva MD

Emergency Medicine

S. Giovanni Bosco Hospital P.za Donatore del Sangue 3. 10154, Torino, Italy

E-mail address: [email protected]

Giovanni Ferrari MD Franco Apra MD

High Dependency Unit

S. Giovanni Bosco Hospital P.za Donatore del Sangue 3. 10154, Torino, Italy E-mail addresses: [email protected]

[email protected]

doi:10.1016/j.ajem.2010.03.035

References

1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257-354.
2. Ratz Bravo AE, Drewe J, Schlienger RG, et al. Hepatotoxicity during rapid intravenous loading with amiodarone: description of three cases and review of the literature. Crit Care Med 2005;33:128-34.
3. Hagmeyer KO, Stein J. Hepatotoxicity associated with carvedilol. Ann Pharmacother 2001;35:1364-6.
4. Giannattasio F, Salvio A, Varriale M, et al. 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;17:180-4.
5. Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute Liver failure. Gastroenterology 2009;137:856-64.