Case Report

Acute toxic hepatitis after amiodarone intravenous loading^B

intravenous amiodarone is the drug of choice for the management of atrial fibrillation in patients in unstable condition with known impairment of ventricular function. The most important adverse effects are hypotension, asystolic/cardiac arrest and/or electromechanical dissocia- tion, cardiogenic shock, congestive heart failure, bradycar- dia, and liver function test abnormalities. We report the case of acute toxic hepatitis in a 79-year-old woman with atrial fibrillation and severe congestive heart failure that occurred soon after administration of intravenous amiodarone. Even if we have no direct (eg, bioptic or autoptic) features of liver damage, the cause-effect relationship between amiodarone infusion and hepatitis seems to be probable (Naranjo Adverse drug reaction probability score, 7). Peculiarity is given by the very short latency time (6 hours) elapsed between infusion and high transaminase elevation (N100-fold).

Amiodarone is the drug of choice for the management of atrial fibrillation in patients in unstable condition with known impairment of ventricular function [1]. However, amiodarone hydrochloride, the intravenous form of amiodarone, shows a considerable interindividual variation in its response. Thus, the recommended starting dose of about 1000 mg over the first 24 hours has to be delivered with caution: a rapid infusion of 150 mg over the first 10 minutes, followed by slow infusion of 360 mg over the next 6 hours, and a further maintenance infusion of 540 mg over the remaining 18 hours [2]. The most important adverse effects are hypotension, asystolic/cardiac arrest and/or electromechanical dissociation, cardiogenic shock, congestive heart failure, bradycardia, and liver function test abnormalities. In controlled and unControlled clinical trials, liver function test abnormalities were observed in 3.9% of patients [2]. Acute hepatitis is a rare adverse effect of treatment with parenteral amiodarone and is usually reversible with discontinuation of the infusion, and maintenance treatment with oral amiodarone is possible also in patients who develop liver disease during intravenous loading [3].

Case report

A 79-year-old woman was admitted to the hospital complaining of nocturnal shortness of breath. Her medical

^B Supported, in part, by a scientific grant (Finanziamento per ricerca locale) from the University of Ferrara, Ferrara, Italy.

history included hypertension, previous acute myocardial infarction treated with coronary stenting, atrial fibrillation, severe heart failure (ejection fraction, 25%), type 2 diabetes mellitus, and chronic obstructive pulmonary disease. Vital signs were as follows: blood pressure, 120/80 mm Hg; pulse, 100 beats per minute; respiration, 20 breaths per minute; axillary temperature, 36.78C (96.48F), pulse oximetry, 94% on room air. Physical examination revealed arrhythmic heart beat with no heart murmur, and bilateral basal crepitations. Electrocardiogram showed atrial fibrillation and Left bundle branch block. Chest radiography showed cardiomegaly and initial signs of interstitium-alveolar stasis. Laboratory data were as follows: white blood cell count, 13800/mm³ with 68% neutrophils; hematocrit, 43.6%; hemoglobin, 13.8 g/ dL; platelets, 319000/mm³; sodium, 141 mEq/L; potassium,

4.47 mEq/L; chloride, 108 mEq/L; creatinine, 1.2 mg/dL; glucose, 220 mg/dL; aspartate aminotransferase, 15 U/L; prothrombin time (international normalized ratio), 1.80; fibrinogen, 365 mg/dL; erythrocyte sedimentation rate, 25 mm; troponin I, 0.19 ng/mL; myoglobin, 128 ng/mL. The result of urinalysis was normal. The patient was treated with digoxin, nitrates, aspirin, furosemide, and low-molec- ular-weight heparin. On the second night, she complained of severe acute dyspnea. Electrocardiogram showed atrial tachyfibrillation (N130 beats per minute). In consideration of the ventricular dilation with severe impairment of systolic contractility, an intravenous loading dose of amiodarone (Cordarone, Sanofi-Synthelabo, Milan, Italy) was given, starting (3:00 am) with 180 mg over the first 60 minutes, followed by slow infusion of 360 mg over the next 5 hours. Average heart rate was reduced (100 beats per minute), and dyspnea was reduced. The morning after, laboratory exam- ination revealed an important elevation of transaminases (Table 1), and amiodarone infusion was promptly stopped (9:00 am). Thus, total dose of amiodarone was 540 mg. Transaminases had their peak on the successive day, then started a progressive decrease (Fig. 1). However, a severe, worsening congestive heart failure, poorly responsive to medical therapy, lead to death on day 7 from admission.

Discussion

Many drugs may cause liver injury infrequently, and these reactions are considered idiosyncratic [4]. They occur at Therapeutic dose in 1 of every 1000 to 100000 patients, are

0735-6757/$ - see front matter D 2007

Table 1 Laboratory examination pattern
	Day 1, 1/26	Day 3, 1/28 (8:00 am)	Day 3, 1/28 (3:00 Pm)	Day 4, 1/29	Day 5, 1/30	Day 6, 1/31	Day 7, 2/1
AST (5-37 IU/L)	13	1568	3397	4202	2352	1164	581
ALT (5-40 IU/L)	15	1088	2060	3387	2387	1800	1260
Bilirubin, total	1.00	1.76	2.20	1.10	1.90	2.52	2.71
(0.16-1.20 mg/dL)
Bilirubin, conjugated	0.45	1.20	1.50	0.80	1.20	1.84	1.90
(0.0-0.5 mg/dL)
INR (0.85-1.25)	1.60	1.80		2.40	2.40	2.50	2.10
Creatinine	1.2	1.6	1.8		1.4	1.5	1.3
(0.6-1.4 mg/dL) AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; INR, international normalized ratio.

characterized by a variable delay or latency period ranging from 5 to 90 days, and often involve damage to hepatocytes throughout the hepatic lobule, with various degrees of necrosis [4]. As for other drugs, for example, acetaminophen, bromfenac, cocaine, phencyclidine, cyclophosphamide, cy- closporine, methotrexate, niacin, and oral contraceptives, amiodarone hepatotoxicity is characterized by dose depen- dency, and amiodarone-induced steatohepatitis is multifacto- rial [4]. Studies on isolated rat liver mitochondria showed that amiodarone has a dose-dependent toxicity on the respiratory chain and on beta oxidation, with a significant reduction of either the respiratory control ratio or oxidation of palmitate [5]. Again, in mice administered amiodarone and examined for changes in hepatic histology and gene regulation, hepatic RNA analysis revealed a dose-dependent increase in the expression of several genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport [6]. Liver enzyme elevation is commonly observed in patients receiving amiodarone [7]. However, there are differences between oral and intravenous amiodarone administration, with the former being safely prescribed also in patients with elevated baseline alanine aminotransferase [8]. Although most hepatic amio- darone-associated adverse effects are transient and reversible with time, one case of fatal hepatotoxicity associated with chronic use of oral amiodarone has been reported [9]. Acute hepatitis may be more frequently observed as an adverse effect of treatment with parenteral amiodarone. This is usually

Fig. 1 Time course of transaminase levels.

reversible with discontinuation of the infusion, and mainte- nance treatment with oral amiodarone is possible also in patients who developed liver disease during intravenous loading [3]. Polysorbate 80, an organic surfactant added to the intravenous infusion as a solvent, is a more likely cause of this complication because similar reactions have been described in neonates receiving an intravenous formulation of vitamin E [10], and a mediation by immunologic mechanisms has been suggested [11]. It is proposed that rapid administration of a high loading dose of amiodarone can cause acute confluent necrotic hepatitis, and 2 fatal cases of amiodarone-induced acute hepatitis are reported. These patients, aged 28 and 64 years, both died of hepatic coma and acute renal failure on 14th and 4th day, respectively. Needle liver biopsy, performed immediately after death, revealed lesions of acute drug- induced hepatitis with confluent and bridging necrosis [12]. More recently, another fatal case occurred in a 64-year-old man admitted as an emergency, with symptomatic uncon- trolled atrial fibrillation [13].

Conclusions

In our case, the diagnosis is based on Drug history, temporal relationship, time course of Liver dysfunction, exclusion of other causes, and rapid improvement after amiodarone withdrawal. Although we have no direct (eg, bioptic or autoptic) features of liver damage, the cause-effect relationship between amiodarone infusion and hepatitis, according to the Naranjo adverse drug reaction probability score [14] (Table 2), is probable. Peculiarity is given by the very short latency time elapsed between infusion and transaminase elevation. Previous reports, in fact, showed intervals of 1 or more days to get significant liver damage, and transaminase elevation was lower [15]. adverse drug events are common among elderly subjects [16], and elderly women seem to be at particular risk for drug-induced liver injuries [17]. In Critically ill elderly patients treated with intravenous amiodarone loading, a high level of alertness should be maintained, and liver function should be moni- tored even during the first hours of infusion.

	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse event appear after the suspected drug was administered?	+2	-1	0	+2
Did the adverse reaction improve when the drug was discontinued or a	+1	0	0	+1
specific antagonist was administered?
Did the adverse reactions appear when the drug was readmnistered?	+2	-1	0	0
Are there alternative causes (other than the drug) that could, on their own,	-1	+2	0	+2
have caused the reaction?
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in the blood (or other fluids) in	+1	0	0	0
concentrations known to be toxic?
Was the reaction more severe when the dose was increased or less severe	+1	0	0	0
when the dose was decreased?
Did the patient have a similar reaction to the same or similar	+1	0	0	0
drugs in any previous exposure?
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score				+7

Acknowledgments

Table 2 Evaluation of possible adverse drug reaction: the Naranjo probability score

Total score

9

5-8

1-4

0

Adverse drug reaction probability classification

Highly probable Probable Possible Doubtful

The authors thank Dr Angela Benini, PharmD, from the Pharmacovigilance Unit, Department of Pharmaceutical Assistance, Azienda USL, Ferrara, Italy, for her valuable collaboration.

Emanuela Rizzioli MD Elena Incasa MD Susanna Gamberini MD Sandra Savelli MD Arnaldo Zangirolami MD Marilena Tampieri MD

Department of Internal Medicine

Hospital of the Delta Lagosanto, Ferrara, Italy

Roberto Manfredini MD

Department of Internal Medicine

Hospital of the Delta Lagosanto, Ferrara, Italy

Department of Clinical and Experimental Medicine

Section of Clinica Medica University of Ferrara

Ferrara, Italy E-mail addresses: [email protected]

[email protected]

doi:10.1016/j.ajem.2007.02.045

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