Abstract

Parenteral amiodarone is used frequently in acutely ill patients, but it can be associated with hepatotoxicity. We present a case of fatal fulminant hepatic failure attributable to intravenous amiodarone. We review the literature and explore possible reasons for the severe reaction seen in our patient.

Key words: amiodarone, drug reaction, hepatic failure

 

Introduction

The potential side effects of oral amiodarone therapy are well established. Asymptomatic hepatotoxicity has been reported in 15-40% of individuals^1-3. Acute hepatotoxicity as a result of parenteral amiodarone appears to be relatively rare. There have been nineteen case reports in the English literature, which range from asymptomatic elevations in transaminases, to three fatal cases of hepatic failure^4-17. We report here a further fatal case of fulminant hepatic failure caused by intravenous amiodarone.

 

Case Report

A 59-year-old man presented to our hospital with a two-month history of palpitations and breathlessness. He had a past history of a posterior circulation cerebrovascular accident 18 months earlier. His medication on admission consisted of aspirin and pravastatin. He was a heavy smoker of 50 pack years and took alcohol occasionally.

 

On admission he was found to be in atrial fibrillation with a ventricular rate of 146 beats per minute. Blood pressure was 109/68, respiratory rate 28/min and oxygen saturation 97% on air. Examination was otherwise unremarkable and in particular there were no signs of cardiac failure. Electrocardiogram confirmed atrial fibrillation with a rapid ventricular response and voltage criteria for left ventricular hypertrophy. Chest radiograph showed a mass lesion at the left hilum with spiculation into the left upper zone, but otherwise lung fields were clear and heart size normal. Routine laboratory results, including liver biochemistry, were normal on admission other than a slightly elevated urea (Table I).

 

Table I. Relevant blood results and timescale. Day 0 is the day of admission. Amiodarone commenced at 1800h on Day 0. AST=aspartate transaminase, ALT=alanine transaminase, AlkP=alkaline phosphatase, PT=prothrombin time.

	Day 0 15.23h	Day1 14.26h	Day 2 06.53h	Day 3 14.26h
Urea mmol/l	11.5	18.8	21	26.1
Creatinine µmol/l	104	236	328	332
AST IU/l	37	6888	7388	2095
ALT IU/l	40	4550	5352	2365
AlkP IU/l	126	147	180	165
Bilirubin nµmol/l	23	68	81	63
PT secs	--	--	35s	49s

 

 

 

 

 

 

 

 

 

 

In view of the atrial fibrillation, he was commenced on intravenous amiodarone. He received a 300mg bolus dose followed by 900mg over the next 23 hours. He remained haemodynamically stable throughout this period. However blood chemistry taken 24 hours after admission (20 hours into his amiodarone infusion) revealed an acute hepatitic picture with deteriorating renal function (Table I). In spite of discontinuing the amiodarone his condition worsened, he developed fulminant hepatic failure and died 90 hours after admission despite optimal supportive therapy including haemodialysis.

 

Although amiodarone was considered the most likely cause of the acute hepatitis, other potential causes were excluded. Computed tomography of chest and abdomen revealed a mass encircling the left upper lobe bronchus consistent with a bronchogenic neoplasm, but no evidence of metastases and the liver was structurally normal. Hepatitis A, B and C serology was negative, blood cultures yielded no growth and paracetamol level was undetectable.

 

The post mortem reported a dilated cardiomyopathy and a localised squamous cell carcinoma in the upper lobe of the left lung with no evidence of metastasis. The lungs were severely congested and oedematous. The liver weighed 1500g and had a normal external appearance. Histologically there was centrilobular necrosis: severe, extensive liver cell necrosis in a multilobular distribution sparing periportal (zone 1) hepatocytes. A collection of mixed inflammatory cells (including eosinophils) were present within the necrotic parenchyma (Figure 1). The cause of death was given as acute hepatic failure. The histopathological findings were reported as consistent with a drug reaction or ischaemic hepatitis.

 

Discussion

There have been nineteen cases reported in the English literature of acute hepatitis attributed to parenteral amiodarone ^4-17. These cases range from a minor (five to tenfold), asymptomatic rise in transaminases^6,14,15, through severe hepatitis (fifty to five hundredfold rise in transmaninases)^4,5,7,13,17 to reversible acute hepatic failure^10-12,  fulminant hepatic failure and death^8,16. In most of the cases, the temporal relationship between commencing parenteral amiodarone and the acute hepatitis was persuasive evidence of cause and effect. As in our case, every effort was made to exclude other causes. A common feature of all cases however was some degree of pre-existing cardiac compromise; the majority had decompensated heart failure, others were post-cardiac surgery or had haemodynamically significant ventricular arrhythmias. It is therefore difficult to completely exclude ischaemic hepatitis (“shock liver”) from the differential diagnosis in most cases.

 

This possibility was not considered in many of the case reports^4-17, though it was addressed in a recent editorial¹⁸. Not only are the histological findings of ischaemic hepatitis and parenteral amiodarone-induced hepatitis similar¹⁸, but it is now believed that “shock liver” can occur without hypotension, particularly in the context of decompensated heart failure or hypoxia¹⁸.

 

In the case we report here, although a dilated cardiomyopathy was diagnosed post mortem, and the lung fields were congested, the patient had been severely ill and had received large volumes of fluid and blood products. At presentation there was no clinical or radiographical evidence of decompensated heart failure, and the patient was haemodynamically stable. The possibility of an ischaemic hepatitis appears unlikely, leaving intravenous amiodarone as the only plausible explanation.

 

It is unclear why this patient should have such a severe reaction. Clinically he was more stable than most of the cases described in the literature who had a less severe hepatitic reaction^4-7,9-15,17. There are however some similarities to the two fatal cases described by Kalantzis et al⁸. Neither had initial haemodynamic compromise, although it is not clear whether they had decompensated heart failure. The other fatal case, described by McFadyen et al¹⁶, appears to have had incipient cardiogenic shock prior to developing hepatic dysfunction, making it particularly difficult to know whether to attribute this to amiodarone or ischaemic hepatitis.

 

The mechanism behind the hepatotoxicity of parenteral amiodarone remains speculative. It seems likely that this is a rare idiosyncratic reaction due to individual handling of the drug/“toxic vehicle”¹¹. There is some evidence that polysorbate 80 (polyoxeneethylated sorbitan ester), which is a stabilising agent added to amiodarone for intravenous use, may actually be responsible¹¹: patients who have sustained an acute hepatitis with parenteral amiodarone have gone on to tolerate the oral preparation without any adverse effects¹². On the basis of the reported cases, it is tempting to speculate that patients with hepatic congestion are particularly vulnerable to the toxic effects of parenteral amiodarone.

 

Should this have any impact on the use of intravenous amiodarone? Acute hepatotoxicity appears to be an extremely rare, but potentially fatal, side-effect. It only appears to affect patients with a degree of cardiac compromise. However these are the cases for whom parenteral amiodarone is most often required. Ideally it should only be used for attempted pharmacological cardioversion of atrial arrhythmias where there is a clear onset within 48 hours and a return to sinus rhythm is deemed necessary, or for the control of ventricular arrhythmias. Although the agent may be useful in simply controlling the rate of atrial fibrillation in patients with decompensated heart failure where other agents are contraindicated, careful consideration should be given to the necessity for using the intravenous formulation, when the oral preparation may be just as useful.

 

References

1. McGovern B, Garan H, Kelly E, Ruskin JN. Adverse reactions during treatment with amiodarone hydrochloride. Br Med J 1983;287:175-180

2. Plonteux G, Heagham C, Ernowald H, Vandeghen N. Long-term hepatic tolerance of amiodarone in the clinic. Eur J Pharmacol 1969;8:369-376

3. Heger JJ, Prystowsky EN, Jackman WM et al. Amiodarone: clinical efficacy and electrophysiology during longterm therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-545

4. Lupon-Rosés J, Simó-Canonge R, Lu-Cortez L, Permanyer-Miralda G, Allende-Monclús. Probable early acute hepatitis with parenteral amiodarone. Clin Cardiol 1986;9:223-229

5. Pye M, Northcote RJ, Cobbe SM. Acute hepatitis after parenteral amiodarone administration Br Heart J. 1988;59:690-691

6. Stevenson RN, Nayani TH, Davies JR. Acute hepatic dysfunction following parenteral amiodarone administration. Postgrad Med J 1989;65:707-708

7. Simon JP, Zannad F, Trechot P, Thisse JY, Huoplon M, Aliot E. Acute hepatitis after a loading dose of intravenous amiodarone. Cardiovasc Drugs Ther 1990;4:1467-1468

8. Kalantzis N, Gabriel P, Mouzas J, Tiniakos D, Tsigas D, Tiniakos G. Acute amiodarone-induced hepatitis. Hepatogastroenterology 1991;38:71-74

9. Morelli S, Guido V, De Marzio P, Aguglia F, Balsano F. Early hepatitis during intravenous amiodarone administration Cardiology 1991;78:291-294

10. Fornaciari G, Monducci I, Barone A, Bassi C, Beltrami M, Tomasi C. Amiodarone-induced acute hepatitis: case report. J Clin Gastroenterol 1992;15:271-273

11. Rhodes A, Eastwood JB, Smith SA. Early acute hepatitis with parenteral amiodarone: A toxic effect of the vehicle? Gut 1993;34:565-566

12. James PR, Hardman SMC. Acute hepatitis complicating parenteral amiodarone does not preclude subsequent oral therapy. Heart 1997;77:583-584

13. Breuer HWM, Bossek W, Haferland C, Schmidt M, Neumann H, Gruszka J. Amiodarone-induced severe hepatitis mediated by immunological mechanisms. Int J Clin Pharmacol Ther 1998;36:350-352

14. Iliopoulou A, Giannakopoulos G, Mayrikakis M, Zafiris E, Stamatelopoulos S. Reversible fulminant hepatitis following intravenous amiodarone loading. Amiodarone hepatotoxicity. Int J Clin Pharmacol Ther 1999;37:312-313

15. Gregory SA, Webster JB. Acute hepatitis induced by parenteral amiodarone. Am J Med 2002;113:254-255

16. MacFadyen RJ, Palmer TJ, Hisamuddin K. Rapidly fatal acute amiodarone hepatitis occurring in the context of multiple organ failure. Int J Cardiol 2003;91:245-247

17. Rätz Bravo AE, Drewe J, Schlienger RG, Krähenbühl S, Pargger H, Ummenhofer W. Hepatotoxicity during rapid intravenous loading with amiodarone: Description of three cases and review of the literature. Crit Care Med 2005;33:128-134

18. Guglin M. Intravenous amiodarone: Offender or bystander? Crit Care Med 2005;33:245-246.