Amiodarone-induced acute liver failure in an infant with paroxysmal supraventricular tachycardia

To the Editor, Paroxysmal supraventricular tachycardia (PSVT) is the most common sustained arrhythmia in infancy and may be associated with myocarditis, structural heart disease, or drug toxicity.[1,2] Amiodarone, an iodine-containing benzofuran derivative used in the management of PSVT, is classified as a Class III antiarrhythmic drug and carries potential risks for photosensitivity, thyroid dysfunction, corneal microdeposits, pneumonitis, and hepatotoxicity in 30%–90% of long-term users.[3] Acute hepatotoxicity due to amiodarone in adults can range from mild asymptomatic transaminitis in 24% to fulminant liver failure in <1% of patients.[3] Although drug-induced liver injury (DILI) is responsible for nearly 10% cases of acute liver failure (ALF) in children, cases of amiodarone-induced liver injury (AILI) and ALF have rarely been reported.[4,5] A 3-month-old female, weighing 4 kg, presented with acute viral pneumonia and myocarditis complicated by refractory PSVT. High-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide levels were 183.68 ng/l (normal: <40 ng/l) and 18,204 pg/ml (normal: 100–200 pg/ml). Despite no hemodynamic instability at presentation, two dimensional-echocardiography revealed a left ventricular ejection fraction (LVEF) of 20%. Electrocardiography depicted multifocal atrial tachycardia [Figure 1a]. Vagal maneuvers, adenosine, metoprolol, flecainide, and intravenous (IV) amiodarone infusion (started at 5 μg/kg/min and increased to 25 μg/kg/min) were unsuccessful in restoring a sinus rhythm. On day 5 of stay, the child developed transaminitis (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] 6970/2700 U/L, normal <40) and coagulopathy (international normalized ratio [INR] 7.61, normal <1.2), with normal gamma-glutamyl transferase (GGT) (64 IU/L, normal: 16–60) consistent with AILI (Naranjo causality assessment score 7, probable) and ALF. The respiratory and blood multiplex polymerase chain reaction panel for evaluating other possible infectious etiologies of ALF was negative. The baby received IV immunoglobulin (2 g/kg) for myocarditis and direct current (DC) cardioversion for refractory PSVT, ultimately leading to its reversal on day 7 of stay [Figure 1b]. Amiodarone infusion was then discontinued, and N-acetylcysteine (NAC) infusion was administered – 150 mg/kg over 1 h, followed by 50 mg/kg over 4 h and then at 6.25 mg/kg/h for 48 h, with a marked reduction of INR and liver enzymes. She was discharged on oral flecainide (4.5 mg/kg/day) and propranolol (1 mg/kg/day), with an LVEF of 60%.Figure 1: (a) Twelve-lead electrocardiography (ECG) of index case showing multifocal atrial tachycardia (a type of paroxysmal supraventricular tachycardia), (b) 12-lead ECG of index case after rate control post direct current cardioversionTo the best of our knowledge, this is the first report depicting AILI with ALF in an infant. The mechanism of AILI in IV amiodarone centers around its solubilizing agent (polysorbate 80) and accumulation of its metabolite, desethyl-amiodarone (DEA). Polysorbate destabilizes the hepatocyte cell membrane, induces lipid peroxidation, and causes mitochondrial dysfunction, whereas DEA inhibits phospholipases A1 and A2, leading to reduced lysosomal lipid removal, phospholipidosis, and microvesicular steatosis.[4,6] Oral formulations, devoid of polysorbate, seem to be safer in AILI. However, the onset of oral drug action is estimated to be 48–72 h, obviating use in critical arrhythmias, like in our case. Although serum GGT elevation to 35 times the upper limit has been reported in an adult after 6 months of oral amiodarone therapy, it was not observed in our case of ALF with IV amiodarone use.[7] Diab et al. showed that predictors of severe AILI (>5 times AST/ALT) include cardiomyopathy, need for inotropic support, congestive hepatomegaly, high baseline total bilirubin, DC cardioversion, and a high cumulative amiodarone dose.[8] Cardiomyopathy, congestive hepatomegaly, cardioversion, and every mg rise in bilirubin and amiodarone dose increase the odds of having AILI by 2, 4, 5, 3, and 1.002-fold, respectively.[8] In most cases, AILI occurs within 24–48 h of therapy and resolves within 2–3 weeks of discontinuation, without sequelae.[8] In our case, low ejection fraction (EF), DC cardioversion, and high dose of amiodarone (25 μg/kg/min) may have augmented hepatic vulnerability. The longer time to onset of ALF could be attributed to the cumulative dose (504 mg over 150 h) and the immediately preceding event of cardioversion in the background of low EF, which, by itself, may further compromise hepatic circulation due to transient cardiac stunning, predisposing to DILI.[8,9] Early identification, immediate discontinuation, and prompt initiation of NAC infusion are the mainstays of AILI management.[10] Liver transplantation remains a consideration for non-responders, although infants often recover with supportive therapy, as in our case. This case underscores the rarity of amiodarone-induced ALF in infants and highlights the importance of vigilance during IV therapy, especially in those with compromised myocardium or refractory arrhythmias. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given her consent for images and other clinical information to be reported in the journal. The guardian understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.