European Journal of Cardiovascular Medicine

Amiodarone is a potent class III antiarrhythmic drug widely employed for managing supraventricular and ventricular arrhythmias, including atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Its broad electrophysiological effects stem from complex pharmacologic actions primarily prolongation of phase 3 repolarization, inhibition of potassium and sodium channels, and non-competitive β-adrenergic and calcium channel blockade. These properties render it uniquely effective in rhythm control, especially in patients refractory to other antiarrhythmics. Despite its efficacy, amiodarone is notorious for multisystem toxicities involving the thyroid, lungs, skin, and liver, with hepatotoxicity being one of its most clinically significant yet under-recognized complications.^[1]

The oral form of amiodarone has long been associated with chronic hepatotoxicity resulting from its lipophilic iodine-rich structure, which leads to accumulation within hepatocytes and lysosomal phospholipidosis. In contrast, acute hepatic injury following intravenous (IV) administration is rare, often presenting abruptly within hours to days of infusion, and can be life-threatening. While fewer than 50 well-documented cases exist in medical literature, the mortality rate approaches 25-50 % in severe cases, particularly if recognition and drug withdrawal are delayed. The IV formulation, unlike the oral form, contains the solvent polysorbate 80 a non-ionic surfactant that facilitates solubility but has been implicated in acute hepatic necrosis and circulatory collapse. Polysorbate 80-induced hypersensitivity, direct mitochondrial dysfunction, and systemic hypotension are considered potential mechanisms underlying this acute presentation.^[2]

The pathogenesis of IV amiodarone-induced hepatic injury is multifactorial. First, the high iodine content of the parent compound and its metabolites may disrupt mitochondrial oxidative phosphorylation, resulting in hepatocellular necrosis. Second, the vehicle polysorbate 80 may induce systemic hypotension and microcirculatory disturbances, predisposing to hepatic ischemia. Third, critically ill patients particularly those in postoperative or intensive-care settings are vulnerable due to pre-existing hepatic hypoperfusion, oxidative stress, and concurrent use of other hepatically metabolized drugs. Finally, idiosyncratic immune-mediated reactions, though rare, have been proposed in certain patients. Histopathological studies from autopsies or biopsies reveal centrilobular (zone 3) necrosis, minimal inflammation, and preserved portal triads, features resembling ischemic hepatitis rather than classical drug-induced liver injury (DILI).^[3]

Clinically, IV amiodarone-related acute liver injury manifests as a rapid and profound elevation of aminotransferases often exceeding 1000 U/L within 6-48 hours of infusion. Alkaline phosphatase and bilirubin may remain normal or mildly elevated, and synthetic dysfunction (INR > 1.5) develops in severe cases. The differential diagnosis includes ischemic hepatitis (“shock liver”), sepsis-related cholestasis, and DILI from concomitant drugs such as acetaminophen, antibiotics, or anesthetic agents. Distinguishing features include the temporal proximity to IV amiodarone infusion, absence of hypotension, and rapid improvement upon discontinuation.^[4]

Therapeutically, there is no specific antidote for amiodarone-induced hepatic injury. Supportive care remains the mainstay, focusing on withdrawal of the offending agent and maintenance of hemodynamic stability. However, increasing evidence supports the use of N-acetylcysteine (NAC) as an adjunctive therapy. NAC, a thiol-containing compound, replenishes hepatic glutathione reserves, scavenges free radicals, improves mitochondrial function, and enhances microcirculatory blood flow. Originally approved for acetaminophen toxicity, NAC has demonstrated survival benefits in non-acetaminophen acute liver failure (ALF), as shown in meta-analyses and randomized trials.^[5]

This report presents a rare case of severe acute hepatocellular injury following intravenous amiodarone therapy in a 74-year-old postoperative patient, managed successfully with prompt drug withdrawal and intravenous N-acetylcysteine therapy. The case underscores the importance of early recognition, pathophysiologic understanding, and evidence-based management to avert fatal outcomes.

Patient Demographics and Clinical Background

A 74-year-old male with long-standing hypertension and dyslipidemia presented to the emergency department with acute, severe epigastric pain radiating to the back, accompanied by abdominal rigidity and vomiting. There was no history of chronic liver disease, alcohol intake, or prior hepatotoxic drug exposure. He was hemodynamically stable on arrival (BP 130/80 mm Hg, HR 96 bpm, SpO₂ 98 % RA). Baseline investigations revealed normal liver enzymes (AST 35 U/L, ALT 40 U/L, ALP 100 U/L, bilirubin 0.8 mg/dL).

Diagnosis and Surgical Intervention

An erect abdominal radiograph showed pneumoperitoneum, and contrast-enhanced CT confirmed a perforated duodenal ulcer. The patient underwent emergency exploratory laparotomy with Graham patch repair. The surgery was uneventful; estimated blood loss was < 250 mL. Postoperatively, he was shifted to the Intensive Care Unit (ICU) for ventilatory support and close monitoring.

Postoperative Course and New-Onset Arrhythmia

On postoperative day 0, the patient developed acute hypoxic respiratory failure requiring endotracheal intubation. Within hours, telemetry revealed new-onset atrial fibrillation with rapid ventricular response (RVR) at 160 bpm, resistant to intravenous diltiazem. Given the hemodynamic instability and underlying respiratory failure, a decision was made to initiate intravenous amiodarone.

Therapeutic Intervention

He received a loading dose of 150 mg IV amiodarone over 10 minutes, followed by a continuous infusion at 1 mg/min for 6 hours and 0.5 mg/min thereafter. The infusion was prepared using the commercial IV formulation containing amiodarone 50 mg/mL dissolved in polysorbate 80 and benzyl alcohol. Sinus rhythm was restored within 24 hours, and the infusion was discontinued thereafter.

Development of Acute Hepatocellular Injury

Approximately 20 hours after starting the infusion, the patient’s routine LFTs revealed dramatic elevations of hepatic transaminases without jaundice or coagulopathy (Table 1). He remained normotensive and adequately oxygenated throughout this period. No vasopressors were required, effectively ruling out ischemic hepatitis.

Table 1: Serial Liver Function Trends during NAC Therapy

Diagnostic Evaluation

Viral hepatitis A, B, and C serologies were negative. Autoimmune hepatitis markers (ANA, ASMA) were non-reactive. Abdominal ultrasound showed a normal hepatic echotexture with patent biliary ducts and no vascular thrombosis. Coagulation profile (INR 1.1) and renal function were normal. No other medications with known hepatotoxic potential (acetaminophen, antibiotics, anesthetics) were implicated. The temporal correlation between IV amiodarone administration and enzyme elevation, combined with exclusion of alternative causes, established a diagnosis of IV amiodarone-induced acute hepatocellular injury.

Differential Diagnosis Considered

1. Ischemic hepatitis (“shock liver”) - excluded by absence of hypotension or hypoxia.
2. Drug-induced injury by anesthetic agents - surgery completed > 24 h earlier, with normal interim LFTs.
3. Sepsis-related cholestasis - cultures sterile, ALP and bilirubin minimally elevated.
4. Viral hepatitis - serology negative. Thus, the diagnosis of drug-induced hepatotoxicity secondary to IV amiodarone was confirmed.

Management and Therapeutic Approach

The infusion was immediately discontinued, and intravenous N-acetylcysteine therapy was initiated per the standard 5-day infusion protocol:

• Loading dose: 150 mg/kg over 1 hour
• Maintenance 1: 50 mg/kg over 4 hours
• Maintenance 2: 100 mg/kg over 16 hours × 4 days

Serial monitoring of hepatic panel, coagulation, and hemodynamics was maintained. Supportive care included IV fluids, proton-pump inhibitor, and ventilatory management. No vasopressors or additional hepatoprotective drugs were required.

Clinical Outcome and Follow-Up

Within 48 hours of NAC initiation, AST and ALT declined by > 70 %. The patient’s bilirubin normalized by day 5, and he remained free of encephalopathy or coagulopathy. He was successfully extubated on postoperative day 5 and transitioned to oral metoprolol for rate control. Follow-up at 2 weeks showed near-complete normalization of liver enzymes (AST 42 U/L, ALT 38 U/L). He remained in stable sinus rhythm with no recurrence of hepatic dysfunction during 3-month outpatient follow-up.

Discussion of Mechanism and Literature Correlation

The clinical presentation in this case mirrors previously published reports describing acute hepatocellular necrosis within 24 hours of IV amiodarone infusion.  Popescu M et al. (2024)^[6] and Shrestha DB et al. (2021)^[7] similarly documented rapid enzyme escalation exceeding 5000 U/L, minimal bilirubin rise, and dramatic reversal following NAC therapy. The plausible mechanism involves polysorbate 80-induced mitochondrial injury and oxidative stress amplified by amiodarone’s iodine-laden structure. NAC’s antioxidative and microcirculatory effects likely explain the rapid recovery observed.

Amiodarone is among the most versatile antiarrhythmic agents, classified under Vaughan Williams Class III, possessing properties across multiple electrophysiologic classes. It has proven efficacy in treating both supraventricular and ventricular arrhythmias, particularly when other drugs fail. However, its clinical usefulness is tempered by well-documented systemic toxicities, of which hepatotoxicity is a serious but infrequent complication. The pathogenesis of hepatic injury varies with the formulation and route of administration. Whereas oral amiodarone is typically associated with chronic hepatic injury secondary to cumulative deposition of iodine-laden metabolites causing phospholipidosis and steatohepatitis, intravenous (IV) amiodarone can, albeit rarely, trigger acute hepatocellular necrosis within hours of infusion.

Pathophysiology and Mechanisms of Injury

The mechanism underlying IV amiodarone-induced acute hepatic injury remains incompletely elucidated but is thought to be multifactorial. The solvent polysorbate 80, used to dissolve the highly lipophilic drug for IV delivery, is a key suspect. Polysorbate 80 has been implicated in hepatic and multiorgan injury due to its ability to impair mitochondrial oxidative phosphorylation and disrupt cell membranes. It can provoke systemic hypotension, capillary leakage, and hepatic ischemia. The temporal relationship between infusion and enzyme elevation as short as 6-24 hours strongly supports an acute toxic or ischemic mechanism rather than an immunologic one. Furthermore, in critically ill or postoperative patients, hepatic microcirculatory compromise, oxidative stress, and pre-existing hypoperfusion may amplify susceptibility to injury.

In this case, the patient developed abrupt and marked elevation of AST (5024 U/L) and ALT (1393 U/L) with only a mild bilirubin rise findings typical of hepatocellular necrosis. The absence of hypotension, hypoxia, or coadministration of other hepatotoxic drugs effectively ruled out ischemic or secondary etiologies. The injury profile paralleled prior published cases, where enzyme spikes exceeding 1000-5000 U/L appeared within a day of infusion and normalized rapidly upon cessation of the drug. Such dramatic transaminase elevations with minimal cholestatic involvement further distinguish IV amiodarone hepatotoxicity from the chronic steatohepatitic picture observed with oral use.

Role of N-Acetylcysteine (NAC) in Management

N-Acetylcysteine (NAC) has emerged as a valuable adjunct in managing acute hepatic injury beyond its classical indication for acetaminophen toxicity. Its therapeutic effects are largely attributed to replenishment of hepatic glutathione stores, which neutralize reactive oxygen species (ROS) generated during oxidative stress. Additionally, NAC enhances hepatic blood flow and oxygen delivery by improving microcirculation, acts as an anti-inflammatory and antioxidant agent, and restores mitochondrial function. Clinical evidence from trials in non-acetaminophen acute liver failure (ALF) has demonstrated improved transplant-free survival and accelerated biochemical recovery with early NAC administration Guardado K et al. (2025)^[8].

In the presented case, NAC was initiated promptly after discontinuation of IV amiodarone. The patient’s transaminases decreased by more than 70 % within 48 hours, and near normalization occurred by day 5, closely mirroring responses reported by Popescu M et al. (2024)^[6]. These studies have shown that the therapeutic effect of NAC is particularly pronounced when administered early, as it counters oxidative hepatocellular damage before irreversible necrosis sets in. Furthermore, NAC’s vasodilatory effect may mitigate hepatic hypoperfusion a proposed secondary contributor in amiodarone toxicity.

Several case reports and small series have reinforced the causal association between IV amiodarone and acute hepatic injury.

• Amar D et al. (2022)^[9] described a similar presentation of massive transaminase elevation following IV amiodarone in a postoperative patient, with rapid recovery upon discontinuation and NAC therapy.
• Naeem KB et al. (2021)^[10] reported a series of patients with acute hepatic failure following IV amiodarone infusion, observing mortality rates up to 30 % in delayed recognition cases.
• Tsai MS et al. (2024)^[11] documented dramatic enzyme normalization after NAC use, highlighting the antioxidant and microcirculatory benefits of the drug.
• Karaarslan U et al. (2022)^[12] provided a comprehensive review of hepatotoxicity profiles among antiarrhythmics, emphasizing that amiodarone’s IV form exhibits a distinctly acute, ischemic-like injury pattern.

The AASLD guidelines for acute liver failure Essrani R et al. (2020)^[13] recommend early NAC therapy for all cases of suspected drug-induced hepatic injury, regardless of etiology. These collective findings reinforce NAC’s role as a rational, evidence-based therapeutic intervention in IV amiodarone hepatotoxicity.

Histopathological and Clinical Correlation

Although histologic confirmation was not pursued in this case due to rapid biochemical recovery, prior reports describe centrilobular necrosis, ballooning degeneration, and minimal portal inflammation findings indistinguishable from ischemic hepatitis. Electron microscopy often reveals swollen mitochondria and lamellar inclusion bodies consistent with phospholipid accumulation. These microscopic observations corroborate the theory of mitochondrial toxicity and oxidative stress as key mechanisms.

Clinically, IV amiodarone-induced hepatic injury presents abruptly and resolves rapidly after drug withdrawal. In contrast, oral amiodarone hepatotoxicity is insidious, dose-dependent, and characterized by gradual enzyme elevation over months. The distinction between these two forms is crucial for clinicians, as IV toxicity may masquerade as sepsis, ischemic hepatitis, or multiorgan dysfunction, leading to misdiagnosis and delayed intervention.

Intravenous amiodarone, though invaluable in managing critical arrhythmias, carries the potential for rapid and severe hepatocellular injury, even in patients with previously normal liver function. The toxicity appears specific to the IV formulation, likely due to the solvent polysorbate 80 and its mitochondrial and circulatory effects. Early recognition of this adverse reaction is essential marked by sudden, disproportionate transaminase elevation within 24 hours of infusion. Immediate discontinuation of the drug, coupled with prompt initiation of N-acetylcysteine therapy, can result in dramatic biochemical and clinical recovery. This case exemplifies that timely diagnosis, supportive management, and vigilant hepatic monitoring are the cornerstones of successful outcomes in IV amiodarone-induced acute liver injury

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