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Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature Abstract Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion. Introduction Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular and supraventricular tachyarrhythmias. The mechanism of action is complex. It involves antagonism of the delayed rectifier potassium channels, in particular the rapid component, thereby increasing membrane refractoriness. This agent also affects inactivated sodium channels (Phase 0), sympathetic activity, and calcium channels (L-type).1 Long-term therapy is associated with various adverse effects due to accumulation of the drug in tissue. The intravenous (IV) preparation of amiodarone has been linked to adverse hepatic reactions such as hypotension, cardiac arrest, bradycardia, heart failure, and hepatic abnormalities.2 We report an unusual case of acute hepatitis immediately after the initiation of IV amiodarone. Case description An 88-year-old Caucasian female presented to the emergency room complaining of shortness of breath with minimal exertion. This was associated with intermittent heart palpitations and fatigue. Her symptoms had gradually worsened over the prior month in response to family and emotional stress. She denied chest pain, cough, hemoptysis, nausea, vomiting, or diarrhea. Her past medical history consisted of hypothyroidism, hypertension, and depression. Her only prior surgery was a hysterectomy. A recent echocardiogram revealed a normal ejection fraction with Grade 1 diastolic dysfunction. Family history was unremarkable. She did not use tobacco, alcohol, or illicit drugs. Her home medications included sertraline 25 mg daily, levothyroxine 25 mg daily, and lisinopril 20 mg daily. A physical examination revealed the following vitals: a blood pressure of 147/52 mmHg, a temperature of 97.6°F, a respiratory rate of 20 breaths/minute, and a heart rate of 130 beats/minute. Cardiac auscultation demonstrated an irregular rhythm with a diastolic murmur heard best at the left upper sternal border, likely to be aortic in origin. An S3 gallop was present, and point of maximal impulse was laterally displaced. Auscultation of the lungs revealed bibasilar rales. Peripheral pulses were strong and equal bilaterally. There was moderate edema present in the lower extremities, and hepatojugular reflux was noted. Laboratory testing identified the following values: white blood cell count of 8.8 × 103/μL, hemoglobin of 13.1 g/dL, platelet count of 277 × 103/μL, glucose level of 108 mg/dL, creatinine of 61.88 μmol/L, aspartate aminotransferase (AST) of 24 units/L, alanine aminotransferase (ALT) of 16 units/L, bilirubin total of 8.5 μmol/L, alkaline phosphatase of 98 units/L, and thyroid-stimulating hormone of 2.92 μIU/mL. All electrolytes were within normal limits. An initial electrocardiogram (ECG) revealed atrial fibrillation with a rapid ventricular response (Figure 1). Intravenous diltiazem was initiated in order to control the ventricular rate. Shortly after, the patient’s rhythm converted to normal sinus rhythm spontaneously. She subsequently developed sinus pauses lasting up to 6 seconds; consequently, diltiazem was discontinued. Until a permanent pacemaker could be inserted, IV amiodarone was commenced in order to maintain sinus rhythm and prevent a rapid ventricular response. Following a loading dose of 150 mg, we administered 360 mg of amiodarone infused at a rate of 1 mg/min over 6 hours, after which a maintenance infusion rate of 0.5 mg/min was continued. The next day, a routine laboratory evaluation illustrated an acute elevation to the following measurements: AST 1,881 units/L (normal high 35 units/L), ALT 1,048 units/L (normal high 35 units/L), alkaline phosphatase 143 units/L (normal high 129 units/L), total bilirubin 15.3 μmol/L (normal high 17 μmol/L), and creatinine 97.2 μmol/L (normal high 88 μmol/L) (Table 1). At that point, we reviewed all medications and obtained a hepatitis panel, which was normal. She had been on the same home medications for months without any change. A hepatic ultrasound identified venous congestion. We suspected amiodarone as a cause; thus, it was discontinued after administering a total dose of 960 mg over a 10-hour period. Signs of a hypersensitivity reaction such as itching, rash, or eosinophilia were not seen. Liver transaminases returned to baseline within 7 days. Further investigation with a cardiac echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 35%. Subsequently, a left heart catheterization revealed significant coronary artery disease with no clear revascularization targets, and a LVEF of 30%. She then received a permanent pacemaker, made an uneventful recovery, and was discharged on carvedilol, lisinopril, warfarin, and levothyroxine. Over the next 12 weeks, the patient suffered from progressive heart failure, which was managed both in the office and at home. Eventually, she died of advanced pump failure with progressive edema and respiratory failure. Discussion Major side effects of oral amiodarone are related to drug accumulation in tissue when given over a long period of time. Adverse reactions include thyroid dysfunction, sinus bradycardia, ventricular arrhythmias, and pulmonary and hepatic toxicity. Approximately 25% of patients taking this medication develop a transient asymptomatic rise in serum aminotransferase levels. Symptomatic hepatitis, cirrhosis, and hepatic failure are rare complications which involve less than 3% of patients.3,4 Histological features of oral amiodarone hepatitis are similar to alcoholic hepatitis and include steatosis, fibrosis, and phospholipid laden lysosomal lamellar bodies. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction.5 There was a mild total bilirubin elevation to 0.9 mg/dL; therefore, this case of drug-induced liver injury (DILI) did not meet Hy’s Law criteria, which states that hepatocellular injury accompanied by a total bilirubin elevation over twice the upper limit of normal is of significant concern and has a mortality of 10%–15%.6 Intravenous amiodarone is typically used as a short-term therapy for various arrhythmias (as mentioned previously). It is metabolized to N-desethylamiodarone (DEA) by cytochrome P450 enzymes (CYP3A4 and CYP2C8). Its metabolite is also an antiarrhythmic. Amiodarone is primarily eliminated by biliary excretion. Left ventricular dysfunction prolongs the half-life of DEA. Acute hepatitis, due to parenteral therapy, is extremely rare.7 Our literature review identified 33 previously reported cases. The underlying mechanism is controversial and still unknown. Ischemic hepatitis, a much more common condition, shares many clinical and histological characteristics that are seen in parenteral amiodarone-induced liver injury. It has been hypothesized by Gluck et al that the acute liver injury following the IV formulation is related to liver ischemia, rather than direct drug toxicity.8 This was based on the observation that the two conditions show similar histological features and clinical events. Furthermore, DILI caused by oral and IV amiodarone demonstrate different histologic findings. The majority of patients receiving the IV form are suffering from unstable tachyarrhythmias, which may result in a decreased cardiac output, hypotension, and ischemia. Most patients described in the reviewed cases had evidence of poor forward output, hepatic venous congestion, impaired circulation and acute kidney injury, predisposing them to ischemic hepatitis. Finally, another report by Lahbabi et al ascribes responsibility of liver toxicity to solubilizers such as polysorbate 80 in the IV amiodarone preparation.9 Polysorbate 80 has been implicated in the E-Ferol syndrome characterized by renal failure, hepatosplenomegaly, and jaundice. Eliminating polysorbate 80 by the oral route demonstrated the safe use of amiodarone even after acute hepatitis in several studies. Our patient showed evidence of impaired left ventricular function with an LVEF of 30% by ECG (decreased from 50% one month prior to admission). Also, there was evidence of acute elevation of her creatinine from 0.7 to 1.1 mg/dL, suggestive of a degree of hypoperfusion. Hepatojugular reflux was elicited and central venous pressure was elevated subsequent to liver injury. The causal correlation is not clear as to which condition (cardio–renal dysfunction or liver failure) induced the other. We believe that in susceptible elderly patients, even the standard intravenous amiodarone dose may cause direct drug toxicity and hypotension, especially in the setting of heart failure, leading to hepatic injury. Further research is needed to support a true acute amiodarone hepatotoxicity versus other proposed or even unknown mechanisms (Figure 2). Six fatal cases of IV amiodarone hepatitis have been reported, suggesting the severity of this condition (Table 2).10–34 Elevation of transaminases occurred within 24 hours of drug administration in most patients. The majority of these cases were associated with some degree of cardiac dysfunction and renal failure. Our case was fatal in 12 weeks due to progressive pump failure, and the DILI event may have been a harbinger of mortality. The mechanism of progressive left ventricular failure may have been secondary to the impact of systemic inflammation, neurohormonal stress, and microcirculatory dysfunction caused in part by the acute organ failure of the liver (Figure 3). We believed persistent hepatic venous congestion played a role and may have been a determinant. This case suggests that one should regularly obtain a liver function panel subsequent to parenteral amiodarone initiation and proceed with caution in the setting of heart failure and hepatic congestion. Conclusion Amiodarone is often used to treat life-threatening arrhythmias in the setting of acutely decompensated heart failure. In the presence of hepatic congestion, the IV preparation of amiodarone may cause acute liver injury, which can be a harbinger for a fatal outcome in the days to months after administration. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.

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Title	Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature
Abstract	Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.
Body	Introduction Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular and supraventricular tachyarrhythmias. The mechanism of action is complex. It involves antagonism of the delayed rectifier potassium channels, in particular the rapid component, thereby increasing membrane refractoriness. This agent also affects inactivated sodium channels (Phase 0), sympathetic activity, and calcium channels (L-type).1 Long-term therapy is associated with various adverse effects due to accumulation of the drug in tissue. The intravenous (IV) preparation of amiodarone has been linked to adverse hepatic reactions such as hypotension, cardiac arrest, bradycardia, heart failure, and hepatic abnormalities.2 We report an unusual case of acute hepatitis immediately after the initiation of IV amiodarone. Case description An 88-year-old Caucasian female presented to the emergency room complaining of shortness of breath with minimal exertion. This was associated with intermittent heart palpitations and fatigue. Her symptoms had gradually worsened over the prior month in response to family and emotional stress. She denied chest pain, cough, hemoptysis, nausea, vomiting, or diarrhea. Her past medical history consisted of hypothyroidism, hypertension, and depression. Her only prior surgery was a hysterectomy. A recent echocardiogram revealed a normal ejection fraction with Grade 1 diastolic dysfunction. Family history was unremarkable. She did not use tobacco, alcohol, or illicit drugs. Her home medications included sertraline 25 mg daily, levothyroxine 25 mg daily, and lisinopril 20 mg daily. A physical examination revealed the following vitals: a blood pressure of 147/52 mmHg, a temperature of 97.6°F, a respiratory rate of 20 breaths/minute, and a heart rate of 130 beats/minute. Cardiac auscultation demonstrated an irregular rhythm with a diastolic murmur heard best at the left upper sternal border, likely to be aortic in origin. An S3 gallop was present, and point of maximal impulse was laterally displaced. Auscultation of the lungs revealed bibasilar rales. Peripheral pulses were strong and equal bilaterally. There was moderate edema present in the lower extremities, and hepatojugular reflux was noted. Laboratory testing identified the following values: white blood cell count of 8.8 × 103/μL, hemoglobin of 13.1 g/dL, platelet count of 277 × 103/μL, glucose level of 108 mg/dL, creatinine of 61.88 μmol/L, aspartate aminotransferase (AST) of 24 units/L, alanine aminotransferase (ALT) of 16 units/L, bilirubin total of 8.5 μmol/L, alkaline phosphatase of 98 units/L, and thyroid-stimulating hormone of 2.92 μIU/mL. All electrolytes were within normal limits. An initial electrocardiogram (ECG) revealed atrial fibrillation with a rapid ventricular response (Figure 1). Intravenous diltiazem was initiated in order to control the ventricular rate. Shortly after, the patient’s rhythm converted to normal sinus rhythm spontaneously. She subsequently developed sinus pauses lasting up to 6 seconds; consequently, diltiazem was discontinued. Until a permanent pacemaker could be inserted, IV amiodarone was commenced in order to maintain sinus rhythm and prevent a rapid ventricular response. Following a loading dose of 150 mg, we administered 360 mg of amiodarone infused at a rate of 1 mg/min over 6 hours, after which a maintenance infusion rate of 0.5 mg/min was continued. The next day, a routine laboratory evaluation illustrated an acute elevation to the following measurements: AST 1,881 units/L (normal high 35 units/L), ALT 1,048 units/L (normal high 35 units/L), alkaline phosphatase 143 units/L (normal high 129 units/L), total bilirubin 15.3 μmol/L (normal high 17 μmol/L), and creatinine 97.2 μmol/L (normal high 88 μmol/L) (Table 1). At that point, we reviewed all medications and obtained a hepatitis panel, which was normal. She had been on the same home medications for months without any change. A hepatic ultrasound identified venous congestion. We suspected amiodarone as a cause; thus, it was discontinued after administering a total dose of 960 mg over a 10-hour period. Signs of a hypersensitivity reaction such as itching, rash, or eosinophilia were not seen. Liver transaminases returned to baseline within 7 days. Further investigation with a cardiac echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 35%. Subsequently, a left heart catheterization revealed significant coronary artery disease with no clear revascularization targets, and a LVEF of 30%. She then received a permanent pacemaker, made an uneventful recovery, and was discharged on carvedilol, lisinopril, warfarin, and levothyroxine. Over the next 12 weeks, the patient suffered from progressive heart failure, which was managed both in the office and at home. Eventually, she died of advanced pump failure with progressive edema and respiratory failure. Discussion Major side effects of oral amiodarone are related to drug accumulation in tissue when given over a long period of time. Adverse reactions include thyroid dysfunction, sinus bradycardia, ventricular arrhythmias, and pulmonary and hepatic toxicity. Approximately 25% of patients taking this medication develop a transient asymptomatic rise in serum aminotransferase levels. Symptomatic hepatitis, cirrhosis, and hepatic failure are rare complications which involve less than 3% of patients.3,4 Histological features of oral amiodarone hepatitis are similar to alcoholic hepatitis and include steatosis, fibrosis, and phospholipid laden lysosomal lamellar bodies. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction.5 There was a mild total bilirubin elevation to 0.9 mg/dL; therefore, this case of drug-induced liver injury (DILI) did not meet Hy’s Law criteria, which states that hepatocellular injury accompanied by a total bilirubin elevation over twice the upper limit of normal is of significant concern and has a mortality of 10%–15%.6 Intravenous amiodarone is typically used as a short-term therapy for various arrhythmias (as mentioned previously). It is metabolized to N-desethylamiodarone (DEA) by cytochrome P450 enzymes (CYP3A4 and CYP2C8). Its metabolite is also an antiarrhythmic. Amiodarone is primarily eliminated by biliary excretion. Left ventricular dysfunction prolongs the half-life of DEA. Acute hepatitis, due to parenteral therapy, is extremely rare.7 Our literature review identified 33 previously reported cases. The underlying mechanism is controversial and still unknown. Ischemic hepatitis, a much more common condition, shares many clinical and histological characteristics that are seen in parenteral amiodarone-induced liver injury. It has been hypothesized by Gluck et al that the acute liver injury following the IV formulation is related to liver ischemia, rather than direct drug toxicity.8 This was based on the observation that the two conditions show similar histological features and clinical events. Furthermore, DILI caused by oral and IV amiodarone demonstrate different histologic findings. The majority of patients receiving the IV form are suffering from unstable tachyarrhythmias, which may result in a decreased cardiac output, hypotension, and ischemia. Most patients described in the reviewed cases had evidence of poor forward output, hepatic venous congestion, impaired circulation and acute kidney injury, predisposing them to ischemic hepatitis. Finally, another report by Lahbabi et al ascribes responsibility of liver toxicity to solubilizers such as polysorbate 80 in the IV amiodarone preparation.9 Polysorbate 80 has been implicated in the E-Ferol syndrome characterized by renal failure, hepatosplenomegaly, and jaundice. Eliminating polysorbate 80 by the oral route demonstrated the safe use of amiodarone even after acute hepatitis in several studies. Our patient showed evidence of impaired left ventricular function with an LVEF of 30% by ECG (decreased from 50% one month prior to admission). Also, there was evidence of acute elevation of her creatinine from 0.7 to 1.1 mg/dL, suggestive of a degree of hypoperfusion. Hepatojugular reflux was elicited and central venous pressure was elevated subsequent to liver injury. The causal correlation is not clear as to which condition (cardio–renal dysfunction or liver failure) induced the other. We believe that in susceptible elderly patients, even the standard intravenous amiodarone dose may cause direct drug toxicity and hypotension, especially in the setting of heart failure, leading to hepatic injury. Further research is needed to support a true acute amiodarone hepatotoxicity versus other proposed or even unknown mechanisms (Figure 2). Six fatal cases of IV amiodarone hepatitis have been reported, suggesting the severity of this condition (Table 2).10–34 Elevation of transaminases occurred within 24 hours of drug administration in most patients. The majority of these cases were associated with some degree of cardiac dysfunction and renal failure. Our case was fatal in 12 weeks due to progressive pump failure, and the DILI event may have been a harbinger of mortality. The mechanism of progressive left ventricular failure may have been secondary to the impact of systemic inflammation, neurohormonal stress, and microcirculatory dysfunction caused in part by the acute organ failure of the liver (Figure 3). We believed persistent hepatic venous congestion played a role and may have been a determinant. This case suggests that one should regularly obtain a liver function panel subsequent to parenteral amiodarone initiation and proceed with caution in the setting of heart failure and hepatic congestion. Conclusion Amiodarone is often used to treat life-threatening arrhythmias in the setting of acutely decompensated heart failure. In the presence of hepatic congestion, the IV preparation of amiodarone may cause acute liver injury, which can be a harbinger for a fatal outcome in the days to months after administration. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.
Section	Introduction Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular and supraventricular tachyarrhythmias. The mechanism of action is complex. It involves antagonism of the delayed rectifier potassium channels, in particular the rapid component, thereby increasing membrane refractoriness. This agent also affects inactivated sodium channels (Phase 0), sympathetic activity, and calcium channels (L-type).1 Long-term therapy is associated with various adverse effects due to accumulation of the drug in tissue. The intravenous (IV) preparation of amiodarone has been linked to adverse hepatic reactions such as hypotension, cardiac arrest, bradycardia, heart failure, and hepatic abnormalities.2 We report an unusual case of acute hepatitis immediately after the initiation of IV amiodarone.
Title	Introduction
Section	Case description An 88-year-old Caucasian female presented to the emergency room complaining of shortness of breath with minimal exertion. This was associated with intermittent heart palpitations and fatigue. Her symptoms had gradually worsened over the prior month in response to family and emotional stress. She denied chest pain, cough, hemoptysis, nausea, vomiting, or diarrhea. Her past medical history consisted of hypothyroidism, hypertension, and depression. Her only prior surgery was a hysterectomy. A recent echocardiogram revealed a normal ejection fraction with Grade 1 diastolic dysfunction. Family history was unremarkable. She did not use tobacco, alcohol, or illicit drugs. Her home medications included sertraline 25 mg daily, levothyroxine 25 mg daily, and lisinopril 20 mg daily. A physical examination revealed the following vitals: a blood pressure of 147/52 mmHg, a temperature of 97.6°F, a respiratory rate of 20 breaths/minute, and a heart rate of 130 beats/minute. Cardiac auscultation demonstrated an irregular rhythm with a diastolic murmur heard best at the left upper sternal border, likely to be aortic in origin. An S3 gallop was present, and point of maximal impulse was laterally displaced. Auscultation of the lungs revealed bibasilar rales. Peripheral pulses were strong and equal bilaterally. There was moderate edema present in the lower extremities, and hepatojugular reflux was noted. Laboratory testing identified the following values: white blood cell count of 8.8 × 103/μL, hemoglobin of 13.1 g/dL, platelet count of 277 × 103/μL, glucose level of 108 mg/dL, creatinine of 61.88 μmol/L, aspartate aminotransferase (AST) of 24 units/L, alanine aminotransferase (ALT) of 16 units/L, bilirubin total of 8.5 μmol/L, alkaline phosphatase of 98 units/L, and thyroid-stimulating hormone of 2.92 μIU/mL. All electrolytes were within normal limits. An initial electrocardiogram (ECG) revealed atrial fibrillation with a rapid ventricular response (Figure 1). Intravenous diltiazem was initiated in order to control the ventricular rate. Shortly after, the patient’s rhythm converted to normal sinus rhythm spontaneously. She subsequently developed sinus pauses lasting up to 6 seconds; consequently, diltiazem was discontinued. Until a permanent pacemaker could be inserted, IV amiodarone was commenced in order to maintain sinus rhythm and prevent a rapid ventricular response. Following a loading dose of 150 mg, we administered 360 mg of amiodarone infused at a rate of 1 mg/min over 6 hours, after which a maintenance infusion rate of 0.5 mg/min was continued. The next day, a routine laboratory evaluation illustrated an acute elevation to the following measurements: AST 1,881 units/L (normal high 35 units/L), ALT 1,048 units/L (normal high 35 units/L), alkaline phosphatase 143 units/L (normal high 129 units/L), total bilirubin 15.3 μmol/L (normal high 17 μmol/L), and creatinine 97.2 μmol/L (normal high 88 μmol/L) (Table 1). At that point, we reviewed all medications and obtained a hepatitis panel, which was normal. She had been on the same home medications for months without any change. A hepatic ultrasound identified venous congestion. We suspected amiodarone as a cause; thus, it was discontinued after administering a total dose of 960 mg over a 10-hour period. Signs of a hypersensitivity reaction such as itching, rash, or eosinophilia were not seen. Liver transaminases returned to baseline within 7 days. Further investigation with a cardiac echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 35%. Subsequently, a left heart catheterization revealed significant coronary artery disease with no clear revascularization targets, and a LVEF of 30%. She then received a permanent pacemaker, made an uneventful recovery, and was discharged on carvedilol, lisinopril, warfarin, and levothyroxine. Over the next 12 weeks, the patient suffered from progressive heart failure, which was managed both in the office and at home. Eventually, she died of advanced pump failure with progressive edema and respiratory failure.
Title	Case description
Section	Discussion Major side effects of oral amiodarone are related to drug accumulation in tissue when given over a long period of time. Adverse reactions include thyroid dysfunction, sinus bradycardia, ventricular arrhythmias, and pulmonary and hepatic toxicity. Approximately 25% of patients taking this medication develop a transient asymptomatic rise in serum aminotransferase levels. Symptomatic hepatitis, cirrhosis, and hepatic failure are rare complications which involve less than 3% of patients.3,4 Histological features of oral amiodarone hepatitis are similar to alcoholic hepatitis and include steatosis, fibrosis, and phospholipid laden lysosomal lamellar bodies. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction.5 There was a mild total bilirubin elevation to 0.9 mg/dL; therefore, this case of drug-induced liver injury (DILI) did not meet Hy’s Law criteria, which states that hepatocellular injury accompanied by a total bilirubin elevation over twice the upper limit of normal is of significant concern and has a mortality of 10%–15%.6 Intravenous amiodarone is typically used as a short-term therapy for various arrhythmias (as mentioned previously). It is metabolized to N-desethylamiodarone (DEA) by cytochrome P450 enzymes (CYP3A4 and CYP2C8). Its metabolite is also an antiarrhythmic. Amiodarone is primarily eliminated by biliary excretion. Left ventricular dysfunction prolongs the half-life of DEA. Acute hepatitis, due to parenteral therapy, is extremely rare.7 Our literature review identified 33 previously reported cases. The underlying mechanism is controversial and still unknown. Ischemic hepatitis, a much more common condition, shares many clinical and histological characteristics that are seen in parenteral amiodarone-induced liver injury. It has been hypothesized by Gluck et al that the acute liver injury following the IV formulation is related to liver ischemia, rather than direct drug toxicity.8 This was based on the observation that the two conditions show similar histological features and clinical events. Furthermore, DILI caused by oral and IV amiodarone demonstrate different histologic findings. The majority of patients receiving the IV form are suffering from unstable tachyarrhythmias, which may result in a decreased cardiac output, hypotension, and ischemia. Most patients described in the reviewed cases had evidence of poor forward output, hepatic venous congestion, impaired circulation and acute kidney injury, predisposing them to ischemic hepatitis. Finally, another report by Lahbabi et al ascribes responsibility of liver toxicity to solubilizers such as polysorbate 80 in the IV amiodarone preparation.9 Polysorbate 80 has been implicated in the E-Ferol syndrome characterized by renal failure, hepatosplenomegaly, and jaundice. Eliminating polysorbate 80 by the oral route demonstrated the safe use of amiodarone even after acute hepatitis in several studies. Our patient showed evidence of impaired left ventricular function with an LVEF of 30% by ECG (decreased from 50% one month prior to admission). Also, there was evidence of acute elevation of her creatinine from 0.7 to 1.1 mg/dL, suggestive of a degree of hypoperfusion. Hepatojugular reflux was elicited and central venous pressure was elevated subsequent to liver injury. The causal correlation is not clear as to which condition (cardio–renal dysfunction or liver failure) induced the other. We believe that in susceptible elderly patients, even the standard intravenous amiodarone dose may cause direct drug toxicity and hypotension, especially in the setting of heart failure, leading to hepatic injury. Further research is needed to support a true acute amiodarone hepatotoxicity versus other proposed or even unknown mechanisms (Figure 2). Six fatal cases of IV amiodarone hepatitis have been reported, suggesting the severity of this condition (Table 2).10–34 Elevation of transaminases occurred within 24 hours of drug administration in most patients. The majority of these cases were associated with some degree of cardiac dysfunction and renal failure. Our case was fatal in 12 weeks due to progressive pump failure, and the DILI event may have been a harbinger of mortality. The mechanism of progressive left ventricular failure may have been secondary to the impact of systemic inflammation, neurohormonal stress, and microcirculatory dysfunction caused in part by the acute organ failure of the liver (Figure 3). We believed persistent hepatic venous congestion played a role and may have been a determinant. This case suggests that one should regularly obtain a liver function panel subsequent to parenteral amiodarone initiation and proceed with caution in the setting of heart failure and hepatic congestion.
Title	Discussion
Section	Conclusion Amiodarone is often used to treat life-threatening arrhythmias in the setting of acutely decompensated heart failure. In the presence of hepatic congestion, the IV preparation of amiodarone may cause acute liver injury, which can be a harbinger for a fatal outcome in the days to months after administration. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.
Title	Conclusion

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