Acetaminophen poisoning-induced heart injury: a case-based review

Abstract

Purpose

Acetaminophen (Paracetamol, APAP) poisoning is frequently implicated in self-harm. Cases of acetaminophen-associated cardiotoxicity are rare in relation to the number of patients with acetaminophen poisoning. A review of acetaminophen cardiotoxicity in 1996 concluded that there was no decisive evidence demonstrating that acetaminophen overdose has a cardiotoxic effect. This review study aimed to determine whether acetaminophen could induce heart injury.

Methods

We searched for keywords of acetaminophen, paracetamol, cardiotoxicity, heart injury, heart damage, myocarditis, pericarditis, myocardial infarction, and myocardial ischemia in Web of Science, PubMed, Scopus, Embase, Google Scholar, and Persian databases. The search included articles published from January 1950 to October 2018 with no language restrictions.

Results

The search yielded 64 citations in English; 36 of the articles were excluded as they were not relevant; 5 articles were excluded since they were duplicates, leaving 23 articles. Full-text articles of the 23 citations were obtained and reviewed. Myocardial infarction, heart dysfunction and failure, cardiac arrhythmias, pericarditis, heart cell necrosis, and sudden cardiac death were reported in acetaminophen overdose.

Conclusions

Ddysrhythmias, heart failure, and various other cardiac effects could occur following acetaminophen induced hepatic failure. However, the evidence for direct injury on cardiac tissue is weak.

Graphical abstract.

Potential mechanisms for cardiotoxicity of acetaminophen

Introduction

Acetaminophen (Paracetamol, APAP) is one of the most commonly used analgesics worldwide. It has an excellent safety profile in therapeutic doses. However, aacetaminophen overdose is a major health problem worldwide [1, 2]. Hepatic injury and less commonly acute kidney injury are the major suggested consequences of acetaminophen overdose [3–8]. Indeed, acetaminophen overdose is the leading cause of fulminant hepatic failure [7, 9, 10]. The toxic effects of acetaminophen on other organ systems including the heart have also been reported [11–15]. According to a report by Lip and Vale [16], there is no decisive evidence suggesting acetaminophen overdose as having a direct cardiotoxic effect. Smilkstein [17] was of the same opinion. Clinically significant disturbances of cardiac function after acetaminophen (APAP) poisoning have been recognized in two circumstances: First, in patients with hepatic damage who do not develop hepatic encephalopathy; secondly in association with APAP-induced hepatic encephalopathy. There are many sparse reports of acetaminophen-induced cardiac effects in these two circumstances and there are few studies that have summarized its cardiac effects comprehensively. So, The aim of the current review was to collect the latest information on the issue and combine them with the previous findings to elucidate heart damage of acetaminophen and its effects on cardiac function in case of overdose. We also aimed to introduce the possible potential mechanisms of this effect.

Methods

A search was done using the following keywords: acetaminophen, Acetaminophen, APAP poisoning, intoxication, cardiotoxicity, heart injury, myocarditis, pericarditis, myocardial infarction, myocardial ischemia, electrocardiogram abnormality, heart failure, arrhythmias in Web of Science, PubMed, Scopus, Embase, Google Scholar, and Persian databases such as Iran Medex, Magiran, and the Scientific Information Database. PubMed central was searched using MeSH terms and keyword searching to gain the most relevant articles. Articles from January 1950 to October 2018 were included. Case-control, cohort, cross-sectional, and case reports were also retrieved. In order to find additional relevant articles, reference lists from the identified studies were also examined. No restrictions were imposed on language and study period. The search yielded 64 citations; 36 of which were excluded as they were not relevant; 5 articles were also duplicates, thereby leaving 22 articles for review. The procedure of the literature search and strategy for the selection of relevant documents is displayed in Fig. 1.

Fig. 1.

Flowchart of the literature search and strategy for the selection of the relevant documents

Myocardial infarction

Our literature search revealed 14 cases reporting evidence of ischemia [11, 12, 14, 15, 18–25]. Nine of these cases were in the context of hepatic encephalopathy [11, 12, 14, 15, 18, 20, 21, 24]. Three developed myocardial infarction [18, 20, 24] and five developed myocardial infarction and congestive heart failure [11, 12, 14, 15, 18].

In the absence of hepatic encephalopathy

Five cases with cardiac ischemia not associated with hepatic encephalopathy and fulminant hepatic failure have been reported [18, 19, 22, 23, 25].

Wakeel et al. [19] reported a 15-year-old female admitted to hospital 55 h after ingestion of an unknown quantity of acetaminophen (Plasma acetaminophen concentration of 41 μg/mL by admission). The patient denied any other co-ingestion. She had developed transaminitis (alanine aminotransferase (ALT):790 U/L; aspartate aminotransferase (AST): 1075 U/L). Her bilirubin concentration was 56 μmol/L and prothrombin time was 65 s. She developed dysrhythmias and hypotension 21 h following her admission (55 h after acetaminophen ingestion). Twenty-one hours after admission her electrocardiogram (ECG) demonstrated ST depression and T-wave inversion in leads II, III, aVF, and V1–4. The patient lost consciousness 25 h after her admission. Her examination revealed mydriasis and absence of brain stem reflexes and she subsequently developed ventricular tachycardia and asystole. Her autopsy revealed a dilated left ventricle, coronary artery disease, and normal valves. Myocardial histology revealed focal areas infiltrated with neutrophils, and occasional mast cells in necrotic myocardial tissue. Liver histology unveiled significant hepatocyte necrosis. Her immediate cause of death was cardiac failure.

Potfay et al. [18] presented a 29-year-old woman with acetaminophen concentration of 115 μg/mL (the time of ingestion was unknown), who developed hepatic damage (AST > 14,000 U/L, ALT >8000 U/L, lactate 5.8 mmol/L) without encephalopathy. She developed acute myocardial infarction as evidenced by the presence of acute ST elevation in inferior leads and ST segment depression in V2 and V3 on ECG. Her laboratory results revealed elevated cardiac enzymes (Creatine kinase (CK): 10,000 U/L, Creatine kinase-MB (CK-MB): 163 ng/mL and troponin >50 ng/mL). Echocardiogram showed mild systolic dysfunction. The patient was discharged and had a repeat echocardiogram done 2 weeks later revealing persistent cardiac dysfunction.

Contractor et al. [25] described a patient who overdosed on acetaminophen (25 g) with serum APAP level of 23 μg/mL 12 h post-ingestion. She developed acute myocardial infarction and heart failure 12 h after ingestion. The patient had ST elevations as well as T-wave inversions on ECG, global hypokinesia, and left ventricle systolic dysfunction on echocardiogram. The laboratory results indicated an increase in cardiac enzymes (Troponin-I: 0.241 mg/l and CK: 503 U/l). The ST-elevation resolved spontaneously within 36 h. Serial EKG’s over the next few days demonstrated the emergence of T- wave inversion, consistent with sub-endocardial injuries. Liver and renal function tests and coronary angiography were determined as normal. The patient was evaluated by a psychiatrist and subsequently discharged.

Will and Tomkins [22] reported a case of acetaminophen overdose (taking 30–50 acetaminophen tablets and serum APAP levels of 184 μg/mL 10 h and 10 μg/mL 24 h after ingestion) in a pregnant 19-year-old woman. She developed ST segment and T wave changes on ECG during days 2 to 4 of admission (ST elevation in the precordial leads and flattening of T waves in leads V3-V6 which resolved by day 7). She developed a dysrhythmia during her hospital stay. She also developed hepatic failure (AST ranged 24–1350 IU/L, serum bilirubin range 0.1–1.6 mg/100 ml). Unfortunately, potassium concentrations were not reported in this case. Note that inappropriate fluid management should also be considered in this case.

Furthermore, Armour and Slater [23] described a 29-year-old man who overdosed on acetaminophen (50 g) 23 h before admission with an acetaminophen level of 31.7 μg/ml. The patient had evidence of cardiac ischemia during days 2 to 5 post ingestion, as evidenced by ST-T segment changes in ECG which improved gradually (upward bowing of the ST segment in leads V2 and V3 with T wave inversion in leads VI to V5). Peak AST and ALT concentrations 3 days after ingestion were 3795 U/l and 6080 U/l respectively. Electrolytes were normal at the time the ECG changes were detected. He was transferred to the psychiatric ward after the resolution of signs/symptoms of acute acetaminophen toxicity.

After evaluating of the cases, it seems that the evidence for direct damage to the cardiac tissue is weak and most of cases had a speculative nature of the causation.

In the presence of hepatic encephalopathy

Ohtani et al. [14] reported a 24-year-old patient with acetaminophen-induced hepatic encephalopathy (4.8 g acetaminophen, serum level of 47.1 μg/ml at 8 h and 10.7 at 24 h after ingestion) which progressed to renal failure on hospital day 3 and heart failure on hospital day 16. The patient had low voltage signals on ECG and ventricular arrhythmia. On hospital day 24, echocardiography showed systolic and diastolic dysfunction of the left ventricle and diminished ejection fraction (EF: 41%). Cardiac dysfunction was still evident after 3 months.

Jacob et al. [24] cited a 23-year-old woman who overdosed on acetaminophen (50 g) with an acetaminophen concentration of 158 μg/mL (the time of ingestion was unknown). She developed fulminant hepatic failure. Specifically, 63 h after ingestion, her electrocardiogram displayed signs of acute ischemia (ST elevation in V1-V3 and ST depression and T-wave inversion in V4-V6 with cardiac troponin I concentration of 227.2 ng/mL). The patient died approximately 72 h off admission. An autopsy showed patchy subendocardial necrosis as well as hemorrhage of ventricles and septum of the heart.

Potfay et al. [18] described a 31-year woman with fulminant hepatic failure (Initial AST/ALT more than 5000 U/L) after acetaminophen overdose (Serum APAP level: 160 μg/mL, the time of ingestion was unknown). She had a myocardial infarction (inferior and anterolateral ST elevation on ECG; increased cardiac enzymes (CK: 811 U/L, CK-MB 65 ng/mL and troponin 32 ng/mL). Echocardiography revealed a thick interventricular septum suggesting toxic myocarditis. She developed ventricular fibrillation and died.

Jophline et al. [15] described a woman who developed hepatic encephalopathy after repeated supratherapeutic doses of acetaminophen (9 g of acetaminophen daily for one week, with an acetaminophen concentration of 35.8 μg/mL). She developed ST segment elevation in the precordial leads of her ECG 12 h after admission followed by a rise in cardiac enzymes. Echocardiography showed evidence of left ventricle dysfunction with a low ejection fraction (43%) Cardiac dysfunction resolved after 3 days and she was diagnosed with Takotsubo cardiomyopathy.

Sanerkin [21] reported a 15-year-old female who died 40 h after an acetaminophen overdose. She took 36 tablets of Lobak (each containing 450 mg paracetamol and 100 mg chlormezanone). An autopsy revealed centrilobular liver necrosis, fatty degeneration of the hepatocytes, fatty degeneration in all renal tubules, intense hyperemic zones, as well as focal areas of myocardial necrosis and fatty degeneration.

Maclean et al. [12] reported a 40-year-old woman who was jaundiced and comatose 5 days after acetaminophen ingestion (30 g). She developed sinus tachycardia (heart rate (HR): 120), hypotension, and persistent ST depressions on ECG. She died 10 h after admission.

Maclean [12] accounted a 41-year-old patient with hepatic encephalopathy and electrocardiographic evidence of myocardial ischemia after ingestion of 12.5 g acetaminophen, 375 mg of phentermine, and a small quantity of barbiturate. On examination, the patient was confused, had right upper quadrant abdominal tenderness, and hepatomegaly. Five days after the overdose, the patient developed ST segment elevation the T-wave flattening on ECG. The findings resolved spontaneously. A liver biopsy demonstrated centrilobular necrosis which resolved after 6 months.

Pimstone [20] gave an account of a 26-year-old woman who ingested acetaminophen in overdose (60–80 tablets of acetaminophen), through serum acetaminophen concentration was not mentioned. She developed hepatic encephalopathy on hospital day 4 (AST:2320, Alkaline phosphatase (KA units): 8). The next day she developed jaundice and coma. Acute ST depression appeared on the ECG without electrolyte abnormalities. The patient died on hospital day 8. Autopsy showed normal heart size with sub-endocardial hemorrhage, diffuse myocardial fibrosis, and focal necrosis in the left ventricle.

Weston et al. [11] reported a patient with inferolateral ST-T changes a few hours after acetaminophen overdose. The patient developed hepatic encephalopathy. After 5 days, he developed cardiac arrest and died. Autopsy revealed a heart with a dilated left ventricle. Petechiae were observed in pericardium and endocardium, and very small degrees of atheroma was present in the coronary arteries.

In conclusion, the patients who suffer from hepatic encephalopathy caused by acetaminophen can develop abnormalities in the ECG and cardiac function. ST/T changes were the most common ECG abnormalities identified in these patients. Almost all patients in these cases who died from acetaminophen poisoning had evidence of cardiac necrosis on autopsy. (Table 1).

Table 1.

Cardiac findings in case reports

References	Age/gender	ECG Changes	Cardiac dysrhythmias	Echocardiography	Cardiac enzymes	Autopsy evaluation	NAC	Organ damage	Out come
Pimston [20]	68F	ST-depression	NM	NM	NM	myocardial necrosis and sub endocardial hemorrhage	NM	Encephalopathy	Death
Maclean [12]	40F	Sinus tachycardia and ST depression	NM	NM	NM	NM	NM	Encephalopathy, kidney damage	Death
Maclean [12]	41 M	Rise in ST segment and Reversal and flattening of T-wave	NM	NM	NM	NM	NM	Encephalopathy	Survived
Will [22]	19F	ST-elevation in precordial leads, T wave inversion in v3- v6	Coronary sinus rhythm	NM	NM	NM	NM	Liver damage	Survived
Sanerkin [21]	15F	NM	NM	NM	NM	Myocardial necrosis	NM	Liver and kidney damage	Death
Jones & Thomas [13]	18F	NM	Ventricular fibrillation	NM	NM	Myocardial damage and liver necrosis	NM	NM	Death
Wakeel [19]	15F	Depression of ST segment and inversion of T wave in leads II, III, avf and v1-v4	Atrial and ventricular arrhythmia, VT	NM	NM	was myocardial fiber necrosis	NM	Liver damage	Death
Ohtani [14]	24F	NM	Multifocal ventricular arrhythmia	CHF and decrease in LV ejection fraction	NM	NM	NM	Encephalopathy, kidney damage	Survived
Mann [33]	31F	NM	NM	NM	NM	Dilation of both ventricular cavities, myocytes fat infiltration	NM	Encephalopathy	Death
Armour [23]	29 M	ST segment upward bowing in V2-V3 and T wave inversion in V1-V5	coronary sinus rhythm	NM	NM	NM	NO	Liver damage	Survived
Jacob [24]	23f	Ischemic injury	Accelerated idioventricular rhythm	NM	Troponin I level was 227.2 ng/ml	Patchy sub-endocardial necrosis and hemorrhage at necropsy	NM	Encephalopathy	Death
Contractour [25]	68F	New widespread ST-elevation. Remained T wave inversion in ECG consistent with subendocardial necrosis	NM	global hypokinesia, and moderate systolic left ventricular impairment	Troponin T level: 0.241 μg/l (reference range: <0.01 μg/l). Ck: 503 U/l (reference range: 26–192 U/l)	NM	Yes	NM	Survived
Mehrpour [34]	24 m	NM	NM	Decrease in LVEF and cardiac dysfunction	NM	NM	yes	Liver and kidney damage	Cardiac and hepatic failure improved but his renal failure needed hemodialysis
Jophline [15]	32F	ST-elevation in leads 1 and aVL	NM	hypokinesis of antero-apical and apical septal region of left ventricle. takotsubo cardiomyopathy	Troponin I level rose	NM	Yes	Encephalopathy	Survived
Potfey [18]	29F	Elevation of ST segmentin inferior leads and ST depression in V2 andV3	NM	mild decrease in systolic function	CK: 10,000 U/L, CK-MB: 163 ng/ml and Troponin >50 ng/mg	NM	NM	Encephalopathy, kidney damage	Survived
Potfey [18]	31F	Wide complex tachycardia and inferior anterolateral ST elevation	Ventricular fibrillation	Abnormal interventricular septal thickness	CK: 811 U/L and CK-MB: 65 ng/ml	NM	NM	Encephalopathy	Death
Weston [11]		Right axis deviation and Inferolateral ST and T-wave abnormalities	NM	NM	rise in CK	Petechial hemorrhage on pericardium and endocardium	NM	Encephalopathy	Death
Weston [11]		ECG showed pericarditis (the details not mentioned)	NM	NM	NM	NM	NM	NM	Survived

NM Not mentioned

Potential mechanisms

Ischemia in these patients may be due to several proposed etiologies. The patients described had hepatic encephalopathy, which is known to potentially cause multi-organ failure including heart failure [26]. Several mechanisms have been suggested for this condition. Liver failure can lead to severe metabolic disorders such as metabolic acidosis and increase in free fatty acids [11], all of which can cause cardiac complications. In fulminant hepatic failure, there is a reduction in vascular resistance, and cardiac output will increase accordingly in order to regulate blood pressure; however, such decompensation may lead to hypotension [27] and culminate in organ damage. These mechanisms may cause myocardial infarction and congestive heart failure in severe cases.

In some cases, ischemia occurred in the absence of fulminant hepatic failure. In these cases, other mechanisms may have contributed to myocardial ischemia. Although there is no decisive evidence regarding the direct cardiotoxic effect of acetaminophen, but some potential mechanisms have been proposed in this regard. Toxicity may be secondary to depletion of sulfhydryl groups which can cause interference with nitric oxide production and tissue perfusion [28, 29]. Further, a decline in sulfhydryl groups may interfere with endothelium-derived vascular relaxing factor (EDRF or nitric oxide), causing functional coronary ischemia [11, 16, 30].

The commonly suggested mechanism for stress cardiomyopathy is the release of catecholamines in a stressful condition [31], where some studies have shown that catecholamines, especially norepinephrine, increase in patients with hepatic coma [32]. With the physiologic insult from acetaminophen overdose, a similar cascade of events could occur leading to stress cardiomyopathy in the case of overdose. The potential mechanisms are summarized in Fig. 2.

Fig. 2.

Potential mechanisms for cardiotoxicity of acetaminophen

Heart failure

In the presence of hepatic encephalopathy

Some cases revealed evidence of congestive heart failure as a cardiac event in the setting of liver dysfunction. Mann et al. [33] observed a 31 -year-old man who developed hepatic encephalopathy and hepato-renal syndrome after acetaminophen overdose (35 g) with serum acetaminophen of 68 mg/ml on 4th day post-ingestion. He had a history of alcohol abuse. Although examination of the heart and ECG were normal on admission, an autopsy showed normal coronary vessels with dilation in both ventricular cavities indicating the presence of heart failure without any ischemic cause.

Mehrpour et al. [34] described a 24-year-old man with acetaminophen overdose (50 tablets of 325 mg acetaminophen) with no history of chronic diseases or ingesting any mediations or illicit drugs. Serum acetaminophen concentration was not reported though. This patient developed heart failure 36 h after acetaminophen ingestion, followed by respiratory distress and hypotension (systolic Blood Pressure (SBP):70 mmHg). ECG demonstrated a sinus tachycardia, and there were no notable ST changes. Chest x-ray revealed cephalization. Cardiac enzymes were normal. Echocardiogram revealed severe left ventricular systolic dysfunction (Ejection Fraction (EF): 10–15%), global hypokinesia, mitral valve regurgitation (MR), and increased pulmonary mean arterial pressure (PAP: 25). He developed renal failure and received dialysis treatment. Finally, he was discharged after 25 days, with normal liver and cardiac function.

As mentioned above, Ohtani [14] published a 24-year-old woman with acute acetaminophen poisoning (4.8 g, serum acetaminophen level of 47.1 μg/ml at 8 h). She developed severe hepatic injury (peak AST, ALT, and lactate dehydrogenase (LDH) were 32.600 U, 119.200 U and 36.500 U, respectively). Also, chest x-ray (CXR) revealed pulmonary congestion. Her ECG was abnormal with low voltage in limb leads, and evidence of ventricular arrhythmia. In this case, acute heart failure appeared approximately 2 weeks after the severe hepatic injury. On the 24th day of admission, she developed congestive heart failure (CHF). Her echocardiogram demonstrated cardiac enlargement and dysfunction of the left ventricle (EF:41%). Three months after admission when she had no clinical symptoms and EF had been normalized. Myocardial imaging revealed a decrease in radionuclide uptake in the myocardium, especially in the anteroseptal wall [14]. In conclusion, the patients that suffer from hepatic encephalopathy caused by APAP demonstrate ventricular dysfunction and heart failure.

In the absence of hepatic encephalopathy

Again in a case reported by Contractor et al. [25], the patient with acetaminophen overdose (25 g, APAP level of 23 μg/ml12 hours after ingestion) developed heart failure and acute ECG changes and experienced elevated cardiac enzymes. Echocardiogram revealed left ventricular dysfunction as well as decreased ejection fraction. On day 4 of admission, repeat echocardiogram showed normalization of ejection function and the hypokinesis observed in the first Echocardiogram. Two days later, coronary angiography indicated a small anteroapical hypokinesia and a normal E. This patient had normal liver function tests as well as a normal coronary angiogram. This patient had no past medical history and was not taking any medications.

Martyn et al. [35] described a 42-year-old female with an acetaminophen overdose (reporting an ingested dose of 372 mg/kg, serum acetaminophen concentration was reported) who developed cardiac dysfunction, a decrease in left ventricle ejection fraction, and hypokinesia. Liver and kidney function was normal, though she developed an elevated troponin at 126 ng/ml (normal range 0-14 ng/dL). After 16 h, she had a normal ECG but troponin–T had grown to 145 ng/ml. Further, 24 h after admission, she developed t-wave inversions (TWI) on ECG and troponin decreased to 84 ng/mg. Then, 36 h after admission, the TWI was still present in the ECG in V2/3/5 and 6, where Troponin T’s level dropped to 42 ng/ml. Echocardiogram showed apical akinesis and dysfunction in the left ventricle with a reduced ejection fraction.

The patient previously described in Wakeel et al. [19] study, a 15-year-old girl, who was admitted 55 h after acetaminophen overdose (unspecified quantity, plasma acetaminophen concentration of 41 μg/mL), developed cardiac failure after 80 h. She had an increase in liver enzymes but no encephalopathy. Then, 21 h after admission, the patients suffered a cardiac arrhythmia and died. The cause of death was attributed to myocardial necrosis which led to left ventricular dysfunction, hypotension, and arrhythmia. Necropsy showed a dilated left ventricle and polymorph infiltration of the myocardium.

Chung and Lin [36] performed a cohort study throughout the country to evaluate the occurrence and risk of CHF in those who suffered acetaminophen poisoning. Specifically, 3546 patients suffering from acetaminophen poisoning and 14,184 patients without poisoning were observed and examined for incidence of congestive heart failure. The rate of CHF was lower in the group that did not have acetaminophen poisoning (8.12 against 5.19 per 10,000 person-years). Subsequent to adjusting for covariates, the risk of CHF increased 1.59 times for the group with acetaminophen poisoning (adjusted hazard ratio = 1.59; 95% confidence interval = 1.43–1.75) compared to the other group.

Hubalewska-Dydejczyk et al. evaluated the myocardial function in acute acetaminophen poisoning using 99mTcMIBI GSPECT among 25 acutely acetaminophen poisoned patients in comparison to the control group. The quantitative analysis of the test revealed that the average value of left ventricle EF in acetaminophen-poisoned patients was lower than in the myocardial control group. In addition, wall motion and wall thickening assessment showed that the left ventricle function was diffusely depressed in acetaminophen-poisoned patients. The disturbances of regional wall motion of the anterior and inferior wall (LV) were mostly visible [37].

Few cases of acetaminophen poisoning showed real evidence of direct cardiotoxicity. Most of the cases had an association with acetaminophen which is not necessarily causality.

Potential mechanisms of acetaminophen induced heart failure

Toxic effects of acetaminophen in overdose leading to myocardial necrosis may contribute to heart failure observed in these patients. Furthermore, oxidative stress from acetaminophen overdose may contribute to heart failure as well [38]. The potential mechanisms have been summarized in Fig. 2.

Cardiac arrhythmias

In the presence of hepatic encephalopathy

In a clinical trial by Weston et al. [11], it was found that 70% of patients with fulminant hepatic failure and encephalopathy had cardiac arrhythmias excluding sinus tachycardia. Cases reported by Ohtani et al. [14], Jacob et al. [24], and Potfay et al. [18] all had hepatic encephalopathy. As previously described, Ohtani et al. [14] expressed a 24-year-old patient with encephalopathy who had a multifocal premature ventricular contraction (PVC) on the 16th day post-admission. This arrhythmia was synchronous with the onset of congestive heart failure.

In the case previously described in detail [24], an idioventricular rhythm developed on day 3, post-ingestion of APAP (50 g). This patient had a myocardial infarction, and the arrhythmia may have been related to that condition [39]. In a case reported previously, Potfay et al. [18] also quoted a case with fulminant hepatic failure, inferior and anterolateral MI which led to ventricular tachycardia and ventricular fibrillation and eventually death.

In the absence of hepatic encephalopathy

As previously detailed, Will & Tomkins [22] noted a pregnant patient admitted 10 h after acetaminophen poisoning (30–50 paracetamol tablets, APAP levels of 41 μg/mL 10 h and 10 μg/mL 24 h after ingestion). On hospital day 2, her ECG showed persistent ST-elevation in the precordial leads resulting in a change in T-wave inversion in v3- v6 and coronary sinus rhythm (an atrial arrhythmia).

Jones and Thomas [13] reported a patient who died due to ventricular fibrillation 40 h after unknown quantity of Paramol 118 (paracetamol 500 mg and dihydrocodeine 10 mg) tablets with Plasma APAP level of 1082 μg/ml. Wakeel et al. [19] also explained a case with acetaminophen poisoning where myocardial infarction led to congestive heart failure as well as atrial and ventricular arrhythmias 21 h after admission, after which ventricular tachycardia occurred and the patient eventually died. Armour & Slater [23] described a case where the patient was admitted 23 h after an acetaminophen overdose (50 g, acetaminophen level of 31.7 μg/ml mmol/l); on hospital day 2, ST segment elevation in V2-V3 and T wave inversions in V1-V5 developed on ECG. Electrolytes were normal when these ECG findings were found.

A cross-sectional descriptive study was conducted on 68 patients who had taken 20 acetaminophen tablets or more. In this study, the patients with multiple drug poisoning were not included. Specifically, 76.47% had a normal heart rate, while 20.59% of the patients had bradycardia and only 2.94% had tachycardia; 14 individuals (20.59%) had 1st degree atrioventricular (AV) block. In 39.70%, 27 individuals, the level of acetaminophen in the serum could be detected, where in 30.88%, 21 individuals, ALT was ≥1000 IU/L [40].

In conclusion, coronary sinus rhythm in acetaminophen overdose could be considered as one of the most important atrial dysrhythmias. Nevertheless, other kinds of atrial dysrhythmia have also been evident [19, 22, 23]. Among the ventricular dysrhythmias, VT and VF were the most common types and responsible for deaths in acetaminophen poisoning [13, 14, 18, 19, 24].

The records used for evaluation of cases with acetaminophen cardiotoxicity reported different times for initiation of a cardiac event. Most cases, with or without hepatic encephalopathy, had a cardiac event within the first 3 days; some experienced on the fifth day; and some showed evidence of cardiotoxicity up to the 16th day after ingestion [14]. As Dixon reported [41], some patients had a cardiac arrest within the first 24 h. Some cases of delayed cardiotoxicity had a cardiac event while there was no evidence of hepatic failure. This suggests that cardiac damage may have occurred even in the absence of liver damage. Furthermore, some cases had a transient cardiac event; accordingly, lack of morphological evidence suggesting cardiotoxicity does not reject this possibility [16]. Therefore, a cardiac event might be expected in patients with acetaminophen poisoning. Nevertheless, there are very few cases of actual evidence which can be considered causality regarding APAP. Note that most of the cases had an association with APAP which is not causality.

Potential mechanisms of acetaminophen induced cardiac arrhythmia

Some suggested mechanisms for cardiac dysrhythmia induced by acetaminophen are as follows: Dysrhythmia may be secondary to ischemia, CHF, free fatty acids, and increasing oxidative stress as well as secondary to metabolic derangements [11]. All cases for whom arrhythmia had been reported had myocardial ischemia with or without hepatic encephalopathy. Hypoxia in patients with fulminant hepatic failure increases susceptibility of the heart to arrhythmias through central nervous system [42]. These causes may be considered as a temporal association. There is no clear evidence for causality of these reasons in heart damage through acetaminophen. Some studies have shown that an increase in free fatty acids is a risk factor for cardiac arrhythmias in patients with myocardial infarction [43]. Rise in intracranial pressure through catecholamines and the vagus nerve may also contribute to arrhythmia [44, 45]. Arrhythmias can also be introduced by myocardial ischemia via increased sympathetic activation [46].

Oxidative stress may be a possible mechanism of arrhythmia. In addition to oxidative stress caused by myocardial ischemia [47], acetaminophen can produce oxidative stress in cells [48] where oxidative stress in turn may cause cardiac arrhythmias [49, 50]. Concerning the cases described with arrhythmia following acetaminophen poisoning, all or some of these mechanisms may explain arrhythmia (Fig. 2).

Pericarditis and myocarditis

In the presence of hepatic encephalopathy

Pericardial involvement was also evident in some cases. Again in the report of Weston et al. [11], pericarditis has been described in one patient of acetaminophen overdose (50 g) with ST-T segment changes in ECG. The patient went into a hepatic coma and subsequently died 5 days later from an asystolic cardiac arrest; the post-mortem examination indicated the dilation of the left ventricle and petechial hemorrhage in the pericardium. In order to assess the cardiotoxic effects of this medicine, they performed 12-lead ECGs and serum cardiac isoenzymes in ten patients with acetaminophen overdose who never became encephalopathic. Among them, one patient showed an increment of serum creatine phosphokinase and the patient’s ECG suggested pericarditis.

In the report mentioned above, Jones and Thomas [13] also described an 18-year-old female who was admitted 12 h after ingesting an unknown quantity of Paramol 118 (paracetamol 500 mg and dihydrocodeine 10 mg) tablets whose serum acetaminophen level was 1082 μg/ml. Her examination revealed mydriasis, cyanosis, and severe hypotension shortly before cardiac arrest. The serum AST level which was 250 U/L upon the patient’s admission, rose to 644 U/L. An autopsy showed hemorrhage in the visceral pericardium as well as necrosis in the center and mid-zone of the liver.

As previously described, Maclean et al. [12] announced a 41-year-old patient with acetaminophen overdose (12.5 g) where cardiac examination on the 5th day of admission revealed a friction rub and ECG changes including ST segment elevation and T-wave flattening and inversion, suggesting pericarditis. Note that electrolytes were normal.

Gosselin et al. [51] reported a case of an 18-year-old woman suffering from personality disorder who had attempted suicide by taking acetaminophen (~40 pills of unspecified strength), quetiapine, acetylsalicylic acid, and ethanol. She had been brought to the hospital a few hours after the ingestion. The time of ingestion was unknown. By admission, the serum acetaminophen was 43.05 μg/mL. Although acute damage to the liver became apparent 12 h after the admission, the patient’s condition was stable, and she was awaiting a liver transplant. Electrolytes were normal. The peak AST and ALT concentrations were 6206 IU/L and 2176 IU/L, respectively. Creatine kinase level was 3614 IU/L. Twenty hours after admission, the electrocardiogram showed ST elevation in leads III and V3 to V6, a corrected QT (QTc) interval of 540 milliseconds, and atrial fibrillation. Cardiac biomarkers suddenly aggravated progressively. She had ST elevation on ECG. Acute myocardial infarction was ruled out by angiography; cerebral edema was also excluded through a computed tomographic scan. However, 40 h after her admission, the patient died due to a cardiac arrest. Autopsy revealed acute toxic myocarditis secondary to acetaminophen poisoning.

Potential mechanisms of acetaminophen induced pericarditis

Pericarditis as a drug side effect is reported for some drugs [52–56]. The possible mechanism suggested for this is allergic reaction and hypersensitivity to the drug [57–60]. Weston et al. [11] demonstrated that thrombocytopenia and hypoalbuminemia which emerge in the subsequent stages of hepatic failure may lead to development of petechial hemorrhage and pericardial effusion. Given the variety of drugs that cause pericarditis, it is possible that pericarditis caused by acetaminophen is also an allergic reaction (Fig. 2).

Toxic metabolites: N-acetyl-p-benzoquinone imine (NAPQI) and reactive oxygen species (ROS)

The hepatotoxic effect of acetaminophen is due to a highly reactive metabolite, NAPQI, which binds to hepatic cells and has probably other toxic effects. It is conjugated and deactivated by glutathione. However, glutathione levels become depleted in acetaminophen overdose. Acetylcysteine is a glutathione precursor and sulfhydryl group donor. Mechanisms involved in acetaminophen induced hepatotoxicity can also be considered for cardiotoxicity [23]. According to studies, increased sulfhydryl availability by administering acetylcysteine has been demonstrated to potentiate the vasodilatory response to nitroglycerine and to reverse nitrate tolerance [23, 61, 62]. It is, therefore, suggested that an acetaminophen-induced depletion of sulfhydryl groups might interfere with endothelium-derived vascular relaxing factor (EDRF), the body’s endogenous nitrate, while also causing a functional coronary insufficiency. It is also possible that the acetaminophen’s toxic metabolite depletes myocyte glutathione, induces a negative effect on the myocardium and, as a free radical, may result in EDRF breakdown [23]. One study assessed the toxic effect of acetaminophen and NAPQI on auditory cells and suggested that acetaminophen and NAPQI induced toxic effect via triggering both oxidative stress and endoplasmic reticulum stress; specifically, one response led to cell apoptosis and the other to cell necrosis where the balance of these two mechanisms was dependent on cell type [63]. According to other studies, NAPQI targets mitochondrial proteins and ion channels, causing loss of production of energy, misbalance in the ion, and cell death [64, 65]. Studies have suggested that acetaminophen itself may induce oxidative stress in cells [66]. However, in addition to its effect in producing ROS, free oxygen radicals can be generated following ischemia developed by the mechanisms discussed above. Exposure to ROS leads to myocardial cell dysfunction and apoptosis via local chemical reactions and genetic alterations such as up-regulation of apoptotic factors and down-regulation of anti-apoptotic factors [43]. Note that ROS impairs contractile function, and triggers a wide range of hypertrophy signaling kinases. It also encourages increased proliferation of cardiac fibroblast while also activating the matrix metalloproteinases (MMPs), which result in the remodeling of the extracellular matrix. All these are involved in the growth and evolution of myocardial remodeling and failure [38]. Some studies also showed that oxidative stress plays some roles in cardiac arrhythmias which is mediated by calcium [50, 67]. Cardiac myocytes have poor antioxidant defense mechanisms making them more susceptible to oxidative stress. Accumulation of reactive oxygen species leads to cardiac Ca2+ overload, which in turn induces delayed after depolarizations (DADs). This is likely to trigger ventricular arrhythmias or sudden death [50].

Other possible mechanisms of cell injury

There are some other suggested mechanisms for acetaminophen cell injury. ATP depletion in cells caused by acetaminophen may lead to cell damage [68]. Acetaminophen binds covalently to proteins of the heart and liver and thus may alter their structure and function [69]. It can also bind with hemoglobin and change its structure and function [70]. In another study, cardiovascular tissue treated with acetaminophen revealed mild vascular congestion inflammatory change ssuch as myocyte coagulation [71]. One study used the heart cells of newborn rats and rat hepatocytes and confirmed that a significant overdose of acetaminophen was cardiotoxic [72]. These explanations present possible pathways of acetaminophen toxicity in cells, especially heart cells. There are, however, many unknown mechanisms related to this drug which can affect cardiac cells and their function, and these need further investigation.

Does Acetylcysteine prevent cardiotoxicity?

Acetylcysteine is the most common antidote administered to patients with acetaminophen poisoning for prevention of hepatotoxicity. This drug is a glutathione precursor and prevents hepatic injury by restoring glutathione [73], and this is its most important mechanism. Another suggested mechanism is scavenging free radicals [74]. Now the question is whether acetylcysteine prevents toxicity in other organs such as the kidney and heart by acetaminophen. It has been proposed that acetylcysteine does not prevent renal toxicity and may even contribute to kidney damage; nevertheless, it is not considered to cause worsening of renal damage [40]. The effect of acetylcysteine on acetaminophen-associated cardiotoxicity requires further research. In other words, the case reports with acetaminophen cardiotoxicity using acetylcysteine are inadequate to develop an understanding for determining an acceptable result. Theoretically, glutathione turnover in the heart is very slow [75]; so acetylcysteine may restore glutathione in the heart, and may have a protective effect for acetaminophen cardiotoxicity or may be beneficial in its ability to limit or even reverse the damage. It is possible that in some cases, given their acetaminophen cardiotoxicity mechanism, acetylcysteine may or may not be protective.

Study limitations

In this review, 23 studies were found which addressed the cardiotoxicity in the setting of acetaminophen overdose. For most reports on acetaminophen overdose, the focus of authors in describing patients was on hepatic and renal complications, and some may have not captured cardiotoxicity associated with this overdose. In those that did report cardiotoxicity, causality between acetaminophen overdose and cardiotoxicity has not been established, and few of these cases meet the criteria for causality between acetaminophen overdose and heart damage. Causality can be deduced based on clear evidence which is lacking in most of these cases. Some cases had ingested multiple agents, and the other compounds may also have contributed to or caused the reported effects [12, 13, 21, 51]. Some cases have been based on only the history of ingestion and did not have evidence such as laboratory levels of APAP [11, 12, 20, 21, 34, 36, 37, 40] and/or other drugs. Without evidence, many of these case reports may be speculative and unproven. Also, the proposed mechanisms are speculative and do not have a robust volume of data to support them.

Conclusions

In this study, we summarized the literature regarding heart injuries in acetaminophen-overdosed patients in two settings of with and without hepatic encephalopathy. In conclusion, reported abnormalities in the ECG, ventricular dysfunction, heart failure, pericarditis, and myocarditis are observed more commonly in patients with acetaminophen-induced hepatic encephalopathy. Note that symptomatic or clinically discernible disturbances of cardiac function are rare after acetaminophen poisoning, and nonspecific ECG changes without any apparent hemodynamic effect may occur. Given the low level of evidence, which was included in this case-based review, we cannot conclusively determine the causal relationships between acetaminophen poisoning and our studied effects. Based on this review, there are still many unknowns about acetaminophen cardiotoxicity. Potential cardiac side effects may be secondary effects to the acetaminophen poisoning on cardiac tissue or conduction fibers. While dysthymias and various other cardiac effects occur following fulminant hepatic failure or other significant toxic episodes, the evidence for direct injury on cardiac tissue is weak. In other words, potential cardiotoxicity due to acetaminophen poisoning may have multiple mechanisms even in one patient.

Further studies are required to characterize this potential important end organ effect of acetaminophen toxicity.

Author contributions

FKZ, SN, TK, PCN, OM contributed to conceptualization, design, and preparation of the manuscript. FKZ, SN, TK, and OM conducted the data collection and contributed to acquisition and interpretation. FKZ, SN, PCN, and OM made substantial contributions to drafting the manuscript and revising it critically for important intellectual content. All authors have read and approved the final version of the manuscript.

Compliance with ethical standards

Competing interests

The authors declare no competing interests.