Paracetamol-Induced Hepatotoxicity

Abstract

Drug-induced hepatotoxicity is common in clinical settings, one of the commonly used drugs leading to liver injury is paracetamol. It is a commonly used analgesic and antipyretic drug. The toxicity of paracetamol has been described in accidental, iatrogenic, and intentional ingestion; also, the extent of liver injury varies from person to person depending on host factors, nutritional status, age, etc. The toxicity of paracetamol is not usually recognized by clinicians as initially, the symptoms are subtle. There is a specific antidote available for paracetamol-induced liver injury to prevent acute liver failure; however, it needs to be given time for proper action, therefore a strong clinical suspicion is to be taken when there is no proper history of ingestion.

1. Introduction

The liver contributes significantly to the metabolism and removal of drugs from the human body [1]. Metabolization of drugs and xenobiotics to nontoxic substances in the liver by enzymes is important for the proper function of the body, alteration in these statuses leads to a shift of metabolism toward the production of oxidants, which coheres to lipids or nuclear proteins which results in mutations, membrane damage, and alteration of enzyme activity respectively which further leads to organ malfunction. The production of oxidants is the most common action in the pathogenesis of liver damage by pharmaceutical drugs and herbal products [2]. Liver damage may occur due to environmental toxicants, drugs, and microbial metabolites. There are two sets of enzymes, phase I and phase II enzymes which play a very important role in the metabolism and detoxification of various drugs and other toxins. Paracetamol is one of the most commonly used drugs as an analgesic and antipyretic, it is a structural analog of phenacetin, which was withdrawn due to concerns for nephrotoxicity. Paracetamol is relatively safe compared with other NSAIDS; however, overdose can cause a spectrum of liver injuries from mild elevation in liver enzymes to acute liver failure and encephalopathy [3]. A lot of research has been conducted to know the pathogenesis of paracetamol-induced liver toxicity. N-acetyl cysteine (NAC) is used as an antidote for paracetamol-overdosed patients; however, it should be administered as early as possible [4]. It has now been recognized that paracetamol toxicity consists of multiple pathways, including paracetamol metabolism, oxidative stress, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and compensatory liver repair and regeneration. Some patients with liver failure require liver transplantation for survival [5]. In this chapter, we have discussed the paracetamol-induced hepatotoxicity, pathophysiology, and factors that increase the risk of its toxicity, prevention, treatment, and patient outcome.

2. Epidemiology and pathogenesis

2.1 Incidence of hepatotoxicity

Paracetamol overdose is among one of the commonest causes of acute liver failure in some countries. The common settings for paracetamol-induced liver injury are suicidal overdose, unintentionally or accidentally in alcoholics, and with therapeutic use [6]. Studies done in the adult population have shown the most common etiology of acute liver failure (40%) was paracetamol overdose, more with unintentional intake rather than taken for suicide [7, 8]. However, a multicenter prospective study of pediatric patients reported that only 14% of acute liver failure is attributed to paracetamol overdose [9]. In a study on patients with an unintentional overdose of narcotic users, around 30% of patients were also taking over-the-counter paracetamol along with narcotic drugs. Patients sometimes are not knowing that their pain-reliving medicines advised by a physician are in combination with paracetamol and thus may take these medications along with oral over-the-counter paracetamol resulting in overdose. Due to delayed presentation and treatment, risk of mortality is comparatively more with unintentional overdose rather than intentional overdosage [10]. In 19% and 12.5% of indeterminate ALF, paracetamol-protein adducts were identified [11, 12]. In chronic alcoholics, paracetamol-induced hepatotoxicity has been well recognized and reported to occur at lower doses compared with non-alcoholics [13, 14]. In a study on chronic alcoholics with paracetamol hepatotoxicity, the average toxic dose of paracetamol was 7 g per day; however, a lower dose of 2.5 g per day has also found to cause toxicity [15]. Paracetamol hepatotoxicity had been found with ingestion of therapeutic doses in individuals with malnutrition, advanced age, chronic pulmonary diseases, cardiac dysfunction, and chronic liver disease [16]. Drug interactions of paracetamol with other drugs (e.g., anticonvulsants, antitubercular) also result in hepatotoxicity at lower doses [17, 18].

2.2 Toxic dose in adults and children

In single oral ingestion, the toxic dose for children is more than 200 mg/kg of body weight, whereas in adults and adolescents, it is more than 7.5 g. In children younger than 6 years of age, toxicity occurs after ingestion of more than 75 mg/kg body weight per day. Acute toxic dose is in a single dose in repeated dosing [19], However, toxic dose also varies in different ethical groups like in Japanese lower doses may cause intoxication [20]. Children are found to be less sensitive to acute intoxication than adults, and this may be due to larger glutathione stores and comparatively larger liver [21].

2.3 Pathophysiology

Paracetamol enters the enterohepatic circulation after absorption in the gut and the liver by glucuronidation and sulfation 95% of its metabolized, and only a small amount of the drug is removed by the kidneys. In therapeutic doses, 2.7 hours is the mean elimination half-life of paracetamol ingestion [22]. N-acetyl-p-benzoquinone imine (NAPQI) is formed by oxidation reaction in approximately 5% fraction of the drug, and this further binds to cysteine, DNA, and lipids. Antioxidant glutathione (GSH) detoxifies NAPQI by forming a mercapturic metabolite, which is removed by the kidneys (Figure 1). On ingestion of a higher dose of paracetamol, intracellular GSH is depleted and there is a relative shunting of the metabolism of paracetamol toward oxidation, thus forming increased amounts of NAPQI. CYP2E1 has a primary role in the oxidation of paracetamol; however, some other CYP isoforms have been identified, including CYP3A4 and CYP1A2. A major portion of CYP2E1 is distributed in the centrilobular regions of the hepatic lobule, leading to centrilobular necrosis as seen on biopsy [23]. The greatest intrinsic activity toward paracetamol is of CYP2E1 and CYP3A among all known CYPs. Studies conducted in the mouse model of paracetamol overdose showed paracetamol adduct formation occurs in centrilobular hepatocytes [24] liver biopsy if done, the histopathology of liver tissue shows centrizonal necrosis and mild inflammation [25]. The main autopsy finding in those who died due to liver failure is centrizonal hemorrhagic necrosis with no or little inflammatory reaction and normal histologic appearance of portal tracts [26].

Figure 1.

Metabolism of paracetamol.

3. Clinical manifestations and laboratory findings

Paracetamol overdose identification is of significant value as an early start of treatment can prevent morbidity and mortality significantly. Many a times, patients may not tell the information about paracetamol ingestion and exact dosage. The most common symptoms are malaise, nausea with/without vomiting, and abdominal pain, as these symptoms are not peculiar leading to difficulty in making the diagnosis in absence of a history of overdose. The clinical course of paracetamol hepatotoxicity has four established sequential phases [27]. Each phase usually occurs following a fixed time interval after the paracetamol over-ingestion; however, these may be modified by factors like the formulation (mixed with opiate preparations, sustained release, etc.), co-ingestion (alcohol, herbal supplements, or other pharmaceutical drugs), and presence of chronic liver disease. The first phase starts within the first 24 hours of intake of the drug and usually has symptoms such as nausea, vomiting, muscle aches, dullness, and perspiration. However, some patients may remain asymptomatic in this phase, which leads to a delay in the diagnosis in patients who are unaware of their overdose. Biochemically liver transaminase values are usually normal in this phase. In the second phase that occurs 24 hours to 72 hours after intake, transaminases and bilirubin begin to rise and prothrombin time may be prolonged [28, 29]. Liver transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] may rise to several thousand IU [30]. There are lesser increases in alkaline phosphatase and bilirubin. In phase III that occurs 72 hours to 96 hours after ingestion, liver injury occurs maximally in this phase and is characterized by continued progression of hepatotoxicity, possibly fulminant hepatic failure, and the onset of multiorgan system failure and hypoglycemia, jaundice, oliguria, acute tubular necrosis, encephalopathy, coagulopathy and lactic acidosis, central nervous system symptoms including confusion, somnolence, or coma. The risk of mortality is maximum in the third phase, mostly due to multi-organ dysfunction. There is a “two-hit” mechanism in the development of lactic acidosis one is that NAPQI in excess causes mitochondrial dysregulation, which is further followed subsequently by tissue hypoxia and decreased hepatic metabolism and clearance of lactate [8, 31]. Phase IV occurs after approximately 96 hours after the recovery from the third phase, the patient may either die from liver failure and its complications or start to recover. Those who improve liver functions usually return to normal within three weeks, with the histological improvement of the liver within 3 months. Usually, the fourth phase lasts for 1 to 2 weeks, but its duration varies from patient to patient. Aminotransferase elevations usually resolve within two weeks duration. An early signal of severe toxicity is prolonged prothrombin time within 30-hour of paracetamol ingestion [32]. Usually, bilirubin levels do not go higher as compared with liver failure due to other etiology [33]. Acute renal failure may occur in association with hepatotoxicity and also can occur as the liver injury is improving and some may even need dialysis [34, 35, 36]. A distinguished feature of paracetamol overdose in chronic alcoholics is seen in which laboratory abnormalities may include extremely high serum aminotransferase levels (AST > ALT) and prolonged prothrombin time within a small time frame of ingestion [37].

3.1 Kings college criteria

King’s College criteria are used for mortality prediction in ALF caused by paracetamol. The criteria include the presence of metabolic acidosis (arterial pH < 7.30) alone OR the presence of these three: Grade III or IV hepatic encephalopathy (HE), prothrombin time (PT) > 100 sec, and creatinine level > 3.4 mg/dL [38].

4. Treatment

4.1 General management

On assessment of paracetamol overdose, a detailed history should be taken, which should include ingested dose, co-intake of other pharmaceutical drugs or herbal medications, alcohol intake (acute and chronic), presence of any liver disease or disorder, and any other co-morbidity. Biochemical parameters including serum AST, ALT, bilirubin, prothrombin time, blood urea nitrogen (BUN), creatinine, electrolytes, complete blood count, and urinalysis should be done. The plasma paracetamol levels should be sent for measurement ideally 4 hours after ingestion or as early as 24 hours, but not before 4 hours because continuous absorption of paracetamol leads to falsely low levels. The test should be repeated after 4 hours of the first test and then at 16, 24, and 32 hours after ingestion. Management for paracetamol overdose includes prevention of absorption from the gut, elimination of absorbed paracetamol from the blood, inhibition of formation of toxic metabolite NAPQI, and detoxification of NAPQI. The timing of presentation and the degree of hepatic decompensation guide the choice of therapy. Gastric lavage, administration of activated charcoal, and ipecacuanha (induces emesis) can prevent or decrease gut absorption within the first few hours after ingestion [39, 40]. NAC is used as an antidote in paracetamol overdose, and if initiated within the first 8 hours from the time of ingestion or overdose, a good response is seen. Methionine and cysteamine also cause detoxification of NAPQI, but have shown severe adverse central nervous system effects so not used commonly [41]. It has been found that starting NAC therapy as late as 36 hours after overdose leads to a significantly better outcome in paracetamol hepatotoxicity [42]. NAC acts by restoring glutathione levels (hydrolyzed to cysteine, which restores glutathione), attaching to NAPQI and by increasing conjugation reaction in hepatocytes leading to the formation of non-toxic products [43]. Mortality from paracetamol overdose had declined from 5% without the use of antidote to 0.7% with the use of NAC. Cimetidine was used initially to prevent the formation of NAPQI as it inhibits cytochrome P450 but was not effective in many trials [44, 45]. Liver transplantation should be considered to prevent mortality in selected cases.

4.2 N-acetylcysteine

The standard dosage of oral NAC is a single dose of 140 mg per kg and after that 17 doses of 70 mg per kg over 72 hours. The total dose thus will be 1330 mg/kg. The standard dosage of intravenous NAC is typically three weight-based doses; the first dose is 150 mg per kg in the first 1 hour, the second dose is 50 mg per kg to be given over 4 hours, and lastly, third dose is 100 mg per kg to be given over 16 hours [46]. Higher hepatic concentrations can be achieved by oral NAC therapy, and the only issue is that it is unpalatable, also difficult for children to consume so many doses, and may cause vomiting. Intravenous N-acetylcysteine therapy results in higher plasma concentrations and is more convenient for those who are vomiting; side effects of parentally given NAC can be an allergic reaction, which is mostly mild and treated by antihistaminics and by temporarily stopping intravenous NAC [47].

4.3 The Rumack: Matthew nomogram

The Rumack–Matthew nomogram is the semilogarithmic plot of plasma paracetamol levels with time and is used to assess potential hepatotoxicity. This nomogram was developed retrospectively based on data from patients who has single paracetamol overdose and acute ingestions of paracetamol and had not received treatment with the antidote. The nomogram forecasts potential toxicity from 4 hours to 24 hours following ingestion. The upper line of the nomogram is the “probable” line, also known as the Rumack–Matthew line (Figure 2). Around two-third of a patient with paracetamol levels above this line will have a liver injury. The lower line is the “possible” line and includes a 25% margin of error in level estimation discrepancy or unreliable ingestion time. Using the Rumack–Matthew nomogram patients treated with supportive care only who had paracetamol levels above the probable hepatic toxicity line had a 14–89% incidence of hepatotoxicity and a mortality of 5–24% [49, 50]. Poor prognostic signs identified are age group >50 years a plasma factor V concentration < 10% of normal [51].

Figure 2.

Rumack–Matthew nomogram: Serum paracetamol concentration vs. time post ingestion. Taken from Rumack and Matthew [48].

4.4 N-acetylcysteine dosing and Rumack–Matthew nomogram

In a case of single ingestion of paracetamol overdose, obtain paracetamol concentration at as early as possible but not before 4 hours. If the paracetamol concentration on the Rumack–Matthew nomogram is above the “treatment line” (the line connecting 150 μg/mL [993 μmol/L] at 4 hours and 4.7 μg/mL [31 μmol/L] at 24 hours), administration of NAC is indicated. If time of ingestion is not known exactly, then it is less than 24 hours post-ingestion NAC should be started, if plotted above treatment line. In a case where patient has ingested extended-release formulations or co-ingested with other drugs like opioids, anticholinergics, or other medications that slows gut motility, if the initial 4-hour concentration plots above the treatment line, NAC should be initiated within 8 hours post-ingestion [52].

4.5 Management for acute liver failure

Acute liver failure is defined as severe acute liver injury for fewer than 26-week duration with encephalopathy and impaired synthetic function (INR >1.5 or higher) in a patient without pre-existing liver disease. ALF can lead to multiorgan dysfunction, which can present as hypotension, acute renal failure, coagulopathy, encephalopathy, sepsis, and cerebral edema. Intensive care is needed for patient with acute liver failure as they may deteriorate rapidly. A proper centra venous line and arterial line for hemodynamic monitoring and, as well as a urinary catheter for urine output monitoring. Coagulation parameters, blood counts, metabolic panels, blood sugar, and arterial blood gases are to be measured with proper time intervals. The neurological status should be evaluated regularly, for cerebral edema and intracranial pressure monitoring when intracranial hypertension is identified [53, 54]. Patient should be admitted in intensive care unit in presence of encephalopathy and coagulopathy. Due to risk of rapid deterioration, a proper communication with liver transplant centers should be done and transfer decisions should be considered for those who had rising INR, rising creatinine or decreasing urine output, metabolic acidosis, hypotension, or/and encephalopathy [55]. Retrospective study showed treatment after 10–36 hours with NAC was associated with a mortality of 37% when compared with 58% in patients given supportive treatment only, while prospective study with 50 patients with established liver failure showed mortality was 20% in the treated group versus 48% (P < 0.05) in the controls [56, 57]. Liver transplantation is another therapeutic option for patients with paracetamol-induced fulminant hepatic failure. Early recognition of poor prognostic factors can be useful in determining need for transplant and providing time to obtain a donor. Many factors affect survival, and the development of ALF after paracetamol overdose ALF in pediatric patients had 100% survival with grade II, but only 18% with grade III, also the development of cerebral edema reduced survival to 22% [58]. Significantly better survival is reported for patients who sought medical care within 24 hours of ingestion compared with later presentation. The overall mortality is as high as 28% for patients who develop ALF from paracetamol overdose, which is better than rates for ALF due to other causes. Reported survival rates for paracetamol-induced ALF vary from 65–73% without liver transplantation. Requirement of inotropic support is a poor survival factor and survival rate is below 10% in patients with metabolic acidosis that failed to respond to adequate fluid resuscitation [59]. Serum creatinine concentrations and PT are closely correlated with survival. Survival rate of 80% patients for peak PT below 90 seconds, which reduces to 8% around for PT beyond 180 seconds [60]. Survival rate is around 65% for patients with serum creatinine below 100 mmol/L, which reduces to 23% if above 300 mmol/L. Requirement of liver transplantation was less in paracetamol-induced ALF than ALF due to other causes [61]. In a recent study, overall survival rate after liver transplantation was about 70%, with 1-year survival of 73% after 1 year and 67% at the end of 5 years. Multiorgan failure and neurologic complications are attributed for most of the deaths after liver transplantation [62].

5. Conclusion

The morbidity and mortality from paracetamol overdose vary from patient to patient, and also depend on underlying comorbidities, nutritional status, history of alcoholism and co ingestion of other drugs. Overdose nay result in mild liver injury, clinically significant hepatotoxicity, or death, and timely administration of antidote directs prognosis. Death from paracetamol overdose in developed countries has decreased to 1–2% after the use of N-Acetyl cysteine, which was previously much higher (6–25%).

Conflict of interest

The authors declare no conflict of interest.