Poisoning, Acetaminophen

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Diagnosis and reasoning

This patient has presented with two disparate groups of findings which combine to form a very worrying whole: - Jaundice, hepatomegaly, right hypochondriac tenderness, altered sensorium, and asterixis: i.e. features suggestive of acute liver failure with hepatic encephalopathy. - Markedly elevated creatinine and urea levels, suggesting at acute kidney injury (AKI). Note that the combination of hepatic encephalopathy with AKI is uncommon; key diagnoses to consider include acetaminophen (paracetamol) toxicity, alcoholic hepatitis, ischemic hepatitis (shock liver), and cirrhosis with hepatorenal syndrome. Leptospirosis is another, albeit less common possibility. Note that acute viral hepatitis is usually not associated with renal impairment. There are no clinical findings suggestive of prolonged hypotension, making ischemic hepatitis unlikely; in addition, his age, the absence of a history of alcohol abuse, and lack of stigmata of chronic liver disease make cirrhosis and alcoholic hepatitis unlikely as well. Leptospirosis is unlikely, given the absence of contact with contaminated water or mud. A liver profile subsequently reveals transaminase levels in the thousands; such profound elevations are encountered in very few conditions: primarily viral hepatitis, ischemic hepatitis or acetaminophen toxicity. Note that liver enzymes are usually less than 500 IU/L in alcoholic hepatitis, and are often only marginally elevated in leptospirosis. Thus, acetaminophen toxicity does indeed appear to be the probable diagnosis; this is confirmed by the toxicology screen. Given the history of social withdrawal over the last few weeks, deliberate self-harm should be considered a likely possibility. N-acetylcysteine is the drug of choice for acetaminophen toxicity, and remains helpful even if the time of ingestion is unknown. Referral to a specialist liver unit is also important, as liver failure is a poor prognostic factor. Activated charcoal is only indicated in individuals who present within 1 to 2 hours post-ingestion. As this patient is stable, with a satisfactory GCS score, intubation is not indicated right now.


Discussion

Acetaminophen (paracetamol) is a very popular analgesic and antipyretic which is widely prescribed, and also frequently purchased over the counter (OTC). Considering its widespread usage, acetaminophen is remarkably safe when used properly; that said, it can be highly toxic in overdose. In the USA, acetaminophen poisoning accounts for 50,000 to 80,000 emergency department visits each year, as well as 26,000 hospitalizations and nearly 500 deaths; it is also responsible for half of all cases of acute liver failure (ALF). Note that the remainder of this monograph pertains to acetaminophen poisoning in adults; however, much of it is applicable to the pediatric age group as well. Acetaminophen is rapidly absorbed from the gastrointestinal tract, reaching peak concentrations within 90 minutes; the half-life typically ranges from 2 to 2.5 hours, but may be prolonged up to 4 hours in individuals with pre-existing liver disease. Subsequently, the drug is metabolized in the liver; about 10% undergoes phase I oxidation to N-acetyl-para-benzoquinone imine (NAPQI), a highly reactive intermediate compound, which is normally conjugated with glutathione to form nontoxic metabolites. High doses of acetaminophen can deplete hepatic glutathione stores, allowing NAPQI to cause damage to the liver; zone 3 hepatocytes are particularly susceptible to this type of injury, explaining the characteristic centrilobular pattern of hepatic necrosis seen in patients who develop fulminant hepatic failure (FHF). Note that acetaminophen poisoning may be due to ingestion of a single overdose (usually as an attempt at self-harm), or following ingestion of excessive repeated doses or too-frequent doses with therapeutic intent; the latter is termed repeated supratherapeutic ingestion (RSTI). In adults, the maximum recommended therapeutic dosage is 4g/day; a single acute ingestion of >7.5g is usually considered to be potentially toxic. Certain conditions are believed to increase the risk of toxicity either by increasing the metabolism of paracetamol to NAPQI, decreasing hepatocellular glutathione stores, or both; these include pregnancy, chronic alcoholism, malnutrition, and isoniazid therapy; for such persons, the toxic limit is >4g in 24 hours, or >100 mg/kg in 24 hours, whichever is less. In cases of RSTI, the toxic limits are the lesser of >10g or 200 mg/kg, in a single 24-hour period, or >6 g or 150 mg/kg, whichever is less, per 24-hour period for 48 hours or longer. Regardless of whether toxicity is a result of a single overdose, or RSTI, the clinical progression of acetaminophen poisoning can be divided into four stages: preclinical toxic effects, hepatic injury, hepatic failure, and recovery. During the preclinical state, symptoms are nonspecific, and may include nausea, vomiting, abdominal pain, and malaise; alanine transaminase (ALT) levels are within normal limits. If treatment is not initiated promptly, hepatic injury may develop as early as 24 hours post-ingestion; these patients may complain of right upper quadrant pain and tenderness, and ALT levels will be elevated. Liver injury typically peaks between 3 to 5 days after ingestion, with jaundice, coagulopathy, encephalopathy, and ALT levels >1000 IU/L; patients may subsequently recover, or progress into FHF over the next several days. Acute kidney injury (AKI) may also occur, although this is less common. The onset is usually after hepatic injury is apparent, and maximal renal injury lags behind peak liver injury. Renal recovery is also more protracted. Note that acetaminophen alone does not usually impair mental status; an altered sensorium indicates either hepatic encephalopathy, or a co-ingested centrally active drug. Metabolic acidosis may also occur, either secondary to lactic acidosis (as hepatic failure results in the inability to clear lactate), or very rarely, due to a product of the gamma-glutamyl cycle, 5-oxoproline. Following acute ingestions, the risk of hepatotoxicity can be determined by the use of treatment nomograms, such as the modified Rumack-Matthews nomogram, or the Prescott nomogram. The modified Rumack-Matthews nomogram is the most popular instrument in this regard; it is based on the principle that peak levels of acetaminophen occur within 4 hours of ingestion, while concentrations rapidly drop afterwards, with a half-life of 2 to 4 hours. A line is drawn between 200 μg/mL at 4 hours after ingestion and 25 μg/mL at 16 hours, this is called the 'probable risk line', and was based on the observation that over half of such patients developed hepatotoxicity. Another parallel line is drawn starting from 150 μg/mL at 4 hours; this is known as the 'treatment line', and is commonly used in the United States to indicate when treatment should be initiated. As mentioned earlier, certain factors are believed to potentially increase the risk for hepatic injury; however, how this should be applied to clinical practice remains controversial. As of writing, several guidelines recommend an arbitrary further lowering of the nomogram line to 100 μg/mL at 4 hours, for patients with such risk factors. It is important to appreciate that the modified Rumack-Matthews nomogram has only been validated for use up to 24 hours after an acute overdose. It is not applicable in cases where the time of ingestion is unknown, where repeated ingestions have taken place, or in patients who present >24 hours post-ingestion. Note also that acetaminophen levels performed before 4 hours will indicate whether the drug has been ingested, but cannot be plotted on the nomogram to assess the risk of toxicity. It is also important to talk about the role of the drug N-acetylcysteine (NAC) in the treatment of these patients. When administered within 8 hours after an acute overdose, NAC provides cysteine for the replenishment and maintenance of hepatic glutathione stores, enhances the sulfation pathway of elimination, and may even directly reduce NAPQI back to acetaminophen. NAC is also beneficial even after hepatic injury has occurred; it appears to enhance recovery by improving hepatic perfusion and oxygen delivery and extraction, increasing scavenging of reactive oxygen and nitrogen species, and improving mitochondrial energy production. These benefits do not appear to be limited to acetaminophen induced liver injury alone. The first step in the management of these patients is a proper risk assessment; factors to consider include the dose and concentration, clinical and laboratory features suggesting liver damage, and presence of risk factors for toxicity. After an acute overdose, a 4-hour acetaminophen level, or as soon thereafter as feasible, should be obtained and plotted on the Rumack-Matthew nomogram to assess risk. Other tests to consider include serum aminotransferase levels, electrolyte and renal function assays, and a prothrombin time and INR; these are particularly useful in patients who present more than 8 hours after an acute overdose, as well as in individuals with a history of RSTI. Activated charcoal can be considered in persons who present within 1 to 2 hours post-ingestion; however, this is not a necessity. NAC should ideally be initiated within 8 hours of ingestion if the patient's acetaminophen level plots above the treatment line in the Rumack-Matthew nomogram; if test results will not be available within this time period, the drug should be started empirically. Both oral and intravenous (IV) regimens of NAC exist; while their duration and dosage is beyond the scope of this monograph, both are highly effective. The choice of oral or IV administration depends on the clinical scenario; oral administration is more convenient, but is contraindicated in the presence of vomiting or altered mentation. Patients with liver failure should ideally receive IV therapy. Vomiting is the most common adverse effect of oral NAC; the most frequent adverse effects of IV NAC are anaphylactoid reactions such as rash, pruritus, angioedema, bronchospasm, tachycardia, and hypotension. Note that flushing alone does not require treatment, while urticaria can be managed by administration of an antihistamine such as diphenhydramine. Angioedema, hypotension, and bronchospasm should be treated with antihistamines, corticosteroids, and bronchodilators (for bronchospasm). The NAC infusion should be stopped, but it can be restarted at a slower rate 1 hour afterwards, if symptoms do not recur. Alternatively, patients with severe symptoms who do not have liver failure can be converted to oral NAC. A small number of patients who present late may develop severe hepatotoxicity and FHF; these individuals should be referred to a specialist liver unit early. The presence of poor prognostic factors such as acidosis, renal impairment, a prothrombin time (PT) in seconds greater than the number of hours since the overdose, an INR greater than 5, hypoglycemia, or encephalopathy should also prompt early referral. In patients with FHF, the King's College Hospital (KCH) criteria, Model for End-Stage Liver Disease (MELD) score, and Acute Physiology and Chronic Health Evaluation (APACHE) II score can be used to determine the potential need for transplantation. Overall, a key determinant of the prognosis is the stage at which treatment is initiated; patients who are treated during the preclinical stage have an excellent prognosis, while those who are not treated until hepatic injury has developed have a variable outcome. Individuals who present with hepatic failure have a mortality rate as high as 20% to 40%.


Take home messages

  1. Acetaminophen toxicity can occur following a single overdose, or following repeated supratherapeutic ingestion (RSTI).
  2. In patients presenting in the first 24 hours following a single acute overdose, treatment nomograms are useful in determining if therapy with N-acetylcysteine (NAC) is indicated. Unfortunately almost half of cases fall outside these parameters.
  3. Treatment with NAC virtually guarantees survival if administered within the first 8 hours following acute ingestion.
  4. As NAC is of benefit in hepatotoxicity, it should be continued beyond the usual course of therapy in any patient with signs of liver injury.
  5. Patients with poor prognostic factors or features of liver failure should be referred to a specialist liver unit early.

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