Acetaminophen: hepatotoxicity and treatment methods Director talks about liver disease

After the oral treatment amount of paracetamol, the plasma concentration reaches a peak
in 30~120 minutes.
90%~95% of acetaminophen entering the human body is metabolized by the liver, of which 4%~5% of the drug is metabolized to N-acetylimidoquinone (NAPQI) by the liver cytochrome P450 oxidase system, which can quickly combine with glutathione in the body into water-soluble non-toxic compounds and excrete
in urine.
If a large amount of acetaminophen is taken, the NAPQI produced by metabolism can not be bound by limited glutathione, but instead binds to the sulfhydryl group of the protein in liver cells, and the product can cause liver cell damage, necrosis, severe cases can cause liver and kidney failure, hepatic encephalopathy, cerebral edema, hypoglycemia, hypotension, and even death
.
Factors that reduce the risk of glutathione (fasting, malnutrition, alcoholism) may exacerbate acetaminophen poisoning
.

The first toxic side effect of acetaminophen is dose-independent and manifests as a constitutional allergic reaction, which can lead to severe allergic reactions when used at standard doses, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Both syndromes can be life-threatening and both may be accompanied by evidence of
liver damage.
Such cases are rare, but once they occur, the condition is often dangerous, and treatment requires a combination of corticosteroid pulse therapy and hemofiltration
.

The second toxic side effect is liver damage at a safe dose, the overall daily dose is less than 3g, still leads to abnormal liver function in some patients, mainly manifested as liver enzymes, especially alanine aminotransferase (ALT), aspartate aminotransferase (AST) increase, usually occurs in 3~7 days, transaminases increase is mildly elevated (<3ULN), but there are still about 30%~40% of patients with transaminases will be more than 3ULN increase
.
Patients are usually not accompanied by symptoms such as nausea and vomiting, and jaundice is uncommon
.
These patients can get a significant decrease in aminotransferase within a week after stopping the drug, and may not require liver protection therapy
.

The third type, acute poisoning
.
Acute poisoning is defined as a single toxic acute intake of acetaminophen greater than 150 mg/kg in children and more than 10 g
in adults.
The average dose of paracetamol taken by Larson's series of 275 patients with acute liver failure was 24 g
.
This is the most classic form of acetaminophen liver injury, which often occurs with intentional or unintentional drug overdose, and is common after suicide
.
A single overdose of more than 7.
5g or more than 10g, liver damage usually occurs within 1~3 days after taking the drug, there are obvious fatigue, reduction, nausea, vomiting, jaundice, lethargy and even coma and other symptoms, liver function transaminases rise rapidly, often AST greater than ALT, AST up to thousands, the author has seen > 10000U/L
.
This is followed by a progressive increase in total bilirubin and a decrease in liver enzymes, typical of the bilithase isolation phase
.
It can develop acute liver failure with hepatic coma, and mortality is very high
.

The fourth type, chronic poisoning
.
The definition of chronic poisoning, or ingestion at multiple time points, varies, but generally more than 90 mg/kg per day in children and more than 4 g per day in adults are considered toxic
.
Liver damage can manifest as persistent abnormalities in liver function or progress to liver failure
.
Such patients often have an underlie of chronic liver disease, such as alcohol-dependent, which is a high-risk factor for acetaminophen liver injury, and glutathione insufficiency in alcohol-dependent patients, which is the basis
of liver injury.

Table 1 Stages of acetaminophen poisoning

In 1988, Smilkstein MJ et al.
conducted a multicenter trial of the results of 2540 patients with acetaminophen overdose taking N-acetylcysteine (NAC): 28 deaths from acetaminophen, but none of the patients taking NAC died within 16 hours after taking acetaminophen overdose; If acetaminophen is given within 10 hours of ingestion of NAC, the rate of ALT > 1000 U/L is 6%, and if acetaminophen is given between 10 and 24 hours after ingestion of NAC, the rate of ALT > 1000 U/L is 26%.

The researchers created a Rumack-Matthew nomogram to determine acute acetaminophen poisoning
.

Figure 1 Rumack-Matthew nomogram

Note: The semi-logarithmic value and time of plasma paracetamol concentration were used as the ordinate and abscissa coordinates
, respectively.
Note when using this graph: Time refers to the time
after ingestion of acetaminophen.
The 4-hour concentration does not necessarily represent the peak concentration
.
Can only be used for evaluation
after a single acute intake.
The 25% interval of the solid line includes errors in the determination of plasma concentrations of paracetamol and time estimates after excessive ingestion
.

NAC is given orally or intravenously, and activated charcoal if possible, and NAC is equally effective with intravenous and oral administration
.
Intravenous administration requires continuous infusion
.
The loading dose is 150mg/kg, dissolved in 200ml 5% D/W, dripping for more than 15 minutes; The post-maintenance amount is 50mg/kg, dissolved in 500ml 5% D/W, and dripped for more than 4 hours; Then 100mg/kg, dissolved in 1000ml 5% D/W, drip for more than 16 hours
.
The dose given to children may need to be adjusted to reduce the total amount
of fluids.

Table 2 NAC treatment regimens

Note: The difference in doses of 140 mg/kg and 150 mg/kg here is due to different specifications of NAC and can be ignored
.

NAC is still available, and the role and status of NAC in the treatment of chronic paracetamol poisoning is unclear
.
Theoretically, if acetaminophen remains (not metabolized) 24 hours > ingestion, the use of an antidote may be beneficial
.
The following methods can be used, although not yet proven effective:

If hepatotoxicity may be present (if AST and ALT are normal, acetaminophen concentrations are initially elevated), a loading dose of NAC 140 mg/kg is given orally, followed by 70 mg/kg orally every 4 hours within the first 24 hours
.
If repeated measurements of AST and ALT are normal after 24 hours, NAC is discontinued; If AST and ALT levels are elevated with repeated measurements, monitor daily and continue administration of NAC until AST and ALT are normal
.
If hepatotoxicity is suspected (particularly initial AST and ALT elevation), NAC
is given entirely.

With reasonable treatment, mortality is not high
.

Symptoms that indicate poor prognosis after 24~48 hours of acetaminophen intake include all of the following:

• The pH remained < 7.
  3 after adequate recovery

• INR>3

• Serum creatinine > 2.
  6

• Grade III (confusion and lethargy) or grade IV (retardation and coma) hepatic encephalopathy

• hypoglycemia

• Thrombocytopenia

• Acute paracetamol poisoning with cirrhosis

Mild aminotransferase elevations that occur during acetaminophen treatment are rarely symptomatic, usually undetected, disappear quickly after discontinuation of acetaminophen, and sometimes even continue at
the same dose.
This transient elevation of aminotransferases does not appear to have lasting effects
on the liver.
However, acute poisoning requires immediate initiation of NAC therapy, which can greatly save lives
.
But NAC is not known to many doctors
.

References: Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH.
Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the National Multicenter Study(1976-1985).
N Engl J Med 1988; 319: 1557-62

Tan Youwen

Chief physician Dr

Master tutor of Jiangsu University

Director of the Department of Hepatology, Zhenjiang Third Hospital, Jiangsu University

Columnist of Medical Pulse Communication