Acetaminophen Intoxication

Acetaminophen has been approved for OTC use since 1960

Although the drug is remarkably safe, toxicity can occur even with therapeutic doses.

Alcoholics are particularly susceptible to hepatotoxicity

Therapeutic dose of acetaminophen is 10-15 mg/kg/dose in children and 325-1000 mg/dose every 4-6 hours in adults, with a maximum of 4g/day.

Biochemical Basis of Acetaminophen Toxicity

At therapeutic doses, 90% of APAP is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine

The remaining 10% is metabolized via the cytochrome CYP2E1 (P450 2E1) to a toxic, reactive, N-acetylimidoquinone (NAPQI)

NAPQI binds covalently with hepatocyte macromolecules, producing hepatic cell lysis

Biochemical Basis of APAP Toxicity With normal doses, NAPQI is rapidly conjugated

with hepatic glutathione, forming a nontoxic compound which is excreted in the urine.

With toxic doses, however, the sulfate and glucuronide pathways become saturated, resulting in an increased fraction of acetaminophen being metabolized by CYP2E1.

NAPQI begins to accumulate once glutathione stores are depleted by about 70%

Biochemical Basis of Acetaminophen Toxicity

Liver damage due to excess NAPQI can occur in four circumstances– Excessive intake of acetaminophen – Excessive CYP2E1 activity due to induction by

other drugs or chronic alcohol use– Competition for conjugation enzymes– Depletion of glutathione stores due to

malnutrition or chronic alcohol ingestion

Factors influencing toxicity

Chronic alcoholics are at increased risk of developing severe hepatic disease even at therapeutic doses

In contrast, acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing for CYP2E1

Alcohol acts at least in part by induction of CYP2E1, which results in enhanced generation of NAPQI

Acetaminophen hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure – The report describes 67 patients who developed

hepatic injury after ingestion of APAP with therapeutic intent.

– All were regular users of alcohol – Doses of APAP were in the "nontoxic" range ( 6

g/d) in 60% of the group, within the recommended range ( 4 g/d) in 40%, and at 4.1 to 6 g/d in 20%

Hepatology 1995 Dec; 22(6):1898

Factors influencing toxicity

Other drugs which induce CYP2E1 enzymes include Phenobarbital and antituberculosis drugs such as isoniazid and rifampin

Drugs such as TMP-Sulfa and AZT potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways resulting in increased CYP2E1-dependent metabolism of acetaminophen

Factors influencing toxicity

Malnutrition may predispose to APAP toxicity by a reduction in glutathione stores

There is a genetic predisposition to toxicity because polymorphisms exist in the cytochrome isoenzymes that contribute to diminished or excessive oxidative metabolism of acetaminophen

Impaired glucuronidation secondary to Gilbert's syndrome also appears to enhance toxicity

2 to 12 hours after ingestion, nausea, vomiting, diaphoresis, pallor, lethargy and malaise are seen

This is followed by temporary symptomatic improvement at 24 to 48 hours

Signs of liver involvement begin at this time, including right upper quadrant pain and hepatomegaly, elevations in the plasma levels of hepatic enzymes, and prolongation of the prothrombin time

Signs of severe hepatic damage become apparent 72 to 96 hours after ingestion

CLINICAL MANIFESTATIONS

Systemic symptoms of the first stage reappear in conjunction with confusion, marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis

Signs of severe hepatotoxicity include plasma AST levels that often 10,000 IU/L, prolongation of the PT, hypoglycemia, lactic acidosis, and a plasma bilirubin concentration above 4.0 mg/dL

Acute renal failure may also be seen at this time, due primarily to ATN

CLINICAL MANIFESTATIONS

Clinical recovery typically begins within 4 to 14 days, leading to resolution of symptoms and normalization of laboratory values over several weeks

Histologic changes vary from cytolysis to centrilobular necrosis

Centrilobular region is preferentially involved because it is the area of greatest concentration of CYP2E1 and therefore the site of maximal production of NAPQI

Histologic recovery lags behind clinical recovery and may take up to three months

CLINICAL MANIFESTATIONS

DIAGNOSIS

In the patient with a history of APAP overdose, a serum APAP level should be measured between 4 and 24 hours after ingestion

The value obtained should be evaluated according to the Rumack-Matthew nomogram for determining the risk of hepatotoxicity and the need for NAC therapy

DIAGNOSIS

Recognition of acetaminophen intoxication is often more difficult in the chronic alcoholic

Several factors contribute to this problem including the insidious onset of symptoms and failure to ask specifically about APAP use

Acetaminophen blood levels are frequently normal if the patient presents late in the course of the disease or toxicity has resulted from multiple, small ingestions over time

DIAGNOSIS Characteristic laboratory findings of APAP

hepatotoxicity include – marked elevation in plasma hepatic enzyme levels

(>5000 IU/L) – rising prothrombin time

These abnormalities distinguish this syndrome from alcoholic liver disease where transaminase values almost never exceed 500 IU/L

AST level typically exceeds that of ALT in both conditions

DIAGNOSIS

The combination of acute renal failure and liver disease with markedly increased transaminases in a chronic alcoholic should suggest the diagnosis of acetaminophen toxicity

TREATMENT

The mainstays of the therapy of APAP intoxication include gastric decontamination with activated charcoal and the administration of N-acetylcysteine (NAC)

Activated charcoal avidly adsorbs APAP, reducing its absorption by 50 to 90%

However, activated charcoal also adsorbs NAC and, by causing nausea and vomiting, may interfere with the administration of NAC

TREATMENT

NAC should optimally be given within 8 to 10 hours after ingestion

More delayed therapy is associated with a progressive increase in hepatic toxicity although some benefit may still be seen 24 hours or later after ingestion

Paracetamol (acetaminophen) poisoning. Vale, JA, Proudfoot, AT. Lancet 1995; 346:547

– No deaths in 169 patients with a treatment delay below 10 hours

– In contrast, 200 patients treated at 10 to 24 hours had a 2.0 to 7.4 percent mortality, which was still lower than the 5.3 to 10.7 mortality in 85 patients who received only supportive care.

– There was a 1.6 to 10 percent incidence of liver damage (defined as a plasma ALT or AST level above 1000 IU/L) when the treatment delay was less than 10 hours

– Comparable values were 27 to 63 percent in patients treated at 10 to 24 hours and 58 to 89 percent in those receiving supportive care.

Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of NAC[Lancet 1990 Jun 30;335(8705):1572-3]– The influence of NAC, administered at

presentation to hospital, on the subsequent clinical course of 100 patients who developed APAP-induced fulminant hepatic failure was analyzed retrospectively

– Mortality was 37% in patients who received NAC 10-36 h after the overdose, compared with 58% in patients not given the antidote

– In patients given NAC, progression to grade III/IV coma was significantly less common than in those who did not receive the antidote (51% vs 75%)

TREATMENT

NAC is indicated in – All patients with a serum APAP concentration

above the possible hepatic toxicity line on the Rumack-Matthew nomogram

– Patients with an estimated ingestion of greater than 140 mg/kg

– Patients with an unknown time of ingestion – Patients with a presentation more than 24 hours

after ingestion with elevated transaminases

TREATMENT

NAC regimen is used in the United States – A loading dose of 140 mg/kg in a five percent

solution is given either orally or via nasogastric tube

– This is followed by 70 mg/kg every four hours for 17 doses; any doses vomited should be repeated

TREATMENT

Cimetidine, an inhibitor of CYP isoenzymes, has been considered for use in acetaminophen intoxication

However, studies in humans have shown that cimetidine, given in a dose of 300 mg every 6 hours, does not reduce peak aminotransferase levels when given eight hours after ingestion

It is possible that earlier administration of higher doses might be beneficial

TREATMENT

Dialysis and hemoperfusion – In the management of patients who present late in

the course (more than 24 hours) when NAC would be of limited value, hemoperfusion may be associated with lesser elevation in plasma transaminases when compared to supportive therapy alone or to the administration of NAC.

TREATMENT

Liver transplantation – Orthotopic liver transplantation should be considered

in severe cases which progress to stage three or four hepatic encephalopathy if the patient is otherwise a suitable candidate

– It is important to appreciate, however, that fulminant hepatic failure due to acetaminophen has a higher rate of spontaneous resolution (particularly if NAC is also given), than other forms of fulminant liver disease, such as viral hepatitis where the mortality rate may approach 100 percent.

Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure

Harrison PM; O'Grady JG; Keays RT; Alexander GJ; Williams R. BMJ 1990 Oct27;301(6758):964-6

Evaluated the prothrombin time as a prognostic indicator in 150 patients with APAP-induced hepatic failure – 92% patients with a peak prothrombin time of >180s

died as did 49% with a time of 130-179 s, 36% with a time of 90-129 s, and 19% with a time of less than 90s

– Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose, 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell

Use and outcome of liver transplantation in acetaminophen-induced acute liver failure. Transplantation 1998; 27:1050

Series of 548 patients admitted to a single institution with APAP toxicity validated the use of the following criteria for liver transplantation– presence of a progressive coagulopathy(PTin

seconds exceeds the time in hours after overdose) – an INR >5 at any time– evidence of metabolic acidosis– hypoglycemia– renal failure

94% of patients without these criteria survived, compared with 44% of patients in whom one or more criteria were present

Of patients meeting criteria for transplantation – 30 percent were too ill from multiple organ failure

to be listed for transplantation– 30 percent deteriorated so rapidly after listing that

they became ineligible for transplantation even though grafts became available for most patients within 24 hours

– Only 35 percent of patients meeting initial criteria for transplantation had no contraindications to the procedure and did not deteriorate while on the waiting list