Acetaminophen Intoxication

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Acetaminophen Intoxication

• Suhail Allaqaband
• Sinai Samaritan Medical Center
• Milwaukee, WI

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• 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.

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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

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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

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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

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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

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• 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
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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

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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

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CLINICAL MANIFESTATIONS

• 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

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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

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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

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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

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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

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DIAGNOSIS

• Characteristic laboratory findings of APAP
  hepatotoxicity include
• marked elevation in plasma hepatic enzyme levels
  (gt5000 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

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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

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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

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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

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Paracetamol (acetaminophen) poisoning. Vale, JA,
Proudfoot, AT. Lancet 1995 346547

• 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.

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Improved outcome of paracetamol-induced fulminant
hepatic failure by late administration of
NACLancet 1990 Jun 30335(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)

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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

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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

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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

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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.

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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.

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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
  Oct27301(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
  gt180s 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

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Use and outcome of liver transplantation in
acetaminophen-induced acute liver failure.
Transplantation 1998 271050

• 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 gt5 at any time
• evidence of metabolic acidosis
• hypoglycemia
• renal failure

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• 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