liver paracetamol poisoning

1

Paracetamol (Acetaminophen) poisoning

Important cause of acute liver failure.

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Liver- highly exposed to drugs and toxins absorbed from the GIT

Phase 1 drug metabolism - alters the parent molecule

Phase 2 - conjugate of the drug or its metabolite with a more water-soluble moiety

Phase 3 - energy-dependent excretion


Phase 1 pathways

Oxidation, reduction, and hydrolytic reactions

Products of phase metabolism can be readily conjugated or excreted without further modification

Catalyzed by microsomal cytochrome P450 or CYP


Hepatic expression of CYP enzyme is genetically determined.

Great differences in drug metabolism

In many severe liver diseases - decreased levels of total CYP and reduced hepatic perfusion

Decrease in the clearance of drugs that are rapidly metabolized by the liver


Phase 2 metabolism (detoxification)

Conjugate of the drug or its metabolite with › glucuronic acid› inorganic sulfate

Highly water-soluble and excreted in bile or urine


Phase 3 metabolism

Involves the ATP-binding cassette (ABC) transport proteins› cystic fibrosis transmembrane

conductance regulator (CFTR)› canalicular and intestinal copper

transporters› multidrug resistance-related

proteins (MRP)


Oxidative stress Hepatocytes - activate oxygen (toxic)

Liver has antioxidant mechanisms


Glutathione

Most important antioxidant in the liver

Liver is the only site of glutathione synthesis


Cysteine Increases synthesis of

glutathione NADPH - essential cofactor that

requires ATP Relation between energy-

generating capacity of the liver and its ability to withstand oxidative stress


Highest concentrations of glutathione - in the cytosol

Mitochondria – ROS constantly formed as a by-product of oxidative respiration

Mitochondrial glutathione is maintained by active uptake from the cytosol

Chronic ethanol exposure alters this transport system - predispose to drug toxicity


Dose related toxicity

Paracetamols Oral contraceptive pills


INH

Not dose related


Toxic dose of paracetamol

Single ingestion > 7 to 10 g (150 mg/kg body weight in children)

Fatal cases usually involve doses of at least 15 to 25 g

In heavy drinkers, daily doses of 2 to 6 g have been associated with fatal hepatotoxicity


Plasma half-life of paracetamol

2 to 4 hours


Main metabolism

Phase 2 reaction ›Conjugation with sulfate and glucuronide to form nontoxic metabolites in


Minor route

Phase 1 reaction› Oxidized by hepatic cytochrome P450 enzymes

› Form n-acetyl-p-benzoquinoneimine (NAPQI)


NAPQI

Toxic Detoxified by conjugation

with glutathione Mercapturic acid

› harmless and water-soluble› renal excretion


Low glutathione levels

NAPQI produce liver injury Hepatic necrosis occurs

only when concentrations of reduced glutathione fall below a critical level


Cysteine Stimulates hepatic synthesis of reduced glutathione

Protects the liver


> 140 mg/kg body weight of paracetamol

Sulfate and glucuronide pathways saturated

Increased amount of paracetamol gets metabolized to NAPQI

Glutathione levels depleted Free NAPQI - centrilobular

necrosis


Alcohol Induces cytochrome P450

Chronic alcoholics - toxic dose of paracetamol may be as low as two grams


Malnutrition

Decreases glutathione reserves


Early manifestations occurring within 12 h

Nonspecific› Nausea and vomiting› Diarrhea› Abdominal pain› Shock


No features of liver injury in the first 2 days

After 48 to 72 hours› ALT - often between 2000 and 10,000 U/L

› Right upper quadrant tenderness

› Jaundice


6 days Maximal hepatic failure may not be evident until 6 days after ingestion

Hepatic failure Renal failure


Most important factor affecting mortality

Time of presentation – cysteine within 12 hours abolishes significant liver injury


Other prognostic factors

Age – Children relatively resistant

Alcohol and fasting › Enhance activity of CYP› Deplete hepatic glutathione


INDICATORS OF A POOR OUTCOME

Grade IV hepatic coma Acidosis - pH less than 7.30 PT - Twofold prolongation Renal failure - Serum creatinine

> 3.3 Falling ALT with worsening PT


Rumack-Matthew nomogram

Risk of liver injury


When should serum paracetamol level be obtained for Rumack-Matthew nomogram?

Between 4 and 24 h after ingestion - reliable indicator

Determine acetaminophen blood levels at the time of presentation

Blood levels within 4 hours of ingestion may not be a reliable estimate - delayed gastric emptying


N-acetylcysteine

Antidote of choice Slow bolus IV injection followed by infusion

Oral


Give immediately before the serum level is known

Most effective if started within 8 to 10 h of an overdose

Discontinue - If the level is subsequently shown to be nontoxic


Level > 300 ug/mL 4 h after ingestion

Predictive of severe damage

< 150 ug/mL - hepatic injury highly unlikely


Side effects of NAC

Nausea, vomiting, and epigastric discomfort

Rash Angioedema Fatal shock Close supervision and only for

appropriate indications


Methionine In patients known to be sensitized to NAC, methionine is probably just as effective


Wide-bore gastric tube

< 4 hours - empty the stomach

Activated charcoal if < 4 h of › does not interfere significantly with acetylcysteine therapy

Osmotic cathartics –not indicated


Etiology-specific therapy

Paracetamol poisoning - NAC Amanita - Penicillin G and NAC HSV – Acyclovir AIH - Methylprednisolone HBV - Lamivudine AFLP/HELLP - Delivery of fetus


Amanita mushroom poisoning

Reduce the toxin load› Gastric lavage› Instillation of charcoal

Hemodialysis - remove toxins from the serum

Lower entero-hepatic toxin load - Uncertain › pencillin, cytochrome c, and silymarin


Liver transplantation

Life-saving

liver paracetamol poisoning

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