DIFFERENTIAL DIAGNOSIS

-Acetaminopheninducedhepatitis

Alcoholichepatitis
Otherdrugortoxininducedhepatitis
Viralhepatitis
Hepatobiliarydisease
Ischemichepatitis("shockliver")
BACKGROUND
-1955
-1966
-Repeated therapeutic or slightly elevated doses
-Prevalence + Access=Use
-Acute liver failure in US
EPIDEMIOLOGY
-avail, blah blah etc
-Acute liver failure in US
-Intentional vs. Unintentional poisonings
PK
-Formulations
-Absorption: GI
-Peak Serum Concentration
-Therapeutic Dose 0.5-2hrs
-Overdose 4hrs
-Delaying factors >4hrs
-Metabolism
-90% Sulfation and Glucuronidation
2% Excreted in urine unchanged
8% Cytochrome P450
-Elimination:
-T1/2: 2-4hrs (IR & ER)
-Delayed onset
-T1/2: >4hrs
DOSE SLIDE:

Therapeutic Dose
Toxic Dose
TOXIC DOSE
-Toxic is unlit (2/15 3 bullet pt)
BIOCHEMICAL TOXICITY
-Therapeutic Doses
--Metabolism:
-90% Sulfation and Glucuronidation
2% Excreted in urine unchanged
8% Cytochrome P450 mixed fxn oxidase pathway (CYP2E1, CYP1A2, CYP3A4
subfamilies) N-acetyl-p-benzoquinoneimine (NAPQI)
-NAPQI conjugated w/hepatic glutathione Cysteine and Mercapta
-Excretion:
-Cysteine and Mercapta: Urine
Toxic Doses
--Metabolism:
-Sulfation and Glucuronidation SATURATED
-CYP450 activity NAPQI
-Deplete hepatic glutathione by 70-80% irreversible hepatic injury
SLIDES DIAGRAMING RXN
NAPQI
-Irreversibly arylates & binds covalently to cysteine NAPQI-protien adducts
-Oxidative injury
-Hepatocellular Centrilobular Necrosis
-Cytokines, Reactive Nitrogen and Oxygen species Spread Hepatic Injury
-Cytokines Kupffer Cells 2ndary Inflammatory Response zone of
hepatic injury (Stage II)
CLINICAL FACTORS INFLUENCING TOXICITY
Mechanism for Hepatic Damage from APAP ingestion
1-4 PG 3/15
Factors that influence above mechanisms above:
-Concombinant use: ETOH or other drugs (opiates, anticholenergic)
-Comorbid illness
- age
-Genetics
-Nutritional Status
ETOH

Acute ETOH ingestion

-NOT a risk factor for hepatotoxicity
-Protective: by competing with APAP for CYP2E1
Chronic ETOH ingestion
-Role remains contentious
- CYP2E1 activity two-fold
-Depletes glutathione levels

Acute ETOH ingestion

Chronic ETOH ingestion
Hepatotoxic

NO
Role remains contentious
CYP2E1

Competes w/APAP (protective)

Inducer: activity two-fold
NAPQI

Glutathione

NONALCOHOLIC VS. CHRONIC ALCOHOLIC

-Single OD:
-NO difference in Hepatotoxic Risk
-Management same
-Multiple supratherapeutic OD:
-Chronic alcoholics: Hepatotoxic Risk
-Delayed recognition (therefore continue use)
-CYP2E1 induction shunting of APAP through CYP2E1 NAPQI
-Net Effect: Clearance Rate of APAP with associated Hepatoticicity Risk
-Nutrition Status:
-Chronic alcoholics:

-Often Malnourished
-Fasting
-Depleted Hepatic Glutathione
PATHWAY INTERACTIONS
CYP2E1 INDUCERS
-Hepatotoxic +/- APAP OD
-Carbamazepine, Phenonarbital, Phenytoin, Isoniazid, Rifampin

GLUCURONIDATION METABOLISM
-TrimethoprimSulfamethoxazoleandZidovudine
-May potentiate hepatotoxicity
-via competition for pathway
-therefore CYP2E1 dependent metabolism of APAP
-Gilberts Syndrome

CLINICAL COURSE
-GRAPH

StageI(0.5to24hours)
DIAGNOSIS

Nonalcoholic
Chronic Alcoholic
Single OD

NO difference in Hepatotoxic Risk

NO difference in Hepatotoxic Risk
Multiple supratherapeutic OD

Hepatotoxic Risk
Clearance of APAP

Glutathione

Hepatotoxic

NO
Role remains contentious
Single O

Hepatotoxic