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Advances in the
Diagnosis and Treatment
of Acetaminophen
ToxicityLAURA P JAMES, MD
ASSOCIATE VICE CHANCELLOR, CLINICAL AND TRANSLATIONAL RESEARCH
UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES
Disclosures
Dr. James is the recipient of a STTR
grant to develop a new assay for the
diagnosis of acetaminophen liver
injury (DK079387).
Current approach: diagnosis
acetaminophen toxicity
Grounded in the Rumack
Nomogram
Elevation of APAP versus
time lapsed since
ingestion
Widely used for single,
acute ingestions
Limitations
Does not predict who will
develop liver injury
Limited to initial 24 hours
following overdose
Does not address
disease-drug interactions
Dependent on accurate
history
Rumack Nomogram - 1976
0 4 8 12 16 20 24 28
Hours post ingestion
Ace
tam
ino
ph
en P
lasm
a C
on
cen
tra
tion
Role of metabolism in acetaminophen toxicity
Drug Metab Dispos 2003;31:1499-1506
Known APAP APAP Other Etiology
Liver Failure Ingestion Liver Failure
A B C D E
0.0
0.5
1.0
1.5
2.0
2.5
3.0
nm
ol A
PA
P-C
YS
/mg
pro
tein
Known APAP APAP Known Other Etiology
ALF Mild ALF
Analysis performed in
blinded fashion
Acetaminophen-Protein
Adducts
Gastroenterology 2006;130(3):687-94
nm
ol A
PA
P-C
YS
/mg
pro
tein
HPLC-EC
Elimination Profile: Adults with Acute
Liver Failure
Mean t1/2 = 1.72 (+0.34) days
Drug Metab Dispos 2009;37(8):1-6
Mean “peak” levels=10.85
(+9.26) nmol/mL
Description HPLC-EC
Adduct
(nmol/mL)
Control, no anti-adduct
antibody
----
Control - Antibody, no
sample
----
Control – no
Acetaminophen exposure
0
Therapeutic Dose
Acetaminophen
0.018
Mild Acetaminophen
Overdose
0.23
Toxic Acetaminophen
Overdose
7.08
Toxic Acetaminophen
Overdose
13.04
Lateral flow assayPrototype
TB CB
9
ALFSG Study Group p value
Controls(19)
APAP(33)
Non-APAP(29)
Study day ALT (IU/L)
19(10-48)
3652(549-8870)
1124(16-7730) <0.001
AcetaSTAT®
Amplitude8971
(5151-11,108)584
(222-1027)3678
(394-8289) <0.001
HPLC-EC(nmol/mL)
0(0-0)
5.2(0.3-16.6)
0(0-5.2) <0.001
Study dayBilirubin (mg/dL)
0(0-0)
3.5(0.6-38.9)
10.2(0.8, 38.8) <0.007
2
Laboratory Data
Clinical Gastroenterology and Hepatology 2017;15:555-562
2Clinical Gastroenterology and Hepatology 2017;15:555-562
Treatment
N-acetylcysteine – oral 72 hour protocol
Acetadote (IV) – 21 hour protocol.
Extension of treatment in patients with persistent
toxicity.
Indicated in suspected acetaminophen
overdose/liver injury.
No RCT’s; observational data, small studies.
Chiew AL, Gluud C, Brok J, Buckley NA
Cochrane Database Syst Rev. 2018;2:CD003328. Epub 2018 Feb 23.