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.