Hepatotoxicity

Associated With
Acetaminophen
Usage in Patients
Receiving
Multiple Drug Therapy for
Tuberculosis*
Charles

M. Nolan,

Kenneth
and

Sidney

We

undergoing

who

women.

Ph.D.;

for active

patient

tuberculosis

agents.
intentionally

of fever
and
to tuberculosis.

symptoms

signs

and

She

symptoms

patterns
of
each patient

of

with

All

were
young
took
a large
typical
signs
and

is a well-known

was

and

this

effect

propensity

impediment
to its use, particularly
for individuals
who are not ill.
Acetaminophen,
antipyretic
drug,
when

taken

intentional

been

also

in supratherapeutic

ALT

proposed,

overdosing.6

on the basis

may be an interaction

oftwo

between

ophen
that results in a more
that which would be expected
alone.

Furthermore,

rifampin,

themotherapy

to potentiate

the

three

have

individuals

isoniazid
active

we

observed

association
and

who
rifampin,

tuberculosis.

#{176}Fromthe

Department

with

Tuberculosis

of Public

were

We

receiving

report

Control

Health

these
Program,

(Dr.

as with
it has
that there

Nolan);

to

of

reactions

in

ingestion

in

therapy

to other
cases

with

agents,

for

in order

to

Seattle-King

the

plus similar
isoniazid

or
of

hepatotoxicity

the

of

cytochrome
to Its toxic

1994;

10,5:

County

Departments

Medicine
(Dr. Nolan),
Medicinal
Chemistry
(Dr. Nelson),
Pharmaceutics
(Drs.
Thummel
and Slattery),
University
Washington;
and the Group Health
Cooperative
ofPuget
Sound
Sandblom),
Seattle.
Manuscript
received
April 16; revision
accepted
May 27.

408

Downloaded From: http://journal.publications.chestnet.org/ on 02/28/2013

aspartate

on a possible

acetaminophen

408-11)

amino-

of
and
of
(Dr.

adverse

interaction

and antituberculosis

to offer a hypothetical
hepatotoxicity
ofisoniazid,

mechanism
rifampin,

drugs

and

for the synergistic

and acetaminophen.

REPORTS

CASE

A woman born in 1960, had been receiving

treatment
for drug-resistant
tuberculosis
with isomazid, rifampin, pyrazmamide,
and streptomycin sinceherimmigration
from the Philippines
in December1990.
In May 1991, she was hospitalized
24 h after ingesting
15 to 20 tablets
ofacetaminophen
300 mg acetaminophen
per tablet); an ingestion
of
4.5 to 6.0 g ofacetaminophen.

than
is taken
of tuber-

hepatotoxic

in addition

and
mainly

hepatotoxicity

acetaminophen

cases
that

AST

CASE

importance

in the modern

Recently,

an

and acetamin-

culosis,
seems
jsonjazid.90

was

successfully

acetaminophen

aminotransferase;

therapy

hepatotoxicity
either drug

that of isoniazid

temporal

aS-

such

of equal

oxidize

information

between

soon

reports,78

severe
when

These

(Chest

= alanine

extend

Recently

isoniazid

was

by induction

perhaps

values

transferase

has been

analgesic
potential,

amounts,

or unintentional

patients.

metabolites.

of drugs

as preventive

a widely
used
has hepatotoxic

and

literature
suggest
or both,
may potentiate

that

were

tuberculosis

the

lsozymes

rises

drugs

The

to be hepatotoxic

determined

ter its introduction,2

P450

for

isoniazid

acetaminophen,

modest

and laboratory

resolved

freatment

in all three
in

only

antituberculous

of

used for tuberculosis

treatment
and prophylaxis.
Isoniazid,
the historic
mainstay
of drug therapy
against
tuberculosis,

then

without

rifampin,

were
similar
serum
elevations

side

normal;

at most

with

All

symptoms

until

became

reports

The
the

bilirubin.

withheld

completed

upper

enzymes

of

resumed

took

hepatotoxicity.

abnormalities
pronounced

those

in

were
subsequently
the rapid
onset

had

isoniazid

liver
function
experienced

epatotoxicity

that

malaise

ofhepatocellular

ingestion

amount
of acetaminophen
and
had
symptoms
of acetaminophen
overdosage;
another
acetaminophen
in combination
form for a minor
respiratory
illness.
She experienced
no symptoms.
remaining
patient took acetaminophen
to ameliorate
attributed

EC.C.P;

hepatotoxic

acetaminophen

other

and

One

M.D.,

T Slattenj,

experienced

with

treatment

rifampin,

isoniazid,

E. Sandblom,

John

Ph.D.

three
patients
in association

report

adult

Robert

Ph.D.;

D. NeLson,

reactions
while

M.D.;

E. Thummel,

On physical
rightcostal
bin time

She complained

examination,

margin.
of 14.1

ofabdominal

the liver was palpable

Admissionlaboratoiyvalues
s, total

bilirubin

2 cm

included

level

of 18.8

pain.
below

the

aprothrom-

micromole/L

(1.1

mg/

(AST), 490 UIL; alanine

aminotransferase
(ALT),
248 U/L
and alkaline
phosphatase,
58 U/L. The blood
acetaminophen
level was 1 1 p.mg/ml.
The admission diagnosis
was hepatotoxicity
due to acetaminophen
overdosage.
Administration
of antituberculous
medications
was
dl);

aspartate

stopped,

aminotransferase

and

the

patient

received

a course

of treatment

acetylcysteine,
1.2 g every 4 h for 3 days.
Liver function
abnormalities
were at their
admission,

with

the

bilirubin

value

being

18.8

worst

with

N-

24 to 48 h after

p.mol/L

(1.1

mg/dl);

AST, 1,200 U/L; and ALT, 1,616 U/L The

patient
experienced
no further
symptoms
and was discharged
on the
eighth
hospital
day. At the time of discharge,
the bilirubin
level was
6.8 p.mol/L
(0.4 mg/dl); the prothrombin
time, 11.8 5; AST, 23 U/L
ALT, 271 UIL; and alkaline phosphatase,
43 U/L.
Treatment
fortuberculosiswas
resumed3
days afterdischarge
from
hospital,
12 days after the ingestion
ofacetaminophen.
Drugs
chosen
for further
therapy
were pyrazinamide,
ethambutol
hydrochloride,
prothrombin

time,

17.2

Hepatotoxicity,

5;

AcetaminOphen

and Tuberculosis

(Nolan eta!)

ciprofloxacin

hydrochloride,

no further
pleted

difficulty,

and capreomycin

and

treatment

sulfate.

for active

The patient

tuberculosis

had

was

corn-

1992.

in July

A Filipino

born in 1949 immigrated

1991, she began to receive

woman

1980. In November
bus

cervical

adenitis

ethambutol.

with

Liver

isoniazid,

function

to the United
treatment

rifampin,

studies

at that

States

in

for tubercu-

pyrazinamide,

time

were

and

within

At a return

appointment

later,

she had

done routinely
drugs,

after

showed

for a refill

of antituberculous

no complaints.

1 month

serum

However,

oftreatment

levels

medications

liver

function

Upon

receipt

telephoned,

of these

advised

clinic.

On

with multiple

of AST

to be 256

function

abnormal

antituberculous

UIL

and
studies

laboratory

to discontinue

interview

asymptomatic

and

there

done

her

and of ALT

phatase,

58 UIL.

B surface

were

no new

on that

be positive,

hepatitis

Serologic

antigen

to be

day period
tions,

interview
had

taken

capsules

Liver

p.molfL

and

hepatitis

showed

to be negative,

the patient

stated

for symptomatic

Hepatic

phos-

and 1gM

anti

that

for the 4

of an upper

studies

were

andlaboratoiyvalues
drugs

were
with

experienced
ber 1992.

respiratory

monitored

gradually

withheld,

rifampin,

the

AST

was

ethambutol,

no further

to normal.
and

pyrazinamide.

and completed

woman,

who

was born

tuberculosis
in November
rifampin,
and pyrazinamide.
nauseated.

The

next

she was

1990.

was

diagnosed

Treatmentwas

Clinically,

ports
taking

and

cation

of the

called

a follow-up

her

attending

of nausea

and vomiting

improved

promptly.

first

rate of production
ophen.

Experimental

strated

that

led to the diagnosis

two
fever,

sweats,

approximately
antituberculous

poorly.
time

usage

ate

function

and

malaise.

that

She

same

treatment

to take

continued
started

taking

for
because

acetaminophen

several
she

noted

days

continued

ofthe acetaminophen
was stopped
the onset of symptoms
of hepatotoxicity.

report,

we

described

re-

et al7 in No-

clinic

while
asked

who

receiving

routinely

about

recent

that
and

recent

four
a less

acetami-

hepatotoxicity

isoniazid

P450

2E1

oxidation

associ-

results

from

the

(CYP2E1),

an

en-

of acetaminophen

to

N-acetyl-p-benzoquinone

metabolites

studies

in animals

induction

acetaminophen

interaction

suggest

may

ate

be complex,

rifampin,

the

Studies
that

and inhibition.415
In addition
to isoniazid,
a drug
Other
and

clinical

the

time

involving
each

known

course

both

of

aceteminophen

etaminophen

in human

to feel

at about the

an

additional

by

reand

cytochrome
P450 inducers,
such
ethanol,
also apparently
potenti-

manifestation

isoform

was

CYP3A46

at

P450

of this

induction

of our patients
to induce

of

this

demon-

can potentiin normal

human

by isoniazid

toxicity.3

however,

of acetaminhave

Recently,
we have obtained
forms N-acetyl-p-benzoquinone

after

liver

microsomes.2

rifampin

risk

may

factor

for

evidence
from acInduction

therefore

of

represent

acetaminophen

hepatotoxicity.
Hepatotoxicity
is an anticipated
side effect of multiple
drug therapy
for tuberculosis
and occurs
with greater

COMMENTS

In this

Murphy

hepatotoxicity.89
that CYP3A4

acetaminophen,

Administration
she

pathat

every 6 h, for reliefofsymptoms

frequency

was

the

for the evaluation

she began

approximately

completed

of acetaminophen,

to presenting

oftuberculosis,

tablets

300-mg

prior

pat-

recent

up by this

of cytotoxic

CYP2E1

CYP2Cmeph.7
as phenobarbital

regarding

to the

reported

metabolite,

toxic

and

that 3 days

were

its putative

experienced

responded

by

followed

in the

The patient

tient

report

zyme implicated

ceiving

complications

case

patients

of cytochrome

and ethambutol.

further

to add

et al7 speculated

it was resumed

no

no consistent

experienced
hepatotoxicity
after
and isoniazid.78
Since the publi-

acetaminophen

was stopped,

therapy in June 1992.

In a specific interview

were

reported

history)

subjects,

ofrifaznpin

se-

usage.

abnormalities,
which peaked 6 days after antituberculous
drugs were
stopped with a bilirubin level of22.3
mol/L
(1.3 mg/dl)
and an AST
value of920 UIL, returned
to normal
by the 21st day after administration ofdrugs was stopped.
In late December
1990, 35 days after treatment
for tuberculosis
and consisted

simi-

imine.2
Those
authors
hypothesized
that greater
activity of the induced
enzyme
could lead to an increased

physi-

of examina-

Liver

were

pronounced

of hepatocellular
enrises in those of biliru-

there

drugs

Murphy

tion 2 days later,the

serum bilirubinleveiwas
22.2 p.mol/L(1.3
mg/dl)
and the AST value was 465 U/L. She was hospitalized
for 2 days. Her
symptoms

in

it

malaise

to tuberculosis.
abnormalities

hepatotoxicity

ated with

was stopped,

At the time

3) took
and

acetaminophen
usage.
Among
nine such patients,
(the three reported
here and one other one with

patient

she became

medications

appointment.

were

1990,

nophen

pulmonary

(patient
of fever

All experienced

however,

cases

well-documented

isoniazid,

oftreatment,

of the antituberculous

given

with

one

function

of patients
who
acetaminophen

was

startedwith

On the 8thday

day she vomited

Administration

and

in 1960,

res-

terns.
Patient
1 had typical signs and symptoms
of mild
acetaminophen
overdosage
and patient
3 had those of
isoniazid
hepatotoxicity.
Patient
2 had no symptoms.

induction

This

cian.

bin.

days

in Septem-

ac-

upper

rum elevations
in concentrations
zymes with at most only modest

for 3

CASE

patients.

basis

The

therapy

lax in all three

Thirty

treatment

2) took

for a minor

attributed

ofliver

antituberculous

4 hours,

illness.

39 UIL,

and

difficulties

containing

(patient

form

symptoms

subsequently

experienced

every

on a weekly

returned

the

vember

medica-

capsule

two capsules

the remaining

disparate.
large

a relatively

another

in combination

illness;

the ingestion

were

1) intentionallytook

to ameliorate

experienced

with

circumstances

of acetaminophen;

These
to

who

association

The

The patterns

hepatitis
antibody

brompheniramine,

(each

approximately

treatment

function

containing

(0.3

alkaline

B surface

acetaminophen

and

mg ofacetaminophen),

resumed

U/L;

antihepatitis

at that time,

phenyipropanolamine,

after

for viral

was

abnormalities.
5.1

to

she

prior to the clinic visit for refill ofantituberculous

she

weeks,

600

was

in report

later,

bilirubin,

B core antibody
to be negative.

antihepatitis

In a further

physical

than

testing

the patient
and

3 days

day showed

to be negative,

A antibody

values,

medication,

examination

AST, 299 U/L; ALT, more

mg/dl);

tuberculosis

in temporal

that were

studies,

517 UIL.

500

amount

order

30 days

active

etaminophen
piratory

normal

limits.

the

for

hepatotoxicity

of acetaminophen.
One patient
(patient

CASE

treated

three

patients

being

frequency

in that

setting

than

CHEST

Downloaded From: http://journal.publications.chestnet.org/ on 02/28/2013

during

I 105

preventive

I 2 I FEBRUARY,

treat1994

409

ment

with

M. Nolan,

isomazid
M.D.
that

it is possible

this report
drugs and
ample,

alone,

as cited

by Steel

et al and C.

(unpublishedobservations,

1992).

any or all of the patients

Thus,

described

in

had liver damage

caused
by antituberculous
not associated
with acetaminophen.
For

in patient

2 elevations

ofhepatocellular

isoniazid
or rifampin
or both, it must be clarified
quickly
so that patients
receiving
treatment
for tuberculosis
can
be advised

uncommon

early

during

isoniazid

therapy,

usually
transient,
and do not ordinarily
require
tion of the drug.#{176}However,
the peak AST level

less

than

On the other
dysfunction

1 could

exclusively

overdosage.
tensive

patient

due

Somewhat

against

liver dysfunction

have

to

this

are
cessaof 299

1 is very

et al.7
Finally,

similar

it must

to the case

is the ex-

be pointed

were

receiving

pyrazinamide

drug

regimens.

Pyrazinamide,

cally

to

isoniazid,

shares

hepatotoxicity.22

The

pyrazinamide
isoniazid,

is less

out

by

the
clinical

pyrazinamide

with

ence a greater
ing isoniazid

frequency
and rifampin

isoniazid

pyrazinamide
plays
tween acetaminophen

all three

and rifampin

for
of
that

of

do not experi-

in the hypothesized
and antituberculous

receivif any,

there is at present
no way to establish
are the cause ofhepatotoxicity
withpatients

poral association
with acetaminophen

with

the combination

of drugs,

of the episodes
of hepatic
dysfunction
usage in these three patients
is Un-

and at least

raises

the possibility

of an adverse

interaction
between
acetaminophen
and antituberculous
drugs. Isoniazid
and rifampin
currently
are the two mainantituberculous

by that

drugs;

of pyrazinamide,

theirjoint

permits

use,

supplemented

the briefest

course

of

therapy
and the best chance
for cure.
With the current
resurgence
oftuberculosis
in the United
States, the value
ofthese
ticularly

Ann Intern

Med

1974;

DN,

CB, SilverAL.
The age threshold
for isoniazid
JAMA 1986; 256:2709-13
BH, Peterson RC, Koch GG, Amara IA. Acetaminophen
662caseswithevaluation
of oral acetylcysteine
treatment.
Schecter

chemoprophylaxis.

6 Rumack
overdose:

Arch Intern
7 Murphy

Med 1981; 1441:381-85

R, Watkins PB. Severe acetaminophen
receiving
isoniazid.
Ann Intern Med 1990;

R, Seartz

Respir

RedekerAG,

Dis

11 Raucy

toxicity

113:799-

Kanel

GC.

Acetaminophen,

isoniazid,

1986;

133:1072-75

JL, Lasker

JM, Lieber
CS, Black M. Acetaminophen
liver cytochromes
P45OIIE1
and P4501A2.
Arch Biochem
Biophys 1989; 271:270-83
12 Thummel
KE, Lee CA, Kunze KL, Nelson
SD, Slattery JT.
Oxidation
of acetoininophen
to n-aeetyl-p-aminobenzo-quinone
activation

13

interaction
bedrugs remains

or at least one of the drugs thought

to be the cause of
the hepatotoxicity
and thereby
putting
the patients
who
receive the challenge
at some risk. Nevertheless,
the tern-

stay

prophylaxis.

by human

imine

by human

Ruck

RF, Hill KE, Hunt

CYP3A4,

ofacetaminophen
inhibition

Biochem

hepatotoxicity
of it. Res

Pharmacol

RWJr, Martin

Commun

1993;

45: 1563-69

Isornazidpotentiation
in the rat and 4-methylpyrazole
AE.

Chem

Pathol

Pharmacol

1990;

69:115-18

Unfortunately,
ifdrug
interactions

deniable

117:991-1001

Stop isoniazid

4 Tsevat J, Taylor WC, Wong JB, Parker SG. Isoniazid

for the
tuberculin
reactor: take it or leave it. Am Rev Respir Dis 1988;

to be determined.

out challenging

1978;

and hepatic
toxicity.
Ann Intern Med 1991; 114:431
9 Steele MA, Bark RF, DesPrez RM. Toxic hepatitis with isoniarid
and rifampin: a meta-analysis.
Chest 1991; 99:465-71
10 Sarma GR, Immanuel C, Kailasam
5, Narayana
ASL, Venkatesan
P. Rifampin-induced
release
ofhydrazine
from isomazid.
Am Rev

receiving

than those
What role,

Caras GJ. Isoniazid-related

hepatitis: a
cooperative
surveillance
study. Am Rev

DR.

Service

800

patients

than

that patients

1972;

80:672-73

by Murphy

latters
potential
hepatotoxicity

of hepatitis
alone.

Dis

HL.

8 MouldingTS,

characterized
shown

Respir

in a patient

in their antituberculous
an agent related
chemi-

well

but it has been

that

Health

3 Isreal

an amount
In this respect,

reported

MB. Isoniazid-

Am RevRespirDis

137:215-20

very high hepatocellular

enzyme
levels and prolonged
prothrombin
times, occurring
in association
with an in-

patient

SH, Gregg

reportofanoutbreak.

Snider

US Public

5 Rose

manifested

gestion
ofat most only 6 g ofacetaminophen,
not usually associatedwith
hepatotoxicity.

2 KopanoffDE,

had hepatic

suggestion

RE, Ferebee

Drusin

106:357-65

acetaminophen

she experienced,

RA,

associatedhepatitis:

100 UIL.2

hand,

the use of acetaminophen.

REFERENCES

1 Garabaldi

UIL for patient

2 was considerably
greater
than levels
associated
with simple isoniazid
transaminasemia,
which
are usually

from

ex-

enzymes

were detected
on routine
testing
and were not associatedwith
symptoms.
Episodes
ofmild
transaminasemia
are not

to refrain

two agents
in patients

in the treatment
oftuberculosis,
parwith HIV infection,
and in the con-

trol oftuberculosis

in our communities,

If an interaction

exists

among

is unmeasurable.
acetaminophen

410

Downloaded From: http://journal.publications.chestnet.org/ on 02/28/2013

and

14 Epstein MM, Nelson SD, SlafteiyJT,

KathomTF,Wall
RA,Wnght
JM. Inhibition
ofthe metabolism
ofparacetamolbyisoniazid.
BrJ
Clin Pharmacol
1991; 31:139-42
15 Zand R, Nelson SD, SlatteiyjT,
ThummelKE,
KalhornTF,
Adams
S, eta!.

Inhibitionandinductionofcytochrome

oxidations

byisoniazidin

humans.

P4502E1-catalyzed
Clin

PharmacolTherap(inpress)

16 Bolt HM, Kappus

H, Bolt M. Effect of rifampicin
treatment
on
the metabolism
ofoestradioland
17-ethinylestradiolbyhuman
liver
microsomes. EurJ Clin Pharmacol 1975; 8:301-07
17 Thou HH, Anthony
LB, Wood
AJJ, Wilkinson CR. Induction of
polymorphic
4-pr-hydroxylation
of S-mephenytoin
by rifampicin.
BrJ Cia, Pharmacol
1990; 30:471-75
18

MitchellJR,

Jollow

DJ, PolterWZ,

Davis

DC,

GilletteJR,

Brodie

BB. Acetaminophen-induced
hepatic necrosis:
1. Role of drug
metabolism.
J Pharmacol
Exp Ther 1973; 187:185-94
19 SeeffLB,
Cuccherini
BA, Zimmerman
HJ, Adler E, Banjamin
SB.
Acetaminophen
misadventure.

hepatotoxicity
Ann

of

alcoholics:

a therapeutic

Intern Med 1985; 104:399-404

JP. Serum transaminase
elevations

L, Smith
and other
abnormalities
in patients
receiving
isoniazid.
Ann Intern
Med 1969; 71:1113-20
21 MouldingTS,
RedekerAG,
KanelGC. 1\ventyisoniazid-associated
20

Scharer

hepatic

Hepatotoxicity.

ACetaminOphen

and Tuberculosis

(Nolan eta!)

Hepatotoxicity
Associated With
Acetaminophen
Usage in Patients
Receiving
Multiple Drug Therapy for
Tuberculosis*
Charles

M. Nolan,

Kenneth
and

Sidney

We

undergoing

who

women.

Ph.D.;

for active

patient

tuberculosis

agents.
intentionally

of fever
and
to tuberculosis.

symptoms

signs

and

She

symptoms

patterns
of
each patient

of

with

All

were
young
took
a large
typical
signs
and

is a well-known

was

and

this

effect

propensity

impediment
to its use, particularly
for individuals
who are not ill.
Acetaminophen,
antipyretic
drug,
when

taken

intentional

been

also

in supratherapeutic

ALT

proposed,

overdosing.6

on the basis

may be an interaction

oftwo

between

ophen
that results in a more
that which would be expected
alone.

Furthermore,

rifampin,

themotherapy

to potentiate

the

three

have

individuals

isoniazid
active

we

observed

association
and

who
rifampin,

tuberculosis.

#{176}Fromthe

Department

with

Tuberculosis

of Public

were

We

receiving

report

Control

Health

these
Program,

(Dr.

as with
it has
that there

Nolan);

to

of

reactions

in

ingestion

in

therapy

to other
cases

with

agents,

for

in order

to

Seattle-King

the

plus similar
isoniazid

or
of

hepatotoxicity

the

of

cytochrome
to Its toxic

1994;

10,5:

County

Departments

Medicine
(Dr. Nolan),
Medicinal
Chemistry
(Dr. Nelson),
Pharmaceutics
(Drs.
Thummel
and Slattery),
University
Washington;
and the Group Health
Cooperative
ofPuget
Sound
Sandblom),
Seattle.
Manuscript
received
April 16; revision
accepted
May 27.

408

Downloaded From: http://journal.publications.chestnet.org/ on 02/28/2013

aspartate

on a possible

acetaminophen

408-11)

amino-

of
and
of
(Dr.

adverse

interaction

and antituberculosis

to offer a hypothetical
hepatotoxicity
ofisoniazid,

mechanism
rifampin,

drugs

and

for the synergistic

and acetaminophen.

REPORTS

CASE

A woman born in 1960, had been receiving

treatment
for drug-resistant
tuberculosis
with isomazid, rifampin, pyrazmamide,
and streptomycin sinceherimmigration
from the Philippines
in December1990.
In May 1991, she was hospitalized
24 h after ingesting
15 to 20 tablets
ofacetaminophen
300 mg acetaminophen
per tablet); an ingestion
of
4.5 to 6.0 g ofacetaminophen.

than
is taken
of tuber-

hepatotoxic

in addition

and
mainly

hepatotoxicity

acetaminophen

cases
that

AST

CASE

importance

in the modern

Recently,

an

and acetamin-

culosis,
seems
jsonjazid.90

was

successfully

acetaminophen

aminotransferase;

therapy

hepatotoxicity
either drug

that of isoniazid

temporal

aS-

such

of equal

oxidize

information

between

soon

reports,78

severe
when

These

(Chest

= alanine

extend

Recently

isoniazid

was

by induction

perhaps

values

transferase

has been

analgesic
potential,

amounts,

or unintentional

patients.

metabolites.

of drugs

as preventive

a widely
used
has hepatotoxic

and

literature
suggest
or both,
may potentiate

that

were

tuberculosis

the

lsozymes

rises

drugs

The

to be hepatotoxic

determined

ter its introduction,2

P450

for

isoniazid

acetaminophen,

modest

and laboratory

resolved

freatment

in all three
in

only

antituberculous

of

used for tuberculosis

treatment
and prophylaxis.
Isoniazid,
the historic
mainstay
of drug therapy
against
tuberculosis,

then

without

rifampin,

were
similar
serum
elevations

side

normal;

at most

with

All

symptoms

until

became

reports

The
the

bilirubin.

withheld

completed

upper

enzymes

of

resumed

took

hepatotoxicity.

abnormalities
pronounced

those

in

were
subsequently
the rapid
onset

had

isoniazid

liver
function
experienced

epatotoxicity

that

malaise

ofhepatocellular

ingestion

amount
of acetaminophen
and
had
symptoms
of acetaminophen
overdosage;
another
acetaminophen
in combination
form for a minor
respiratory
illness.
She experienced
no symptoms.
remaining
patient took acetaminophen
to ameliorate
attributed

EC.C.P;

hepatotoxic

acetaminophen

other

and

One

M.D.,

T Slattenj,

experienced

with

treatment

rifampin,

isoniazid,

E. Sandblom,

John

Ph.D.

three
patients
in association

report

adult

Robert

Ph.D.;

D. NeLson,

reactions
while

M.D.;

E. Thummel,

On physical
rightcostal
bin time

She complained

examination,

margin.
of 14.1

ofabdominal

the liver was palpable

Admissionlaboratoiyvalues
s, total

bilirubin

2 cm

included

level

of 18.8

pain.
below

the

aprothrom-

micromole/L

(1.1

mg/

(AST), 490 UIL; alanine

aminotransferase
(ALT),
248 U/L
and alkaline
phosphatase,
58 U/L. The blood
acetaminophen
level was 1 1 p.mg/ml.
The admission diagnosis
was hepatotoxicity
due to acetaminophen
overdosage.
Administration
of antituberculous
medications
was
dl);

aspartate

stopped,

aminotransferase

and

the

patient

received

a course

of treatment

acetylcysteine,
1.2 g every 4 h for 3 days.
Liver function
abnormalities
were at their
admission,

with

the

bilirubin

value

being

18.8

worst

with

N-

24 to 48 h after

p.mol/L

(1.1

mg/dl);

AST, 1,200 U/L; and ALT, 1,616 U/L The

patient
experienced
no further
symptoms
and was discharged
on the
eighth
hospital
day. At the time of discharge,
the bilirubin
level was
6.8 p.mol/L
(0.4 mg/dl); the prothrombin
time, 11.8 5; AST, 23 U/L
ALT, 271 UIL; and alkaline phosphatase,
43 U/L.
Treatment
fortuberculosiswas
resumed3
days afterdischarge
from
hospital,
12 days after the ingestion
ofacetaminophen.
Drugs
chosen
for further
therapy
were pyrazinamide,
ethambutol
hydrochloride,
prothrombin

time,

17.2

Hepatotoxicity,

5;

AcetaminOphen

and Tuberculosis

(Nolan eta!)