Propafenone-induced liver injury: Report of a case and review of the literature

GASTROENTEROLOGY 1963;104:1524-1526

CASE REPORTS Propafenone-Induced of the Literature

Liver Injury: Report of a Case and Review

ALESSANDRA MONDARDINI,* PAOLA PASQUINO,* PAOLO BRUNO TARTAGLINO,* GIANNA MAZZUCCO,’ FERRUCCIO FRANCESCO NEGRO* *Departments

of Gastroenterology,

*Emergency Medicine, and %omedical

A case of an acute cholestatic syndrome associated with use of the antiarrhythmic drug propafenone is reported here. The close time relationship between the administration of the drug and the acute onset of the liver damage, the histological findings, and the reappearance of biochemical signs of liver dysfunction upon rechallenge with the same medication strongly suggest that propafenone was involved in the pathogenesis of this syndrome. Although rare, hepatotoxicity from this widely used antiarrhythmic medication should be kept in mind in the differential diagnosis of sudden cholestatic syndrome of obscure origin.

Sciences and Human Oncology, Molinette

numerous

hydrochloride

I?

drug widely

ular

and

propafenone continued,

tions

rarely

arrhythmias.‘,’

followed

months

consistent

with

sis.%’ In all cases, gested

to explain

Here,

we report

propafenone ture

a picture

after

reaction

pathogenesis

and

rechallenge

a relapse

eleva-

been

later,

damage.

because

persisting

Unit

following

of the clinical

syn-

the onset

On physical

Italy, because pruritus,

of the sudden

abdominal

rant, acholic

stools,

The patient’s mellitus U/day)

history with

showed

with

in Torino,

of jaundice,

diffuse

for IO years with

of a diabetes

insulin

(total

known

30

(5 mg

for 4 years

a daily dose of 20 mg of enalapril.

fever

the drug

beats. Again,

The

the patient

was frankly

showed

a slightly

enlarged,

lungs and heart

were normal,

was negative.

The temperature

patient

was

10

it was stopped. jaun-

or signs of liver encephalopathy.

pulse was 76, and the blood

pressure

moderately

tender

and neurological was 36.6”C, the

was 150/85

overweight

Blood tests on admission

0.5% basophils.

showed

Liver

tests performed 8 months before presentation were normal and included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), 7 glutamyltranspeptidase (GGT), and alkaline phosphatase activities. The daily alcohol intake was <20 g. The patient was also a smoker (about 20 cigarettes a day). The patient reported a l-year history of premature heartbeats. A 24-hour monitoring had shown the presence of

3% monocytes, The platelet

AST level was 64 IU/L,

mm Hg.

(198

lb; height,

a hematocrit

of 41.6%;

eosinophils,

was 264,000.

the alkaline

level was 87 IU/L,

bin level was 141 pmol/L concentration

and

The serum

the ALT level was 127 IU/L, phosphatase

and the lactic dehydrogenase

The amylase

trogen

0.5%

count

level was 890 IU/L,

the level

level was 354

and the total biliru-

(8.8 mg/lOO

was 19.5 mmol/L

mL). The urea ni(55 mg/lOO

mL),

and the glucose concentration was 9.2 mmol/L (168 mg/ 100 mL). The prothrombin time was 12.6 seconds (with a control

of glibenclamide

hypertension

quad-

urines.

the presence

small doses

once a day). A mild arterial was treated

to the Emergency

to the right upper

and hyperchromic

type II treated together

appearance

admission,

to ectopic

of symptoms

examination

The

IU/L.

pain localized

related

examination,

but without

GGT

Hospital

Sev-

before

with the antiarrhythmic

symptoms

20% lymphocytes,

pic-

the drug.

of the San Giovanni

occa-

the drug was taken for no more than 2 weeks, and about days before

was 553 IU/L,

Medicine

therapy

On that complaint.

the white blood cell count was 7340, with 76% neutrophils,

a histological

man was admitted

any reason. any specific

1 month

2

had been dis-

6’1”).

sug-

Case Report A 66-year-old

about

had resumed

examination

cholesta-

has

cholestasis

with with

level

of liver

on a case of acute administration,

of cholangiolitis

drome

enzyme

of intrahepatic

an allergic the

of supraventric-

without

depolar-

a day. After

administration

did not report

patient

liver.

Its administration

by liver

apparently

ectopic

had been prescribed

of 200 mg twice

propafenone

sion, the patient eral

the patient

at the dosage

weeks of therapy,

and

Hospital, Torino, Italy

and ventricular

As a consequence,

Physical

antiarrhythmic

used for the treatment

ventricular

has been

is an

supraventricular

izations.

diced, ropafenone

BERNARDI,s ENZO ALUFFI,* BONINO,* GIORGIO VERME,*

of 13.9 seconds),

was 29 seconds, 421 mg/lOO min

the partial

the serum

mL, and the protein

43 g and the globulins

hepatitis

B, delta, and C viruses

the immunoglobulin cytomegalovirus, absent.

Epstein-Barr antibodies

A radiograph

of the

time

concentration

was

level was 65 g (the albu-

22 g) per liter.

Serology

for

was negative.

Antibodies

of

(1g)M class against

Tests for antinuclear,

mitocondrial

thromboplastin

fibrinogen

virus,

hepatitis

A virus,

and adenovirus

antismooth

muscle,

were

and anti-

were negative. chest

and

an electrocardiogram

Abbreviations used in this paoer: GGT, y glutamyltranspeptidase; PAS, periodic acid-Schiff. 0 1993 by the American Gastroenterological Association 0016-5085/93/$3.00

May 199:3

PROPAFENONE

showed scan

normal

showed

increase

results.

An

a slightly

of the acustic

overall

,architecture.

peared

normal

findings

tomography

scan performed

of a contrast

medium

the stools

serum

testinal

antigen,

cancer

A percutaneous Menghini

needle.

specimen tions

was embedded

were cut and stained.

H&E, periodic diastase, with

was present. evidence

pattern

Portal

diffusely

ductules.

No evidence

trate.

Scanty

alkaline after

phosphatase,

admission,

the epithelium

and total of serum

ALT,

70 IU/L;

IU/L;

and the total bilirubin

GGT,

enlarged

levels.

alkaline

A month

phosphatase

425 mL).

The patient asked to be discharged. Four

months

later, the patient

week course of therapy ical counseling. weeks

general

after discontinuation

some blood the serum

activity

the ALT

reverted

to their

During

The

of ectopic

values

period

taking both the antidiabetic interruptions. He is now complains

to 901 IU/L

(1.6 mg/lOO

normal

who

serum

a 2-

any medsaw him

2

performed

a new significant

level was 64 IU/L

the whole

resumed

without

of the propafenone

to 615 W/L.

level was 26 mol/L

more

practitioner

tests that showed GGT

phosphatase IU/L,

The

once

increase

of

and of the alkaline AST

level

was 50

and the total bilirubin

mL). All liver tests slowly within

5 months.

of illness,

the patient

had been

drugs and the enalapril without well, although occasionally he

heartbeats.

He did not quit smoking.

Comment drome

We report temporally

here of an acute cholestatic synassociated with the administration

serum

level

to occur,

ings though

and

4 days later by the

vomiting

and

Clearly,

subsequent

for the altersome modimetabolized metabolites

could

of eosinophil in vitro

a conspicous

levels

a different inflammatory

in the

on some histologistimulation

reaction

injury.3-5

de-

in serum.

of the

with the drug, previous

of the liver

in the portal tracts, stainings ruled out

found

cell count,

a hyperergic-allergic

en-

the slow clear-

and the gradual

activities

on the

to indicate

The continuous

explain

metabolites

blood

lymphocytes

seem

and

of toxic

on the increase

mechanism

activities

the drug in one pa-

for the liver injury.

white

by the

is mostly

of the putative

indicated

the propa-

propafenone

recirculation

cal findings

complaints

accumulation

crease of liver enzyme

patient’s

and in

the drug needs to undergo

because

Based

the drug,

transaminase

and

re-

after a

was underlined

elevations.

liver,8-‘0 account

previously occurred

the initial

3) followed

of nausea

enzyme

differential

with propafenone,

behavior

(case 1, reference

fications;

ance

(3.5 mg/lOO

starting

levels after discontinuing

terohepatic

still 57 IU/L;

to those

of symptoms from

in our patient

days after withdrawing

of normal

might

GGT,

l-10

finding

by the disappeared

weeks

This peculiar

ations

a new alkaline

to the present

observed

respects

1). Onset

fenone.

and

and

is very rare, and

described

syndrome

in many

were reported

of bile ducts

syndrome,

GGT

propafenone been

two cases,3’4 as well as in ours,

liver

of serum

from

of 2-4

appearance

for

Second,

drug elicited

in the serum

cases have

(Table

that

AST were

56 pmol/L

three

ported

injury.

activities.

Hepatotoxicity

The

was seen in the infil-

bilirubin

phosphatase

granulocytes

decrease

419 IU/L;

the cholestatic

tient

a conspicuous

jaundice

a gradual

recovery

with the implicated

of

guidelines

after partial

bilirubin

was observed.

although

levels

with

of moderate

markedly

many

glycogenosis with

included

was also observed.

of eosinophils

followed,

in parallel

were

infiltration;

contained

into

nuclear

Recovery slowly,

spaces

proliferation

1Iogistic infiltrate

penetrated

sec-

Cholestasis

of inflammatory

of ductular

portal

and 3 l.trn-thick

of signs of liver hepatotoxicity.’

increase

a

the administration

drug-induced

latency

the

(PAS), PAS after treatment

and Carbol-chromotrope.’

degree

was obtained

The stains performed

acid-Schiff

a

After dehydration,

in paraffin,

between

from

of this

First, we observed

with the suggested

day. 3-5 The clinical

with

We believe

diagnosing the rechallenge

1525

in the pathogenesis

and the appearance

was similar

performed

liver fragment

formalin.

close time relationship

only

limits.

was then

A 4-cm-long

gastroin-

and ceruloplasmin.

the normal

liver biopsy

of the gut and

fetoprotein,

ferritin,

of

propafenone.

for at least two reasons.

significant

infections

iron,

and fixed in 10% buffered

with a

mucosa.

levels of alpha

All of these were within

cho-

examination

drug

This is in agreement

endos-

hiatus

syndrome the drug

computed

retrograde

the microscopical

to rule out parasitic

assays tea detect

These

gastrointestinal

of the esophageal

supracardial

tests included

tree ap-

and after administration

upper

a small hernia

hyperemic

Further

by an abdominal

before

An

that the drug was involved

of the

of gallstones.

and by an endoscopic

langiopancreatography.

of the antiarrhythmic

significant

and the biliary

any evidence

confirmed

ultrasound

without

or derangement

The gallbladder

were further

slightly

abdominal liver

impedance

without

copy showed

upper

enlarged

HEPATOTOXICITY

reports

as the likely

However,

our find-

pathogenesis. infiltrate

Al-

was seen

routine and specific histological the presence of eosinophils. It

should be noted that the patient described here did not show an increase of the eosinophil count among the peripheral white blood cells nor did he complain of symptoms suggestive of an allergic reaction (cutaneous rash, fever, or arthralgia). The marked inflammatory reaction surrounding the bile cholangioles suggests a toxic, idiosyncratic reaction mediated by the interaction between propafenone metabolites excreted in the bile stream and the bile epithelial cells. As stated, we

1526

MONDARDINI ET AL.

GASTROENTEROLOGY Vol. 104, No. 5

Table 1. Clinical Characteristics

of Patients

With Propafenone-induced

Hepatotoxicity Blood tests

Patient no. (reference)

Peak alkaline

Peak

ALT/AST ratio

phosphate level

GGT level

289

2.6

826

353

11

115

2.1

NI

96

a

Jaundrce

75

1.2

540

190

a

Fever, nausea, pruntus. jaundrce. abdomrnal parn

57

2.1

515

142

6

Prurrtus, Jaundrce, abdomrnal

127

2

553

a90

0.5

1.3

615

901

0.5

Symptoms at presentation

Sex/Age

*WV

F/35

Malarse.

nausea,

F/60 M/a4

Nausea,

vomrtrng

2nd exposure 4 (present report) 1 st exposurea

Peak ALT level

jaundrce

Eosinophrls (%)

None

2nd exposure

64

NOTE. Serum enzyme acbvrtres are expressed rn W/L. NI, not Indicated; NP, not performed. aPatrent 4 reported a prevrous exposure to propafenone

have no evidence

that this reaction

wrthout any specrfic complarnt

was allergic

in na-

ture. Glibenclamide

may have

acute cholestatic

hepatitis,”

under

with

years without

caused

an acute

but our patient

this hypoglycemic

signs or symptoms

of adverse

of hepatocytes

noticed

or subhad been

drug

for 10

effects. In

particular, liver tests performed 1 year before to our institution had been within the normal Toxic changes

Balloonrng of hepatocytes. lrpofuscrn deposits; portal tract enlargement, wrth eosinophrls. lympohocytes, and macrophage InfIltrates; brie duct proliferabon w&h eprthelral cell vacuokzatron and nuclear pyknosrs NP wrth Portal tracts enlargement, granulocytes. lymphocytes and macrophage Infiltrates; round cell rnfrltration of brie ducts NP

M/66

parn

treatment

Liver bropsy

coming ranges.

in one case4 were

wcth Portal tracts enlargement, granulocyte rnfrltrates; brie duct prolrferabon NP

(see text)

2

Funck-Brentano C. Kroemer HK, Lee JT, Roden DM. Propafenone. N Engl J Med 1990;322:518-525.

3. Schuff-Werner P, Karser D. Cholestatische Hepatitis nach antiarrhythmrscher Therapie mlt Propafenon. Dtsch Med Wochenschr 1980;105:137-138. 4. Schuff-Werner P, Kaiser D, Lueders CJ, Berg PA. Propafenoninduzrerte cholestatische Hepatitis. Z Gastroenterol 198 1; 19:673679. 5. Konz K-H, Berg PA, Seipel L. Cholestase nach antiarrhythmrscher Therapie mit Propafenon. Dtsch Med Wochenschr 1984; 109: 1525- 1527.

not seen, neither was the perivenous fibrosis.5 The patient had none of the histological signs observed in diabetes mellitus type 2,” with the possible exception

6. Bancroft P, Stevens J. Theory and practice of histological techniques. London: Churchrll-Livingstone, 1982.

of the glycogen nuclear inclusions. In conclusion, a case is reported titis following the administration

8. Siddoway LA, Roden DM, Woosley RL. Clinical pharmacology of propafenone: pharmacokinebcs, metabolrsm and concentrationresponse relations. Am J Cardiol 1984;54:9D- 12D.

fenone.

The liver injury

of cholestatic hepaof the drug propa-

was likely to be supported

by a

propafenone metabolite, but at variance with the three previously reported cases, the pathogenesis did not seem allergic. This adverse phenomenon associated with the administration of such widely used antiarrhythmic drug remains extremely rare, although it should not be overlooked in patients taking propafenone and complaining of an acute cholestatic syndrome of otherwise obscure origin.

References 1. Schlepper M. Propafenone, 1987;8:27-32.

a review of its profrle. Eur Heart J

7. Cnteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990; 1 1:272-276.

9. Connolly SJ, Kates RE, Lebsack CS, Harnson DC, Winkle RA. Clinical pharmacology of propafenone. Circulation 1983;68: 589-596. 10. Siddoway LA, Wang T, Bergstrand RH. Roden DM, Woosley RL. Polymorphic oxidabve metabolism of propafenone in man (abstr). Circulation 1983;68(Suppl 3):64. 11. Stricker BHCh, Spoelstra P. Drug-induced hepabc inJury. Amsterdam: Elsevier Science, 1985. 12. Sherlock S. Diseases of the liver and biliary system. Oxford: Blackwell Scientific, 1990.

Received August 17, 1992. Accepted November 17, 1992. Address requests for reprints to: Francesco Negro, M.D., Department of Gastroenterology, Molinette Hospital, Corso Bramante 88, 10126 Torino, Italy.