review article amiodarone-induced cirrhosis of...

Hindawi Publishing CorporationISRN CardiologyVolume 2013, Article ID 617943, 14 pageshttp://dx.doi.org/10.1155/2013/617943

Review ArticleAmiodarone-Induced Cirrhosis of Liver:What Predicts Mortality?

Nasir Hussain, Anirban Bhattacharyya, and Suartcha Prueksaritanond

Department of Internal Medicine, Saint Joseph Hospital, Resurrection Health Care, 2900 North Lake Shore Drive,Chicago, IL 60657, USA

Correspondence should be addressed to Nasir Hussain; [email protected]

Received 18 January 2013; Accepted 11 February 2013

Academic Editors: A. Bobik, C. Hassager, and B. Strasberg

Copyright © 2013 Nasir Hussain et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. Amiodarone has been used for more than 5 decades for the treatment of various tachyarrhythmias and previouslyfor the treatment of refractory angina. There are multiple well-established side effects of amiodarone. However, amiodarone-induced cirrhosis (AIC) of liver is an underrecognized complication.Methods. A systematic search of Medline from January 1970to November 2012 by using the following terms, amiodarone and cirrhosis, identified 37 reported cases of which 30 were used inthis analysis. Patients were divided into 2 subsets, survivors versus nonsurvivors, at 5 months. Results. Aspartate aminotransferasewas significantly lower (𝑃 = 0.03) in patients who survived at 5-months (mean 103.33 IU/L) compared to nonsurvivors (mean216.88 IU/L).There was no statistical difference in the levels of prothrombin time, total bilirubin, alanine aminotransferase, alkalinephosphatase, gamma-glutamyl transpeptidase, cumulative dose, and latency period between the two groups. The prevalence ofDM, HTN, HLD, CAD, and CHF was similar in the two groups. None of the above-mentioned variables could be identified as apredictor of survival at 5 months. Conclusion. AIC carries a mortality risk of 60% at 5 months once the diagnosis is established.Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC.

1. Introduction

Amiodarone has been used since the 1960s for the manage-ment of various tachyarrhythmias and in the past for refrac-tory angina.There are multiple reported and well-establishedside effects of amiodarone therapy such as effects on the thy-roid, skin, lungs, nerves, and cornea.

The effect of amiodarone on the liver resulting in hepato-toxicity is a recognized complication of amiodarone, but thishepatotoxicity leading to cirrhosis of the liver is unfortunatelyan underrecognized side effect. Little has been written onamiodarone-induced cirrhosis (AIC) of the liver due to itsrarity [1–4]. The purpose of this paper is to review what weknow so far about AIC of the liver.

2. Materials and Methods

2.1. Selection of Studies. A systematic search of Medlinefrom January 1970 to November 2012 by using the following

terms, amiodarone and cirrhosis, was performed; 37 reportedcases were identified (Table 1) of which 30 were used inthis analysis. We also searched the reference lists of allreported cases to identify citations that were not identifiedduring the initial search. Data that were extracted for eachpatient included age, gender, latency period in years, whether≥200mg/day amiodarone dosage was used (it is thoughtthat low-dose amiodarone has lesser side effects), cumulativedose, presence or absence of hypertension (HTN), dia-betes (DM), hyperlipidemia (HLD), coronary artery disease(CAD), congestive heart failure (CHF), values of bilirubin,aspartate transaminase (AST), alkaline phosphatase (ALKP), albumin, alanine transaminase (ALT), and prothrombintime. The outcomes in terms of survival or mortality at5 months were used. This specific timeline was selectedbecause more than 50% of patients in these case reportsdied within 5 months after the diagnosis was established.Not all of the studies we found had all these data; however,they were included if the outcome was provided. In some

2 ISRN Cardiology

Table1

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

163 M W

CADs/pCA

BG,D

M,

HLD

,Noetoh

,(amiodarone,w

arfarin

,aspirin

,rosiglitazon

e,and

lovastatin)

Nootherh

epatotoxicdrugs

Abdo

minal

diste

nsion

Pulietal.[2]

23.94

114 ? 23 82

Microno

dularc

irrho

sis,

bridging

fibrosis

,lym

phocytic

infiltrate,macroph

ages,

plasmac

ells,

microvesic

ular

steatosis,

andlysosomal

bodies

onele

ctron

microscop

y

600m

g/dayfor10days,

then

200m

g/dayfor2

2.5

mon

thsc

umulatived

oseo

fapprox.141

g

Survived

281 F —

Digito

xin,

alph

amethyldop

aNoDM,and

noetoh

Cirrho

sisdiagno

sed

durin

gstu

dyGuigu

ietal.[3]

15,28

186,

?,53

GGT151,

PT76%

Portalfib

rosis

,steatosis,

PMN,m

yelin

figures,dense

depo

sits,andcirrho

sis

120mon

ths,cumulative

dosage

of520g

Cou

ldno

testa

blish

anou

tcom

e

372 M W

DM,H

TN,and

CKD

Noetoh

,(am

iodarone,

simvastatin,and

glipizide)

Ascitesa

ndfatig

ueAtiq

etal.[5]

32.49,106,

147,?,75,

PT20

Steatohepatitis,

Mallory

hyaline,neutroph

ilic

infiltrate,andcirrho

sis

200P

Omg/day∗

3years

Cumulatived

oseo

fapp

rox.

219g

Dieddu

ringthes

ame

admissiondu

eto

complicationof

liver

disease

467 F AA

CAD,C

HF,ands/pAICD

Noetoh

Con

fusio

nAtiq

etal.[5]

? 377

551 ? 277

PT12.7

Mallory

hyaline,neutroph

ilinfiltrate,

peric

ellular/bridging

fibrosis

,anddegeneratin

ghepatocytes

(cirr

hosis

foun

don

autopsy)

Lowdo

se∗2years

Died2weeks

after

the

workup

dueto

cardiopu

lmon

aryfailu

re

563 M —

COPD

,DM,and

hypo

thyroidism

(digoxin,furosem

ide,and

thyroxin)

Abno

rmal

LFTs

onscreening

Rigase

tal.[6]

? 59 207 ? 28

Portal,central,and

sinusoidal

fibrosis

andlossof

lobu

lar

architecturea

ndregenerativ

eno

dules,centralveinsclerosis

,Mallory

bodies,lysosom

alinclu

sion,

andcirrho

sis

400m

g/day

Amiodarone∗18

mon

ths

Cumulatived

ose2

16

Noinform

ationabou

tthe

outcom

e

673 M —

Heartfailu

re,nosig

nificant

etoh

,com

pleter

ight

and

leftanterio

rhem

iblock

(transla

tedthroug

hGoo

gle)

Jaun

dice,

hepatomegaly

Capron

-Chivrac

etal.[7]

269

55 708

68 ? 224

GGT781

Portal,periportalfi

brosis,

mixed

inflammatoryinfiltrate,

ductalproliferatio

n,lysosomalinclu

sions,no

Mallory

bodies,and

cirrho

sis

Amiodarone

100m

g/day∗

5days/w

k∗2

mon

ths

Cumulatived

oseo

f4g

“Wes

trong

lysuspectinthis

case

cirrho

sismay

have

been

duetosomeo

ther

cause”

Died2mon

thsa

fter

stopp

ingam

iodarone,died

ofpu

lmon

aryedem

a

770 F —

—Weightloo

sandblurred

visio

n

Chaabane

etal.

[8]

—Microno

dularc

irrho

sis,

steatoh

epatitis

200m

g/day∗

15years

Cumulatived

oseo

fapp

rox.

1095

g

Cou

ldno

testa

blish

anou

tcom

e

ISRN Cardiology 3

Table1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

862 M —

CAD,H

TN,C

HF,

emph

ysem

a,pu

lmon

ary

HTN

,HLD

,renal

insufficiency,m

igraine,

ulcerativ

ecolitis,

cholelithiasis,and

noetoh

Progressive

weakn

ess,

abdo

minal

discom

fort,

andjaun

dice

Ano

nymou

s[9]

51.3

734

119 29 781

PT12.4

Microno

dularc

irrho

siswith

ballo

oningdegeneratio

nof

hepatocytesa

ndMallory

bodies,som

esteatosis

150–

1000

mg/day,averaging

400m

g/day∗

8.5years

Cumulatived

oseo

fapp

rox.

1241

g

Died2weeks

after

stopp

ing

medicine,prob

ablyhepatic

enceph

alop

athy

973 M —

Obesity,mod

eratea

lcoh

olintake

Fatig

ue,

weakn

ess

Ano

nymou

s[9]

34.2 ? 115 ? 67

Mallory

bodies,m

inim

alfatty

change,and

cirrho

sis

Amiodarone

300m

g/day∗

approx.6

mon

ths

Cumulatived

oseo

fapp

rox.

55g

Survived

form

orethan3

years

1064 M —

Gou

t,CA

D,and

renal

failu

resecond

aryto

lead

intoxicatio

n,MI,

pulm

onaryedem

a,and

sylvianmicroem

bolism

(digoxin,w

arfarin

,diclo

fenac,am

iodarone,

andallopu

rinol)

Fatig

ue,

weightloss,

1-2alcoho

licbeverageso

nsocial

occasio

ns

Richer

andRo

bert

[10]

12 149

176 ? 112

INR2.4

GGT277

Ballo

oned

hepatocytes,

Mallory

bodies,fibrosis,

phosph

olipidosis,

inflammatoryinfiltrate,and

cirrho

sis

2.8g∗4days,then

amiodarone

400m

g–60

0/day∗

13mon

ths,

cumulatived

oseo

fapp

rox.

206g

Died69

days

after

cessation

oftherapy,du

eto

hepatorenalsyn

drom

e

1174 M —

Ischem

icheartd

isease,

CVA,poliomyelitis,

carotid

endarterectomy,and

perip

heraln

europathy

Etoh

Con

sumption=negligible

Muscle

weakn

ess,

hepatomegaly

Gilinsky

etal.[11]

133.4

110 275 16 231

PT17

Fibrosis,

Mallory

hyaline,

lysosomalinclu

sions,

amiodarone,and

desm

ethylamiodarone

conc.

0.6,0.5m

g/L,respectiv

ely

Amiodarone

300–

600m

g/day∗

28mon

ths

Cumulatived

oseo

fapp

rox.

378g

Dieddespite

discon

tinuatio

nof

therapy,

prob

ablyliver

failu

re

1276 F —

Nosig

nificantp

asth

istory

otherthanrecurrentS

VTs

Abdo

minal

pain,

anorexia,and

wastin

g

Tordjm

anetal.

[12]

n 225

317 29 ?

Mallory

bodies,fibrosis,

severelydamaged

hepatocytes,biledu

ctproliferatio

n,andcirrho

sis

200m

gdaily∗5years

Cumulatived

oseo

dapprox.365

g

Died2weeks

after

evaluatio

ndu

etohepatic

enceph

alop

athy

1377 F —

—

Ano

rexia,

abdo

minal

pain,and

malaise

Rene

etal.[13]

20.52

,16

324,39

10,

GGT66

PT70%

Microno

dularc

irrho

sis,

centraland

perip

ortalfi

brosis,

andprob

able

phosph

olipidosis

400m

g/day∗

9years

Cumulatived

oseo

fapp

rox.

1314g

Outcomec

ould

notb

edeterm

ined

4 ISRN CardiologyTa

ble1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

1479 M —

CADs/pCA

BG,H

LDhypo

thyroidism

,and

s/p

pacemaker

(amiodarone,A

SA,

furosemide,atorvastatin,

andranitid

ine)

<2un

itsetoh

/mon

thNoherbalmedicines

Upp

erGI

bleed,

lethargy∗2

mon

ths

Sing

haletal.[14

]

14 67 216 27

GGT44

3

PMNinfiltrate,redu

plicating

biledu

ctsinhepatic

nodu

les,

degeneratin

ghepatocytes,

Mallory

bodies,extensiv

efib

rosis,and

cirrho

sis

200PO

mg/

day∗

33mon

ths

Cumulatived

oseo

fapp

rox.

198g

Died3mon

thsa

fter

diagno

sisdespite

ofsto

pping

amiodarone

duetoheart

andrenalfailure

and

hepatic

enceph

alop

athy

1575 F —

s/pMI,leftventric

ular

aneurysm

,and

norm

alcoronarie

s

Abno

rmal

LFTs —

Bach

etal.[15]

? 140

850 ? ?

Microno

dularc

irrho

sis,

portalfib

rosis

,Mallory

bodies,balloon

ing

hepatocytes,

phosph

olipidosis,

inflammatorycells,and

lysosomalinclu

sions

800m

g/day∗

7mon

ths,

then

600m

g/day∗

24mon

ths,then

200m

g/day

for3

mon

ths

Cumulatived

oseo

fapp

rox.

624g

Survived

form

orethan3

years

1663 F —

Mitralvalves

teno

siss/p

replacem

ent5

yearsa

go,

mod

erateT

R,no

obesity,

andno

diabetes

(amiodarone,cou

madin

deriv

ative)

Asthenia,

anorexia,and

weightlosso

f8kg

for5

mon

ths

Martin

ezetal.

[16]

18.8

198

301

35 86,

GGT475

PT20%

Postmortem

liver

biop

syshow

edincipientcirr

hosis,

portalfib

rosis

,infl

ammatory

ductalinfiltrationandmixed

leuk

ocyticinfiltration,

steatosis,

Mallory

bodies,and

acidop

hilic

change

400mgdaily∗5d

ays/week,

duratio

nno

tspecified,may

be>12

years

Cumulatived

oseo

fapp

rox.

>1152

g

Dieddu

etomassiv

eupp

erGIb

leed

durin

gsame

admission

1758 M —

CAD,M

I(amiodarone,aspirin,

furosemide,diltiazem

,iso

sorbided

initrate,

digoxin,

famotidine)

Noetoh

,noherbsu

sed

Abdo

minal

diste

nsion

andfatig

ue

Cobanetal.

[17]

? 64 ? 11 ?PT

16.9

GGT133

Polymorph

nucle

arinfiltrate,

ductalproliferatio

n,fib

rosis

,bridging

necrosis,

vacuolar

degeneratio

n,lysosomal

inclu

sions

(73+

),andcirrho

sis

200m

gdaily∗1y

ear,

stopp

eddu

etosid

eeffects,

resta

rted

200m

gdaily∗6

years

Cumulatived

oseo

fapp

rox.

511g

Died3mon

thsa

fter

diagno

sisdu

eto

hepatorenalsyn

drom

eand

hepatic

enceph

alop

athy

1885 M —

Ischem

icheartd

isease

Noob

esity,noetoh

,and

noDM

Cardiac

congestio

nOikaw

aetal.[18]

20.52 81 452 ? 35

GGT210

PT59%

Polymorph

nucle

arinfiltrate,

ductalproliferatio

n,fib

rosis

,micro/m

acrovesic

ular

steatosis,

lysosomal

inclu

sions,and

cirrho

sis(cum

ulatived

oseg

iven

byauthor

=528)

400m

gdaily∗17

days,then

200m

gdaily

for8

4mon

ths

Cumulatived

oseo

fapp

rox.

518g

Died5mon

thsa

fter

diagno

sisdu

etorenal

failu

reandpn

eumon

ia

1949 M —

Rheumaticheartd

isease,

endo

carditis,HTN

,and

DM

(amiodarone,acebu

tolol,

andglibencla

mide)

Pain

inRU

Qandfever

Lamproyee

tal.

[19]

n n n n∗

5ULN

PTn

Microno

dularc

irrho

sis,

portalfib

rosis

,leuko

cytic

infiltrates,M

allory

bodies,

micro

andmacrovesic

ular

steatosis

400m

g/day∗

5days

aweek∗

12years

Cumulatived

oseo

fapp

rox.

1152

Noou

tcom

egiven

ISRN Cardiology 5

Table1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

2056 F —

s/ppacemaker,goiter

NoDM,noob

esity,and

noetoh

abuse

(digoxin,aceno

coum

arin,

andam

iodarone

)

—Ba

bany

etal.[20]

15 38 73 ? 63PT

100%

Microno

dularc

irrho

sis,

markedste

atosis,


Mallory

bodies,lysosom

alinclu

sions

(268

gcumulative

dose

givenby

author)

Amiodarone

and

N-desmethylamiodarone

plasmac

onc.0.42,0.70g

/L

400m

g/day∗

5days

per

week2years,then

200m

g∗5days

per

week∗

11mon

ths.

Cumulatived

oseo

fapp

rox.

236g

Survived

form

orethan10

mon

ths

2183 F —

Ang

inap

ectoris

NoDM,noob

esity,and

noetoh

abuse

(amiodarone

)

Hepatom

egaly

Babany

etal.[20]

15 63 139 ? 139

PT100%

,GGT46

0

Fibrosis,

steatosis,

Mallory

bodies,infl

ammatory

infiltrate,cirrho

sis,and

lysosomalinclu

sions

onelectro

nmicroscop

y(220

gcumulatived

oseg

iven

byauthor)

Amiodarone

200m

g/day∗

3.5years

Cumulatived

oseo

fapp

rox.

256g

Survived

form

orethan1.5

years

2268 F —

Com

missurotom

yfor

mitralste

nosis

NoDM,N

oob

esity,N

oetoh

abuse

(hydroxyzine,amiodarone,

tiodo

marol,and

clonazepam)

Abno

rmal

LFTs

Babany

etal.[20]

11 43 88 ? 60PT

100%

Mod

eratefi

brosis,

steatosis,

polymorph

nucle

arinfiltrate,

Mallory

bodies,cirr

hosis

,and

lysosomalinclu

sions

(211gcumulatived

oseg

iven

byauthor)

Amiodarone

200m

gdaily∗5days/w

eekfor3

years,then

100m

g/dayfor2

years,andthen

200m

g/day∗

6mon

ths

Cumulatived

oseapprox.

=254g

Survived

atleastm

orethan

9mon

ths

2368 M —

Nosig

.PMH

(isosorbide,w

arfarin

)Noetoh

Nosig

nificant

histo

rybesid

esarrhythm

ia

Rind

eretal.[21]

? 180

422 ? ?

Activ

ecirr

hosis

,ongoing

hepatocytesd

estructio

n,and

Mallory

bodies

(165

ggivenby

author)

Loadingdo

sefor1

mon

th,

then

400m

g/day∗

13.5

mon

ths.Cu

mulatived

ose

ofapprox.162

g

Diedon

emon

thaft

erdiscon

tinuatio

nof

drug

due

tohepatic

enceph

alop

athy

andhepatorenalsyn

drom

e

2464 F —

WPW

synd

rome,no

significantP

MH

(amiodarone,diuretic

,and

betablocker)

Noetoh

used

Weakn

ess,

bedridden,

andascites

Shepherd

etal.

[22]

44 172

150 ? ?

Microno

dularc

irrho

siswith

extensiven

ecrosis

ofregeneratin

gno

dules,fib

rosis,

andsw

ollenhepatocytes

600m

g/day∗

4years

Cumulatived

oseo

fapp

rox.

876g

Dieddu

eto

bron

chop

neum

onia,

diagno

sisof

cirrho

sismade

atpo

stmortem

2576 M —

Ischem

icheartd

isease,

pulm

onaryedem

a(amiodarone,isosorbide

dinitrate,furosemide,and

potassium)

Noetoh

—Jeyamalar

etal.

[23]

? 66 148 35 69

PTno

rmal

Mod

erateinfl

ammatorycells,

nodu

lesenclo

sedin

fibrous

band

s,fatty,bile

ductules

proliferatio

nchange,and

early

cirrho

sisTo

talcum

ulatived

ose2

15g

600m

g/day∗

1week,

400m

g/day∗

1mon

th,and

200m

g∗5days/w

eek∗4

years

Estim

ated

dose

=208.2g

Survived

form

orethan4

years

6 ISRN Cardiology

Table1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

2667 M —

Hypertro

phicob

structiv

ecardiomyopathy,s/pICD,

noob

esity,noetoh

,and

noDM

B/Lhand

tremor

Ishida

etal.[24]

32.49

88 463 ? 167

PT17.4

Microno

dularc

irrho

sis,

swollenhepatocytes,

proliferatin

gbiledu

ctules,


micro/m

acrovesic

ular

steatosis,

Mallory

bodies,and

lysosomalinclu

sionbo

dies

Calculated

dose

comes

outto

158

200m

g/day∗

26mon

ths

Cumulatived

oseo

f206

gDied8days

after

admiss

ion

duetoprerenalfailu

re

27

57 M —MI

Lethargy,

abdo

minal

diste

nsion

Harris

onand

Elias[25]

—

Microno

dularc

irrho

sis,

proliferatin

gbiledu

cts,

neutroph

ilinfiltrate,

Ballo

oningdegeneratio

nof

hepatocytes,Mallory

hyaline,

lysosomalinclu

sionbo

dies,

andepith

elioidgranulom

as

200m

gtwice/day∗

4years

6mon

ths

Cumulatived

oseo

fapp

rox.

657g

Neededliver

transplant

2877 F —

HTN

,DM,

hypo

thyroidism

,and

GER

D(Lisino

pril,

glim

epiride,esomeprazole,

levothyroxine,am

iodarone,

furosemide,

spiro

nolacton

e,prop

rano

lol,andiso

sorbide

dinitrate)

Noob

esity,n

oalcoho

l

New

onset

ascitesa

ndvaric

eal

hemorrhage

Abdo

minal

diste

nsion,

lower

extre

mity

swellin

g,and

SOB

Rajaetal.[26]

10.26

54 216 39 32

INR1.2

GGT230

Lymph

ocyticinfiltration,

macro/m

icrovesic

ular

steatosis,

Mallory

hyaline,

ballo

oningdegeneratio

n,peric

ellularfi

brosis,

cirrho

sis,

andbridging

fibrous

septa

Amiodarone

200m

g/day∗

3years

Cumulatived

oseo

fapp

rox.

219g

(Noherbalmedicines)

Survived

morethan6

mon

thsc

onfirmed

with

author

2977 M —

CAD,s/p

MI,s/pCA

BG,

hep.Binfection,

andCH

FNoetoh

forlast14years

(serum

amiodarone

and

N-desmethylamiodarone

levels=3&2.6m

g/L)

Fatig

ue,

weightloss,

and

abdo

minal

swellin

g

Flahartyetal.[27]

46.17

223

459

30 124

PT39

GGT738

Markedfib

rosis,

inflammatoryinfiltrate

Mallory

bodies,cirr

hosis

,proliferatin

gdu

ctules,and

lysosomalinclu

sions

Cumulatived

oseo

f202

g(given

byauthor)

1200

mg∗

13days,

400–

600m

g/day∗

12mon

ths

Cumulatived

oseo

fapp

rox.

200g

Diedon

day21

ofho

spita

lizationdu

eto

bradycardiae

pisode

3062 F W

Noetoh

Weakn

essa

ndjaun

dice

Sniretal.[28]

92.3,520

329,22

131

GGT1493

Microno

dularc

irrho

sis,

mod

eratetosevere

fibrosis

ofpo

rtaltract,peric

ellular

fibrosis

,Mallory

bodies,and

cirrho

sison

postmortem

Amiodarone

800m

g/day

dose∗1y

ear

Estim

ated

cumulative

dose=292g

Dieddu

etoliver

failu

re3

weeks

after

stopp

ingdrug

ISRN Cardiology 7

Table1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

3184 F W

HTN

,CHF,ob

esity

(amiodarone,felod

ipine,

furosemide,po

tassium

supp

lement,aspirin

,and

cisapride)

Nootherd

rugs

Noetoh

Darkbrow

nurinefor

7days

Changetal.[29]

142

130

610 30 50

Portalfib

rosis

,pericellular

sinusoidalfi

brosis,

lysosomal

inclu

sions,M

allory

bodies,

andcirrho

sis1.3

/1.3am

iodarone/

desm

ethylamiodarone

serum

levels

400m

g/day∗

5years

Cumulatived

ose=

730g

Died4mon

thsa

fter

diagno

sisdespite

ofsto

ppingdrug

,nocauseo

fdeathestablish

ed

3272 M

Korean

HTN

(amiodarone,felod

ipine,

HCT

Z,andaspirin

)Noetoh

EF70%

Sudd

enon

set

abdo

minal

diste

nsion

Sung

andYo

on[30]

46.1

317

137 27 237

GGT385

INR1.3

2

Cirrho

sis,polym

orph

nucle

arinfiltrate,Mallory

bodies,

ballo

oningdegeneratio

n,and

lysosomalinclu

sions

Amiodarone

200m

g/day∗

5years

Estim

ated

cumulativdo

se=365g

Survived,amiodarone

discon

tinued,andother

antia

rrhythmicstarted

3364 F —

Unstabler

ecurrent

angina,

ventric

ular

aneurysm

,and

MI

Noetoh

,noDM

Forsurgical

resectionof

ventric

ular

aneurysm

Poucelletal.[31]

12 ? 188 38 82 PT11

Microno

dularc

irrho

sis,

Mallory

bodies,balloon

ing,

macrovesic

ular

steatosis,

fibrosis

,infl

ammation,

pleomorph

icmito

chon

dria,

andlysosomalinclu

sion

600m

g∗5days/w

k∗2

years

Cumulatived

oseo

f288

Diedshortly

after

liver

biop

sy,cause

unkn

ownmay

beMI,andno

postm

ortem

3462 M —

Etoh

85g/day,s/pMI,CA

D

Hepatom

egaly

despite

norm

alLF

Ts∗1y

ear,

presentedfor

liver

biop

sy

Poucelletal.[31]

8.5 ? 98 37 80 PT11

Micro

nodu

larc

irrho

sis,

Mallory

bodies,balloon

ing,

macro

vesic

ular

steatosis,

fibrosis

,infl

ammation,

pleomorph

icmito

chon

dria,

lysosomalinclu

sion

600m

g∗5days/w

k∗2

years

Cumulatived

ose2

88g

Con

tinuedon

amiodarone

andsurvived

3570 M —

Alcoh

oliccardiomyopathy,

adrenalinsuffi

ciency

(amiodarone,

hydrocortison

e)Etoh

was

DCwhenheart

prob

lem

diagno

sed

Jaun

dice,

pruritu

s,and

deterio

ratio

nof

cond

ition

Salti

etal.[32]

481

95 1451 ? 92

GGT1231

Portalandseptalfib

rosis,

polymorph

infiltrate,Mallory

bodies,lysosom

alinclu

sions,

macrovesic

ular

steatosis,

and

cirrho

sis

Amiodarone

200m

g∗5

days/w

k∗2years

Estim

ated

cumulative

dose

of96

Survived

form

orethan5

mon

thsa

tleast

3677 F —

Afib

Weakn

ess,

nausea,

vomiting

,abdo

minal

diste

nsion,

lethargy,and

confusion

Chandraprakasam

andWhitcraft

[33]

? 192

122 ? 162

Neutro

philics

atellitosis,

Mallory

hyaline,foam

cells

representin

gph

osph

olipidosis,

macrovesic

ular

steatosis,

and

cirrho

sis

Amiodarone

200m

g/day∗

4years

Cumulatived

ose=

292

Noinform

ationabou

tou

tcom

e

8 ISRN Cardiology

Table1:Con

tinued.

𝑁

Age Sex

Race

PMHotherthan

arrhythm

ias,drugs

Presentatio

nEtoh

use

Authors

Labs

Patholog

yDurationanddo

sages

Outcomea

fterd

iagn

osisof

AIC

3768 M —

Depression,

heartfailure

(digoxin,doxepin,and

bumetanide)

Vomiting

and

muscle

weakn

esso

fon

emon

thdu

ratio

n

Lim

etal.[34]

28 142

854

29 ?

—

400m

g/day∗

5mon

ths,

then

600m

g/dayfor16

mon

ths

Cumulatived

oseo

fapp

rox.

348g

Dieddu

etoliver

failu

re5

mon

thsa

fterd

iagn

osis

despite

ofsto

pping

amiodarone

𝑁:n

umber,DM:d

iabetesm

ellitus,H

TN:h

ypertension,

HLD

:hyperlip

idem

ia,C

AD:coron

aryartery

disease,CA

BG:coron

aryartery

bypass

graft

ing,

SVT:

supraventric

ular

tachycardia,CH

F:congestiv

eheart

failu

re,etoh:alcoho

l,HCT

Z:hydrochlorothiazide,ASA

:aspirin,

SOB:

shortnesso

fbreath,n:

norm

al,T

R:tricuspidregurgitatio

n,ULN

:upp

erlim

itof

norm

al,and

W:w

hite.

Labs

arewrittenin

thefollo

wingsequ

ence,B

ili,A

ST,A

LKP,Album

in,and

ALT

inalltables.AST,A

LT,A

LKP,andGGTvalues

aregivenin

IU/L,bilirubinisgivenas

Mmol:m

icromole/L(2–17)

norm

alrange,

albu

min

isgivenas

g/L.

∗

ULN

stand

sfor

upperlim

itsof

then

ormalandthew

rittenlabisforA

LTbeing5tim

estheU

LN.

ISRN Cardiology 9

cases, the outcome was not available, authors were contacted,and the outcome was determined. Those cases, for whichoutcome could not be determined, were excluded from thefinal analysis. Of seven cases that were excluded from the finalanalysis, one case had indeterminate cause of cirrhosis andfor the rest of cases, outcome could not be established. Someauthors provided cumulative doses for amiodarone. If totalcumulative dose was not given, a formula (cumulative dose ingrams = 365∗ no. of years∗ total daily dose/1000) was used toestimate the final cumulative doses, with an assumption thatthe patient had been 100% compliant with the medicine.

Prothrombin time for some cases was given as percentageactivity rather than in seconds. We could not find any con-vertor for percentage activity to seconds (which is a normallyreported unit). For cases in which prothrombin time wasreported as a percentage prothrombin activity, values werenot used in this analysis.

2.2. Statistical Analysis. Of 37 cases analyzed, outcome wasavailable only for 31 cases. One case had indeterminate causeof cirrhosis and was excluded, and 30 cases were used for ouranalysis.

Survival at 5 months determined the patient subset andcommon pathophysiologic factors like DM, HTN, HLD,CAD, and CHF; lab values comprising of prothrombin time,total bilirubin, AST, ALT, ALK P, and GGT were comparedbetween these two subsets. Logistic regression was used forcomparing continuous independent variables, and chi-squaretest was used for comparing categorical variables. When theexpected frequency was less than five, Fisher’s exact testwas used for categorical variables. Cox proportional hazardsratios were employed in determining prognosis. All statisticaltests were two tailed with significance set at 95% level (𝑃 <0.05). STATA 11 IC software was used for statistical analysis.

3. Results

AST was significantly lower (𝑃 = 0.03) in patients whosurvived at 5 months (mean 103.33 IU/L) compared to non-survivors (mean 216.88 IU/L). AST levels overall were raisedin both groups and ranged between 64 IU/L and 734 IU/L(Tables 2 and 3). There was no significant difference in thelevels of prothrombin time, total bilirubin, ALT, ALK P, andGGT between the two groups. The prevalence of DM, HTN,HLD, CAD, and CHF was similar in these two groups. Meancumulative dose in cases of AIC was 280 g with a medianlatency period of 2.92 years and was statistically nonsignifi-cant.

The risk of dying at 5 months was marginally higher inpatients with high aspartate aminotransferase. Hazard ratiofor death is 1.003 (95% CI ranging between 1.001 and 1.006).This finding was statistically significant (𝑃 = 0.03) (Table 3).Prothrombin time, total bilirubin, ALT, ALK P, GGT, andcoexistence of DM, HTN, HLD, CAD, and CHF did notpredict survival. Results are summarized in Tables 2 and 3.

Median age at the time of diagnosis of AIC was 68 yearsfor all cases, 69.5 among survivors, and 67.5 among non-survivors. Most cases of AIC were observed among femalesthough most who died were males.

4. Discussion

4.1. Pathogenesis of AIC. Amiodarone is a lipophilic agent[5] and tends to accumulate in lipid-laden organelles suchas the liver. Amiodarone causes liver damage by differentpathogenic mechanisms, one of which may include phos-pholipidosis. There are two different mechanisms by whichamiodarone causes phospholipidosis.

(I) Amiodarone and its metabolites (N-desmethylam-iodarone) accumulate in lysosomes of hepatocytes,bile duct epithelium, and kupffer cells and leads toinhibition of phospholipase A1 andA2 [35, 36], whichthereby inhibits removal of lysosomal lipids and leadsto phospholipidosis.

(II) Amiodarone binds to phospholipids in lysosomes andforms a nondigestible complex [37, 38], which leads tophospholipidosis.

The exact mechanism of phospholipidosis-induced liverdamage is unclear. Phospholipidosis has been reported tooccur within two months of starting amiodarone therapy[6, 7]. Phospholipidosis occurs in amuch larger percentage ofpatients receiving amiodarone [5] than actual hepatocellulardamage (1% to 3%), which suggests that phospholipidosismay ormay not have a role in the pathogenesis of AIC. In fact,development of phospholipidosis is considered a marker foraccumulation of amiodarone [4] rather than a marker ofhepatotoxicity.

Leakage [3, 4, 39, 40] of proteolytic enzymes from abnor-mal lysosomes represents another pathogenic mechanism ofamiodarone-induced liver damage. Leakage of proteolyticenzymes may contribute to the elevation of aminotrans-ferases and may over time lead to hepatic necrosis, fibrosis,and eventually cirrhosis.

Immunologic mechanisms may be involved in pathogen-esis in instances of amiodarone-induced acute hepatitis inpatients with positive Coombs’ test [41].

Amiodarone-induced inhibition of cellular respirationis another possible pathogenic mechanism for amiodarone-induced liver damage. Impairment of mitochondrial 𝛽-oxi-dation and uncoupling of oxidative phosphorylation leads tothe formation of reactive oxygen species, which in turn has arole in the development of AIC [42–44].

4.2. Pathology. On histologic examination of biopsy samplesobtained fromamiodarone-induced cirrhotic patients; leuko-cytic infiltrate and strikingly high Mallory’s hyaline alongwith other usual pathologic findings of cirrhosis are noted.High Mallory’s hyaline or Mallory’s bodies are suggestive ofAIC.

Mallory’s hyaline is an eosinophilic inclusion made upof intermediate keratin filaments. Mallory’s hyaline is notspecific for AIC andmay be seen in primary biliary cirrhosis,alcoholic cirrhosis or hepatitis, nonalcoholic cirrhosis, hepa-tocellular cancer, morbid obesity, and some other conditions.Mallory hyaline in AIC is present in zone 1 of acinus, whereasin alcoholic liver disease they are located usually in zone 3 [4].

Histologic findings in patients with amiodarone-inducedhepatic damage are similar to those caused by alcohol [4, 45].

10 ISRN Cardiology

Table 2: Characteristics of reported cases.

All cases,𝑁 = 30 Survivors𝑁 = 12

Nonsurvivors at 5 months𝑁 = 18

𝑃

Median age (years) 68 (56–85) 69.5 (56–83) 67.5 (58–85) 0.84Male/female 18/12 7/5 11/7 1.00Diabetes 𝑁 = 3 2 1 0.23HTN 𝑁 = 7 2 5 1.00Hyperlipidemia 𝑁 = 5 2 3 1.00CAD 𝑁 = 16 5 11 0.26CHF 𝑁 = 11 3 8 0.39>200mg/<200mgAmiodarone dose given 18/12 5/7 13/5 0.33

Latency period 2.92 (0.5–12) 3.06 (0.5–5.5) 2.54 (1–12) 0.45Cumulative dose 279.92 (55–1241) 279.92 (55–657) 465 (165–1241) 0.07Prothrombin time 16.76 (11–39) 13.68 (11–17) 18.92 (11–39) 0.08Bilirubin (micromole/liter) 55.73 (9–481) 71.67 (9–481) 46.16 (12–142) 0.53AST 177.58 (64–734) 103.33 (38–317) 216.88 (64–734) 0.03ALK P 352.96 (73–1451) 331.5 (73–1451) 365.59 (119–854) 0.78Albumin 28 (11–39) 31 (23–39) 26.91 (11–38) 0.32ALT 134.59 (32–781) 92.1 (32–237) 170 (35–781) 0.16GGT 569 (133–1493) 640.33 (230–1231) 538.43 (133–1493) 0.74𝑁 refers to the number of patients in each group. Not all studies had data on all variables.Median values given for latency period, and for all other variables, mean values are given.

The complete pathologic spectrum of alcoholic like liverinjury due to amiodarone includes micro- and macrove-sicular steatosis, steatonecrosis, mega mitochondria, portalinflammation, fibrosis, and cirrhosis. Amiodarone-associat-ed epithelloid granulomas have also been reported [8].

Presence of phospholipids laden lamellar lysosomal in-clusion bodies on electron microscopy [1, 4, 37] is anothercharacteristic pathologic finding of AIC of liver. Yap et al.observed that amiodarone-induced lysosomal inclusionsdeveloped in nearly 100% of patients at a period of 2 weeks[46].

4.3. Diagnostic Workup. AIC is a diagnosis of exclusion.Extensive workups are normally done to exclude other diag-noses including viral etiology, Wilson’s disease, hemochro-matosis, alpha 1 antitrypsin deficiency, alcoholic hepatitis,congestive liver damage, autoimmune liver pathologies, andhepatitis due to other drugs and toxins. There is no specificdiagnostic lab test for AIC of the liver.

Furthermore, there is no specific imaging characteristicfor AIC of the liver although sometimes increased liver den-sitymay be noted on a noncontract CT scan of liver. Increasedliver density is thought to be secondary to increased iodinecontent in the liver. Amiodarone has two atoms of iodine thatconstitute 37% of molecular weight of the drug. Enhanceddensity due to amiodarone is reversible upon discontinuationof amiodarone [47].

Diagnosis of AIC is usually based on liver biopsy.Malloryhyaline and lamellar lysosomal inclusions are typical ofamiodarone-induced liver damage.

4.4. Presentation. Amiodarone-induced liver damage maypresent as Reye’s syndrome in kids [9] and may present as

asymptomatic elevation of liver enzymes in adults. Asymp-tomatic liver enzyme elevation occurs in 25% of the popu-lation treated with amiodarone [1] and is usually reversibleupon discontinuation of therapy [45]. Normalization of liverenzymes may take place anywhere from three weeks to ninemonths [48]. Symptomatic hepatic dysfunction occurs inless than 1% of the population treated with amiodaroneand includes acute and chronic liver injuries. Acute liverinjury includes acute hepatitis (idiosyncratic reaction maybe involved in pathogenesis), whereas chronic liver injuryincludes steatosis (macro and microvesicular steatosis) andcirrhosis.

5. General Discussion

Amiodarone is an iodinated benzofuran derivative, lipophilicdrug with a half-life of 35–110 days and a very large volumeof distribution (VD). Amiodarone comes as number eightin drugs that cause drug-related hepatic fatalities [9]. Majormetabolite of amiodarone, N-desmethylamiodarone, is notonly pharmacologically active but has a longer eliminationhalf-life and a larger VD than the parent drug [1, 10, 49–51].Amiodarone and N-desmethylamiodarone may be detectedeven months after stopping the drug [51] as amiodaroneaccumulates in lipid reservoirs and is released slowly fromthese reservoirs. Due to this storage mechanism, amiodaroneconcentration in liver may be as high as 500-fold of serumlevel [52]. Based on these facts, damaging effects of amio-darone may persist up to one year after complete discontinu-ation of therapy [1]. Since amiodarone is mainly metabolizedin the liver, any damage to the liver from any cause wouldhamper amiodarone metabolism and lead to a vicious cycle

ISRN Cardiology 11

Table 3: Prognostic indicators of 5-month survival.

Hazardratio

95% Confidenceinterval 𝑃

Age 0.99 (0.94–1.05) 0.80Sex 0.90 (0.34–2.37) 0.83Diabetes 0.40 (0.05–3.08) 0.32HTN 1.34 (0.43–4.10) 0.62Hyperlipidemia 1.09 (0.29–4.03) 0.90CAD 1.49 (0.51–4.36) 0.46CHF 1.74 (0.52–5.80) 0.36>200mg/ <200mgAmiodarone dosegiven

1.35 (0.48–3.84) 0.56

Latency period 1.12 (0.90–1.38) 0.33Cumulative dose 1.001 (0.999–1.003) 0.09Prothrombin time 1.04 (0.97–1.11) 0.36Bilirubin(micromole/liter) 0.998 (0.99–1.00) 0.45

AST 1.003 (1.001–1.006) 0.03ALK P 1.000 (0.999–1.001) 0.98Albumin 0.99 (0.91–1.09) 0.89ALT 1.002 (0.999–1.005) 0.21GGT 1.000 (0.998–1.002) 0.87Not all studies had data on all the variables.

of accumulation of amiodarone and further amiodarone-induced hepatic damage [53].

Why some patients develop cirrhosis or hepatic damageas a side effect of amiodarone is not entirely clear. It has beensuggested that differing sensitivity to amiodarone toxicity inpopulation may exist [54]. Most patients who developed AICusually used amiodarone PO 200mg or more per day formore than 1-2 years. In light of the above-mentioned fact,researchers propose that the total cumulative dose of amio-daronemay be important in estimating the risk of irreversibleliver injury [55]. A cumulative dose of 380 g is suggested toassociate with hepatotoxicity leading to cirrhosis [50]. Otherprospective studies showed that amiodarone hepatic toxicitycorrelates to steady state serum levels of amiodarone ratherthan daily or cumulative doses [54, 56–58]. For example,if daily dosage of amiodarone during long-term therapy isreduced, despite increasing lifetime cumulative dose, thesteady state serum concentration will still be reduced andthus decreasing risk of hepatotoxicity from amiodarone.Researchers have suggested that amiodarone level less than1.5mg/L has a minimal risk of hepatotoxicity, whereas a levelabove 2.5mg/L may have a risk up to 6% for hepatotoxicity[5]. Patients with lower eject fraction may be more prone tohepatotoxic effects of amiodarone as suggested by Tisdale etal. [59]. Although it seems logical that patients with preexist-ing liver damage may be more prone to amiodarone-inducedAIC of the liver, results by Kum et al. suggest otherwise [60].

Besides chronic liver injury due to prolonged amiodaroneuse, acute hepatic side effects from amiodarone intravenousloading dose have been reported and are thought to be caused

by polysorbate 80; a solvent used in drug preparation. Thisformof acute hepatotoxicity usually improveswith discontin-uation of medication, although fatalities have been reported[61].

To prevent amiodarone-induced cirrhosis, the amio-darone should be titrated to lowest effective dose. Patientsshould have baseline LFTs and then periodic monitoring ofLFTs while on amiodarone (at 1, 3, and 6 months and thensemiannually) [62]. Studies have suggested that baseline LFTsmonitoring is performed only in 44% of patients, and afollow-up testing at 6 months and 1 year is done in only41% and 35% of patients, respectively [63]. Patients foundto have asymptomatic elevation of transaminases while onamiodarone should have a thorough investigation of thecause [56]; repeated testing may be necessary before label-ing diagnosis of amiodarone-induced hepatotoxicity [45].According to some authors, discontinuation of amiodaronefor liver-related toxicity may not be necessary [57]. Kumet al. noted in their study that 50% of patients with increasedtransaminases while on amiodarone did not improve evenafter 1.5 years of drugwithdrawal [60].However,most authorssuggest that if aminotransferases are two times above baselinevalue or above three times the upper normal limit, thenamiodarone either should be reduced or discontinued [58, 61,64, 65]. Withdrawal of drug, when irreversible liver damagehas already occurred, has a very little effect on restoration ofliver function. Despite what is said, discontinuation of amio-darone for liver-related hepatotoxicity may not be necessaryexcept in cases to prevent irreversible loss of liver function[11]. After discontinuation of amiodarone, monitoring periodshould continue for at least one year as the damaging effect ofamiodarone might persist. Patients on amiodarone should beadvised to avoid any potentially hepatotoxic agent to preventadditive hepatic damage. Discontinuation of amiodarone isreported to occur in nearly 20–40% of patients if changes inaminotransferases are detected during amiodarone therapy[66].

To date, the role of routine monitoring of amiodarone orits metabolite’s serum levels for predicting hepatic damageis not well established. Nonetheless, there are numerouspatients who may develop AIC without any abnormality inliver enzymes. Such patient population will not be detecteduntil very late. Routine imagingmay have a role in this subsetof patients, but there is no study to support this.

Based on our review (Table 1), we noted that AIC isextremely rare. However, once the diagnosis is established,the mortality risk may be as high as 60% at 5 months. Themost common cause of death among reported cases was dueto liver- and GI-related complications. Ethnic predispositionto AIC could not be determined due to lack of the publishedliterature.Themost common symptoms reportedwere gener-alized weakness, abdominal pain, and abdominal distension.

A cumulative dose of 380 g has been suggested to asso-ciate with cirrhosis. By reviewing published cases, we realizethat cirrhosis has been reported to occur with a cumulativedose as low as 55 g [9]. Why some patients with a cumulativedose of 200 g develop cirrhosis and others do not untilcumulative dose crosses above 1000 g is unclear, but it doessuggest that it may be a steady state concentration rather

12 ISRN Cardiology

than cumulative dose that may be important in predictingrisk of cirrhosis. The diagnosis in most patients was madeby liver biopsy. Although Mallory hyaline and lysosomalinclusions are characteristic features of amiodarone-inducedcirrhosis, the dilemma is that the above-mentioned patho-logic characteristics may be identified in patients on amio-darone who do not have cirrhosis. Liver biopsy alone fordiagnosis of AIC may not be enough. In fact, a thoroughevaluation for all possible causes of cirrhosis should be done.Once all possible causes of cirrhosis have been ruled out,then only the presence of Mallory hyaline and lysosomalinclusions in cirrhotic liver may be suggestive of AIC ofthe liver. In all published cases, a thorough investigation forthe cause of cirrhosis was carried out. In most publishedcases, obesity, DM, and ethanol consumption were givenspecial attention to rule out the possibility of alcoholic andnonalcoholic steatohepatitis (NASH). Risk factors for devel-opment of amiodarone-induced hepatotoxicity and cirrhosishave not been clearly defined. Whether it is cumulative doseor steady state concentration of amiodarone that predictsrisk of cirrhosis has not been determined. In most patientseven after discontinuation of amiodarone, toxicity effectsdid not subside. Majority of patients have had amiodarone-related hepatotoxicity before onset of cirrhosis leading to adecrease in dose or discontinuation of the drug. However, thedrug was restarted for various reasons, which unfortunatelylead to cirrhosis. Although AST and ALTs are said to bemainly elevated in amiodarone-related hepatotoxicity andnot the ALK P or GGT [56], our analysis suggests otherwise.According to our analysis, the only statistically significantvariable different among survivors versus nonsurvivors at 5months was the level of AST at time of diagnosis of AIC.We suggest that if patients on amiodarone have a persistentincrease in aminotransferases, a liver imaging and a liverbiopsy should be done.

There is no treatment available for amiodarone-inducedhepatotoxicity or cirrhosis besides discontinuation of theoffending agent and switching to some other antiarrhythmicagent. Previously, antioxidants vitamin E and selenium havebeen tried without any success.We recommend against usingantioxidants for counteracting amiodarone hepatotoxicity, asthere is no strong scientific evidence for such practices.

We are aware that there are limitations in our studybecause of the smaller sample size, which may have affectedour analysis. Future prospective studies using larger patientpopulation may be able to identify predictors of survival incase of AIC.

6. Conclusion

Although amiodarone does have very serious and fatal effectson the liver, such effects are rare. With a closer monitoringand taking appropriate actions when prompted, amiodaronecan be safely used on long-term basis. Further prospectivestudies are needed to identify predictors of AIC and ofmortality or survival in cases of AIC. Role of routine imagingand biopsy of the liver in patients taking amiodarone isunclear; future studies are needed to address this issue.

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