Vol. 57 - No.

2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 213

MINERVA GASTROENTEROL DIETOL 2011;57:213-29

Funding.Dr. Rangnekar is supported by a Clinical and
Translational Science Award from the Michigan Institute for
Clinical and Health Research. Dr. Fontana is a member of
DILIN and the ALFSG and supported, in part, by grants
from the National Institutes of Diabetes and Digestive and
Kidney Diseases (U01-DK-065184 and RO-1-DK-58369-01).
Corresponding author: R. J. Fontana, MD, Professor of
Medicine, Medical Director of Liver Transplantation, 3912
Taubman Center, Ann Arbor, MI 48109-0362 USA.
E-mail: rfontana@med.umich.edu
Department of Internal Medicine
University of Michigan Medical Center
Ann Arbor, MI, USA
Drug induced liver injury (DILI) is an uncom-
mon cause of acute and chronic liver injury
of increasing importance to patients, clini-
cians, and regulators. The incidence of DILI
due to an individual agent is not well defned
but population-based studies suggest that the
overall incidence of DILI may be as high as 10
to 15 cases per 100 000 patient years. Bona
fde risk factors for DILI are also not well es-
tablished, but ongoing multicenter registry
studies such as the Drug Induced Liver Injury
Network are attempting to identify the role of
genetic, environmental, and immunological
factors in DILI pathogenesis and outcomes.
Acute hepatocellular injury (~50%) is more
common than mixed or cholestatic liver injury
but jaundiced DILI subjects with either type
of liver injury have a ~10% risk of short-term
mortality. Antibiotics are the most commonly
implicated agents associated with DILI, but
there are emerging reports of liver injury as-
sociated with the use of a multitude of herbal
and dietary supplements. Despite their wide-
spread use, the HMG-CoA reductase inhibi-
tors or statins are an uncommon cause of idi-
osyncratic DILI. Furthermore, recent studies
have shown that statins are actually safe and
effcacious to use in hyperlipidemic patients
with chronic liver disease. Acetaminophen
hepatotoxicity remains a leading cause of se-
vere acute liver injury. Limiting the amount
of acetaminophen in prescription narcotic
products may help reduce the incidence of
future non-intentional overdoses but educat-
ing patients and providers of the multitude of
over the counter products that contain aceta-
minophen is also recommended.
Key words: Acetaminophen - Dietary supple-
ments - Pharmacogenetics.
D
rug-induced liver injury (DILI) is an
increasingly recognized cause of acu-
te and chronic liver injury. The overall inci-
dence of DILI in western population-based
studies ranges between 1 per 10 000 to
100 000 individuals, although these values
may be underestimated due to challenges
in diagnosis and reporting.
1
In the United
States, idiosyncratic DILI accounts for 13%
of adult acute liver failure (ALF) cases while
acetaminophen (APAP) overdose accounts
for 40-50% of cases. Since mortality from
drug-induced jaundice may approach 10%,
prompt discontinuation of the offending
agent as well as early recognition of DILI
patients with adverse prognostic factors is
important for optimal outcomes.
2, 3
Idiosyn-
cratic DILI is also a leading reason for drugs
A. S. RANGNEKAR, R. J. FONTANA
An update on drug induced liver injury
Anno: 2011
Mese: June
Volume: 57
No: 2
Rivista: MINERVA GASTROENTEROLOGICA E DIETOLOGICA
Cod Rivista: MINERVA GASTROENTEROL DIETOL
Lavoro:
titolo breve: AN UPDATE ON DRUG INDUCED LIVER INJURY
primo autore: RANGNEKAR
pagine: 213-29
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

214 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
in development to fail to obtain regulatory
approval or to be subsequently withdrawn
or restricted in their use, as recently noted
with troglitazone and telithromycin, respec-
tively.
4, 5
Acetaminophen, a dose-dependent
hepatotoxin found in multiple over-the-
counter and prescription products, is the
most common cause of DILI in the western
world.
6
However, most other instances of
DILI appear to be idiosyncratic reactions
that are independent of the dose ingested.
The aim of this review is to provide an
update on the epidemiology, natural histo-
ry, and emerging causes of DILI in western
patients. In addition, a summary of clinical,
pharmacogenetic, and immunological risk
factors involved in DILI pathogenesis from
several ongoing multicenter registry studies
is provided.
Epidemiology
The epidemiology of DILI has been diff-
cult to study for several reasons. First, DILI
TABLE I.Minimal elements required to make a diagnosis of DILI.
Feature Comments
Presenting clinical features
Age
Gender
Indication for drug
Fever, rash, itching Immunoallergic features frequently absent
Medication history
Implicated drug or HDS with generic name, dose, and fre-
quency of administration
Duration of therapy
Other drugs taken in 2 months prior to DILI onset
Prior implicated drug exposure
Diffcult when taking multiple herbals
Diffcult to determine in some cases
Rechallenge infrequently encountered and not al-
ways reliable
Initial evaluation
Time from drug start to symptoms or jaundice (if present)
Time from drug start to frst abnormal lab
Eosinophils (number/L or %) at onset or early in course
of injury
Initial and serial AST and ALT levels
Initial and serial alk phos or GGT levels
Initial and serial bilirubin levels
Initial and serial INR
Some patients are asymptomatic
First lab value meeting diagnostic criteria is DILI on-
set date
Eosinophilia defned as Absolute Eos > 500/ml or
>5% on diff
Review available pretreatment, peak, and post-di-
scontinuation lab values
Include direct bilirubin if available.
Potential risk factors/ competing causes
Alcohol use
Risk factors for acute and chronic liver disease including
family history
Exclusion of heart failure, shock, sepsis, parenteral nutri-
tion prior to DILI onset
Blood tests to exclude other causes of acute liver disease
IgM anti-HAV (or negative anti-HAV)
HBsAg and IgM anti-HBc (or negative anti-HBc)
Anti-HCV and HCV RNA
ANA, SmAb (and titer if positive)
Imaging of the liver (type and results)
Liver USN and abdominal CT/ MRI
Liver histology
Amount and pattern of use in 2 months prior to drug
start and thereafter
Include parenteral exposures
Based on medical history and cardiac imaging
Consider anti-HEV IgM if possible
Quantitative immunoglobulins, anti-HIV, CPK, CMV
DNA by PCR, and EBV-DNA by PCR of value in se-
lected cases
MRCP and ERCP helpful in some
Useful to review injury pattern and severity if availa-
ble
Adapted from Fontana RJ, et al. Hepatology August 2010.107
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 215

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
nal Registry of Hepatotoxicity in southern
Spain represents a consortium of centers
that gather clinical data and biological sam-
ples on DILI patients. In addition, the U.S.
Acute Liver Failure Study Group (ALFSG),
and the Drug-Induced Liver Injury Network
(DILIN) are multicenter networks enrolling
patients with ALF and DILI, respectively.
Between 1994 and 2004, the Regional Re-
gistry of Hepatotoxicity in Spain identifed
461 cases of DILI and estimated the annual
incidence of DILI at approximately 34 cases
per 1 million persons. Nearly 58% of the
DILI patients exhibited a hepatocellular li-
ver injury pattern at presentation and 12%
of patients with drug-induced jaundice pro-
gressed to liver transplant or death.
11
The
ALFSG, which collects data from 17 tertia-
ry care centers across the U.S., has found
that idiosyncratic DILI accounts for 12% of
ALF cases with isoniazid and nitrofurantoin
most commonly implicated.
2, 6
From 2003 to
2006, DILIN enrolled 300 consecutive DILI
patients and noted that 73% of the cases
were attributed to a single medication, 9%
accounts for <1% of patients presenting
with acute hepatocellular or cholestatic li-
ver injury,
7
with viral hepatitis, alcohol, au-
toimmune, and pancreaticobiliary diseases
being much more commonly encountered
in clinical practice. In addition, a lack of
standardized diagnostic criteria and confr-
matory objective biomarkers has precluded
accurate and reliable identifcation of DILI
patients (Table I).
10-107
The time to onset
and laboratory presentation of DILI due to
a specifc agent also can be quite variable.
Furthermore, the severity of DILI can vary
from asymptomatic laboratory abnorma-
lities to symptomatic cholestatic reactions
and rare instances of ALF.
8
Finally, since the
diagnosis of DILI requires a high index of
suspicion and the stepwise elimination of
competing causes of liver injury, a diagnosis
of DILI is often delayed or missed altoge-
ther.
9, 10
Several groups have initiated prospec-
tive multicenter registry studies to recruit
and enroll patients with bona fde DILI for
further assessment (Table II). The Regio-
TABLE II.Baseline features and outcomes in selected cohorts of DILI .patients
Chalasani et al.
13
Andrade et al.
11
De Valle et al.
19
Study type Prospective Prospective Retrospective
Country US Spain Sweden
DILI patients (N.) 300 446 77
Mean age (yrs) 48 53 58
% Female 60% 49% 56%
Ethnicity (%)
Caucasian
African-American
Other
79%
11%
10%
100% 100%
% Hepatocellular/ mixed/ cho-
lestatic
57%/20%/23% 58%/22%/20% 48%/12%/40%
% Jaundice 69% 71% 38%
% Liver biopsy 50% 25% 13%
Most frequently implicated
agents, (N.)
Amoxicillin-Clavulanate
(23) Nitrofurantoin (13)
Isoniazid (13) TMP/SMX
(9)
Amoxicillin-Clavulanate
(59) Anti-TB meds (31)
Ebrotidine (22) Ibupro-
fen (18)
Diclofenac (14) Flucloaxcil-
lin (8) Azathioprine (5)
Atorvastatin (4)
% Herbal/dietary supplements 11% 2% 5%
% Hospitalized 60% 53% 51%
% Death/transplant 8%/2% 5%/2% N/a
% Chronic DILI * 14% 10% N/a
*Defnition varies by study
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

216 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
initial use, and the majority of patients will
recover with discontinuation but rare cases
of ALF have been reported.
13, 17
Catechins
are polyphenols in green tea extract that
are thought to lead to cellular injury throu-
gh mitochondrial disruption and generation
of reactive oxygen species, but the actual
mechanism of liver injury remains unclear.
18

Risk factors for DILI
Many experts believe that certain patients
may have increased susceptibility to DILI.
While early retrospective studies suggested
that women were at higher risk of deve-
loping DILI possibly due to reduced body
weight and greater overall use of medica-
tions,
1, 2, 19
subsequent studies have shown
no difference between men and women.
11,
13, 20-22
Nonetheless, two recent studies sho-
wed that women are more likely to present
with hepatocellular liver injury,
13, 21
and that
women with DILI may be at higher risk of
progressing to ALF.
11, 21, 23
The elderly (i.e. those over the age of
65) may be at increased risk for developing
DILI, due to altered drug pharmacokineti-
cs and inadvertent drug interactions asso-
ciated with polypharmacy.
24, 25
However,
there is no clear and convincing evidence
from prospective studies that advancing age
confers a higher susceptibility to DILI per
se, although the elderly may be at higher
risk of developing DILI with certain medi-
cations such as isoniazid.
26
Elderly patients
may also be more likely to present with a
mixed or purely cholestatic liver injury pat-
tern compared to younger patients.
11, 13, 21, 27

However, it should also be noted that chil-
dren may be at increased risk of developing
valproate hepatotoxicity as well as Reyes
syndrome from aspirin.
28, 29

Underlying liver disease has long been
considered a risk factor for the develop-
ment of DILI. Both chronic hepatitis B virus
(HBV) and hepatitis C virus (HCV) infection
may predispose patients to developing DILI
from several medications including anti-
tuberculosis agents, methimazole, and ibu-
profen.
30, 31
Although an attenuated intra-
to herbal or dietary supplements (HDS), and
18% to multiple suspect agents. The most
commonly implicated agents in this study
include antimicrobials, central nervous sy-
stem agents, and immunomodulatory medi-
cations. Interestingly, both the Spanish and
DILIN registries identifed amoxicillin-cla-
vulanate as the most commonly implicated
individual agent (59 and 23 cases, respecti-
vely). Of the initial 300 patients enrolled in
DILIN, asymptomatic laboratory abnormali-
ties, overall mortality, and liver-related mor-
tality were reported in 14%, 8%, and 3%,
respectively.
12, 13
Herbal and dietary supplements
In recent years, there has been an increa-
se in the use of over-the-counter herbal and
dietary supplements due to the public per-
ception that these natural products are ef-
fcacious and safe to take in large quantities.
Common indications to use these products
include intentional weight-loss, muscle-
building, and enhancement of general well
being. However, regulation of the marke-
ting and manufacturing of HDS products is
currently limited, and there are increasing
reports of hepatotoxicity associated with
some of these agents. Since under-reporting
of over-the counter product use is com-
mon, it is diffcult to accurately determine
the rates of adverse events associated with
their use. However, supplements containing
Hydroxycut, Herbalife, green tea, black co-
hash, and anabolic steroids have all been
implicated with severe and life-threatening
DILI.
14
Green tea is a common ingredient in
many herbal preparations. It is derived from
the leaves of Camellia sinensis and is a pur-
ported weight loss agent and energy enhan-
cer. Multiple cases of hepatitis have been
observed in patients consuming green tea
extract.
15, 16
In 2003, Exolise, a product con-
taining green tea extract, was withdrawn
from the market in France and Spain due
to reports of hepatotoxicity. In most cases
of green tea hepatotoxicity, acute hepato-
cellular injury develops within 3 months of
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 217

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
of competing etiologies, evidence of prior
reports of liver injury, and re-challenge.
While this model is quite comprehensive, it
does have several limitations. First, missing
data for most of the criteria automatically
lowers the total score, which may be par-
ticularly problematic when studying a new
drug or HDS product. Secondly, several
criteria require subjective decision-making
such as use of other hepatotoxic drugs and
the amount of alcohol consumed. Thirdly,
inter-rater reliability has been low, even in
instances when this tool is utilized by ex-
perts for research purposes.
37
Finally, the
means by which competing causes of liver
injury are to be excluded are not provided,
and the instrument does not mandate te-
sting for acute HCV or HEV infection that
can mimic DILI.
13, 40
Despite these limita-
tions, the RUCAM continues to be the most
commonly cited causality instrument in
DILI studies.
Historically, consensus expert opinion
has been regarded as the gold standard
in diagnosing DILI. However, many studies
have demonstrated low inter-observer relia-
bility among experts, and this methodology
is not widely available or generalizable.
41, 42

In DILIN, a consensus opinion is determined
by the site investigator as well as two addi-
tional independent study investigators who
review an extensive clinical narrative and
prospectively assembled dataset that inclu-
des serial serum alanine aminotransferase
(ALT) values and a host of diagnostic tests
in each case. In DILIN, expert opinion is
further strengthened by involving multiple
other investigators by conference call du-
ring discussion of these cases.
43
The pattern
of liver injury is categorized by the R value
which is calculated as the initial serum ALT/
upper limit of normal (ULN) divided by the
serum alkaline phosphatase (AP)/ULN. An
R value <2 is considered cholestatic, an R >5
is hepatocellular, and all other R values are
considered mixed.
While expert opinion may be the gold
standard for diagnosing DILI, this is not
a practical approach for most clinicians.
A probabilistic approach to causality as-
sessment requires the availability of a lar-
hepatic immune response and altered drug
metabolism have been implicated, it can be
very diffcult to distinguish a chronic liver
disease fare due to a surge in viral replica-
tion versus a true DILI episode. Nonethe-
less, multiple studies have shown that HBV
or HCV coinfection appears to increase the
risk of DILI in patients with human immu-
nodefciency virus (HIV) infection. In fact,
treatment of HCV with interferon-based
therapy may lower the risk of DILI due to
highly active antiretroviral therapy (HAART)
in HIV patients with HCV co-infection.
32, 33
In contrast to the above, most studies
have not found non-alcoholic fatty liver di-
sease (NAFLD) to be an independent risk
factor for DILI. Furthermore, patients with
NAFLD do not have an increased suscepti-
bility to statin-induced DILI.
11, 13, 34, 35
Alco-
hol consumption was previously conside-
red to be a risk factor for DILI. However,
despite its presumed role in exacerbating
acetaminophen-induced hepatotoxicity,
alcohol has not been shown to be a risk
factor for developing idiosyncratic DILI in
several studies.
11, 13, 26, 36

Causality assessment
Establishing a diagnosis of DILI remains
diffcult given the lack of standardized dia-
gnostic criteria and the fact that DILI is
largely a clinical diagnosis of exclusion.
Existing diagnostic algorithms are cumber-
some and unfamiliar to most clinicians. De-
veloping a single instrument to easily assess
causality has been particularly problematic
given the low incidence of DILI and its un-
predictable onset and variable natural hi-
story.
37
The Rousel Uclaf Causality Assessment
Model (RUCAM) algorithm, which was de-
veloped in 1989, is the most widely used li-
ver-specifc causality assessment method.
38,
39
The information domains of the RUCAM
include a determination of the chronologi-
cal relationship between the suspect medi-
cation use and liver injury onset as well as
changes after drug discontinuation, identif-
cation of concurrent risk factors, exclusion
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

218 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
cib were recently associated with specifc
class I and class II human leukocyte anti-
gen (HLA) genotypes.
48
The delayed onset
of DILI in many cases further supports the
notion that the adaptive immune response
may be involved in DILI pathogenesis. Ho-
wever, most other idiosyncratic DILI cases
have not been shown to correlate with HLA
genotypes.
49
Autoimmunity due to an al-
tered host protein or drug-metabolite/host
protein complex is another potential me-
chanism of DILI.
50
For example, several me-
dications such as hydralazine, diclofenac,
nitrofurantoin, and minocycline, are asso-
ciated with both hepatotoxicity and autoim-
mune syndromes. Although many of these
DILI patients present with high titer auto-
antibodies, the fundamental pathogenesis
of sporadic autoimmune hepatitis unfor-
tunately remains elusive. A third potential
mechanism of hepatotoxicity involves poly-
morphisms in metabolic and/or detoxifca-
tion pathways leading to the development
of toxic metabolites.
50
However, it has been
diffcult to reliably identify reactive meta-
bolites in humans as well as in in vitro and
animal model test systems.
Clarifying the role of host genetic factors
in DILI pathogenesis has proven diffcult
due to the variability of presentation, the
large number of different drugs causing in-
jury, and until recently, a lack of reliable
ge number of well-vetted cases wherein a
pre-test odds can be determined as well as
complex analytic methods to apply Baye-
sian statistics.
44, 45
Although Bayesian appro-
aches are attractive for adverse drug events
like DILI that frequently have missing data,
the need for precise data from a large num-
ber of cases is a limitation with a rare dise-
ase like DILI. The identifcation of validated
biomarkers may help make a more accurate
and reliable diagnosis of DILI possible. In
addition, use of computerized algorithms
wherein available data elements can be
analyzed in the setting of prior reports may
lead to improved diagnostic instruments.
Pathogenesis
The overwhelming majority of DILI cases
are thought to be idiosyncratic (i.e. inde-
pendent of drug dose and due to a unique
mixture of ones own characteristics). Ho-
wever, a recent review of drugs that were
withdrawn from the marketplace or recei-
ved black-box warnings for hepatotoxicity
showed that most were prescribed at doses
exceeding 50 mg per day.
46, 47
Recent stu-
dies have also suggested that some DILI ca-
ses may, in part, be immune-mediated. For
example, hepatotoxicity due to amoxicillin-
clavulanate, ximelagatran, and lumiracox-
TABLE III.Studies of genetic polymorphisms in DILI patients.
Drug (ref #) DILI cases (N.) Implicated Gene * Odds ratio P-value Comment
Isoniazid
54
26 CYP2E1
1
3.4 0.02 Involved in metabolite
bioactivation
Isoniazid
53
49 CYP2E1
1
2.5 0.009
Isoniazid
52
33 NAT 2
1
3.7 0.003 Involved in detoxifcation
of metabolite
Amoxicillin-clavulanate
56
22 HLA DRB1*1501
1
9.3 2.510
-6
Valproate
61
17 POLG
1
23.6 5.110
-7
Included 6 children
Flucloxacillin
57
51 HLA B*5701
2
80.6 910
-19
Replication cohort inclu-
ded
Ximelagatran
48
74 HLA DRB1*07
2
N/a N/a Not approved for use
Lumiracoxib
60
139 HLA DRB1*1501
2
5.0 6.810
-25
Not approved for use;
Replication cohort in-
cluded
*Studies with a 1 used a candidate gene approach while 2 denotes GWA study.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 219

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
The frst successful GWA study in DILI
identifed a strong association between
fucloxacillin-induced liver injury and the
HLA-B*5701 allele.
57
In this study, 51 case
patients who experienced a typical chole-
static hepatitis following the use of fuclo-
xacillin in England were genotyped as well
as 64 drug-exposed controls. In the initial
cohort as well as a validation cohort, pos-
session of the HLA-B*5701 allele was asso-
ciated with an 80-fold increased risk of de-
veloping DILI (P=910
-19
). Interestingly, this
HLA allele has also been associated with
abacavir-hypersensitivity in HIV patients.
58

A subsequent analysis also revealed a se-
cond gene, ST6GAL1, to be associated with
fucloxacillin hepatotoxicity and a follow-
up study suggested an independent role for
polymorphisms in the promoter region of
the pregnane X receptor (PXR) which is ac-
tivated by fucloxacillin.
57, 59
Another recent
GWA study identifed an association betwe-
en the HLA class II allele, HLA-DRB1*07,
and elevations in serum ALT levels in 74
subjects treated with ximelagatran, a throm-
bin inhibitor that was withdrawn, and 130
treated controls.
48
Finally, a GWA study was
undertaken in 41 patients with lumiracox-
cib induced liver injury and in a validation
cohort of 98 patients. Fine mapping demon-
strated a strong link between lumiracoxcib
hepatotoxicity and a commonly occurring
HLA haplotype, HLA-DRB1*150, with an
odds ratio of 5.
60

These studies show that GWA methodo-
logies promise to become an increasingly
useful method for the evaluation of com-
plex disease traits like DILI. In addition,
use of whole exome and whole genome
sequencing may prove to be even more in-
formative in the future as the cost and fea-
sibility of these studies improve. However,
challenges will likely remain in applying
these powerful genetic techniques to rare
disease phenotypes like DILI due to the li-
mited number of cases attributed to an in-
dividual agent enrolled in the ongoing re-
gistries worldwide. However, collection of
even a small number of DILI cases can pro-
ve very informative, as was recently shown
in studies implicating rare polymorphisms
prospective data and samples to test. Pre-
vious genetic association studies have lar-
gely focused on evaluating candidate ge-
nes involved in the uptake, metabolism,
transport, or detoxifcation of a drug (Table
III). For example, reduced activity in the
NAT2 gene, which is involved in the me-
tabolism of isoniazid, has been associated
with isoniazid hepatotoxicity in multiple
studies.
51, 52
Isoniazid is initially metaboli-
zed to acetylhydrazine, which can then be
further metabolized by NAT2 to the less to-
xic diacetylhydrazine, while CYP2E1 me-
diated oxidative metabolism leads to the
generation of an hepatotoxic intermediate
metabolite. Polymorphisms in CYP2E1 ex-
pression have been correlated with isonia-
zid hepatotoxicity, although these results
have not been consistently replicated
53, 54
.
Amoxicillin-clavulanate hepatotoxicity has
also been associated with HLA DRB1*1501
in at least 2 studies, with 57-64% of affected
patients having this allele.
55, 56
Both xime-
lagatran and fucloxacillin have also been
associated with specifc HLA haplotypes.
48,
57
Among the patients in the Spanish regist-
ry, both HLA-DRB1*07 and DQB1*02 were
less prevalent in DILI patients, and as such
have been proposed to confer a generally
protective effect.
49
Several other genetic po-
lymorphisms have been reported in the lite-
rature, but many of these studies are small,
and the fndings have not been replicated.
The recent advent of genome-wide asso-
ciation (GWA) methodologies has enhan-
ced the ability of researchers to identify the
genetic basis of several common and rare
diseases. GWA studies involve comparing
common single nucleotide polymorphisms
(SNP) present in at least 1 to 5% of indivi-
duals across the entire genome of case pa-
tients to unselected population controls of
the same ethnic background. A DNA sam-
ple extracted from whole blood is plated
onto a gene chip which can assess up to
1 million SNPs simultaneously using high
throughput methods. Based on the frequen-
cy of identifying associations by chance,
GWA studies usually require a strict thre-
shold for statistical signifcance that exceeds
1 x 10
-6
or more.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

220 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
rates are similar between patients with ALF
due to acetaminophen overdose and idio-
syncratic DILI, a greater percentage of pa-
tients with idiosyncratic DILI require tran-
splantation for long-term survival (53% vs.
6%).
2

The ALFSG recently published prospec-
tive data regarding idiosyncratic drug-in-
duced ALF in the US over a 10 year pe-
riod.
62
Among a total of 1198 ALF patients,
133 were ultimately diagnosed with DILI
by expert opinion. Of these patients, 70.7%
were women and 57.1% white, with a mean
age of 43.8 years (Table IV). Antimicrobials
(46%) were the most commonly implicated
class of drugs and the top cited agents were
isoniazid, nitrofurantoin, and trimethoprim-
sulfamethoxazole. Overall 3-week patient
in the mitochondrial gamma polymerase
gene (POLG) in patients with valproate he-
patotoxicity.
61
Natural history
After discontinuation of the suspected
drug, the majority of patients with DILI will
achieve complete clinical and laboratory
recovery. However, nearly 10% of patients
with drug-induced jaundice will eventual-
ly progress to transplant or death. Patients
who progress to ALF with concomitant co-
agulopathy and encephalopathy are at high
risk of death, but independent predictors
of poor outcome in DILI-induced ALF are
yet to be elucidated. While overall survival
TABLE IV.Adult patients with acute liver failure due to idiosyncratic DILI from the US ALFSG 1998 to 2007.
ALF DILI cases (N.=133)
Mean age 44
% Female 71%
Ethnicity (%)
Caucasian
African American
Hispanic
Other
57%
16%
15%
12%
Labs at presentaton
Median ALT (IU/ml)
Mean Alk phos (IU/ml)
Mean Bilirubin (mg/dl)
Median INR
574
166
21
2.6
% Rash at presentation 8%
% Eosinophilia at presentation 11%
Duration of drug use prior to ALF 1-8 weeks
Causality score *
% Highly likely
% Probable
% Possible
81%
15%
4%
3-week outcomes
% Spontaneous survival
% Transplanted
% Died
27%
42%
31%
Implicated drugs, (N.) ^ Isoniazid (21)
Nitrofurantoin (12)
TMP/SMX (9)
Phenytoin (8)
Antifungal agents (azoles) (6)
Various HDS products (12)
*Determined by expert opinion. ^Most frequently implicated agents.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 221

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
defnes chronic DILI as persistently eleva-
ted liver biochemistries on at least 2 occa-
sions, abnormal liver histology, or radiolo-
gical evidence of persistent liver injury at 6
months or more after DILI onset.
43
Patients
who present with a cholestatic injury pat-
tern may be at increased risk of developing
chronic DILI but confrmatory prospective
studies are needed.
36
To date, neither cor-
ticosteroids nor ursodeoxycholic acid have
been convincingly shown to improve pro-
gnosis or outcomes or reduce the likeliho-
od of developing chronic DILI.
67

N-acetylcysteine (NAC) is an approved
treatment for patients with acetaminophen
overdose at risk for liver injury. In 2009,
the ALFSG reported the results of a ran-
domized, double-blind, placebo-controlled
trial which demonstrated the beneft of a
72-hour infusion of intravenous NAC in pa-
tients with non-acetaminophen ALF.
68
Spe-
cifcally, transplant-free survival was signif-
cantly higher for patients receiving NAC as
compared to placebo (40% vs. 27% respec-
tively, P=0.043) and this beneft was prima-
rily confned to patients with early stage
ALF, defned as coma grade I-II. Interestin-
gly, patients with idiosyncratic DILI appe-
ared to experience the greatest beneft in
transplant-free survival (58% vs. 27%). The-
refore, additional studies of NAC or other
anti-oxidants/hepatoprotective agents are
needed in patients with severe DILI.
Liver histopathology
While liver biopsy may be useful to de-
termine the pattern and degree of liver in-
jury, no specifc histological changes are
considered diagnostic of DILI. However,
certain patterns of injury are associated
with specifc drugs, and a liver biopsy is
frequently obtained to exclude other pos-
sible competing etiologies of liver injury.
For example, isolated non-necrotizing gra-
nulomas are associated with phenytoin and
allopurinol hepatotoxicity.
69, 70
In addition,
tamoxifen, amiodarone, and HAART may
cause macrovesicular steatohepatitis,
71-73

while tetracycline and valproic acid have
survival was 66.2%, but transplant-free sur-
vival was only 27.1%.
Information regarding medication factors
in the outcomes of patients with DILI is
sparse. In general, a longer duration of the-
rapy with an offending medication is asso-
ciated with increasing severity of liver injury
as well as an increased risk of developing
chronic DILI.
13, 36, 65
In addition, specifc
drugs such as halothane may be associated
with a higher case fatality rate in compari-
son to other agents such as erythromycin
and amoxicillin-clavulanate which are gene-
rally associated with self-limited disease.
66

Patients with underlying diabetes mellitus
are more likely to develop severe DILI and
perhaps even ALF.
13, 63
The role of chronic
alcohol consumption in DILI remains lar-
gely unclear and has not been associated
with development of DILI or evolution into
chronic liver injury.
11, 36
A past history of
DILI due to any medication increases the
risk of future DILI.
64
However, the role of
other factors such as diet, smoking, and un-
derlying illnesses in the development and
outcome of DILI are largely unknown.
In regards to clinical presentation, early
studies suggested that hepatocellular liver
injury may portend a poorer prognosis,
11, 13,
66
although recent prospective data do not
support this observation.
22
In patients with
hepatocellular injury, the ratio of aspartate
aminotransferase (AST) to ALT may corre-
late with progression to ALF, transplanta-
tion, and death.
65, 66
The combination of
hepatocellular injury and jaundice has been
associated with higher mortality (i.e. Hys
rule), and several recent studies have con-
frmed higher rates of death and liver tran-
splantation in patients with this clinical pre-
sentation.
11, 13, 66
Treatment of DILI
The vast majority of patients with DILI
will achieve complete recovery after cessa-
tion of the suspect medication. However,
approximately 5% to 14% of patients may
develop chronic DILI which has been va-
riably defned in different studies.
2, 36
DILIN
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

222 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
ber of case studies have described severe
statin-induced hepatotoxicity.
77
The dura-
tion of time to development of DILI in the-
se case reports was highly variable, ranging
from 5 days to 4 years. Mortality has also
been rare, and most patients seem to expe-
rience resolution of laboratory abnormali-
ties within weeks to months. Among 51741
adult American liver transplant recipients,
only 3 had probable statin-induced liver fai-
lure. Of note, 2 of these 3 cases were attri-
buted to cerivastatin, an agent which was
subsequently withdrawn from the market.
23

Among 598 cases of severe or fatal DILI in
Sweden, simvastatin was only linked to one
death and another statin-treated patient re-
quired liver transplantation.
46
Serious statin-
induced hepatotoxicity has also been rarely
identifed in two ongoing prospective stu-
dies. The DILIN group reported that 3.4%
of the frst 300 collected DILI cases were
attributed to lipid-lowering agents. Among
these patients, one patient with cirrhosis ta-
king ezetimibe and simvastatin died of liver
failure, while another patient taking lova-
statin as well as concurrent lefunomide for
rheumatoid arthritis subsequently required
liver transplantation.
13
In the Spanish regist-
ry, 11 of 461 DILI cases were related to sta-
tins.
11
Of the 28 cases of chronic DILI in this
registry, 2 were attributed to lipid-lowering
agents, and interestingly a cholestatic pat-
tern of liver injury was seen in both cases.
36
In several case reports of statin-induced
liver injury, the patients were exposed to
other potential hepatotoxic medications,
which may have directly induced liver in-
jury. Alternatively several drugs such as
diltiazem and amiodarone may potentiate
statin-induced hepatotoxicity by competi-
tively inihibiting CYP3A4, the enzyme re-
sponsible for metabolizing statins.
77
Among
the reported cases of statin-induced hepato-
toxicity, a subset has been associated with
development of autoantibodies, including
antinuclear, anti-smooth muscle, and anti-
histone antibodies.
77
Whether the statin it-
self acts as a hapten in the development of
an autoimmune response, or whether these
cases refect sporadic autoimmune hepatitis
remains unclear.
been associated with microvesicular steato-
hepatitis.
74
Vascular injury of the liver may
occur after use of estrogens (Budd-Chiari
syndrome), chemotherapeutic agents (sinu-
soidal obstruction syndrome), and immuno-
modulators (nodular regenerative hyperpla-
sia).
74
The presence of hepatic necrosis has
been associated with a higher mortality rate
in published reports of DILI. In addition, it
has also been observed that hepatic or peri-
pheral eosinophilia may be associated with
more favorable outcomes and a greater abi-
lity to regenerate, but confrmatory studies
are needed.
75
Statin hepatotoxicity
The statins or hydroxymethylglutaryl co-
enzyme A (HMG-CoA) reductase inhibitors
are used to lower circulating LDL choleste-
rol levels, and are among the most frequen-
tly prescribed medications in the world. In
clinical trials, less than 3% of patients recei-
ving statins developed elevated serum AST
and ALT levels, defned as 3 times the ULN.
However, few if any developed progres-
sive liver injury or jaundice even despite
continued dosing. As such, statin-induced
aminotransferase elevation is a commonly
identifed phenomenon of unclear clinical
signifcance. In addition, nearly 30% of pa-
tients on statins can also develop asympto-
matic elevations in serum creatinine pho-
sphokinase (CPK) levels. Therefore, serum
aminotransferase elevations in some pa-
tients may actually be due to statin-induced
CPK elevations, rather than liver injury.
35

Recently, a GWA study identifed a SNP
in the SLCO1B1 gene which was associa-
ted with an increased risk of statin-induced
myopathy which occurs in <1% of treated
patients.
76
The SLCO1B1 gene, which is in-
volved in the hepatic uptake of statins, ac-
counted for nearly 60% of the risk of deve-
loping myopathy.
While statins may cause elevated serum
AST/ALT levels to 3 times ULN in up to 3%
of treated patients, clinically signifcant sta-
tin-induced hepatotoxicity is very uncom-
mon. In a recent review , only a small num-
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 223

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
pravastatin 80 mg daily or placebo. No si-
gnifcant difference in the frequency of se-
rum ALT elevation was noted between the
two groups.
80
A post-hoc analysis of another
large multicenter randomized controlled
study also demonstrated the effcacy and
safety of statins in coronary artery disease
patients with abnormal baseline liver bio-
chemistries.
81
Other studies have reported
potential benefts of statin use in NAFLD,
including improvement of aminotransfera-
se levels,
82-85
as well as a reduction in both
hepatic steatosis and progression of hepa-
tic fbrosis.
86
In the US, the National Lipid
Association Safety Task Force, a group of
experts in cardiology and hepatology, has
concluded that statins are safe for use in pa-
tients with compensated chronic liver disea-
se including NAFLD. In addition, this group
determined that compensated cirrhosis is
not a contraindication to statin therapy, but
use of these drugs in patients with decom-
pensated liver disease is not recommended
due to altered pharmacokinetics.
87
Statins in patients with liver disease
There is a common misconception that
statins may be unsafe to use in patients with
underlying liver disease. However, the ma-
jority of evidence supports the use of statins
in hyperlipidemic patients with stable chro-
nic liver disease. In general, patients with
NAFLD are known to have a substantially
elevated risk of cardiovascular mortality.
78

Furthermore, patients with chronic HCV
have a higher incidence of insulin resistan-
ce and metabolic syndrome, which may
also increase their risk of cardiovascular
mortality.
79
In retrospective studies, patients
with abnormal baseline liver biochemistri-
es did not demonstrate a higher incidence
of further laboratory abnormalities after 12
months of statin therapy compared to un-
treated controls.
34
In addition, a randomi-
zed, double-blind, placebo-controlled trial
by Lewis et al. confrmed the safety of sta-
tin use in patients with liver disease (Table
V). In this study, patients with underlying
liver disease were randomized to receive
TABLE V.Effcacy and safety of statins in hyperlipidemic patients with liver disease.
Lewis et al.
80
(2007) Athyros et al.
81
(2010)
Number of pts N.=326 N.=437
Patient characteristics Chronic liver disease with LDL cholesterol Coronary artery disease with LDL choleste-
rol
Mean age (yrs) 50 60
% Male 52% 80%
Liver disease
% Chronic HCV
% NAFLD
% Other
25%
64%
11%
100% presumed NAFLD
with AST/ALT<3xULN
Pravastatin
(N.=163)
Placebo
(N.= 163)
Atorvastatin
(N.=227)
Untreated
(N.=210)
Baseline ALT (IU/mL)
Baseline AST (IU/mL)
65
42
77
50
57
49
56
49
Duration of follow-up 36 weeks 36 weeks 3 years 3 years
% LDL reduction -26% -1% * -44% -5% *
% Cardiovascular events NA NA 9.7% 30% *
% ALT > 2 X baseline 7.5% 12.5% NA NA
% ALT change
% AST change
% GGTP change
NA NA -35%
-47%
-46%
+12%*
+12%*
+16%*
% Jaundice 0% 0% 0% 0%
*P<0.05 in these studies.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

224 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
Serum acetaminophen levels can be
useful in estimating the risk of liver inju-
ry after a single time point ingestion. Ho-
wever, an initially low serum acetamino-
phen level may be unreliable, especially
in patients with a delayed presentation or
in those that overdose over several days.
In addition, serum bilirubin levels greater
than 10 grams per deciliter can lead to fal-
se positive serum acetaminophen levels in
some assays.
98
Based on these limitations,
there has been ongoing investigation into
identifying more reliable serum markers
of acetaminophen hepatotoxicity. In ear-
ly studies, acetaminophen protein adducts
were detected in the serum up to 12 days
after ingestion. If a point of care test could
be developed, this new assay may serve as
a more specifc and even potentially sensi-
Acetaminophen hepatotoxicity
Acetaminophen overdose is the leading
cause of ALF in Western countries, and the
majority of patients overdose on acetamino-
phen due to suicidal ideation.
2
However, an
increasing proportion of patients are pre-
senting with unintentional overdoses, like-
ly due to the ubiquity of APAP in multiple
products and its often under-recognized
hepatotoxic potential.
88, 90
Acetaminophen
is well known to exhibit dose-dependent
hepatotoxicity. With stable dosing, only a
small proportion of APAP is oxidatively me-
tabolized by cytochrome P450 to N-acetyl-
P-benzoquinone imine (NAPQI) which can
then be detoxifed in the liver by gluta-
thione transferase. However, when exces-
sive doses are ingested, there is an incre-
ased amount of NAPQI generated which
can covalently bind to hepatic proteins to
form adducts, deplete glutathione stores,
and subsequently lead to pericentral ne-
crosis.
91
Chronic consumption of alcohol or
ingestion of agents such as isoniazid and
phenytoin can increase the formation of
NAPQI through induction of CYP2E1.
92, 93

Recent animal and human studies have also
implicated a potential role of the innate im-
mune response in explaining the variable
susceptibility to acetaminophen hepatoto-
xicity. Interestingly, subjects with reduced
CD44 expression on lymphocytes may be
at increased risk of developing acetamino-
phen hepatotoxicity.
94, 95
A high index of suspicion is necessary to
diagnose acetaminophen overdose inclu-
ding a careful review of all over-the-counter
medication use since acetaminophen is an
ingredient in several hundred products.
Acetaminophen doses greater than 4 grams
per day generally increase the risk of hepa-
totoxicity.
96
The classic laboratory fndings
associated with acetaminophen liver injury
include elevated serum aminotransferase le-
vels, prolonged prothrombin time, metabo-
lic acidosis, and renal failure in up to 50%
of patients with ALF (Figure 1). However, it
should be noted that serum bilirubin levels
at presentation are most commonly normal
or minimally elevated.
97

Figure 1.Non-intentional acetaminophen overdose
case. A 28 year old Caucasian woman with a history of
chronic abdominal pain and depression presented with
nausea, vomiting, and altered mental status. She had ta-
ken 4 to 8 tablets per day of Vicodin (5 mg hydroco-
done-500 mg acetaminophen) for several months and
recently took additional vicodin and tylenol tabs for
worsening pain. Her initial serum acetaminophen level
was 95 mcg/ml with a pH of 7.12, ALT of 2600 IU/ml,
and INR of 5.6. After 2 days of N-acetylcysteine therapy,
she required intubation for worsening mental status and
cerebral edema on head CT. Although her serum ALT
and INR continued to improve, she required placement
of an intracranial pressure monitor on hospital day #4
and induction of a pentobarbital coma. Following a pro-
longed and complicated hospital course, she eventually
improved and was discharged home on hospital day #30
with a normal ALT, bilirubin, and INR.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 225

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
thorities have been looking at efforts to re-
duce the frequency of this avoidable cause
of liver injury. For example, there are an
estimated 56000 acetaminophen overdose
cases, 26000 hospitalizations, and greater
than 500 deaths due to acetaminophen
overdose each year in the United States
alone.
88
In the United Kingdom where the
majority of APAP overdose cases appear to
be intentional/suicidal circumstances, bli-
ster packaging and dispensing restrictions
have led to a signifcant reduction in the
number of patients with intentional over-
dose.
104
In the United States, an advisory
panel to the FDA made a series of recom-
mendations to reduce the incidence of
both intentional and non-intentional APAP
hepatotoxicity.
105
On January 13
th
, 2011
the FDA announced that they will requi-
re all manufacturers of prescription drug
products to limit the maximum amount of
APAP to 325 mg per tablet and to place
Black-Box warnings on these products.
106

Hopefully, these actions and others direc-
ted at the multitude of over-the-counter
products containing acetaminophen will
reduce future instances of acetaminophen
hepatotoxicity.
Riassunto
Attualit sul danno epatico indotto da farmaci
Il danno epatico indotto da farmaci (drug indu-
ced liver injury, DILI) una causa non comune di
danno epatico acuto o cronico, che sta acquistan-
do sempre maggiore importanza per i pazienti, i
medici e gli organismi di controllo. Lincidenza di
DILI legato ad un singolo agente non defnita con
precisione, ma studi basati sulla popolazione sugge-
riscono che lincidenza complessiva del DILI possa
essere nellordine di 10-15 casi per 100000 anni/pa-
ziente. Anche i fattori di rischio per DILI non sono
ben defniti, ma studi multicentrici basati su registro
attualmente in corso, come il Drug Induced Liver
Injury Network, stanno cercando di identifcare il
ruolo dei fattori genetici, ambientali ed immunolo-
gici nella patogenesi e negli outcome del DILI. Il
danno epatocellulare acuto (~50%) pi comune
del danno epatico di tipo misto o colestatico; i sog-
getti itterici con DILI, indipendentemente dal tipo
di danno epatico, hanno un rischio di mortalit a
breve termine del 10% circa. Gli antibiotici sono gli
agenti pi comunemente implicati nello sviluppo di
tive biomarker of acetaminophen hepato-
toxicity.
99, 100

Initial management of suspected APAP
overdose includes inducing emesis with ipe-
cac syrup, gastric lavage of pill fragments,
and administering activated charcoal to mi-
nimize absorption in patients presenting
within 12 to 24 hours of a single time point
ingestion.
101
The likelihood of hepatotoxi-
city can be assessed with the Rumack no-
mogram, which takes into account the time
since overdose as well as the serum ace-
taminophen level. Patients with known or
suspected acetaminophen overdose should
be admitted to the hospital for assessment
of suicidality as well as initiation of NAC
therapy. Patients with hemodynamic insta-
bility, acute renal failure, or altered mental
status should be directly admitted to the in-
tensive care unit and urgently referred for
liver transplant evaluation.
102
NAC should
be administered immediately to patients at
risk for hepatotoxicity, as based on initially
elevated serum acetaminophen, aminotran-
sferase, or INR levels. Oral NAC is given as
an initial loading dose of 140 mg/kg follo-
wed by 70 mg/kg every 4 hours for a total
of 72 hours or until the INR is less than
1.5.
91
Patients who are unable to tolerate
oral NAC can be given intravenous NAC as
a continuous infusion until the INR is less
than 1.5. Mild to moderate hypersensitivity
reactions develop in up to 5% of patients
receiving NAC and can be managed by a re-
duction in the rate of NAC infusion and/or
concurrent administration of antihistamines
and corticosteroids for patients with more
severe reactions.
103
With supportive care, the majority of pa-
tients with acetaminophen overdose can
be successfully treated. However, amongst
those who progress to ALF, 3-week spon-
taneous survival is only 60% with 5-10% of
patients requiring liver transplantation and
the remainder dying of ALF.
Prevention of acetaminophen overdose
Due to increasing reports of APAP over-
dose in multiple countries, regulatory au-
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

226 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
injury: an analysis of 461 incidences submitted to
the Spanish registry over a 10-year period. Gastro-
enterology 2005;129:512-21.
12. Hoofnagle JH. Drug-induced liver injury network
(DILIN). Hepatology 2004;40:773.
13. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins
PB, Davern T, Serrano J et al. Causes, clinical fea-
tures, and outcomes from a prospective study of
drug-induced liver injury in the United States. Gas-
troenterology 2008;135:1924-34, 34 e1-4.
14. Navarro VJ. Herbal and dietary supplement hepato-
toxicity. Semin Liver Dis 2009;29:373-82.
15. Gloro R, Hourmand-Ollivier I, Mosquet B, Mosquet
L, Rousselot P, Salame E et al. Fulminant hepatitis
during self-medication with hydroalcoholic ex-
tract of green tea. Eur J Gastroenterol Hepatol
2005;17:1135-7.
16. Jimenez-Saenz M, Martinez-Sanchez Mdel C. Acute
hepatitis associated with the use of green tea infu-
sions. J Hepatol 2006;44:616-7.
17. Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F,
Raschetti R, Santuccio C et al. Hepatotoxicity from
green tea: a review of the literature and two unpub-
lished cases. Eur J Clin Pharmacol 2009;65:331-41.
18. Galati G, Lin A, Sultan AM, OBrien PJ. Cellular
and in vivo hepatotoxicity caused by green tea
phenolic acids and catechins. Free Radic Biol Med
2006;40:570-80.
19. De Valle MB, Av Klinteberg V, Alem N, Olsson R,
Bjornsson E. Drug-induced liver injury in a Swed-
ish University hospital out-patient hepatology clinic.
Aliment Pharmacol Ther 2006;24:1187-95.
20. Shapiro MA, Lewis JH. Causality assessment of drug-
induced hepatotoxicity: promises and pitfalls. Clin
Liver Dis 2007;11:477-505, v.
21. Lucena MI, Andrade RJ, Kaplowitz N, Garcia-Cortes
M, Fernandez M, Romero-Gomez M et al. Pheno-
typic characterization of idiosyncratic drug-induced
liver injury: the infuence of age and sex. Hepatol-
ogy 2009;49:2001-9.
22. Ibanez L, Perez E, Vidal X, Laporte JR. Prospective
surveillance of acute serious liver disease unrelated
to infectious, obstructive, or metabolic diseases: epi-
demiological and clinical features, and exposure to
drugs. J Hepatol 2002;37:592-600.
23. Russo MW, Galanko JA, Shrestha R, Fried MW, Wat-
kins P. Liver transplantation for acute liver failure
from drug induced liver injury in the United States.
Liver Transpl 2004;10:1018-23.
24. Abboud G, Kaplowitz N. Drug-induced liver injury.
Drug Saf 2007;30:277-94.
25. Schenker S, Bay M. Drug disposition and hepatotox-
icity in the elderly. J Clin Gastroenterol 1994;18:232-
7.
26. Fountain FF, Tolley E, Chrisman CR, Self TH. Iso-
niazid hepatotoxicity associated with treatment
of latent tuberculosis infection: a 7-year evalua-
tion from a public health tuberculosis clinic. Chest
2005;128:116-23.
27. Onji M, Fujioka S, Takeuchi Y, Takaki T, Osawa T,
Yamamoto K et al. Clinical characteristics of drug-
induced liver injury in the elderly. Hepatol Res
2009;39:546-52.
28. Ferrajolo C, Capuano A, Verhamme KM, Schuemie
M, Rossi F, Stricker BH et al. Drug-induced hepatic
injury in children: a case/non-case study of sus-
pected adverse drug reactions in VigiBase. Br J Clin
Pharmacol 2010;70:721-8.
29. Schror K. Aspirin and Reye syndrome: a review of
the evidence. Paediatr Drugs 2007;9:195-204.
30. Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW,
DILI; tuttavia, report recenti riferiscono danni epati-
ci associati alluso di una molteplicit di integratori
alimentari e prodotti a base di erbe. Nonostante la
loro grande diffusione, gli inibitori della HMG-CoA
reduttasi (statine) sono una causa non frequente di
DILI idiosincratico. Inoltre, recenti studi hanno mo-
strato che le statine possono essere effettivamente
usate in modo sicuro ed effcace in pazienti iperli-
pidemici con epatopatia cronica. Lepatotossicit del
paracetamolo continua ad essere una casa prima-
ria di danno epatico acuto severo. Una limitazio-
ne della quantit di paracetamolo nelle specialit
contenenti stupefacenti pu contribuire a ridurre
lincidenza di sovradosaggi non intenzionali, ma
si consiglia anche di promuovere uninformazione
adeguata sia nei pazienti che nei soggetti che ven-
dono gli innumerevoli prodotti da banco contenenti
paracetamolo.
Parole chiave: Acetaminofene - Integratori alimenta-
ri - Farmacogenetica.
References
1. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C,
Guilleminet C et al. Incidence of drug-induced he-
patic injuries: a French population-based study.
Hepatology 2002;36:451-5.
2. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A,
Davern TJ, Han SH et al. Results of a prospective
study of acute liver failure at 17 tertiary care centers
in the United States. Ann Intern Med 2002;137:947-
54.
3. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N
Engl J Med 2006;354:731-9.
4. Graham DJ, Green L, Senior JR, Nourjah P. Troglita-
zone-induced liver failure: a case study. Am J Med
2003;114:299-306.
5. Brinker AD, Wassel RT, Lyndly J, Serrano J, Avigan
M, Lee WM et al. Telithromycin-associated hepato-
toxicity: Clinical spectrum and causality assessment
of 42 cases. Hepatology 2009;49:250-7.
6. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E,
Hynan LS et al. Acetaminophen-induced acute liver
failure: results of a United States multicenter, pro-
spective study. Hepatology 2005;42:1364-72.
7. Galan MV, Potts JA, Silverman AL, Gordon SC. The
burden of acute nonfulminant drug-induced hepa-
titis in a United States tertiary referral center [cor-
rected]. J Clin Gastroenterol 2005;39:64-7.
8. Andrade RJ, Robles M, Fernandez-Castaner A, Lopez-
Ortega S, Lopez-Vega MC, Lucena MI. Assessment of
drug-induced hepatotoxicity in clinical practice: a
challenge for gastroenterologists. World J Gastroen-
terol 2007;13:329-40.
9. Jinjuvadia K, Kwan W, Fontana RJ. Searching for
a needle in a haystack: use of ICD-9-CM codes
in drug-induced liver injury. Am J Gastroenterol
2007;102:2437-43.
10. Duh MS, Walker AM, Kronlund KH, Jr. Descriptive
epidemiology of acute liver enzyme abnormalities
in the general population of central Massachusetts.
Pharmacoepidemiol Drug Saf 1999;8:275-83.
11. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G,
Pachkoria K, Garcia-Ruiz E et al. Drug-induced liver
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 227

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
Bengtsson OF, Andersson TB et al. Genome-wide
pharmacogenetic investigation of a hepatic adverse
event without clinical signs of immunopathology
suggests an underlying immune pathogenesis. Phar-
macogenomics J 2008;8:186-95.
49. Andrade RJ, Lucena MI, Alonso A, Garcia-Cortes M,
Garcia-Ruiz E, Benitez R et al. HLA class II genotype
infuences the type of liver injury in drug-induced
idiosyncratic liver disease. Hepatology 2004;39:1603-
12.
50. Uetrecht J. Immunoallergic drug-induced liver injury
in humans. Semin Liver Dis 2009;29:383-92.
51. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T,
Yokota S, Maekura R et al. Slow N-acetyltransferase
2 genotype affects the incidence of isoniazid and
rifampicin-induced hepatotoxicity. Int J Tuberc Lung
Dis 2000;4:256-61.
52. Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY
et al. Polymorphism of the N-acetyltransferase 2 gene
as a susceptibility risk factor for antituberculosis drug-
induced hepatitis. Hepatology 2002;35:883-9.
53. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chi-
ang CH et al. Cytochrome P450 2E1 genotype and
the susceptibility to antituberculosis drug-induced
hepatitis. Hepatology 2003;37:924-30.
54. Vuilleumier N, Rossier MF, Chiappe A, Degoumois
F, Dayer P, Mermillod B et al. CYP2E1 genotype
and isoniazid-induced hepatotoxicity in patients
treated for latent tuberculosis. Eur J Clin Pharmacol
2006;62:423-9.
55. Hautekeete ML, Horsmans Y, Van Waeyenberge C,
Dermanet C, Henrion J, Verbist L et al. HLA asso-
ciation of amoxicillin-clavulanate--induced hepatitis.
Gastroenterology 1999;117:1181-6.
56. ODonohue J, Oien KA, Donaldson P, Underhill J,
Clare M, MacSween RN et al. Co-amoxiclav jaundice:
clinical and histological features and HLA class II as-
sociation. Gut 2000;47:717-20.
57. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Peer
I, Floratos A et al. HLA-B*5701 genotype is a major
determinant of drug-induced liver injury due to fu-
cloxacillin. Nat Genet 2009;41:816-9.
58. Mallal S, Phillips E, Carosi G, Molina JM, Workman
C, Tomazic J et al. HLA-B*5701 screening for hyper-
sensitivity to abacavir. N Engl J Med 2008;358:568-
79.
59. Andrews E, Armstrong M, Tugwood J, Swan D,
Glaves P, Pirmohamed M et al. A role for the preg-
nane X receptor in fucloxacillin-induced liver injury.
Hepatology 2010;51:1656-64.
60. Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X,
Klickstein L et al. A genome-wide study identifes
HLA alleles associated with lumiracoxib-related liver
injury. Nat Genet 2010;42:711-4.
61. Stewart JD, Horvath R, Baruffni E, Ferrero I, Bulst
S, Watkins PB et al. Polymerase gamma gene POLG
determines the risk of sodium valproate-induced
liver toxicity. Hepatology 2010;52:1791-6.
62. Reuben A, Koch DG, Lee WM. Drug-induced acute
liver failure: results of a U.S. multicenter, prospective
study. Hepatology 2010;52:2065-76.
63. El-Serag HB, Everhart JE. Diabetes increases the
risk of acute hepatic failure. Gastroenterology
2002;122:1822-8.
64. Bjornsson E, Davidsdottir L. The long-term follow-
up after idiosyncratic drug-induced liver injury with
jaundice. J Hepatol 2009;50:511-7.
65. Ohmori S, Shiraki K, Inoue H, Okano H, Yamanaka
T, Deguchi M et al. Clinical characteristics and prog-
nostic indicators of drug-induced fulminant hepatic
failure. Hepatogastroenterology 2003;50:1531-4.
Wong PC et al. Antituberculosis drug-related liver
dysfunction in chronic hepatitis B infection. Hepa-
tology 2000;31:201-6.
31. Gupta NK, Lewis JH. Review article: The use of po-
tentially hepatotoxic drugs in patients with liver dis-
ease. Aliment Pharmacol Ther 2008;28:1021-41.
32. Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-
Carbonero L, Castellares C et al. Hepatotoxicity of
antiretroviral drugs is reduced after successful treat-
ment of chronic hepatitis C in HIV-infected patients.
J Infect Dis 2007;196:670-6.
33. Soriano V, Puoti M, Garcia-Gasco P, Rockstroh JK,
Benhamou Y, Barreiro P et al. Antiretroviral drugs
and liver injury. AIDS 2008;22:1-13.
34. Chalasani N, Aljadhey H, Kesterson J, Murray MD,
Hall SD. Patients with elevated liver enzymes are not
at higher risk for statin hepatotoxicity. Gastroenter-
ology 2004;126:1287-92.
35. Chalasani N. Statins and hepatotoxicity: focus on pa-
tients with fatty liver. Hepatology 2005;41:690-5.
36. Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz
B, Borraz Y, Pachkoria K et al. Outcome of acute
idiosyncratic drug-induced liver injury: Long-term
follow-up in a hepatotoxicity registry. Hepatology
2006;44:1581-8.
37. Hayashi PH. Causality assessment in drug-induced
liver injury. Semin Liver Dis 2009;29:348-56.
38. Benichou C, Danan G, Flahault A. Causality assess-
ment of adverse reactions to drugs--II. An original
model for validation of drug causality assessment
methods: case reports with positive rechallenge. J
Clin Epidemiol 1993;46:1331-6.
39. Danan G, Benichou C. Causality assessment of ad-
verse reactions to drugs--I. A novel method based
on the conclusions of international consensus meet-
ings: application to drug-induced liver injuries. J Clin
Epidemiol 1993;46:1323-30.
40. Dalton HR, Fellows HJ, Stableforth W, Joseph M,
Thurairajah PH, Warshow U et al. The role of hepa-
titis E virus testing in drug-induced liver injury. Ali-
ment Pharmacol Ther 2007;26:1429-35.
41. Arimone Y, Begaud B, Miremont-Salame G, Fourrier-
Reglat A, Moore N, Molimard M et al. Agreement of
expert judgment in causality assessment of adverse
drug reactions. Eur J Clin Pharmacol 2005;61:169-73.
42. Arimone Y, Begaud B, Miremont-Salame G, Four-
rier-Reglat A, Molimard M, Moore N et al. A new
method for assessing drug causation provided
agreement with experts judgment. J Clin Epidemiol
2006;59:308-14.
43. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani
N, Davern T, Serrano J et al. Drug-Induced Liver In-
jury Network (DILIN) prospective study: rationale,
design and conduct. Drug Saf 2009;32:55-68.
44. Stephens MD. The diagnosis of adverse medical
events associated with drug treatment. Adverse Drug
React Acute Poisoning Rev 1987;6:1-35.
45. Arimone Y, Miremont-Salame G, Haramburu F, Moli-
mard M, Moore N, Fourrier-Reglat A et al. Inter-ex-
pert agreement of seven criteria in causality assess-
ment of adverse drug reactions. Br J Clin Pharmacol
2007;64:482-8.
46. Lammert C, Einarsson S, Saha C, Niklasson A,
Bjornsson E, Chalasani N. Relationship between dai-
ly dose of oral medications and idiosyncratic drug-
induced liver injury: search for signals. Hepatology
2008;47:2003-9.
47. Uetrecht J. Idiosyncratic drug reactions: cur-
rent understanding. Annu Rev Pharmacol Toxicol
2007;47:513-39.
48. Kindmark A, Jawaid A, Harbron CG, Barratt BJ,
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

228 MINERVA GASTROENTEROLOGICA E DIETOLOGICA June 2011

RANGNEKAR AN UPDATE ON DRUG INDUCED LIVER INJURY
83. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in
patients with nonalcoholic steatohepatitis: results of
a pilot study. Atherosclerosis 2004;174:193-6.
84. Gomez-Dominguez E, Gisbert JP, Moreno-
Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A
pilot study of atorvastatin treatment in dyslipemid,
non-alcoholic fatty liver patients. Aliment Pharmacol
Ther 2006;23:1643-7.
85. Antonopoulos S, Mikros S, Mylonopoulou M, Kok-
koris S, Giannoulis G. Rosuvastatin as a novel treat-
ment of non-alcoholic fatty liver disease in hyperli-
pidemic patients. Atherosclerosis 2006;184:233-4.
86. Ekstedt M, Franzen LE, Mathiesen UL, Holmqvist M,
Bodemar G, Kechagias S. Statins in non-alcoholic
fatty liver disease and chronically elevated liver en-
zymes: a histopathological follow-up study. J Hepa-
tol 2007;47:135-41.
87. Cohen DE, Anania FA, Chalasani N. An assess-
ment of statin safety by hepatologists. Am J Cardiol
2006;97:77C-81C.
88. Nourjah P, Ahmad SR, Karwoski C, Willy M. Esti-
mates of acetaminophen (Paracetomal)-associated
overdoses in the United States. Pharmacoepidemiol
Drug Saf 2006;15:398-405.
89. Fontana RJ. Unintentional acetaminophen over-
dose on the rise: who is responsible? Dr Robert J
Fontana is interviewed by Paul C Adams. Can J Gas-
troenterol 2006;20:319-24.
90. Myers RP, Li B, Fong A, Shaheen AA, Quan H. Hospi-
talizations for acetaminophen overdose: a Canadian
population-based study from 1995 to 2004. BMC
Public Health 2007;7:143.
91. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH.
Effcacy of oral N-acetylcysteine in the treatment of
acetaminophen overdose. Analysis of the national
multicenter study (1976 to 1985). N Engl J Med
1988;319:1557-62.
92. Zimmerman HJ, Maddrey WC. Acetaminophen (pa-
racetamol) hepatotoxicity with regular intake of al-
cohol: analysis of instances of therapeutic misadven-
ture. Hepatology 1995;22:767-73.
93. Nolan CM, Sandblom RE, Thummel KE, Slattery JT,
Nelson SD. Hepatotoxicity associated with acetami-
nophen usage in patients receiving multiple drug
therapy for tuberculosis. Chest 1994;105:408-11.
94. Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE,
Stylianou IM et al. Mouse population-guided rese-
quencing reveals that variants in CD44 contribute
to acetaminophen-induced liver injury in humans.
Genome Res 2009;19:1507-15.
95. Kimura K, Nagaki M, Kakimi K, Saio M, Saeki T,
Okuda Y et al. Critical role of CD44 in hepatotoxin-
mediated liver injury. J Hepatol 2008;48:952-61.
96. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR,
Colucci SV, Stewart PW et al. Aminotransferase el-
evations in healthy adults receiving 4 grams of
acetaminophen daily: a randomized controlled trial.
JAMA 2006;296:87-93.
97. Fontana RJ. Acute liver failure including acetami-
nophen overdose. Med Clin North Am 2008;92:761-
94, viii.
98. Polson J, Wians FH, Jr., Orsulak P, Fuller D, Murray
NG, Koff JM et al. False positive acetaminophen con-
centrations in patients with liver injury. Clin Chim
Acta 2008;391:24-30.
99. Davern TJ, 2nd, James LP, Hinson JA, Polson J, Lar-
son AM, Fontana RJ et al. Measurement of serum
acetaminophen-protein adducts in patients with
acute liver failure. Gastroenterology 2006;130:687-
94.
100. James LP, Letzig L, Simpson PM, Capparelli E,
66. Bjornsson E, Olsson R. Outcome and prognostic
markers in severe drug-induced liver disease. Hepa-
tology 2005;42:481-9.
67. Dechene A, Treichel U, Gerken G, Hilgard P. Effec-
tiveness of a steroid and ursodeoxycholic acid com-
bination therapy with drug-induced subacute liver
failure. Hepatology 2005;42:358A.
68. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz
RT, Larson AM et al. Intravenous N-acetylcysteine
improves transplant-free survival in early stage non-
acetaminophen acute liver failure. Gastroenterology
2009;137:856-64, 64 e1.
69. Cook IF, Shilkin KB, Reed WD. Phenytoin in-
duced granulomatous hepatitis. Aust N Z J Med
1981;11:539-41.
70. Medline A, Cohen LB, Tobe BA, Sellers EM. Liver
granulomas and allopurinol. Br Med J 1978;1:1320-1.
71. Murata Y, Ogawa Y, Saibara T, Nishioka A, Fujiwara
Y, Fukumoto M et al. Unrecognized hepatic stea-
tosis and non-alcoholic steatohepatitis in adjuvant
tamoxifen for breast cancer patients. Oncol Rep
2000;7:1299-304.
72. Lewis JH, Mullick F, Ishak KG, Ranard RC, Rags-
dale B, Perse RM et al. Histopathologic analysis of
suspected amiodarone hepatotoxicity. Hum Pathol
1990;21:59-67.
73. Akhtar MA, Mathieson K, Arey B, Post J, Prevette R,
Hillier A et al. Hepatic histopathology and clinical
characteristics associated with antiretroviral therapy
in HIV patients without viral hepatitis. Eur J Gastro-
enterol Hepatol 2008;20:1194-204.
74. Kleiner DE. The pathology of drug-induced liver in-
jury. Semin Liver Dis 2009;29:364-72.
75. Bjornsson E, Kalaitzakis E, Olsson R. The impact
of eosinophilia and hepatic necrosis on prognosis
in patients with drug-induced liver injury. Aliment
Pharmacol Ther 2007;25:1411-21.
76. Link E, Parish S, Armitage J, Bowman L, Heath S,
Matsuda F et al. SLCO1B1 variants and statin-in-
duced myopathy--a genomewide study. N Engl J
Med 2008;359:789-99.
77. Russo MW, Scobey M, Bonkovsky HL. Drug-induced
liver injury associated with statins. Semin Liver Dis
2009;29:412-22.
78. Dunn W, Xu R, Wingard DL, Rogers C, Angulo P,
Younossi ZM et al. Suspected nonalcoholic fatty liver
disease and mortality risk in a population-based co-
hort study. Am J Gastroenterol 2008;103:2263-71.
79. Conjeevaram HS, Wahed AS, Afdhal N, Howell CD,
Everhart JE, Hoofnagle JH. Changes in Insulin Sen-
sitivity and Body Weight During and After Peginter-
feron and Ribavirin Therapy for Hepatitis C. Gastro-
enterology 2010.
80. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Med-
off JR, Belder R. Effcacy and safety of high-dose
pravastatin in hypercholesterolemic patients with
well-compensated chronic liver disease: Results
of a prospective, randomized, double-blind, pla-
cebo-controlled, multicenter trial. Hepatology
2007;46:1453-63.
81. Athyros VG, Tziomalos K, Gossios TD, Griva T, An-
agnostis P, Kargiotis K et al. Safety and effcacy of
long-term statin treatment for cardiovascular events
in patients with coronary heart disease and abnor-
mal liver tests in the Greek Atorvastatin and Coro-
nary Heart Disease Evaluation (GREACE) Study: a
post-hoc analysis. Lancet 2010;376:1916-22.
82. Kiyici M, Gulten M, Gurel S, Nak SG, Dolar E, Savci
G et al. Ursodeoxycholic acid and atorvastatin in the
treatment of nonalcoholic steatohepatitis. Can J Gas-
troenterol 2003;17:713-8.
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T

Vol. 57 - No. 2 MINERVA GASTROENTEROLOGICA E DIETOLOGICA 229

AN UPDATE ON DRUG INDUCED LIVER INJURY RANGNEKAR
before and after study of long term effect on poison-
ings. BMJ 2004;329:1076.
105. Summary minutes of the joint meeting of the drug
safety and risk management advisory committee,
nonprescription drugs advisory committee, and the
anesthetic and life support drugs advisory committee
[Internet]. Available from http://www.fda.gov/down-
loads/AdvisoryCommittees/CommitteesMeetingMate-
rials/Drugs/DrugSafetyandRiskManagementAdvisory-
Committee/UCM179888.pdf . [cited 2011, Feb 1].
106. FDA drug safety communication: prescription aceta-
minophen products to be limited to 325 mg per dos-
age unit; boxed warning will highlight potential for
severe liver failure [Internet]. Available from http://
www.fda.gov/Drugs/DrugSafety/ucm239821.htm
[cited 2011, Feb 1].
107. Fontana RJ, Seeff LB, Andrade RJ, Bjornsson E, Day
CP, Serrano J et al. Standardization of nomenclature
and causality assessment in drug-induced liver inju-
ry: summary of a clinical research workshop. Hepa-
tology 2010;52:730-42.
Roberts DW, Hinson JA et al. Pharmacokinetics of
acetaminophen-protein adducts in adults with aceta-
minophen overdose and acute liver failure. Drug
Metab Dispos 2009;37:1779-84.
101. Sato RL, Wong JJ, Sumida SM, Marn RY, Enoki NR,
Yamamoto LG. Effcacy of superactivated charcoal
administered late (3 hours) after acetaminophen
overdose. Am J Emerg Med 2003;21:189-91.
102. Stravitz RT, Kramer AH, Davern T, Shaikh AO, Cald-
well SH, Mehta RL et al. Intensive care of patients
with acute liver failure: recommendations of the
U.S. Acute Liver Failure Study Group. Crit Care Med
2007;35:2498-508.
103. Kao LW, Kirk MA, Furbee RB, Mehta NH, Skinner
JR, Brizendine EJ. What is the rate of adverse events
after oral N-acetylcysteine administered by the in-
travenous route to patients with suspected acetami-
nophen poisoning? Ann Emerg Med 2003;42:741-
50.
104. Hawton K, Simkin S, Deeks J, Cooper J, Johnston
A, Waters K et al. UK legislation on analgesic packs:
M
I
N
E
R
V
A

M
E
D
I
C
A
C
O
P
Y
R
I
G
H
T