Outcome and Prognostic Markers in Severe

Drug-Induced Liver Disease

Einar Bjornsson
and Rolf Olsson
The combination of high aminotransferases (hepatocellular injury) and jaundice has been
reported to lead to a mortality rate of 10% to 50% for different drugs, a phenomenon known
as Hys rule. However, Hys rule has never been validated, and limited data exist on
predictors for outcome in hepatocellular and other forms of drug-induced liver disease. All
reports of suspected hepatic adverse drug reactions received by the Swedish Adverse Drug
Reactions Advisory Committee (1970-2004) were reviewed. Cases with bilirubin levels 2 or
more times the upper limit of normal (ULN) were analyzed. A total of 784 cases were
retrieved 409 with hepatocellular injury, 206 with cholestatic injury, and 169 with mixed
liver injury. The mortality/transplantation rate was 9.2%, and bilirubin (median 18.7
ULN [IQR 12.6-25]; range 4.5-42) was higher (P < .0001) in the deceased/transplant
recipients compared with the surviving patients (median 5.5 ULN [IQR 3.3-9.5]; range
2.0-38). A total of 7.8% with cholestatic and 2.4% with a mixed pattern died. The mortality
rate in hepatocellular injury for different drugs varied from 40% (6 of 15) for halothane to
0% (0 of 32) for erythromycin, in total 12.7%. Using logistic regression analysis, age,
aspartate aminotransferase (AST) and bilirubin were found to independently predict death
or liver transplantation in the hepatocellular group, whereas among patients with cholestatic/mixed liver injury, bilirubin was the only independent predictor. In conclusion, hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved.
The AST and bilirubin levels are the most important predictors of death or liver transplantation. (HEPATOLOGY 2005;42:481-489.)

rug-induced liver disease (DILD) is a potential

complication with many drugs. Acute hepatic
injury due to drugs has been reported to occur in
5% to 10% of patients hospitalized for jaundice.1-4 Furthermore, drugs are the most common cause of fulminant
hepatic failure, both in the United States and Europe.5-7
In reports from the United States and Sweden, idiosyncratic drug reactions were the presumptive causes in 13%
to 17% of cases of acute liver failure.5,6 The prognosis for
Abbreviations: ULN, upper limit of normal; AST, aspartate aminotransferase;
DILD, drug-induced liver disease; HC, hepatocellular; ALT, alanine aminotransferase; CS, cholestatic; SADRAC, Swedish Adverse Drug Reaction Advisory Committee; RUCAM, Roussel Uclaf causality assessment method; ALP, alkaline
phosphatase.
From the Section of Gastroenterology and Hepatology, Department of Internal
Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Received February 11, 2005; accepted May 25, 2005.
Supported by the Faculty of Medicine, University of Gothenburg, Gothenburg,
Sweden.
Address reprint requests to: Einar Bjornsson, Department of Internal Medicine,
Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. E-mail:
einar.bjornsson@medic.qu.se; fax: (46) 31822152.
Copyright 2005 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.20800
Potential conict of interest: Nothing to report.

patients with acute liver failure due to idiosyncratic drug

reactions is usually poor, with 60% to 80% mortality
without liver transplantation.8,9 During the last decade,
drug-induced liver injury has led to the withdrawal of a
number of drugs from the market.10-14
The combination of high serum aminotransferases
(hepatocellular injury) and jaundice has in earlier studies
been reported to result in a mortality of 10% to 50% for
different drugs.11-13 These observations have been named
Hys rule after Hyman Zimmerman, who rst described them. The rule states that if both drug-induced
hepatocellular (HC) injury and jaundice occur at the
same time without biliary obstruction, mortality of at
least 10% can be expected.11,13,14 Hys rule dened as
DILD with serum alanine aminotransferase (ALT) levels
3 or more times the upper limit of normal (ULN)
serum bilirubin levels 2 or more times the ULN has been
advocated by the U.S. Food and Drug Administration for
use in the assessment of the hepatotoxicity of newly developed drugs.13,15 However, this rule has never been scientically validated. The sensitivity and specicity of
clinical jaundice for the outcome in patients with druginduced HC injury is thus unknown. The most impor481

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tant predictors of outcome in drug-induced liver disease

with HC injury have not been analyzed in a large number
of patients; furthermore, information about the prognosis
in other forms of DILD (e.g., DILD with cholestatic or
mixed patterns) is limited.
In Sweden, a systematic monitoring system of DILD
has been in use since 1966, with regular causality assessment offering the opportunity to evaluate a large number
of patients with DILD. The aim of this study was to
analyze the outcome of patients with severe DILD associated with jaundice with HC, cholestatic (CS), or mixed
liver injury to evaluate the validity of Hys rule and to
analyze the most important predictors for outcome.

Materials and Methods

All reports of suspected drug-induced liver injury received by the Swedish Adverse Drug Reactions Advisory
Committee (SADRAC) between 1970 and 2004 have
been computerized and are available for legally acceptable
users with a password online. Since 1975, the reporting of
fatal, otherwise serious, and new reactions is compulsory.
The quality of the reports may vary, because there is no
standardized report form. Full medical records, including
results of laboratory tests, imaging studies, biopsies, and
autopsies, are requested for all fatal cases and for the majority of serious cases. The opinion of an expert hepatologist with extensive experience in DILD is requested in
difcult assessments. This assessment is based on a clinical
judgement, not on any published method for assessment
of causality.
We retrieved those reports in which a possible or probable relationship had been assessed by SADRAC to exist.
Our analysis was restricted to patients with serum bilirubin levels more than twice the ULN. Furthermore, in
patients with a HC type of injury, our analysis was restricted to those patients with ALT levels 3 or more times
the ULN as well as serum bilirubin levels 2 or more times
the ULN.
The altogether 838 reports fullling these criteria were
evaluated using international consensus criteria (Roussel
Uclaf causality assessment method [RUCAM])16,17 to assess the probability of a causal relationship between drug
exposure and liver disease (Fig. 1). The causality assessment is based on information about the time of onset of
the reaction from the beginning of the drug, the development of liver tests after cessation of the drug, the presence
of risk factors, and known hepatotoxicity of the suspected
drug and concomitant drug or drugs.16 Furthermore, the
investigations performed to exclude nondrug causes for
the reaction are looked for. Thus, abnormal liver tests
developing shortly after beginning of a new drug, rapid
decline of these after stopping the drug, and exclusion of

Fig. 1. Diagram of the patients included in the study. SADRAC,

Swedish Adverse Drug Reaction Advisory Committee; ULN, upper limit of
normal.

other causes give high scores compatible with the drug as

a possible, probable, or highly probable cause of the reaction.16 If the report does not receive a high enough score
to consider a causal relationship with the suspected drug
the reaction is according to the criteria unlikely or the
relationship was excluded.16 Each author scored approximately half of the cases. We performed assessment of 50
cases independently and found very low intraobserver
variability with no disagreement in the assessment of cases
into unlikely or not.
In case more than one drug could possibly have been
responsible for the liver disease, we gave no minus scores
for concomitant drug(s), because the main purpose of
the present investigation was to study prognostic predictors in DILD in general, not outcomes with specic
drugs. On the other hand, the reports only rarely stated
whether or not the patient was an ethanol user (giving
plus scores), and if so, it was only to report that the patient
abused alcohol. Data on search for nondrug causes (e.g.,
an anti hepatitis C virus test) were often missing, particularly in the early cases, causing a relatively low likelihood
of a relationship in many cases.
Because many patients had been exposed to several
drugs at the time of the appearance of the liver injury, it is
not always possible to deduce which drug is most likely
responsible. In such cases, we judged the reaction to have
been potentially caused by more than one drug. On the
other hand, if there was a close temporal relationship between the liver injury and treatment with only one of

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483

Table 1. Incidence of Drug-Induced Liver Disease in Reports With Bilirubin >2 ULN With a Possible/Probable/Highly
Probable Relationship in Time Periods (1970 2004)
Number
Deaths/TX
HC/CS/mixed
Antibiotics
Anesthetics
NSAIDs
Analgetics
Others
Multiple
Antiepileptic
Tuberculostatics

19701979

19801984

19851989

19901994

19951999

20002004

10
9
8/0/2
1 (10)
6 (60)
1 (10)
0
0
0
1 (10)
1 (10)

11
9
8/1/2
2 (18)
1 (9)
0
2 (18)
2 (18)
3 (27)
1 (9)
0

150
6 (4)
67/45/38
47 (31)
7 (4.7)
9 (6)
7 (4.7)
51 (34)
20 (13.3)
4 (2.7)
5 (3.3)

222
21 (9.5)
113/62/47
77 (35)
4 (1.8)
15 (6.8)
5 (2.3)
79 (35.6)
33 (14.9)
7 (3.2)
2 (0.9)

209
17 (8.1)
115/59/35
59 (28)
0
11 (5.3)
4 (1.9)
77 (36.8)
55 (26.3)
3 (1.4)
0

182
10 (5.5)
91/41/50
57 (31)
0
16 (8.8)
2 (1.1)
64 (35.2)
40 (22)
1 (0.5)
2 (1.1)

NOTE. HC, CS, and mixed injury were considered. The major types of drugs associated with DILD and concomitant jaundice during the different time periods are listed.
The number of cases and the percentage (in parentheses) are given for each type of drug.
Abbreviation: NSAIDs, nonsteroidal anti-inammatory drugs.

many drugs with which the patient was treated, this drug
has been considered to be the only suspected one.
Intoxications with acetaminophen were excluded from
this analysis, because in contrast to other cases of DILD,
they represent a direct, dose-dependent, and predictable
type of liver injury for which predictors of outcome have
previously been studied extensively. Such cases are usually
reported to the Swedish Poisons Information Centre and
only exceptionally to SADRAC.
The computerized reports include all relevant facts
from medical records and the results of laboratory investigations. The following information was retrieved from
the reports: year of exposure; drug(s) suspected to be responsible; age and sex of the patient; duration of treatment; type of liver injury; results of AST, ALT, alkaline
phosphatase (ALP), and bilirubin tests; search for nondrug causes; and outcome of the patient (recovery, death
or liver transplantation). The outcome of the SADRAC
database was also compared with a central registry of patients undergoing liver transplantation in Sweden. Eleven
of 13 patients who underwent transplantation for idiosyncratic drug reactions had been reported to SADRAC,
and the rest of the patients were also included in our
analysis.
Classication of the liver injury was also based on International Consensus Criteria.16-17 In the current study,
the maximum (peak) values for serum bilirubin, AST,
ALT, and ALP were used for analysis.
Statistics. For descriptive purposes, sensitivity, specicity, positive predictive values, and negative predictive
values were calculated. The Fisher exact test was used to
test differences between groups regarding dichotomous
variables; the Mann-Whitney test was used for continuous variables. Stepwise logistic regression was performed
for multivariate purposes to predict death. All tests were
two-tailed and were conducted at a 5% signicance level.

Results
During the period 1970-2004, SADRAC received a
total of 4,396 reports of suspected drug-induced liver injury. A total of 3,841 (87.4%) were considered to have a
possible or probable causal relationship with drug exposure. Of these 3,841 cases, a total of 873 cases (22.9%)
with bilirubin levels 2 or more times the ULN and ALT
levels 3 or more times the ULN were retrieved. Among
these 873 cases, 35 cases had to be excluded because of a
lack of important clinical or laboratory data, leaving 838
cases for analysis (Fig. 1).
As a result of the RUCAM, another 42 cases had to be
excluded because they did not fulll the RUCAM criteria for
at least a possible relationship, and 12 reports on acetaminophen-associated liver injury were also excluded (see Materials and Methods). Thus, a total of 784 cases were included
in the nal analysis. According to the RUCAM, 360 cases
(46%) had a possible relationship, 331 (42%) had a probable
relationship, and 93 (12%) had a highly probable relationship. The incidence of DILD and the different types of drugs
reported during the different time periods is demonstrated in
Table 1. The low numbers during the early time period may
be explained by a lower incidence of reports in general during
the earlier years as well as by a poorer quality of the reports,
precluding a possible or probable assessment. The 784 cases
with a possible/probable/highly probable causal relationship
to drug(s) include a total of 409 cases with HC injury, 206
with CS injury, and 169 with mixed liver injury (Table 2). In
a total of 633 cases, one drug was suspected of being responsible for the liver injury, whereas in 151 cases more than one
drug could potentially have been responsible. Table 2 shows
age and sex, duration of treatment, and peak liver test values
in patients with different types of DILD.
The patients with CS injury were signicantly older
than those with a mixed or HC pattern (P .003 and P

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Table 2. Clinical and Laboratory Data in the Total Study Population as Well as in the Subgroups According
to Type of Liver Injury
Number
Age
Sex (F/M)
Duration of treatment (d)
Bilirubin (100%)
AST (94%)
ALT (99%)
ALP (99%)

Total

Hepatocellular

Cholestatic

Mixed

784
58 (4274)
452/332
21 (1055)
6.2 (3.510.7)
7.2 (3.519.5)
12.5 (5.928.1)
2.1 (1.43.4)

409
55 (3969)
237/172
28 (1066)
6.0 (3.310.6)
17.1 (7.234.3)
25.6 (14.344.3)
1.4 (0.92.1)

206
69 (4980)
121/87
21 (1035)
6.6 (4.012.4)
3.4 (2.05.7)
3.9 (2.66.6)
3.8 (2.66.0)

169
59 (4372)
96/73
18 (1035)
5.7 (3.38.8)
4.8 (2.98.0)
8.7 (6.513.4)
2.6 (1.93.7)

NOTE. The liver laboratory values are expressed as multiples of the ULN (median, with IQR in parentheses). The laboratory parameters are all peak values. The number
of patients with available data of bilirubin, AST, ALT, and ALP are provided in percentages.
Abbreviations: F, female; M, male.

.0001, respectively) (Table 2). A higher proportion of

females was observed in all the different subgroups, with
approximately 58% females in all groups (Table 2). Patients with CS injury had higher ULN bilirubin levels
compared with those with a mixed type (P .01) and HC
injury (P value not signicant) (Table 2). For obvious
reasons, the AST, ALT, and ALP values differed between
those with HC injury compared with those with CS or a
mixed pattern, because these differences constituted the
basis for the classication into the different types of injury.
A total of 72 (9.2%) of the 784 patients died from liver
failure or underwent liver transplantation (Table 3). The
following drugs were associated with death/liver transplantation: ucloxacillin (n 7), halothane (n 6),
diclofenac (n 4), naproxen (n 4), isoniazide (n 3),
disulram (n 3), chlorpromazine (n 2), ciprooxacin
(n 2), enalapril (n 2), trimethoprim/sulfametoxazol
(n 2), or other drugs (n 1 each) (ranitidin, rofecoxib,
sulfasalazine, carbamazepine, ticlopidine, simvastatin,
acetylsalicylic acid, atorvastatin, bleomycin, ibuprufen,
danazol, dicloxacillin, dikumarol, dextropropoxiphen,
donepezil, estradiol, pyrimethamin/sulfadoxine, phenytoin, uorouracil, interferon, chlormezanon, nefazodon,
omeprazol). In 14 cases multiple drugs were involved, any
of which could therefore have caused the reaction.
Table 3. Outcome of All Patients as Well as Those With
Hepatocellular, Cholestatic, or Mixed Liver Injury
Outcome

Total

Recovered
712
Died from liver
72 (9.2%)
failure/liver
transplantation
Liver
13
transplantation
784

Hepatocellular

Cholestatic

Mixed

357
52 (12.7%)

190
16 (7.8%)

165
4 (2.4%)

13
409

0
206

0
169

NOTE. The number of transplant recipients (13) is included within the total of
72 patients from the total study group and of those 50 within the hepatocellular
group.

Another 5 patients hospitalized for drug-induced jaundice died of other causes, namely cardiac death (2 cases) or
multiorgan failure (3 cases). Patients with HC injury had
the highest mortality (12.7%) compared with 7.8% of
patients with CS drug-induced jaundice (P value not signicant) and 2.4% of those with mixed liver injury pattern (P .0001 compared with HC injury). Patients with
HC injury had a signicantly higher mortality than those
with CS and mixed injury combined (12.7% vs. 5.3%;
P .0005). A total of 13 patients, all with HC injury,
underwent transplantation. The reason no transplantations were performed in the CS/mixed injury group was
either that most of the patients were more than 70 years of
age and considered too old or had contraindication for
transplantation or that these cases occurred before liver
transplantation was available in Sweden (1986).
Comparison Between Nonsurvivors and Survivors
The patients who died (or underwent transplantation)
were older than those who recovered (Table 4). The proportion of females and males was similar in those who
recovered and in those who did not and no difference was
observed in the duration of treatment in the two groups

Table 4. Comparison Between Patients Who Died or

Underwent Transplantation and Patients Who Survived
Drug-Induced Liver Injury
Age
Sex (F/M)
Duration of treatment
Bilirubin
AST
ALT
ALP
AST/ALT ratio

Died/Transplantation

Recovered

P Value

65 (4777)
43/29
25 (1094)
18.7 (12.625.3)
34 (14.059)
31 (15.756)
1.9 (1.13.3)
1.1 (0.81.4)

58 (4174)
409/303
21 (1049)
5.5 (3.39.5)
6.7 (3.417.1)
11.4 (5.724)
2.1 (1.43.4)
0.6 (0.40.9)

.04
NS
NS
.0001
.0001
.0001
NS
.0001

NOTE. The laboratory parameters are all peak values. Results are expressed as
medians, with IQRs in parentheses.
Abbreviations: F, female; M, male; NS, not signicant.

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485

Table 5. Comparison Between Patients With Hepatocellular Injury and Patients With Cholestatic/Mixed Liver Injury Among
Those Who Died or Underwent Transplantation and Those Who Survived Drug-Induced Liver Injury
Hepatocellular Injury

Number
Age
Sex, F/M (%)
Duration
Bilirubin
AST
ALT
ALP
AST/ALT ratio
NOTE.
*P
P
P

Cholestatic/Mixed Injury

Died

Recovered

Died

Recovered

52
64 (4873)
34/18 (65/35)
23 (690)
17.3 (12.624.6)
49.3 (3069)
44.3 (3061)
1.5 (0.92.4)
1.1 (0.91.4)

357
53 (3868)*
204/153 (57/43)
28 (1060)
5.2 (3.19.2)
13.9 (627)
22.8 (1339.7)
1.4 (0.92.0)
0.6 (0.40.9)

20
75 (4383)
10/10 (50/50)
28 (15112)
24.3 (12.731.8)
3.3 (3.06.9)
4.6 (2.611.3)
4.3 (2.19.0)
0.8 (0.61.4)

355
63 (4777)
205/150 (57/43)
21 (1035)
6.0 (3.69.8)
4.0 (2.36.6)
6.3 (3.710)
3.1 (2.24.8)
0.7 (0.51.0)

The results are expressed as medians, IQRs in parentheses. The laboratory parameters are all peak values.
.001.
.0001.
.05.

(Table 4). Deceased patients or patients who underwent

transplantation had higher serum bilirubin, AST, and
ALT values and AST/ALT ratio than surviving patients,
whereas ALP levels were similar in the two groups (Table
4). A comparison between the survivors and nonsurvivors
within the HC group revealed no differences regarding
sex, duration of treatment, or ALP (Table 5). Patients
with HC injury who died or underwent transplantation
were older than those who recovered and had higher AST
and ALT levels, AST/ALT ratio, and bilirubin levels (Table 5). In the CS/mixed group, bilirubin levels and AST/
ALT ratio were signicantly higher in deceased patients
and transplant recipients (Table 5).
Using a forward stepwise analysis, AST (P .0001,
odds ratio [OR] 1.013 for each increase ULN) and
bilirubin (P .0001, OR 1.092) were found to independently predict death or transplantation in the total study
population. Within the HC group, age (P .0063, OR
1.032 for each year increase), AST (P .0001, OR
1.012), and bilirubin (P .0001, OR 1.202) were independent predictors of death or transplantation. Among
patients with CS or mixed injury, bilirubin (P .0001,
OR 1.194) was an independent predictor of death.
Because in the univariate analysis ALT and AST/ALT
ratio were also shown to be signicantly related to death
or transplantation, and because there was a strong correlation between AST and ALT, we calculated the OR for
combinations of not only AST and bilirubin, but also for
ALT and bilirubin (i.e., what is included in Hys rule) and
AST/ALT and bilirubin in HC injuries, as well as the OR
for bilirubin in CS injuries. Based on these logistic regression models, we found ALT levels 3 times the ULN plus
bilirubin levels 2 times the ULN (which is in agreement
with Hys rule) in HC injury to have a positive predictive
value of 0.13, a negative predictive value of 1.00, a sensi-

tivity of 1.00, and a specicity of 0.04 for prediction of

death or transplantation. Table 6 describes the logistic
regression models considered above, as well as predictive
values, sensitivities, and specicities for other combinations of risk factors.
The Role of Specic Drugs
Hepatocellular Injury. The highest number of reports of drug-induced fatal jaundice and HC injury with
a probable or possible causal relationship was related to
halothane (Table 7). Unfortunately, a total of 9 out of the
25 reported cases, 7 of whom died, had to be excluded
because of missing laboratory data (mostly cases during
the earliest part of the time period), and one did not fulll
the RUCAM criteria for a possible relationship. Consequently, only 15 cases with complete laboratory and clinical data remained for full analysis of data with a least
possible relationship, and 6 of these died (40%). The
second most commonly reported drug associated with
mortality was disulram (31 reports total). Four reports of
disulram-associated hepatoxicity had to be excluded (1
of whom died) because of a lack of laboratory data. Three
(11%) of the remaining 27 cases died (Table 7). Mortality
ranged from 40% of the halothane and naproxen cases to
zero in reports related to many other drugs (Table 7).
Notably, all 32 patients with probable or possible erythromycin-associated HC injury survived this adverse drug
reaction (Table 7). Because of the absence of fatal cases
among erythromycin-treated patients, we compared the
laboratory data in the erythromycin and nonerythromycin cases. As seen in Table 8, the test results in the identied markers of poor outcome were signicantly less
abnormal in the erythromycin cases than in the nonerythromycin cases.

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Table 6. Results of Logistic Regression

Model

HC Injury
1
ALT
Bilirubin
2
AST
Bilirubin
3
AST/ALT 1
Bilirubin
CS injury or mixed type
4
Bilirubin
5
Bilirubin

OR

95% CI

P Value

Limits*

PPV

NPV

Sensitivity

Specicity

1.014
1.200

1.0051.023
1.1461.256

.0022
.0001

3ULN
2ULN

0.13

1.00

1.00

0.04

1.011
1.198

1.0051.017
1.1431.256

.0001
.0001

3ULN
2ULN

0.13

1.00

1.00

0.10

1.756
1.198

1.2162.537
1.1441.255

.0027
.0001

1
2ULN

0.33

0.95

0.69

0.81

1.193

1.1321.258

.0001

2ULN

0.25

0.94

0.04

0.99

1.193

1.1321.258

.0001

5ULN

0.50

0.94

0.04

1.00

NOTE. ORs are given for each increase of ULN with one unit (AST, ALT, and bilirubin) or for each increase of the AST/ALT ratio with 1, respectively, for positive
and negative predictive values, sensitivity, and specicity, for each model when predicting DILD.
Abbreviations: PPV, positive predictive value; NPV, negative predictive value.
*Cutoff limits when calculating PPV, NPV, sensitivity, and specicity.

Table 7. Number of Cases with Hepatocellular, Cholestatic, or Mixed-Type Liver Injury and Proportion of Cases Leading to
Death or Transplantation for Drugs With at Least Three Reports of Drug-Induced Liver Disease, With a Possible or Probable
Causality Assessment
Hepatocellular

Antibiotics
Erythromycin
Flucloxacillin
Isoniazid
Trimethoprim/sulfametoxazol
Ciprooxacin
Nitrofurantoin
Anesthetics
Halothane
NSAIDs
Diclofenac
Naproxen
Ibuprufen
Rofecoxib
Other drugs
Disulram
Carbamazepine
Ranitidin
Chlorpromazine
Azathioprine
Flutamide
Omeprazol
Nefazodon
Sulfasalazine
Thiamazol
Mianserin
Clomipramine
Cimetidine
Ticlopidine
1 drug suspected

76
32
25
7
6
3
3
15
15
29
13
10
4
2
77
24
8
7
5
4
4
4
3
3
3
3
3
3
3
82

Death/LT

Cholestatic or Mixed

Death/LT

7
0
1
3
2
1
0
6
6
8
2
4
1
1
8
3
1
1
0
0
0
1
1
1
0
0
0
0
0
8

Antibiotics
149
Flucloxacillin
104
Trimethoprim/sulfametoxazol 14
Erythromycin
10
Ciprooxacin
4
Amoxicillin/Clavulonic acid
4
Trimethoprim
4
Dicloxacillin
3
Cloxacillin
3
Rifampicin
3
NSAIDs
15
Diclofenac
7
Sulindac
5
Naproxen
3
Other drugs
61
Carbamazepine
9
Chlorpromazine
4
Terbenan
5
Clomipramine
5
Natriumaurothiomalate
5
Ticlopidine
4
Dextropropoxiphen
4
Sulfasalazine
4
Disulram
3
Atorvastatin
3
Thiamazol
3
Ranitidin
3
Ethinylestradiol
3
Desogestrel
3
Glibenclamide
3
Acetarsol
3
1 drug suspected
69

9
6
1
0
1
0
0
1
0
0
2
2
0
0
6
2
2
0
0
0
1
0
0
0
1
0
0
0
0
0
0
3

Abbreviation: NSAIDs, nonsteroidal anti-inammatory drugs.

Total Study Group

Antibiotics
Flucloxacillin
Erythromycin
Trimethoprim/sulfametoxazol
Isoniazide
Ciprooxacin
Dicloxacillin
Pivmecillinam
Anesthetics
Halothane
NSAIDs
Diclofenac
Naproxen
Ibuprufen
Rofecoxib
Other drugs
Disulram
Carbamazepine
Ranitidin
Enalapril
Chlorpromazine
Sulfasalazine
Omeprazol
Cyclophosphamid
Ticlopidine
Atorvastatin
Simvastatin
Nefazodon
1 drug suspected

Death/LT

212
129
42
21
7
7
3
3
15
15
38
20
11
4
3
106
27
17
10
8
8
7
6
5
5
4
4
4
151

16
7
0
2
3
2
1
1
6
6
10
4
4
1
1
19
3
3
1
2
2
1
1
2
1
1
1
1
11

 RNSSON AND OLSSON

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HEPATOLOGY, Vol. 42, No. 2, 2005

Table 8. Comparison of Liver Laboratory Tests and Age in

Patients With Erythromycin (n 32) Versus
Nonerythromycin (n 377) Hepatocellular Injury

Bilirubin ULN
AST ULN
ALT ULN
Age, yrs

Erythromycin
Cases

Nonerythromycin
Cases

P Value

2.93 (2.44.0)
11.0 (5.417.1)
11.6 (8.925.6)
40 (3248)

6.38 (3.611.1)
18.0 (7.335.7)
27.1 (15.745.7)
56 (4069)

.0001
.0048
.0001
.0001

NOTE. Values are expressed as medians, with IQRs in parentheses.

In 82 cases of HC jaundice, the patients were being

treated with more than one drug with temporal relationship to the diagnosis of liver injury and positive dechallenge, any of which could therefore have caused the
reaction. Eight (9.8%) of these patients died, which was
not signicantly different from the 12.9% mortality
among patients with only one suspected drug.
CS and Mixed Liver Injury. The highest number of
reports of CS or mixed type of jaundice with a probable or
possible causal relationship to a drug was related to ucloxacillin (Table 7). Mortality ranged from 0% with
most of the drugs to 50% (2 out of 4 chlorpromazineassociated cases). Both diclofenac and carbamazepine
were associated with CS/mixed injury in addition to a
similar number of reactions with a HC pattern (Table 7).
Similar to the patients with HC injury considered to be
related to erythromycin, all 10 patients with probable or
possible erythromycin-associated CS/mixed injury recovered. The drug suspected of the reaction, its indication,

487

duration of treatment, and liver tests for the 20 patients

with CS/mixed injury associated with fatal outcome are
demonstrated in Table 9.
In 69 cases of CS/mixed jaundice, the patients were
being treated with more than one drug, with temporal
relationship to the diagnosis of liver injury and positive
dechallenge, any of which could therefore have caused the
reaction. Only 3 of these patients (4.3%) died, which was
not signicantly different from the 6.5% mortality when
only one drug was suspected.

Discussion
Because most of the knowledge of the severity of DILD
comes from case reports and case series,12,14 the assessment of the prognosis of patients with DILD suffers from
lack of prognostic markers.13,18-20 Hyman Zimmerman,
the legendary pioneer researcher in the eld of DILD,
observed that the combination of HC injury (high aminotransferases) and jaundice induced by a drug was associated with a poor prognosis, with a fatality rate of 10% to
50% for the different drugs involved (Hys rule).11-14 In a
previous National Institutes of Health conference, a consensus was reached that a new drug should be stopped in
a person with previously normal liver tests if AST and
ALT levels were more than 3 times the ULN and bilirubin
levels were more than twice the ULN.15 Concomitant
jaundice and hepatocellular injury observed in clinical
trials of a new drug have thus been considered to cause
serious trouble concerning safety in the postmarketing

Table 9. Individual Subjects With Cholestatic/Mixed-Type Liver Injury Associated With Fatal Outcome
M 64
M 16
M 83
F 85
F 45
F 78
F 85
M 77
F 83
F 41
M 78
M 39
F 58
M 73
F 39
M 40
M 69
M 90
F 77
M 83

Drug

Indication

Duration

AST

ALT

ALP

Bilirubin

ALT/ALP

Enalapril
Diclofenac
Chlorpromazine
Flucloxacillin
Multiple
Flucloxacillin
Flucloxacillin
Dicloxacillin
Flucloxacillin
Trimethoprim/sulfametoxazol
Flucloxacillin
Multiple
Estradiol
Chlorpromazine
Atorvastatin
Diclofenac
Ciprooxacin
Flucloxacillin
Ticlopidine
Danazol

Heart failure
Back pain
Psychosis
Cellulitis
Multiple
Cellulitis
Cellulitis
Osteomyelitis
Cellulitis
HIV
Oral abscess
Prostate cancer
Osteoporosis
Psychosis
Hyperlipemia
Arthralgia
Cellulitis
Cellulitis
Uremia
Thrombocytopenia

60d
360d
28d
26d
14d
18d
21d
87d
10d
180d
21d
32d
365d
13d
120d
6d
23d
11d
35d
270d

3.1
17.1
3.2
1.9
4.0
13.2
19.4
3.1

15.7
10.3
5.3
2.9
3.0
12.3
24.4
3.1
5.9
2.4
17.1
1.9
3.0
2.2
0.8
2.0
5.1
8.4
15.7
4.1

1.7
8.6
13.6
2.8
7.7
16.1
19.2
3.1
9.4
5.8
23.8
1.8
1.74
4.4
4.2
2.1
2.1
4.1
4.8
2.0

25.2
12.4
4.6
7.4
27.4
15.4
21.2
32
36.4
13.8
18
5.7
35.2
12.9
31.7
10.4
32.6
25.3
39.1
24.8

1.8
1.2
0.38
1.0
0.39
0.76
1.3
1.0
0.63
0.41
1.32
1.1
1.72
0.5
0.19
0.95
2.4
2.0
3.3
2.1

7.0
14.3
1.9
4.1
1.4
2.9
3.0
3.3
6.9
6.1
3.0

NOTE. Cholestatic reaction was dened as R 2 (R [ratio] which is N for serum activity of ALT/N for serum activity of ALP). The pattern was regarded as mixed
when both ALT (above 2 N) and ALP are increased, and 2 R 5.17 The four subjects at the bottom with an ALT/ALP ratio 2 had a mixed pattern.
Abbreviations: M, male; F, female.

488

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phase, when a much larger number of patients are exposed

to the drug.13 Although still used by the U.S. Food and
Drug Administration in the assessment of the hepatotoxicity of different drugs, a validation of Hys rule has been
requested, because the information about its sensitivity
and specicity are largely lacking.13 Although the ndings
of Zimmerman and coworkers are important contributions to our knowledge of DILD, the mortality rate according to Hys rule has been reported for only a few
compounds, such as isoniazid, iproniazid, cinchophen,
dantrolene, halothane, methyldopa, and tienillic acid.21-25 Isoniazid is probably the only compound out of
those analyzed and reported previously by Zimmerman et
al. to cause DILD, which still is in widespread use nowadays.
Our analysis is unique because it is performed in a large
cohort of patients with severe DILD, giving the opportunity to elucidate the most important predictors for outcome. It is well recognized that adverse drug reactions are
signicantly underreported. The true incidence of hepatic
adverse drug reactions has until recently been largely obscure. However, a recent, careful prospective survey of
drug-induced liver injury in the general population in
France suggests that at the most, only 1 out of 16 cases of
DILD in France is actually reported.26 Spontaneous reporting was found to be at least twice as high in Sweden
compared with gures from France.27 It is of course possible that severe adverse drug reactions are reported more
frequently, although this has not been assessed in a welldesigned study. Further limitations of the present study
are its retrospective nature and the lack of international
normalized ratio data.
In the current study, approximately 20% of patients
with probable or possible DILD had serum bilirubin levels 2 or more times the ULN, the limit suggested by the
U.S. Food and Drug Administration to correspond to the
presence of jaundice. Most of the patients in this study
with DILD and concomitant jaundice had a good prognosis with complete recovery, but approximately 10% of
the patients either died or underwent liver transplantation. However, our gures on the drug-specic incidence of icteric DILD cannot be used as an estimate of
the drug-specic risk of icteric DILD, because the gures are not sales-related. The small number of patients
precludes an assessment of the inherent risk of developing
serious liver reaction once a DILD has occurred, at least
for most of the drugs.
Our results are in accordance with Hys rule insofar as
HC jaundice was found to have a mortality of approximately 10%. A total of 72 (9.2%) of 784 patients in the
total study group either died or underwent transplantation. However, because a signicant number of halothane

HEPATOLOGY, August 2005

reports (7 suspected lethal reactions) and 1 suspected disulram case associated with mortality had to be excluded
because of a lack of clinical and laboratory data, the true
proportion of deaths and transplantations could be underreported. If these cases had been included, the overall
mortality would not have been more than 9.9% in the
total study population.
However, the mortality rate of our patients fullling
Hys rule seemed to be highly variable when related to
which drug was associated with the DILD. Thus, a notable nding in the present study is that all of the 32 patients
with erythromycin-induced HC jaundice (fullling Hys
rule) recovered. Although erythromycin is among the top
ve reported hepatic adverse drug reactions in Sweden,
with approximately 200 reports between 1966 and 2004,
not a single case has been associated with a fatal outcome.28 All patients with erythromycin-induced liver injury recovered in the current study. This was probably due
to relatively mild erythromycin-associated DILD. The
prognosis among patients fullling RUCAM criteria for
DILD but in whom the specic drug could not be identied because of multiple drug exposure was not different
from those patients with one specied drug suspected to
have caused the reaction.
In the current study, the International Consensus Criteria were applied to the classication of hepatic reaction
into HC, CS, and mixed adverse drug reactions.16-17
These criteria were rst published in 1990, and because
most of the work by Zimmerman et al. was published
before that time, these publications did not apply the
modern strict criteria for the classication of hepatic reactions.11,14,21-25 As a consequence, many of the cases with
DILD-associated HC jaundice reported by Zimmerman
et al. would possibly be classied as mixed type of DILD
using the International Consensus Criteria.16-17
CS injury due to drugs has been reported to have a
good prognosis, and fatalities were considered to be the
results of underlying disease rather than hepatic injury.11
However, in our cohort, patients with CS injury also had
a high mortality rate of 7.8%, whereas those with mixed
injury had a mortality rate of 2.4%. The mortality rate of
5.4% among patients suffering from ucloxacillin-induced liver injury is in line with previous reports from
Sweden and Australia.29-32 In a recent study from Japan,
age was not found to differ between patients with DILD
who developed fulminant hepatic failure versus those who
did not.33 However, in the current study, nonsurvivors
with the HC type of DILD were signicantly older than
those who recovered. Age was found to independently
predict death or transplantation in the HC group. Furthermore, in HC injury as well as in CS/mixed injury, the
peak level of bilirubin was found to be an independent

HEPATOLOGY, Vol. 42, No. 2, 2005

risk factor for death or liver transplantation. Interestingly,

forward stepwise analysis identied AST but not ALT to
be an independent predictor of bad outcome in the total
study. This is in line with results reported by Ohmori et
al.33 in patients with DILD showing higher aminotransferase levels, especially AST in patients who progressed to
fulminant hepatic failure compared with those who did
not. Furthermore, our data are consistent with those of
Gitlin,34 who observed a higher AST/ALT ratio in fatal
cases than in survivors with severe acute viral hepatitis. A
hypothetical explanation put forward by the author was
that when the serum ALT level is exceeded by the serum
AST level, this reects additional AST release from the
hepatocyte mitochondrial AST component as a consequence of more severe hepatocyte damage. In contrast to
the results obtained by Ohmori et al., we did not nd
longer duration of drug therapy to be a risk factor for bad
outcome.
In summary, in accordance with Hys rule, HC jaundice has a high but variable mortality rate, depending on
the drug involved. AST and bilirubin levels are the most
important predictors of death or liver transplantation.

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