Outcome and Prognostic Markers in SevereDrug-Induced Liver Disease

Einar Bjornsson and Rolf Olsson

The combination of high aminotransferases (hepatocellular injury) and jaundice has beenreported to lead to amortality rate of 10% to 50% for different drugs, a phenomenon knownas Hys rule. However, Hys rule has never been validated, and limited data exist onpredictors for outcome in hepatocellular and other forms of drug-induced liver disease. Allreports of suspected hepatic adverse drug reactions received by the Swedish Adverse DrugReactions Advisory Committee (1970-2004) were reviewed. Cases with bilirubin levels 2 ormore times the upper limit of normal (ULN) were analyzed. A total of 784 cases wereretrieved409 with hepatocellular injury, 206 with cholestatic injury, and 169 with mixedliver 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/transplantrecipients compared with the surviving patients (median 5.5 ULN [IQR 3.3-9.5]; range2.0-38). A total of 7.8% with cholestatic and 2.4% with a mixed pattern died. The mortalityrate in hepatocellular injury for different drugs varied from 40% (6 of 15) for halothane to0% (0 of 32) for erythromycin, in total 12.7%. Using logistic regression analysis, age,aspartate aminotransferase (AST) and bilirubin were found to independently predict deathor liver transplantation in the hepatocellular group, whereas among patients with choles-tatic/mixed liver injury, bilirubin was the only independent predictor. In conclusion, hep-atocellular 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 transplan-tation. (HEPATOLOGY 2005;42:481-489.)

Drug-induced liver disease (DILD) is a potentialcomplication with many drugs. Acute hepaticinjury due to drugs has been reported to occur in5% to 10% of patients hospitalized for jaundice.1-4 Fur-thermore, drugs are the most common cause of fulminanthepatic failure, both in the United States and Europe.5-7

In reports from the United States and Sweden, idiosyn-cratic drug reactions were the presumptive causes in 13%to 17% of cases of acute liver failure.5,6 The prognosis for

patients with acute liver failure due to idiosyncratic drugreactions is usually poor, with 60% to 80% mortalitywithout liver transplantation.8,9 During the last decade,drug-induced liver injury has led to the withdrawal of anumber of drugs from the market.10-14

The combination of high serum aminotransferases(hepatocellular injury) and jaundice has in earlier studiesbeen reported to result in a mortality of 10% to 50% fordifferent drugs.11-13 These observations have been namedHys rule after Hyman Zimmerman, who rst de-scribed them. The rule states that if both drug-inducedhepatocellular (HC) injury and jaundice occur at thesame time without biliary obstruction, mortality of atleast 10% can be expected.11,13,14 Hys rule dened asDILD with serum alanine aminotransferase (ALT) levels3 or more times the upper limit of normal (ULN) serum bilirubin levels 2 or more times the ULN has beenadvocated by the U.S. Food and Drug Administration foruse in the assessment of the hepatotoxicity of newly de-veloped drugs.13,15 However, this rule has never been sci-entically validated. The sensitivity and specicity ofclinical jaundice for the outcome in patients with drug-induced HC injury is thus unknown. The most impor-

Abbreviations: ULN, upper limit of normal; AST, aspartate aminotransferase;DILD, drug-induced liver disease; HC, hepatocellular; ALT, alanine aminotrans-ferase; CS, cholestatic; SADRAC, Swedish Adverse Drug Reaction Advisory Com-mittee; RUCAM, Roussel Uclaf causality assessment method; ALP, alkalinephosphatase.

From the Section of Gastroenterology and Hepatology, Department of InternalMedicine, 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.20800Potential conict of interest: Nothing to report.

481

tant predictors of outcome in drug-induced liver diseasewith HC injury have not been analyzed in a large numberof patients; furthermore, information about the prognosisin other forms of DILD (e.g., DILD with cholestatic ormixed patterns) is limited.

In Sweden, a systematic monitoring system of DILDhas been in use since 1966, with regular causality assess-ment offering the opportunity to evaluate a large numberof patients with DILD. The aim of this study was toanalyze the outcome of patients with severe DILD asso-ciated with jaundice with HC, cholestatic (CS), or mixedliver injury to evaluate the validity of Hys rule and toanalyze the most important predictors for outcome.

Materials and MethodsAll reports of suspected drug-induced liver injury re-

ceived by the Swedish Adverse Drug Reactions AdvisoryCommittee (SADRAC) between 1970 and 2004 havebeen computerized and are available for legally acceptableusers with a password online. Since 1975, the reporting offatal, otherwise serious, and new reactions is compulsory.The quality of the reports may vary, because there is nostandardized report form. Full medical records, includingresults of laboratory tests, imaging studies, biopsies, andautopsies, are requested for all fatal cases and for the ma-jority of serious cases. The opinion of an expert hepatolo-gist with extensive experience in DILD is requested indifcult assessments. This assessment is based on a clinicaljudgement, not on any published method for assessmentof causality.

We retrieved those reports in which a possible or prob-able relationship had been assessed by SADRAC to exist.Our analysis was restricted to patients with serum biliru-bin levels more than twice the ULN. Furthermore, inpatients with a HC type of injury, our analysis was re-stricted to those patients with ALT levels 3 or more timesthe ULN as well as serum bilirubin levels 2 or more timesthe ULN.

The altogether 838 reports fullling these criteria wereevaluated using international consensus criteria (RousselUclaf causality assessment method [RUCAM])16,17 to as-sess the probability of a causal relationship between drugexposure and liver disease (Fig. 1). The causality assess-ment is based on information about the time of onset ofthe reaction from the beginning of the drug, the develop-ment of liver tests after cessation of the drug, the presenceof risk factors, and known hepatotoxicity of the suspecteddrug and concomitant drug or drugs.16 Furthermore, theinvestigations performed to exclude nondrug causes forthe reaction are looked for. Thus, abnormal liver testsdeveloping shortly after beginning of a new drug, rapiddecline of these after stopping the drug, and exclusion of

other causes give high scores compatible with the drug asa possible, probable, or highly probable cause of the reac-tion.16 If the report does not receive a high enough scoreto consider a causal relationship with the suspected drugthe reaction is according to the criteria unlikely or therelationship was excluded.16 Each author scored approxi-mately half of the cases. We performed assessment of 50cases independently and found very low intraobservervariability with no disagreement in the assessment of casesinto unlikely or not.

In case more than one drug could possibly have beenresponsible for the liver disease, we gave no minus scoresfor concomitant drug(s), because the main purpose ofthe present investigation was to study prognostic predic-tors in DILD in general, not outcomes with specicdrugs. On the other hand, the reports only rarely statedwhether or not the patient was an ethanol user (givingplus scores), and if so, it was only to report that the patientabused alcohol. Data on search for nondrug causes (e.g.,an antihepatitis C virus test) were often missing, partic-ularly in the early cases, causing a relatively low likelihoodof a relationship in many cases.

Because many patients had been exposed to severaldrugs at the time of the appearance of the liver injury, it isnot always possible to deduce which drug is most likelyresponsible. In such cases, we judged the reaction to havebeen potentially caused by more than one drug. On theother hand, if there was a close temporal relationship be-tween the liver injury and treatment with only one of

Fig. 1. Diagram of the patients included in the study. SADRAC,Swedish Adverse Drug Reaction Advisory Committee; ULN, upper limit ofnormal.

482 BJORNSSON AND OLSSON HEPATOLOGY, August 2005

many drugs with which the patient was treated, this drughas been considered to be the only suspected one.

Intoxications with acetaminophen were excluded fromthis analysis, because in contrast to other cases of DILD,they represent a direct, dose-dependent, and predictabletype of liver injury for which predictors of outcome havepreviously been studied extensively. Such cases are usuallyreported to the Swedish Poisons Information Centre andonly exceptionally to SADRAC.

The computerized reports include all relevant factsfrom medical records and the results of laboratory inves-tigations. The following information was retrieved fromthe reports: year of exposure; drug(s) suspected to be re-sponsible; age and sex of the patient; duration of treat-ment; type of liver injury; results of AST, ALT, alkalinephosphatase (ALP), and bilirubin tests; search for non-drug causes; and outcome of the patient (recovery, deathor liver transplantation). The outcome of the SADRACdatabase was also compared with a central registry of pa-tients undergoing liver transplantation in Sweden. Elevenof 13 patients who underwent transplantation for idio-syncratic drug reactions had been reported to SADRAC,and the rest of the patients were also included in ouranalysis.

Classication of the liver injury was also based on In-ternational 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, speci-city, positive predictive values, and negative predictivevalues were calculated. The Fisher exact test was used totest differences between groups regarding dichotomousvariables; the Mann-Whitney test was used for continu-ous variables. Stepwise logistic regression was performedfor multivariate purposes to predict death. All tests weretwo-tailed and were conducted at a 5% signicance level.

Results

During the period 1970-2004, SADRAC received atotal of 4,396 reports of suspected drug-induced liver in-jury. A total of 3,841 (87.4%) were considered to have apossible or probable causal relationship with drug expo-sure. Of these 3,841 cases, a total of 873 cases (22.9%)with bilirubin levels 2 or more times the ULN and ALTlevels 3 or more times the ULN were retrieved. Amongthese 873 cases, 35 cases had to be excluded because of alack of important clinical or laboratory data, leaving 838cases for analysis (Fig. 1).

As a result of the RUCAM, another 42 cases had to beexcluded because they did not fulll theRUCAMcriteria forat least a possible relationship, and 12 reports on acetamin-ophen-associated liver injury were also excluded (see Mate-rials and Methods). Thus, a total of 784 cases were includedin the nal analysis. According to the RUCAM, 360 cases(46%)had apossible relationship, 331 (42%)had aprobablerelationship, and 93 (12%) had a highly probable relation-ship.The incidence ofDILDand the different types of drugsreportedduring the different timeperiods is demonstrated inTable 1. The low numbers during the early time period maybe explainedby a lower incidence of reports in general duringthe earlier years as well as by a poorer quality of the reports,precluding a possible or probable assessment. The 784 caseswith a possible/probable/highly probable causal relationshipto drug(s) include a total of 409 cases with HC injury, 206withCS injury, and169withmixed liver injury (Table 2). Ina total of 633 cases, one drug was suspected of being respon-sible for the liver injury, whereas in 151 cases more than onedrug could potentially have been responsible. Table 2 showsage and sex, duration of treatment, and peak liver test valuesin patients with different types of DILD.

The patients with CS injury were signicantly olderthan those with amixed orHCpattern (P .003 andP

Table 1. Incidence of Drug-Induced Liver Disease in Reports With Bilirubin >2 ULN With a Possible/Probable/HighlyProbable Relationship in Time Periods (19702004)

19701979 19801984 19851989 19901994 19951999 20002004

Number 10 11 150 222 209 182Deaths/TX 9 9 6 (4) 21 (9.5) 17 (8.1) 10 (5.5)HC/CS/mixed 8/0/2 8/1/2 67/45/38 113/62/47 115/59/35 91/41/50Antibiotics 1 (10) 2 (18) 47 (31) 77 (35) 59 (28) 57 (31)Anesthetics 6 (60) 1 (9) 7 (4.7) 4 (1.8) 0 0NSAIDs 1 (10) 0 9 (6) 15 (6.8) 11 (5.3) 16 (8.8)Analgetics 0 2 (18) 7 (4.7) 5 (2.3) 4 (1.9) 2 (1.1)Others 0 2 (18) 51 (34) 79 (35.6) 77 (36.8) 64 (35.2)Multiple 0 3 (27) 20 (13.3) 33 (14.9) 55 (26.3) 40 (22)Antiepileptic 1 (10) 1 (9) 4 (2.7) 7 (3.2) 3 (1.4) 1 (0.5)Tuberculostatics 1 (10) 0 5 (3.3) 2 (0.9) 0 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.

HEPATOLOGY, Vol. 42, No. 2, 2005 BJORNSSON AND OLSSON 483

.0001, respectively) (Table 2). A higher proportion offemales was observed in all the different subgroups, withapproximately 58% females in all groups (Table 2). Pa-tients with CS injury had higher ULN bilirubin levelscompared with those with amixed type (P .01) andHCinjury (P value not signicant) (Table 2). For obviousreasons, the AST, ALT, and ALP values differed betweenthose with HC injury compared with those with CS or amixed pattern, because these differences constituted thebasis for the classication into the different types of in-jury.

A total of 72 (9.2%) of the 784 patients died from liverfailure or underwent liver transplantation (Table 3). Thefollowing drugs were associated with death/liver trans-plantation: 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, phenyt-oin, uorouracil, interferon, chlormezanon, nefazodon,omeprazol). In 14 cases multiple drugs were involved, anyof which could therefore have caused the reaction.

Another 5 patients hospitalized for drug-induced jaun-dice died of other causes, namely cardiac death (2 cases) ormultiorgan failure (3 cases). Patients with HC injury hadthe highest mortality (12.7%) compared with 7.8% ofpatients with CS drug-induced jaundice (P value not sig-nicant) and 2.4% of those with mixed liver injury pat-tern (P .0001 compared withHC injury). Patients withHC injury had a signicantly higher mortality than thosewith 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 transplanta-tions were performed in the CS/mixed injury group waseither that most of the patients were more than 70 years ofage and considered too old or had contraindication fortransplantation or that these cases occurred before livertransplantation was available in Sweden (1986).

Comparison Between Nonsurvivors and SurvivorsThe patients who died (or underwent transplantation)

were older than those who recovered (Table 4). The pro-portion of females and males was similar in those whorecovered and in those who did not and no difference wasobserved in the duration of treatment in the two groups

Table 2. Clinical and Laboratory Data in the Total Study Population as Well as in the Subgroups Accordingto Type of Liver Injury

Total Hepatocellular Cholestatic Mixed

Number 784 409 206 169Age 58 (4274) 55 (3969) 69 (4980) 59 (4372)Sex (F/M) 452/332 237/172 121/87 96/73Duration of treatment (d) 21 (1055) 28 (1066) 21 (1035) 18 (1035)Bilirubin (100%) 6.2 (3.510.7) 6.0 (3.310.6) 6.6 (4.012.4) 5.7 (3.38.8)AST (94%) 7.2 (3.519.5) 17.1 (7.234.3) 3.4 (2.05.7) 4.8 (2.98.0)ALT (99%) 12.5 (5.928.1) 25.6 (14.344.3) 3.9 (2.66.6) 8.7 (6.513.4)ALP (99%) 2.1 (1.43.4) 1.4 (0.92.1) 3.8 (2.66.0) 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 numberof patients with available data of bilirubin, AST, ALT, and ALP are provided in percentages.

Abbreviations: F, female; M, male.

Table 3. Outcome of All Patients as Well as Those WithHepatocellular, Cholestatic, or Mixed Liver Injury

Outcome Total Hepatocellular Cholestatic Mixed

Recovered 712 357 190 165Died from liver

failure/livertransplantation

72 (9.2%) 52 (12.7%) 16 (7.8%) 4 (2.4%)

Livertransplantation

13 13 0 0784 409 206 169

NOTE. The number of transplant recipients (13) is included within the total of72 patients from the total study group and of those 50 within the hepatocellulargroup.

Table 4. Comparison Between Patients Who Died orUnderwent Transplantation and Patients Who Survived

Drug-Induced Liver Injury

Died/Transplantation Recovered P Value

Age 65 (4777) 58 (4174) .04Sex (F/M) 43/29 409/303 NSDuration of treatment 25 (1094) 21 (1049) NSBilirubin 18.7 (12.625.3) 5.5 (3.39.5) .0001AST 34 (14.059) 6.7 (3.417.1) .0001ALT 31 (15.756) 11.4 (5.724) .0001ALP 1.9 (1.13.3) 2.1 (1.43.4) NSAST/ALT ratio 1.1 (0.81.4) 0.6 (0.40.9) .0001

NOTE. The laboratory parameters are all peak values. Results are expressed asmedians, with IQRs in parentheses.

Abbreviations: F, female; M, male; NS, not signicant.

484 BJORNSSON AND OLSSON HEPATOLOGY, August 2005

(Table 4). Deceased patients or patients who underwenttransplantation had higher serum bilirubin, AST, andALT values and AST/ALT ratio than surviving patients,whereas ALP levels were similar in the two groups (Table4). A comparison between the survivors and nonsurvivorswithin the HC group revealed no differences regardingsex, duration of treatment, or ALP (Table 5). Patientswith HC injury who died or underwent transplantationwere older than those who recovered and had higher ASTand ALT levels, AST/ALT ratio, and bilirubin levels (Ta-ble 5). In the CS/mixed group, bilirubin levels and AST/ALT ratio were signicantly higher in deceased patientsand transplant recipients (Table 5).

Using a forward stepwise analysis, AST (P .0001,odds ratio [OR] 1.013 for each increase ULN) andbilirubin (P .0001, OR 1.092) were found to indepen-dently predict death or transplantation in the total studypopulation. Within the HC group, age (P .0063, OR1.032 for each year increase), AST (P .0001, OR1.012), and bilirubin (P .0001, OR 1.202) were inde-pendent predictors of death or transplantation. Amongpatients 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/ALTratio were also shown to be signicantly related to deathor transplantation, and because there was a strong corre-lation between AST and ALT, we calculated the OR forcombinations of not only AST and bilirubin, but also forALT and bilirubin (i.e., what is included in Hys rule) andAST/ALT and bilirubin in HC injuries, as well as the ORfor bilirubin in CS injuries. Based on these logistic regres-sion models, we found ALT levels 3 times the ULN plusbilirubin levels 2 times the ULN (which is in agreementwith Hys rule) in HC injury to have a positive predictivevalue of 0.13, a negative predictive value of 1.00, a sensi-

tivity of 1.00, and a specicity of 0.04 for prediction ofdeath or transplantation. Table 6 describes the logisticregression models considered above, as well as predictivevalues, sensitivities, and specicities for other combina-tions of risk factors.

The Role of Specic Drugs

Hepatocellular Injury. The highest number of re-ports of drug-induced fatal jaundice and HC injury witha probable or possible causal relationship was related tohalothane (Table 7). Unfortunately, a total of 9 out of the25 reported cases, 7 of whom died, had to be excludedbecause of missing laboratory data (mostly cases duringthe earliest part of the time period), and one did not fulllthe RUCAM criteria for a possible relationship. Conse-quently, only 15 cases with complete laboratory and clin-ical data remained for full analysis of data with a leastpossible relationship, and 6 of these died (40%). Thesecond most commonly reported drug associated withmortality was disulram (31 reports total). Four reports ofdisulram-associated hepatoxicity had to be excluded (1of whom died) because of a lack of laboratory data. Three(11%) of the remaining 27 cases died (Table 7). Mortalityranged from 40% of the halothane and naproxen cases tozero in reports related to many other drugs (Table 7).Notably, all 32 patients with probable or possible eryth-romycin-associated HC injury survived this adverse drugreaction (Table 7). Because of the absence of fatal casesamong erythromycin-treated patients, we compared thelaboratory data in the erythromycin and nonerythromy-cin cases. As seen in Table 8, the test results in the iden-tied markers of poor outcome were signicantly lessabnormal in the erythromycin cases than in the noneryth-romycin cases.

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

Hepatocellular Injury Cholestatic/Mixed Injury

Died Recovered Died Recovered

Number 52 357 20 355Age 64 (4873) 53 (3868)* 75 (4383) 63 (4777)Sex, F/M (%) 34/18 (65/35) 204/153 (57/43) 10/10 (50/50) 205/150 (57/43)Duration 23 (690) 28 (1060) 28 (15112) 21 (1035)Bilirubin 17.3 (12.624.6) 5.2 (3.19.2) 24.3 (12.731.8) 6.0 (3.69.8)AST 49.3 (3069) 13.9 (627) 3.3 (3.06.9) 4.0 (2.36.6)ALT 44.3 (3061) 22.8 (1339.7) 4.6 (2.611.3) 6.3 (3.710)ALP 1.5 (0.92.4) 1.4 (0.92.0) 4.3 (2.19.0) 3.1 (2.24.8)AST/ALT ratio 1.1 (0.91.4) 0.6 (0.40.9) 0.8 (0.61.4) 0.7 (0.51.0)

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

HEPATOLOGY, Vol. 42, No. 2, 2005 BJORNSSON AND OLSSON 485

Table 6. Results of Logistic Regression

Model OR 95% CI P Value Limits* PPV NPV Sensitivity Specicity

HC Injury1ALT 1.014 1.0051.023 .0022 3ULNBilirubin 1.200 1.1461.256 .0001 2ULN 0.13 1.00 1.00 0.04

2AST 1.011 1.0051.017 .0001 3ULNBilirubin 1.198 1.1431.256 .0001 2ULN 0.13 1.00 1.00 0.10

3AST/ALT 1 1.756 1.2162.537 .0027 1Bilirubin 1.198 1.1441.255 .0001 2ULN 0.33 0.95 0.69 0.81

CS injury or mixed type4Bilirubin 1.193 1.1321.258 .0001 2ULN 0.25 0.94 0.04 0.99

5Bilirubin 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 positiveand 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 toDeath or Transplantation for Drugs With at Least Three Reports of Drug-Induced Liver Disease, With a Possible or Probable

Causality Assessment

Hepatocellular Death/LT Cholestatic or Mixed Death/LT Total Study Group Death/LT

Antibiotics 76 7 Antibiotics 149 9 Antibiotics 212 16Erythromycin 32 0 Flucloxacillin 104 6 Flucloxacillin 129 7Flucloxacillin 25 1 Trimethoprim/sulfametoxazol 14 1 Erythromycin 42 0Isoniazid 7 3 Erythromycin 10 0 Trimethoprim/sulfametoxazol 21 2Trimethoprim/sulfametoxazol 6 2 Ciprooxacin 4 1 Isoniazide 7 3Ciprooxacin 3 1 Amoxicillin/Clavulonic acid 4 0 Ciprooxacin 7 2Nitrofurantoin 3 0 Trimethoprim 4 0 Dicloxacillin 3 1

Anesthetics 15 6 Dicloxacillin 3 1 Pivmecillinam 3 1Halothane 15 6 Cloxacillin 3 0 Anesthetics 15 6

NSAIDs 29 8 Rifampicin 3 0 Halothane 15 6Diclofenac 13 2 NSAIDs 15 2 NSAIDs 38 10Naproxen 10 4 Diclofenac 7 2 Diclofenac 20 4Ibuprufen 4 1 Sulindac 5 0 Naproxen 11 4Rofecoxib 2 1 Naproxen 3 0 Ibuprufen 4 1

Other drugs 77 8 Other drugs 61 6 Rofecoxib 3 1Disulram 24 3 Carbamazepine 9 2 Other drugs 106 19Carbamazepine 8 1 Chlorpromazine 4 2 Disulram 27 3Ranitidin 7 1 Terbenan 5 0 Carbamazepine 17 3Chlorpromazine 5 0 Clomipramine 5 0 Ranitidin 10 1Azathioprine 4 0 Natriumaurothiomalate 5 0 Enalapril 8 2Flutamide 4 0 Ticlopidine 4 1 Chlorpromazine 8 2Omeprazol 4 1 Dextropropoxiphen 4 0 Sulfasalazine 7 1Nefazodon 3 1 Sulfasalazine 4 0 Omeprazol 6 1Sulfasalazine 3 1 Disulram 3 0 Cyclophosphamid 5 2Thiamazol 3 0 Atorvastatin 3 1 Ticlopidine 5 1Mianserin 3 0 Thiamazol 3 0 Atorvastatin 4 1Clomipramine 3 0 Ranitidin 3 0 Simvastatin 4 1Cimetidine 3 0 Ethinylestradiol 3 0 Nefazodon 4 1Ticlopidine 3 0 Desogestrel 3 0 1 drug suspected 151 111 drug suspected 82 8 Glibenclamide 3 0

Acetarsol 3 01 drug suspected 69 3

Abbreviation: NSAIDs, nonsteroidal anti-inammatory drugs.

486 BJORNSSON AND OLSSON HEPATOLOGY, August 2005

In 82 cases of HC jaundice, the patients were beingtreated with more than one drug with temporal relation-ship to the diagnosis of liver injury and positive dechal-lenge, any of which could therefore have caused thereaction. Eight (9.8%) of these patients died, which wasnot signicantly different from the 12.9% mortalityamong patients with only one suspected drug.

CS and Mixed Liver Injury. The highest number ofreports of CS or mixed type of jaundice with a probable orpossible causal relationship to a drug was related to u-cloxacillin (Table 7). Mortality ranged from 0% withmost of the drugs to 50% (2 out of 4 chlorpromazine-associated cases). Both diclofenac and carbamazepinewere associated with CS/mixed injury in addition to asimilar number of reactions with a HC pattern (Table 7).Similar to the patients with HC injury considered to berelated to erythromycin, all 10 patients with probable orpossible erythromycin-associated CS/mixed injury recov-ered. The drug suspected of the reaction, its indication,

duration of treatment, and liver tests for the 20 patientswith CS/mixed injury associated with fatal outcome aredemonstrated in Table 9.

In 69 cases of CS/mixed jaundice, the patients werebeing treated with more than one drug, with temporalrelationship to the diagnosis of liver injury and positivedechallenge, any of which could therefore have caused thereaction. Only 3 of these patients (4.3%) died, which wasnot signicantly different from the 6.5% mortality whenonly one drug was suspected.

DiscussionBecausemost of the knowledge of the severity of DILD

comes from case reports and case series,12,14 the assess-ment of the prognosis of patients with DILD suffers fromlack 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 amin-otransferases) and jaundice induced by a drug was associ-ated with a poor prognosis, with a fatality rate of 10% to50% for the different drugs involved (Hys rule).11-14 In aprevious National Institutes of Health conference, a con-sensus was reached that a new drug should be stopped ina person with previously normal liver tests if AST andALT levels weremore than 3 times theULN and bilirubinlevels were more than twice the ULN.15 Concomitantjaundice and hepatocellular injury observed in clinicaltrials of a new drug have thus been considered to causeserious trouble concerning safety in the postmarketing

Table 8. Comparison of Liver Laboratory Tests and Age inPatients With Erythromycin (n 32) Versus

Nonerythromycin (n 377) Hepatocellular Injury

ErythromycinCases

NonerythromycinCases P Value

Bilirubin ULN 2.93 (2.44.0) 6.38 (3.611.1) .0001AST ULN 11.0 (5.417.1) 18.0 (7.335.7) .0048ALT ULN 11.6 (8.925.6) 27.1 (15.745.7) .0001Age, yrs 40 (3248) 56 (4069) .0001

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

Table 9. Individual Subjects With Cholestatic/Mixed-Type Liver Injury Associated With Fatal Outcome

Drug Indication Duration AST ALT ALP Bilirubin ALT/ALP

M 64 Enalapril Heart failure 60d 3.1 15.7 1.7 25.2 1.8M 16 Diclofenac Back pain 360d 17.1 10.3 8.6 12.4 1.2M 83 Chlorpromazine Psychosis 28d 3.2 5.3 13.6 4.6 0.38F 85 Flucloxacillin Cellulitis 26d 1.9 2.9 2.8 7.4 1.0F 45 Multiple Multiple 14d 4.0 3.0 7.7 27.4 0.39F 78 Flucloxacillin Cellulitis 18d 13.2 12.3 16.1 15.4 0.76F 85 Flucloxacillin Cellulitis 21d 19.4 24.4 19.2 21.2 1.3M 77 Dicloxacillin Osteomyelitis 87d 3.1 3.1 3.1 32 1.0F 83 Flucloxacillin Cellulitis 10d 5.9 9.4 36.4 0.63F 41 Trimethoprim/sulfametoxazol HIV 180d 7.0 2.4 5.8 13.8 0.41M 78 Flucloxacillin Oral abscess 21d 14.3 17.1 23.8 18 1.32M 39 Multiple Prostate cancer 32d 1.9 1.9 1.8 5.7 1.1F 58 Estradiol Osteoporosis 365d 4.1 3.0 1.74 35.2 1.72M 73 Chlorpromazine Psychosis 13d 1.4 2.2 4.4 12.9 0.5F 39 Atorvastatin Hyperlipemia 120d 2.9 0.8 4.2 31.7 0.19M 40 Diclofenac Arthralgia 6d 3.0 2.0 2.1 10.4 0.95M 69 Ciprooxacin Cellulitis 23d 3.3 5.1 2.1 32.6 2.4M 90 Flucloxacillin Cellulitis 11d 6.9 8.4 4.1 25.3 2.0F 77 Ticlopidine Uremia 35d 6.1 15.7 4.8 39.1 3.3M 83 Danazol Thrombocytopenia 270d 3.0 4.1 2.0 24.8 2.1

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 mixedwhen 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.

HEPATOLOGY, Vol. 42, No. 2, 2005 BJORNSSON AND OLSSON 487

phase, when amuch larger number of patients are exposedto the drug.13 Although still used by the U.S. Food andDrug Administration in the assessment of the hepatotox-icity of different drugs, a validation of Hys rule has beenrequested, because the information about its sensitivityand specicity are largely lacking.13 Although the ndingsof Zimmerman and coworkers are important contribu-tions to our knowledge of DILD, the mortality rate ac-cording to Hys rule has been reported for only a fewcompounds, such as isoniazid, iproniazid, cinchophen,dantrolene, halothane, methyldopa, and tienillic ac-id.21-25 Isoniazid is probably the only compound out ofthose analyzed and reported previously by Zimmerman etal. to cause DILD, which still is in widespread use nowa-days.

Our analysis is unique because it is performed in a largecohort of patients with severe DILD, giving the opportu-nity to elucidate the most important predictors for out-come. It is well recognized that adverse drug reactions aresignicantly underreported. The true incidence of hepaticadverse drug reactions has until recently been largely ob-scure. However, a recent, careful prospective survey ofdrug-induced liver injury in the general population inFrance suggests that at the most, only 1 out of 16 cases ofDILD in France is actually reported.26 Spontaneous re-porting was found to be at least twice as high in Swedencompared with gures from France.27 It is of course pos-sible that severe adverse drug reactions are reported morefrequently, although this has not been assessed in a well-designed study. Further limitations of the present studyare its retrospective nature and the lack of internationalnormalized ratio data.

In the current study, approximately 20% of patientswith probable or possible DILD had serum bilirubin lev-els 2 or more times the ULN, the limit suggested by theU.S. Food and Drug Administration to correspond to thepresence of jaundice. Most of the patients in this studywith DILD and concomitant jaundice had a good prog-nosis with complete recovery, but approximately 10% ofthe patients either died or underwent liver transplanta-tion. However, our gures on the drug-specic inci-dence of icteric DILD cannot be used as an estimate ofthe drug-specic risk of icteric DILD, because the g-ures are not sales-related. The small number of patientsprecludes an assessment of the inherent risk of developingserious liver reaction once a DILD has occurred, at leastfor most of the drugs.

Our results are in accordance with Hys rule insofar asHC jaundice was found to have a mortality of approxi-mately 10%. A total of 72 (9.2%) of 784 patients in thetotal study group either died or underwent transplanta-tion. However, because a signicant number of halothane

reports (7 suspected lethal reactions) and 1 suspected di-sulram case associated with mortality had to be excludedbecause of a lack of clinical and laboratory data, the trueproportion of deaths and transplantations could be un-derreported. If these cases had been included, the overallmortality would not have been more than 9.9% in thetotal study population.

However, the mortality rate of our patients fulllingHys rule seemed to be highly variable when related towhich drug was associated with the DILD. Thus, a nota-ble nding in the present study is that all of the 32 patientswith erythromycin-induced HC jaundice (fullling Hysrule) recovered. Although erythromycin is among the topve 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 out-come.28 All patients with erythromycin-induced liver in-jury recovered in the current study. This was probably dueto relatively mild erythromycin-associated DILD. Theprognosis among patients fullling RUCAM criteria forDILD but in whom the specic drug could not be iden-tied because of multiple drug exposure was not differentfrom those patients with one specied drug suspected tohave caused the reaction.

In the current study, the International Consensus Cri-teria were applied to the classication of hepatic reactioninto HC, CS, and mixed adverse drug reactions.16-17

These criteria were rst published in 1990, and becausemost of the work by Zimmerman et al. was publishedbefore that time, these publications did not apply themodern strict criteria for the classication of hepatic re-actions.11,14,21-25 As a consequence, many of the cases withDILD-associated HC jaundice reported by Zimmermanet al. would possibly be classied as mixed type of DILDusing the International Consensus Criteria.16-17

CS injury due to drugs has been reported to have agood prognosis, and fatalities were considered to be theresults of underlying disease rather than hepatic injury.11

However, in our cohort, patients with CS injury also hada high mortality rate of 7.8%, whereas those with mixedinjury had a mortality rate of 2.4%. The mortality rate of5.4% among patients suffering from ucloxacillin-in-duced liver injury is in line with previous reports fromSweden and Australia.29-32 In a recent study from Japan,age was not found to differ between patients with DILDwho developed fulminant hepatic failure versus those whodid not.33 However, in the current study, nonsurvivorswith the HC type of DILD were signicantly older thanthose who recovered. Age was found to independentlypredict death or transplantation in the HC group. Fur-thermore, in HC injury as well as in CS/mixed injury, thepeak level of bilirubin was found to be an independent

488 BJORNSSON AND OLSSON HEPATOLOGY, August 2005

risk factor for death or liver transplantation. Interestingly,forward stepwise analysis identied AST but not ALT tobe an independent predictor of bad outcome in the totalstudy. This is in line with results reported by Ohmori etal.33 in patients with DILD showing higher aminotrans-ferase levels, especially AST in patients who progressed tofulminant hepatic failure compared with those who didnot. Furthermore, our data are consistent with those ofGitlin,34 who observed a higher AST/ALT ratio in fatalcases than in survivors with severe acute viral hepatitis. Ahypothetical explanation put forward by the author wasthat when the serum ALT level is exceeded by the serumAST level, this reects additional AST release from thehepatocyte mitochondrial AST component as a conse-quence of more severe hepatocyte damage. In contrast tothe results obtained by Ohmori et al., we did not ndlonger duration of drug therapy to be a risk factor for badoutcome.

In summary, in accordance with Hys rule, HC jaun-dice has a high but variable mortality rate, depending onthe drug involved. AST and bilirubin levels are the mostimportant predictors of death or liver transplantation.

References1. Bjrneboe M, Iversen O, Olsen S. Infective hepatitis and toxic jaundice in

a municipal hospital during a ve-year period: incidence and prognosis.Acta Med Scand 1967;182:491-501.

2. Malchow-Mller A, Matzen P, Bjerregaard B, Hilden J, Holst-ChristensenJ, Staehr Johansen T, et al. Causes and characteristics of 500 consecutivecauses of jaundice. Scand J Gastroenterol 1981;16:1-6.

3. Whitehead MW, Hainsworth I, Kingham JGC. The causes of obviousjaundice in South West Wales: 2000. Gut 2001;48:409-413.

4. Bjornsson E, Ismael S, Nejdet S, Kilander A. Severe jaundice in Sweden inthe new millennium: causes, investigations, treatment and prognosis.Scand J Gastroenterol 2003;38:86-94.

5. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, etal. U.S. Acute Liver Failure Study Group. Results of a prospective study ofacute liver failure at 17 tertiary care centers in the United States. AnnIntern Med 2002;137:947-954.

6. Wei G, Bergqvist A, BroomeU, Bjornsson E. Acute liver failure in Sweden:etiology and prognosis [Abstract]. Scand J Gastroenterol 2004;39(Suppl240):48A.

7. Williams R. Classication, etiology, and considerations of outcome inacute liver failure. Semin Liver Dis 1996;16:343-348.

8. OGrady JG, AlexanderGJM,Hayllar KM,Williams R. Early indicators ofprognosis in fulminant hepatic failure. Gastroenterology 1989;97:439-445.

9. Hoofnagle JH, Carithers RL Jr, Shapiro C, Nascher H. Fulminant hepaticfailure: summary of a workshop. HEPATOLOGY 1995;21:240-252.

10. Bakke OM, Manocchia M, de Abajo F, Kaitin KI, Lasagna L, et al. Drugsafety discontinuations in the United Kingdom, the United States, andSpain from 1974 through 1993: a regulatory perspective. Clin PharmTherap 1995;58:108-117.

11. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis 2000;4:73-96.12. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-

associated hepatitis in 114 patients. Gastroenterology 1975;69:289-302.

13. Senior JR. Regulatory perspectives. In: Drug-Induced Liver Disease.Kaplowitz N, DeLeve LD, eds. New York: Marcel Dekker, 2003:739-754.

14. Zimmerman HJ. Drug-induced liver disease. In: Sciff ER, Sorrell MF,Maddrey WC, eds. Sciffs Diseases of the Liver. 8th edition. Philadelphia:Lippincott-Raven Publishers, 1999:973-1064.

15. Davidson CS, Leevy CM, Chamberlayne EC, eds. Guidelines for Detec-tion of Hepatotoxicity Due to Drugs and Chemicals. Fogarthy Confer-ence, 1978. NIH publication no. 79-313. Washington, DC: USGovernment Printing Ofce, 1979.

16. Danan G, Benichou C. Causality assessment of adverse reactions todrugsI. A novel method based on the conclusions of international con-sensus meetings: application to drug-induced liver injuries. J Clin Epide-miol 1993;46:1323-1330.

17. Benichou C. Criteria of drug-induced liver disorders. Report of an Inter-national Consensus Meeting. J Hepatol 1990;11:272-276.

18. Lee WM. Assessing causality in drug-induced liver injury. J Hepatol 2000;33:1003-1005.

19. Larrey D. Epidemiology and individual susceptibility to adverse drug re-actions affecting the liver. Semin Liver Dis 2002;22:145-155.

20. Kaplowitz N. Drug-induced liver disorders: implications for drug devel-opment and regulation. Drug Saf 2001;24:483-490.

21. Zimmerman HJ. Agents employed in the treatment of infectious andparacitic diseases. In: Hepatotoxicity. The Adverse Effects of Drugs andOther Chemicals on the Liver. 1st ed. New York: Appelton-Century-Crofts, 1978:468-509.

22. Zimmerman HJ. Psychotropic and anticonvulsant agents. In: Hepatotox-icity. The Adverse Effects of Drugs and Other Chemicals on the Liver. 1sted. New York: Appelton-Century-Crofts, 1978:395-417.

23. ZimmermanHJ. Antiinammatory and other drugs employed in the treat-ment of rheumatic and musculoskeletal diseases. In: Hepatotoxicity. TheAdverse Effects of Drugs and Other Chemicals on the Liver. 1st ed. NewYork: Appelton-Century-Crofts, 1978:418-435.

24. Zimmerman HJ. Anesthetic agents. In: Hepatotoxicity. The Adverse Ef-fects of Drugs and Other Chemicals on the Liver. 1st ed. New York:Appelton-Century-Crofts, 1978:370-394.

25. Zimmerman HJ. Drugs used in cardiovascular disease. In Hepatotoxicity.The Adverse Effects of Drugs and Other Chemicals on the Liver. 1st ed.New York: Appelton-Century-Crofts, 1978:510-522.

26. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al.Incidence of drug-induced hepatic injuries: a French population-basedstudy. HEPATOLOGY 2002;36:451-455.

27. Olsson R, Brunlof G, Johansson ML, Persson M. Drug-induced hepaticinjury in Sweden. HEPATOLOGY 2003;38:531-532.

28. Bjornsson E, Jerlstad P, Bergquist A, Olsson R. Fulminant drug-inducedhepatic failure leading to death or liver transplantation in Sweden [Ab-stract]. Gastroenterology 2004;126(Suppl):1185A.

29. Olsson R, Wiholm BE, Sand C, Zettergren L, Hultcrantz R, Myrhed M.Liver damage from ucloxacillin, cloxacillin and dicloxacillin. J Hepatol1992;15:154-161.

30. Devereaux BM, Crawford DH, Purcell P, Powell LW, Roeser HP. Flu-cloxacillin associated cholestatic hepatitis. An Australian and Swedish ep-idemic? Eur J Clin Pharmacol 1995;49:81-85.

31. Fairley CK, McNeil JJ, Desmond P, Smallwood R, Young H, Forbes A, etal. Risk factors for development of ucloxacillin associated jaundice. BMJ1993;306:233-235.

32. McNeil JJ, Grabsch EA, McDonald MM. Postmarketing surveillance:strengths and limitations. The ucloxacillin-dicloxacillin story. Med J Aust1999;170:270-273.

33. Ohmori S, Shiraki K, Inoue H, Yamanaka T, Deguchi M, Sakai T, et al.Clinical characteristics and prognostic indicators of drug-induced fulmi-nant hepatic failure. Hepato-Gastroenterology 2003;50:1531-1534.

34. Gitlin N. The serum glutamic oxaloacetic transaminase/serum glutamicpyruvic transaminase ratio as a prognostic index in severe acute viral hep-atitis. Am J Gastroenterol 1982;77:2-4.

HEPATOLOGY, Vol. 42, No. 2, 2005 BJORNSSON AND OLSSON 489