Consensus meetings on: Causality assessment of drug-induced liver injury

132

Journal of Hepatology, 1988; 7:132-136

Elsevier HEP 00426

Leader

Consensus Meetings on:

Causality assessment of drug-induced liver injury G. Danan Direction de la Pharmacovigilance, Roussel Ucla]~ Paris"(France)

Summary None of the various methods for drug reaction assessment has been adapted to the well-defined damage of a specific organ. There are disagreements between the parties involved in this issue: practitioners, and experts in drug surveillance either in regulatory agencies or in the pharmaceutical industry. Consensus Meetings were therefore organized in order to answer the three basic questions related to the diagnosis of drug-induced liver injury: (a) is the liver involved? (b) what chronological and clinical criteria suggest a drug-induced reaction'? (c) can non-drug-related causes be excluded? On the basis of the method for drug reaction assessment used in France, we describe criteria adapted to the case of acute cytolytic hepatitis, which constitutes only one aspect of the task of the Hepatology Working Group.

Almost all types of hepatobiliary disease can be induced by drugs [11 and there is no specific test for diagnosing drug-induced liver disorder. Therefore, one of the most difficult issues in medical practice is the assessment of the causal relationship between administration of the drug and liver injury. For the practitioner, a mere suspicion should lead to the cessation of the drug. His assessment of the relationship is often intuitive, based on his own experience of drug hepatotoxicity, and will not always agree with

that of other practitioners. For the expert in drug surveillance, a member of a regulatory agency or pharmaceutical firm who evaluates the overall benefit/ risk ratio of the drug, information on each case is often incomplete. Any method for drug reaction assessment is questionable because of the lack of reference data [2,7]; here also, causality assessment may differ from one expert to another. In addition, in several countries, including France, practitioners and drug manufacturers have to report to the regulatory

Participants in Consensus Mcetings: J.-P. Benhamou (H6pita[ Beaujon, Clichy); P. Berthelot (H6pital Laennec, Paris); P. Couzigou (H6pital Haut-L6v6que, Bordeaux-Pessac): B. Begaud (H6pital Pellegrin, Bordeaux); M. Biour (H6pital Saint-Antoine, Paris); J.C. Evreux (H6pital E. Herriot. Lyon): G. Lagier (H6pital Fernand Widal. Paris); C. Benichou and G. Danan (Rousse[ Uclaf, Paris). Correspondence: G. Danan, Direclion de la Pharmacovigilance, Rousse[ Uclaf, 35, Bd des Invalides, 75(107 Paris, France. Tel: ( 1) 40 62 43 72. 0168-8278/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)

ASSESSMENT OF DRUG-INDUCED LIVER INJURY

133

TABLE I FRENCH MEFHOD FOR DRUG REACTION ASSESSMENT [5]: ASSESSMENT OF THE CHRONOLOGICAL CRITERIA R( + ). R([)). R(-): positive, uninterpretable (or not done), negative response to drug readministration, respectively, C0, CI, C2, C3: incompatible, dubious, possible, suggestive chronology, respectively. Course of the reaclion

Time lo onset of the reaction very suggestive Readministration: R( + )

SuGgestive Non-suggestive Non-conclusive

C3 CI C3

compatible

incompatible

R(0)

R(-)

R( + )

R(0)

(R-)

C3 C1 C2

CI CI CI

C3 C1 C3

C2 C1 CI

C1 C1 CI

authority all adverse drug reactions ( A D R s ) with which they are faced [3]. On their side, regulatory agencies have to transmit A D R s to the W H O Collaborating Center for International Drug Monitoring in Uppsala. Therefore. all parties involved in this issue need standardized definitions of each A D R and standardized procedures for assessment of a causal relationship. It a p p e a r e d that consensus meetings would constitute the best way to settle this problem. The Hepatology Working G r o u p consisted of: three hepatologists from university hospitals, three members of the French Drug Surveillance Network [3] and two m e m b e r s of the International Drug Surveillance D e p a r t m e n t of Roussel Uclaf, the p h a r m a c e u tical firm which organized these meetings. Objectives were to provide for each of the most frequent drug-induced liver injuries: (a) a strict definition: (b) precise chronological and clinical criteria suggesting a drug-induced reaction; (c) a list of investigations necessary to exclude other possible causes.

C0 C0 CO

In this paper, we report the conclusions of a Consensus Meeting on the criteria for ascribing acute cytolytic hepatitis to a drug.

Description of the French method for drug reaction assessment The method for drug reaction assessment, which has been compulsory in France since 1984, has been described elsewhere [5]'. Briefly, it is based on two sets of criteria: chronological and clinical. The three chronological criteria are: (a) time to onset of the reaction described as very suggestive of, compatible with or incompatible with drug-induced reaction; (b) the course of the reaction described as suggestive (i.e., in favour of the causal role of the drug), nonsuggestive, or non-conclusive, depending on the cessation or the continuation of the drug; (c) response to drug readministration described as positive, negative or uninterpretable (or not done). Responses to these

TABLE 2 FRENCH METHOD FOR DRUG REACTION ASSESSMENT [5]: ASSESSMENT OF CLINICAL CRITERIA L(+ ), L(0), L(-): positive, t.ninterpretable (or not done), negative specific laboratory test, respectively. SI, $2, $3: dubious, possible. suggestive clinical pattern (semiology), respectively. Other non-drug

Signs and symptoms of the reaction

causes

suggestive of the role of the drug (or risk factor) Laboratory test: L(+ )

None Possible or present

$3 $3

other situations

L(0)

L(-)

L(+ )

L(0)

L(-)

$3 $2

S1 S1

$3 $3

$2 S1

S1 SI

134

G. DANAN

TABLE 3

TABLE 5

FRENCH METHOD FOR DRUG REACTION ASSESSMENT [5]: CAUSALITY ASSESSMENT

ACUTE CYTOLYTIC HEPATITIS: ASSESSMENT OF TIME TO ONSET OF REACTION IN CASE OF nth COURSE OFTREATMENT WITH SUSPECTED DRUG

I0 = unlikely, I1 = dubious, I2 = possible, I3 = likely, I4 = very likely. Chronological score

Clinical score SI

$2

$3

C0 C1 C2 C3

I0 I1 I1 I3

I0 I1 12 13

I0 I2 I3 I4

Time from the last dose

Time from the first dose Drug taken after onset of reaction

Immediately to 15 days

> 15 days

~<15 days >15 days

incompatible

suggestive~

compatible incompatibleb

Instead of 'very suggestive' mentioned in the original method [5]. h Except for slowly metabolized drugs.

three criteria are c o m b i n e d in a decision table leading to the assessment of the c h r o n o l o g y expressed as a score: i n c o m p a t i b l e , d u b i o u s , possible or suggestive (of d r u g - i n d u c e d reaction) ( T a b l e 1). T h e three clinical criteria are: (a) signs and symptoms suggesting the causal role of the drug a n d / o r presence of a risk factor; (b) result of a specific test p r o v i n g the causal role of the drug; (c) assessment of n o n - d r u g - r e l a t e d causes. These three criteria are c o m b i n e d in a decision table leading to the clinical assessment expressed as a score: d u b i o u s , possible or suggestive (Table 2). Finally, chronological a n d clinical scores are comb i n e d in a decision table resulting in causality assessm e n t : very likely, likely, d u b i o u s , possible or unlikely ( T a b l e 3).

this criterion d e p e n d s on the dates of the first a n d last dose of the drug a n d on w h e t h e r it is the first or the n t h course of a d m i n i s t r a t i o n of the suspected drug ( T a b l e s 4, 5).

(2) Course of the reaction. A s s e s s m e n t of this criterion d e p e n d s on cessation ( d e c h a l l e n g e ) or c o n t i n u a tion of the drug ( T a b l e 6). (3) Response to the drug readministration (rechallenge). D r u g r e a d m i n i s t r a t i o n is h a z a r d o u s and unethical, particularly in the case of cytolytic-type hepatitis. H o w e v e r , s o m e case reports include u n i n t e n tional r e a d m i n i s t r a t i o n a n d should therefore be accurately i n t e r p r e t e d . T a b l e 7 gives the definitions of positive, negative a n d u n i n t e r p r e t a b l e r e s p o n s e , with the respective c o n d i t i o n s for drug r e a d m i n i s t r a tion.

Adaptation to drug-related acute cytolytic hepatitis Chronological criteria (1) Time to onset of the reaction. A s s e s s m e n t of

Clinical criteria (Table 8) (1) Signs and symptoms suggesting the causal role of the suspected drug. This criterion c a n n o t be applied to liver i n j u r y since there is no specific drug-in-

TABLE 4 ACUTE CYTOLYTIC HEPATITIS: ASSESSMENT OF TIME TO ONSET OF REACTION IN CASE OF FIRST COURSE OF TREATMENT WITH SUSPECTED DRUG Time from the last dose

Time from the first dose Drug taken after onset of reaction

<8 days

8-90 days

>90 days

~<15 days > 15 days

incompatible

compatible

suggestive ~ incompatiblet'

compatible incompatiblet,

Instead of 'very suggestive" mentioned in the original method [5]. b Except for slowly metabolized drugs.

ASSESSMENT OF DRUG-INDUCED LIVER INJURY

135

TABLE 6 ACUTE CYTOLYTIC HEPATITIS: ASSESSMENT OF THE COURSE OF THE REACTION Cessation of

Course of the reaction

the drug

very suggestive~'

suggestive

non-suggestive

non-conclusive

Yes

decrease of AT/> 50% of D h within 8 days and no elevation of AT within 1 month

decrease of AT 1> 50% of D b within 30 days

other variations of AT within or after 1 month

no information on liver tests

No

stable or increased level of AT

partial decrease of AT or return to normal

This situation is not considered in the original method. b Difference between the peak of the most elevated aminotransferase and the upper limit of normal values; AT = the most elevated aminotransferase.

TABLE 7 ACUTE CYTOLYTIC HEPATITIS: ASSESSMENT OF RESPONSE TO READMINISTRATION Response to readministration positive

negative

uninterpretable

Definition

ATr'~ > 2 ATb

ATb- ATr ~< 1 N or ATr ~< N

other variations

Conditions

• ATb below 5 N • drug: any dose, any duration, alone or combined with the other uninterrupted drugs

• ATb below 5 N • drug: same dose, same duration, same combined drugs as at the first administration

other

ATb = level of the most elevated aminotransferase just before readministration; ATr = level of the same aminotransferase during the drug readministration: N = upper limit of normal values.

duced

manifestation.

However,

some

situations

listed in T a b l e 8 suggest that the d r u g m a y be the

main n o n - d r u g - r e r a t e d

causes c a p a b l e of inducing

acute cytolytic hepatitis are listed in T a b l e 9.

cause of the hepatitis. (2) Specific test. T h e r e is no test specific e n o u g h to p r o v e the causal role of a drug: n e i t h e r i m m u n o l o g i -

Comments

cal tests in the p r e s e n c e of the s u s p e c t e d drug, such as the l y m p h o c y t e t r a n s f o r m a t i o n test, m a c r o p h a g e in-

A m o n g the great n u m b e r of m e t h o d s of causality

hibition test and h u m a n basophil d e g r a n u l a t i o n test,

assessment

nor histological lesions. H o w e v e r , s e r u m antiorga-

authors [7], n o n e has b e e n d e s i g n e d for r e a c t i o n s

nelle a n t i b o d i e s h a v e b e e n s h o w n to be specific for a

specifically involving an o r g a n , such as the liver. All

few drugs, such as a n t i m i t o c h o n d r i a l a n t i b o d y , type 6

the m e t h o d s are s u p p o s e d to be used w h a t e v e r the

( A M A , M6) for iproniazid and antiliver and k i d n e y

target o r g a n , and no criterion has b e e n strictly de-

m i c r o s o m e a n t i b o d i e s , type 2 (LKM2) for tienilic

fined. T h e i r p o o r specificity e n h a n c e s the n u m b e r of

acid [6].

cases with a ' d u b i o u s ' causal relationship. F o r t h e s e

(3) Assessment of non-drug-related causes. T h e

proposed

by

regulatory

agencies

or

reasons, criteria of the F r e n c h m e t h o d for d r u g reac-

G. DANAN

136 TABLE 8

TABLE 9

ACUTE CYTOLYTIC HEPATITIS: ASSESSMENT OF CLINICAL CRITERIA

ACUTE CYTOLYTIC HEPATITIS: MAIN NON-DRUGRELATED CAUSES

Risk factor:

(1) Serological markers for recent viral infection (HAV: antiHAV antibody, IgM; HBV: anti-HBc, lgM; CMV, EBV, Herpes viruses: increase in specific antibody titres) (2) Circumstantial arguments for contamination by a non-A, non-B virus (blood transfusions, intravenous drug addict, recent travel in endemic areas: Africa, Asia) (3) Hepatobiliary ultrasonography (4) Alcohol consumption (5) Heart or vascular disease (ischemic liver necrosis) (6) Pregnancy (7) Cancer

concomitant administration of a strong enzyme inducer

Suggestive of drug origin: concomitant disorder such as fever, rash, renal failure, eosinophilia Specific test:

there is no specific test to confirm the causal role of a drug~

Exceptionally. specific drug-induced serum autoantibodies.

tion assessment have been defined and adapted to liver reactions. In this paper only the criteria for assessing acute cytolytic hepatitis are fully described, but the Hepatology Working G r o u p has also reviewed the following liver injuries: acute cholestatic hepatitis [4], acute mixed hepatitis [4], chronic hepatitis without liver biopsy, and histologically proven chronic hepatitis and cirrhosis. The principle of the method is similar to that of the medical diagnosis process. It should be easy to use. Furthermore, this method, which is reproducible since all situations have been considered for every criterion, can be used as a common language for all parties involved in drug surveillance and can be of assistance to reviewers of

References 1 Sherlock S. The spectrum of hepatotoxicity due to drugs. Lancet 1986: ii: 4411-444. 2 Pere JC, Begaud B, Haramburu F, Albin H. Computerized comparison of six adverse drug assessment procedures. Clin Pharmacol Ther 1986; 40:451-461. 3 Moore N. Biour M. Paux G, et al. Adverse drug reaction monitoring: do it the French way. Lancet 1985; ii: 1056-1058. 4 Danan G. Benichou C, Begaud B, et al. Crit~res d'imputa-

journals when A D R s are submitted for publication. The specificity of the method could be improved by weighting each criterion: this is our next goal. The conclusions of these meetings reflect the opinion of experts in hepatology and drug surveillance based on their experience in drug-induced reactions. They should be regarded as the first step towards an international agreement for drug-induced liver injury assessment. In the future, these conclusions may be modified depending on our knowledge of drug hepatotoxicity, the discovery of serum markers for nonA, non-B viral hepatitis and specific tests to confirm the causal role of a drug.

tion d'une hdpatite aiguE 'a un mddicament. Rdsultats de rdunions de consensus. Gastroenterol Clin Biol 1987; 11: 581-585. 5 Begaud B, Evreux JC, Jouglard J, Lagier G. Unexpected or toxic drug reaction assessment (imputation). Actualization of the method used in France Therapie 1985;40:111-118. 6 Homberg JC, Abuaf N, Helmy-Khalil S, et al. Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 1985; 5: 722-727. 7 Stephens MDB. The Detection of New Adverse Drug Reactions. New York: Stockton Press, 1985;39-64.