Causality Assessment Methods

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The lack of specific tests for diagnosing drug hepatotoxicity poses particular problems for definitively attributing a liver reaction to an implicated drug. The approach to the diagnosis of a drug-induced liver disease involves physician awareness, exclusion of other causes of the reaction and an objective weighing of the circumstantial evidence. These considerations have been termed ''causality assessment" and form the cornerstone to the diagnosis of drug-induced hepatotoxicity.

Decision Tree Model

An algorithm-based model developed by Stricker considers three factors:

1. the specificity of the clinico-pathological pattern and its course;

2. the temporal relationship between intake/ discontinuation of the suspected drug and onset/disappearance of hepatic injury; and

3. exclusion of other possible causes for the observed pattern (Stricher, 1992).

The model assesses the degree of certainty of a causal relationship between hepatic injury and drug intake; however, it has several major disadvantages. First, all the factors are given equal weight; second, the quantitative data are reduced to qualitative "yes" or "no" answers. Finally, categories such as ''probable'' and ''possible'' lead to a semantic cause of inter-observer variation.

Bayesian Model

A logical approach to the problem of causality assessment is based on Bayes' theorem. This model uses the background incidence of an event, the individual clinical features of a particular case and the probability of other potential causes. The model estimates the probability of a specific reaction in a particular individual in a given situation being related to the drug therapy. However, the Bayesian model is time consuming and, hence, impracticable to use in the evaluation of a large number of adverse hepatotoxic reactions. In addition, the background incidence of a given reaction may not be known, thus further limiting its use. In a large survey, the Bayesian model had an accuracy of only 45% in the diagnosis of drug-induced liver disease when compared with the final diagnosis after investigations (Lavelle and Kavanagh, 1995).

International Consensus Criteria

In 1990, under the auspices of the Council for International Organizations of Medical Sciences (CIOMS), an international group of "experts" proposed definitions of adverse hepatotoxic reactions and criteria for assessing causality of drug-induced liver diseases in order to standardise the evaluation of drug hepatotoxicity by physicians, health authorities of different countries and pharmaceutical manufacturers (Benichou, 1990). For causality assessment the French method of ADR assessment was adapted to suit the evaluation of drug-induced liver disease (Danan, 1988). "International consensus criteria" combined the basic principles of "chronological criteria" (establishing a temporal relationship between the drug treatment and the reaction) and "clinical criteria" (exclusion of alternative causes for the particular pattern of liver injury) to determine the probability of the reaction being related to the drug. A detailed scoring system was developed (CIOMS scale) and validated using cases of drug-induced liver injury with known positive rechallenge (Danan and Benichou, 1993). The CIOMS scale performed well when these cases were assessed using the data prior to rechallenge. In a recent study (Aithal et al., 1999) 86% of the suspected hepatic ADRs could be classified as "drug-related" or "unrelated" using a simplified form of consensus classification (see Table 37.2).

Even though the "International consensus criteria" are considered to be "state of the art'', they cannot be used rigidly in all circumstances, especially to exclude a drug as a cause of a given reaction. For example, the classification of a causal relationship between a drug and cholestatic injury as "incompatible" if the onset occurs more than one month after the last drug intake would unduly refute such cases attributable to co-amoxiclav intake (Larrey et al., 1992a). Similarly, flucloxacillin-induced cholestasis which, in one-third of patients may take up to 18 months after the drug withdrawal to resolve (Turner et al., 1989), may be classified as "inconclusive" according to the consensus criteria. The CIOMS scale also defines alcohol, pregnancy and age over 55 years as risk factors which would reduce the

Table 37.2. Classification of suspected adverse reactions using International Consensus Criteria (simplified version).


1. The time from drug intake and withdrawal to the apparent onset of the reaction was ''suggestive'' of drug hepatotoxicity (5-90 days from initial drug intake) or ''compatible'' with drug hepatotoxicity (<5 or >90 days from initial drug intake and <15 days from drug withdrawal for ''hepatocellular'' reactions or <30 days from drug withdrawal for ''cholestatic'' reactions).

2. The course of the reaction after cessation of the drug was ''very suggestive'' (decrease in the liver enzymes by >50% of the excess over the upper limit of normal within 8 days) or ''suggestive'' (decrease in the liver enzymes by >50% within 30 days for ''hepatocellular'' reactions and 180 days for ''cholestatic'' reactions) of drug hepatotoxicity.

3. Alternative cause of the reaction had been excluded by relevant investigations.

4. There was a positive response to rechallenge (at least a doubling of liver enzymes) when such information was available.

Reactions were classified as ''drug-related'' if all of the first three criteria were met or if two out of the first three criteria were met in the presence of a positive rechallenge response.


1. The time from drug intake and withdrawal to the apparent onset of the reaction was ''incompatible'' with drug hepatotoxicity (drug taken after the onset of the reaction or reaction >15 days from cessation of the drug except for slowly metabolised drugs).

2. Time course of the reaction after drug withdrawal ''not suggestive'' of drug hepatotoxicity (decrease in liver enzymes <50% decrease in liver enzymes within 30 days for hepatocellular reactions and 180 days for cholestatic reactions). Both ''indeterminate'' and ''inconclusive'' cholestatic reactions were included in this group.

3. The presence of an alternative cause for the reaction.

A reaction was classified as drug-unrelated if one or both of the first two criteria were met in the presence of an alternative cause for the reaction.


1. A temporal relationship between drug intake and the reaction in the presence of a likely alternative cause for the reaction.

2. A temporal relationship between drug intake and the reaction not suggestive of drug-induced hepatotoxicity but no alternative cause for the reaction.

flexibility to weigh other risk factors relevant to the clinical setting.

Clinical Diagnostic Scale

More recently, a simplified scoring system called the ''Clinical Diagnostic Scale'' (CDS) (otherwise called the Maria & Victorino scale) has been developed (Maria and Victorino, 1997). Scores are attributed in seven different components of a given reaction (Table 37.3) and the reactions are graded according to the final score. The original validation of the CDS used real and fictitious cases and

IV. Intentional or accidental re-exposure to the drug

Positive rechallenge Negative or absent rechallenge the opinion of a panel of experts as the gold standard. A detailed comparison of the CIOMS scale and the CDS concluded that the latter performed poorly while evaluating reactions with long latency periods and evolution to chronicity after withdrawal (e.g. cholestasis due to amox-iclav) (Lucena et al., 2001).

The CDS generally underscores the reactions. Even in the initial study, only four (all of which had positive rechallenge) were classified as definite adverse hepatic reaction (score >17) (Maria and Victorino, 1997). The reason for low scoring is due to the emphasis given to positive rechallenge as attributed

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