Causality Assessment of Drug-Induced Hepatotoxicity: Promises and Pitfalls
Section snippets
Historical basis of assessing causality
Causality assessment began as more of an art than a science. A number of early studies explored the process by which a variety of non–organ-specific adverse drug reactions were assessed [19], [20], [21], [22], [23], [24]. Arimone and colleagues [25] recently reviewed these methods and divided the nearly 2 dozen approaches into three main categories: expert judgment, probabilistic methodologies, and algorithms. In general, none was considered highly satisfactory. For example, they cited evidence
Causality assessment method and drug-induced liver injury
Zimmerman and other early pioneers in the field of hepatotoxicity employed many of the same components found in the current WHO guideline [26] and other authors' criteria for causality assessment of drug reactions in general [19], [20], [25] and applied them to a common-sense clinical approach to establishing the cause of suspected DILI [30]. Examining the circumstances of the liver injury, the host factors, the clinicopathologic features of the reaction, its course and outcome, excluding other
Roussel Uclaf Causality Assessment Method
The RUCAM was developed at the request of the Council for International Organizations of Medical Sciences (CIOMS) by an internationally recognized panel of experts brought together by Danan and Benichou of the Drug Safety Department of the French pharmaceutical maker Roussel Uclaf in 1989 and 1990 [14], [15]. A major goal was to adapt existing methods for assessing non–organ-specific drug reaction to well-defined hepatic reactions [31], [32]. From these meetings, a consensus opinion emerged
The Maria and Victorino clinical diagnostic scale
The complexity of the RUCAM prompted Maria and Victorino [16] from Portugal to propose and validate a somewhat simpler scoring system to assess DILI. These authors constructed a CDS, based on a modification of the RUCAM criteria, that also used the time to onset and time course of the reaction, the exclusion of alternative causes, the response to re-exposure (by intentional or accidental rechallenge), and previous reports in the literature implicating the drug. They added a fifth criterion
Drug-induced Liver Injury Network assessment
The DILI Network was established by the National Institutes of Health in 2003 as a consortium of five clinical centers around the United States to develop tools to improve the diagnostic accuracy of suspected DILI along with a prospective registry and clinical database of cases and a repository of serum for future pharmacogenomic and related research purposes. All cases are scored by the principal investigators using the RUCAM, who then assign a 5-point scale for certainty of diagnosis that
Comparing methods of causality assessment
Two studies have compared RUCAM with the Maria and Victorino CDS. Aithal and colleagues [39] found that the Maria and Victorino system performed equally as well as the CIOMS score (an early version of RUCAM) in the assessment of causality of 135 suspected hepatotoxic drug reactions when classifying DILI as drug-related, drug-unrelated, or indeterminate. Based on their assessment that only 36% of the cases were drug-related, they found that in routine clinical practice it was easier to apply the
Consequences of inaccurate causality assessment
No clinically based CAM is necessarily accurate in all DILI scenarios. As noted previously, the CDS is weighted toward drugs acting through immunoallergic mechanisms, whereas the RUCAM gives more significance to a positive response to rechallenge without regard to previously published literature reports. For most instances of acute DILI, however, these criteria are lacking, and their absence often reduces the accuracy of the assessment. The failure to make an accurate diagnosis as to the true
Pitfalls in causality assessment
Because DILI can mimic many other forms of acute and chronic liver injury [30], [35], [46], a high index of suspicion that a drug may be responsible is paramount. The basic clinical criteria that are used to establish causality of DILI are given in Box 1. How diligently they are searched for and how they are interpreted can vary considerably among clinicians and even among skilled experts. Because all the currently employed causality-assessment scales use the same criteria to establish a
Summary
Because of the wide spectrum of DILI and its varied presentations, often among the same drug or class of drugs, making and confirming a diagnosis of DILI remains a daunting task. Even experienced clinicians may encounter difficulties in assigning causality, as shown by the lack of agreement among experts documented in a number of published studies. The current lack of a highly specific biochemical, histologic, genetic, or other biomarker to point to a specific drug or class of drugs as the
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