Because of the variability of manifestations and the lack of specific diagnostic markers for drug induced liver injury, attribution of causality to a specific medication is difficult and depends upon identification of a typical clinical signature and exclusion of other causes of liver disease. Drug induced liver injury is a diagnosis of exclusion that rests upon ruling out other common causes of liver disease, and knowledge of the pattern of injury associated with the specific drug. Unlike in hepatitis A or B, for instance, there are no specific diagnostic tests that establish causality for drug induced liver injury. The diagnosis can also be very challenging and even experts can disagree on the likelihood of the causality. For these reasons, attempts have been made to standardize causality assessment in drug induced adverse events including hepatotoxicity. These methods generally rely upon careful delineation of the timing of onset of the adverse event in relation to starting the medication (challenge), and the timing of resolution in relation to stopping the medication (dechallenge). The causality is greatly strengthened if there is a recurrence on reexposure (rechallenge). Other helpful features are signs and symptoms of hypersensitivity, know drug allergies, the absence of competing diagnoses, and previous information on the occurrence of a similar adverse event with the medication. These factors are variously captured in the causality instruments and given various weights to achieve a rating score for the likelihood of the medication causing the injury. Commonly used instruments include the Naranjo Probability Scale, which is not specific to liver injury and can be used for any type of adverse drug reaction. In contrast, the Roussel Uclaf Causality Assessment Method (RUCAM) and its modification known as the Maria and Victorino (M & V) System, were developed specifically for drug induced liver injury. All three causality instruments have been used widely and perform reasonably well in comparison to the "gold standard" of expert opinion.
RUCAM Scale
The RUCAM scale was developed after an international meeting in Paris in 1989, under the auspices of the Council for International Organizations of Medical Scientists (CIOMS), directed at developing uniform diagnostic criteria for drug induced liver injury. The eight international experts invited to the meeting created a diagnostic instrument that came to be referred to as RUCAM (Roussel Uclaf Causality Assessment Method). Points are awarded for seven components:
Total scores range from less than 0 to 14 with scores below 3 indicating unlikely, 4-5 possible, 6-8 probable, and >8 highly probable hepatotoxicity. Although available for almost two decades, RUCAM is not commonly used in clinical practice and does not have full endorsement even by specialists in hepatotoxicity. One reason is that many of the factors included in the RUCAM score are not well described and open to variable interpretation. Another reason is that it is difficult to develop a single instrument that is accurate for all forms of drug induced liver injury. A more thorough discussion of the RUCAM including a printable copy of the RUCAM form and a manual of operation for its completion is given below.
Maria & Victorino (M & V) Scale
A second scale was developed by investigators from Portugal and referred to as the M & V Clinical scale. In this instrument, points are awarded for five components:
The value of this scale was later examined by investigators in the United Kingdom who concluded that it compared favorably to developed international consensus criteria for adverse drug reactions. A larger study from Spain, in contrast, directly compared the RUCAM and the M & V scale on a large number of cases and concluded that RUCAM was the preferable instrument. A more complete discussion of the M & V scale as well as a printable copy of the scale and a manual of operations is given below.Naranjo Scale
|
Definite | ………………… | Greater than 95% |
Very likely | ………………… | 75-95% |
Probable | ………………… | 50-75% |
Possible | ………………… | 25-50% |
Unlikely | ………………… | Less than 25% |
Definite (>95% assurance) implies that the association is “beyond a reasonable doubt”; that the agent is known to cause liver injury; the drug causes a specific clinical pattern of liver injury; and, that other possible competing diagnoses have been adequately ruled out.
Very likely (75% to 95% assurance) suggests that the association is “clear and convincing”; that the agent is known to cause liver injury; and, that most, but perhaps not all, competing diagnoses have been excluded or the pattern of injury is not completely typical.
Probable (50% to 75% assurance) suggests that “the predominance of the evidence” supports the association. The agent may not have been previously linked to liver disease; and/or the pattern of injury may be atypical; and/or not all competing diagnoses have been completely excluded. Nevertheless, the reviewer believes that the weight of the evidence is in favor of the drug having caused the liver injury.
Possible (25% to 50% assurance) suggests that the association is weak but cannot be ruled out completely. Perhaps the agent has not been clearly linked to liver injury; or, the pattern of injury is unusual for the medication; or, another cause of liver injury is present.
Unlikely (<25% assurance) suggests that the liver injury is clearly due to another condition or its association with the medication is not at all convincing.
WHO 4 Levels |
Naranjo 4 Levels |
RUCAM 5 Levels |
M & V 5 Levels |
DILIN 5 Levels |
Level 1 [Certain] | Definite | Highly Probable | Definite | Definite and Highly Likely |
Level 2 [Probable] | Probable | Probable | Probable | Probable |
Level 3 [Possible] | Possible | Possible | Possible | Possible |
Level 4 [Unlikely] | Doubtful | Not Likely and Excluded | Not Likely and Excluded | Unlikely |