A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?
Table 2
Comparison of three liver-specific causality assessment scales on multiple sequential drug exposure.
Causality assessment scales and criteria
CIOMS/RUCAM
Maria and Victorino clinical diagnostic scale
(DDW-J) scale
Chronological criteria
From drug intake until onset
Score range: +1 to +2 (i) 5–90 days: +2 (ii) <5 or >90 days: +1
Score range: +1 to +3 (i) 4 d–8 wks: +3 (ii) <4 d or >8 wks: +1
Score range: +1 to +2 (i) 5–90 d/1–90 days: +2 (ii) <5 or >90 d/>15 days: +1
Withdrawal until onset
Score range: 0 to +1 (i) ≤30 d: +1 (ii) 0–29 d: 0
Score range: −3 to +3 (i) 0–7 d: +3 (ii) 8–15 d: 0 (iii) >15 d: –3
Score range: 0 to +1 (i) ≤30 d: +1 (ii) >30 d: 0
Course of the reaction
Score range: −2 to +3 Improvement in 180 days: (i) >50%: +2 (ii) <50%: +1 (iii) Lack of info or no improvement: +0
Score range: 0 to +3 (i) <6 mths (cholestatic/mixed) or <2 mths (hepatocellular): +3 (ii) >6 or 2 mths: +0
Score range: −2 to +3 After cessation of drug Difference in ALP peak and ULN (i) not applicable: +3 (ii) decrease in liver enzymes ≥50% in 180 d: +2 decrease <50% in 180 d: +1 (iii) no information/ persistence/increase: +0 (iv) N/A: −2
Extrahepatic manifestations
N/A
Score range: 0 to +3 (rash, fever, arthralgia, eosinophilia >6%, and cytopenia) (i) ≥4: +3 (ii) 2 or 3: +2 (iii) 1: +1 (iv) None: 0
Score range: 0 to +2 (i) Age ≥55: +1 (ii) Alcohol or pregnancy: +1
N/A
Score range: 0 to +1 (i) alcohol/pregnancy: +1
Concomitant therapy
Score range: −3 to 0 Time to onset: (i) incompatible: +0 (ii) compatible but with unknown reaction: −1 (iii) compatible but known reaction: −2 (iv) role proved in this case: −3 (v) none or information not available: +0
N/A
N/A
Exclusion of other causes
Score range: −3 to +2 (i) ruled out: +2 (ii) “possible” to “not investigated”: −2 to +1 (iii) probable: −3
Score range: −3 to +3 (i) complete: +3 (ii) partial: +0 (iii) possible alt cause: −1 (iv) probable alt cause: −3
Score range: −3 to +2 (i) ruled out: +2 (ii) 6 causes of Group I ruled out: +1 (iii) 5/4 causes of Group I ruled out: +0 (iv) <4 causes of Group I ruled out: −2 (v) nondrug cause highly probable: −3
Previous information or known reaction
Score range: 0 to +2 Reaction: (i) unknown: +0 (ii) published but unlabelled: +1 (iii) labeled in the product’s characteristics: +2
Score range: −3 to +2 (i) yes: +2 (ii) no (drug marketed for ≤5 yrs): +0 (iii) no (drug marketed for <5 yrs): −3
Score range: 0 to +1 (i) reaction labelled in product characteristics or published: +1 (ii) reaction unknown: +0
Rechallenge
Score range: −2 to +3 (i) positive: +3 (ii) compatible: +1 (iii) negative: −2 (iv) Not available/interpretable: +0 (v) plasma conc. of drug toxic: +3
Score range: 0 to +3 (i) positive: +3 (ii) negative/absent: +0
Score range: 0 to +3 (i) ALP/TB ≥ 2x with drug alone: +3 (ii) ALP/TB ≥ 2x with drug already given at time of 1st reaction: +1 (iii) ALP/TB increases but <: −2 (iv) Other situations: +0
DLST
N/A
N/A
Score range: 0 to +2 DLST (i) positive: +2 (ii) semipositive: +1 (iii) negative/unavailable: +0
Scores interpretation
(i) >8 points: definite (ii) 6–8 points: probable (iii) 3–5 points: possible (iv) 1-2 points: unlikely (v) <0 points: excluded
(i) >17 points: definite (ii) 14–17 points: probable (iii) 10–13 points: possible (iv) 6–9 points: unlikely (v) <6 points: excluded
CIOMS, Council for the International Organization of Medical Sciences; DDW-J, Digestive Disease Week-Japan; DLST, Drug lymphocyte stimulation test; N/A, not available; d, days.
