Maribel Lucena Servicio de Farmacologa Clnica, H.Universitario, Facultad de Medicina, Universidad de Mlaga, Spain
On behalf of the Spanish Group for the Study of Drug-Induced Liver Injury. CIBERehd
NIH Workshop December 1-2, 2008 Lister Hill Auditorium - NIH Campus, Bethesda, MD
Opportunity for a global dialogue Causality assessment is the Achilles heel of DILI Barrier for progress in mechanism research Need of agreement on instrument for validating DILI cases.
DILI Diagnosis
DILI may resemble any acute and chronic liver disease The signature (consistent clinical, pathologic and latency presentation) for a given drug may be variable. Hypersensitivity features occur in less than a quarter of patients DILI diagnosis relies on exclusion of other causes of liver injury Dechallenge requires follow-up
Diagnostic scales
General scales for the assessment of ADR
Karch y Lasagna 1977 Kramer 1979 Naranjo 1981 Jones 1982 The French Method, Begaud 1984 Arimone 2006
Specific scales for DILI Striker decision tree 1992 Council International Organizations Medical Sciences / Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003
Numerical score 0 to 1 -1 to 2 0 to 1 -1 to 2 1 to 2 0 to 1 0 to 1 0 to 1 0 to 1 0 to 1
GARCIA-CORTES M, LUCENA MI, PACHKORIA K, ANDRADE RJ. Evaluation of the Naranjo Adverse Drug Reactions Probability Scale in the Causality Assessment of Drug-Induced Liver Injury Aliment Pharmacol Ther 2008; 27:780-789.
NARANJO
2
Obs 2
3
Obs 1
4
Obs 2
Diagnostic scales
General scales for the assessment of ADR
Karch y Lasagna 1977 Kramer 1979 Naranjo 1981 Jones 1982 The French Method, Begaud 1984 Arimone 2006
Specific scales for DILI Striker decision tree 1992 Council International Organizations Medical Sciences / Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003
Scores for individual axes of the diagnostic scales CIOMS/RUCAM and Maria & Victorino
CIOMS/RUCAM (1990)
AXIS
CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction RISK FACTORS Age Alcohol +2 to +1 +1 to 0 -2 to +3
SCORE
SCORE
Highly probable>8; Probable 6-8; Possible 3-5; Unlikely 1-2; -3 to 0 -3 to +2 CONCOMITANT THERAPY BIBLIOGRAPHICAL DATA Excluded 0
EXCLUSION NON-DRUG RELATED -3 to +2
0 to +3
Definite: > 17; Probable: 14-17; Possible: 10-13; Unlikely: 6-9; 0 to +2 BIBLIOGRAPHICAL DATA Excluded < 6
RECHALLENGE -2 to +3
CIOMS
(1990)
1 43 40 84
16 53 69
1 1
Omitted
287 Japanese DILI Cases classified the scores according to CIOMS scale or a modified diagnostic scale (DDW-J)
200 180 160 140 120 100 80 60 40 20 0 Unrelated Unlikely Possible CIOMS Probable Definite 5 0 4 1 39 11 102 69 170
173
DDW-Y
Strenghts
Provide an uniform approach. Adds consistency to the diagnostic process Excellent teaching tool, emphasizes the features that merit attention Help improve the quality of the information recorded Improvement in inter-intra rater agreement Help standardize the reporting manner
Do not substitute common sense clinical judgement Designed for finding support for and less for excluding causality
RUCAM Limitations
Complexity. Ambiguous instructions Mixed cases included into the cholestatic group Disagreements in calculating time to onset Assignment difficult for cases with atypical time course Arbitrary risk factors: age 55y, alcohol, pregnant Unclear criteria for competing drug(s) Subjective interpretation of the drug hepatotoxic potential Relies largely on re-challenge, seldom done Incomplete work-up: uncertainty score Drug-induced adaptation or tolerance
RUCAM Limitations
Complexity. Ambiguous instructions Mixed cases included into the cholestatic group No evidence supporting the weighting and selection of domains
HC pattern (N=247)
TIME TO ONSET
From beginning of the +2 drug (5-90d) From cessation of the +1 drug(<15d, <30d) 77% 94% 81% 94%
COURSE
After cessation of the drug: decrease 50% within 30d for HC, 180d
for Chol/mix
60%
66%
RISK FACTOR
Age 55 y Alcohol ( or pregnancy in Chol/mix) 53% 20% 67% 21%
N=598
300 250 200 150 100 50 0 0-5
5-30
30-90
90-180
180-365
>365
days
P75 P25
18 d
28 d
270
329
N=598
300 250 200 150 100 50 0 0-5
5-30
30-90
90-180 180-365
>365
days
29 d
32 d
270
329
8d
9d
61
64
HC pattern (N=247)
TIME TO ONSET
From beginning of the drug (5-90d) From cessation of the drug(<15d, <30d) 77% 94% 81% 94%
COURSE
After cessation of the +2 drug: decrease 50% within
30d for HC, 180d for Chol/mix
60%
66%
RISK FACTOR
Age 55 y Alcohol ( or pregnancy in Chol/mix) 53% 20% 67% 21%
HC pattern (N=247)
TIME TO ONSET
From beginning of the drug (5-90d) From cessation of the drug(<15d, <30d) 77% 94% 81% 94%
COURSE
After cessation of the drug: decrease 50% within 30d for HC, 180d
for Chol/mix
60%
66%
RISK FACTOR
Age 55 y +1 Alcohol +1 ( or pregnancy) in Chol/mix) 53% 20% 67% 21%
Incidence of drug-induced liver disease according to Age and Sex in 603 DILI patients
Incidence
90 80 70 60 50 40 30 20 10 0 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89
Man
Woman
Type of liver damage according to sex in patients younger or older than 60 years of age (n=603)
P<0.0001
100% 80% 60% 40% 20% 0% Cholestatic Hepatocellular Mixed
Point values might be assigned to both sexes over 60 men < 60y men >60y damage women >60y years of age with cholestaticwomen <60y and perhaps just to women less than 60 years of age with hepatocellular damage.
Risk Factors
Risk factors drug or drug class specific Incorporating immunological and genetic risk factors identified
HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic
84%
84%
84%
67% 95%
72% 96%
RECHALLENGE
Not done or not interpretable
+0
Concomitant drugs
Inability to ascertain causality when two o more drugs are taken concomitantly and with the same temporal sequence. A given drug may cause different patterns of injury in different individuals When more than one drug could be the culprit, a blinded application of the scale can lead to a misleading causality assessment if only chronological criteria are taken into account potential for pharmacokinetic drug-drug interactions This domain should be removed
HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic
84%
84%
84%
67% 95%
72% 96%
RECHALLENGE
Not done or not interpretable
+0
Test/Clinical features
1.Viral serology IgM anti HVA,IgM antiHBc Anti HCV, PCR-HCV IgM CMV,IgM EBV 8. Radiologic/endoscopy test 3. Autoimmunity( ANA, ANCA, AMA, ASMA, antiLKM1) 7. Hypotension, shock, cardiac insuficiency, vascular disease 2. Bacterial serology: if persistent fever,diarrhoea (Salmonella, Campylobacter,Listeria, Coxiella) 4. Ceruloplasmine ( patients<40y) 5. Alfa-1 Antitrypsin 6. Transferrin saturation( in anicteric hepatocellular damage)
Diseases
Viral hepatitis
HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +2 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic
84%
84%
84%
67%
72%
RECHALLENGE
Not done or not interpretable
+0
95%
96%
HC pattern (N=247)
NO INFORMATION OR +0 INCOMPATIBLE ONSET WITH CONCOMITANTS DRUG(S) SEARCH FOR ALL NON DRUG +3 CAUSES PREVIOUS INFORMATION ON +2 HEPATOTOXICITY OF THE DRUG:
labelled in the products characteristic
84%
84%
84%
67%
72%
RECHALLENGE
Not done or not interpretable
+0
95%
96%
RUCAM Challenges
Underlying liver disease Atypical presentation: Autoimmune hepatitis triggered by drugs Potential hepatotoxic drugs taken concomitantly and with the same temporal sequence No dechallenge information: FHF, Tx, Death Chronic outcome
H.Torrecrdenas, Almera: MC Fernndez, G Pelez, M. Casado, JL Vega, H. Virgen Macarena, Sevilla: JA Durn, M. Villar . H. Universitario Virgen de Valme, Sevilla: M Romero, H. Central de Asturias, Oviedo: L Rodrigo-Saez, V. Cadaha, R. De Francisco. H. de Puerto Real, Cdiz: JM Prez-Moreno, M Puertas. H. Universitario San Cecilio, Granada: J Salmern, A Gila. H. Germans Trias i Puyol, Barcelona: R Planas,I Barriocanal, Eva Montan,J Costa. H. Universitario Virgen de las Nieves, Granada: R Martn-Vivaldi, F Nogueras. H. Costa del Sol, Mlaga: JM Navarro, JF Rodrguez. H. La Inmaculada. Hurcal-Overa, Almera: H Snchez-Martinez. H. Puerta del Mar, Cdiz: F Daz, MJ Soria, L Martn-Herrera H. Reina Sofa, Crdoba: JL Montero, M De la Mata. H. 12 de Octubre, Madrid: T. Muoz-Yage, J.A. Solis-Herruzo. H. Marqus de Valdecilla, Santander: F. Pons, R. Taheri.Amox/Clav H. Sant Pau, Barcelona: C Guarner, D Monfort. Fenitoina Furantoin H. Carlos Haya, Mlaga: M Jimnez. H. Xeral-Calde, Lugo: S. Avila-Nasi. Valproic Labetalol REG HEPATOX H. Nuestra Sra. de Aranzazu, San Sebastin: M. Garca-Bengoechea, A. Castiella. H. de Mendaro, Guipuzcuoa: S. Blanco. Paracetamol Troglitazone H. Clnico Provincial: M Bruguera H. Morales Messeguer: H Hallaf
Isoniazid Diclofenac
(GEHAM)