# Presentation: 802350

## Causality Assessment in Drug Induced Liver InjuryFDA, PhRMA, AASLD SymposiumJanuary 28, 2005 

**Robert J. Fontana, MD**
**University of Michigan Medical School**

## DILI- Causality Assessment

**Epidemiology**
**Differential diagnosis**
**Causality instruments**
**RUCAM**
**CDS**
**DILIN network**

## Spectrum of DILI

## DILI Population based study81,300 French ’97-’00

**95 suspected cases**
**34 probable DILI**
**25% antibiotics 23% psychotropic 13% antilipid**
**80% outpatients **
**2 (7%) deaths****	****	****	****	****	****	**
**Incidence: ****14 to 24 per 100,000**
**8,000 annual cases, 500 deaths**
**16 X > than ADR surveillance**

***(Hepatology 2002; 36)***

## DILI Manifestations

**Acute hepatitis**
**Acute cholestasis**
**Chronic hepatitis**
**Fatty liver/ NASH**
**Granulomatous disease**
**Fibrosis/ cirrhosis**
**Vanishing bile duct**
**VOD, peliosis**
**Benign & malignant neoplasia**

## DILI  Diagnosis

**Temporal relationship**
**Not dose related**
** ****? Clinical risk factors**
**Biochemical injury pattern**
**“****Signature” vs protean**
**Prior reports/ cases**
**Exclude other likely causes**
**Improvement with discontinuation**

## Acute DILI

**Hepatocellular:****  R > 5 and ALT > 2x ULN or baseline**
**Cholestatic:****  R < 2 and Alk > ULN**
**Mixed:****   2< R < 5**

**R= (ALT/ULN)/ (Alk / ULN)**

**(J Hepatol 1990; 11: 272)**

## Acute hepatitis: Differential Dx

**Ultrasound/ CT**

**Viral****(A, B, C, CMV, EBV**
**HEV, HSV)**

** ****+ + **

**Mass**
**(AFP, MRI)**

**Drug**

**Autoimmune****(SPEP, ANA, SmAb)**

**Metabolic****(Iron, TIBC, ferritin, ceruloplasmin, SPEP)**

**Ischemia****(History, 2D-Echo)**

**NAFLD**

**Biliary**
**(ERCP)**

**Observe/ biopsy**

## Idiopathic Hepatitis

**22 hospitalizations/ 1,000,000 medicaid- pt yrs for idiopathic acute hepatitis **
**HCV not excluded (’80-’87) ***
**Acute “non-A, non-B” hepatitis**
**5- 8% of post-Txf hepatitis**
**17% of ALF is indeterminate**

**(Arch Intern Med 1993; 153: 1331)**

## DILI Diagnosis

**DILI is a diagnosis of exclusion based on circumstantial evidence due to lack of objective confirmatory lab test, rechallenge, or ****“GOLD”**** standard **
**Requires a high index of suspicion****	****	**
**DILI diagnosis is usually retrospective**
**Exclude other causes**
**Dechallenge requires follow-up**

## ADR:  Causality Assessment

- ●   **Definite**
**●   ****Highly probable**
**●   ****Probable**
**●   ****Possible**
**●   ****Unlikely**
**●   ****Excluded / other**

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**100%**
**50%**
**0%**

## DILI: Causality Assessment

**Generic instruments**
**WHO**
**Bayesian**
**Liver specific**
**Expert opinion **
_**R**_**oussel **_**U**_**claf **_**C**_**ausality **_**A**_**ssessment **_**M**_**ethod (RUCAM) ‘89**
_**C**_**linical **_**D**_**iagnostic **_**S**_**cale (CDS)  ‘97**
**DILIN approach**

## DILI Causality Instrument

**Sensitive**
**Specific- Low probability in non-drug cases**
**Reproducible **
**Content validity- weighting is evidence based **
**Criterion validity- “Gold Standard”  expert panel**
**Discrimination- a semi-quantitative estimate **
**Validated in independent groups**
**Generalizability- Young vs old, mild vs severe, hepatocellular vs cholestatic, normal vs abnormal baseline LFT’s **
**Ease of use**

## RUCAM 

**Temporal relationship ****	****	****	****(0 to 2)**
**Course ****	****	****	****	****	****	****(-2 to 3)  **
**Risk factors ****	****	****	****	****	****(0 to 2)**
**Concomitant drug ****	****	****	****	****(0 to -3)**
**Non-drug causes ****	****	****	****	****(-3 to 2)**
**Prior reports/ information ****	****	****	****(0 to 2)**
**Re-challenge ****	****	****	****	****	****(-2 to 3)  **
**  **
_**Score (-8 to 14**_**)**
**	****Highly probable >8****	****Possible 3-5  Excluded ≤0**
**	****Probable 6-8****	****	****Unlikely 1-2**

*J Clin Epidemiol 1993;46:1323-1330*

## RUCAM limitations

**Ambiguous instructions**
**Criteria for competing cause/drug not clear**
**Onset > 30 days after d/c ****(e.g. Augmentin)**
**Derived from expert opinion rather than prospectively collected data set **
**Limited risk factors**
**Overweighting of rechallenge**

## Clinical Diagnostic Scale

**Temporal association****	****	****	**
**From initiation****	****	****	****	****(1 to 3)**
**From cessation****	****	****	****	****(-3 to 3)**
**Normalization****	****	****	****	****(0 to 3)**
**Non-drug causes****	****	****	****	****(-3 to 3)**
**Extrahepatic manifestations****	****	****	****(0 to 3)**
**Rechallenge****	****	****	****	****	****(0 to 3)**
**Prior reports****	****	****	****	****	****(-3 to 2)**

_**Score (- 9 to 20)**_
**Definite > 17****	****	****Possible 10-13****	****	****Excluded < 6**
**Probable 14-17****	****	****Unlikely  6-9**

**(Hepatology 1997;26: 664)**

## 228 Spanish cases ’94-’00Gold standard:  Expert panel

**(Hepatology 2001; 33: 123)**

**	****	****	****     ****	****CDS**
**RUCAM      **_**Exclude**_**     **_**Unlike**_**    **_**Poss**_**     **_**Prob**_**   **_**Def**_
**Exclude          ****21****	****      2****	**
**Unlike****	****       4****	****    ****	****      ****3**
**Poss****	****	****	****     ****	****      8****	****           ****1**
**Prob****	****	****       1****	****              30          43         ****16**
**Definite****	****	****	****      5           40         53       ****1**

**K = 0.28**

*** 30 non-drug cases**

## CDS vs RUCAM

**RUCAM performed better overall **
**CDS performed poorly if**
**Delayed onset (> 15 days) **
**Prolonged recovery (Cholestasis)**
**ALF/ Death (6%)**
**CDS:       6 possible  7 unlikely/ excluded**
**RUCAM: 6 definite    6 probable 1 possible**
**Idiosyncratic (75%)**

**(Hepatology 2001; 33: 123)**

##  To collect biological samples from bonafide cases and controls to study pathogenesis using biochemical, serological and genetic techniques 								

**To develop standardized instruments, definitions, and terminology for drug and CAM induced liver injury ****	****	****	****	****	**

**Drug Induced Liver Injury Network Objectives**

## DILIN Prospective study

**Inclusion criteria**
**Age > 2**
**Liver injury due to a drug or CAM within 6 months of presentation**
**On 2 consecutive blood draws**
**AST/ ALT >  5 X ULN or baseline**
**Alk phos > 2X ULN or baseline**
**T bilirubin > 2.5 mg/dl**

## DILIN Prospective study

**Exclusion criteria **
**Acetaminophen hepatotoxicity**
**Prior liver transplant**
**Pre-existing AIH, PSC, PBC which may confound ability to diagnose DILI**
**Chronic HBV, HCV allowed**

## DILIN: Baseline visit

_**All patients**_
**HAV (IgM)**
**HBsAg, HBcAb**
**HCV ab**
**ANA, SmAb**
**Monospot**
**HIV ab**
**Liver ultrasound**
**Ceruloplasmin ( < 50)**
**AMA (Cholestatic)**

_**Chronic HBV**_
**HBV DNA**
**HBeAg, HBeAb**
**HDV Ab**
_**Chronic HCV**_
**HCV RNA**

## DILIN Causality assessment

**Causality committee**
**5 site PI’s, 1 DCC, 1 NIH**
**3 independent reviewers per case**
**Site PI and 2 others**
**Review clinical narrative, subset CRF, labs**
**Assess causality, RUCAM, Data completeness checklist**
**Conference call if not unanimous**

## DILIN Clinical Narrative

**Presentation**
**Detailed medication hx/ compliance**
**Concomitant meds/ CAM**
**PMH**
**Soc/ fam hx**
**Physical exam**
**Liver enzymes & labs**
**Diagnostic tests**
**Central path review**
**Outcome**

## DILIN Causality assessment

_**Likelihood**_**	****	****	****	**_**Category**_
**> 95%         ****	****	****	****	****Definite**
**75 -95%                       ****	****	****Likely**
**50 -75%                        ****	****	****Probable**
**25 -50%                             ****	****Possible**
**< 25%                 ****	****	****	****Unlikely**

## Causality Assessment in 2005

**Need Bonafide cases of DILI**
**? Features ? Risk factors ? Mechanism ? Outcome**
**Surveillance system**
**Improved causality assessment instruments**
**Key data, sensitive/ specific, validated**
**User friendly, widely available**
**Objective lab test to confirm diagnosis**
**? Lymphocyte proliferation assays/ biomarker**
**? Genetic susceptibility test**
**Reference database for DILI**

## 287 Japanese DILI cases ’78-’0255% hepatocellular 24% mixed 22% cholestatic

**(Hep Research 2003: 27: 191)**

**Latency > 15 or 30 d changed, other drugs omitted,**
** ****+ DLST = +2  Eosinophils > 6% = + 1**

## Fulminant DILI in the US

**138 DILI ALF LT recipients (15%) ’90-’02**
**Mean age 35  75% female 70% Cau 26% AA**
**17% INH  9 % PTU  7% dilantin  7% valproate ****	****	****	****	****	****	****	****	****	****	**
**40 DILI (13%) ALFSG ’98-’03**
**Med age 41  72% female  58% Cau  **
**27% antibiotics 10% troglitazone 10% bromfenac**
**25% spont survival  53% transplant**

**(Ann Intern Med 2002: 137: 947)**
**(Liver Transp 2004; 10: 1018)**